Differences in nocturnal basal and rhythmic prolactin secretion in untreated compared to treated HIV-infected men are associated with CD4+ T-lymphocytes.
The existence of decreased hypothalamic dopaminergic tone in HIV-infected men has been suggested. In a cross-sectional study, we determined 12 h nocturnal basal and pulsatile prolactin (PRL) release levels (by blood sampling every 10 min) and their correlation with CD4+ T cells in seven volunteer HIV-negative, healthy men (group 1), and 21 normoprolactinemic, euthyroid, HIV-infected men divided into 3 groups (each group = 7): (i) group 2, asymptomatic HIV-infected stage A1 men, untreated; (ii) group 3, AIDS stage C3 without active opportunistic infections, untreated; and (iii) group 4, previously stage C3 after at least 6 months of successful highly active antiretroviral therapy. Serum PRL was measured by radioimmunoanalysis and the results were analysed by waveform-independent deconvolution analysis. CD4+ T lymphocytes were measured by flow cytometry and viral load by a nucleic acid sequence-based amplification assay. No differences were detected in the first two groups. In the third group, however, 100% of prolactin secretion was found to be pulsatile with a shorter secretory burst duration (P = 0.04), and a greater circulating half-life and pulse amplitude (P < or = 0.04). Group 4 had the greatest basal prolactin secretion (P < or = 0.04), and a shorter secretory burst duration (P = 0.04 vs group 2), circulating half-life (P = 0.01 vs group 3) and intersecretory burst interval (P = 0.06 vs group 1). PRL approximate entropy was similar among all groups. Linear correlations existed between CD4+ T cell counts and PRL secretory burst half duration (r = 0.62, P = 0.002) and amplitude (r = -0.63, P = 0.001), and in circulating serum half-life (r = - 0.61, P = 0.002) in HIV-infected groups. Viral load showed no correlations. It is suggested that differential changes in nocturnal prolactin secretion among HIV-infected men occurred while maintaining the normal coordinate feedback and/or feedforward control within the lactotropic axis. These changes may represent an adaptative mechanism to sustain, by different means, the maximal physiologic PRL production to stimulate the highest cellular immune response and/or reconstitution in attempting to survive.


IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.
We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1alpha. Rat bone marrow-derived MSCs were used as nontransduced ((Norm)MSCs) or transduced with adenoviral-null vector ((Null)MSCs) or vector encoding for IGF-1 ((IGF-1)MSCs). (IGF-1)MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus (Null)MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3beta besides release of SDF-1alpha in parallel with IGF-1 expression in (IGF-1)MSCs. For in vivo studies, 70 muL of DMEM without cells (group 1) or containing 1.5x10(6) (Null)MSCs (group 2) or (IGF-1)MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of (IGF-1)MSCs (P<0.06 versus (Null)MSCs) (n=6 per group). SDF-1alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.


To theoretically compare the behavior of different algorithms, compatible performance measures are necessary. Thus in the first part, an analysis approach, developed for evolution strategies, was applied to simultaneous perturbation stochastic approximation on the noisy sphere model. A considerable advantage of this approach is that convergence results for non-noisy and noisy optimization can be obtained simultaneously. Next to the convergence rates, optimal step sizes and convergence criteria for 3 different noise models were derived. These results were validated by simulation experiments. Afterward, the results were used for a comparison with evolution strategies on the sphere model in combination with the 3 noise models. It was shown that both strategies perform similarly, with a slight advantage for SPSA if optimal settings are used and the noise strength is not too large.


Luminescent Assay for the Screening of SARS-CoV-2 MPro Inhibitors.
Since the outbreak of SARS-CoV-2 in December 2019 millions of infections have been reported globally. The viral chymotrypsin-like main protease (MPro ) exhibits a crucial role in viral replication and represents a relevant target for antiviral drug development. In order to screen potential MPro inhibitors we developed a luminescent assay using a peptide based probe containing a cleavage site specific for MPro . This assay was validated showing IC50 values similar to those reported in the literature for known MPro inhibitors and can be used to screen new inhibitors.


The effect of inhaled leukotriene D4, histamine, or antigen on central and peripheral airways of guinea pigs: analysis of bronchograms with an interactive image analysis system.
The effect on guinea pig airways of the inhalation of leukotrienes, histamine or antigen was investigated by measuring changes in lung volume and analyzing the airway area on bronchograms with the Zeiss interactive image analysis system (IBAS). LTC4, LTD4, LTE4 and histamine inhaled through an ultrasonic nebulizer caused inflation of the lung: LTD4 was the most potent of the leukotrienes and was 100 times more potent than histamine on a molar basis. The results of analyses of areas of large and small bronchi and bronchioles on the bronchograms indicated that LTD4 selectively decreased the area of the peripheral airways. Inhalation of an antigen in actively sensitized animals resulted in inflation of the lung and in a selective decrease in the area of the peripheral airways. Anaphylactic bronchoconstriction provoked by antigen inhalation was clearly inhibited by AA-861, a 5-lipoxygenase inhibitor but not significantly by mepyramine, an antihistamine. These observations indicate that LTD4 is a potent constrictor of the peripheral airways in guinea pigs and that the anaphylactic bronchoconstriction provoked by antigen inhalation could be mediated by LTD4 in actively sensitized guinea pigs.


Effect of fenclofenac on prostaglandin production in carageenin air bleb exudates in rats.
Employing a modified carrageenin air bleb technique in rats, the effect was studied of fenclofenac and standard drugs (acetylsalicylic acid, indomethacin and phenylbutazone) on prostaglandin production in inflammatory exudate. In common with the standard drugs, fenclofenac reduced exudate prostaglandin levels, being approximately equipotent with phenylbutazone in this respect. Also, an attempt was made to relate the effect of fenclofenac and standard drugs on prostaglandins to their acute anti-inflammatory activity as determined in a modified carrageenin paw oedema test in rats. Whilst acetylsalicylic acid and phenybutazone significantly inhibited oedema at doses producing 80% inhibition of prostaglandin production in air bleb exudate, fenclofenac and indomethacin did not. The overall results were considered to support the view expressed by other workers that the acute anti-inflammatory activity of acidic anti-inflammatory agents does not result solely, if at all, from inhibition of prostaglandin synthesis.


Treatment of seasonal affective disorder with morning light.
Three subjects afflicted with seasonal affective disorder (winter depression) were treated with 2-hour morning light exposures. Within 2 to 5 days, all responded, and remission of their symptoms was sustained during the 2-month treatment period.


Parallel olfactory processing in a hemimetabolous insect.
To represent specific olfactory cues from the highly complex and dynamic odor world in the brain, insects employ multiple parallel olfactory pathways that process odors with different coding strategies. Here, we summarize the anatomical and physiological features of parallel olfactory pathways in the hemimetabolous insect, the cockroach Periplaneta americana. The cockroach processes different aspects of odor stimuli, such as odor qualities, temporal information, and dynamics, through parallel olfactory pathways. These parallel pathways are anatomically segregated from the peripheral to higher brain centers, forming functional maps within the brain. In addition, the cockroach may possess parallel pathways that correspond to distinct types of olfactory receptors expressed in sensory neurons. Through comparisons with olfactory pathways in holometabolous insects, we aim to provide valuable insights into the organization, functionality, and evolution of insect olfaction.


Chlamydia screening in England: a qualitative study of the narrative behind the policy.
The rationale for the English National Chlamydia Screening Programme (NCSP) has been questioned. There has been little analysis, however, of what drove the NCSP's establishment and how it was implemented. Such analysis will help inform the future development of the NCSP. This study used a qualitative, theory-driven approach to evaluate the rationale for the NCSP's establishment and implementation. Semi-structured interviews with 14 experts in chlamydia screening were undertaken. The interview data were analysed with policy documents and commentaries from peer-reviewed journals (published 1996-2010) using the Framework approach. Two themes drove the NCSP's establishment and implementation. The first, chlamydia control, was prominently referenced in documents and interviews. The second theme concerned the potential for chlamydia screening to advance wider improvements in sexual health. In particular, screening was expected to promote sexual health services in primary care and encourage discussion of sexual health with young people. While this theme was only indirectly referenced in policy documents, it was cited by interviewees as a strong influence on implementation in the early years. However, by full rollout of the Programme, a focus on screening volume may have limited the NCSP's capacity to improve broader aspects of sexual health. A combination of explicit and implicit drivers underpinned the Programme's establishment. This combination may explain why there was widespread support for its introduction and why implementation of the NCSP was inconsistent. The potential to improve young people's sexual health more comprehensively should be made explicit in future planning of the NCSP.


Retinoic acid induction of stress proteins in fetal mouse limb buds.
Retinoic acid (RA) is teratogenic in rodent embryos. Several teratogens have been shown to induce the synthesis of a subset of heat shock proteins (stress proteins) in Drosophila. To determine if RA induces the synthesis of these proteins in rodent embryos, pregnant ICR mice were dosed with 100 mg/kg RA on Day 11 of gestation. Forelimb buds were removed from embryos 2.5 hr post-RA-treatment and nuclei were isolated, stained, and sorted from stages of the cell cycle. Nuclear proteins were extracted and analyzed by two-dimensional polyacrylamide gel electrophoresis. Nuclear proteins with molecular weights of approximately 84 and 25 kDa were synthesized in embryos in the G0 + G1 phase after pregnant dams were treated with RA. Isoelectric points, molecular weights, immunochemical blotting, and polypeptide mapping demonstrated that these proteins are indistinguishable from stress proteins isolated under a variety of conditions from rat submaxillary glands and mouse lymphoma cells. These results suggest that treatment with RA induces the synthesis of a subset of stress proteins; the role of these proteins in the teratogenic effects of RA is not known.


Mass Casualty Incident (MCI) training in a metropolitan university hospital: short-term experience with MAss Casualty SIMulation system MACSIM®.
The aim of this study was to test and validate a new hospital Mass Casualty Incident (MCI) training using MACSIM® (MAss Casualty SIMulation) system adapted to the specifications and MCI plan of a single hospital. The original MCI training format called MACSIM-PEMAF (Piano di Emergenza per il Massiccio Afflusso di Feriti, i.e., hospital disaster plan for massive influx of casualties) was developed for the Italian Society for Trauma and Emergency Surgery (SICUT) in 2016. It uses MACSIM®, a simulation tool for the training and assessment of healthcare professionals in MCI management. Between 2016 and 2018 the course was held several times at a university hospital in the Milan metropolitan area. The MACSIM® tool was used to reproduce different MCI scenarios with actual hospital resources. During the simulations, participants acted in their usual professional functions, testing both the local MCI plan as well as the individuals' knowledge and skills. Course effectiveness was validated by a pre- and post-curse self-assessment questionnaire. MACSIM-PEMAF was tested over 7 courses, with a total of 258 participants. Pre- and post-course questionnaires showed a significant improvement for hospital staff in self-reported perceptions of knowledge and skills in MCI management. In total, on a 1-10 scale, all the staff increased their competencies from a value of 4.4 ± 2.5 to 7.5 ± 1.9 (p < 0.001). MACSIM-PEMAF demonstrated efficacy in fulfilling the requirements of Italian law for PEMAF implementation, testing local resources and resilience, as well as increasing the self-reported perception of the hospital staff ability to respond to a MCI.


Infection with Toxoplasma gondii does not Alter TNFalpha and IL-6 Secretion by A human Astrocytoma Cell Line.
The secretion of tumour necrosis factor-alpha (TNFalpha), interleukin-1alpha (IL-alpha) and interleukin-6 (IL-6) by a human astrocytoma cell fine was studied 1 h, 3 h, 6 h and 24 h after infection with tachyzoites from three Toxoplasma gondii strains (virulent, RH; cystogentc, 76K and Prugniaud strains). The astrocytoma cell fine constitutively secreted TNFalpha and IL-6, but no IL-1alpha. A positive control was obtained by stimulation with phorbol esters inducing a significant increase (p < 0.05) in TNFalpha and IL- 6 secretion but not in IL-1alpha, while lipopolysaccharide (alone and after priming), interferon gamma, ionophore A 23187 and sera positive to T. gondii did not induce any increase in cytokine levels. None of the tachyzoites, whatever their virulence, induced a significant increase in cytokine production at any time in the study. Tachyzoites did not inhibit the secretion induced by phorbol esters.


Effects of experimental scotomata on sequential pattern-onset, pattern-reversal and pattern-offset visual evoked potentials.
The effect of experimental scotomata on visual evoked potentials to half-field stimulation using sequential checkerboard onset, reversal and offset was investigated in 10 normal subjects to assess the relative sensitivity of the three stimulus modes, and the contributions of pathways subserving macular and paramacular parts of the visual field. Four scotoma sizes (0-1.5 degrees , 0 degrees - 2 degrees, 0 degrees -3 degrees and 0 degrees -4.5 degrees ) were used to mask the central part of the stimulus field (0 degrees -12 degrees ). Five check sizes (6', 12', 20', 50' and 80') were presented for each scotoma size. Peak-to-peak amplitudes and peak latencies of components on the ipsilateral and contralateral sides of the scalp to the stimulated half-field were measured. Scotoma size was highly significant in influencing component amplitude (p < 0.0001) and latency (p < 0.03) of all ipsilateral and contralateral onset components and all ipsilateral reversal and offset components. Components that were attenuated to the greatest extent with the smallest 0 degrees -1.5 degrees scotoma were the contralateral onset P105 and ipsilateral reversal P100 and N145. Onset CIII, reversal N80, and offset N85 and P110 only showed a significant attenuation after the use of scotomata of 0 degrees -3 degrees and larger. Our results show that scotoma size is a significant factor in influencing all the major visual evoked potential components, with the exception of reversal and offset contralateral potentials (N105 and N115), probably reflecting their paramacular origins. Reversal, ipsilateral P100 and N145, and onset, contralateral P105, appear to be predominantly of macular origin and the most sensitive potentials for detecting effects of small central scotomata.


Chimeras of human lysozyme and alpha-lactalbumin: an interesting tool for studying partially folded states during protein folding.
Protein folding is an extremely active field of research where biology, chemistry, computer science and physics meet. Although the study of protein-folding intermediates in general and equilibrium intermediates in particular has grown considerably in recent years, many questions regarding the conformational state and the structural features of the various partially folded intermediate states remain unanswered. Performing kinetic measurements on proteins that have had their structures modified by site-directed mutagenesis, the so-called protein-engineering method, is an obvious way to gain fine structural information. In the present review, this method has been applied to a variety of proteins belonging to the lysozyme/alpha-lactalbumin family. Besides recombinants obtained by point mutations of individual critical residues, chimeric proteins in which whole structural elements (10-25 residues) from alpha-lactalbumin were inserted into a human lysozyme matrix are examined. The conformational properties of the equilibrium intermediate states are discussed together with the structural characterization of the partially unfolded states encountered in the kinetic folding pathway.


The distribution of acetylcholinesterase in the central nervous system of jumping spiders and wolf spiders (Arachnida, Araneida: Salticidae et Lycosidae).
The distribution and activity pattern of acetylcholinesterase in the central nervous system of salticid and lycosid spiders has been studied. Enzyme activity was limited to the neuropile mass. The salticid and lycosid species investigated showed different intensities of enzyme reactions in the protocerebrum. The differences observed may be related to the somewhat contrasting habits of these spider families. Reactions were strong especially in the optic ganglia (lamina glomerularis, corpora pedunculata) and in the cerebral ganglion, while the central body showed only weak to moderate activity. In the cheliceral ganglia, as in the pedipalpal and the leg ganglia, including the fibre tracts of the ventral cord the demonstration of acetylcholinesterase was of moderate to strong intensity.


Child maltreatment: An intergenerational cascades model of risk processes potentiating child psychopathology.
Child maltreatment poses substantial risk for compromised mental health in children. Further, child abuse and neglect are potentiated within a cascade of intergenerational and current familial risk processes that require clarification to inform understanding of adverse outcomes and direct prevention and intervention efforts. Using a multi-informant design, the current study applied an intergenerational cascades approach to examine the interconnected pathways among several familial risk factors associated with child maltreatment and its consequences. Participants were 378 children (aged 10-12) and their mothers from economically disadvantaged, ethnically diverse backgrounds. The sample included maltreated children recruited via CPS records and demographically comparable non-maltreated children. Structural equation modeling (SEM) was conducted to test sequential mediation pathways examining the independent and cascading effects of maternal history of childhood maltreatment, maternal adolescent childbearing, current maternal depression, and the child's lifetime history of maltreatment on the child's internalizing and externalizing symptoms. Multigenerational developmental cascades were identified. Maternal history of maltreatment predicted chronic maltreatment for offspring, which in turn predicted greater internalizing (β = .167, p = .03) and externalizing symptoms (β = .236, p = .005) in late childhood. Similarly, children born to mothers who began childbearing in adolescence were more likely to experience chronic maltreatment during childhood and develop subsequent symptoms. Effects were found over and above a parallel cascade from maternal maltreatment to offspring psychopathology via a maternal depression pathway. Findings reveal targets to prevent or ameliorate progressions of intergenerational risk pathways.


Whole venom of Loxosceles similis activates caspases-3, -6, -7, and -9 in human primary skin fibroblasts.
Spiders of the Loxosceles genus represent a risk to human health due to the systemic and necrotic effects of their bites. The main symptoms of these bites vary from dermonecrosis, observed in the majority of cases, to occasional systemic hemolysis and coagulopathy. Although the systemic effects are well characterized, the mechanisms of cell death triggered by the venom of these spiders are poorly characterized. In this study, we investigated the cell death mechanisms induced by the whole venom of the spider Loxosceles similis in human skin fibroblasts. Our results show that the venom initiates an apoptotic process and a caspase cascade involving the initiator caspase-9 and the effector caspases-3, -6, and -7.


Expression of endothelial (type III) nitric oxide synthase in cytotrophoblastic cell lines: regulation by hypoxia and inflammatory cytokines.
Expression of endothelial nitric oxide synthase (eNOS) has been localized to the villous syncytiotrophoblasts suggesting that NO release from these cells could prevent platelet adhesion and aggregation in the intervillous space. Hypoxia- or inflammation-dependent changes in the release of this vasoactive substance may result in thrombus formation and altered vascular resistance which occur in the placental bed of pre-eclamptic patients. To evaluate the influence of low-oxygen tension and inflammation on eNOS production in the trophoblast steady-state eNOS mRNA and protein levels were investigated in cytotrophoblastic BeWo and Jeg-3 cells cultured at 3.5 per cent oxygen and/or in the presence of the pro-inflammatory cytokines IL-1 and TNF-alpha. By RT-PCR and immunocytochemistry we demonstrate that BeWo cells produce eNOS mRNA and protein while eNOS polypeptide was undetectable in JEG-3 cells. In BeWo cells addition of both cytokines decreases eNOS mRNA and protein abundancies within 24 h of incubation while each substance alone had no effect. Compared to controls, the amount of eNOS transcripts was found to be elevated at low-oxygen tension, however, cNOS protein was downregulated after 24 h in the hypoxic environment, as shown by immunocytochemistry and Western blot analysis. Forskolin and methotrexate, which induce biochemical differentiation/ growth arrest in choriocarcinoma cells, stimulate eNOS mRNA and protein synthesis, but cannot overcome the decline of eNOS polypeptide levels during hypoxic incubation. It is speculated that acute hypoxia and inflammation impair eNOS/NO production of the trophoblast in vivo, which might contribute to pathological conditions of gestational diseases.


Do chimpanzees (Pan troglodytes) understand single invisible displacement?
Previous research suggests that chimpanzees understand single invisible displacement. However, this Piagetian task may be solvable through the use of simple search strategies rather than through mentally representing the past trajectory of an object. Four control conditions were thus administered to two chimpanzees in order to separate associative search strategies from performance based on mental representation. Strategies involving experimenter cue-use, search at the last or first box visited by the displacement device, and search at boxes adjacent to the displacement device were systematically controlled for. Chimpanzees showed no indications of utilizing these simple strategies, suggesting that their capacity to mentally represent single invisible displacements is comparable to that of 18-24-month-old children.


Hematological phenotype of the IVS-I-5 (G > C) beta-thalassemia mutation and assessment of Iran's national screening criteria.
In a recent study, we demonstrated that, in the Iranian province of Sistan-Baluchestan (S-B), the IVS-I-5 (G > C) beta-thalassemia (beta-thal) mutation is highly prevalent. In the present article we report the hematological phenotype as measured in 289 carriers of this mutation. We evaluate the use of MCV and MCH parameters as proposed in Iran's national screening guidelines for use in this province. The Hb A(2) cut off of 3.5%, also recommended in the national guidelines, gave 2.7% false negative, as is to be expected due to coexisting elements such as measurement artefacts and delta-thal.


Sodium gradient dependence of proline and glycine uptake in rat renal brush-border membrane vesicles.
The sodium-dependent entry of proline and glycine into rat renal brush-border membrane vesicles was examined. The high Km system for proline shows no sodium dependence. The low Km system for glycine entry is strictly dependent on a Na+ gradient but shows no evidence of the carrier system having any affinity for Na+. The low Km system for proline and high Km system for glycine transport appear to be shared. Both systems are stimulated by a Na+ gradient and appear to have an affinity for the Na+. The effect of decreasing the Na+ concentration in the ionic gradient is to alter the Km for amino acid entry and, at low Na+ concentrations, to inhibit the V for glycine entry.


In silico designing, in vitro and in vivo evaluation of potential PPAR-γ agonists derived from aryl propionic acid scaffold.
Attributed to several side effects, especially on hepatic tissues and body weight, there is always an urge of innovation and upgrading in already existing medication being used in maintaining diabetic condition. Therefore, in the present work, forty-eight molecules derived from arylpropionic acid scaffold were synthesized and their evaluation against diabetes was carried out. The synthesis of these molecules attributed to excellent dock score displayed by all the structures performed against PPAR-γ receptor site. Subsequently, all the derivatives were primarily deduced for their antidiabetic potential by OGTT. The compounds that showed significant antidiabetic activity in OGT Test and also exhibited high dock scores were assessed further by in vitro PPAR transactivation assay to assure analogy between in vivo and in vitro studies. The antidiabetic activity of these active compounds was then evaluated on STZ induced diabetic model in vivo. The most active compounds were scrutinized for its effect on PPAR-γ gene expression and hepatotoxic effect. Finally, it was recapitulated that these derivatives can provide a new prospect towards the development of antidiabetic agents with fewer side effects.


Pathogenic factors in early recurrence of cholesterol gallstones.
Supersaturation of bile with cholesterol, rapid nucleation of cholesterol crystals, and/or incomplete emptying of the gallbladder are believed to be required for gallstone formation. The importance of these factors for the recurrence of gallbladder stones was studied. Twenty patients, untreated after successful shock wave therapy, were studied in a matched case-control design for bile acid turnover, composition of duodenal bile, and gallbladder emptying. In 10 of them, gallstones had recurred within 12 +/- 2 months (X +/- SEM); the other 10 had been free of stones since 22 +/- 3 months. In each group, duodenal bile was supersaturated with cholesterol in 8 of 10 patients and showed abnormal nucleation time of cholesterol crystals in half of the patients. Patients with recurrent stones had smaller pool sizes of cholic acid (-43%) and enhanced conversion of cholic acid to deoxycholic acid. The odds for stone recurrence were ninefold increased in the presence of excessive deoxycholic acid (exceeding cholic acid) in the bile acid pool or incomplete emptying of the gallbladder (residual volume > 5 mL) in response to cholecystokinin. The odds ratio was over 20-fold increased when incomplete emptying of the gallbladder coincided with supersaturated bile or with excessive deoxycholic acid. Enhanced conversion of cholic acid to deoxycholic acid and incomplete emptying of the gallbladder could be important cofactors for the recurrence of gallstones.


AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells.
Basement membrane (BM) proteins accumulate chemical modifications with age. One such modification is glycation, which results in the formation of advanced glycation endproducts (AGEs). In a previous study, we reported that AGEs in the human lens capsule (BM) promote the TGFβ2-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells, which we proposed as a mechanism for posterior capsule opacification (PCO) or secondary cataract formation. In this study, we investigated the role of a receptor for AGEs (RAGE) in the TGFβ2-mediated EMT in a human lens epithelial cell line (FHL124). RAGE was present in FHL124 cells, and its levels were unaltered in cells cultured on either native or AGE-modified BM or upon treatment with TGFβ2. RAGE overexpression significantly enhanced the TGFβ2-mediated EMT responses in cells cultured on AGE-modified BM compared with the unmodified matrix. In contrast, treatment of cells with a RAGE antibody or EN-RAGE (an endogenous ligand for RAGE) resulted in a significant reduction in the TGFβ2-mediated EMT response. This was accompanied by a reduction in TGFβ2-mediated Smad signaling and ROS generation. These results imply that the interaction of matrix AGEs with RAGE plays a role in the TGFβ2-mediated EMT of lens epithelial cells and suggest that the blockade of RAGE could be a strategy to prevent PCO and other age-associated fibrosis.


Utility of biomarkers in the differential diagnosis of heart failure in older people: findings from the heart failure in care homes (HFinCH) diagnostic accuracy study.
The performance of biomarkers for heart failure (HF) in older residents in long-term care is poorly understood and has not differentiated between left ventricular systolic dysfunction (LVSD) and HF with preserved ejection fraction (HFpEF). This is the first diagnostic accuracy study in this population to assess the differential diagnostic performance and acceptability of a range of biomarkers against a clinical diagnosis using portable echocardiography. A total of 405 residents, aged 65-100 years (mean 84.2), in 33 UK long-term care facilities were enrolled between April 2009 and June 2010. For undifferentiated HF, BNP or NT-proBNP were adequate rule-out tests but would miss one in three cases (BNP: sensitivity 67%, NPV 86%, cut-off 115 pg/ml; NT-proBNP: sensitivity 62%, NPV 87%, cut-off 760 pg/ml). Using higher test cut-offs, both biomarkers were more adequate tests of LVSD, but would still miss one in four cases (BNP: sensitivity 76%, NPV 97%, cut-off 145 pg/ml; NT-proBNP: sensitivity 73%, NPV 97%, cut-off 1000 pg/ml). At these thresholds one third of subjects would test positive and require an echocardiogram. Applying a stricter 'rule out' threshold (sensitivity 90%), only one in 10 cases would be missed, but two thirds of subjects would require further investigation. Biomarkers were less useful for HFpEF (BNP: sensitivity 63%, specificity 61%, cut-off 110 pg/ml; NT-proBNP: sensitivity 68%, specificity 56%, cut-off 477 pg/ml). Novel biomarkers (Copeptin, MR-proADM, and MR-proANP) and common signs and symptoms had little diagnostic utility. No test, individually or in combination, adequately balanced case finding and rule-out for heart failure in this population; currently, in-situ echocardiography provides the only adequate diagnostic assessment. Controlled-Trials.com ISRCTN19781227.


Anti-myelin oligodendrocyte glycoprotein (MOG) associated disease masquerading as prolonged intractable nausea and vomiting.
The clinical and radiological spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody associated disease continues to expand. Here, we describe a case of prolonged, relapsing, intractable nausea and vomiting misdiagnosed as a functional disorder for more than one year. The patient did not receive a neurological workup until clear neurological signs developed. This case exemplifies the delay in diagnosis when neurological disease presents with seemingly non-neurological symptoms and illustrates brainstem and upper spinal cord radiological findings that can help guide the treating physician to test for MOG antibodies and provide the appropriate treatment.


EGFR inhibitor enhances cisplatin sensitivity of oral squamous cell carcinoma cell lines.
Epidermal growth factor receptor (EGFR) is involved in multiple aspects of cancer cell biology. EGFR has already been identified as an important target for cancer therapy, with various kinds of EGFR inhibitors currently used in treatment of several human cancers. Recently, EGFR and its downstream signaling pathways were identified as being associated with cisplatin sensitivity. In addition, EGFR inhibitors have shown significant promise for patients who failed cisplatin-based therapy. In this study, we investigated whether treatment with an EGFR inhibitor improves cisplatin sensitivity in oral squamous cell carcinoma (OSCC) cell lines. The effects of a combination of AG1478, a specific EGFR tyrosine kinase inhibitor, with cisplatin were evaluated in cultured OSCC cell lines and cisplatin-resistant sublines. Higher expression of EGFR and p-EGFR was found in the two cisplatin-resistant cell lines compared with the corresponding parental cell lines. In addition, augmented inhibition of OSCC cell growth by the combination of AG1478 with cisplatin was found in both cell lines. These results suggest that the combination of an EGFR inhibitor and cisplatin may be useful as a rational strategy for the treatment of patients with oral cancer with acquired cisplatin resistance.


[Massive subretinal hemorrhages. A challenge for vitreous body surgeons].
In patients with advanced age-related macular degeneration (AMD), massive subretinal hemorrhage may sometimes be the reason for a loss of peripheral vision, leading to a significantly reduced quality of life. During the years 1995-2001 we operated five eyes (five consecutive patients) with acute massive subretinal hemorrhage extending into all four quadrants and profoundly reduced vision in the fellow eye due to a Junius-Kuhnt macular scar. Within an interval of 1-2 weeks after the bleeding, pars plana vitrectomy with peripheral retinotomy was performed. After the retina was turned upside down and the partially liquified blood was removed, the underlying subfoveal CNV membrane was removed with a vitrectome. Three phakic eyes required additional cataract surgery and IOL implantation. The retina reattached under PFCL and a silicone oil tamponade applied for 3-6 months. The removal of the subretinal hemorrhage was without complications. The size of the subretinal membrane was between 4 and 6 PD with partially fibrovascular tissue. After the membrane was removed, a large central pigment epithelium defect made a macular rotation impossible. Visual acuity of hand motion improved from preoperatively 0.05 to postoperatively 1/35 to 0.1 after a follow-up of 3-6 months. In patients with such an extremely reduced visual acuity and visual field, subretinal surgery with removal of the subretinal blood may achieve sufficient vision for the patients' orientation.


Structure of the DNA binding domain of E. coli SSB bound to ssDNA.
The structure of the homotetrameric DNA binding domain of the single stranded DNA binding protein from Escherichia coli (Eco SSB) bound to two 35-mer single stranded DNAs was determined to a resolution of 2.8 A. This structure describes the vast network of interactions that results in the extensive wrapping of single stranded DNA around the SSB tetramer and suggests a structural basis for its various binding modes.


Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity.
We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (P<0.05) the development of CNV for 4-6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P>0.05) in mean severity score at 2 months (2.86+/-0.09), 4 months (2.15+/-0.17) or 6 months (2.7+/-0.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases.


Identification and Inhibitory Mechanism of Angiotensin I-Converting Enzyme Inhibitory Peptides Derived from Bovine Hemoglobin.
Angiotensin I-converting enzyme (ACE, EC.220.127.116.11) inhibitory peptide is an efficacious therapy for hypertension. In this study, four dipeptides, TY, FD, FL and FG, were identified from the desalted fraction of bovine hemoglobin hydrolysate, obtained by in vitro simulated gastrointestinal digestion, via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The IC50 value of TY and FL are 96.43 ± 6.17 and 290.66 ± 57.92 μM, respectively. The result of molecular docking indicated that TY occupied the ACE subsite S1 and S1' with a lowest estimated binding energy of -9.96 Kcal/mol, while FL occupied the subsite S5 with a lowest estimated binding energy of -9.37 Kcal/mol. The subsite S1' and S2' are closer to the ACE active center (Zn2+) than S5, and the lowest estimated binding energy of TY is lower than that of FL. This work provided new ACE-inhibitory peptides derived from bovine hemoglobin hydrolysate and explained their inhibitory mechanism.


Estimating network changes from lifespan measurements using a parsimonious gene network model of cellular aging.
Cellular aging is best studied in the budding yeast Saccharomyces cerevisiae. As an example of a pleiotropic trait, yeast lifespan is influenced by hundreds of interconnected genes. However, no quantitative methods are currently available to infer system-level changes in gene networks during cellular aging. We propose a parsimonious mathematical model of cellular aging based on stochastic gene interaction networks. This network model is made of only non-aging components: the strength of gene interactions declines with a constant mortality rate. Death of a cell occurs in the model when an essential node loses all of its interactions with other nodes, and is equivalent to the deletion of an essential gene. Stochasticity of gene interactions is modeled using a binomial distribution. We show that the exponential increase of mortality rate over time can emerge from this gene network model during the early stages of aging.We developed a maximal likelihood approach to estimate three lifespan-influencing network parameters from experimental lifespans: t0, the initial virtual age of the network system; n, the average lifespan-influencing interactions per essential node; and R, the initial mortality rate. We applied this model to yeast mutants with known effects on replicative lifespans. We found that deletion of SIR2, FOB1, and HXK2 considerably altered the initial virtual age but not the average lifespan-influencing interactions per essential node, suggesting that these mutations mainly influence the reliability of gene interactions but not the overall configurations of gene networks.We applied this model to investigate replicative lifespans of yeast natural isolates. We estimated that the average number of lifespan-influencing interactions per essential node is 7.0 (6.1-8) and the average estimated initial virtual age is 45.4 (30.6-74) cell divisions in these isolates. We also found that t0 could potentially mediate the observed Strehler-Mildvan correlation in yeast natural isolates. Our theoretical model provides a parsimonious interpretation of experimental lifespan data from the perspective of gene networks. We hope that our work will stimulate more interest in developing network models to study aging as a pleiotropic trait.


Determination by photon correlation spectroscopy of particle size distributions in lipid vesicle suspensions.
A method of determining particle size distributions in lipid vesicle preparations is outlined. A vesicle suspension is modeled as a polydisperse mixture of spherical shells. The distribution of particle sizes in this mixture is approximated by a continuous, piecewise linear function called a first-order spline. Excellent simultaneous fits to photon correlation spectroscopy data gathered at several different angles are presented. An error analysis is included to indicate the resolution of the method.


Removal rates of dissolved munitions compounds in seawater.
The historical exposure of coastal marine systems to munitions compounds is of significant concern due to the global distribution of impacted sites and known toxicological effects of nitroaromatics. In order to identify specific coastal regions where persistence of these chemicals should be of concern, it is necessary to experimentally observe their behavior under a variety of realistic oceanographic conditions. Here, we conduct a mesocosm scale pulse addition experiment to document the behavior of two commonly used explosives, 2,4,6-trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in simulated marine systems containing water and sediments collected from Long Island Sound, CT. The addition of sediments and sediment grain-size had a major influence on the loss rates of all compounds detected. RDX and reduced TNT products were removed from seawater only in the presence of sediment, and TNT degraded significantly faster in the presence of sediment. Both compounds were removed from the system faster with decreasing grain-size. Based on these findings and a thorough review of the literature, we hypothesize that in addition to bacterial abundance and nutrient availability, TNT removal rates in coastal marine waters may be controlled by sorption and rapid surface-mediated bacterial transformation, while RDX removal rates are controlled by diffusion into sedimentary anoxic regions and subsequent anaerobic bacterial breakdown. A comparison of published removal rates of RDX and TNT highlights the extreme variability in measured degradation rates and identifies physicochemical variables that covary with the breakdown of these munitions compounds.


Mucinous cystadenoma of the ovary with stromal luteinization and hilar cell hyperplasia during pregnancy.
A 32-year-old woman was delivered of a healthy, full-term infant by cesarean section, at which time a large ovarian cyst was removed. The cyst proved to be a mucinous cystadenoma with prominent luteinization of the stroma subtending the epithelium and with numerous foci of hyperplastic Leydig cells in the cyst wall and ovarian hilum. These hormonally induced changes must be recognized in order to avoid mistaking them for invasive epithelial components.


Location of forelimb motoneurons in the Japanese toad (Bufo japonicus): a horseradish peroxidase study.
To label the spinal motoneurons innervating the forelimb muscles of the Japanese toad, horseradish peroxidase (HRP) was injected into these muscles or applied to the cut end of the brachial nerves (N. radialis and N. ulnaris). Spatial distribution of the HRP-labeled motoneurons was reconstructed from serial frontal sections of the spinal cord and their location was examined. Motoneurons innervating forelimb muscles were distributed in the lateral cell column from segment 3 to segment 5 of the ipsilateral brachial spinal cord. In the transverse plane of the spinal cord, motoneurons innervating the medial forearm muscles (innervated by N. ulnaris) were located in the more medial part of the lateral cell column, whereas those innervating the lateral forearm muscles and the upper arm muscle (innervated by N. radialis) were located in the more lateral part of the lateral cell column. Along the longitudinal axis of the spinal cord, motoneurons innervating the more anterior (flexor side) forearm muscles were located in the more rostral part of the spinal cord, whereas those innervating the more posterior (extensor side) forearm muscles were located in the more caudal part of the spinal cord. Thus, motoneurons innervating forearm muscles were well organized somatotopically not only in the transverse plane, but also along the longitudinal axis of the spinal cord. Such a somatotopic organization of motoneurons along the longitudinal axis could also be regarded as a functional one; the flexor motoneurons were located rostrally to the extensor motoneurons.


Relative atherogenicity of different plasma lipoproteins.
Originally, data from the Framingham study appeared to show that serum lipoprotein fractions were no better in predicting coronary heart disease than the total serum cholesterol. More recently, the concentration of high density lipoprotein has been shown to exhibit a strong negative correlation with coronary heart disease, especially in the older age groups in which total serum cholesterol shows little or no correlation with clinical events. Biochemical mechanisms that might clarify the role of high density lipoprotein in atherogenesis are forthcoming. Another aspect of the lipoprotein-atherogenesis question pertains to the possible role of chylomicrons. Animal experiments show that cholesterol feeding is frequently accompanied by an increase in beta-migrating, very low density lipoproteins which appear to be chylomicron remnants. The atherogenic effect of serum low- and very low-density lipoproteins, including chylomicron remnants, appears to depend more on their contribution to the total cholesterol concentration than to their origin in liver versus intestines.


Larval competition in serially transferred populations of Drosophila melanogaster.
Experiments showed that larval competition for food is not always the result of decreases in the amount of food available per larva as population density increases. The feeding period during which the larvae try to attain the minimum survival weight may be restricted when food quantity is not limiting. The scramble type competition involves both exploitation and interference components, in degrees which vary with population density.


Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results.
Previous systematic reviews have indicated that pesticide exposure is possibly associated with Parkinson disease (PD). However, considerable heterogeneity has been observed in study results. We aimed at providing an update of the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis. In addition, we investigated whether methodological differences between studies could explain the heterogeneity in study results. We identified studies through a systematic literature search. We calculated summary risk ratios (sRRs) for pesticide exposure and subcategories using random effects meta-analyses and investigated sources of heterogeneity by meta-regression and stratified analyses. Thirty-nine case-control studies, four cohort studies, and three cross-sectional studies were identified. An sRR of 1.62 [95% confidence interval (CI): 1.40, 1.88] for pesticide exposure (ever vs. never) was found. Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. Heterogeneity in individual study results was not related to study design, source of control population, adjustment of results for potential confounders, or geographical area. However, results were suggestive for heterogeneity related to differences in the exposure assessment. Job title-based exposure assignment resulted in a higher sRR (2.5; 95% CI: 1.5, 4.1) than did assignment based on self-reported exposure (e.g., for self-reported ever/never exposure, sRR = 1.5; 95% CI: 1.3, 1.8). This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.


PERson-centredness in Hypertension management using Information Technology: a randomized controlled trial in primary care.
To increase the proportion of individuals with hypertension obtaining a blood pressure (BP) of less than 140/90 mmHg by improving the management of hypertension in daily life from a person-centred perspective. In this unblinded randomized controlled trial, we tested an interactive web-based self-management system for hypertension. A total of 949 patients with hypertension from 31 primary healthcare centres (PHCCs) in Sweden were randomized 1 : 1 to either the intervention or usual care group. The intervention included daily measurement - via the participant's mobile phone - of BP and pulse and reports of well being, symptoms, lifestyle, medication intake and side effects for eight consecutive weeks. It also included reminders and optional motivational messages. The primary outcome was the proportion of participants obtaining BP of less than 140/90 mmHg at 8 weeks and 12 months. Significance was tested by Pearson's chi 2 -test. A total of 862 patients completed the trial, 442 in the intervention group and 420 in the control group. The primary outcome (BP <140/90 mmHg) at 8 weeks was achieved by 48.8% in the intervention group and 39.9% in the control group ( P = 0.006). At 12 months, 47.1% (intervention) and 41.0% (control group) had a BP less than 140/90 mmHg ( P = 0.071). The proportion of participants with a controlled BP of less than 140/90 mmHg increased after using the interactive system for self-management of hypertension for 8 weeks compared with usual care. Although the trend continued, there was no significant difference after 12 months. The results indicate that the effect of the intervention is significant, but the long-term effect is uncertain. The study was registered with ClinicalTrials.gov (NCT03554382).


Cobalt/rhodium heterobimetallic nanoparticle-catalyzed carbonylative [2+2+1] cycloaddition of allenes and bisallenes to Pauson-Khand-type reaction products.
The first catalytic intra- and intermolecular [2+2+1] cocyclization reactions of allenes and carbon monoxide have been developed. In the Co(2)Rh(2) heterobimetallic nanoparticle-catalyzed carbonylative [2+2+1] cycloaddition of allenes and carbon monoxide, the allenes formally serve both as an excellent alkene- and alkyne-like moiety within a Pauson-Khand-type process.


An abnormal early diastolic impedance waveform: a predictor of poor prognosis in the cardiac patient?
The first derivative of the thoracic impedance (dZ/dt) was recorded in 81 patients entering the Cardiac Care Unit with diverse acute cardiovascular illnesses. An abnormal diastolic impedance waveform was identified in 30 of the patients. These were compared with the other 51 patients admitted under similar circumstances who did not show this abnormal waveform. Retrospective analysis of these 81 patients reveals that the ones showing the abnormal wave eventually had a poorer prognosis (66 per cent were eventually classified as Class III and IV) versus 90 per cent of the patients without the abnormality who were eventually classified under Class I and II (X2 = 28.6; p less than .001). More than 50 per cent of the 30 patients who showed the abnormality died, and 16 out of the 18 who died belonged to the group who showed the abnormal waveform (X2 = 26.7; P less than .001). From this analysis it appears that the presence of this abnormal early diastolic waveform of the dZ/dt tracing can be used as a predictor of outcome in patients with several myocardial insults, both in terms of functional disability and death.


Melatonin membrane receptors in peripheral tissues: distribution and functions.
Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.


In Silico Studies of Phytoconstituents from Piper longum and Ocimum sanctum as ACE2 and TMRSS2 Inhibitors: Strategies to Combat COVID-19.
The recent pandemic due to the COVID-19 virus has caused a global catastrophe. ACE2 and TMPRSS2 are recognized as key targets for viral entry into the host cells. The pandemic has led to the utilization of many synthetic drugs; however, due to various side effects, there is still no effective drug available against the virus. Several natural approaches have been devised, including herbal and ayurvedic medicines, that have proven to be effective against the COVID-19 virus. In the present study, the effect of phytocompounds of Piper longum and Ocimum sanctum on ACE2 and TRMPSS2 proteins has been studied. The in silico study is done using computational tools of networks of protein-protein interaction, molecular docking, and drug assessment in terms of physicochemical properties, drug-likeness, lipophilicity, water solubility, and pharmacokinetics. Out of selected phytoconstituents, vicenin 2, rosmarinic acid, and orientin were found to have the highest efficacy in terms of molecular interaction and drug-likeness properties against ACE2 and TMPRSS2 host receptor proteins. Our in silico study proposes the therapeutic potential of phytocompounds from Piper longum and Ocimum sanctum in modulating ACE2 and TMPRSS2 expression. Targeting ACE2 and TMPRSS2 against the SARS-CoV2 by phytomolecules can serve as a rational approach for designing future anti-COVID drugs.


Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages.
Physical activity has been shown to reduce the risk of CVD mortality in large-cohort longitudinal studies; however, the mechanisms underpinning the beneficial effects of exercise remain incompletely understood. Emerging data suggest that the risk reducing effect of exercise extends beyond changes in traditional CVD risk factors alone and involves alterations in immunity and reductions in inflammatory mediator production. Our study aimed to determine whether exercise-enhanced production of proresolving lipid mediators contribute to alterations in macrophage intermediary metabolism, which may contribute to the anti-inflammatory effects of exercise. Changes in lipid mediators and macrophage metabolism were assessed in C57Bl/6 mice following 4 weeks of voluntary exercise training. To investigate whether exercise-stimulated upregulation of specialized proresolving lipid mediators (SPMs) was sufficient to enhance mitochondrial respiration, both macrophages from control mice and human donors were incubated in vitro with SPMs and mitochondrial respiratory parameters were measured using extracellular flux analysis. Compound-C, an ATP-competitive inhibitor of AMPK kinase activity, was used to investigate the role of AMPK activity in SPM-induced mitochondrial metabolism. To assess the in vivo contribution of 5-lipoxygenase in AMPK activation and exercise-induced mitochondrial metabolism in macrophages, Alox5-/- mice were also subjected to exercise training. Four weeks of exercise training enhanced proresolving lipid mediator production, while also stimulating the catabolism of inflammatory lipid mediators (e.g., leukotrienes and prostaglandins). This shift in lipid mediator balance following exercise was associated with increased macrophage mitochondrial metabolism. We also find that treating human and murine macrophages in vitro with proresolving lipid mediators enhances mitochondrial respiratory parameters. The proresolving lipid mediators RvD1, RvE1, and MaR1, but not RvD2, stimulated mitochondrial respiration through an AMPK-dependent signaling mechanism. Additionally, in a subset of macrophages, exercise-induced mitochondrial activity in vivo was dependent upon 5-lipoxygenase activity. Collectively, these results suggest that exercise stimulates proresolving lipid mediator biosynthesis and mitochondrial metabolism in macrophages via AMPK, which might contribute to the anti-inflammatory and CVD risk reducing effect of exercise.


The relationship between anemia and hyperuricemia and hypertension in Korean adults: the Korea National Health and Nutrition Examination Survey 2016-2018.
It is unclear whether uric acid (UA) has a negative or positive effect on anemia, and this may vary depending on the presence or absence of chronic disease such as hypertension (HTN). The present study was conducted to assess the relationship between anemia and hyperuricemia in Korean adults with or without hypertension. Data from 16,740 adults (age ≥20 years) in the Korean National Health and Nutrition Examination Survey (2016 - 2018) were analyzed. Several key findings were identified. First, after adjusting for the related variables in the non-HTN group, the odds ratio (OR) of anemia (hemoglobin [Hb] ≥ 13.0 mg/dL in men and ≥12.0 mg/dL in women), using the normouricemia (UA < 7.0 mg/dL in men and UA < 6.0 mg/dL in women) as a reference, was inversely significant for the hyperuricemia (UA ≥ 7.0 mg/dL in men and ≥6.0 mg/dL in women) in the overall population (OR, 0.589; 95% confidence interval [CI], 0.409-0.848) and women (OR, 0.575; 95% CI, 0.363-0.909) but not in men (OR, 0.836; 95% CI, 0.441-1.586). Second, after adjusting for the related variables in the HTN group, the OR of anemia, using the normouricemia as a reference, was positively significant for the hyperuricemia in the overall population (OR, 1.501; 95% CI, 1.167-1.930), men (OR, 1.706; 95% CI, 1.154-2.523), and women (OR, 1.512; 95% CI, 1.079-2.210). Hyperuricemia was positively associated with anemia in men and women with HTN. Hyperuricemia was inversely associated with anemia in women without HTN but not in men without HTN.


A non-mammalian Toll-like receptor 26 (TLR26)gene mediates innate immune responses in yellow catfish Pelteobagrus fulvidraco.
In this study, we identified a fish-specific Toll-like receptor (TLR) in Pelteobagrus fulvidraco, an economically important freshwater fish in China. This TLR, PfTLR26, was shown to be encoded by a 3084 bp open reading frame (ORF), producing a polypeptide 1027 amino acids in length. The PfTLR26 protein contains a signal peptide, eight leucine-rich repeat (LRR) domains, two LRR_TYP domains in the extracellular region, and a Toll/interleukin (IL)-1 receptor (TIR) domain in the cytoplasmic region, consistent with the characteristic TLR domain architecture. This predicted 117.1 kDa protein was highly homologous to those of other fish, with phylogenetic analysis revealing the closest relation to TLR26 of Ictalurus punctatus. Real-time quantitative reverse transcription-PCR (qRT-PCR) analysis showed that the PfTLR26 gene was expressed in all tissues tested, with the highest expression levels seen in the head kidney and blood, and the lowest seen in muscle. PfTLR26 exhibited significant upregulation in liver, spleen, head kidney, and blood at different time points following challenge with the common TLR agonists lipopolysaccharide (LPS) and polyriboinosinic polyribocytidylic acid (Poly I:C). Taken together, these results suggest that PfTLR26 may be an important component of the P. fulvidraco innate immune system, participating in the transduction of TLR signaling under pathogen stimulation.


Assessment of Measurement of Salivary Urea by ATR-FTIR Spectroscopy to Screen for CKD.
Stages of CKD are currently defined by eGFR and require measurement of serum creatinine concentrations. Previous studies have shown a good correlation between salivary and serum urea levels and the stage of CKD. However, quantitative salivary urea assays in current clinical use require costly and labor-intensive commercial kits, which restricts the advantage of using saliva and limits wider applicability as a quick and easy means of assessing renal function. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy has been shown to provide a potentially straightforward, reagent-free method for the identification of a range of disease-related biomarkers and is in current clinical use for analyses of the chemical composition of kidney stones. We assessed the feasibility of ATR-FTIR spectroscopy as an alternative method to measure salivary urea in patients with different stages of CKD. The ATR-FTIR spectra of dried saliva samples from six healthy controls and 20 patients with CKD (stages 1-5) were analyzed to provide their urea concentrations. The lower limit of detection of salivary urea by the ATR-FTIR spectroscopy method was 1-2 mM, at the lower end of the clinically relevant range. Statistically significant differences in salivary urea concentrations were demonstrated between healthy subjects (4.1±0.5 mM) and patients with CKD stages 3-5 (CKD stage 3, 6.8±0.7 mM; CKD stage 4, 9.1±1 mM; CKD stage 5, 14.8±1.6 mM). These salivary urea concentrations correlated well with serum urea levels in the same patients measured by an automated analyzer (Spearman rank correlation coefficient of 0.71; P<0.001). The ability of the method to detect and stage CKD was assessed from the sensitivity and specificity parameters of a receiver operating characteristics (ROC) curve analysis. This proof-of-concept study demonstrates that quantitation of salivary urea by ATR-FTIR spectroscopy could provide a viable tool for rapid and cost-effective diagnosis of stages 3-5 CKD.


Determination of putrescine in brain tissue using gas chromatography-mass spectrometry.
We used gas chromatography-mass spectrometry to assay putrescine in minute regions of single rat brains. Acid extraction, partial purification on Amberlite CG 120, and derivatization with pentafluoropropionic anhydride preceded the gas chromatography-mass spectrometry. A moving-needle solventless system and a direct inlet system were also used to increase sensitivity. Putrescine was measured accurately at the picomole level; the mean concentration of this polyamine in five regions of rat brain found by this method was 2.7-3.8 times higher than reported by other researchers.


Effect of 7-day daily replacement of culture medium containing Eurycoma longifolia Jack constituents on the Malaysian Plasmodium falciparum isolates.
Six Malaysian chloroquine-resistant Plasmodium falciparum isolates were cultured in vitro following the candle-jar method. Antimalarial evaluations of daily replacement of culture medium containing chloroquine and a semi-purified extract of Eurycoma longifolia Jack (containing 13 beta, 18-dihydroeurycomanol (1), eurycomanol-2-O-beta-D-glucopyranoside (2), eurycomanol (3) and eurycomanone (4)) were performed on 6-well plates at 37 degrees C for a week. Presence or absence of the parasites was determined microscopically on thin-film Giemsa-stained preparations. Results showed that the antimalarial activity of Eurycoma longifolia Jack was dose-dependent and reached a maximum of < 50% at 0.07-5.00 micrograms ml-1 after 1 day post-treatment. However, complete inhibitions were observed at 1.25-5.00 micrograms ml-1 extract after 3 days post-treatment and 0.62 and 0.31 micrograms ml-1 after 4 and 6 days post-treatment, respectively. Further results indicated that chloroquine exhibited total inhibition at concentrations > 2.50 and 0.62 micrograms ml-1 after 1 and 2 days post-treatment, respectively and at all concentrations after 3 days post-treatment.


Biodiversity of antifungal lactic acid bacteria isolated from raw milk samples from cow, ewe and goat over one-year period.
Antifungal lactic acid bacteria (ALAB) biodiversity was evaluated in raw milk from ewe, cow and goat over one year period. Lactic acid bacteria were enumerated using 8 semi-selective media, and systematically screened for their antifungal activity against 4 spoilage fungi commonly encountered in dairy products. Depending on the selective medium, between 0.05% (Elliker agar) and 5.5% (LAMVAB agar) screened colonies showed an antifungal activity. The great majority of these active colonies originated from cow (49%) and goat (43%) milks, whereas only 8% were isolated from ewe milk. Penicillium expansum was the most frequently inhibited fungus with 48.5% of colonies active against P. expansum among the 1235 isolated, followed by Mucor plumbeus with 30.6% of active colonies, Kluyveromyces lactis with only 12.1% of active colonies and Pichia anomala with 8.7% of active colonies. In the tested conditions, 94% of the sequenced active colonies belonged to Lactobacillus. Among them, targeted fungal species differed according to the Lactobacillus group, whose presence largely depended on year period and milk origin. The Lb. casei and Lb. reuteri groups, predominantly recovered in summer/fall, were overrepresented in the population targeting M. plumbeus, whereas isolates from the Lb. plantarum group, predominantly recovered in spring, were overrepresented in the population targeting K. lactis, the ones belonging to the Lb. buchneri group, predominantly recovered in spring, were overrepresented in the population targeting P. anomala. Raw milk, especially cow and goat milks from the summer/fall period appeared to be a productive reservoir for antifungal lactobacilli.


[Human bocavirus (HBoV)].
The human bocavirus (HBoV) has been recently identified by means of molecular screening techniques in respiratory tract secretions from children with acute respiratory tract disease. This virus, which belongs to the Parvoviridae family, has been detected worldwide with a 5 to 10% prevalence among children with upper or lower respiratory tract infections, essentially during the winter period. A seroepidemiological study has shown that almost all the children have antibodies to HBoV by the age of five years, and HBoV infection seems to be rare in adults. HBoV is often detected in association with other respiratory viruses. This virus has also been detected in stools, but its role in gastroenteritis has not been yet established. Virological diagnostic of HBoV infection is based on the detection of viral DNA by PCR. Viral load determination by viral DNA quantitation in respiratory tract secretions could be a tool to differentiate between symptomatic HBoV infection and virus carriage.


A One Health strategy for emerging infectious diseases based on the COVID-19 outbreak.
Coronavirus disease 2019 (COVID-19) is as an emerging infectious disease (EID) that has caused the worst public health catastrophe of the 21st century thus far. In terms of impact, the COVID-19 pandemic is second only to the Spanish Flu pandemic of 1918 in modern world history. As of 7 September 2021, there have been 220 million confirmed cases of COVID-19 and more than 4.5 million deaths. EIDs pose serious public health and socio-economic risks, and 70% of EIDs originate from wildlife. Preventing development of EIDs such as COVID-19 is a pressing concern. Here, taking the COVID-19 pandemic as an example, we illustrate the disastrous effects of EIDs and assess their emergence and evolution from a One Health perspective. We propose a One Health strategy, centered on 'moving the gates forward', for EID prevention and control at the human-animal-environment interface. This strategy may be instructive and provide early warnings of EIDs in the future.


A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats.
Activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²⁺ channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²⁺ channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²⁺ channels in a voltage-dependent fashion (IC₅₀ = 2 μM) and attenuates LVA currents in rat DRG neurons (IC₅₀ = 8 μM). ABT-639 was significantly less active at other Ca²⁺ channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC₅₀ > 30 μM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED₅₀ = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states.


We need to talk about the analytical performance of our laboratory developed clinical LC-MS/MS tests, and start separating the wheat from the chaff.
With the upcoming EU regulation on the use of in-vitro diagnostic devices, a critical evaluation of the current status of our in-house developed LC-MS/MS methods is timely and of great relevance. Recently, much attention has been devoted to the need for better specification of analytical and clinical performance. Appropriate reporting of the actual achieved analytical performance is an important determinant of the clinical performance and subsequent clinical effectiveness of a test. We advocate for the application of CLSI C62-A guidelines for method validation and suggest some adaptations for analytical validation of in-house developed LC-MS/MS methods for endogenous substances. Additionally, we underline the importance of well-equipped reviewers and standardized method description, including the presentation of figural evidence of obtained method performance. Achieving this ensures future quality of our in-house developed LC-MS/MS methods.


The differentiation potential of precursor cells from the mouse lateral ganglionic eminence is restricted by in vitro expansion.
We have investigated whether the differentiation potential of attached cultures derived from the mouse lateral ganglionic eminence (LGE) is influenced by in vitro expansion. Primary neuronal cultures derived from the LGE give rise to neurons expressing the striatal projection neuron markers Islet1 (ISL1) and dopamine and cAMP-regulated phosphoprotein of 32 kilodaltons (DARPP-32) as well as the olfactory bulb interneuron marker Er81. Our previous results showed that after expansion in vitro, LGE precursor cells can be induced to differentiate into neurons which exhibit molecular characteristics of the LGE, such as the homeobox transcription factors DLX and MEIS2. We show here that while attached LGE cultures maintain Er81 expression through five passages, they lose the ability to generate ISL1- or dopamine and cAMP-regulated phosphoprotein of 32 kilodaltons-expressing neurons already after the first passage. This indicates that the expansion of LGE precursor cells restricts their differentiation potential in vitro. Interestingly, the undifferentiated LGE cultures retain the expression of both the Isl1 and Er81 genes, suggesting that precursor cells for both striatal projection neurons and olfactory bulb interneurons are present in these cultures. Thus the restriction in differentiation potential of the expanded LGE cultures likely reflects deficiencies in the differentiation conditions used.


Psychosocial Needs and Preferences for Care among Adolescent and Young Adult Cancer Patients (Ages 15-39): A Qualitative Study.
Adolescents and young adults (AYAs) require a multidisciplinary approach to cancer care due to their complex biopsychosocial situations and varied developmental maturity. Currently, age and diagnosis determine referral to pediatric or adult oncology, with differing treatment paradigms and service utilization patterns, contributing to suboptimal improvements in outcomes. Understanding the unique perspectives of AYAs is essential to designing patient-centered AYA services. Thus, we conducted six focus groups with AYAs (n = 25) treated by medical or pediatric oncologists to evaluate: (1) the unique experiences of cancer care as an AYA; (2) AYA-specific information needs and communication preferences; and (3) recommendations for service provision, delivery and accommodations for AYAs. Transcripts were analyzed using inductive thematic content analysis and identified six major themes to inform clinically-actionable recommendations and the development of a patient-reported outcome measure: (1) AYAs experience social isolation and loss of independence; (2) AYAs have an uncertain sense of the future and need conversations around survivorship and long-term and late effects; (3) AYAs desire greater control over discussions with their care team; (4) AYAs need additional navigational and social/caregiver supports; (5) AYAs prefer an inclusive AYA space in the hospital; and (6) LGBTQ+ patients experience distinct concerns as AYA cancer patients. These will form the basis for specific and tailored clinical recommendations to improve AYA cancer care delivery.


Gender differences in prosthesis-related outcomes among veterans: Results of a national survey of U.S. veterans.
Women with lower extremity amputations (LEAs) tend to have poorer prosthesis-related outcomes than men, although the literature is sparse. To our knowledge, there are no prior studies examining prosthesis-related outcomes of women veterans with LEAs. To examine gender differences (overall and by type of amputation) among veterans who underwent LEAs between 2005 and 2018, received care at the Veterans Health Administration (VHA) prior to undergoing amputation, and were prescribed a prosthesis. It was hypothesized that compared to men, women would report lower satisfaction with prosthetic services, poorer prosthesis fit, lower prosthesis satisfaction, less prosthesis use, and worse self-reported mobility. Furthermore, it was hypothesized that gender differences in outcomes would be more pronounced among individuals with transfemoral than among those with transtibial amputations. Cross-sectional survey. Linear regressions were used to assess overall gender differences in outcomes and gender differences based on type of amputation in a national sample of veterans. VHA medical centers. The sample consisted of 449 veterans who self-identified their gender (women = 165, men = 284) with transtibial (n = 236), transfemoral (n = 135), and bilateral LEAs (n = 68) including all amputation etiologies. Not applicable. The Orthotics and Prosthetics User's Survey, Trinity Amputation and Prosthesis Experiences Scale, and Prosthetic Limb Users Survey of Mobility-Short Form were used to assess satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, prosthesis use, and self-reported mobility. Women had poorer self-reported mobility than men (d = -0.26, 95% confidence interval -0.49 to -0.02, p < .05); this difference was small. There were no statistically significant gender differences in satisfaction with prosthetic services, prosthesis fit, prosthesis satisfaction, daily hours of prosthesis use, or by amputation type. Contrary to the hypothesis, prosthesis-related outcomes were similar between men and women with LEAs. Minimal differences may in part be due to receiving care from the VHA's integrated Amputation System of Care.


Photocytotoxic effect of pseudohypericin versus hypericin.
Pseudohypericin and hypericin, the major photosensitizing constituents of Hypericum perforatum, are believed to cause hypericism. Since hypericin has been proposed as a photosensitizer for photodynamic cancer therapy, the photocytotoxicity of its congener pseudohypericin has been investigated. The presence of foetal calf serum (FCS) or albumin extensively inhibits the photocytotoxic effect of pseudohypericin against A431 tumour cells, and is associated with a large decrease in cellular uptake of the compound. These results suggest that pseudohypericin, in contrast to hypericin, interacts strongly with constituents of FCS, lowering its interaction with cells. Since pseudohypericin is two to three times more abundant in Hypericum than hypericin and the bioavailabilities of pseudohypericin and hypericin after oral administration are similar, these results suggest that hypericin, and not pseudohypericin, is likely to be the constituent responsible for hypericism. Moreover, the dramatic decrease of photosensitizing activity of pseudohypericin in the presence of serum may restrict its applicability in clinical situations.


Spectroscopic techniques for study of phosphodiester bond formation by Escherichia coli RNA polymerase.
Nucleotides containing the fluorophore 1-aminonaphthalene-5-sulfonate attached to the gamma phosphoryl group via a phosphoamidate bond are excellent substrates for Escherichia coli DNA-dependent RNA polymerase. Cleavage of the alpha-beta-phosphoryl bond produces significant changes in both absorption and fluorescence spectra. These alterations provide a sensitive and precise means for continuous monitoring of transcription. Under appropriate conditions one can detect the utilization of less than 1 nmol of nucleotide. Since the spectroscopic techniques measure nucleotide utilization they can be used in conjunction with measurements of incorporation of radiolabeled precursor such as [3H]UTP into acid-insoluble material to determine whether significant amounts of acid-soluble oligonucleotides are formed.


A simulation program examining the use of ratios as raw variables in analyses of variance.
An interactive, BASIC-PLUS, simulation program is described for performing a large number of multivariate analyses in accord with, or in violation of, known underlying models. Using a PDP 11/40 computer, random numbers are generated and converted into bivariate normal observations X and Y. These data are then analyzed according to three models. The three analyses are: (1) a standard analysis of variance ignoring the concomitant variable; (2) an analysis of covariance; (3) an analysis of variance on the ratio Y/X. The program can be used to examine the effect of performing multivariate analyses on data transformed into ratios. The utility of the program is the simplicity with which one can alter the underlying models and/or the mathematical relationships between X and Y. Output provides comparisons between models by accumulating rejections and other statistics on critical F-values for each model.


PET/CT with 18F-Fluordesoxyglucose in patients with suspected endovascular prosthesis infection.
Infection of large vessel prostheses is a rare but critical complication. The aim of this work is to assess the impact of PET/CT with 18F-Fluordesoxyglucose (PET-FDG) on the diagnosis of infection in our environment. Thirty-five patients (38 scans) were evaluated for suspected prosthetic infection. A qualitative analysis was performed taking into account the distribution of the radiopharmaceutical, categorizing the studies as positive or negative for infection. Those with focal or multifocal deposits along the vascular prosthesis were considered positive, and negative if a homogeneous and diffuse distribution over the whole prosthesis was observed, or a total absence of uptake. A semi-quantitative analysis was performed using SUVmax and average SUV values, and a metabolic index was calculated (SUVmax of the graft / average SUV of the normal vascular pool). The PET-FDG study was positive in 20 patients, with a diagnostic accuracy of 84%. The 38 PET-FDG scans performed showed positive capture patterns (focal in 6, multifocal in 15, diffuse in 4) and negative pattern in the remaining 13. The sensitivity, specificity, positive and negative predictive values obtained for the PET-FDG were 95%, 89%, 90% and 94%, and for the AngioTC study 50%, 73%, 73% and 50%, respectively. The area values under the ROC curve were as follows: for the AngioTC 0.642 (not significant), and for the SUVmax values of 0.925 (p<0.005), average SUV of 0.922 (p<0.005) and for the metabolic index of 0.917 (p<0.005). The PET-FDG proves to be a tool with high diagnostic accuracy in the infection of vascular prosthesis, both visual analysis according to patterns and semi-quantitative.


Direct determination of the effects of genotype and extreme temperature on the transposition of roo in long-term mutation accumulation lines of Drosophila melanogaster.
Transposable elements (TEs) are mobile repetitive DNA sequences that constitute a structurally dynamic component of genomes. In order to understand the dynamics of TEs it is necessary to have information about the control of transposition and its dependence of environmental factors. After a great deal of previous work on transposition conducted on long-term mutation accumulation (MA) lines of Drosophila melanogaster started in 1987, only roo out of 16 families was found active in this genotype. Here we test the effect of the modification of the genetic background by introducing a Cy chromosome, and the effect of extreme temperature (28 degrees C) on the transposition rate of roo. Thermal stress did not affect the transposition rate, whereas the presence of a Cy chromosome in heterozygosis lowered it. There was an excess of insertions in the X chromosome, with respect to autosomes, and in the proximal and distal regions of chromosome arms that can be interpreted as target site preference. One of the control lines became highly unstable with mean insertion and excision rates of 3.0 x 10(-3) and 8.5 x 10(-4), respectively. Instability arose spontaneously during generations of mutation accumulation, and can be attributed to "de novo" mutation. Transposition in the unstable line could be directly studied on the progeny of individual males and females, from where we deduced that transposition occurs mainly, if not exclusively, in males, with a rate of 1.125 insertions per gamete. In situ hybridization with an LTR probe showed that most excisions (12 out of 14) were precise. Our data show the prominent role of genotype in transposition control and can explain rapid turnovers in the genome without increasing the number of copies.


One-year clinical outcome in an unselected patient population treated with the Genous™ endothelial progenitor cell capturing stent.
We assessed the 1-year clinical outcome in a large cohort of unselected patients treated with an endothelial progenitor cell (EPC) capturing coronary stent. The novel EPC capturing stent is coated with CD34+ antibodies that bind circulating EPCs to the stent surface, thereby accelerating endothelialization of the stent struts; it is hypothesized that this may prevent restenosis and stent thrombosis. A total of 405 unselected patients were treated percutaneously with the EPC capturing stent. The majority of patients had complex lesions with an estimated high risk of restenosis. The primary endpoint defined as the composite of cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR) at 1-year was 13.3%, mainly attributable to TLR which was 10.9%. The occurrence of definite and probable ST was low, 0.5 and 0.7%, respectively. Based on the risk of restenosis, in patients with an estimated high risk of restenosis (n = 249), the composite primary endpoint was 16.1% versus 9.0% in patients with an estimated low risk (n = 155). Moreover, the 1 year clinical outcomes in diabetic patient compared well with the nondiabetic patients. In this single-center study, the 1-year clinical follow-up in a "real-world" population treated with the EPC capturing stent showed good results. Currently, large randomized studies are conducted to evaluate the long-term safety and efficacy of this stent.


Previous appendicitis may affect peritoneal overlap of the mesh in laparoscopic inguinal hernia repair.
Laparoscopic inguinal hernia repair is now increasingly performed in bilateral and recurrent groin hernias. The avoidance of direct exposure of the commonly used meshes to the abdominal viscera is considered essential to reduce the risk of bowel adhesions. We report a case of bilateral inguinal hernia repair in a patients who had had an appendectomy performed 8 years earlier for a perforated appendicitis. Probably as a result of previous inflammation, any attempt to dissect the preperitoneal layer in the right side resulted in peritoneal lacerations. Since the peritoneum could not be used to cover the mesh, we decided to position an expanded polytetrafluoroethylene (e-PTFE) mesh to avoid postoperative adhesions. The mesh was fixed with tacks to the symphysis pubis, Cooper's ligament, the ilio-pubic tract, and the transversalis fascia 2 cm above the hernia defect. This case suggests that in patient with previous appendicitis, a difficult preperitoneal dissection can be expected. In such cases, especially in young patients for whom future surgical operations cannot be excluded, any attempt to reduce adhesions is justified. At the present time, the use of e-PTFE meshes, which induce no tissue reaction, is a good option in this situation.


Effects of pre-exercise sucrose ingestion on thermoregulatory responses to near-maximal 5-km running.
Research has shown that carbohydrate consumption can increase body temperature at rest and, in some cases, during exercise. Most exercise studies, however, haven't matched exercise intensity between carbohydrate and placebo conditions. The purpose of this randomized, double-blind, placebo-controlled trial was to examine whether pre-exercise carbohydrate consumption independently accelerates the usual temperature rise with intense exercise. Twenty-eight runners self-reported 5-km performance (16-23 min) and were randomized, using a matched-pairs design, to 750 ml water containing 100 g sucrose or 0.8 g aspartame. Beverages were consumed 60 min before running at 93% of maximum 5-km speed in temperate conditions. Gastrointestinal temperature, Thermal Sensation Scale (TSS) and Feeling Scale (FS) were recorded before ingestion, every 10 min during 60 min of rest, and every 1-km during the 5-km run. Rating of Perceived Exertion was recorded every 1-km. Independent samples t-tests and two-way mixed ANOVAs with repeated measures assessed whether there were baseline differences or treatment effects. Gastrointestinal temperature didn't differ between carbohydrate (38.7 ± 0.4 °C) and placebo (38.6 ± 0.4 °C) by the end of the 5-km (p = 0.49). No group x time interactions or main group effects were found, except for a modest interaction for TSS (F = 2.1, p = 0.02, partial η2 = 0.075). Time effects were found for all outcomes, with temperature, TSS, and RPE increasing, and FS decreasing, during the run. Ingesting 100 g of sucrose prior to intense running lasting < 25 min didn't influence gastrointestinal temperature and therefore doesn't likely impact on the risk of heat illness.


A Prospective Study of Fatty Liver Index and Incident Hypertension: The KoGES-ARIRANG Study.
Although non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. We investigated whether fatty liver disease, as assessed by the fatty liver index, could predict the development of hypertension independently of systemic insulin resistance, inflammatory status and adipokine levels. Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined. An equation was used to calculate fatty liver index and classify patients as follows: fatty liver index <30, no non-alcoholic fatty liver disease; fatty liver index ≥ 60, non-alcoholic fatty liver disease; and 30 ≤ fatty liver index <60, intermediate fatty liver index. During an average of 2.6 years of follow-up, 153 subjects (10.06%) developed hypertension. Fatty liver index was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein. After adjustment for confounding factors, including markers of insulin resistance, systemic inflammation and adiponectin levels, the odds ratio [95% confidence interval] for the incident hypertension increased in a graded manner with fatty liver index (<30 vs. 30-59 vs. ≥ 60 = 1 vs. 1.83 [1.16~2.88] vs. 2.09 [1.08~4.055], respectively). Non-alcoholic fatty liver disease assessed by fatty liver index was an independent risk factor for hypertension. Our findings suggest that fatty liver index, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice.


Suppression by interleukin 4 of activation of human blood monocytes to the tumoricidal state.
The effect of interleukin 4 (IL-4) on expression of antitumor activity of blood monocytes purified by counter-flow centrifugal elutriation from healthy donors was examined. The blood monocytes were incubated for 24 h in medium with lipopolysaccharide, interferon gamma (IFN-gamma) or desmethyl muramyl dipeptide (norMDP) or with IFN-gamma and norMDP in the presence of IL-4, and then their tumoricidal activity was assayed by measuring 125IUdR release from human melanoma (A375) cells. Irrespective of activation stimulus, addition of IL-4 to cultures of monocytes and activators resulted in dose-dependent suppression of the tumoricidal activity of monocytes against parent A375 melanoma cells and the variant cells, A375-R resistant to IL-1 and tumor necrosis factor alpha. IL-4 suppressed the early induction phase of monocyte activation. Rabbit anti-IL-4 antisera completely blocked the IL-4-mediated suppression of monocyte activation to the tumoricidal state. These findings suggest that IL-4 is important in vivo in down-regulation of anti-tumor expression of monocytes.


Hypomethylation of RPTOR in peripheral blood is associated with very early-stage lung cancer.
Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Novel biomarkers for LC detection are urgently needed. Here we aimed to investigate the association between RPTOR methylation in peripheral blood and LC. The methylation levels were measured by mass spectrometry in two independent case-control studies (159 LC cases vs. 188 controls in Study I, 413 LC cases vs. 687 controls in Study II). Logistic regression and Bonferroni correction were conducted to analyze the association. RPTOR hypomethylation was discovered in Study I and validated in Study II. Combining the two studies, RPTOR_CpG_2 and RPTOR_CpG_8 showed significantly lower methylation levels in stage I cases (ORs per -10% methylation = 1.22 and 1.27, respectively, both P-values < 0.005). The significance kept between RPTOR_CpG_8 and LC cases with tumor length ≤ 1 cm (OR per -10% methylation = 1.39, P = 0.001). Moreover, methylation levels of all CpG sites were lower in cases at stage II & III than in those at stage I (all P-values less than 0.017). Our study disclosed the association between RPTOR hypomethylation in peripheral blood and LC even in very early stage, suggesting the feasibility of blood-based DNA methylation for LC early detection.


Yield of endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography for solid pancreatic neoplasms.
Both endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) cytology may provide tissue diagnoses in solid pancreatic neoplasms. However, there are scant data comparing these two methods. This study aims at retrospectively comparing EUS-FNA and ERCP tissue sampling and ability of cytopathological diagnosis in solid pancreatic neoplasms and to determine usefulness and adverse events of combining both procedures. Two hundred and thirty four patients suspected to have solid pancreatic mass on abdominal ultrasound and/or computed tomography (CT) were enrolled. EUS-FNA (group A), ERCP cytology (group B) and combined procedures (Group C) performed in 105, 91 and 38 cases, respectively. Sensitivity, specificity and accuracy were 98.9%, 93.3% and 98.1% for group A, and 72.1%, 60% and 71.4% for group B. Those for group C were all 100%. Sensitivity for malignancy in the pancreas head was 100% for group A and 82.4% for group B, and in the pancreas body and tail, 97.6% for group A and 57.1% for group B. EUS-FNA was more sensitive than ERCP cytology in diagnosing malignant pancreatic neoplasms 21-30 mm in size (p = 0.0068), 31-40 mm (p = 0.028) and ≥ 41 mm (p < 0.0001). Sensitivity for pancreatic malignancy with group C was 100% regardless of mass location or size. Adverse events were 1.9%, 6.6% and 2.6% following EUS-FNA, ERCP and combined procedures, respectively. EUS-FNA is superior to ERCP cytology for diagnosis of solid pancreatic neoplasms. Although combination of both procedures provide efficient tissue diagnosis and with a minimal adverse events rate, a prospective study including larger number of patients is required.


A large-scale mass casualty simulation to develop the non-technical skills medical students require for collaborative teamwork.
There is little research on large-scale complex health care simulations designed to facilitate student learning of non-technical skills in a team-working environment. We evaluated the acceptability and effectiveness of a novel natural disaster simulation that enabled medical students to demonstrate their achievement of the non-technical skills of collaboration, negotiation and communication. In a mixed methods approach, survey data were available from 117 students and a thematic analysis undertaken of both student qualitative comments and tutor observer participation data. Ninety three per cent of students found the activity engaging for their learning. Three themes emerged from the qualitative data: the impact of fidelity on student learning, reflexivity on the importance of non-technical skills in clinical care, and opportunities for collaborative teamwork. Physical fidelity was sufficient for good levels of student engagement, as was sociological fidelity. We demonstrated the effectiveness of the simulation in allowing students to reflect upon and evidence their acquisition of skills in collaboration, negotiation and communication, as well as situational awareness and attending to their emotions. Students readily identified emerging learning opportunities though critical reflection. The scenarios challenged students to work together collaboratively to solve clinical problems, using a range of resources including interacting with clinical experts. A large class teaching activity, framed as a simulation of a natural disaster is an acceptable and effective activity for medical students to develop the non-technical skills of collaboration, negotiation and communication, which are essential to team working. The design could be of value in medical schools in disaster prone areas, including within low resource countries, and as a feasible intervention for learning the non-technical skills that are needed for patient safety.