Control group improvements in physical activity intervention trials and possible explanatory factors: a systematic review.
Several recent physical activity intervention trials have reported physical activity improvements in control group participants. Explanations have been proposed, but not systematically investigated. A systematic review of physical activity intervention trials was conducted to investigate the frequency of meaningful improvements in physical activity among control group participants (increase of ≥60 minutes [4 MET·hours] of moderate-to-vigorous physical activity per week, or a 10% increase in the proportion of participants meeting physical activity recommendations), and possible explanatory factors. Explanatory factors include aspects of behavioral measurement, participant characteristics, and control group treatment. Eight (28%) of 29 studies reviewed reported meaningful improvements in control group physical activity, most of which were of similar magnitude to improvements observed in the intervention group. A number of factors were related to meaningful control group improvements in physical activity, including the number of assessments, mode of measurement administration, screening to exclude active participants, and preexisting health status. Control group improvement in physical activity intervention trials is not uncommon and may be associated with behavioral measurement and participant characteristics. Associations observed in this review should be evaluated empirically in future research. Such studies may inform minimal contact approaches to physical activity promotion.


One Health in South Asia and its challenges in implementation from stakeholder perspective.
One Health is a concept which fosters collaborative relationships between human health, animal health and environmental health partners. Diseases are emerging and re-emerging in South Asia due to poor sanitation, close proximity of people to livestock, deforestation, porous borders, climate change, changes in human behaviour and unhygienic food preparation and consumption practices. This review was completed in two stages. First, we conducted a review of peer-reviewed literature and grey literature available in Google search engine related to One Health in four countries (Bangladesh, Bhutan, India and Nepal). Second, we used a structured questionnaire completed by the key stakeholders working on One Health for the collection of information related to the challenges in implementing One Health. Most of the One Health activities in South Asia are determined by donor preferences. Bangladesh and India did considerable work in advancing One Health with limited support from the government agencies. Weak surveillance mechanisms, uncertain cost-effectiveness of One Health compared with the existing approach, human resources and laboratory capacity are some of the factors hindering implementation of the One Health concept. Implementation of One Health is growing in the South Asia region with limited or no government acceptance. To institutionalise it, there is a need for leadership, government support and funding.


[Strategy for identification of new neuropeptides].
Neuropeptides play a crucial role in cell communication as neurotransmitters, neuromodulators or neurohormones, and are involved in a number of biological activities including neuroendocrine regulations, control of neurovegetative functions, trophic effects and modulation of the immune response. The number of neuropeptides that have been fully characterized so far is rather limited, as compared to the number of precursor proteins that are actually expressed in nerve cells. Owing to the development of powerful analytical and structural identification methods, and the rapid advance in molecular biology techniques, a number of novel neuropeptides have been characterized during the last decade, in both vertebrates and invertebrates. The aim of the present review is to provide a comprehensive coverage of the different approaches which are currently used to identify novel neuropeptides.


The baroreceptor mechanism for controlling renin secretion: effect of calcium channel blockers.
Renin secretion is inversely related to afferent arteriolar transmural pressure, or to some function of it such as stretch (the baroreceptor mechanism). It has been suggested that increased pressure depolarizes the renin-secreting juxtaglomerular cells, and that increased Ca influx through voltage-operated Ca channels mediates the inhibitory effect on renin secretion. If true, then Ca channel blockers should antagonize the inhibitory effect of increased pressure on renin secretion. To test this prediction, isolated rat kidneys were perfused with an oxygenated physiological salt solution in a single-pass system. Perfusate flow rate and renin concentration in the venous effluent were measured and their product, the renin secretory rate (RSR), was calculated. During the control period, increasing renal perfusion pressure (RPP) from 100 to 120 mm Hg decreased RSR to 42 +/- 5% of the control value. This inhibitory effect of increased RPP was blunted by 1 microM nifedipine, nearly blocked by 5 microM verapamil and completely blocked by 50 microM diltiazem. Inasmuch as nifedipine, verapamil and diltiazem are Ca channel blockers and because all three have been shown previously to block the inhibitory effect of depolarization on RSR, these results are consistent with the hypothesis that a depolarization-induced influx of Ca mediates the inhibitory effect of increased RPP on RSR.


Longitudinal associations between adolescents' individualised risk for depression and inflammation in a UK cohort study.
Inflammation is associated with poor physical and mental health including major depressive disorder (MDD). Moreover, there is evidence that childhood adversity - a risk factor for MDD - becomes biologically embedded via elevated inflammation. However, the risk of developing MDD arises from multiple sources and yet there has been little investigation of the links between individuals' constellation of MDD risk and subsequent inflammation. We therefore examined associations between individual risk for MDD calculated in early adolescence and levels of inflammation six years later. We use data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK birth cohort of 2,232 children followed to age 18 with 93% retention. Participants' individual risk for developing future MDD was calculated at age 12 using a recently developed prediction model comprising multiple psychosocial factors. Plasma levels of three inflammation biomarkers were measured at age 18: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to reflect the level of systemic chronic inflammation. MDD risk scores calculated at age 12 were positively associated with levels of suPAR (but not CRP or IL-6) at age 18 after adjusting for key covariates (b = 1.70, 95% CI = 0.46 - 2.95, p = 0.007). Adolescents at high risk of MDD (risk scores ≥ 90th centile) had significantly higher mean levels of suPAR six years later than adolescents who had been identified as low risk (risk scores ≤ 10th centile) (b = 0.41, 95% CI = 0.18 - 0.64, p < 0.001). Findings support the notion that childhood psychosocial risk for MDD leads to increased levels of low-grade inflammation. If replicated in studies with repeated assessments of inflammation biomarkers throughout childhood and adolescence, these findings would support targeted interventions to reduce inflammation, as measured by suPAR, for adolescents at high risk of MDD to potentially prevent development of depression and physical health problems related to chronic inflammation.


Improvement of desolvation and resilience of alginate binders for Si-based anodes in a lithium ion battery by calcium-mediated cross-linking.
Si-based anodes in lithium ion batteries (LIBs) have exceptionally high theoretical capacity, but the use of a Si-based anode in LIBs is problematic because the charging-discharging process can fracture the Si particles. Alginate and its derivatives show promise as Si particle binders in the anode. We show that calcium-mediated "egg-box" electrostatic cross-linking of alginate improves toughness, resilience, electrolyte desolvation of the alginate binder as a Si-binder for LIBs. Consequently, the improved mechanical properties of the calcium alginate binder compared to the sodium alginate binder and other commercial binders extend the lifetime and increase the capacity of Si-based anodes in LIBs.


Changes in adhesion complexes define stages in the differentiation of lens fiber cells.
During their differentiation, lens fiber cells elongate, detach from the lens capsule, associate at the sutures, and degrade all cytoplasmic membrane-bound organelles. Changes in the expression or organization of cell adhesion and cytoskeleton-associated proteins were correlated with these events during fiber cell differentiation in chicken embryos. Fixed or living lenses were sliced with a tissue slicer, permeabilized or extracted with detergents, stained with antibodies or fluorescent-labeled phalloidin, and viewed with a confocal microscope. The distribution of N-cadherin in elongating and mature fiber cells was determined by Western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the distribution of vinculin and paxillin transcripts. Staining for N-cadherin and band 4.1 protein decreased soon after fiber cells detached from the capsule. Detergent extraction of lens sections and Western blots of dissected lens regions showed that much of this decrease in staining was due to epitope masking. Vinculin immunoreactivity was barely detectable on the lateral membranes of elongating fiber cells but increased markedly once these cells reached their maximum length and formed the sutures. Staining for paxillin was also low in elongating fiber cells but increased late in fiber cell differentiation, just before the cells destroyed their membrane-bound organelles. Spectrin and ankyrin immunoreactivity did not change when fiber cells reached the sutures. Staining for F-actin increased transiently in cells that had just reached the sutures. Messenger RNAs for vinculin and paxillin were more abundant in maturing than in elongating fiber cells. The adhesion complexes of lens fiber cells change in organization and composition soon after these cells finish elongating and detach from the capsule. Increased staining for vinculin and paxillin defines distinct stages of fiber cell differentiation that are intermediate between the completion of cell elongation and the time when lens fiber cells degrade their membrane-bound organelles. Remodeling adhesion complexes during fiber cell maturation may assure the stability of fiber-fiber associations, once these cells are no longer transcriptionally active.


Surgical treatment of esophago-tracheobronchial fistulas after esophagectomy.
The aim of this study was to evaluate the surgical treatment of esophago-tracheobronchial fistulas (ETBFs) that occurred after esophagectomy with gastric conduit reconstruction in a tertiary referral center for esophageal surgery. All patients who underwent surgical repair for an ETBF after esophagectomy with gastric conduit reconstruction were included in a tertiary referral center. The primary outcome was successful recovery after surgical treatment for ETBF, defined as a patent airway at 90 days after the surgical fistula repair. Secondary outcomes were details on the clinical presentation, diagnostics, and postoperative course after fistula repair. Between 2007 and 2022, 14 patients who underwent surgical repair for an ETBF were included. Out of 14 patients, 9 had undergone esophagectomy with cervical anastomosis and 5 esophagectomy with intrathoracic anastomosis after which 13 patients had developed anastomotic leakage. Surgical treatment consisted of thoracotomy to cover the defect with a pericardial patch and intercostal flap in 11 patients, a patch without interposition of healthy tissue in 1 patient, and fistula repair via cervical incision with only a pectoral muscle flap in 2 patients. After surgical treatment, 12 patients recovered (86%). Mortality occurred in two patients (14%) due to multiple organ failure. This study evaluated the techniques and outcomes of surgical repair of ETBFs following esophagectomy with gastric conduit reconstruction in 14 patients. Treatment was successful in 12 patients (86%) and generally consisted of thoracotomy and coverage of the defect with a bovine pericardial patch followed by interposition with an intercostal muscle.


Medroxyprogesterone Acetate Regulates HIV-1 Uptake and Transcytosis but Not Replication in Primary Genital Epithelial Cells, Resulting in Enhanced T-Cell Infection.
Although clinical and experimental evidence indicates that female sex hormones and hormonal contraceptives regulate susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, the underlying mechanism remains unknown. Genital epithelial cells (GECs) are the first cells to encounter HIV during sexual transmission and their interaction with HIV may determine the outcome of exposure. This is the first report that HIV uptake by GECs increased significantly in the presence of the hormonal contraceptive medroxyprogesterone acetate (MPA) and progesterone and that uptake occurred primarily via endocytosis. No productive infection was detected, but endocytosed virus was released into apical and basolateral compartments. Significantly higher viral transcytosis was observed in the presence of MPA. In GEC and T-cell cocultures, maximum viral replication in T cells was observed in the presence of MPA, which also broadly upregulated chemokine production by GECs. These results suggest that MPA may play a significant role in regulating susceptibility to HIV.


[Non pharmacological treatment for Alzheimer's disease: comparison between musical and non-musical interventions].
On account of the limited effectiveness of pharmacological treatments in Alzheimer's disease (AD), there is a growing interest on nonpharmacological treatments, including musical intervention. Despite the large number of studies showing the multiple benefits of music on behavioral, emotional and cognitive disorders of patients with AD, only a few of them used a rigorous method. Finally, the specificity of musical as compared to non-musical and pleasant interventions has rarely been addressed. To investigate this issue, two randomized controlled trials were conducted contrasting the effects of musical to painting (Study 1) or cooking (Study 2) interventions on emotional state of 33 patients with AD. The patients' emotional state was assessed by analyzing professional caregivers' judgments of the patient's mood, then facial expressions and valence of the discourse from short-filmed interviews. In the first study (n=22), each intervention lasted 3 weeks (two sessions per week) and the patients' emotional state was assessed before, during and after intervention periods. After the interventions, the results showed that facial expression, discourse content and mood assessment improved (more positive than negative expressions) as compared to pre-intervention assessment. However, musical intervention was more effective and had longer effects as compared with painting. In the second study (n=11), we further examined long lasting effects of music as compared to cooking by adding evaluation of the patients' emotional state 2 and 4 weeks after the last intervention. Again, music was more effective to improve the emotional state. Music had positive effects that remained significant up to 4 weeks after the intervention, while cooking only produced short-term effect on mood. In both studies, benefits were significant in more than 80% of patients. Taken together, these findings show that music intervention has specific effects on patients' emotional well being, offering promising methods to improve the quality of life of patients with AD.


ER-alpha-cDNA as part of a bicistronic transcript gives rise to high frequency, long term, receptor expressing cell clones.
Within the large group of Estrogen Receptor alpha (ERα)-negative breast cancer patients, there is a subgroup carrying the phenotype ERα(-), PR(-), and Her2(-), named accordingly "Triple-Negative" (TN). Using cell lines derived from this TN group, we wished to establish cell clones, in which ERα is ectopically expressed, forming part of a synthetic lethality screening system. Initially, we generated cell transfectants expressing a mono-cistronic ERα transcription unit, adjacent to a separate dominant selectable marker transcription unit. However, the yield of ERα expressing colonies was rather low (5-12.5%), and only about half of these displayed stable ectopic ERα expression over time. Generation and maintenance of such cell clones under minimal exposure to the ERα ligand, did not improve yield or expression stability. Indeed, other groups have also reported grave difficulties in obtaining ectopic expression of ERα in ERα-deficient breast carcinoma cells. We therefore switched to transfecting these cell lines with pERα-IRES, a plasmid vector encoding a bicistronic translation mRNA template: ERα Open Reading Frame (ORF) being upstream followed by a dominant-positive selectable marker (hygro(R)) ORF, directed for translation from an Internal Ribosome Entry Site (IRES). Through usage of this bicistronic vector linkage system, it was possible to generate a very high yield of ERα expressing cell clones (50-100%). The stability over time of these clones was also somewhat improved, though variations between individual cell clones were evident. Our successful experience with ERα in this system may serve as a paradigm for other genes where ectopic expression meets similar hardships.


Ectoparasite Load Is Reduced in Side-Blotched Lizards (Uta stansburiana) at Wind Farms: Implications for Oxidative Stress.
AbstractWind-generated power is one of the fastest growing alternative energy strategies worldwide and will likely account for 20% of US energy production by 2030. The installation and maintenance of wind farms are associated with increased human activity and can generate noise pollution, disturb and fragment habitat, and even alter community composition and structure. These environmental and ecological changes can increase physiological stress for vertebrates and affect important life-history attributes, such as immune function. However, little is known about how wind farms influence physiology and disease or parasite resistance in nonvolant wildlife. Here, we test the notion that renewable wind farms increase physiological stress and correlated aspects of disease resistance (parasite load) in a common desert vertebrate, the side-blotched lizard (Uta stansburiana). We captured lizards from three wind farms and three undisturbed reference sites in the San Gorgonio Pass wind resource area in the Mojave Desert, California. We quantified individual external parasite loads and measured plasma antioxidant capacity and concentrations of reactive oxygen metabolites as a combined metric of oxidative stress. Contrary to our expectations, individuals at wind farm sites had significantly fewer external parasites than at undeveloped sites. Additionally, we found a slight positive correlation between parasite load and oxidative stress for individuals at wind farm sites but not at reference sites. Our results demonstrate a complex, potentially context-dependent relationship between stress physiology and disease resistance for lizards in anthropogenically disturbed environments. Understanding how wind farms affect the physiology and ecoimmunology of terrestrial fauna is necessary to mitigate the ecological costs of alternative energy development.


Anthocyanin Color Stabilization by Host-Guest Complexation with p-Sulfonatocalix[n]arenes.
Flavylium-based compounds in their acidic and cationic form bring color to aqueous solutions, while under slightly acidic or neutral conditions they commonly bring discoloration. Selective host-guest complexation between water-soluble p-sulfonatocalix[n]arenes (SCn) macrocycles and the flavylium cationic species can increase the stability of the colored form, expanding its domain over the pH scale. The association constants between SCn and the cationic (acid) and neutral basic forms of flavylium-based compounds were determined through UV-Vis host-guest titrations at different pH values. The affinity of the hosts for synthetic chromophore was found to be higher than for a natural anthocyanin (Oenin). The higher affinity of SC4 for the synthetic flavylium was confirmed by 1H NMR showing a preferential interaction of the flavylium phenyl ring with the host cavity. In contrast with its synthetic counterpart, the flavylium substitution pattern in the anthocyanin seems to limit the inclusion of the guest in the host's binding pocket. In this case, the higher affinity was observed for the octamer (SC8) likely due to its larger cavity and higher number of negatively charged sulfonate groups.


An RNA biology perspective on species-specific programmable RNA antibiotics.
Our body is colonized by a vast array of bacteria the sum of which forms our microbiota. The gut alone harbors >1,000 bacterial species. An understanding of their individual or synergistic contributions to human health and disease demands means to interfere with their functions on the species level. Most of the currently available antibiotics are broad-spectrum, thus too unspecific for a selective depletion of a single species of interest from the microbiota. Programmable RNA antibiotics in the form of short antisense oligonucleotides (ASOs) promise to achieve precision manipulation of bacterial communities. These ASOs are coupled to small peptides that carry them inside the bacteria to silence mRNAs of essential genes, for example, to target antibiotic-resistant pathogens as an alternative to standard antibiotics. There is already proof-of-principle with diverse bacteria, but many open questions remain with respect to true species specificity, potential off-targeting, choice of peptides for delivery, bacterial resistance mechanisms and the host response. While there is unlikely a one-fits-all solution for all microbiome species, I will discuss how recent progress in bacterial RNA biology may help to accelerate the development of programmable RNA antibiotics for microbiome editing and other applications.


Clinical use of erythropoietin in chronic kidney disease: outcomes and future prospects.
The introduction of erythropoietin (Epo) in clinical practice, more than two decades ago, altered completely the management of patients with chronic kidney disease (CKD). The successful correction of anemia of CKD has resulted in reduction of associated morbidity and improvement of functionality, exercise tolerance, cognitive function and overall quality of life. Moreover, significant reduction of cardiovascular morbidity and mortality has occurred. Recently, large randomized clinical studies suggested that administration of Epo targeting at complete anemia correction is accompanied by significant increase of morbidity and mortality, compared to partial anemia correction. This observation has led to thorough investigation of the mechanisms of Epo actions and the possible contribution of other parameters including iron availability, comorbidities and resistance or hyporesponsiveness to Epo. In this context, it has been proposed that high doses of Epo are likely to exert toxic effects and pleiotropic systemic actions. Recognition of the extra-hematopoietic biologic actions of erythropoietin is a result of the better understanding of its interaction with Epo receptors in several tissues and organ systems, during fetal development as well as in the adult organism. More specifically, antiapoptotic, anti- inflammatory, angiogenetic and cytoprotective effects have been revealed in the kidneys, cardiovascular system, brain and retina. Until future studies are able to clarify the multiple beneficial or unfavorable effects of Epo, it is advisable to remain prudent in its administration, yet optimistic about its possible contribution in a number of pathologic conditions.


Influence of electron doping on the hydrogenation of fullerene C60 : a theoretical investigation.
The influence of electron attachment on the stability of the mono- and dihydrogenated buckminsterfullerene C(60) was studied using density functional theory and semiempirical molecular orbital techniques. We have also assessed the reliability of computationally accessible methods that are important for investigating the reactivity of graphenic species and surfaces in general. The B3LYP and M06L functionals with the 6-311+G(d,p) basis set and MNDO/c are found to be the best methods for describing the electron affinities of C(60) and C(60)H(2) . It is shown that simple frontier molecular orbital analyses at both the AM1 and B3LYP/6-31G(d) levels are useful for predicting the most favourable position of protonation of C(60)H(-) , that is, formation of the kinetically controlled product 1,9-dihydro[60]fullerene, which is also the thermodynamically controlled product, in agreement with experimental and previous theoretical studies. We have shown that reduction of exo- and endo-C(60)H makes them more stable in contrast to the reduction of the exo,exo-1,9-C(60)H(2) , reduced forms of which decompose more readily, in agreement with experimental electrochemical studies. However, most other dihydro[60]fullerenes are stabilized by reduction and the regioselectivity of addition is predicted to decrease as the less stable isomers are stabilized more by the addition of electrons than the two most stable ones (1,9 and 1,7).


Does local recurrence impact survival in low-grade chondrosarcoma of the long bones?
We hypothesized local recurrence of Grade 1 chondrosarcoma in the long bones of the extremity negatively influences survival. To explore that notion, we retrospectively reviewed 164 patients treated surgically for Grade 1 chondrosarcoma of the long bones. Local recurrence occurred in 21 (13%) patients. Four patients had progression of tumor grade on recurrence, and six patients had more than one local recurrence. Seven of the 21 patients with local recurrences had metastasis. Six of the 21 patients with local recurrences died secondary to chondrosarcoma. Local recurrence, progression of grade at recurrence, and distant metastases all were associated with a decrease in overall survival. The difference in survival was not apparent until after 5 years and was more pronounced after 10 years. Recurrence may be regarded as a declaration of an aggressive phenotype and should be treated as such.


Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation.
Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.


Photon-counting computed tomography of lanthanide contrast agents with a high-flux 330-μm-pitch cadmium zinc telluride detector in a table-top system.
Purpose: We present photon-counting computed tomography (PCCT) imaging of contrast agent triplets similar in atomic number ( Z ) achieved with a high-flux cadmium zinc telluride (CZT) detector. Approach: The table-top PCCT imaging system included a 330 - μ m -pitch CZT detector of size 8 mm × 24 mm 2 capable of using six energy bins. Four 3D-printed 3-cm-diameter phantoms each contained seven 6-mm-diameter vials with water and low and high concentration solutions of various contrast agents. Lanthanum ( Z = 57 ), gadolinium (Gd) ( Z = 64 ), and lutetium ( Z = 71 ) were imaged together and so were iodine ( Z = 53 ), Gd, and holmium ( Z = 67 ). Each phantom was imaged with 1-mm aluminum-filtered 120-kVp cone beam x rays to produce six energy-binned computed tomography (CT) images. Results: K -edge images were reconstructed using a weighted sum of six CT images, which distinguished each contrast agent with a root-mean-square error (RMSE) of < 0.29 % and 0.51% for the 0.5% and 5% concentrations, respectively. Minimal cross-contamination in each K -edge image was seen, with RMSE values < 0.27 % in vials with no contrast. Conclusion: This is the first preliminary demonstration of simultaneously imaging three similar Z contrast agents with a difference in Z as low as 3.


Role of nitric oxide and prostaglandins in the long-term control of renal function.
Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 microg x kg(-1) x min(-1)) during 4 consecutive days (n=8) elicited a continuous decrease (P<0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion. NG-Nitro-L-arginine methyl ester (L-NAME) infusion (5 microg x kg(-1) x min(-1)) during 6 days (n=8) produced a significant increase in arterial pressure and a transitory decrease (P<0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (n=7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (P<0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced.


Association of mir-196a-2 rs11614913 and mir-149 rs2292832 Polymorphisms With Risk of Cancer: An Updated Meta-Analysis.
Background: Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences. This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies. Methods: PubMed, Embase, Scopus, and ScienceDirect databases were searched until 9 April 2018 to identify eligible studies. Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI). Studies that met the following criteria were excluded: review articles, meta-analysis, abstracts or conference papers; duplicate publications; studies on animals or cell-lines; studies without a case-control design; studies that did not report genotype frequencies. Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832. Stratified analysis according to quality scores, genotyping method, ethnicity, broad cancer category and cancer type was also performed. Results: Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population. The association was only significant in Asians but not Caucasians. In subgroup analysis, significant associations were found in high quality studies, gynecological cancers, ovarian, breast, and hepatocellular cancer. Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians. However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model. Conclusions: The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians. Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer. This study had some limitations such as significant heterogeneity in most contrasts, limited number of studies enrolling Africans or Caucasians ancestry and lack of adjustment for covariates and environmental interactions.


Structures of Echovirus 30 in complex with its receptors inform a rational prediction for enterovirus receptor usage.
Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure. Enterovirus B (EV-B) consists of several subgroups according to receptor usage, among which echovirus 30 (E30), a leading causative agent for human aseptic meningitis, utilizes FcRn as an uncoating receptor. However, receptors for many EVs remain unknown. Here we analyzed the atomic structures of E30 mature virion, empty- and A-particles, which reveals serotype-specific epitopes and striking conformational differences between the subgroups within EV-Bs. Of these, the VP1 BC loop markedly distinguishes E30 from other EV-Bs, indicative of a role as a structural marker for EV-B. By obtaining cryo-electron microscopy structures of E30 in complex with its receptor FcRn and CD55 and comparing its homologs, we deciphered the underlying molecular basis for receptor recognition. Together with experimentally derived viral receptor identifications, we developed a structure-based in silico algorithm to inform a rational prediction for EV receptor usage.


Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer.
HIV-1, hepatitis B virus, hepatitis C virus, and human papillomavirus type 16 cause persistent infections that frequently precede cancer development. Virions of these viruses are weak inducers of interferon-α and impair Toll-like receptor (TLR)9 function. Loss of TLR9 responsiveness also occurs in tumors without viral etiology such as breast, ovary, and head and neck carcinomas. Recent reports have suggested that viruses and components of the tumor microenviroment interact with regulatory receptors on plasmacytoid dendritic cells (pDCs) to impair TLR7 and TLR9 signaling, and to downregulate TLR9 gene expression. The limited responsiveness of pDCs might contribute to reduced innate immune responses during chronic viral infections and oncogenesis, and represent a target for new therapeutic approaches based on TLR agonists.


Residual myelotoxicity of lindane in mice.
Lindane (gamma-1,2,3,4,5,6-hexachlorocyclohexane), a widely used insecticide, may be found at low concentrations in the human diet. Male B6C3F1 mice given lindane daily at doses of 20 and 40 mg/kg body wt by gavage in corn oil for 3 days had suppressed bone marrow cellularity, erythrocyte precursors, granulocyte-macrophage progenitor cells (CFU-GM), and residual progenitor cell damage, which could be demonstrated by two whole-body irradiations (WBI) at 200 rads. Lindane exposure for 10 consecutive days at doses of 0, 10, or 20 mg/kg did not cause clinical abnormality or changes in body weights, but there were dose-dependent decreases in marrow cellularity, in more pluripotent stem cells and in committed CFU-GMs, which returned to control values by 4 weeks. These mice were then subjected to two 100-rad exposures of WBI at 4 and 9 weeks following cessation of lindane treatment. This level of irradiation caused only a transient drop in number of marrow progenitor cells. Control and lindane-exposed mice were examined at 1 and 6 weeks following the last irradiation, which was 10 and 15 weeks following the final lindane exposure. The lindane-exposed mice had lower progenitor cell numbers and slower recovery from the irradiation. These results indicate that lindane has significant myelotoxicity in mice and short-term lindane exposure can induce residual progenitor cell damage that can be demonstrated by subsequent irradiation.


Regulation of renal organic anion and cation transporters by thymoquinone in cisplatin induced kidney injury.
In previous studies, we have demonstrated the biological activity of thymoquinone (TQ), an active compound extracted from the Nigella sativa plant, against cisplatin-induced neurotoxicity. Recenty, it was observed that there is an inherent lack in regulation of renal organic anion and cation transporters in cisplatin-induced nephrotoxicity. Here, we report, for the first time, the effect of TQ on alterations in the renal expression of organic anion transporters (OATs) and organic cation transporters (OCTs), as well as multidrug resistance-associated proteins (MRPs) in rats treated with cisplatin. Twenty-eight 8-week-old male Wistar rats were divided into four groups of control, TQ treated (10 mg/kg b.w. in drinking water for 5 days), cisplatin (7 mg/kg b.w., i.p.) and TQ and cisplatin combination treatment. Cisplatin-induced malondialdehyde (MDA) and 8-isoprostane increase was found to be markedly reduced in rats treated with TQ. In cisplatin only treated rats, the induced renal injury increased protein levels of the efflux transporters MRP2 and MRP4 while expression of OAT1, OAT3, OCT1 and OCT2 was reduced. In combination TQ- and cisplatin-treated rats, expression of MRP2 and MRP4 proteins was decreased in the kidneys. Conversely, TQ treatment increased levels of OCT1, OCT2, OAT1 and OAT3 and decreased levels of 8-isoprostane and MDA levels in cisplatin-treated rats. In conclusion, the present study shows that the TQ synergizes with its nephroprotective effect against cisplatin-induced acute kidney injury in rats.


Safety and efficacy of switching from infliximab biosimilar CT-P13 to infliximab biosimilar SB2 in patients with inflammatory bowel disease.
For patients with inflammatory bowel diseases, switching from infliximab originator to biosimilars is effective and safe. Few data on single switch have been published, and data on multiple switches of different infliximab are unavailable. A retrospective analysis of patients who switched from CT-P13 to SB2, and of those with multiple switches among different infliximab compounds was conducted. Clinical activity, C reactive protein (CRP), adverse events (AE) and loss of response (LOR) were recorded. Thirty-six patients (26 males, 14 Crohn's disease and 22 ulcerative colitis) were enrolled and followed up for >6 months. All patients switched from CT-P13 to SB2; 12 of them (33.3%) had already switched from reference Infliximab to CT-P13, and for the remaining patients CT-P13 was the first infliximab. The clinical remission rate six months before and three months after SB2-switch was the same (58.3%) and the rate of mild activity varied from 27.8 to 33.3% (P = 0.68); the percentage of patients with normal CRP values passed from 94.4 to 91.7% (P = 1). Two patients (5.5%) had AE and 11 (30.5%) a LOR. At univariate analysis, patients with a single switch had a non-significant risk of LOR during SB2 [odds ratio (OR) = 7.86; 95% confidence interval (CI) 0.87-71, P = 0.06]. SB2-LOR was associated with previous AE under CT-P13 (OR = 9.1, 95% CI 0.82-100, P = 0.07). None of such factors was significant at multivariate analysis. Switching from CT-P13 to SB2 seems to be safe and effective either in patients with a single than in those with multiple switches.


In vitro assessment of the contact mechanics of reverse-engineered distal humeral hemiarthroplasty prostheses.
Distal humeral hemiarthroplasty alters cartilage contact mechanics, which may predispose to osteoarthritis. Current prostheses do not replicate the native anatomy, and therefore contribute to these changes. We hypothesized that prostheses reverse-engineered from the native bone shape would provide similar contact patterns as the native articulation. Reverse-engineered hemiarthroplasty prostheses were manufactured for five cadaveric elbows based on CT images of the distal humerus. Passive flexion trials with constant muscle forces were performed with the native articulation intact while bone motions were recorded using a motion tracking system. Motion trials were then repeated after the distal humerus was replaced with a corresponding reverse-engineered prosthesis. Contact areas and patterns were reconstructed using computer models created from CT scan images combined with the motion tracker data. The total contact areas, as well as the contact area within smaller sub-regions of the ulna and radius, were analyzed for changes resulting from hemiarthroplasty using repeated-measures ANOVAs. Contact area at the ulna and radius decreased on average 42% (SD 19%, P=.008) and 41% (SD 42%, P=.096), respectively. Contact area decreases were not uniform throughout the different sub-regions, suggesting that contact patterns were also altered. Reverse-engineered prostheses did not reproduce the same contact pattern as the native joints, possibly because the thickness of the distal humerus cartilage layer was neglected when generating the prosthesis shapes or as a consequence of the increased stiffness of the metallic implants. Alternative design strategies and materials for hemiarthroplasty should be considered in future work.


Comparative validation of quantitative coronary angiography systems. Results and implications from a multicenter study using a standardized approach.
Computerized quantitative coronary angiography (QCA) has fundamentally altered our approach to the assessment of coronary interventional techniques and strategies aimed at the prevention of recurrence and progression of stenosis. It is essential, therefore, that the performance of QCA systems, upon which much of our scientific understanding has become integrally dependent, is evaluated in an objective and uniform manner. We validated 10 QCA systems at core laboratories in North America and Europe. Cine films were made of phantom stenoses of known diameter (0.5 to 1.9 mm) under four experimental conditions: in vivo (coronary arteries of pigs) calibrated at the isocenter or by use of the catheter as a scaling device and in vitro with 50% contrast and 100% contrast. The cine films were analyzed by each automated QCA system without observer interaction. Accuracy and precision were taken as the mean and SD of the signed differences between the phantom stenoses, and the measured minimal luminal diameters and the correlation coefficient (r), the SEE, the y intercept, and the slope were derived by their linear regression. Performance of the 10 QCA systems ranged widely: accuracy, +0.07 to +0.31 mm; precision, +/- 0.14 to +/- 0.24 mm; correlation (r), .96 to .89; SEE, +/- 0.11 to +/- 0.16 mm; intercept, +0.08 to +0.31 mm; and slope, 0.86 to 0.64. There is a marked variability in performance between systems when assessed over the range of 0.5 to 1.9 mm. The range of accuracy, intercept, and slope values of this report indicates that absolute measurements of luminal diameter from different multicenter angiographic trials may not be directly comparable and additionally suggests that such absolute measurements may not be directly applicable to clinical practice using an on-line QCA system with a different edge detection algorithm. Power calculations and study design of angiographic trials should be adjusted for the precision of the QCA system used to avoid the risk of failing to detect small differences in patient populations. This study may guide the fine-tuning of algorithms incorporated within each system and facilitate the maintenance of high standards of QCA for scientific studies.


Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine.
Ketamine is a racemic mixture of equal amounts of R-ketamine and S-ketamine and is well known to anesthesiologists for its unique dissociative anesthetic properties. The pharmacological properties of ketamine, namely, its sympathetic excitation, mild respiratory depression, and potent analgesia, are still highly valued in its use as an anesthetic for some patients. In particular, since its advent, S-ketamine has been widely used as an anesthetic in many countries due to its increased affinity for NMDA receptors and its enhanced anesthetic and analgesic effects. However, the anesthetic and analgesic mechanisms of S-ketamine are not fully understood. In addition to antagonizing NMDA receptors, a variety of other receptors or channels may be involved, but there are no relevant mechanistic summaries in the literature. Therefore, the purpose of this paper is to review the mechanisms of action of S-ketamine on relevant receptors and systems in the body that result in its pharmacological properties, such as anesthesia and analgesia, with the aim of providing a reference for its clinical applications and research.


Body integrity identity disorder: the persistent desire to acquire a physical disability.
Body integrity identity disorder (BIID) is a rare and unusual psychiatric condition characterized by a persistent desire to acquire a physical disability (e.g., amputation, paraplegia) since childhood that to date has not been formally described in the psychiatric nosology. Most BIID sufferers experience a chronic and dysphoric sense of inappropriateness regarding their being able-bodied, and many have been driven to actualize their desired disability through surreptitious surgical or other more dangerous methods. This review aims to characterize the history and phenomenology of this condition, to present its differential diagnosis, and to consider possible etiologies, treatment options, and ethical considerations. Review of the psychiatric and neurological literature. A growing body of data suggests the existence of a discrete entity with onset by early adolescence and a negative impact on functioning. Parallel neurological conditions and preliminary experimental investigations suggest a possible neurobiological component in at least a portion of cases. While attempts at treatment have been described, no systematic evidence for efficacy has emerged. BIID is a unique nosological entity with significant consequences for its sufferers and as such may warrant inclusion in some form in the forthcoming DSM-5 and ICD-11.


A Review of the Relationship of the Cerebrospinal Fluid Changes During the Dysregulation of Parathyroid Hormone With Psychiatric or Neurological Manifestations.
It is established that normal calcium and vitamin D concentrations are maintained in the body through parathyroid hormone (PTH), a signaling molecule secreted from parathyroid glands. A massive role is played by PTH in increasing calcium levels when they are extremely low in the body through different mechanisms. The dysregulation of this hormone is due to either over functioning of the gland (hyperparathyroidism) or compromised functioning in hypoparathyroidism. A detailed review was done to identify if any changes are happening in the cerebrospinal fluid (CSF) due to any pathology causing the parathormone to be dysregulated enough to, in turn, cause any further pathology in the nervous system. This may then lead to various disabling neuropsychiatric features. The calcium and vitamin D abnormalities are both directly and indirectly connected to psychiatric features like delusions, schizophrenia, disabled cognition, psychosis, coma, mania, and depression of all kinds. Moreover, their irregularities are also linked to Alzheimer's. During these manifestations, the CSF is altered concentration-wise, where elevated calcium levels inside are observed during different studies. Despite PTH's indirect connection to the CSF modifications, their association hasn't been potently proven yet, considering more observational studies should be conducted in humans and for a more extended period, along with bigger and greater numbers of CSF samples. Suppose there is a possibility of the link of CSF alterations to PTH. In that case, we can consider a pronounced increase of CSF calcium or PTH as a risk factor for debilitating neuropsychiatric diseases. In this review, the possible correlation of CSF and PTH has been discussed.


Exercise Behavior and Mood during the COVID-19 Pandemic in Taiwan: Lessons for the Future.
The Coronavirus disease 2019 (COVID-19) pandemic and its associated governmental recommendations and restrictions have influenced many aspects of human life, including exercise and mental health. This study aims to explore the influence of COVID-19 on exercise behavior and its impact on mood states, as well as predict changes in exercise behavior during a similar future pandemic in Taiwan. A cross-sectional online survey was conducted between 7 April and 13 May 2020 (n = 1114). Data on exercise behavior pre and during the pandemic and mood states were collected. A cumulative link model was used to predict changes in exercise frequency during a similar future pandemic by exercise frequency during the pandemic. A linear model was used to predict the influence of exercise frequency before and during the pandemic on mood states during the pandemic. A total of 71.2%, 67.3%, and 58.3% of respondents maintained their exercise intensity, frequency, and duration, respectively, during the pandemic. Frequent exercisers are more likely to maintain their exercise frequency during a similar pandemic (p < 0.001). Higher exercise frequencies during the pandemic were associated with better mood states (p < 0.05). Moreover, the effects of prepandemic exercise frequency on mood states are moderated by changes in exercise frequency during the pandemic (p < 0.05). Additionally, maintenance of exercise frequency during a pandemic specifically for frequent exercisers are recommended to preserve mood states. These results may provide evidence for health policies on exercise promotion and mental health before and during a future pandemic.


Patient-based not problem-based learning: an Oslerian approach to clinical skills, looking back to move forward.
There have been significant changes in the past decade in both the curriculum and its delivery, in undergraduate medical education. Many of these changes have been made simultaneously, preventing clear assessment of outcome measures. The move away from a pre-clinical science grounding, to an integrated 'problem-based learning (PBL) approach' has been widespread in many countries across the world. One effect of these changes has been the way in which clinical skills, in particular history and examination are taught. By integrating clinical scenarios earlier in the undergraduate course, clinical skills are increasingly taught in tutorials. This approach, when used in the pre-clinical setting may have shortcomings in the development of the ability to construct a differential diagnosis. There has been little evidence that PBL improves problem-solving ability and this is critical to the differential diagnostic process. The concurrent decline in anatomical teaching and understanding contributes to this difficulty. The authors outline a model which clinicians can re-emphasize to students and juniors based on the fundamentals of clinical practice. The apprenticeship is more important than ever in the days of small group learning. The relinquishing of the traditional model of undergraduate medicine is of concern. The effects of educational reform should be examined by further research into the competencies of graduates entering higher professional training, before it is accepted that this change has been for the better.


Use of Raman and Raman optical activity to extract atomistic details of saccharides in aqueous solution.
Sugars are crucial components in biosystems and industrial applications. In aqueous environments, the natural state of short saccharides or charged glycosaminoglycans is floating and wiggling in solution. Therefore, tools to characterize their structure in a native aqueous environment are crucial but not always available. Here, we show that a combination of Raman/ROA and, on occasions, NMR experiments with Molecular Dynamics (MD) and Quantum Mechanics (QM) is a viable method to gain insights into structural features of sugars in solutions. Combining these methods provides information about accessible ring puckering conformers and their proportions. It also provides information about the conformation of the linkage between the sugar monomers, i.e., glycosidic bonds, allowing for identifying significantly accessible conformers and their relative abundance. For mixtures of sugar moieties, this method enables the deconvolution of the Raman/ROA spectra to find the actual amounts of its molecular constituents, serving as an effective analytical technique. For example, it allows calculating anomeric ratios for reducing sugars and analyzing more complex sugar mixtures to elucidate their real content. Altogether, we show that combining Raman/ROA spectroscopies with simulations is a versatile method applicable to saccharides. It allows for accessing many features with precision comparable to other methods routinely used for this task, making it a viable alternative. Furthermore, we prove that the proposed technique can scale up by studying the complicated raffinose trisaccharide, and therefore, we expect its wide adoption to characterize sugar structural features in solution.


Metabolic acidosis and generalized seizures secondary to citalopram overdose: a case report.
Selective serotonin re-uptake inhibitors (SSRIs) are widely used in the community for treating many forms of mental illnesses. Citalopram, a newer generation SSRI, is commonly prescribed, but despite its low toxicity profile has a potential to cause seizures and dysarrythmias in overdose. Data on citalopram overdose-induced metabolic acidosis are scarce. There have been only three cases of metabolic acidosis reported in the literature due to citalopram overdose in humans and we are reporting the fourth one. We report a case of citalopram overdose with metabolic acidosis and generalized seizure. To our best knowledge, this is the first case reported in Saudi Arabia.


The impact of a low glycemic index (GI) breakfast and snack on daily blood glucose profiles and food intake in young Chinese adult males.
Low glycemic index (GI) foods have been suggested to minimize large fluctuations in blood glucose levels and reduce food intake. However, the majority of studies have been conducted on Caucasian populations with limited data on Asians. The objective of this study was to investigate how the provision of a low GI breakfast and afternoon snack affected daily blood glucose profiles and food intake. In a randomized, controlled crossover non blind design, 11 healthy Chinese male adults (body mass index 22.4 ± 1.3 kg m-2) attended two sessions where they consumed either a high or low GI breakfast and afternoon snack, and a standardized buffet lunch. Daily changes in glycemic response (GR) were measured using the Medtronic MiniMed (Northridge, CA) iPro™2 continuous glucose monitoring system (CGMS). The GR was further calculated to obtain the incremental area under the curve (IAUC). Glycemic variability was calculated as mean amplitude of glycemic excursion (MAGE) and energy intake (kcal) was measured quantitatively at the buffet lunch. Compared to the high GI intervention, the low GI intervention significantly reduced the GR following breakfast (p = 0.02), lunch (p = 0.02) and dinner (p = 0.05). The low GI treatment showed a reduction in daily AUC (p = 0.03). There was a significant reduction in IAUC after a low GI breakfast compared to the high GI breakfast (p = 0.03). The low GI breakfast resulted in a significantly lower food intake at lunch and a resulting decreased energy intake of 285 kcal (p = 0.02). The MAGE was significantly lower during the entire low GI treatment (p = 0.03). Consumption of a low GI breakfast and afternoon snack was capable of attenuating 24-h blood glucose profiles, minimize glycemic excursions and reduce food intake in healthy Asian males. This simple dietary intervention may be an acceptable approach in improving overall glycemia and energy balance in Asians. NCT02340507.


Metabolomic Profiling in Mouse Model of Menopause-Associated Asthma.
Menopause-associated asthma impacts a subset of women, tends to be more severe, and is less responsive to current treatments. We recently developed a model of menopause-associated asthma using 4-Vinylcyclohexene Diepoxide (VCD) and house dust mites (HDM). The goal of this study was to uncover potential biomarkers and drivers of menopause-onset asthma by assessing serum and bronchoalveolar lavage fluid (BALF) samples from mice with and without menopause and HDM challenge by large-scale targeted metabolomics. Female mice were treated with VCD/HDM to model menopause-associated asthma, and serum and BALF samples were processed for large-scale targeted metabolomic assessment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine metabolites of potential biological significance. We identified over 50 individual metabolites, impacting 46 metabolic pathways, in the serum and BALF that were significantly different across the four study groups. In particular, glutamate, GABA, phosphocreatine, and pyroglutamic acid, which are involved in glutamate/glutamine, glutathione, and arginine and proline metabolisms, were significantly impacted in the menopausal HDM-challenged mice. Additionally, several metabolites had significant correlations with total airway resistance including glutamic acid, histamine, uridine, cytosine, cytidine, and acetamide. Using metabolic profiling, we identified metabolites and metabolic pathways that may aid in discriminating potential biomarkers for and drivers of menopause-associated asthma.


[Microelement profile of Aral region adult population].
Nowadays, environmental pollution has become a global, stable and constant hazard, in some regions consistent totality of pollutants determine toxic situation. In recent years, much attention in Kazakhstan is paid to Aral region. Despite multiple studies, problem connected with chemical influence on public health in Kazakhstan, Aral region, remains unsolved. Special place is taken by microelement state in the population. Microelements were studied in serum of the adult population residing in polluted area of Aral region. Findings are microelements dysbalances manifested by increased copper content and decreased zincum, selenium and iodine contents. Serum microelements disorders are objective criteria for various ecologically induced diseases.


State Gun Law Environment and Youth Gun Carrying in the United States.
Gun violence and injuries pose a substantial threat to children and youth in the United States. Existing evidence points to the need for interventions and policies for keeping guns out of the hands of children and youth. (1) To examine the association between state gun law environment and youth gun carrying in the United States, and (2) to determine whether adult gun ownership mediates this association. This was a repeated cross-sectional observational study design with 3 years of data on youth gun carrying from US states. The Youth Risk Behavior Survey comprises data of representative samples of students in grades 9 to 12 from biennial years of 2007, 2009, and 2011. We hypothesized that states with more restrictive gun laws have lower rates of youth gun carrying, and this association is mediated by adult gun ownership. State gun law environment as measured by state gun law score. Youth gun carrying was defined as having carried a gun on at least 1 day during the 30 days before the survey. In the fully adjusted model, a 10-point increase in the state gun law score, which represented a more restrictive gun law environment, was associated with a 9% decrease in the odds of youth gun carrying (adjusted odds ratio [AOR], 0.91 [95% CI, 0.86-0.96]). Adult gun ownership mediated the association between state gun law score and youth gun carrying (AOR, 0.94 [ 95% CI, 0.86-1.01], with 29% attenuation of the regression coefficient from -0.09 to -0.07 based on bootstrap resampling). More restrictive overall gun control policies are associated with a reduced likelihood of youth gun carrying. These findings are relevant to gun policy debates about the critical importance of strengthening overall gun law environment to prevent youth gun carrying.


Conservatively treated perforation of the neovagina in a male to female transsexual patient.
An unknown number of patients have had male to female gender transformation. Various surgical techniques have been employed to construct the neovagina. The more traditional techniques include inverted penile grafts and vascular pedicle grafts, but also the small bowel and sigmoid colon have been used. In this case, the authors present a patient who previously had a gender transformation from male to female with use of bowel for the neovagina. The patient presented with severe abdominal pain, fever and leukocytosis. A CT scan revealed retroperitoneal free air, and an x-ray examination with contrast through the neovagina showed leakage from the neovaginal top. The patient was treated conservatively with antibiotics and discharged after 7 days.


[Dermatopathies in the domestic worker: the Lombard experience].
In order to identify the etiopathogenesis of cutaneous diseases in housewives, a questionnaire was made, and the gathered data are here described. 1,824 people have answered this questionnaire: 1,007 have reported lesions with a suspicious immunological pathogenesis. The commercial products which were reported as a cause of the dermatitis have been 834. In a group of 142 housewives (86 with allergic contact dermatitis and 56 with irritative contact dermatitis), the allergic sensitizations to the chemicals in the detergents were tested. 21% of the cases had positive cutaneous reactions for nickel salts and 8.4% for chromium salts. The analysis in atomic absorption method of these metals in 34 commercial products has shown their presence in almost all the samples. Hypothesis are formulated to find the source of these polluting substances. The aims and the methods of a investigation carried out on 1.800 housewives, who are going to be controlled in order to estimate the prevalence, the clinical kinds and the etiopathogenesis of dermatitis related to house work, are described. The study will be carried out at the Occupational Health Institute "Clinica del Lavoro L. Devoto" of Milan and at the Dermatological Departments of the Universities of Bari and Florence.


Vocal cord dysfunction and feeding difficulties after pediatric cardiovascular surgery.
To evaluate the impact of vocal cord dysfunction on feeding in children after cardiovascular surgery. Of the 2255 children who had cardiovascular surgery between January 2000 to January 2006, 38 (1.7%) had postoperative vocal cord dysfunction confirmed at laryngoscopy. The following data were obtained retrospectively: type of surgery, laryngoscopic examination results, swallowing studies, upper gastrointestinal (UGI) studies, and feeding route: oral, nasogastric tube (NG), and gastrostomy. Surgeries included aortic arch reconstruction (n = 20), patent ductus arteriosus ligation (n = 8), arterial switch (n = 3), cervical cannulation for extracorporeal membrane oxygenation (n = 2), and others (n = 5). A swallowing study confirmed dysfunction in 27 of 29 patients. Gastrostomy was placed in 18/38 patients. At discharge, 18 patients were fed by gastrostomy, 13 orally, 3 by NG, and 4 by combination oral/NG. At a median follow-up of 12 months, 20 were fed orally, 1 by NG, 7 by gastrostomy, 7 by combination gastrostomy/orally, 1 was lost to follow-up, 2 died. Vocal cord dysfunction after pediatric cardiovascular surgery is associated with significant feeding problems and may require prolonged gastrostomy feeding. These findings support aggressive surveillance for vocal cord dysfunction, especially in patients undergoing aortic arch surgery.


Decreased ¹³N-labeled ammonia uptake in the ipsilateral and contralateral hemispheres following carotid endarterectomy.
Carotid artery plaques are a leading cause of ischemic stroke, and carotid endarterectomy (CEA) is one of the major treatment approaches for this disease. Changes in cerebral metabolism following CEA remain unclear. The present study aimed to evaluate the effect of cerebral ammonia metabolism following CEA using 13N‑labeled ammonia positron emission tomography (PET) in humans. A total of 20 patients were enrolled in the present study, with a mean age of 59.5 years, comprising 16 males and four females. Of these patients, eight underwent right CEA and 12 underwent left CEA. The rate of carotid artery stenosis was between 50‑69% in six of the patients, between 70‑99% in 11 of the patients and was at 100% (thrombosis) in three of the patients, measured by computerised tomography digital subtraction angiography prior to CEA. 13N‑labeled ammonia (137 MBq) PET scanning was performed prior and subsequent to CEA surgery for each patient. The first ammonia PET scan was performed 1 day prior to CEA, while the second PET scan was performed 1‑4 weeks following CEA. Following injection of 13N‑labeled ammonia, static PET was acquired for 10 min. The region of interest (ROI), covering the major cerebral hemisphere, was selected and ammonia uptake in the ROI was determined in the ipsilateral and contralateral hemispheres. No hyperperfusion syndrome was observed in the patients subsequent to CEA. No significant change in cerebral hemisphere ammonia uptake was observed between the ipsilateral and contralateral hemispheres prior to (ratio =0.98; P>0.01) or following (ratio =1.09; P>0.01) CEA. Ammonia uptake in the ipsilateral and contralateral hemispheres was significantly reduced to 23.2 and 23.5%, respectively, following CEA. Using 13N‑labeled ammonia PET to evaluate cerebral ammonia metabolism following CEA in patients with severe carotid artery stenosis, the present study demonstrated that uptake of ammonia in the ipsilateral and contralateral hemispheres was significantly reduced.


Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics.
Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.


Neuropeptide CART prevents memory loss attributed to withdrawal of nicotine following chronic treatment in mice.
Although chronic nicotine administration does not affect memory, its withdrawal causes massive cognitive deficits. The underlying mechanisms, however, have not been understood. We test the role of cocaine- and amphetamine-regulated transcript peptide (CART), a neuropeptide known for its procognitive properties, in this process. The mice on chronic nicotine treatment/withdrawal were subjected to novel object recognition task. The capability of the animal to discriminate between the novel and familiar objects was tested and represented as discrimination index (DI); reduction in the index suggested amnesia. Nicotine for 49 days had no effect on DI, but 8-hour withdrawal caused a significant reduction, followed by full recovery at 24-hour withdrawal timepoint. Bilateral CART infusion in dorsal hippocampus rescued deficits in DI at 8-hours, whereas CART-antibody infusion into the dorsal hippocampus attenuated the recovery at 24-hours. Commensurate changes were observed in the CART as well as CART mRNA profiles in the hippocampus. CART mRNA expression and the peptide immunoreactivity did not change significantly following chronic nicotine treatment. However, there was a significant reduction at 8-hour withdrawal, followed by a drastic increase in CART immunoreactivity as well as CART mRNA at 24-hour withdrawal, compared with 8-hour withdrawal. Distinct α7-nicotinic receptor immunoreactivity was detected on the hippocampal CART neurons, suggesting cholinergic inputs. An increase in the synaptophysin immunoreactive elements around CART cells in the dentate gyrus, cornu ammonis 3 and subiculum at 24-hour post-withdrawal timepoint suggested neuronal plasticity. CART circuit dynamics in the hippocampus seems to modulate short-term memory associated with nicotine withdrawal.


Typing and subtyping of influenza viruses in clinical samples by PCR.
Type A and B influenza viruses can cause a wide spectrum of illness, and these viruses are responsible for considerable mortality and morbidity. Rapid typing of isolates is desirable when amantadine treatment or prophylaxis of contacts of type A influenza virus carriers is considered, but the available rapid techniques lack sensitivity and standard diagnostic methods require expansion of virus in tissue culture or embryonated hens' eggs. We developed a series of oligonucleotide primers able to detect, type, and subtype type A influenza viruses in a single reverse transcription-PCR. RNA was isolated from clinical specimens, and cDNA was generated with random primers. PCR was carried out with a mixture of primers specific for influenza viruses of types B, A/H1 and A/H3, and subtyping of the neuraminidase was carried out on the same cDNA template under identical conditions. Amplified products were detected by ethidium bromide staining of amplified products after agarose gel electrophoresis. When it was used to test 98 clinical specimens, this method was comparable to standard culture techniques in the detection, typing, and subtyping of influenza viruses.


Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval.
We have studied the influence of pre-training psychological stress on the expression of c-fos mRNA following long-term spatial memory retrieval. Rats were trained to learn the location of a hidden escape platform in the radial-arm water maze, and then their memory for the platform location was assessed 24 h later. Rat brains were extracted 30 min after the 24-h memory test trial for analysis of c-fos mRNA. Four groups were tested: (1) Rats given standard training (Standard); (2) Rats given cat exposure (Predator Stress) 30 min prior to training (Pre-Training Stress); (3) Rats given water exposure only (Water Yoked); and (4) Rats given no water exposure (Home Cage). The Standard trained group exhibited excellent 24 h memory which was accompanied by increased c-fos mRNA in the dorsal hippocampus and basolateral amygdala (BLA). The Water Yoked group exhibited no increase in c-fos mRNA in any brain region. Rats in the Pre-Training Stress group were classified into two subgroups: good and bad memory performers. Neither of the two Pre-Training Stress subgroups exhibited a significant change in c-fos mRNA expression in the dorsal hippocampus or BLA. Instead, stressed rats with good memory exhibited significantly greater c-fos mRNA expression in the dorsolateral striatum (DLS) compared to stressed rats with bad memory. This finding suggests that stressed rats with good memory used their DLS to generate a non-spatial (cue-based) strategy to learn and subsequently retrieve the memory of the platform location. Collectively, these findings provide evidence at a molecular level for the involvement of the hippocampus and BLA in the retrieval of spatial memory and contribute novel observations on the influence of pre-training stress in activating the DLS in response to long-term memory retrieval.


New and incremental FDA black box warnings from 2008 to 2015.
The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval. We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features. There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW. New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.


Late middle Miocene caviomorph rodents from Tarapoto, Peruvian Amazonia.
Miocene deposits of South America have yielded several species-rich assemblages of caviomorph rodents. They are mostly situated at high and mid- latitudes of the continent, except for the exceptional Honda Group of La Venta, Colombia, the faunal composition of which allowed to describe the late middle Miocene Laventan South American Land Mammal Age (SALMA). In this paper, we describe a new caviomorph assemblage from TAR-31 locality, recently discovered near Tarapoto in Peruvian Amazonia (San Martín Department). Based on mammalian biostratigraphy, this single-phased locality is unambiguously considered to fall within the Laventan SALMA. TAR-31 yielded rodent species found in La Venta, such as the octodontoid Ricardomys longidens Walton, 1990 (nom. nud.), the chinchilloids Microscleromys paradoxalis Walton, 1990 (nom. nud.) and M. cribriphilus Walton, 1990 (nom. nud.), or closely-related taxa. Given these strong taxonomic affinities, we further seize the opportunity to review the rodent dental material from La Venta described in the Ph.D. volume of Walton in 1990 but referred to as nomina nuda. Here we validate the recognition of these former taxa and provide their formal description. TAR-31 documents nine distinct rodent species documenting the four extant superfamilies of Caviomorpha, including a new erethizontoid: Nuyuyomys chinqaska gen. et sp. nov. These fossils document the most diverse caviomorph fauna for the middle Miocene interval of Peruvian Amazonia to date. This rodent discovery from Peru extends the geographical ranges of Ricardomys longidens, Microscleromys paradoxalis, and M. cribriphilus, 1,100 km to the south. Only one postcranial element of rodent was unearthed in TAR-31 (astragalus). This tiny tarsal bone most likely documents one of the two species of Microscleromys and its morphology indicates terrestrial generalist adaptations for this minute chinchilloid.


A Continuous Noninvasive Method to Assess Mixed Venous Oxygen Saturation: A Proof-of-Concept Study in Pigs.
Mixed venous oxygen saturation (Svo2) is important when evaluating the balance between oxygen delivery and whole-body oxygen consumption. Monitoring Svo2 has so far required blood samples from a pulmonary artery catheter. By combining volumetric capnography, for measurement of effective pulmonary blood flow, with the Fick principle for oxygen consumption, we have developed a continuous noninvasive method, capnodynamic Svo2, for assessment of Svo2. The objective of this study was to validate this new technique against the gold standard cardiac output (CO)-oximetry Svo2 measurement of blood samples obtained from a pulmonary artery catheter and to assess the potential influence of intrapulmonary shunting. Eight anesthetized mechanically ventilated domestic-breed piglets of both sexes (median weight 23.9 kg) were exposed to a series of interventions intended to reduce as well as increase Svo2. Simultaneous recordings of capnodynamic and CO-oximetry Svo2 as well as shunt fraction, using the Berggren formula, were performed throughout the protocol. Agreement of absolute values for capnodynamic and CO-oximetry Svo2 and the ability for capnodynamic Svo2 to detect change were assessed using Bland-Altman plot and concordance analysis. Overall bias for capnodynamic versus CO-oximetry Svo2 was -1 percentage point (limits of agreement -13 to +11 percentage points), a mean percentage error of 22%, and a concordance rate of 100%. Shunt fraction varied between 13% at baseline and 22% at the end of the study and was associated with only minor alterations in agreement between the tested methods. In the current experimental setting, capnodynamic assessment of Svo2 generates absolute values very close to the reference method CO-oximetry and is associated with 100% trending ability.


Cyclic AMP-dependent protein kinase A regulates the alternative splicing of CaMKIIδ.
Ca(2+)/calmodulin-dependent protein kinase (CaMK) IIδ is predominantly expressed in the heart. There are three isoforms of CaMKIIδ resulting from the alternative splicing of exons 14, 15, and 16 of its pre-mRNA, which is regulated by the splicing factor SF2/ASF. Inclusion of exons 15 and 16 or of exon 14 generates δA or δB isoform. The exclusion of all three exons gives rise to δC isoform, which is selectively increased in pressure-overload-induced hypertrophy. Overexpression of either δB or δC induces hypertrophy and heart failure, suggesting their specific role in the pathogenesis of hypertrophy and heart failure. It is well known that the β-adrenergic-cyclic AMP-dependent protein kinase A (PKA) pathway is implicated in heart failure. To determine the role of PKA in the alternative splicing of CaMKIIδ, we constructed mini-CaMKIIδ genes and used these genes to investigate the regulation of the alternative splicing of CaMKIIδ by PKA in cultured cells. We found that PKA promoted the exclusion of exons 14, 15, and 16 of CaMKIIδ, resulting in an increase in δC isoform. PKA interacted with and phosphorylated SF2/ASF, and enhanced SF2/ASF's activity to promote the exclusion of exons 14, 15, and 16 of CaMKIIδ, leading to a further increase in the expression of δC isoform. These findings suggest that abnormality in β-adrenergic-PKA signaling may contribute to cardiomyopathy and heart failure through dysregulation in the alternative splicing of CaMKIIδ exons 14, 15, and 16 and up-regulation of CaMKIIδC.


Associations between childhood hearing loss and behavioural and academic difficulties: A Danish cohort study.
Negative associations between hearing loss (HL) and behavioural and academic difficulties have been reported. However, most studies are based on small clinical samples. The aim of the present study was to investigate such associations using data from a large-scale non-clinical Danish birth cohort controlling for a large number of relevant confounding factors. The study applied data from the Aarhus Birth Cohort's 10-12-year-old follow-up (N = 7599). Associations between parent-reported HL on the one hand, and parent- and teacher-reported behavioural difficulties measured by the Strengths and Difficulties Questionnaire (SDQ) and parent-reported academic difficulties on the other hand, were investigated. After controlling for relevant confounding factors, significant associations were observed between parent-reported HL and parent- and teacher-reported Externalising scores, and academic difficulties. Childhood HL is associated with behavioural and academic difficulties. Parent reported HL in a non-clinical cohort is indicative for academic and behavioural difficulties.


Daily Physical Activity and Symptom Reporting in Breast Cancer Patients Undergoing Chemotherapy: An Intensive Longitudinal Examination.
Increased activity is beneficial during chemotherapy, but treatment-related symptoms may be a barrier. This study examines the relationship between daily fluctuations in symptoms and activity during chemotherapy. Women undergoing chemotherapy for breast cancer [n = 67; M age = 48.6 (SD = 10.3)] wore an accelerometer 24 hours/day and received four text prompts/day to rate symptoms for 10 consecutive days at the beginning, middle, and end of chemotherapy. Mixed-effects models were used to examine the between and within-person relationships between symptom ratings on a given day and moderate to vigorous physical activity (MVPA) and light physical activity (LPA) on that day and the following day controlling for relevant covariates and using the Bonferroni correction for multiple comparisons. For MVPA and LPA, within-person associations were statistically significant for same day affect, fatigue, pain, walking, activities of daily living (ADL) physical function, and cognitive function. Previous day anxiety was associated with next day LPA. Every one point worse symptom rating than an individual's overall average was associated with: (i) between 1.49 (pain) and 4.94 (fatigue) minutes less MVPA and between 4.48 (pain) and 24.72 (ADL physical function) minutes less LPA that day, and (ii) 11.28 minutes less LPA the next day. No between-person effects were significant for MVPA or LPA. Daily within-person variations in symptoms were associated with MVPA and LPA during chemotherapy for breast cancer. Future work should explore relationships between symptoms and activity further and identify whether tailoring to symptoms enhances efficacy of physical activity promotion interventions during chemotherapy.


Colon capsule endoscopy in colorectal cancer screening: a systematic review.
Primary colonoscopy and fecal immunochemical test (FIT) are the most commonly used colorectal cancer (CRC) screening modalities. Colon capsule endoscopy (CCE) might be an alternative. Data on the performance of CCE as a CRC screening tool in a screening population remain scarce. This is the first systematic review to provide an overview of the applicability of CCE as a CRC screening tool. A systematic search was conducted of literature published up to September 2020. Studies reporting on CRC screening by second-generation CCE in an average-risk screening population were included. 582 studies were identified and 13 were included, comprising 2485 patients. Eight studies used CCE as a filter test after a positive FIT result and five studies used CCE for primary screening. The polyp detection rate of CCE was 24 % - 74 %. For polyps > 6 mm, sensitivity of CCE was 79 % - 96 % and specificity was 66 % - 97 %. For polyps ≥ 10 mm, sensitivity of CCE was 84 % - 97 %, which was superior to computed tomographic colonography (CTC). The CRC detection rate for completed CCEs was 93 % (25/27). Bowel preparation was adequate in 70 % - 92 % of examinations, and completion rates varied from 57 % to 92 %, depending on the booster used. No CCE-related complications were described. CCE appeared to be a safe and effective tool for the detection of CRC and polyps in a screening setting. Accuracy was comparable to colonoscopy and superior to CTC, making CCE a good alternative to colonoscopy in CRC screening programs, although completion rates require improvement.


Comparison of outcomes after two standards-of-care reduced-intensity conditioning regimens and two different graft sources for allogeneic stem cell transplantation in adults with hematologic diseases: a single-center analysis.
Recent advances in allogeneic stem cell transplantation (allo-HSCT) have included the advent of reduced-intensity conditioning (RIC) regimens to decrease the toxicity of myeloablative allo-SCT and the use of double umbilical cord blood (dUCB) units as a graft source in adults lacking a suitable donor. The FB2A2 regimen (fludarabine 30 mg/kg/day for 5-6 days + i.v. busulfan 3.6 mg/kg/day for 2 days + rabbit antithymocyte globulin 2.5 mg/kg/day for 2 days) supported by peripheral blood stem cells (PBSCs) and the TCF regimen (fludarabine 200 mg/m² for 5 days + cyclophosphamide 50 mg/kg for 1 day + low-dose [2 Gy] total body irradiation) supported by dUCB units are currently the most widely used RIC regimens in many centers and could be considered standard of care in adults eligible for an RIC allo-SCT. Here we compared, retrospectively, the outcomes of adults patients who received the FB2A2-PBSC RIC regimen (n = 52; median age, 59 years; median follow-up, 19 months) and those who received the dUCB-TCF RIC regimen (n = 39; median age, 56 years; median follow-up, 20 months) for allo-SCT between January 2007 and November 2010. There were no significant between-group differences in patient and disease characteristics. Cumulative incidences of engraftment, acute grade II-IV and chronic graft-versus-host disease were similar in the 2 groups. The median time to platelet recovery, incidence of early death (before day +100), and 2-year nonrelapse mortality were significantly higher in the dUCB-TCF group (38 days versus 0 days [P <.0001]; 20.5% versus 4% [P = .05], and 26.5% versus 6% [P = .02], respectively). The groups did not differ in terms of 2-year overall survival (62% for FB2A2-PBSC versus 61% for dUCB-TCF), disease-free survival (59% versus 50.5%), or relapse incidence (35.5% versus 23%). In multivariate analysis, the presence of a lymphoid disorder was associated with a significantly higher 2-year overall survival (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P = .02), whereas patients receiving a FB2A2-PBSC allo-SCT had a significantly lower 2-year nonrelapse mortality (hazard ratio, 0.24; 95% confidence interval, 0.1-0.7; P = .01). There were no factors associated with higher 2-year disease-free survival or lower relapse incidence. This study suggests that the dUCB-TCF regimen provides a valid alternative in adults lacking a suitable donor and eligible for RIC allo-SCT. Prospective and randomized studies are warranted to establish the definitive role of dUCB RIC allo-SCT in adults. In addition, strategies for decreasing nonrelapse mortality after dUCB RIC allo-SCT are urgently needed.


Patients' osteometabolic control improves the management of medication-related osteonecrosis of the jaw.
Osteonecrosis of the jaw (ONJ) is a concern in patients taking anti-resorptive drugs. The aim of this study was to test the hypothesis that preoperative individualized pharmacologic control of the patient's osteometabolic profile could lead to predictable healing of the surgically treated region and minimize the incidence of complications. This prospective study included 95 test patients (53 with osteoporosis and 42 with cancer), and 94 control patients (49 with osteoporosis and 45 with cancer) who were on anti-resorptive therapy and were candidates for ONJ treatment. Test patients underwent osteometabolic profile assessment and personalized pharmacologic supplementation before intervention. In all cases, a drug holiday was scheduled for 3 months before and at least 3 months after the intervention. Healing was assessed clinically and radiographically. In the test group, after a mean follow-up of 28.2 ± 7.8 months, there was only 1 ONJ recurrence, and it was successfully resolved after the pharmacologic protocol was resumed. Five patients reported minor complications. Overall, 100% treatment success was observed. In the control group, after 28.1 ± 4.9 months follow-up, 6 fistulae, 19 abscesses, and 34 dehiscences occurred. In total, 62.8% of patients in the control group had complications or adverse events. The difference between the 2 groups was highly significant. Strict osteometabolic control should be a routine measure in the management of patients taking anti-resorptive drugs.


Dose-response relationship of inhaled metaproterenol sulfate in preschool children with mild asthma.
The dose-response relationship of single doses of nebulized metaproterenol sulfate 5% inhalant solution was evaluated by placebo-controlled, parallel-group study of 30 children, aged 3 to 6 years old, with stable asthma. Total respiratory resistance, the primary variable used to assess response, was measured by the forced oscillation method for a period of 6 hours from the start of inhalation. When comparisons were made between metaproterenol sulfate and saline, only 0.01 and 0.02 mL/kg showed significant bronchodilation (P less than .05) in percent change from baseline and area under the curve. However, no significant differences were seen between these doses. Moreover, the effect was sustained for 3 hours with both higher doses. Minimal side effects were observed. Metaproterenol sulfate 5% inhalant solution at a dose of 0.01 mL/kg seems to be optimal to elicit significant and sustained bronchodilatory response in preschool children with mild asthma.


Isoenzyme patterns of pathogenic and non-pathogenic Naegleria spp. using agarose isoelectric focusing.
Using agarose isoelectric focusing, the isoenzyme patterns of 7 different enzymes were compared in 52 Naegleria strains. The pathogenic N. fowleri was found the most homogeneous species. N. lovaniensis seems to be constituted of different types which form nevertheless a cohesive group. Within N. gruberi, large interstrain band variations were found in almost all enzyme systems. A re-examination of the taxonomic position of this species may therefore be taken into consideration. High temperature strains from Australia were confirmed to be different from N. lovaniensis. Members of a new pathogenic Naegleria sp., N. australiensis, seem to occur in Europe. Large thermophilic strains with many large pores in the cysts show identical zymograms and may constitute a new species or genus.


Sensory cues mediating mating-induced potentiation of sexual receptivity in female rats.
Repeated mating of estradiol-primed female rats increases sexual receptivity. Two studies were conducted to determine the contribution of vaginal--cervical stimulation (VCS) to this increase. In the first study, female rats were repeatedly mated for 165 min. The vaginas of half of the females were covered with tape (masked) to prevent intromissions by the males. The remaining females were unmasked. Only females receiving intromissions (unmasked) showed a significant increase in sexual receptivity during repeated mating, suggesting that VCS from intromissions is necessary for repeated mating to increase sexual receptivity. In the second experiment, female rats received either experimentally administered VCS or control scapular stimulation administered with a plastic probe 1 h prior to testing for sexual receptivity. VCS applied in this manner significantly increased sexual receptivity. Together, these findings suggest that VCS from intromissions is one of the primary factors responsible for increases in sexual receptivity following repeated mating.


[Eating disorders on the internet: an experimental study on the effects of pro-eating disorders websites and self-help websites].
Pro-eating disorders (ED) websites are assumed to have a negative impact on internet users because these sites promote ED as a lifestyle, and present an extreme thin ideal as well as extreme weight loss measures. We tested the impact of reading pro-ED contents in a sample of 421 women. The participants were randomly assigned to one of 3 conditions in which they were exposed to either a pro-ED blog, a self-help blog, or a neutral control blog. Post-exposure negative affect was higher in participants of the pro-ED and the self-help conditions compared to the neutral blog condition. Participants with an elevated risk for developing an ED had a lower appearance self esteem after exposure to the pro-ED, or the self-help blog. According to the study, a subgroup of high risk individuals might be affected by ED-related internet content. The implications of this study are discussed in the context of the ongoing controversy around pro-ED websites.


Context-Specific Drinking Risks Among Young People.
Limited research suggests the context in which drinking occurs may contribute to specific alcohol-related consequences. Therefore the aims are to (i) determine whether the use of drinking contexts affects risks for several drinking consequences among young people in the general population and (ii) assess the degree to which additional risks are associated with greater levels of drinking in those contexts. A New Zealand survey of 16- to 29-year-olds asked about context-specific drinking and incidence of alcohol-related consequences grouped as follows: total, alcohol-related disorderly behavior, symptoms of dependence, effects of heavier drinking, and felt effects the next day. A context-specific dose-response model separated the effects of frequency (i.e., how often someone consumes 1 drink in each context) and context-specific quantity (i.e., the count of each successive drink consumed above the first), and these were estimated as predictors of consequences. Demographic covariates were included. Exposure (number of visits): Increased exposure to drinking at bars/nightclubs, even at a very low level of consumption, that is, 1 drink, was independently related to the experience of greater consequences, including alcohol-related disorderly behavior. Risks for alcohol-related consequences were more strongly related to exposure to bars/nightclubs than they were to heavier drinking in that context. Greater use of private motor vehicles and outdoor public places was also associated with greater consequences (independently of the heavier drinking in these contexts). Quantity: Risk of consequences associated with others' home, restaurants, and own home depended primarily on quantity consumed. Bars/nightclubs are inherently risky contexts for drinking by young people and improved controls are required. Drinking at others' home, private motor vehicles, and outdoor public places were also associated with consequences; prevention efforts increasing the price and reducing the availability of takeaway alcohol should work to reduce consequences at these contexts. Innovative context-specific interventions may be useful.


Expression of basolateral and canalicular transporters in rat liver and cultures of primary hepatocytes.
Basolateral and canalicular proteins are expressed in the liver and besides their role in the transport of bilirubin, glutathione, hormones and various glucuronides, they also function as transporters of a wide range of drugs. Despite their frequent use in drug research, little is known about the expression of genes coding for transporters in cultures of primary sandwiched hepatocytes. The kinetics of gene expression of canalicular and basolateral membrane transporters in cultures of primary rat sandwiched hepatocytes were investigated, and the expression of cMOAT, spgp, mdrla and mdr2 were shown to be comparable with transcript levels observed in vivo. Strikingly, expression of the basolateral membrane transporter ntcp and oatpl and 2 were dramatically reduced, the level being < 10 and < 5%, respectively, of those found in vivo in rat liver tissue. Notably, mRNA expression of the canalicular membrane transporter mdrlb was increased up to 13-fold. The findings point to a dramatic change in the expression of basolateral and canalicular transporters in cultured hepatocytes, and this should be considered when hepatocytes are used for drug profiling studies.