Expression of cytokine-like genes JE and KC is increased during renal ischemia.
Both mitogenic and inflammatory phenomena accompany the renal response to ischemic injury. Previous studies have shown that several nuclear-binding members of the immediate early genes are prominently expressed after renal ischemia and may underlie the mitogenic response to such injury. We now report on the expression of JE and KC, other growth-factor-responsive genes that code for small secreted glycoproteins with cytokine-like properties, which may play a role in inflammation. The expression of the immediate early genes JE and KC was determined in rat kidney tissue at varying time points after release of a 50-min period of bilateral renal hilar clamping. Relative levels of mRNA for JE and KC were analyzed by Northern blot analysis of cortical and outer stripe mRNA. KC mRNA rose rapidly to peak values at 1 h and returned toward low baseline levels by 24 h after release of the hilar clamp. By contrast, JE mRNA reached peak levels later and remained elevated for at least 96 h after ischemia. JE antigen was localized immunocytochemically to the apical regions of the cortical and medullary thick ascending limbs as well as in the lumen of the distal nephron in ischemic kidneys. Cells of the glomerulus and proximal tubules were negative for JE antigen. In contrast to the increase in JE and KC mRNA, steady-state levels of uromodulin (Tamm Horsfall) mRNA, a cytokine binding protein also made by the thick ascending limb, declined to virtually undetectable levels by 24 h after ischemia. Thus the increases in JE and KC are not generalized phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)


[Hypnosis and self-hypnosis administered and taught by nurses for relief of chronic pain: a controlled clinical trial].
In this controlled clinical trial hypnosis and self-hypnosis were evaluated when used as an adjuvant treatment to instrumental and pharmacological management of chronic pain. The study took place in a hospital specialized in the treatment of outpatients suffering from chronic pain. Hypnosis and self-hypnosis were administered and taught by nurses who had been trained just recently for this very purpose. Under the conditions of the study it was not possible to measure an effect of hypnosis on pain despite some subjective feeling of usefulness. However, it should be taken into account that this form of adjuvant therapy was used for the first time in that hospital for the purpose of the study and, therefore, took place in an artificial setting. It could well be that the same therapy administered in the proper therapeutic environment of a specialized institution could show beneficial effects on pain.


Nucleoside phosphatases of fetal and maternal blood cells: electron microscope study.
Surface membranes of the blood cells located within the maternal blood sinuses of the rat placenta contain reaction products of nucleoside phosphatases. Fetal blood cells separated from maternal blood by the placental labyrinth show no activity during normal or prolonged gestation. Neonatal blood cells examined 34 hours after parturition show these enzyme activities.


Diagnostic performance of computed tomography coronary angiography to detect and exclude left main and/or three-vessel coronary artery disease.
To determine the diagnostic performance of CT coronary angiography (CTCA) in detecting and excluding left main (LM) and/or three-vessel CAD ("high-risk" CAD) in symptomatic patients and to compare its discriminatory value with the Duke risk score and calcium score. Between 2004 and 2011, a total of 1,159 symptomatic patients (61 ± 11 years, 31 % women) with stable angina, without prior revascularisation underwent both invasive coronary angiography (ICA) and CTCA. All patients gave written informed consent for the additional CTCA. High-risk CAD was defined as LM and/or three-vessel obstructive CAD (≥50 % diameter stenosis). A total of 197 (17 %) patients had high-risk CAD as determined by ICA. The sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios of CTCA were 95 % (95 % CI 91-97 %), 83 % (80-85 %), 53 % (48-58 %), 99 % (98-99 %), 5.47 and 0.06, respectively. CTCA provided incremental value (AUC 0.90, P < 0.001) in the discrimination of high-risk CAD compared with the Duke risk score and calcium score. CTCA accurately excludes high-risk CAD in symptomatic patients. The detection of high-risk CAD is suboptimal owing to the high percentage (47 %) of overestimation of high-risk CAD. CTCA provides incremental value in the discrimination of high-risk CAD compared with the Duke risk score and calcium score. • Computed tomography coronary angiography (CTCA) accurately excludes high-risk coronary artery disease. • CTCA overestimates high-risk coronary artery disease in 47 %. • CTCA discriminates high-risk CAD better than clinical evaluation and coronary calcification.


[Association between maternal and newborn vitamin A status and economic stratum in Rio de Janeiro, Brazil].
Retinol was determined spectrophotometrically in the blood of 291 mothers at delivery and in the umbilical cord of the newborn. The mothers came from different socioeconomic strata in Rio de Janeiro. Levels of retinol were determined using spectrophotometry (Bessey et al). The circulation levels of retinol were low (below 1.05 micromol/L) in 22.0% of the mothers and in 54.2% of the newborn. A close association was found between low levels in the mothers' serum and those in the children's umbilical cord (p <0.0001). There was no association between maternal vitamin A deficiency (DVA) and socioeconomic stratum, family income or level of education. DVA is a distressing health problem among mothers and newborns and its diagnosis must be included in antenatal care. This reinforces the concept that intervention programs must emphasize changes in feeding practices and focus on the most vulnerable groups, of which pregnant women warrant special attention, regardless of socioeconomic stratum.


Induction of aquaporin 3 by corticosteroid in a human airway epithelial cell line.
Although aquaporin 3 (AQP3) is expressed in many tissues in the kidney, gastrointestinal tract, lung, and other organs, its physiological significance in the body still remains to be clarified. To determine whether AQP3 expression is regulated by dexamethasone in human airway epithelium, we studied mRNA expression, protein expression, and water permeability of the cell membrane in a human airway epithelial cell line (A549 cells). Expression of AQP3 mRNA and protein was studied by Northern blot analysis and immunoblot analysis, and osmotic water permeability (Pf) was measured by a stopped-flow light-scattering method. Expression of AQP3 mRNA and protein was detectable in A549 cells and was stimulated by dexamethasone. Pf in A549 cells after incubation with dexamethasone was approximately 2.5-fold greater than that without dexamethasone. Moreover, this dexamethasone-induced increase in Pf was inhibited after treatment with HgCl2. In conclusion, the present study shows that A549 cells express AQP3 and that dexamethasone upregulates the expression of AQP3 and increases the water permeability of the cell membrane. Dexamethasone-regulated AQP3 expression might be important in certain forms of pulmonary diseases accompanied by airway hypersecretion that are treated by corticosteroid administration.


Participation of rab5, an early endosome protein, in hepatitis C virus RNA replication machinery.
Like most positive-strand RNA viruses, hepatitis C virus (HCV) is believed to replicate its genome on the surface of rearranged membranes. We have shown previously that HCV NS4AB, but not the product NS4B, inhibits endoplasmic reticulum (ER)-to-Golgi protein traffic (K. V. Konan, T. H. Giddings, Jr., M. Ikeda, K. Li, S. M. Lemon, and K. Kirkegaard, J. Virol. 77:7843-7855). However, both NS4AB and NS4B can induce "membranous web" formation, first reported by Egger et al. (D. B Egger, R. Gosert, L. Bianchi, H. E. Blum, D. Moradpour, and K. Bienz, J. Virol. 76:5974-5984), which is also observed in HCV-infected cells (Y. Rouille, F. Helle, D. Delgrange, P. Roingeard, C. Voisset, E. Blanchard, S. Belouzard, J. McKeating, A. H. Patel, G. Maertens, T. Wakita, C. Wychowski, and J. Dubuisson, J. Virol. 80:2832-2841) and cells that bear a subgenomic NS5A-green fluorescent protein (GFP) replicon (D. Moradpour, M. J. Evans, R. Gosert, Z. Yuan, H. E. Blum, S. P. Goff, B. D. Lindenbach, and C. M. Rice, J. Virol. 78:7400-7409). To determine the intracellular origin of the web, we examined NS4B colocalization with endogenous cellular markers in the context of the full-length or subgenomic replicon. We found that, in addition to ER markers, early endosome (EE) proteins, including Rab5, were associated with web-inducing protein NS4B. Furthermore, an immunoisolated fraction containing NS4B was found to contain both ER and EE proteins. Using fluorescence microscopy, we showed that wild-type and constitutively active Rab5 proteins were associated with NS4B. Interestingly, expression of dominant-negative Rab5 resulted in significant loss of GFP fluorescence in NS5A-GFP replicon cells. We also found that a small reduction in Rab5 protein expression decreased HCV RNA synthesis significantly. Furthermore, transfection of labeled Rab5 small interfering RNAs into NS5A-GFP replicon cells resulted in a significant decrease in GFP fluorescence. Finally, Rab5 protein was found to coimmunoprecipitate with HCV NS4B. These studies suggest that EE proteins, including Rab5, may play a role in HCV genome replication or web formation.


Experience with surgery for thymoma associated with pure red blood cell aplasia. Report of three cases.
We present three cases of thymoma associated with pure red blood cell aplasia in which thymomectomy and thymectomy were performed. Case 1, a patient with pure red blood cell aplasia and hypogammaglobulinemia, was treated after surgery with immunosuppressive agents. She did not show any remission and died eight months after the operation. Case 2, a patient with pure red blood cell aplasia alone, showed transient erythropoiesis only in the early post-operative period and died one year and seven months after the operation. Patient 3 had pure red blood cell aplasia alone before surgery and was treated after surgery with prednisolone and fluoxymesterone. He showed good remission from the aplasia after these treatments; however, myasthenia gravis appeared seven months after the operation. These results seem to show that such combined therapy as applied in case 3 may be effective for some of the patients with pure red blood cell aplasia and thymoma; however, the effects of thymomectomy or thymectomy (or both) are still controversial for the treatment of pure red blood cell aplasia.


Infertility, Pregnancy Loss and Adverse Birth Outcomes in Relation to Maternal Secondhand Tobacco Smoke Exposure.
A substantial proportion of the etiology involved in female infertility and adverse pregnancy outcomes remains idiopathic. Recent scientific research has suggested a role for environmental factors in these conditions. Secondhand tobacco smoke (STS) contains a number of known or suspected reproductive toxins, and human exposure to STS is prevalent worldwide. Robust evidence exists for the toxic effects of active smoking on fertility and pregnancy, but studies of passive exposure are much more limited in number. While the association between maternal STS exposure and declined birth weight has been fairly well-documented, only recently have epidemiologic studies begun to provide suggestive evidence for delayed conception, altered menstrual cycling, early pregnancy loss (e.g. spontaneous abortion), preterm delivery, and congenital malformations in relation to STS exposure. There is also new evidence that developmental exposures to tobacco smoke may be associated with reproductive effects in adulthood. To date, most studies have estimated maternal STS exposure through self-report even though exposure biomarkers are less prone to error and recall bias. In addition to utilizing biomarkers of STS exposure, future studies should aim to identify vital windows of STS exposure, important environmental co-exposures, individual susceptibility factors, and specific STS constituents associated with female infertility and adverse pregnancy outcomes. The role of paternal exposures/factors should also be investigated.


Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919).
Introduction: Intracerebral microglia play a vital role in mediating central immune response, neuronal repair and synaptic pruning, but its precise role and mechanism in fast action of antidepressants have remained unknown. In this study, we identified that the microglia contributed to the rapid action of antidepressants ketamine and YL-0919. Methods: The depletion of microglia was achieved with the diet containing the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in mice. The tail suspension test (TST), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were employed to evaluate the rapid acting antidepressant behavior of ketamine and YL-0919 in the microglia depletion model. The number of microglia in the prefrontal cortex (PFC) was assayed by the immunofluorescence staining. The expressions of synaptic proteins (synapsin-1, PSD-95, GluA1) and brain-derived neurotrophic factor (BDNF) in the PFC were tested by Western blot. Results: The immobility duration in FST and the latency to feed in NSFT were shortened 24 h after an intraperitoneal (i.p.) injection of ketamine (10 mg/kg). The microglial depletion of PLX3397 blocked the rapid antidepressant-like effect of ketamine in mice. In addition, the immobility time in TST and FST as well as latency to feed in NSFT were reduced 24 h after the intragastric (i.g.) administration of YL-0919 (2.5 mg/kg), and the rapid antidepressant effect of YL-0919 was also blocked by the microglial depletion using PLX5622. About 92% of microglia in the prefrontal cortex was depleted in PLX5622 diet-fed mice, while both ketamine and YL-0919 promoted proliferation on the remaining microglia. YL-0919 significantly increased the protein expressions of synapsin-1, PSD-95, GluA1 and BDNF in the PFC, all of which could be blocked by PLX5622. Conclusion: These results suggested the microglia underlying the rapid antidepressant-like effect of ketamine and YL-0919, and microglia would likely constitute in the rapid enhancing impact of synaptic plasticity in the prefrontal cortex by YL-0919.


Exogenous Serotonin (5-HT) Promotes Mesocotyl and Coleoptile Elongation in Maize Seedlings under Deep-Seeding Stress through Enhancing Auxin Accumulation and Inhibiting Lignin Formation.
Serotonin (5-HT), an indoleamine compound, has been known to mediate many physiological responses of plants under environmental stress. The deep-seeding (≥20 cm) of maize seeds is an important cultivation strategy to ensure seedling emergence and survival under drought stress. However, the role of 5-HT in maize deep-seeding tolerance remains unexplored. Understanding the mechanisms and evaluating the optimal concentration of 5-HT in alleviating deep-seeding stress could benefit maize production. In this study, two maize inbred lines were treated with or without 5-HT at both sowing depths of 20 cm and 3 cm, respectively. The effects of different concentrations of 5-HT on the growth phenotypes, physiological metabolism, and gene expression of two maize inbred lines were examined at the sowing depths of 20 cm and 3 cm. Compared to the normal seedling depth of 3 cm, the elongation of the mesocotyl (average elongation 3.70 cm) and coleoptile (average elongation 0.58 cm), secretion of indole-3-acetic acid (IAA; average increased 3.73 and 0.63 ng g-1 FW), and hydrogen peroxide (H2O2; average increased 1.95 and 0.63 μM g-1 FW) in the mesocotyl and coleoptile were increased under 20 cm stress, with a concomitant decrease in lignin synthesis (average decreased 0.48 and 0.53 A280 g-1). Under 20 cm deep-seeding stress, the addition of 5-HT activated the expression of multiple genes of IAA biosynthesis and signal transduction, including Zm00001d049601, Zm00001d039346, Zm00001d026530, and Zm00001d049659, and it also stimulated IAA production in both the mesocotyl and coleoptile of maize seedlings. On the contrary, 5-HT suppressed the expression of genes for lignin biosynthesis (Zm00001d016471, Zm00001d005998, Zm00001d032152, and Zm00001d053554) and retarded the accumulation of H2O2 and lignin, resulting in the elongation of the mesocotyl and coleoptile of maize seedlings. A comprehensive evaluation analysis showed that the optimum concentration of 5-HT in relieving deep-seeding stress was 2.5 mg/L for both inbred lines, and 5-HT therefore could improve the seedling emergence rate and alleviate deep-seeding stress in maize seedlings. These findings could provide a novel strategy for improving maize deep-seeding tolerance, thus enhancing yield potential under drought and water stress.


[Programming an automated system for processing radioisotope information for work with multichannel radiodiagnostic equipment].
The purpose of the study is to develop the basic software compatible with a computerized system for data collection and processing from multi-channel radiodiagnostic units. As clinical tests have shown functional capabilities of specially designed system ensure data collection and processing for all practical methods presently accepted in nuclear medicine.


IgM, IgG, and IgA antibody responses to influenza A(H1N1)pdm09 hemagglutinin in infected persons during the first wave of the 2009 pandemic in the United States.
The novel influenza A(H1N1)pdm09 virus caused an influenza pandemic in 2009. IgM, IgG, and IgA antibody responses to A(H1N1)pdm09 hemagglutinin (HA) following A(H1N1)pdm09 virus infection were analyzed to understand antibody isotype responses. Age-matched control sera collected from U.S. residents in 2007 and 2008 were used to establish baseline levels of cross-reactive antibodies. IgM responses often used as indicators of primary virus infection were mainly detected in young patient groups (≤5 years and 6 to 15 years old), not in older age groups, despite the genetic and antigenic differences between the HA of A(H1N1)pdm09 virus and pre-2009 seasonal H1N1 viruses. IgG and IgA responses to A(H1N1)pdm09 HA were detected in all age groups of infected persons. In persons 17 to 80 years old, paired acute- and convalescent-phase serum samples demonstrated ≥4-fold increases in the IgG and IgA responses to A(H1N1)pdm09 HA in 80% and 67% of A(H1N1)pdm09 virus-infected persons, respectively. The IgG antibody response to A(H1N1)pdm09 HA was cross-reactive with HAs from H1, H3, H5, and H13 subtypes, suggesting that infections with subtypes other than A(H1N1)pdm09 might result in false positives by enzyme-linked immunosorbent assay (ELISA). Lower sensitivity compared to hemagglutination inhibition and microneutralization assays and the detection of cross-reactive antibodies against homologous and heterologous subtype are major drawbacks for the application of ELISA in influenza serologic studies.


Novel passive implantable atrial defibrillator using transcutaneous radiofrequency energy transmission successfully cardioverts atrial fibrillation.
Conventional methods for cardioversion of atrial fibrillation (AF) to sinus rhythm have numerous difficulties. A novel method for cardioversion using the passive implantable atrial defibrillator (PIAD) was tested in acute animal models. This device does not have a battery or a capacitor to store energy and is activated by transferring RF energy across the skin from an external transmitter to the subcutaneously implanted defibrillator. On activation, a novel monophasic shock waveform with 5% tilt is delivered to the heart via 2 intracardiac defibrillation leads. Cardioversion attempts with the device were assessed in 2 phases: a feasibility and efficacy study and randomized comparison against standard waveforms. Defibrillation leads were placed transvenously into the distal coronary sinus and the right atrial appendage. These were connected to the subcutaneously implanted PIAD. Sustained AF was induced by rapid atrial pacing. The transmitter coil was placed on the skin overlying the defibrillator, and defibrillation synchronized to the R wave was attempted. The method was found to be efficacious at very low voltage and energy, with 100% cardioversion success observed for 10-ms 100-V shocks (mean energy, 1.54+/-0.02 J). The PIAD waveform had a higher cardioversion success rate than a truncated, 70% tilt monophasic exponential pulse (100 V, 100% versus 78.0+/-7.57%; P=0.001). There were no postshock complications. Considering these animal results, this method is promising for cardioverting AF in symptomatic patients.


Cellular growth in iron-deficient rat pups.
Groups of 10 pregnant rats weighing 200-215 g were fed ad libitum diets containing 10, 100, or 250 ppm iron (Fe) throughout gestation and lactation. Litters were adjusted at birth to contain 7 pups, and on day 17 of lactation, dams and pups were sacrificed. Fe status was determined, and tissues from pups were assayed for parameters of cellular growth. Fe-deficient pups (10 ppm Fe) had slightly lower body weights, lower hemoglobin, serum Fe, and liver Fe levels than those fed diets containing 100 or 250 ppm Fe. Thymus was most severely affected by Fe-deficiency. Organ weight, per cent body weight, and total DNA were decreased by at least 40% in Fe-deficient pups. Spleens from 10 ppm Fe pups had 30% less total DNA compared to controls due to decreased organ weight. There were no changes in spleen protein, lipid or DNA concentrations due to Fe deficiency. Measures of DNA and protein parameters in liver were similar among groups, although a 60% increase in liver lipid concentration was observed in pups from dams fed 10 ppm Fe. The results suggest that nutritional Fe deficiency during reproduction produces alterations in cellular growth of rapidly-divided lymphoid organs in offspring, while accumulation of DNA and protein in the liver is unaffected.


Identification of the Gender-Specific Health Needs of Women Following Lung Transplantation.
Little is known of the prevalence and severity of menstrual dysfunction, climacteric symptoms, pelvic floor disorders, sexual problems, and psychological wellbeing after lung transplantation in women. Adult female lung transplant recipients, attending the Alfred Hospital Lung Transplant Service in Melbourne, Australia participated in a women's health, cross-sectional questionnaire-based study. The 123 of 149 potential participants were recruited between September 2014 and July 2015. Their median age was 53.5 years, and 44 were premenopausal, 3 perimenopausal, and 76 postmenopausal. Moderate-severe menstrual and premenstrual symptoms were common, and 43% of partnered premenopausal women were not using contraception. Vasomotor symptoms (VMS) were common in postmenopausal women <55 years (80.0%), and the use of menopausal hormone therapy was low (8.9%). The estimated prevalence of low sexual desire associated with distress was 24.4%. Low wellbeing was significantly and independently associated with being aged 50 ≤ 60 years, moderate-severe VMS, impaired forced expiratory volume in 1 second, and psychotropic medication use. Our findings demonstrate that premenopausal lung transplant recipients need to be asked about bothersome menstrual symptoms, and contraceptive compliance needs regular review. Transplant recipients at midlife have substantially lower wellbeing than women of other ages and this needs attention, including assessment and management of menopausal symptoms.


Investigation of the relationship between lysogeny and lysis of Lactococcus lactis in cheese using prophage-targeted PCR.
The ability of lactococcal strains to lyse (and release intracellular enzymes) during cheese manufacture can be a very desirable trait and has been associated with improvement in flavor and acceleration of cheese ripening. Using a laboratory-scale cheese manufacturing assay, the autolytic behavior of 31 strains of Lactococcus lactis was assessed. In general, marked variation was observed between strains with a 20-fold difference between the best and worst lysing strains based on the release of the intracellular enzyme lactate dehydrogenase. In a parallel experiment, the genomes of these strains were examined for the presence of prophage integrase (int) sequences by using conserved primer sequences from known lysogenic phage. Results demonstrated that the lytic behavior of lactococcal starter strains significantly correlates with the presence of prophage sequences. These results highlight not only the contribution of prophage to starter cell lysis but also the potential of PCR as a useful initial screen to assess strains for this important industrial trait.


Just-About-Right and ideal scaling provide similar insights into the influence of sensory attributes on liking.
Just-about-right (JAR) scaling is criticized for measuring attribute intensity and acceptability simultaneously. Using JAR scaling, an attribute is evaluated for its appropriateness relative to one's hypothetical ideal level that is pre-defined at the middle of a continuum. Alternatively, ideal scaling measures these two constructs separately. Ideal scaling allows participants to rate their ideal freely on the scale (i.e., without assuming the "Too Little" and "Too Much" regions are equal in size). We hypothesized that constraining participants' ideal to the center point, as is done in the JAR scale, may cause a scaling bias and, thereby, influence the magnitude of "Too Little" and "Too Much". Furthermore, we hypothesized that the magnitude of "Too Little" and "Too Much" would influence liking to different extents. Coffee-flavored dairy beverages (n=20) were formulated using a fractional, constrained-mixture design that varied the ratio of water, milk, coffee extract, and sucrose. Participants tasted 4 of 20 prototypes that were served in a monadic sequential order using a balanced incomplete block design. Data reported here are for participants randomly assigned to one of two research conditions: ideal scaling (n=129) or JAR scaling (n=132). For both conditions, participants rated overall liking using a 9-point hedonic scale. Four attributes (sweetness, milk flavor, coffee flavor and thickness) were evaluated. The reliability of an individual participant's ideal rating for an attribute was evaluated using the standard deviation of their ideal ratings (n=4). All data from a participant were eliminated from further analyses when his/her standard deviation of the ideal ratings for any of the four rated attributes was identified as a statistical outlier. This resulted in the elimination of 15 of 129 (12 %) of participants in the ideal scaling group. Multiple linear regression was employed to model liking as a function of "Too Little" or "Too Much" attribute intensities. Mean ideal ratings (averaged across participants) for all four attributes were significantly different from the central point of the scale (i.e., 50). However, Coffee flavor was the only attribute for which the mean ideal rating (57.2) fell outside the central 10% (45.0-55.0). Even so, the magnitude of "Too Little" and "Too Much" was not affected by the scaling method. The influence of the magnitude of "Too Little" and "Too Much" on liking was asymmetrical. Both scaling methods agreed that sweetness and coffee flavor were the main sensory attributes affecting liking. Overall, JAR scaling and ideal scaling were comparable for measuring "Too Little" and "Too Much", and identifying the main factors affecting liking.


Latest progress in the identification of novel synthetic ligands for the cannabinoid CB2 receptor.
Cannabinoid receptors, belonging to the superfamily of G-protein coupled receptors, play a major role in pathophysiology of a wide range of disparate diseases. Cannabinoid CB2 receptor, which mainly locates in peripheral tissues, represents as a promising drug target for the treatment of pain, osteoporosis, liver disorders, and so on without serious CNS side effects. In the past decades, the identification and optimization of selective ligands for the CB2 receptor has been a major objective in drug discovery. In the present review, we describe recent advances in the development of novel chemotypes of the CB2 receptor selective ligands, and give a simple discussion for the corresponding structure-activity relationships of them.


Collective decision making in bacterial viruses.
For many bacterial viruses, the choice of whether to kill host cells or enter a latent state depends on the multiplicity of coinfection. Here, we present a mathematical theory of how bacterial viruses can make collective decisions concerning the fate of infected cells. We base our theory on mechanistic models of gene regulatory dynamics. Unlike most previous work, we treat the copy number of viral genes as variable. Increasing the viral copy number increases the rate of transcription of viral mRNAs. When viral regulation of cell fate includes nonlinear feedback loops, very small changes in transcriptional rates can lead to dramatic changes in steady-state gene expression. Hence, we prove that deterministic decisions can be reached, e.g., lysis or latency, depending on the cellular multiplicity of infection within a broad class of gene regulatory models of viral decision-making. Comparisons of a parameterized version of the model with molecular studies of the decision structure in the temperate bacteriophage lambda are consistent with our conclusions. Because the model is general, it suggests that bacterial viruses can respond adaptively to changes in population dynamics, and that features of collective decision-making in viruses are evolvable life history traits.


Zebrafish as an Emerging Model for Sarcopenia: Considerations, Current Insights, and Future Directions.
Sarcopenia poses a significant challenge to public health and can severely impact the quality of life of aging populations. Despite extensive efforts to study muscle degeneration using traditional animal models, there is still a lack of effective diagnostic tools, precise biomarkers, and treatments for sarcopenia. Zebrafish models have emerged as powerful tools in biomedical research, providing unique insights into age-related muscle disorders like sarcopenia. The advantages of using zebrafish models include their rapid growth outside of the embryo, optical transparency during early developmental stages, high reproductive potential, ease of husbandry, compact size, and genetic tractability. By deepening our understanding of the molecular processes underlying sarcopenia, we may develop novel diagnostic tools and effective treatments that can improve the lives of aging individuals affected by this condition. This review aims to explore the unique advantages of zebrafish as a model for sarcopenia research, highlight recent breakthroughs, outline potential avenues for future investigations, and emphasize the distinctive contributions that zebrafish models offer. Our research endeavors to contribute significantly to address the urgent need for practical solutions to reduce the impact of sarcopenia on aging populations, ultimately striving to enhance the quality of life for individuals affected by this condition.


Quinolone-resistant gyrase mutants demonstrate decreased susceptibility to triclosan.
Cross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance. WT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined. All gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance. Our data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials.


Effect size of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.
To examine duration of efficacy of lisdexamfetamine dimesylate (LDX) in adults with attention-deficit/hyperactivity disorder (ADHD) by effect size in performance and symptom improvement in a simulated adult workplace environment (AWE). Adults (aged 18-55 years) with ADHD enrolled in the AWE study of LDX with open-label dose-optimization and randomized, placebo-controlled, double-blind, 2-way crossover phases. Efficacy measures included the Permanent Product Measure of Performance (PERMP)-Attempted (-A) and PERMP-Correct (-C) scores assessed throughout the day and the ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts. Model-based least-squares (LS) mean effect size was assessed for PERMP and post-hoc ADHD-RS-IV with adult prompts. Remission was defined as an ADHD-RS-IV total scores ≤ 18. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Least-squares mean (standard error [SE]) effect sizes were 0.9 (0.17) for PERMP-A and 0.8 (0.16) for PERMP-C for all postdose sessions. For PERMP-A, postdose LS mean (SE) effect sizes were 0.5 (0.15), 0.8 (0.16), 0.7 (0.16), 0.7 (0.16), 0.7 (0.16), and 0.6 (0.16) at 2, 4, 8, 10, 12, and 14 hours, respectively. Medium-to-large effect sizes (0.5-0.8) were generally maintained from 2 to 14 hours for all PERMP assessments. Overall LS mean (SE) ADHD-RS-IV total and subscale effect sizes were -1.2 (0.19), -1.2 (0.19), and -1.0 (0.17), respectively. Remission was achieved in 67.6% of participants receiving LDX. Treatment-emergent adverse events (≥ 5% with LDX) during the 4-week dose-optimization phase were decreased appetite, dry mouth, headache, insomnia, upper respiratory tract infection, irritability, nausea, anxiety, and feeling jittery. During the crossover week on LDX, there were no TEAEs ≥ 5%. In adults studied in the AWE, medium-to-large model-based effect sizes were maintained from 2 to 14 hours postdose, on a performance-based measure of productivity, suggesting participants experienced improvement in sustained attention throughout the day and into the evening hours. Lisdexamfetamine dimesylate demonstrated a safety profile consistent with long-acting stimulants.


Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia.
During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.


Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer.
Pancreatic cancer is one of the most aggressive solid malignancies with a dismal survival rate. Recent studies have shown that high expression levels of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) correlate with several solid tumors. However, the underlying molecular mechanisms and its clinical significance in pancreatic cancer remain to be elucidated. In the present study, our results showed that MALAT-1 expression levels were upregulated in pancreatic cancer tissues compared with adjacent noncancerous controls. Consistently, higher expression level of MALAT-1 was found in all seven pancreatic cancer cell lines relative to the human pancreatic ductal epithelial cell. Further function analysis revealed that downregulation of MALAT-1 could inhibit tumor cell proliferation and decrease cell migration and invasion in vitro. The underlying mechanisms are possibly involved in inducing G2/M cell cycle arrest, promoting cell apoptosis, suppressing epithelial-mesenchymal transition and reducing cancer stem-like properties. In conclusion, this study indicated that MALAT-1 may serve as an oncogenic lncRNA that is involved in malignancy phenotypes of pancreatic cancer. Therefore, it may be used as a potential therapeutic target.


Group action planning as a support strategy for Hispanic families: parent and professional perspectives.
Focus group interviews were conducted to obtain participants' preliminary reactions to the responsiveness of group action planning, a person-centered planning approach, as a support strategy for Hispanic families of individuals with disabilities. Focus group participants were 38 Hispanic parents of youth/young adults with developmental disabilities and 22 professionals who provided support services to Hispanic youth/young adults with developmental disabilities and their families. Both constituency groups identified advantages and disadvantages of group action planning. We focus our key recommendations on the implications of this information for education and human service systems as well as directions for future research.


Fresh produce and microbial contamination: persistence during the shelf life and efficacy of domestic washing methods.
The transmission of enteric pathogens by fresh produce depends on the survival of the bacteria organisms during the product shelf-life. The removal of any potentially hazardous microorganism from the vegetables is therefore dependent on the washing and sanitizing techniques employed by individual households. For this purpose, in this work we investigated the persistence of enteric bacteria, using as model Salmonella enterica serovar Napoli (S. Napoli) and Yersinia enterocolitica, in vegetables stored at refrigeration temperature (4 °C). The efficiency of tap water and different chlorine solutions for cleaning vegetables experimentally contaminated with Y. enterocolitica were tested. The results showed that in lettuce spiked with different concentrations of S. Napoli and Y. enterocolitica, both microorganisms were still detected after seven days of storage at 4 °C. Lettuce contaminated with low concentrations of Y. enterocolitica was not decontaminated by washing with tap water or with water added with 60 ppm of chlorine. The presence of Y. enterocolitica in lettuce was reduced of about 1-2 logs after washing with water added with 220 ppm of chlorine. The addition of low concentration of chlorine in post harvest washing processes represents a useful tool to reduce the contamination of the vegetables, with consequent reduction of the risks. However, since complete decontamination was not achieved, foodborne infections linked to fresh produce can still be possible, although contamination is avoided during primary production.


"Do I stay or do I go?"--job change and labor market exit intentions of employees providing informal care to older adults.
This article examines whether providing informal eldercare to an older dependent person predicts employees' intentions to change jobs or exit the labor market and, if so, which particular aspects of both caregiving (e.g. time demands, physical/cognitive care burden) and their current work environment shape these intentions. We used data from a sample of 471 caring and 431 noncaring employees in Austria and split the analyses by gender. We found different aspects of informal caregiving to be associated with the intention to change jobs and with the anticipated labor market withdrawal of male and female workers. A time-based conflict between informal eldercare and paid work was significantly and positively related to the intended job change of female workers but not of their male counterparts. Flexible work arrangements were found to facilitate the attachment of female workers to their jobs and the labor market. Intentions to exit the labor market of male workers appeared to be triggered by a physical care burden rather than time demands. We studied the effects of providing informal eldercare on the turnover intention of men and women in a group of workers who were also the main carers providing support to a dependent older person with substantial care needs. The intention of male and female workers to change jobs and exit the labor market is shaped by the different characteristics of informal caregiving. Time-based conflicts between informal care and paid work are associated with a higher relative risk of anticipating job changes for female workers. Flextime facilitates the job and labor market attachment of female workers with eldercare responsibilities. The intensity of personal care provided to an older relative is significantly positively related to male workers' relative risk of anticipated labor market exit. Care to an older person in need of supervision makes the labor market exit of female workers less likely, lending thus support to the idea of the respite effect of work.


Analysis of the contribution of MTP and the predicted Flp pilus genes to Mycobacterium tuberculosis pathogenesis.
Mycobacterium tuberculosis (Mtb) is one of the world's most successful pathogens. Millions of new cases of tuberculosis occur each year, emphasizing the need for better methods of treatment. The design of novel therapeutics is dependent on our understanding of factors that are essential for pathogenesis. Many bacterial pathogens use pili and other adhesins to mediate pathogenesis. The recently identified Mycobacterium tuberculosis pilus (MTP) and the hypothetical, widely conserved Flp pilus have been speculated to be important for Mtb virulence based on in vitro studies and homology to other pili, respectively. However, the roles for these pili during infection have yet to be tested. We addressed this gap in knowledge and found that neither MTP nor the hypothetical Flp pilus is required for Mtb survival in mouse models of infection, although MTP can contribute to biofilm formation and subsequent isoniazid tolerance. However, differences in mtp expression did affect lesion architecture in infected lungs. Deletion of mtp did not correlate with loss of cell-associated extracellular structures as visualized by transmission electron microscopy in Mtb Erdman and HN878 strains, suggesting that the phenotypes of the mtp mutants were not due to defects in production of extracellular structures. These findings highlight the importance of testing the virulence of adhesion mutants in animal models to assess the contribution of the adhesin to infection. This study also underscores the need for further investigation into additional strategies that Mtb may use to adhere to its host so that we may understand how this pathogen invades, colonizes and disseminates.


Objective integrated assessment of functional outcomes in reduction mammaplasty.
The aim of our study was an objective integrated assessment of the functional outcomes of reduction mammaplasty. The study involved 17 women undergoing reduction mammaplasty from March 2009 to June 2011. Each patient was assessed before surgery and 2 months postoperatively with the original association of 4 subjective and objective assessment methods: a physiatric clinical examination, the Roland Morris Disability Questionnaire, the Berg Balance Scale, and a static force platform analysis. All of the tests proved multiple statistically significant associated outcomes demonstrating a significant improvement in the functional status following reduction mammaplasty. Surgical correction of breast hypertrophy could achieve both spinal pain relief and recovery of performance status in everyday life tasks, owing to a muscular postural functional rearrangement with a consistent antigravity muscle activity sparing. Pain reduction in turn could reduce the antalgic stiffness and improved the spinal range of motion. In our sample, the improvement of the spinal range of motion in flexion matched a similar improvement in extension. Recovery of a more favorable postural pattern with reduction of the anterior imbalance was demonstrated by the static force stabilometry. Therefore, postoperatively, all of our patients narrowed the gap between the actual body barycenter and the ideal one. The static force platform assessment also consistently confirmed the effectiveness of an accurate clinical examination of functional impairment from breast hypertrophy. The static force platform assessment might help the clinician to support the diagnosis of functional impairment from a breast hypertrophy with objectively based data.


Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation.
Because mammalian target of rapamycin (mTOR) inhibitors combine anticancer and immunosuppressive properties we investigated: 1) the activation status and prognostic significance of the mTOR pathway in hepatocellular carcinoma (HCC) tissues of patients undergoing orthotopic liver transplantation (OLT) for HCC, and 2) the single and combinatorial efficacy of RAD001 in HCC cells. PTEN, p-AKT, p-mTOR, p-p70S6K, and p-4EBP-1 were analyzed by immunohistochemistry in explanted HCCs of 166 patients undergoing OLT. Efficacy of RAD001 as mono- and combination therapy with doxorubicin was tested in Hep3B and SNU398 cells. The mTOR pathway is activated in about 40% of patients undergoing OLT for HCC but no direct correlation between up- and downstream proteins was observed. We found no influence of mTOR pathway protein expression on disease free survival (DFS) or overall survival (OS). There was a marked single agent and chemo-sensitizing effect of RAD001 against HCC cells in vitro. The mTOR pathway is active in 40% of patients with HCC undergoing OLT, but has no influence of DFS or OS. No direct correlation was observed between up- and downstream proteins limiting the use of upstream proteins to predict mTOR activity. Prospective clinical trials are needed to test whether the activation status of the mTOR pathway in HCCs predicts the antitumor effect of rapamycin derivative in the posttransplantation course.


Cloning and functional analysis of novel short-chain cis-prenyltransferases.
cis-Prenyltransferase catalyzes the synthesis of Z,E-mixed prenyl diphosphates by sequential condensation of isopentenyl diphosphate with allylic diphosphate. cis-Prenyltransferases can be classified into three subgroups: short-, medium-, and long-chain cis-prenyltransferase, according to their product chain lengths. cis-Farnesyl diphosphate synthase from Mycobacterium tuberculosis has been the only example as short-chain cis-prenyltransferase so far characterized. In this study, we cloned the novel short-chain cis-prenyltransferases from three different bacteria, and characterized their enzymatic activities to compare and elucidate a common feature of the short-chain cis-prenyltransferases. Furthermore, we identified a specific isoleucine that is conserved in short-chain cis-prenyltransferases and located in close proximity of the omega-end of the geranyl diphosphate. Several site-directed mutants with respect to the isoleucine residue synthesized longer prenyl chain products and showed broader allylic substrate specificity. These results suggested that the isoleucine plays an important role in the substrate specificity and chain length determination mechanism of cis-prenyltransferase.


Muscle-Mimetic Synergistic Covalent and Supramolecular Polymers: Phototriggered Formation Leads to Mechanical Performance Boost.
A thin filament stimulated by Ca2+ to combine with myosin is the structural basis to achieve filament sliding and muscle contraction. Though a large variety of artificial materials has been developed by mimicking muscle, the on-demand combination of the actin filament and myosin has never been precisely reproduced in polymeric systems. Herein, we show that both the combination process and the combined structure of actin filament and myosin have been mimicked to construct synergistic covalent and supramolecular polymers (CSPs). Specifically, photoirradiation as a stimulus induces the independently formed covalent polymers (CPs) and supramolecular polymers (SPs) to interact with each other through activated quadruple H-bonding. The resultant CSPs possess a unique network structure which not only facilitates the synergistic effect of CPs and SPs to afford stiff, strong, yet tough materials but also provides efficient pathways to dissipate energy with the damping capacity of the representative material being higher than 95%. Furthermore, muscle functions, for example, by becoming stiff during contraction and self-growth by training, are imitated well in our system via in situ phototriggered formation of CSP in the solid state. We hope that the fundamental understanding gained from this work will promote the development of synergistic CSP systems with emergent functions and applications by mimicking the principle of muscle movements.


Visual Attention Modulates Phenomenal Consciousness: Evidence From a Change Detection Study.
The distinction between phenomenal and access consciousness has been influential in the field of consciousness studies. Both Block and Lamme proposed that access consciousness, or narrow cognitive accessibility, is related to a limited capacity working memory, and that phenomenal consciousness, or broad cognitive accessibility, is related to iconic memory or, more recently, to a fragile (intermediate) short-term memory store with a larger capacity than working memory. They have also highlighted the preattentive nature of phenomenal consciousness and of the related iconic and fragile visual short-term stores, thus selectively linking attention with access consciousness, in line with Baars and Dehaene, among others. However, a range of electrophysiological and neurophysiological studies suggest that visual attention can affect early responses of neurons in visual cortex, before conscious access. Furthermore, some theories and neurocomputational models suggest earlier attentional biases related to phenomenal consciousness. To solve this controversy, and to shed light on the relationships of attention with iconic memory and subsequent stages of visual maintenance, we conducted an experiment with a novel procedure of change detection based on delayed cueing of the target for report with high- and low-priority objects marked by color. In line with our hypothesis, the results show an attentional bias toward high-priority objects in the memory array with the longer (600 and 1,200 ms) cueing delays associated with a fragile (intermediate) visual short-term memory, but not with the shorter cueing delays (16.6 and 200 ms) associated with iconic memory. These findings therefore suggest two stages of phenomenal consciousness before access consciousness: a first preattentive stage related to iconic memory and a second stage related to fragile visual short-term memory intermediate between iconic and visual working memory, which is modulated by visual attention in a time-dependent manner. Finally, our results suggest the dissociation between a mid-level visual attention modulating phenomenal consciousness and a central attention directing access consciousness.


Glycoproteins of bovine viral diarrhoea-mucosal disease virus in infected bovine cells.
Bovine cell cultures infected with bovine viral diarrhoea-mucosal disease (BVD) virus were radiolabelled with L-[35S]methionine or D-[2-3H]mannose followed by analysis of the labelled polypeptides by radioimmunoprecipitation and polyacrylamide gel electrophoresis in one and two dimensions. Six glycoproteins were detected in infected cells. Two abundant species had Mr of 48K and 56K to 58K while the less abundant species had Mr of 118K, 75K, 65K and 25K. When cells were radiolabelled with L-[35S]methionine in the presence of tunicamycin 56K to 58K migrated with apparent masses of 54K (a minor species) and 48K to 50K (the major molecular species) in PAGE. Endoglycosidase F digestion of virus-induced polypeptides caused a 4K to 6K reduction in the apparent molecular mass of 56K to 58K yielding a single 52K digested product, indicating that the heterogeneity of 56K to 58K was due to differences in the oligosaccharide moieties. Tunicamycin caused a drastic reduction in the yield of infectious virus indicating that the carbohydrate moieties serve a critical role in the infectious cycle of BVD virus.


Syntrophic interactions among anode respiring bacteria (ARB) and Non-ARB in a biofilm anode: electron balances.
We demonstrate that the coulombic efficiency (CE) of a microbial electrolytic cell (MEC) fueled with a fermentable substrate, ethanol, depended on the interactions among anode respiring bacteria (ARB) and other groups of micro-organisms, particularly fermenters and methanogens. When we allowed methanogenesis, we obtained a CE of 60%, and 26% of the electrons were lost as methane. The only methanogenic genus detected by quantitative real-time PCR was the hydrogenotrophic genus, Methanobacteriales, which presumably consumed all the hydrogen produced during ethanol fermentation ( approximately 30% of total electrons). We did not detect acetoclastic methanogenic genera, indicating that acetate-oxidizing ARB out-competed acetoclastic methanogens. Current production and methane formation increased in parallel, suggesting a syntrophic interaction between methanogens and acetate-consuming ARB. When we inhibited methanogenesis with 50 mM 2-bromoethane sulfonic acid (BES), the CE increased to 84%, and methane was not produced. With no methanogenesis, the electrons from hydrogen were converted to electrical current, either directly by the ARB or channeled to acetate through homo-acetogenesis. This illustrates the key role of competition among the various H(2) scavengers and that, when the hydrogen-consuming methanogens were present, they out-competed the other groups. These findings also demonstrate the importance of a three-way syntrophic relationship among fermenters, acetate-consuming ARB, and a H(2) consumer during the utilization of a fermentable substrate. To obtain high coulombic efficiencies with fermentable substrates in a mixed population, methanogens must be suppressed to promote new interactions at the anode that ultimately channel the electrons from hydrogen to current.


Twelve tips for applying the think-aloud method to capture cognitive processes.
The think-aloud method is an established technique for studying human thought (cognitive) processes. Problem-solving and decision-making are essential skills for medical professionals, and the cognitive processes underlying these skills are complex. Studying these thought processes would enable educators, clinicians, and researchers to modify or refine their approaches and interventions. The think-aloud method has been utilized for capturing cognitive processes in a variety of fields, including computer usability, sports and cognitive psychology. Medical education also recognizes thought processes as valuable data for research and education. This article aims to guide researchers and educators through the preparation and implementation of a think-aloud method to record participants' thought processes during an activity.


Tissue-specific expression of splice variants of the mouse voltage-gated calcium channel alpha2/delta subunit.
Five different splice variants of mouse alpha2/delta subunit isoforms (alpha2a-e), which arose from various combinations of three alternatively spliced regions, were cloned with a combination of cDNA library screening and RT-PCR. Expression patterns and relative abundance of the various isoforms in mouse tissues were determined with an RNAse protection assay. Skeletal muscle and brain expressed single isoforms, alpha2a and alpha2b, respectively; however, the cardiovascular system expressed all five isoforms. Heart expressed mainly isoforms alpha2c and alpha2d while, in contrast to other species, aorta expressed predominantly alpha2a, the 'skeletal muscle' isoform. Smooth muscle-containing tissues expressed alpha2d and alpha2e. Thus, alpha2/delta isoforms are restricted in their tissue expression, suggesting an important functional role for the differentially spliced variants.


Comorbid Conditions in Persons Exposed to Ionizing Radiation and Veterans of the Soviet-Afghan War: A Cohort Study in Kazakhstan.
This study investigated the prevalence and characteristics of comorbid conditions in patients exposed to ionizing radiation and those who were involved in the Soviet-Afghan war. This study analyzed the frequency and spectrum of morbidity and comorbidity in patients over a long-term period (30-35 years) following exposure to ionizing radiation at the Semipalatinsk nuclear test site or the Chornobyl nuclear power plant, and among participants of the Soviet-Afghan war. A cohort study, both prospective and retrospective, was conducted on 675 patients who underwent comprehensive examinations. Numerical data were analyzed using the STATISTICA 6 program. The results are presented as the mean ± standard deviation, median, and interquartile range (25th-75th percentiles). The statistical significance of between-group differences was assessed using the Student t-test and Pearson chi-square test. A p-value of less than 0.05 was considered statistically significant. We found a high prevalence of cardiovascular diseases, including hypertension (55%) and cardiac ischemia (32.9%); these rates exceeded the average for this age group in the general population. The cumulative impact of causal occupational, environmental, and ultra-high stress factors in the combat zone in participants of the Soviet-Afghan war, along with common conventional factors, contributed to the formation of a specific comorbidity structure. This necessitates a rational approach to identifying early predictors of cardiovascular events and central nervous system disorders, as well as pathognomonic clinical symptoms in this patient cohort. It also underscores the importance of selecting suitable methods and strategies for implementing treatment and prevention measures.


Miniature Compressive Ultra-spectral Imaging System Utilizing a Single Liquid Crystal Phase Retarder.
Spectroscopic imaging has been proved to be an effective tool for many applications in a variety of fields, such as biology, medicine, agriculture, remote sensing and industrial process inspection. However, due to the demand for high spectral and spatial resolution it became extremely challenging to design and implement such systems in a miniaturized and cost effective manner. Using a Compressive Sensing (CS) setup based on a single variable Liquid Crystal (LC) retarder and a sensor array, we present an innovative Miniature Ultra-Spectral Imaging (MUSI) system. The LC retarder acts as a compact wide band spectral modulator. Within the framework of CS, a sequence of spectrally modulated images is used to recover ultra-spectral image cubes. Using the presented compressive MUSI system, we demonstrate the reconstruction of gigapixel spatio-spectral image cubes from spectral scanning shots numbering an order of magnitude less than would be required using conventional systems.


Long-term follow-up of hexamethylene diisocyanate-, diphenylmethane diisocyanate-, and toluene diisocyanate-induced asthma.
In 1976-1992 245 new cases of asthma induced by diisocyanates were diagnosed, caused by hexamethylene diisocyanate (HDI) in 39%, diphenylmethane diisocyanate (MDI) in 39%, and toluene diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 () yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.


Measurement and clinical significance of circulating hematopoietic growth factor levels.
Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo regulation of hematopoiesis under conditions of steady state or stress, providing insights into the physiological roles of hematopoietic growth factors and their importance in the pathogenesis of disease. As mediators of pathological processes, hematopoietic growth factors may be targets for antagonist therapy in some diseases. Exogenous hematopoietic growth factors may also be useful therapeutically to augment physiological responses, so understanding hematopoietic growth factor regulation and serum levels may assist the development of specific therapies. Hematopoietic growth factor levels may also serve as tumor markers and assist prognostication or monitoring during the clinical course of an illness. The growth factors of particular interest include the four classic colony-stimulating factors: granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and multi-colony-stimulating factor, also known as interleukin-3. Other cytokines with hematopoietic growth factor activity include interleukin-1, interleukin-6, interleukin-11, stem cell factor (also known as Steel factor or mast cell growth factor), and leukemia inhibitory factor.


Syringocystadenocarcinoma papilliferum with squamous cell carcinoma differentiation and with locoregional metastasis.
Syringocystadenocarcinoma papilliferum is the rare malignant counterpart of a more common, benign adnexal neoplasm known as syringocystadenoma papilliferum. Review of the literature identified 21 cases of syringocystadenocarcinoma papilliferum. Most reported SCACP seem to represent examples of in situ adenocarcinoma or invasive adenocarcinomas, whereas to our knowledge, only 3 cases were described as SCACP with squamous cell carcinoma. In the present series of 2 cases, we report of SCACP with squamous differentiation and 1 case of SCACP with regional lymph node metastasis. The risk of regional lymph node metastasis is low with SCACP, but it should be kept in mind for the risk of regional metastasis of its morphological type of invasive squamous cell carcinoma.


Accuracy of statin assignment using the 2013 AHA/ACC Cholesterol Guideline versus the 2001 NCEP ATP III guideline: correlation with atherosclerotic plaque imaging.
Accurate assignment of statin therapy is a major public health issue. The American Heart Association and the American College of Cardiology released a new guideline on the assessment of cardiovascular risk (GACR) to replace the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III recommendations. The aim of this study was to determine which method more accurately assigns statins to patients with features of coronary imaging known to have predictive value for cardiovascular events and whether more patients would be assigned to statins under the new method. The burden of coronary atherosclerosis on computed tomography angiography was measured in several ways on the basis of a 16-segment model. Whether to assign a given patient to statin therapy was compared between the NCEP and GACR guidelines. A total of 3,076 subjects were studied (65.3% men, mean age 55.4 ± 10.3 years, mean age of women 58.9 ± 10.3 years). The probability of prescribing statins rose sharply with increasing plaque burden under the GACR compared with the NCEP guideline. Under the NCEP guideline, 59% of patients with ≥50% stenosis of the left main coronary artery and 40% of patients with ≥50% stenosis of other branches would not have been treated. The comparable results for the GACR were 19% and 10%. The use of low-density lipoprotein targets seriously degraded the accuracy of the NCEP guideline for statin assignment. The proportion of patients assigned to statin therapy was 15% higher under the GACR. The new American Heart Association/American College of Cardiology guideline matches statin assignment to total plaque burden better than the older guidelines, with only a modest increase in the number of patients who were assigned statins.


The regenerated bone quality by implantation of octacalcium phosphate collagen composites in a canine alveolar cleft model.
Synthetic octacalcium phosphate and porcine atelocollagen composites significantly enhanced bone regeneration more than β-tricalcium phosphate collagen composite and hydroxyapatite collagen composite in a rat cranial defect model. However, the long-term stability and quality of octacalcium phosphate collagen (OCP/Col) composites-derived regenerated bone, when implanted in a canine alveolar cleft model, have yet to be elucidated. The present study investigated the longterm stability and quality of bone regenerated by OCP/Col. Disks of OCP/Col or collagen were implanted in a canine alveolar-cleft model (n = 6). Then, bone regeneration in the implanted areas was investigated macroscopically, radiographically, and histologically at 10 months after implantation. In addition, three-dimensional quantitative images of regenerated bone were analyzed by microcomputed tomography. Macroscopically, the OCP/Col treated alveolus was clearly augmented, and radio-opacity in the OCP/Col implanted area was comparable to that of the original alveolus bone. On histological analysis, the area was mostly filled with newly formed bone, and a few granules of implanted OCP/Col were enclosed in it. In the microcomputed tomography analysis, the regenerated bone volume in the OCP/Col group was larger than that in the collagen group. OCP/Col-derived bone consisted of outer cortical and inner cancellous structure with dense trabeculae and seemed like the original bone structure. OCP/Co composites could be a useful bone regenerative material to substitute for autogenous bone because their implantation could elicit high bone regeneration and active structural reconstitution.


Anatomical Variations in the Origin of the Lumbar Artery: A Cadaveric Study Augmented by CT Findings.
Anatomical variations of lumbar arteries predispose them to iatrogenic injury during endovascular intervention or surgery. Due to limited morphological data on lumbar arteries in our setting, we aimed to determine their variant anatomy among Kenyans. We performed the study on 90 cadaveric specimens and 120 computed tomography (CT) scans. Cadavers were dissected to expose the aorta and the lumbar arteries emerging from them. The number, origins, location relative to the vertebral bodies, and relations to aortic bifurcation were determined in cadavers and CT scans. Data were analyzed using SPSS (version 21.0). On average, 3 (3/90 [3.3%]), 4 (63/90 [70%]) or 5 (24/90 [26.7%]) pairs of lumbar arteries were observed among the cadaveric specimens, whereas 4 (100/120 [83.3%]) or 5 (20/120 [16.7%]) pairs were observed in CTs. Differences in the number of pairs observed in the cadaveric versus CT study were not statistically significant (P = .542). There were no sex differences in the number of lumbar artery pairs observed in CT scans (P = .178). The first 3 lumbar artery pairs had a single-origin, whereas the fourth lumbar artery had a common-stem origin. The first, second, and third lumbar arteries mostly originated at the upper third of their respective vertebral bodies. The fourth lumbar artery predominantly originated at the lower third. Our study's findings show unique variation in the lumbar arteries' relation to the vertebral bodies and the distances between artery pairs. IV (cross-sectional study). Variations in the anatomy of the lumbar arteries should be taken into consideration, especially in surgical or interventional procedures to avoid inadvertent injury of the vessels.


Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology--a systematic review.
Histopathology has initially been and is still used to diagnose infectious, degenerative or neoplastic diseases in humans or animals. In addition to qualitative diagnoses semiquantitative scoring of a lesion`s magnitude on an ordinal scale is a commonly demanded task for histopathologists. Multiparametric, semiquantitative scoring systems for mouse models histopathology are a common approach to handle these questions and to include histopathologic information in biomedical research. Inclusion criteria for scoring systems were a first description of a multiparametric, semiquantiative scoring systems which comprehensibly describe an approach to evaluate morphologic lesion. A comprehensive literature search using these criteria identified 153 originally designed semiquantitative scoring systems for the analysis of morphologic changes in mouse models covering almost all organs systems and a wide variety of disease models. Of these, colitis, experimental autoimmune encephalitis, lupus nephritis and collagen induced osteoarthritis colitis were the disease models with the largest number of different scoring systems. Closer analysis of the identified scoring systems revealed a lack of a rationale for the selection of the scoring parameters or a correlation between scoring parameter value and the magnitude of the clinical symptoms in most studies. Although a decision for a particular scoring system is clearly dependent on the respective scientific question this review gives an overview on currently available systems and may therefore allow for a better choice for the respective project.


LncRNA MIAT Modulates LPS-Induced Acute Kidney Injury via BECN1-Dependent Autophagy by Interacting with PTBP1.
Autophagy plays critical adaptive and nonadaptive roles in the pathogenesis of Sepsis-associated acute kidney injury (Sepsis-AKI). However, it remains unknown whether myocardial infarction associated transcript (MIAT) is involved in the process of autophagy in Sepsis-AKI. This study aimed to explore the exact association between MIAT1 and Beclin 1 (BECN1)-mediated autophagy in Sepsis-AKI in vitro. HK-2 (human renal tubular epithelial cell line) cells were stimulated by lipopolysaccharide (LPS) to construct a septic kidney injury cell model in vitro. The relative expression changes of genes or proteins in clinical samples and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell survival was detected by cell counting kit-8 (CCK-8) and flow cytometry analysis. The production of inflammatory mediators was determined using Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR assays. The interlinked relationship between polypyrimidine tract-binding protein 1 (PTBP1) and MIAT or BECN1 was validated by RNA immunoprecipitation (RIP) and RNA pull-down detections. The expression of MIAT was up-regulated in Sepsis-AKI patients and LPS-stimulated HK-2 cells. Down-regulation of MIAT strikingly lightened LPS-induced cell apoptosis and inflammation, but enhanced cell viability. Evidenced by mechanistic experiments, MIAT silencing was confirmed to activate BECN1-mediated cell autophagy by interacting with PTBP1. Furthermore, the elimination of BECN1 remarkably reversed the antiapoptotic and anti-inflammatory roles mediated by MIAT silencing. In summary, the experimental data reinforced that MIAT downregulation attenuated LPS-stimulated renal cell inflammatory injury by promoting BECN1-mediated autophagy activation through binding to PTBP1, providing some new insights into the function and mechanism of MIAT in Sepsis-associated acute kidney injury (Sepsis-AKI).


Expanding Access to Malaria Diagnosis through Retail Shops in Western Kenya: What Do Shop Workers Think?
Background. The common symptoms of malaria reduce the specificity of clinical diagnosis. Presumptive treatment is conventional but can lead to overdiagnosis of malaria, delay of appropriate treatment, overprescription of antimalarials, and drug resistance. Routine use of diagnostic tests can address many of these concerns. Though treatment is often procured from retailers, there is low availability of rapid diagnostic tests for malaria (MRDTs), a simple, inexpensive, and accurate diagnostic solution. We know little about the challenges to expanding access to diagnostics through these outlets. Methods. To understand the perceptions of the benefits and challenges to selling rapid diagnostic tests for malaria, we conducted focus group discussions with antimalarial retailers who serve the residents of the Webuye Health and Demographic Surveillance Site in western Kenya. Results. Medicine retailers perceived MRDTs to be beneficial to their customers and businesses but also included cost, fear of the tests, risks of self-treatment, and regulatory concerns among the challenges to using and selling MRDTs. Conclusion. MRDTs represent a viable approach to increase access to malaria diagnostic testing. Medicine retailers are eager for MRDTs to be made available to them. However, certain challenges remain to implementation in retail outlets and should be addressed in advance.


Review of literature of radial nerve injuries associated with humeral fractures-an integrated management strategy.
Radial nerve palsy associated with fractures of the shaft of the humerus is the most common nerve lesion complicating fractures of long bones. However, the management of radial nerve injuries associated with humeral fractures is debatable. There was no consensus between observation and early exploration. The PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, CINAHL, International Bibliography of the Social Sciences, and Social Sciences Citation Index were searched. Two authors independently searched for relevant studies in any language from 1966 to Jan 2013. Thirty studies with 2952 humeral fractures participants were identified. Thirteen studies favored conservative strategy. No significant difference between early exploration and no exploration groups (OR, 1.03, 95% CI 0.61, 1.72; I(2) = 0.0%, p = 0.918 n.s.). Three studies recommend early radial nerve exploration in patients with open fractures of humerus with radial nerve injury. Five studies proposed early exploration was performed in high-energy humeral shaft fractures with radial nerve injury. The conservative strategy was a good choice for patients with low-energy closed fractures of humerus with radial nerve injury. We recommend early radial nerve exploration (within the first 2 weeks) in patients with open fractures or high-energy closed fractures of humerus with radial nerve injury.


Crystal and rotator phases of n-alkanes: A molecular dynamics study.
Normal alkanes have a simple molecular structure, but display a surprising variety of ordered phases, including an orthorhombic crystal, followed on heating by two partially ordered rotator phases RI and RII. These phases are interesting both because of the weakly first-order transitions that separate them, and because rotator phases are implicated in the nucleation of crystals in polyethylene. To understand this interesting and technologically important phenomenon, a clear picture of the rotator phase is essential. We conducted all-atom simulations of pure C(23) and mixed C(21)-C(23) normal alkanes. Among potentials we tried, only Flexible Williams gave good agreement with the experimental sequence of phases and transition temperatures. Physical properties of the simulated phases, including lattice dimensions and transition entropy between orthorhombic and rotator RII phase are in good agreement with experiment. We define order parameters for investigating pretransitional fluctuations in RI and RII phases; we observed only very short-range correlations in these phases, but slower temperature scans may be necessary to properly investigate these weakly first-order transitions.


Neighborhood structural disadvantage and biological aging in a sample of Black middle age and young adults.
Research on the social determinants of health has suggested that neighborhood disadvantage may undermine healthy aging and is particularly relevant for understanding health disparities. Recently, this work has examined deoxyribonucleic acid methylation (DNAm)-based measures of biological aging to understand the risk factors for morbidity and mortality. However, it is unknown whether neighborhood disadvantage is related to different indices of DNAm-based aging among Black Americans and whether such neighborhood effects vary as a function of age or gender. Our analyses of a Black American sample included 448 young adults and 493 middle-aged adults. We measured neighborhood disadvantage using the Area Deprivation Index at the census block group level. DNAm-based accelerated aging indices were measured using established procedures. Regressions with clustered standard errors were used for the analysis. Neighborhood disadvantage was independently associated with acceleration in PhenoAge, GrimAge, and DunedinPoAm, among young and middle-aged adults. Further, there was no evidence that gender conditioned the effects of neighborhood disadvantage on the aging indices. Regardless of age groups or gender, accelerated biological aging among Black Americans is partly rooted in differences in neighborhood disadvantage. From a policy standpoint, our findings suggest that programs that decrease neighborhood disadvantage are likely to increase healthy aging, especially among Black Americans.


National Trends in Hepatitis C Infection by Opioid Use Disorder Status Among Pregnant Women at Delivery Hospitalization - United States, 2000-2015.
Hepatitis C virus (HCV) is transmitted primarily through parenteral exposures to infectious blood or body fluids that contain blood (e.g., via injection drug use, needle stick injuries) (1). In the last 10 years, increases in HCV infection in the general U.S. population (1) and among pregnant women (2) are attributed to a surge in injection drug use associated with the opioid crisis. Opioid use disorders among pregnant women have increased (3), and approximately 68% of pregnant women with HCV infection have opioid use disorder (4). National trends in HCV infection among pregnant women by opioid use disorder status have not been reported to date. CDC analyzed hospital discharge data from the 2000-2015 Healthcare Cost and Utilization Project (HCUP) to determine whether HCV infection trends differ by opioid use disorder status at delivery. During this period, the national rate of HCV infection among women giving birth increased >400%, from 0.8 to 4.1 per 1,000 deliveries. Among women with opioid use disorder, rates of HCV infection increased 148%, from 87.4 to 216.9 per 1,000 deliveries, and among those without opioid use disorder, rates increased 271%, although the rates in this group were much lower, increasing from 0.7 to 2.6 per 1,000 deliveries. These findings align with prior ecological data linking hepatitis C increases with the opioid crisis (2). Treatment of opioid use disorder should include screening and referral for related conditions such as HCV infection.


Bismuth-containing quadruple therapy for Helicobacter pylori: lessons from China.
Antimicrobial resistance has continued to undermine many popular anti-Helicobacter pylori therapies. Antibiotic resistance to commonly used anti-H. pylori drugs in China has increased markedly, making China an ideal site to identify regimens that remain effective despite widespread antimicrobial resistance. Bismuth is one of the few antimicrobials to which resistance does not develop. Factors contributing to H. pylori treatment success include host factors (e.g., genetic differences in the metabolism of the drugs used), bacterial factors (e.g., susceptibility), and details of the regimen (e.g., doses, dosing interval, dosing in relation to meals, formulation, etc.). We reviewed the recent experience in China with bismuth-containing quadruple therapies. The experience consists of 16 studies with 25 arms involving 1971 patients to identify successful regimens (defined as reliably obtaining 90% or greater eradication per protocol) deserving further study. Despite high rates of resistance to commonly used antimicrobials, several regimens could achieve high success. These were characteristically 14-day regimens containing a proton pump inhibitor and either tetracycline and metronidazole or furazolidone and amoxicillin. We propose approaches for further development including for optimization and simplification related to convenience and side effects (e.g., twice rather than three or four times daily or administration at the noon and evening meal instead of at breakfast and evening) while maintaining effectiveness of at least 90%. Studies in China identified regimens that were highly effective despite the high prevalence of resistance to metronidazole, fluoroquinolones, and macrolides. Multicenter randomized studies will be required to confirm which is the best.


Toward an Understanding of Healthy Cognitive Aging: The Importance of Lifestyle in Cognitive Reserve and the Scaffolding Theory of Aging and Cognition.
The World Health Organization (WHO) aims to improve our understanding of the factors that promote healthy cognitive aging and combat dementia. Aging theories that consider individual aging trajectories are of paramount importance to meet the WHO's aim. Both the revised Scaffolding Theory of Aging and Cognition (STAC-r) and Cognitive Reserve theory (CR) offer theoretical frameworks for the mechanisms of cognitive aging and the positive influence of an engaged lifestyle. STAC-r additionally considers adverse factors, such as depression. The two theories explain different though partly overlapping aspects of cognitive aging. Currently, it is unclear where the theories agree and differ and what compensation mechanism of age-related cognitive decline might be better explained by either STAC-r, CR, or by both. This review provides an essential discussion of the similarities and differences between these prominent cognitive aging theories, their implications for intervention methods and neurodegenerative disease, and significant shortcomings that have not yet been addressed. This review will direct researchers to common insights in the field and to intervention targets and testable hypotheses for future research. Future research should investigate the potential use of STAC-r in neurodegenerative diseases and provide clarity as to what combination of factors build CR, including their relative importance and when in life they are most effective.


Health care access for low-income people: significant safety net gaps remain.
Despite signs that low-income and uninsured people's access to primary health care services has improved, serious gaps in care exist, especially for specialty physician, mental health and dental care, according to the Center for Studying Health System Change's (HSC) 2002-03 site visits to 12 nationally representative communities. Key factors contributing to these gaps in the safety net include declining private physician and dentist involvement, changes in funding and facilities, and more people in need. Community leaders have developed a variety of innovative strategies to add specialty, mental health and dental services but could benefit from more support from state and federal policy makers.


[The Bambuí Health and Aging Study (BHAS): ways of thinking and acting among hypertensive older adults].
The ways older adults think about and react to high blood pressure were studied through an anthropological approach based on the Signs, Meanings, and Actions model (1). Twenty-six older adults (> or = 60 years) participated in the study, randomly selected among hypertensive participants in the baseline of the Bambuí cohort study. The central thrust of narratives showed a clear distinction between a "blood pressure problem" and high blood pressure. High blood pressure is perceived as caused mainly by family problems and is easily recognized by the identification of certain specific manifestations; blood pressure is only considered problematic when it increases, and this is the only moment in which interventions are considered necessary. Consequently, the importance of seeking treatment or following a medical prescription depends on the identification of rising blood pressure, either by the presence of specific symptoms or subjective conditions favoring the rise. Economic difficulties are also identified by seniors as factors hindering their ability to initiate or continue treatment of hypertension.


The use of A23187 to demonstrate the role of intracellular calcium in causing ultrastructural damage in mammalian muscle.
Electron micrographs show that treatment of mouse diaphragm with the divalent cation ionophore A23187 causes major ultrastructural damage in the muscle. During the first 30 min of exposure to A23187, the mitochondria swell markedly but after 40 min they undergo further ultrastructural changes and a rapid dissolution of the myofilaments is also seen at this time. In place only remnants of the filaments remain. It is suggested that the ionophore causes the release of Ca2+ from the sarcoplasmic reticulum which, initially, is taken up by the mitochondria, causing then to swell; after 40 min the mitochondria release the accumulated Ca2+. It is argued that the rise in [ca2+]i stimulates neutral proteases in the myoplasm and that the sequence of events following ionophore treatment may act as a model for the involvement of Ca2+ in various myopathies. We have shown previously (29) that treatment of the cutaneous pectoris muscle of the frog with the divalent cation ionophore A23187 has three major effects: (i) The membrane potential (Em) is depolarized, an action that is found only when the Ca2+ -concentration of the bathing saline is very low. (ii) It causes an increase in resting tension and the development of contraction. This effect is found at both normal (1.8 mM) and low values of [Ca2+]o and is, therefore, independent of Ca2+ entry and of changes in Em. The ionophore is believed to act primarily by releasing Ca2+ from intracellular stores. (iii) It causes major ultrastructural damage to the muscle filaments. The evidence suggests that A23187 acts at the sarcoplasmic reticulum of frog muscle, causing the release of stored Ca2+ , and the consequent rise in [Ca2+]i stimulates a Ca2+ -activated protease which is responsible for the myofilament degradation. A calcium-activated factor has been isolated from rabbit skeletal muscle; this enzyme operates at neutral pH, hydrolyses denatured casein, and specifically removes the Z-lines and alpha-actinin from skeletal muscle (24). A Ca2+ -activated protease with a pH optimum of 7.5 has also been purified from porcine skeletal muscle; it removes Z-discs, degrades troponin and tropomyosin and partly degrades M lines, and it has been suggested that it may have a physiological role in the disassembly of intact myofibrils during the metabolic turnover of myofibrillar proteins (6, 7). This protases is not localized in membrane-bounded sub-cellular particles, but is believed to be in direct contact with the cytoplasm (26). These findings are of particular interest in thelight of recent suggestions that the cellular necrosis observed in various muscle diseases is a consequence of an increased net influx of calcium into cells which causes, in turn, calcium overloading of the muscle mitochondria (34, 35). We have, therefore, extended our previous studies with frog muscle by the examination of the action of A23187 on the mammalian skeletal muscle of mouse diaphragm...


Multipoint Thermal Sensors Associated with Improved Oncologic Outcomes Following Cryoablation.
Cryoablation (CA) is a minimally invasive modality for the management of small renal cortical neoplasms (RCN). Effective ablation is dependent on achieving target temperatures during CA that result in tumor cell death. We investigated long-term oncologic outcomes following CA using multipoint thermal sensors (MTS), which allow precise temperature determination at four points along the needle. We performed a retrospective review of 20 patients with <4 cm RCN who underwent de novo CA from 2005 to 2009. In 11 procedures, MTS needles were deployed with the goal of obtaining -20°C at the tumor margin, while 9 were done without MTS. Patient demographics, tumor characteristics, and CA procedure data were retrieved and analyzed. Follow-up CT or MRI was used to assess recurrence status. With a mean follow-up of 45 months, none of the 11 patients experienced a recurrence in the MTS group, compared with 4 of 9 (44.4%) patients in the non-MTS group (p = 0.026). Of the biopsy-confirmed renal cancers, none of the 6 in the MTS group, compared with 3 of 6 (50%) in the non-MTS group, recurred (p = 0.182). Age, tumor size, surgical approach, tumor histopathology, grade, follow-up time, and skin-to-tumor distance were similar between the MTS and non-MTS groups. The MTS group was also associated with increased total length of freeze (p = 0.041), procedure time (p = 0.020), cryoprobe utilization (p = 0.049), and a greater ratio of cryoprobes used per cm diameter of tumor (p = 0.003). In this small renal mass pilot study, the use of MTS needles to monitor temperature and guide cryoneedle deployment was associated with improved oncologic outcomes.


Outcomes of patients subjected to aortic valve replacement surgery using mechanical or biological prostheses.
This paper evaluates outcomes in patients subjected to surgery for replacement of the aortic valve using biological or mechanical substitutes, where selection of the type of prosthesis is relevant. Three hundred and one patients, randomly selected, who had been subjected to aortic valve replacement surgery between 1990 and 2005, with a maximum follow-up period of 20 years. Survival at 5, 10 and 15 years after surgery using mechanical substitute was 83.9%, 75.4% and 60.2% and, for biological substitute, was 89.3%, 70.4% and 58.4%, respectively (P = 0.939). Factors associated with death were: age, obesity, pulmonary disease, arrhythmia, bleeding and aortic valve failure. Probability free of reoperation for these patients at 5, 10 and 15 years after surgery using mechanical substitute was 97.9%, 95.8% and 95.8% and, for those using bioprostheses, was 94.6%, 91.0% and 83.3%, respectively (P = 0.057). Factors associated with reoperation were: renal failure, prosthesis endocarditis and age. Probability free of bleeding events at 5, 10 and 15 years after surgery using mechanical substitute was 94.5%, 91.7% and 91.7% and, for bioprostheses, was 98.6%, 97.8% and 97.8%, respectively (P = 0.047). Factors associated with bleeding events were: renal failure and mechanical prostheses. The authors have concluded that: 1) mortality was statistically similar in the groups; 2) patient characteristics at baseline were a major determinant of late mortality after surgery; 3) there was a tendency toward reoperation in the bioprostheses group; 4) patients using mechanical prosthesis had more bleeding events as time passed; 5) data presented in this paper is in accordance with current literature.


The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone.
Bone metastases are a frequent complication of solid tumors, leading to significant skeletal sequelae that negatively impact quality of life and survival. Prevention and management of skeletal-related complications are critical treatment goals in oncology. Endpoints used in clinical trials to evaluate skeletal-related complications have evolved. In contrast to single measures of bone health, contemporary clinical trial endpoints reflect composite measures of skeletal-related complications, and increasingly also survival. In addition, key symptomatic components, which are more reflective of quality of life and the patient experience, are being incorporated. Given the evolution and resulting diversity of the endpoints being used in pivotal trials, it is becoming increasingly relevant to clarify the utility and the potential clinical impact of these measures not only within the context of trials but also in the real-world setting. Here, we describe the development and evolution of skeletal endpoints used in trials, and discuss their clinical relevance.


A cost analysis of enterally administered lorazepam in the pediatric intensive care unit.
To determine the cost savings of replacing intravenous midazolam with enterally administered lorazepam in mechanically ventilated children who require long-term continuous sedation. Retrospective review of patients treated according to a preestablished pediatric intensive care unit (ICU) sedation protocol. Twenty-six-bed pediatric ICU in a tertiary care children's hospital. The records of 30 mechanically ventilated children were analyzed. The median age was 1.5 yrs and the median weight was 8.0 kg. Patients required continuous sedation for a total of 16 days (median). According to our pediatric ICU sedation protocol, midazolam infusion was continued until the hourly midazolam requirement was stable for at least 24 hrs. Thereafter, patients with a nasojejunal tube who were likely to require a minimum of three additional days of continuous sedation were transitioned from intravenous midazolam to enterally administered lorazepam. The goal in transitioning therapy was to titrate the lorazepam dose and reduce midazolam administration while maintaining an unchanged level of sedation. The rate of midazolam administration was significantly (p<.05) reduced beginning on day 1 of lorazepam treatment. Midazolam was successfully discontinued in 24 (80%) patients in 3 days (median), and adequate and appropriate sedation was maintained with lorazepam monotherapy. Six patients in whom midazolam could not be discontinued experienced a 52% reduction in the rate of midazolam administration as a result of adding lorazepam. Total projected midazolam utilization was defined as the sum of midazolam administration before initiating lorazepam and the projected midazolam requirement after initiating lorazepam. Projected midazolam cost was calculated as the product of total projected midazolam utilization and midazolam acquisition cost. Actual expenditures for both midazolam and lorazepam were subtracted from the projected midazolam cost to calculate the estimated cost savings. Overall, midazolam utilization (in milligrams) was reduced by 46.7+/-27.6% (median 52). Total projected midazolam cost for the 30 patients was $90,771. The actual cost of midazolam and lorazepam combined was $47,867, resulting in a cost savings of $42,904. Transitioning from intravenous midazolam to enterally administered lorazepam in critically ill children who require long-term sedation results in significant cost savings. The oral formulation of lorazepam was convenient to use, inexpensive, and effective in maintaining a continuous and appropriate level of sedation once midazolam was discontinued.


[Laparoscopic cholecystectomy as trendsetter in minimal-invasive surgery].
Only 10 years after the introduction of laparoscopic cholecystectomy in 1986 this method has become the "gold-standard" in the treatment of uncomplicated and complicated gallbladder disease. Laparoscopic cholecystectomy was so successfull, that it became the trendsetter in minimal-invasive surgery leading to revolutionary changes in all fields of surgery. Although nowadays self-evident, minimal-invasive surgery passed through a protracted and hindrance history of development. In this article we will review the history of laparoscopy and laparoscopic cholecystectomy and discuss its influence in the development of minimal-invasive surgery.