Initial and late results of coronary angioplasty for early postinfarction unstable angina.
Unstable angina that occurs in the early postinfarction period is associated with an increased incidence of unfavorable cardiac events despite aggressive medical therapy. We examined the results of coronary angioplasty in 47 consecutive patients with postinfarction unstable angina who were referred for the procedure 12.9 +/- 7 days following myocardial infarction, 14 of which were Q wave and 33 of which were non-Q-wave. Coronary angioplasty was performed on a total of 55 arteries with a mean predilatation stenosis of 95 +/- 8%. These included 46 infarct-related arteries and nine noninfarct arteries. Double-vessel angioplasty was performed in eight patients. Successful coronary angioplasty (greater than 30% reduction of predilatation stenosis) was achieved in 43 patients (91%), with a mean residual stenosis of 33 +/- 28%. There was one in-hospital death, one patient required emergency bypass surgery, and two patients had early reocclusion resulting in myocardial infarctions. The 39 patients who had successful angioplasty procedures and who were discharged from the hospital without an unfavorable outcome were followed for 16.3 +/- 7 months, and repeat coronary angioplasty was required in five patients from 45 to 105 days after the initial procedure. Two patients had subsequent elective bypass surgery, one had a recurrent myocardial infarction, and one patient had a noncardiac death. For selected patients with suitable coronary anatomy, coronary angioplasty appears to offer an efficacious therapeutic option for early postinfarction unstable angina.


New developments in our knowledge of blood pressure regulation.
This paper reviews recent information about neural and humoral control of arterial blood pressure. Considerable evidence is accumulating in support of the concept that neural and humoral systems interact at both central and peripheral sites to modulate arterial pressure and to participate in the mechanisms of hypertension. The neural mechanisms reviewed include reflexes originating from sinoaortic receptors, and afferents arising from the kidney. Humoral agents discussed include angiotensin and vasopressin and the participation of their central and peripheral actions in the pathogenesis of hypertension.


Quantitative mutagenesis at the adenosine kinase locus in Chinese hamster ovary cells. Development and characteristics of the selection system.
Stable mutants exhibiting high degree of resistance (100-1000-fold) to various nucleoside analogs viz, toyocamycin, tubercidin, 6-methyl mercaptopurine riboside (6-MeMPR) and pyrazofurin, are obtained at similar frequency (congruent to 1 X 10(-4] in CHO cells. The mutants resistant to any of the above analogs exhibit similar degree of cross-resistance to the other three nucleoside analogs, and all of the mutants examined contained no measurable activity of the purine salvage pathway enzyme adenosine kinase (AK) which converts these analogs to their phosphorylated derivatives. These results indicate that very similar mutants are selected using any of these analogs. The recovery of AK- mutants in CHO cells is not affected by cell density (up to at least 5 X 10(5) cells per 100-mm diameter dish) and after treatment with mutagen(s) maximum mutagenic effect is observed after 7-8 days, which then remains unchanged for the next several days. Treatment of CHO cells with a number of mutagenic agents e.g. ethyl methanesulfonate, ICR170, ultraviolet light, and benzo[a]pyrene, led to a nearly linear concentration-dependent increase in the frequency of the AK- mutants in cultures. The mutagenic response of the AK locus to these agents compared favorably with that of the HGPRT locus (6-thioguanine resistance) within the same experiments. These results show that the selection system for AK- mutants provides an additional valuable genetic marker for quantitative mutagenesis studies in CHO cells.


Transethosomes of Econazole Nitrate for Transdermal Delivery: Development, In-vitro Characterization, and Ex-vivo Assessment.
Transdermal drug delivery is an attractive approach for both local and systemic therapeutics of various diseases. Transdermal drug delivery systems show various advantages like reduction of local irritation, prevention of first-pass hepatic metabolism, and bioavailability enhancement of bioactive molecules over conventional drug delivery systems. The main objective of the present research work was to develop and characterize (in-vitro and ex-vivo) econazole nitrate loaded transethosomes and their comparison with marketed cream of econazole nitrate [Ecoderm, Brown and Burk Pharmaceutical (Pvt.) Ltd., Bengaluru, India] for effective transdermal delivery. Transethosomes loaded with econazole nitrate were developed by homogenization method and evaluated for entrapment (%), vesicular size, zeta potential, polydispersity index (PDI), and invitro drug release. Furthermore, optimized econazole nitrate loaded transethosomes were added to Carbopol 934 gel and this gel was evaluated for viscosity, pH, drug content, ex-vivo skin permeation and retention studies followed by in-vitro antifungal activity against C. albicans fungus. The optimized transethosomes loaded with econazole nitrate showed vesicle size of 159.3 ± 4.3 nm, entrapment efficiency about 78.3 ± 2.8%, acceptable colloidal properties like (zeta potential = -27.13 ± 0.33 mV, PDI = 0.244 ± 0.045), approximately 57.56 ± 2.33% drug release up to 24 h. Results of DSC analysis confirmed the encapsulation of econazole nitrate inside transethosomes. Optimized transethosomes showed drug release following zero order through diffusion mechanism. Transethosomal gel showed high drug content (92.35 ± 0.63%) and acceptable values of pH (5.68 ± 0.86) or viscosity (10390 ± 111 cPs). Transethosomal gel showed less ex-vivo skin penetration (17.53 ± 1.20%), high ex-vivo skin retention (38.75 ± 2.88%), and high in-vitro antifungal activity compared to the marketed cream of econazole nitrate. Therefore, it can be concluded that econazole nitrate loaded transethosomes are effective to deliver econazole nitrate transdermally in a controlled fashion for effective elimination of cutaneous candidiasis.


Evaluation of dose prediction errors and optimization convergence errors of deliverable-based head-and-neck IMRT plans computed with a superposition/convolution dose algorithm.
The purpose of this study is to evaluate dose prediction errors (DPEs) and optimization convergence errors (OCEs) resulting from use of a superposition/convolution dose calculation algorithm in deliverable intensity-modulated radiation therapy (IMRT) optimization for head-and-neck (HN) patients. Thirteen HN IMRT patient plans were retrospectively reoptimized. The IMRT optimization was performed in three sequential steps: (1) fast optimization in which an initial nondeliverable IMRT solution was achieved and then converted to multileaf collimator (MLC) leaf sequences; (2) mixed deliverable optimization that used a Monte Carlo (MC) algorithm to account for the incident photon fluence modulation by the MLC, whereas a superposition/convolution (SC) dose calculation algorithm was utilized for the patient dose calculations; and (3) MC deliverable-based optimization in which both fluence and patient dose calculations were performed with a MC algorithm. DPEs of the mixed method were quantified by evaluating the differences between the mixed optimization SC dose result and a MC dose recalculation of the mixed optimization solution. OCEs of the mixed method were quantified by evaluating the differences between the MC recalculation of the mixed optimization solution and the final MC optimization solution. The results were analyzed through dose volume indices derived from the cumulative dose-volume histograms for selected anatomic structures. Statistical equivalence tests were used to determine the significance of the DPEs and the OCEs. Furthermore, a correlation analysis between DPEs and OCEs was performed. The evaluated DPEs were within +/- 2.8% while the OCEs were within 5.5%, indicating that OCEs can be clinically significant even when DPEs are clinically insignificant. The full MC-dose-based optimization reduced normal tissue dose by as much as 8.5% compared with the mixed-method optimization results. The DPEs and the OCEs in the targets had correlation coefficients greater than 0.71, and there was no correlation for the organs at risk. Because full MC-based optimization results in lower normal tissue doses, this method proves advantageous for HN IMRT optimization.


Higher prevalence of depressive symptoms in middle-aged men with low serum cholesterol levels.
Investigators from several studies have reported a positive relationship between low cholesterol levels and death due to violent causes (eg, suicide and accidents), possibly mediated by depressive symptoms, aggression or hostility, or impulsivity. We set out to establish whether middle-aged men with chronically low cholesterol levels (< or =4.5 mmol/liter) have a higher risk of having depressive symptoms, according to scores on the Beck Depression Inventory, compared with a reference group of men with cholesterol levels between 6 and 7 mmol/liter. A similar comparison was also made for measures of anger, hostility, and impulsivity. Cholesterol measurements were obtained as part of a population-based cholesterol screening study in 1990-1991. These levels were remeasured in 1993-1994. Only those whose cholesterol level remained in the same range were included in the study. Depressive symptoms were assessed by using the Beck Depression Inventory; anger, by questionnaires based on the Spielberger Anger Expression Scale and State-Trait Anger Scale; hostility, by the Buss-Durkee Hostility Inventory; and impulsivity, by the Eysenck and Eysenck Impulsivity Questionnaire. Men with chronically low cholesterol levels showed a consistently higher risk of having depressive symptoms (Beck Depression Inventory score > or =15 or > or =17) than the reference group, even after adjusting for age, energy intake, alcohol use, and presence of chronic diseases. No differences in anger, hostility, and impulsivity were observed between the two groups. Men with a lower cholesterol level (< or =4.5 mmol/liter) have a higher prevalence of depressive symptoms than those with a cholesterol level between 6 and 7 mmol/liter. These data may be important in the ongoing debate on the putative association between low cholesterol levels and violent death.


Therapeutic Role of Yoga in Type 2 Diabetes.
Yoga originated in India more than 5,000 years ago and is a means of balancing and harmonizing the body, mind, and emotions. Yoga practice is useful in the management of various lifestyle diseases, including type 2 diabetes. Psycho-neuro-endocrine and immune mechanisms are involved in the beneficial effects of yoga on diabetes. Incorporation of yoga practice in daily life helps to attain glycaemic control and reduces the risk of complications in people with diabetes. In this review, we briefly describe the role of various yoga practices in the management of diabetes based on evidence from various clinical studies.


Effects of oleanolic acid on acute liver injury triggered by lipopolysaccharide in broiler chickens.
1. Infectious injury caused by lipopolysaccharide (LPS), a metabolite of gram-negative bacteria, can induce stress responses in animals and is a significant cause of morbidity and mortality in young birds. The purpose of this study was to investigate the effects of dietary supplementation with oleanolic acid (OA) on acute liver injury in broiler chickens challenged with LPS.2. In total, 120 broiler chickens were randomly divided into six groups and fed a basal diet containing 0, 50, 100, or 200 mg/kg OA or 100 mg/kg aureomycin. On d 15, broiler chickens were injected with either LPS or an equivalent volume of normal saline. Six hours after LPS injection, two broiler chicks were randomly selected for sampling in each replicate.3. The results indicated that dietary aureomycin was ineffective in alleviating LSP-associated liver injury, but protected broiler chickens from LPS-induced liver damage. This promoted a significant reduction in the levels of malondialdehyde and an increase in the levels of superoxide dismutase in liver. In addition, OA was found to cause significant reductions in the relative expression of IL-1β, IL-6, and TNF-α in broiler liver tissues, whereas the relative expression of IL-10 was significantly increased.4. In conclusion, oleanolic acid can alleviate oxidative stress and injury in the livers of broiler chickens induced by lipopolysaccharide. Consequently, oleanolic acid has potential utility as a novel anti-inflammatory and antioxidant feed additive.


Investigation of two-layered turbid media with time-resolved reflectance.
Light propagation in two-layered turbid media that have an infinitely thick second layer is investigated with time-resolved reflectance. We used a solution of the diffusion equation for this geometry to show that it is possible to derive the absorption and the reduced scattering coefficients of both layers if the relative reflectance is measured in the time domain at two distances and if the thickness of the first layer is known. Solutions of the diffusion equation for semi-infinite and homogeneous turbid media are also applied to fit the reflectance from the two-layered turbid media in the time and the frequency domains. It is found that the absorption coefficient of the second layer can be more precisely derived for matched than for mismatched boundary conditions. In the frequency domain, its determination is further improved if phase and modulation data are used instead of phase and steady-state reflectance data. Measurements of the time-resolved reflectance were performed on solid two-layered tissue phantoms that confirmed the theoretical results.


Proenkephalin-processing enzymes in chromaffin granules: model for neuropeptide biosynthesis.
Our discovery of precursor preference of processing enzymes indicates possible development of future drugs that target specific proteases uniquely associated associated with processing of a particular prohormone. For example, selective processing of PE by the PTP suggests that future evaluation of modulation of PTP through central nervous system drug reagents may modify the endogenous analgesic effects of the enkephalins. With respect to blood pressure, neuropeptide Y (NPY) that is released from sympathetic nerve terminals is a strong vasoconstrictor. Our finding that only PTP (not PC1/3, PC2, or the aspartic proteinase) possesses the ability to convert pro-NPY to NPY suggests that investigation of inhibitors of peripheral PTP in blood pressure regulation should be initiated. Overall, elucidation of the proteolytic components required in prohormone processing will provide insights into the molecular mechanisms of human disease.


Galnon, a galanin receptor agonist, improves intrinsic cortical bone tissue properties but exacerbates bone loss in an ovariectomised rat model.
Previous studies have shown galanin (GAL) injections onto mouse calvaria increased bone thickness and osteoblast number. This study investigated the effects of the GAL receptor agonist galnon on bone loss using the ovariectomised (OVX) rat model. OVX rats were treated with either vehicle or galnon for 6 weeks via mini-osmotic pumps. Plasma osteocalcin concentrations, osseous cell gene expression, morphological and biomechanical properties of the skeleton were compared between the two groups. Treatment with galnon increased RANKL:OPG gene ratio (p<0.001) plus expression of TNF-α (p<0.05) and cathepsin K (p<0.05). μCT analyses revealed galnon-treated OVX animals had reduced trabecular and cortical morphology compared to control animals. Biomechanically, galnon OVX animals required similar peak force to failure to that of control OVX animals although galnon treatment did enhance the mechanical properties of Young's modulus and ultimate tensile stress. Our research suggests that galnon, a GAL receptor agonist, may enhance osteoclastic bone resorption in OVX rats. Although galnon reduced bone volume, biomechanical testing revealed that bone of galnon-treated animals was mechanically superior per unit area. Taken together, galnon simultaneously improves the intrinsic quality of cortical bone whilst stimulating osteoclastic activity in the OVX rat model.


The effects of blurring vision on medio-lateral balance during stepping up or down to a new level in the elderly.
Visual impairment is an important risk factor for falls, but relatively little is known about how it affects stair negotiation. The present study determined how medio-lateral (ML) dynamics of stepping and single limb support stability when stepping up or down to a new level were affected by blurring the vision of healthy elderly subjects. Twelve elderly subjects (72.3 +/- 4.2 years) were analysed performing single steps up and single steps down to a new level (7.2, 14.4 and 21.6 cm). Stepping dynamics were assessed by determining the ML ground reaction force (GRF) impulse, lateral position of the centre of mass (CM) relative to the supporting foot (average horizontal ML distance between CM and CP during single support) and movement time. Stability was determined as the rms fluctuation in ML position of the centre of pressure (CP) during single support. Differences between optimal and blurred visual conditions were analysed using a random effects model. Duration of double and single support, and the ML GRF impulse were significantly greater when vision was blurred, while the average CM-CP ML distance and ML stability was reduced. ML stability decreased with increasing step height and was further decreased when stepping down than when stepping up. These findings indicate that ML balance during stepping up and down was significantly affected by blurring vision. In particular, single limb support stability was considerably reduced, especially so during stepping down. The findings highlight the importance of accurate visual feedback in the precise control of stepping dynamics when stepping up or down to a new level, and suggest that correcting common visual problems, such as uncorrected refractive errors and cataract may be an important intervention strategy in improving how the elderly negotiate stairs.


Selective cephalic upregulation of p-ERK, CamKII and p-CREB in response to glyceryl trinitrate infusion.
Background A common characteristic of migraine-inducing substances is that they cause headache and no pain in other areas of the body. Few studies have compared pain mechanisms in the trigeminal and spinal systems and, so far, no major differences have been noted. We compared signalling molecules in the trigeminal and spinothalamic system after infusion of the migraine-provoking substance glyceryltrinitrate. Method A catheter was placed in the femoral vein of rats and one week later glyceryltrinitrate 4 µg/kg/min was infused for 20 min. Protein expression in the dura mater, trigeminal ganglion, nucleus caudalis, dorsal root ganglion and the dorsal horn of the thoracic spinal cord was analysed at different time points using western blotting and immunohistochemistry. Results Glyceryltrinitrate caused a threefold increase in expression of phosphorylated extracellular signal-regulated kinases at 30 min in the dura mater and nucleus caudalis ( P < 0.05) and at 2 h in the trigeminal ganglion with very few expressions in the dorsal root ganglion. In the nucleus caudalis, expression of phosphorylated extracellular signal-regulated kinases and Cam KII increased 2.6-fold and 3.2-fold, respectively, at 2 h after glycerytrinitrate infusion ( P < 0.01). p-CREB/ATF-1 upregulation was observed only at 30 min ( P < 0.05) in the nucleus caudalis. None of these markers showed increased expression in the regions of thoracic spinal cord dorsal horn. Conclusion The dura, trigeminal ganglion and nucleus caudalis are activated shortly after glycerytrinitrate infusion with long-lasting expression of phosphorylated extracellular signal-regulated kinases observed in the nucleus caudalis. These activations were not observed at the spinal level.


Conserved BK channel-protein interactions reveal signals relevant to cell death and survival.
The large-conductance Ca(2+)-activated K(+) (BK) channel and its β-subunit underlie tuning in non-mammalian sensory or hair cells, whereas in mammals its function is less clear. To gain insights into species differences and to reveal putative BK functions, we undertook a systems analysis of BK and BK-Associated Proteins (BKAPS) in the chicken cochlea and compared these results to other species. We identified 110 putative partners from cytoplasmic and membrane/cytoskeletal fractions, using a combination of coimmunoprecipitation, 2-D gel, and LC-MS/MS. Partners included 14-3-3γ, valosin-containing protein (VCP), stathmin (STMN), cortactin (CTTN), and prohibitin (PHB), of which 16 partners were verified by reciprocal coimmunoprecipitation. Bioinformatics revealed binary partners, the resultant interactome, subcellular localization, and cellular processes. The interactome contained 193 proteins involved in 190 binary interactions in subcellular compartments such as the ER, mitochondria, and nucleus. Comparisons with mice showed shared hub proteins that included N-methyl-D-aspartate receptor (NMDAR) and ATP-synthase. Ortholog analyses across six species revealed conserved interactions involving apoptosis, Ca(2+) binding, and trafficking, in chicks, mice, and humans. Functional studies using recombinant BK and RNAi in a heterologous expression system revealed that proteins important to cell death/survival, such as annexinA5, γ-actin, lamin, superoxide dismutase, and VCP, caused a decrease in BK expression. This revelation led to an examination of specific kinases and their effectors relevant to cell viability. Sequence analyses of the BK C-terminus across 10 species showed putative binding sites for 14-3-3, RAC-α serine/threonine-protein kinase 1 (Akt), glycogen synthase kinase-3β (GSK3β) and phosphoinositide-dependent kinase-1 (PDK1). Knockdown of 14-3-3 and Akt caused an increase in BK expression, whereas silencing of GSK3β and PDK1 had the opposite effect. This comparative systems approach suggests conservation in BK function across different species in addition to novel functions that may include the initiation of signals relevant to cell death/survival.


Long-term behavior of an arterial autograft: a new role for intimal hyperplasia?
The long-term behavior of an arterial autograft was studied with special attention to the evolution of intimal hyperplasia. An arterial autograft measuring approximately 5 mm in length was implanted in the right common iliac artery of female Sprague-Dawley rats. Animals were sacrificed at 90, 120, 150, 180, 240, 360, 400, 540 and 730 days after implantation. Grafts were evaluated by optical microscopy, electron microscopy, and morphometry. Myointimal cells were marked using an antiactin monoclonal antibody and studied by transmission electron microscopy. In the long term, the myointima of the arterial wall appeared as a consolidated layer formed by smooth muscle cells of contractile phenotype, abundant extracellular material consisting of clumps of elastin and collagen fibers. Cell maturity and degree of differentiation were demonstrated by the incorporation of antiactin antibody. The medial layer of the grafted segment suffered a marked long-term loss of cells and became an acellular layer sustained by the elastic layers. The adventitial layer was markedly cellular and had abundant vasa vasorum. Morphometry showed that the myointimal layer in the operated territory was not uniform and consisted of tongues of varying thickness. The total thickness of the arterial wall did not differ significantly (p > 0.05) between the graft and the proximal and distal areas. The results suggest that the intimal hyperplasia originating during the repair process could assume some functions of the degenerated medial layer, maintaining long-term vascular homeostasis.


Functional CD25(bright+) alloresponsive T cells in fully immunosuppressed renal allograft recipients.
Evidence from animal studies indicate a crucial role for CD25(bright+) regulatory T cells in transplantation tolerance. To assess whether peripheral CD25(bright+) T cells control immune responses in immunosuppressed kidney transplant patients, we analyzed the suppressive capacities of these cells using mixed lymphocytes reactions. Allogeneic stimulation of patients peripheral blood mononuclear cells was associated with IL-2 production and T-cell proliferation. Depletion of CD25(bright+) T cells resulted in a 35% (median) higher IL-2 production and a 38% higher proliferative response against third party cells, showing that functional regulatory CD25(bright+) T cells were present (p = 0.03 and 0.02 respectively). In eight out of 11 patients, we also demonstrated regulation activity against donor-activated T cells (p = 0.03). These data were confirmed in coculture experiments with isolated CD25(-/dim) T cells plus CD25(bright+) T cells. At a 1:2 ratio, the CD25(bright+) T cells suppressed the proliferation of CD25(-/dim) donor- and third party-stimulated responder T cells. CD25(bright+) T cells with immune regulatory activities against anti-donor-responsive T cells are readily detectable in renal allograft recipients during treatment with full dosage immunosuppression. Whether CD25(bright+) T cells indeed play a role in graft acceptance after organ transplantation in patients remains to be elucidated.


Engaging GPs in insulin therapy initiation: a qualitative study evaluating a support program in the Belgian context.
A program supporting the initiation of insulin therapy in primary care was introduced in Belgium, as part of a larger quality improvement project on diabetes care. This paper reports on a study exploring factors influencing the engagement of general practitioners (GPs) in insulin therapy initiation (research question 1) and exploring factors relevant for future program development (research question 2). We have used semi-structured interviews to answer the first research question: two focus group interviews with GPs who had at least one patient in the insulin initiation program and 20 one-to-one interviews with GPs who were not regular users of the overall support program in the region. To explore factors relevant for future program development, the data from the GPs were triangulated with data obtained from individual interviews with patients (n = 10), the diabetes nurse educator (DNE) and the specialist involved in the program, and data extracted from meeting reports evaluating the insulin initiation support program. We found differences between GPs engaged and those not engaged in insulin initiation in attitude, subjective norm and perceived behavioural control regarding insulin initiation. In general the support program was evaluated in a positive way by users of the program. Some aspects need further consideration: job boundaries between the DNE and GPs, job boundaries between GPs and specialists, protocol adherence and limited case load. The study shows that the transition of insulin initiation from secondary care to the primary care setting is a challenge. Although a support program addressing known barriers to insulin initiation was provided, a substantial number of GPs were reluctant to engage in this aspect of care. Important issues for future program development are: an interdisciplinary approach to job clarification, a dynamic approach to the integration of expertise in primary care and feedback on protocol adherence. ClinicalTrials.gov Identifier: NCT00824499.


Split-face double-blind study comparing the onset of action of onabotulinumtoxinA and abobotulinumtoxinA.
To report and discuss the outcome of a prospective, internally controlled, randomized, double-blind, split-face study comparing the onset of action of 2 commercially available botulinum neuromodulators. Ninety individuals with moderate-to-severe lateral orbital rhytids were treated with onabotulinumtoxinA, 10 U, and abobotulinumtoxinA, 30 U, for the treatment of lateral orbital rhytids. Participants were assessed live with a validated 5-point photographic scale before treatment and on days 2, 4, and 6 after treatment. Photographs were taken at each encounter. Statistical analysis was applied to evaluate for any significant difference in onset of action between the 2 products. AbobotulinumtoxinA and onabotulinumtoxinA demonstrated statistically significant change from baseline at day 2 in the treatment of lateral orbital rhytids at maximal contraction and rest when evaluated independently by investigator and participant (P.001). Also at day 2, the improvement with abobotulinumtoxinA was better than that with onabotulinumtoxinA for the primary end point of maximal contraction graded by the investigator, although this did not reach statistical significance (P=.21); by day 4, the greater improvement achieved with abobotulinumtoxinA reached statistical significance (P=.02) and remained superior at day 6 (P=.02). The primary findings were strengthened by similar results in the secondary end points of patient self-grade at maximal contraction and at rest and of investigator grade at rest. In conclusion, both abobotulinumtoxinA and onabotulinumtoxinA achieved statistically significant onset of action at day 2. This improvement was seen in all end points, with abobotulinumtoxinA demonstrating a trend toward greater improvement than onabotulinumtoxinA at day 2 and a statistically significant greater improvement at days 4 and 6 when looking at maximal contraction.


Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice.
The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.


Nanoscale depth control of implanted shallow silicon vacancies in silicon carbide.
Color centers in silicon carbide have recently attracted broad interest as high bright single photon sources and defect spins with long coherence time at room temperature. There have been several methods to generate silicon vacancy defects with excellent spin properties in silicon carbide, such as electron irradiation and ion implantation. However, little is known about the depth distribution and nanoscale depth control of the shallow defects. Here, a method is presented to precisely control the depths of the ion implantation induced shallow silicon vacancy defects in silicon carbide by using reactive ion etching with little surface damage. After optimizing the major etching parameters, a slow and stable etching rate of about 5.5 ± 0.5 nm min-1 can be obtained. By successive nanoscale plasma etching, the shallow defects are brought close to the surface step by step. The photoluminescence spectrum and optically detected magnetic resonance spectra are measured, which confirm that there were no plasma-induced optical and spin property changes of the defects. By tracing the mean counts of the remaining defects after each etching process, the depth distribution of the defects can be obtained for various implantation conditions. Moreover, the spin coherence time T2* of the generated VSi defects is detected at different etch depths, which greatly decreases when the depth is less than 25 nm. The method of nanoscale depth control of silicon vacancies would pave the way for investigating the surface spin properties and the applications in nanoscale sensing and quantum photonics.


[Relation between Parkinson disease and dementia conditions studied with proton NMR imaging parameters].
The value of the spin lattice relaxation time (T1) obtained during nuclear magnetic resonance imaging of the brain in patients with Idiopathic Parkinson's disease with and without dementia is studied. T1 increases significantly in the basal ganglia and cerebral white matter of the demented and nondemented groups. T1 of the cerebral white matter correlates with the severity of dementia.


Radio-imaging for quantitative autoradiography in biology.
We present here an overview of new in vitro and ex vivo radio-imaging systems developed to overcome the limitations of films and emulsions currently used in histological autoradiography experiments. The shortcomings of films for quantitative studies are first introduced. Principles and performances of each family of imagers are discussed and illustrated in various biological contexts. Finally, perspectives of development including nonradioactive labeling techniques are briefly presented.


Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway.
Monocyte-endothelial adhesion plays an important role in monocyte trafficking and hence is important for immune responses and pathogenesis of inflammatory diseases including atherosclerosis. The cross-talk between different integrins on monocytes may be crucial for a coordinated regulation of the cellular adhesion during the complex process of transendothelial migration. By using monoclonal antibodies and recombinant intercellular adhesion molecule 1 (ICAM-1) to engage lymphocyte function-associated antigen 1 (LFA-1) on monocytic cells, we found that the cellular adhesion to vascular cell adhesion molecule 1 (VCAM-1) mediated by very late antigen 4 (VLA-4) was suppressed after this treatment and the suppression depended on the presence of reactive oxygen species (ROSs). Inhibition of production of ROSs through the use of inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, but not inhibitors of mitochondrial electron transport chain or xanthine oxidase, revealed that this suppression on VLA-4-mediated cellular binding was mediated by ROSs produced by phagocyte NADPH oxidase. Activation of phosphoinositol-3 kinase and Akt appears to mediate this NADPH oxidase activation through p47phox phosphorylation and Rac-1 activation. Our results provide a novel pathway in which ROSs play a critical role in integrin cross-talk in monocytes. This signaling pathway may be important for cellular transition from firm arrest to diapedesis during monocyte trafficking.


Ironing-out mechanisms of neuronal injury under hypoxic-ischemic conditions and potential role of iron chelators as neuroprotective agents.
Iron is the most abundant transition metal in the brain, where it functions as an important cofactor in a host of vital metabolic processes and plays an absolutely essential role in cell viability. Free iron is also very toxic when present in high concentrations, thus placing this essential metal at the core of neurotoxic injury in a number of neurological disorders. The pivotal role of iron in cellular homeostasis, including its latent toxicity, necessitates a tight regulation of iron metabolism. Oxygen and iron appear to play an important role in iron homeostasis. They appear to exert their homeostatic role by modulating the proteins involved in a complex interplay between iron sensing, transport, and storage. These key regulatory proteins include ferritin (intracellular storage), transferrin (extracellular transport), transferrin receptor, and iron regulatory protein (sensor of intracellular iron concentration). The interplay of iron and oxygen is most intriguing in the setting of stroke, where hypoxia and free iron appear to interact in causing the subsequent neuronal death.


ACEI/ARB Medication During ICU Stay Decrease All-Cause In-hospital Mortality in Critically Ill Patients With Hypertension: A Retrospective Cohort Study Based on Machine Learning.
Background: Hypertension is a rather common comorbidity among critically ill patients and hospital mortality might be higher among critically ill patients with hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg). This study aimed to explore the association between ACEI/ARB medication during ICU stay and all-cause in-hospital mortality in these patients. Methods: A retrospective cohort study was conducted based on data from Medical Information Mart for Intensive Care IV (MIMIC-IV) database, which consisted of more than 40,000 patients in ICU between 2008 and 2019 at Beth Israel Deaconess Medical Center. Adults diagnosed with hypertension on admission and those had high blood pressure (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) during ICU stay were included. The primary outcome was all-cause in-hospital mortality. Patients were divided into ACEI/ARB treated and non-treated group during ICU stay. Propensity score matching (PSM) was used to adjust potential confounders. Nine machine learning models were developed and validated based on 37 clinical and laboratory features of all patients. The model with the best performance was selected based on area under the receiver operating characteristic curve (AUC) followed by 5-fold cross-validation. After hyperparameter optimization using Grid and random hyperparameter search, a final LightGBM model was developed, and Shapley Additive exPlanations (SHAP) values were calculated to evaluate feature importance of each feature. The features closely associated with hospital mortality were presented as significant features. Results: A total of 15,352 patients were enrolled in this study, among whom 5,193 (33.8%) patients were treated with ACEI/ARB. A significantly lower all-cause in-hospital mortality was observed among patients treated with ACEI/ARB (3.9 vs. 12.7%) as well as a lower 28-day mortality (3.6 vs. 12.2%). The outcome remained consistent after propensity score matching. Among nine machine learning models, the LightGBM model had the highest AUC = 0.9935. The SHAP plot was employed to make the model interpretable based on LightGBM model after hyperparameter optimization, showing that ACEI/ARB use was among the top five significant features, which were associated with hospital mortality. Conclusions: The use of ACEI/ARB in critically ill patients with hypertension during ICU stay is related to lower all-cause in-hospital mortality, which was independently associated with increased survival in a large and heterogeneous cohort of critically ill hypertensive patients with or without kidney dysfunction.


Double cross-linked supramolecular hydrogels with tunable properties based on host-guest interactions.
We report a novel double cross-linked hydrogel system based on polyacrylamide and poly(2-methyl-2-oxazoline) (PMOXA) network chains, as well as on supramolecular host-guest interactions with on-demand tailored mechanical properties. Well-defined vinyl-bearing PMOXA macromonomers, functionalized with either β-cyclodextrin units (β-CD-PMOXA) or adamantane units (Ada-PMOXA), were synthesized and confirmed using 1H NMR, MALDI-TOF-MS and GPC measurements. The complexation between adamantane and β-CD modified macromonomers in solution towards bismacromonomers was confirmed by 2D NOESY NMR and DLS. After introducing these bismacromonomers into the polyacrylamide hydrogel, the supramolecular non-covalent Ada/β-CD bond was responsible for the presence of PMOXA network chains to form a dense network. Once the interactions broke, the PMOXA chains no longer contributed to the network, but became dangling graft side chains in a predominated polyacrylamide network. Their dissociative nature influenced the physical properties, including the swelling behavior and mechanics of the final hydrogel. Rheological experiments proved that the E-modulus of the network was significantly increased by the supramolecular host-guest interactions. Tuning the lengths of PMOXA network chains even allowed the modification of the changes in mechanical strength, also through the addition of free β-CD. The tunable properties of the double cross-linked supramolecular hydrogel proved their unique strength for future applications.


Intraosseous infusions: an important but forgotten method of vascular access.
Patients with malignancies or other prolonged illnesses such as acquired immune deficiency syndrome, require long-term vascular access. Unfortunately, currently available technologies which access the vascular system, such as intravenous catheters (external or implanted ports), have frequent complications including clotting and infection which limit their long-term usefulness. An important but forgotten method to access the central venous system is through the intraosseous route. This review summarizes past experience with the intraosseous route of access to the central venous system as well as describes a new device which might eventually make intraosseous access more convenient for the patient. It is anticipated this forgotten method of vascular access will be used more frequently in patients who have exhausted conventional venous access systems.


Acute inflammation induces hyporetinemia and modifies the plasma and tissue response to vitamin A supplementation in marginally vitamin A-deficient rats.
Plasma retinol is reduced during numerous infections, and inflammation alters the hepatic synthesis of retinol-binding protein (RBP). In this study, we have investigated the effects of endotoxin-induced inflammation on vitamin A (VA) supplementation in a rat model of marginal VA deficiency. Marginally VA-deficient rats received an intraperitoneal dose of lipopolysaccharide (LPS, n = 14) or saline (n = 10); 6 h later, six LPS + VA and six saline + VA rats received 7.1 micromol VA orally. Twenty-four hours after endotoxin administration, rats with inflammation (LPS) had lower plasma retinol, RBP, and hepatic RBP than saline rats (37, 31 and 44%, respectively, P < 0.05). Inflammation did not affect VA concentrations in liver and perirenal adipose tissue, although kidney VA was reduced relative to saline rats. However, urinary VA was not detected. Eighteen hours after VA supplementation, inflammation reduced the plasma unesterified retinol response (P < 0. 05) in LPS + VA relative to saline + VA rats, although total VA increased as a result of the presence of retinyl esters in LPS + VA rats. Hepatic esterified retinol concentration was reduced (P < 0. 01) in LPS + VA compared with saline + VA rats; however, hepatic unesterified retinol did not differ. Renal total retinol increased in VA-supplemented rats, but urinary retinol excretion, when observed, was low, independently of inflammation. These findings indicate that inflammation-induced hyporetinemia does not necessarily imply a loss of VA, but rather represents a redistribution of tissue VA brought about by a reduced hepatic synthesis of RBP. Practical implications from these collective results are to recommend the determination of both unesterified and esterified retinol to fully assess the plasma response to VA supplementation and to caution the use of VA assessment methodologies that depend on the hepatic synthesis of RBP during acute inflammation.


Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.
Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.


[Prevalence of sexually transmitted infections and associated risk factors among female commercial sex workers in Cuautla, Morelos].
To determine the prevalence of sexually transmitted infections (STI) among female commercial sex workers in Cuautla, Morelos, Mexico. A cross-sectional survey was conducted in 1998, in the red-light district of Cuautla, Morelos, Mexico. It included 100 female commercial sex workers who labored permanently in bars and night clubs. Data were collected using two questionnaires, one on socio-demographic characteristics, and the other on commercial sex, risk perception, and knowledge on preventive measures and contagion of sexually transmitted diseases/AIDS. Blood and cervicovaginal specimens were also collected to assess the prevalence of sexually transmitted and reproductive system infections (RSI). Outcome variables were STI (syphilis and chlamydiasis) and RSI (vaginosis and candidiasis). Sexually transmitted prevalence was of 11%, reproductive system infections prevalence was of 39%. When candidiasis was included in the sexually transmitted infections group, prevalence was of 31%. The main factors associated with sexually transmitted infections were: who instructed on condom use, time having intercourse with partner, and years of commercial sex work. Factors related to reproductive system infections were: illiteracy, use of condom with partner, who instructed on condom use, and years of commercial sex work. Multivariate analysis showed an increased likelihood of acquiring a sexually transmitted infection and/or reproductive system infection with illiteracy, instruction on condom use by a person other than a healthcare worker, and lack of condom use. Regular use of condoms during intercourse is the most important preventive measure to avoid and control STI and RSI. Study findings pinpoint spatial and temporal factors that contribute to infection. Intervention measures directed at these factors should strengthen preventive and educational programs to improve medical care for these infections.


A reliable radiographic measurement technique for extra-articular scapular fractures.
Currently, neither well-defined nor standardized measurement techniques exist for assessing deformity of extra-articular scapular fractures. To properly evaluate these injuries, compare observations across studies, and make clinical decisions, a validated measurement protocol for evaluating scapular fractures is needed. We describe techniques to quantitatively characterize extra-articular scapular fracture deformity; evaluate the reliability of these characterizations in plain film radiographs and CT scans; and determine potential differences in the characterization of the deformity between the two imaging modalities. We evaluated injury radiographs and three-dimensional CT images of 45 patients with extra-articular scapular fracture. Techniques for measuring medial/lateral displacement, angulation, translation, glenopolar angle, and glenoid version were established and utilized in two trials, performed 6 weeks apart, by three observers. We determined descriptive statistics for each measurement parameter. Interobserver reliability based upon interclass correlation coefficients ranged from 0.36 to 0.76 for radiographs and from 0.48 to 0.87 for three-dimensional CT. Intraobserver reliability using Pearson r coefficient ranged from 0.60 to 0.75 for radiographs and 0.64 to 0.89 for three-dimensional CT. Both individual and pooled measurements for angulation and glenopolar angle were higher on three-dimensional CT versus radiographs. Our data suggest three-dimensional CT is more reliable than plain radiography in the assessment of scapula fracture displacement. Therefore, we believe this modality should be utilized if fracture deformity warrants surgical consideration and to adequately compare data across studies. Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.


Androgen levels in women using Norplant implants.
Plasma concentrations of sex hormone binding globulin (SHBG), testosterone, free testosterone, androstenedione (A4) and levonorgestrel were studied in 17 women before and during use of two levonorgestrel covered rods resulting in identical plasma concentrations of levonorgestrel as Norplant implants. There was a highly significant decrease in SHBG during treatment. Total testosterone and A4 also decreased significantly. Free testosterone remained unchanged. Diurnal variations were found to occur for A4, total and free testosterone, but not for SHBG or levonorgestrel. Moreover, plasma concentrations of testosterone, free testosterone, levonorgestrel and SHBG were measured in a second group of 88 women participating in a clinical study on Norplant implants, who at the one year follow-up visit either denied or claimed to have developed increased facial acne during treatment. There was no difference regarding SHBG, total testosterone, free testosterone or levonorgestrel between the groups of women with and without facial acne. However, the women in the group noticing increased acne during treatment, reported significantly more often to have had acne before treatment compared to the women who did not notice increased acne during treatment. It is concluded that treatment with Norplant implants does not result in increasing plasma levels of androgens.


Stressing-out DNA? The contribution of serine-phosphodiester interactions in catalysis by uracil DNA glycosylase.
The DNA repair enzyme uracil DNA glycosylase (UDG) pinches the phosphodiester backbone of damaged DNA using the hydroxyl side chains of a conserved trio of serine residues, resulting in flipping of the deoxyuridine from the DNA helix into the enzyme active site. We have investigated the energetic role of these serine-phosphodiester interactions using the complementary approaches of crystallography, directed mutagenesis, and stereospecific phosphorothioate substitutions. A new crystal structure of UDG bound to 5'-HO-dUAAp-3' (which lacks the 5' phosphodiester group that interacts with the Ser88 pinching finger) shows that the glycosidic bond of dU has been cleaved, and that the enzyme has undergone the same specific clamping motion that brings key active site groups into position as previously observed in the structures of human UDG bound to large duplex DNA substrates. From this structure, it may be concluded that glycosidic bond cleavage and the induced fit conformational change in UDG can occur without the 5' pinching interaction. The S88A, S189A, and S192G "pinching" mutations exhibit 360-, 80-, and 21-fold damaging effects on k(cat)/K(m), respectively, while the S88A/S189A double mutant exhibits an 8200-fold damaging effect. A free energy analysis of the combined effects of nonbridging phosphorothioate substitution and mutation at these positions reveals the presence of a modest amount of strain energy between the compressed 5' and 3' phosphodiester groups flanking the bound uridine. Overall, these results indicate a role for these serine-phosphodiester interactions in uracil flipping and preorganization of the sugar ring into a reactive conformation. However, in contrast to a recent proposal [Parikh, S. S., et al. (2000) Proc Natl. Acad. Sci. 94, 5083], there is no evidence that conformational strain of the glycosidic bond induced by serine pinching plays a major role in the 10(12)-fold rate enhancement brought about by UDG.


Assessing calibration of prognostic risk scores.
Current methods used to assess calibration are limited, particularly in the assessment of prognostic models. Methods for testing and visualizing calibration (e.g. the Hosmer-Lemeshow test and calibration slope) have been well thought out in the binary regression setting. However, extension of these methods to Cox models is less well known and could be improved. We describe a model-based framework for the assessment of calibration in the binary setting that provides natural extensions to the survival data setting. We show that Poisson regression models can be used to easily assess calibration in prognostic models. In addition, we show that a calibration test suggested for use in survival data has poor performance. Finally, we apply these methods to the problem of external validation of a risk score developed for the general population when assessed in a special patient population (i.e. patients with particular comorbidities, such as rheumatoid arthritis).


Monitoring pharmacotherapy response, safety, and tolerability to enhance adherence in bipolar disorder.
Among patients with bipolar disorder, treatment nonadherence can be triggered by lack of response or by medication-induced adverse effects. To track treatment response, clinicians can have patients complete daily life and mood charts to provide accurate information over time on patients' mood, adherence, side effects, and life events. Rating scales like the CGI-BP are also an option for assessing treatment response. In addition, clinicians should monitor patients for common side effects related to bipolar depression treatments, such as sedation and weight gain/metabolic abnormalities, which lead to increased medical problems and shortened life expectancy. By implementing specific interventions to address these effects, clinicians can help promote optimal outcomes for patients with bipolar disorder.


Comparison of Meglumine Antimoniate and Miltefosine in Cutaneous Leishmaniasis.
To compare the efficacy and safety of meglumine antimoniate and miltefosine in the treatment of cutaneous leishmaniasis in Pakistan. Randomised-controlled trial. Place and Duration of the Study: Department of Dermatology, Combined Military Hospital, Lahore and Peshawar, from January to December 2021. Smear positive and/or skin biopsy-confirmed cases of cutaneous leishmaniasis in adult males aged between 18-60 years were enrolled after receiving informed consent. Patients were randomly divided into Group A and Group B by lottery method. Group A received intramuscular meglumine antimoniate 15-20mg/kg/day, and Group B received oral miltefosine 50 mg thrice a day for a duration of 28 days. Data were analysed by SPSS 22. Effectiveness and safety of therapeutic agents were calculated by Independent t-test and p-value of 0.05 or less was taken as significant. Sixty-six patients, 33 in each group, participated in the study. Total number of cutaneous leishmaniasis lesions were 77 in Group A and 76 in Group B. The duration of lesions was 3.5 months in Group A and 3.2 months in Group B. Treatment response, in terms of complete or near complete resolution of lesions, was significantly higher in Group A as compared to Group B (p = 0.011). Both therapeutic agents had considerable side-effects with more patients withdrawn from Group A as compared to Group B (p = 0.010). Intra-muscular meglumine antimoniate was more effective in comparison to oral miltefosine in the treatment of cutaneous leishmaniasis. However, efficacy of meglumine antimoniate is mired by its side-effect profile. Cutaneous leishmaniasis, Meglumine antimoniate, Miltefosine, Efficacy, Side-effects, Adverse effects, Safety, Treatment, Old world cutaneous leishmaniasis.


[Vigilance of veterinary medicinal products: Reports of adverse reactions in the year 2014].
During the year 2014, a total of 268 adverse reactions due to Swissmedic-authorized veterinary medicinal products were reported representing an increase of 7% compared to the previous year. Similar to previous years, most of the reactions reported were linked to the use of antiparasitic products (47.8%) or antiinfectives (9.3%). In 10.8% of the reports, reactions were described after the use of products acting on the hormonal system. The affected animal species were primarily dogs (182 reports), cats (58 reports), and cattle (16 reports). Additionally, 33 reports were provided within the frame of consultations with the toxicological information centre in Zurich (Tox Info Suisse). We present a short overview of the safety of COX-2 inhibitors and a series of reactions following the use of a parenteral buprenorphine solution. Finally, the vaccinovigilance program received 124 declarations following the application of various vaccines, but no detailed analysis of those reports is available.


The effect of altruistic tendency on fairness in third-party punishment.
Third-party punishment, as an altruistic behavior, was found to relate to inequity aversion in previous research. Previous researchers have found that altruistic tendencies, as an individual difference, can affect resource division. Here, using the event-related potential (ERP) technique and a third-party punishment of dictator game paradigm, we explored third-party punishments in high and low altruists and recorded their EEG data. Behavioral results showed high altruists (vs. low altruists) were more likely to punish the dictators in unfair offers. ERP results revealed that patterns of medial frontal negativity (MFN) were modulated by unfairness. For high altruists, high unfair offers (90:10) elicited a larger MFN than medium unfair offers (70:30) and fair offers (50:50). By contrast, for low altruists, fair offers elicited larger MFN while high unfair offers caused the minimal MFN. It is suggested that the altruistic tendency effect influences fairness consideration in the early stage of evaluation. Moreover, the results provide further neuroscience evidence for inequity aversion.


Effects of adjunct testosterone on cardiac morphology and function in advanced cancers: an ancillary analysis of a randomized controlled trial.
Adjunct testosterone therapy improves lean body mass, quality of life, and physical activity in patients with advanced cancers; however, the effects of testosterone on cardiac morphology and function are unknown. Accordingly, as an ancillary analysis of a randomized, placebo-controlled trial investigating the efficacy of testosterone supplementation on body composition in men and women with advanced cancers, we explored whether testosterone supplementation could prevent or reverse left ventricular (LV) atrophy and dysfunction. Men and women recently diagnosed with late stage (≥IIB) or recurrent head and neck or cervical cancer who were scheduled to receive standard of care chemotherapy or concurrent chemoradiation were administered an adjunct 7 week treatment of weekly intramuscular injections of either 100 mg testosterone (T, n = 1 M/5F) or placebo (P, n = 6 M/4F) in a double-blinded randomized fashion. LV morphology (wall thickness), systolic function (ejection fraction, EF), diastolic function (E/A; E'/E), arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were assessed. No significant differences were observed in LV posterior wall thickness in placebo (pre: 1.10 ± 0.1 cm; post: 1.16 ± 0.2 cm; p = 0.11) or testosterone groups (pre: 0.99 ± 0.1 cm; post: 1.14 ± 0.20 cm; p = 0.22). Compared with placebo, testosterone significantly improved LVEF (placebo: - 1.8 ± 4.3%; testosterone: + 6.2 ± 4.3%; p < 0.05), Ea (placebo: 0.0 ± 0.2 mmHg/mL; testosterone: - 0.3 ± 0.2 mmHg/mL; p < 0.05), and Ea/Ees (placebo: 0.0 ± 0.1; testosterone: - 0.2 ± 0.1; p < 0.05). In patients with advanced cancers, testosterone was associated with favorable changes in left ventricular systolic function, arterial elastance, and ventricular-arterial coupling. Given the small sample size, the promising multisystem benefits of testosterone warrants further evaluation in a definitive randomized trial. This study was prospectively registered on ClinicalTrials.gov (NCT00878995; date of registration: April 9, 2009).


Effects of acute alcohol ingestion on eye movements and cognition: A double-blind, placebo-controlled study.
Alcohol is one of the most consumed psychoactive substances in the world, and the negative impact related to alcohol use has become a worldwide public health issue. Alcohol is able to affect diffusely several areas of the Central Nervous System, which could impair visual functions, including eye movements, and cognitive processes. The objective of the present study was to investigate the effects of moderate alcohol intake in eyes movements, as an indicator of cognitive processing underlying the visual search in a the Maze task. We investigated the concentration of 0.08% blood alcohol concentration (BAC), using an intra-subject, double-blind, and placebo-controlled experimental design with a sample size of 20 young adults (11 men and nine women). All volunteers participated in both conditions, i.e., alcohol (0.08%) and placebo (0.00%), in a counterbalanced order. We use the Tobii TX300 eye tracker to evaluate eye movements during completion of Visual Maze Test. The results showed significant differences in the following eye movement patterns: the first fixation latency, number and duration of fixations (mean and total), the number and duration of saccades (mean and total), and the total execution time in the test. In addition, we investigate the areas of interest (AOI), decision points in which the participant must decide which course to follow. We verified that the participants in the alcohol condition had a significantly greater number of fixations in both AOI, in comparison to the placebo condition. Overall, our findings confirm that moderate doses of alcohol can change the eye movements of young adults. These alterations may evidence the influence of alcohol in cognitive processes, such as flexibility, attention, and planning, which are required during resolution of Maze Task.


Relationship between hunger-satiety feelings and various metabolic parameters in women with obesity during controlled weight loss.
Satiety plays an important role in weight control. The meaning of fasting hormone levels and satiety feelings, and how post-absorptive changes after meals high in carbohydrate regulate appetite remains to be demonstrated. Prospective metabolic study with 25 non-diabetic obese women at the Energy Metabolism Research Unit of the Department of Nutrition Sciences, University of Alabama at Birmingham. We analyzed fasting and postprandial ratings of hunger-satiety and values of various metabolic parameters (serum glucose and insulin, plasma cholecystokinin, respiratory quotient) during controlled weight loss. The postprandial measures were assessed following a test meal providing 320 kcal and yielding a food quotient of 0.89. In the fasting state, there was no correlation between hunger-satiety ratings and any of the measured metabolic parameters. Under postprandial conditions, satiety was positively related to glucose (p=0.002) and insulin (p=0.002) responses to the test meal. In multivariate analysis including glucose, insulin, cholecystokinin, hunger-satiety ratings and respiratory quotient, insulin was the only independent predictor of satiety in the postprandial state. These data suggest an association between the endogenous insulin response and feelings of postprandial satiety. Insulin's satiation properties, which could well be mediated by other hormones, may represent a primary factor of food intake regulation after meals relatively high in carbohydrate.


How useful is the concept of somatization in cross-cultural studies of maternal depression? A contribution from the Mothers in a New Country (MINC) study.
Somatization of depression symptoms has been assumed to characterize particular cultural groups, yet evidence for this has often been anecdotal. The Mothers in a New Country (MINC) study aimed to explore cultural assumptions about somatization in three groups of immigrant women who had recently given birth in Melbourne, Australia. Physical health (SF-36 physical health dimensions and a symptom list) and depression (EPDS, SF-36 mental health dimension and self assessment) data from personal interviews with Vietnamese (n = 104), Turkish (n = 107) and Filipino (n = 107) women, conducted in women's language of choice, six to nine months after childbirth were analyzed. Comparisons with data from a statewide postal survey of Victorian women are also made. Contrary to the study hypothesis that Turkish and Vietnamese women in particular would exhibit a high degree of somatization (leading to low depression scores on the standard measures and greater reporting of somatic symptoms), Turkish women were in fact most likely of the three groups to be assessed as depressed on the two psychological measures and by self-assessment, to report high levels of somatic symptoms, and Vietnamese and Filipino women had a low prevalence of depression on all measures and relatively lower levels of somatic symptom reporting. The MINC study findings thus call into question some common cultural assumptions about depression and demonstrate the importance of designing studies which can put hypothesized cultural differences to the test.


Current regenerative periodontal therapy.
Healing, after subgingival curettage, leads to the formation of a long junctional epithelium. This is a repair process and not one of regeneration. Flap procedures of themselves also seem to lead to the formation of a long junctional epithelium, notwithstanding some evidence of bone repair. Bone grafts favour osseus repair without creating new attachment, for the previous architecture and function of the tissues is not restored. Recently, use of porous hydroxyapatite implants in block or granular form has led to pocket depth reduction and attachment gain. Conditioning of the root surface, after planing, with citric acid, attachment proteins or tetracycline has been widely investigated. The use of citric acid has not led to significant periodontal regeneration but the local use of slow-release tetracycline may prove to be of value. Guided regeneration aims to re-populate the root surface with active periodontal ligament cells. In recent experiments substantial reductions in pocket depth have been achieved.


Preadmission beta-blocker use and 30-day mortality among patients in intensive care: a cohort study.
Beta-blockers have cardioprotective, metabolic and immunomodulating effects that may be beneficial to patients in intensive care. We examined the association between preadmission beta-blocker use and 30-day mortality following intensive care. We identified 8,087 patients over age 45 admitted to one of three multidisciplinary intensive care units (ICUs) between 1999 and 2005. Data on the use of beta-blockers and medications, diagnosis, comorbidities, surgery, markers of socioeconomic status, laboratory tests upon ICU admission, and complete follow-up for mortality were obtained from medical databases. We computed probability of death within 30 days following ICU admission for beta-blocker users and non-users, and the odds ratio (OR) of death as a measure of relative risk using conditional logistic regression and also did a propensity score-matched analysis. Inclusion of all 8,087 ICU patients in a logistic regression analysis yielded an adjusted OR of 0.82 (95% confidence interval (CI): 0.71 to 0.94) for beta-blocker users compared with non-users. In the propensity score-matched analysis we matched all 1,556 beta-blocker users (19.2% of the entire cohort) with 1,556 non-users; the 30-day mortality was 25.7% among beta-blocker users and 31.4% among non-users (OR 0.74 (95% CI: 0.63 to 0.87)]. The OR was 0.69 (95% CI: 0.54 to 0.88) for surgical ICU patients and 0.71 (95% CI: 0.51 to 0.98) for medical ICU patients. The OR was 0.99 (95% CI: 0.67 to 1.47) among users of non-selective beta-blockers, and 0.70 (95% CI: 0.58 to 0.83) among users of cardioselective beta-blockers. Preadmission beta-blocker use is associated with reduced mortality following ICU admission.


Urogenital blastomycosis in a dog.
Blastomycosis was diagnosed in a dog by finding the causative organism in preputial exudate and urine. Prostatic involvement was confirmed by transrectal biopsy. The dog was not treated, and, after it was euthanatized, a complete necropsy was performed. The only other sites where organisms were found were the iliac lymph nodes and the lungs. Although organisms were not found in any other part fo the genitourinary tract, both kidneys had diffuse glomerulonephritis and tubular degeneration.


Identification and analysis of four candidate symbiosis genes from 'Chlorochromatium aggregatum', a highly developed bacterial symbiosis.
The consortium 'Chlorochromatium aggregatum' currently represents the most highly developed interspecific association between prokaryotes. It consists of green sulfur bacteria, so-called epibionts, which surround a central, motile, chemotrophic bacterium. Four putative symbiosis genes of the epibiont were recovered by suppression subtractive hybridization and bioinformatics approaches. These genes are transcribed constitutively and do not occur in the free-living relatives of the epibiont. The haemagglutinin-like putative gene products of open reading frames (ORFs) Cag0614 and Cag0616 are unusually large and contain repetitive regions and RGD tripeptides. Cag0616 harbours two betagamma-crystalline Greek key motifs. Cag1920 codes for a putative haemolysin whereas the gene product of Cag1919 is a putative RTX-like protein. Based on detailed analyses of Cag1919, the C-terminal amino acid sequence comprises six repetitions of the motif GGXGXD predicted to form a Ca(2+)-binding beta roll. Intact 'C. aggregatum' consortia disaggregated upon the addition of EGTA or pyrophosphate, but stayed intact in the presence of various lectine-binding sugars or proteolytic enzymes. Unlike other RTX toxins, a gene product of Cag1919 could not be detected by (45)Ca(2+) autoradiography, indicating a low abundance of the corresponding protein in the cells. The RTX-type C-terminus coded by Cag1919 exhibited a significant similarity to RTX modules of various proteobacterial proteins, suggesting that this putative symbiosis gene has been acquired via horizontal gene transfer from a proteobacterium.


Hospice: an organizational systems model for the integration of acute and long-term care.
In recent years, the realization of a need for increased integration of acute care and long-term care (LTC) systems has grown. For the most part, however, a person requiring both types of care is treated as though he or she is two discrete individuals with separate needs. Organizations that have the integration of acute and LTC as a goal serve relatively small numbers of people. Integration efforts could be facilitated through the identification and application of an organizational systems model. Hospice can provide such a model. The hospice interdisciplinary team integrates not only multiple disciplines but also acute care and LTC. The hospice model is also appropriate from a financial standpoint in that Medicare hospice funding has employed a prospective payment system (PPS) since the inception of the Medicare Hospice Benefit. In this article, the application of the hospice model to the integration of the acute care and LTC systems in the U.S. is demonstrated, using a subsystem approach.


Burden of community-acquired and nosocomial rotavirus gastroenteritis in the pediatric population of Western Europe: a scoping review.
Rotavirus affects 95% of children worldwide by age 5 years and is the leading cause of severe dehydrating diarrhea. The objective of this review was to estimate the burden of rotavirus gastroenteritis (RVGE) in the Western European pediatric population. A comprehensive literature search (1999-2010) was conducted in PubMed and other sources (CDC; WHO, others). Data on the epidemiology and burden of RVGE among children < 5 years-old in Western Europe --including hospital-acquired disease--were extracted. 76 studies from 16 countries were identified. The mean percentage of acute gastroenteritis (AGE) cases caused by rotavirus ranged from 25.3%-63.5% in children < 5 years of age, peaking during winter. Incidence rates of RVGE ranged from 1.33-4.96 cases/100 person- years. Hospitalization rates for RVGE ranged from 7% to 81% among infected children, depending on the country. Nosocomial RVGE accounted for 47%-69% of all hospital-acquired AGE and prolonged hospital stays by 4-12 days. Each year, RVGE incurred $0.54- $53.6 million in direct medical costs and $1.7-$22.4 million in indirect costs in the 16 countries studied. Full serotyping data was available for 8 countries. G1P[8], G2P[4], G9P[8], and G3P[8] were the most prevalent serotypes (cumulative frequency: 57.2%- 98.7%). Serotype distribution in nosocomial RVGE was similar. This review confirms that RVGE is a common disease associated with significant morbidity and costs across Western Europe. A vaccine protecting against multiple serotypes may decrease the epidemiological and cost burden of RVGE in Western Europe.


111In-platelets dynamic study in chronic immune thrombocytopenic purpura.
The aim of this work was to estimate the significance of a dynamic study performed during the first 20 minutes after autologous (111)In-oxinate-platelets injection in patients with chronic immune thrombocytopenic purpura (ITP). Two hypotheses were tested: a) dynamic study indicates the place of platelet sequestration; b) dynamic study reflects the quality of platelet separation and labelling procedure. Thirty-nine persons were investigated: 25 with shortened platelet life span (ITP), and 14 with normal platelet life span (6 healthy subjects and eight patients with myelodysplastic syndrome--MDS). Platelet blood count on the day of platelet labelling, general yield of platelet labelling (GYL), differential yield of platelet labelling (DYL), platelet life span, dynamic study with initial platelet accumulation in the liver (IPAL), sequential static study for determining the platelet sequestration index (SI) and platelet sequestration site (SS) were investigated. Two types of labelled platelet kinetics were determined in both groups of patients: IPAL < 20% and IPAL > 20%. A statistically significant difference in GYL and DYL was noted between the patients with IPAL < 20% and IPAL > 20%. No significant difference was registered in platelet blood count, life span, SS and SI between the two groups of patients. Both yields of platelet labelling were higher in the group with IPAL < 20%. There was no correlation between IPAL and platelet SI, or between IPAL and platelet SS. Dynamic study with (111)In-platelets cannot predict platelet sequestration site in ITP patients, but it is a useful and sensitive method of platelet labelling procedure quality control.


Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease.
Transcriptional deregulation and changes in mitochondrial bioenergetics, including pyruvate dehydrogenase (PDH) dysfunction, have been described in Huntington's disease (HD). We showed previously that the histone deacetylase inhibitors (HDACIs) trichostatin A and sodium butyrate (SB) ameliorate mitochondrial function in cells expressing mutant huntingtin. In this work, we investigated the effect of HDACIs on the regulation of PDH activity in striatal cells derived from HD knock-in mice and YAC128 mice. Mutant cells exhibited decreased PDH activity and increased PDH E1alpha phosphorylation/inactivation, accompanied by enhanced protein levels of PDH kinases 1 and 3 (PDK1 and PDK3). Exposure to dichloroacetate, an inhibitor of PDKs, increased mitochondrial respiration and decreased production of reactive oxygen species in mutant cells, emphasizing PDH as an interesting therapeutic target in HD. Treatment with SB and sodium phenylbutyrate, another HDACI, recovered cell viability and overall mitochondrial metabolism in mutant cells. Exposure to SB also suppressed hypoxia-inducible factor-1 (HIF-1α) stabilization and decreased the transcription of the two most abundant PDK isoforms, PDK2 and PDK3, culminating in increased PDH activation in mutant cells. Concordantly, PDK3 knockdown improved mitochondrial function, emphasizing the role of PDK3 inactivation on the positive effects achieved by SB treatment. YAC128 mouse brain presented higher mRNA levels of PDK1-3 and PDH phosphorylation and decreased energy levels that were significantly ameliorated after SB treatment. Furthermore, enhanced motor learning and coordination were observed in SB-treated YAC128 mice. These results suggest that HDACIs, particularly SB, promote the activity of PDH in the HD brain, helping to counteract HD-related deficits in mitochondrial bioenergetics and motor function.SIGNIFICANCE STATEMENT The present work provides a better understanding of mitochondrial dysfunction in Huntington's disease (HD) by showing that the pyruvate dehydrogenase (PDH) complex is a promising therapeutic target. In particular, the histone deacetylase inhibitor sodium butyrate (SB) may indirectly (through reduced hypoxia-inducible factor 1 alpha stabilization) decrease the expression of the most abundant PDH kinase isoforms (e.g., PDK3), ameliorating PDH activity and mitochondrial metabolism and further affecting motor behavior in HD mice, thus constituting a promising agent for HD neuroprotective treatment.


Solubility and accumulation of metals in Chinese brake fern, vetiver and rostrate sesbania using chelating agents.
Greenhouse experiments were conducted to study the effects of chelating agents on the growth and metal accumulation of Chinese brake fern (Pteris vittata L.), vetiver (Vetiveria zizanioides L.), and rostrate sesbania (Sesbania rostrata L.) in soil contaminated with arsenic (As), Cu, Pb, and Zn. Among the five chelating agents used [ethylenediaminetriacetic acid (EDTA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), oxalic acid (OA), and phytic acid (PA)], OA was the best to mobilize As, EDTA to mobilize Cu and Pb, and HEDTA to mobilize Zn from soil, respectively. The biomass of vetiver was the highest, followed by rostrate sesbania. All chelating agents inhibited the growth of Chinese brake fern and rostrate sesbania, but HEDTA significantly increased the aboveground biomass of vetiver. Dry weights of both Chinese brake fern and rostrate sesbania decreased with increasing EDTA concentrations amended in the soil, especially in treatments with high EDTA concentrations. EDTA and HEDTA enhanced Cu, Zn, and Pb, but lowered As accumulation in all three plant species, except for As in vetiver, while OA significantly enhanced As accumulation in the aboveground part of vetiver. Concentrations of Cu, Zn, and Pb in the aboveground parts of plants increased significantly with the increase of EDTA concentrations and treatment time. In addition to As, Chinese brake fern also accumulated the highest Cu, Pb, and Zn in its aboveground parts among the three plant species grown in metal-contaminated soil with EDTA/HEDTA treatments. This species, therefore, can be used to simultaneously clean up As, Cu, Pb, and Zn from contaminated soils with the aid of EDTA or HEDTA.


Developing a "Tailor-Made" Precision Lifestyle Medicine Intervention for Weight Control among Middle-aged Latino Men.
To identify what is important to middle-aged Latino men and their personal goals and values as foundations for a future precision lifestyle medicine intervention that is rooted in Self-Determination Theory. We used a phenomenological, thematic approach to analyze data from 20 semi-structured, individual interviews with Latino men aged 35-60 years. Community-based settings between November 2017 and May 2018 in South Florida. Latino or Hispanic men who were aged 35-60 years. The mean age of the men was 49.8 years. Two key themes emerged: a) the characteristics that these men say define what it means to be a man; and b) the characteristics that these men say define what is important to them. "What defines a man" includes three primary subthemes: a) the attributes, characteristics and behaviors that participants understood to be ideals that a man should embody and the roles he should fulfill; b) lessons learned growing up about what it means to be a man; and c) how Latino men relate to the ideal of machismo. "What defines me" includes the subthemes: a) comparing themselves with the ideal of machismo; b) caring for family and others; and c) supporting and modeling positive behavior for their children. We found key candidate mechanisms that may be novel yet critical foundations on which to build a precision lifestyle medicine intervention for Latino men. We identified actionable psychosocial factors that map onto motivational constructs that can shape behaviors that are essential for weight control and be a useful foundation for improving the health of middle-aged Latino men.


Retinoids Enhance the Expression of Cathelicidin Antimicrobial Peptide during Reactive Dermal Adipogenesis.
A subset of dermal fibroblasts undergo rapid differentiation into adipocytes in response to infection and acutely produce the cathelicidin antimicrobial peptide gene Camp Vitamin A and other retinoids inhibit adipogenesis yet can show benefit to skin disorders, such as cystic acne, that are exacerbated by bacteria. We observed that retinoids potently increase and sustain the expression of Camp in preadipocytes undergoing adipogenesis despite inhibition of markers of adipogenesis, such as Adipoq, Fabp4, and Rstn Retinoids increase cathelicidin in both mouse and human preadipocytes, but this enhancement of antimicrobial peptide expression did not occur in keratinocytes or a sebocyte cell line. Preadipocytes undergoing adipogenesis more effectively inhibited growth of Staphylococcus aureus when exposed to retinoic acid. Whole transcriptome analysis identified hypoxia-inducible factor 1-α (HIF-1α) as a mechanism through which retinoids mediate this response. These observations uncouple the lipid accumulation element of adipogenesis from the innate immune response and uncover a mechanism, to our knowledge previously unsuspected, that may explain therapeutic benefits of retinoids in some skin disorders.


Circulating Fibroblast Growth Factor-2, HIV-Tat, and Vascular Endothelial Cell Growth Factor-A in HIV-Infected Children with Renal Disease Activate Rho-A and Src in Cultured Renal Endothelial Cells.
Renal endothelial cells (REc) are the first target of HIV-1 in the kidney. The integrity of REc is maintained at least partially by heparin binding growth factors that bind to heparan sulfate proteoglycans located on their cell surface. However, previous studies showed that the accumulation of two heparin-binding growth factors, Vascular Endothelial Cell Growth Factor-A (VEGF-A) and Fibroblast Growth Factor-2 (FGF-2), in combination with the viral protein Tat, can precipitate the progression of HIV-renal diseases. Nonetheless, very little is known about how these factors affect the behavior of REc in HIV+ children. We carried out this study to determine how VEGF-A, FGF-2, and HIV-Tat, modulate the cytoskeletal structure and permeability of cultured REc, identify key signaling pathways involved in this process, and develop a functional REc assay to detect HIV+ children affected by these changes. We found that VEGF-A and FGF-2, acting in synergy with HIV-Tat and heparin, affected the cytoskeletal structure and permeability of REc through changes in Rho-A, Src, and Rac-1 activity. Furthermore, urine samples from HIV+ children with renal diseases, showed high levels of VEGF-A and FGF-2, and induced similar changes in cultured REc and podocytes. These findings suggest that FGF-2, VEGF-A, and HIV-Tat, may affect the glomerular filtration barrier in HIV+ children through the induction of synergistic changes in Rho-A and Src activity. Further studies are needed to define the clinical value of the REc assay described in this study to identify HIV+ children exposed to circulating factors that may induce glomerular injury through similar mechanisms.


Evaluating the reliability of different preprocessing steps to estimate graph theoretical measures in resting state fMRI data.
With resting-state functional MRI (rs-fMRI) there are a variety of post-processing methods that can be used to quantify the human brain connectome. However, there is also a choice of which preprocessing steps will be used prior to calculating the functional connectivity of the brain. In this manuscript, we have tested seven different preprocessing schemes and assessed the reliability between and reproducibility within the various strategies by means of graph theoretical measures. Different preprocessing schemes were tested on a publicly available dataset, which includes rs-fMRI data of healthy controls. The brain was parcellated into 190 nodes and four graph theoretical (GT) measures were calculated; global efficiency (GEFF), characteristic path length (CPL), average clustering coefficient (ACC), and average local efficiency (ALE). Our findings indicate that results can significantly differ based on which preprocessing steps are selected. We also found dependence between motion and GT measurements in most preprocessing strategies. We conclude that by using censoring based on outliers within the functional time-series as a processing, results indicate an increase in reliability of GT measurements with a reduction of the dependency of head motion.


[Krukenberg's tumor as the first clinical manifestation of fibrolamellar hepatocarcinoma].
Krukenberg's tumor refers to unilateral or bilateral ovarian metastatic tumors whose origin may be known or unknown. The incidence of this type of tumor is difficult to evaluate but may represent between 3% and 8% of ovarian tumors. In most cases, the primary tumor is identified and is usually digestive (basically gastric or colorectal). There are some references to primary hepatic tumors (gall bladder tumor and hepatocarcinoma) but none to fibrolamellar hepatocarcinoma as the primary tumor. We present the case of a 45-year-old woman who presented with lower hemiabdominal pain and who was diagnosed with Krukenberg's tumor of hepatic origin. Although ovarian involvement in primary digestive tumors is possible, hepatic origin is rare.


Effect of degeneration on gene expression of chondrogenic and inflammatory marker genes of intervertebral disc cells: a preliminary study.
New techniques for biological repair in the treatment of degenerative disc disease (DDD) have been developed recently. The question arises whether it is possible to find a predictive marker to identify a patient population which could benefit from this new treatment option. Standard magnetic resonance imaging (MRI) fails to differentiate between pathologic painful and asymptomatic aging discs. Neurological symptoms contribute to identifying the pathological level. In this preliminary translational research study we analysed the gene expression of structure proteins and inflammatory mediators as well as histological features of lumbar intervertebral discs in symptomatic patients with various signs of degeneration in the MRI. Specimens of intervertebral disc tissue were obtained from 20 patients undergoing lumbar nucleotomy. Preoperatively, a group selection based on four pre-defined MRI-criteria was performed: Group 1 (mild signs of degeneration), group 2 (moderate), group 3 (moderate-severe), group 4 (severe). An increase of the expression of structural proteins and inflammatory markers could be observed in MRI-groups 2 and 3. Gene expression of collagen type I and II and aggrecan went along with levels of cyclooxygenase-2 (COX-2) and (fibroblast growth factor-2) FGF-2 expression. Histological examination showed signs of granulation tissue in only 35% of cases, but no differences between the groups. Our findings implicate that the gene expression of structural proteins might correlate with the appearance of inflammatory mediators in symptomatic patients with moderate disc changes in the MRI in this preliminary clinical subset. The assessment of cell activity and protein expression in a larger number of patients could be next step to support and supplement the present data.


Clusternomics: Integrative context-dependent clustering for heterogeneous datasets.
Integrative clustering is used to identify groups of samples by jointly analysing multiple datasets describing the same set of biological samples, such as gene expression, copy number, methylation etc. Most existing algorithms for integrative clustering assume that there is a shared consistent set of clusters across all datasets, and most of the data samples follow this structure. However in practice, the structure across heterogeneous datasets can be more varied, with clusters being joined in some datasets and separated in others. In this paper, we present a probabilistic clustering method to identify groups across datasets that do not share the same cluster structure. The proposed algorithm, Clusternomics, identifies groups of samples that share their global behaviour across heterogeneous datasets. The algorithm models clusters on the level of individual datasets, while also extracting global structure that arises from the local cluster assignments. Clusters on both the local and the global level are modelled using a hierarchical Dirichlet mixture model to identify structure on both levels. We evaluated the model both on simulated and on real-world datasets. The simulated data exemplifies datasets with varying degrees of common structure. In such a setting Clusternomics outperforms existing algorithms for integrative and consensus clustering. In a real-world application, we used the algorithm for cancer subtyping, identifying subtypes of cancer from heterogeneous datasets. We applied the algorithm to TCGA breast cancer dataset, integrating gene expression, miRNA expression, DNA methylation and proteomics. The algorithm extracted clinically meaningful clusters with significantly different survival probabilities. We also evaluated the algorithm on lung and kidney cancer TCGA datasets with high dimensionality, again showing clinically significant results and scalability of the algorithm.


Two new quinoline-based regenerable fluorescent probes with AIE characteristics for selective recognition of Cu2+ in aqueous solution and test strips.
Two novel highly selective quinoline-based fluorescent probes (1 and 2) with an aggregation induced emission (AIE) feature have been designed and synthesized for the rapid analysis of Cu2+ ions in aqueous media and on paper strips with a fluorescence quenching mechanism. Moreover, probes 1 and 2 exhibit excellent sensitivity and anti-interference for Cu2+ detection, and the detection limits are as low as 1.3 × 10-8 M and 8.5 × 10-8 M, respectively, which are much lower than the allowable standard of Cu2+ (∼20 μM) in drinking water (EPA). More importantly, these two probes were successfully applied for the determination of Cu2+ in real aqueous samples and fabrication of simple device test strips for rapid and on-site detection of Cu2+ ions. Interestingly, they can also be regenerated by adding an excess of S2-. Additionally, the crystallographic structure of probe 1 was confirmed through a single crystal X-ray study. Job's plot analysis and ESI-MS spectroscopic studies reflect the 1 : 1 complexation of the 1-Cu2+ and 2-Cu2+ complexes. Furthermore, DFT/TDDFT calculations were performed in order to help in understanding the electronic properties of the complexes and the chelation-induced quenching mechanism.


Feasibility of cord blood transplantation in chemosensitive adult T-cell leukemia/lymphoma: a retrospective analysis of the Nagasaki Transplantation Network.
It has been reported that cord blood transplantation (CBT) for patients with aggressive adult T-cell leukemia/lymphoma (ATL) results in poorer outcomes than transplantation using other stem cell sources. To identify a subset of ATL in which CBT is feasible, we retrospectively analyzed 27 patients treated with CBT at three institutions in Nagasaki Prefecture, Japan. The estimated overall survival (OS) rate at 3 years was 27.4 %. Of 16 patients who received CBT during remission (complete, CR, or partial, PR), the OS rate at 3 years was 50 %, while during refractory periods (non-CR or non-PR), the OS rate was 9.1 %. Reduced intensity conditioning (RIC) was given to 18 patients, and myeloablative conditioning (MAC) was used in nine, with 3-year OS of 50.0 and 0 %, respectively. Of the 19 deaths, nine were due to progressive disease, eight (five MAC and three RIC) to infection, and two to multiple organ failure. These results suggest that CBT provides similar results with those in other transplantation procedures for selected ATL patients, such as those in CR or PR. Further studies are needed to evaluate the use of CBT in aggressive ATL.


High-affinity binding by the periplasmic iron-binding protein from Haemophilus influenzae is required for acquiring iron from transferrin.
The periplasmic iron-binding protein, FbpA (ferric-ion-binding protein A), performs an essential role in iron acquisition from transferrin in Haemophilus influenzae. A series of site-directed mutants in the metal-binding amino acids of FbpA were prepared to determine their relative contribution to iron binding and transport. Structural studies demonstrated that the mutant proteins crystallized in an open conformation with the iron atom associated with the C-terminal domain. The iron-binding properties of the mutant proteins were assessed by several assays, including a novel competitive iron-binding assay. The relative ability of the proteins to compete for iron was pH dependent, with a rank order at pH 6.5 of wild-type, Q58L, H9Q>H9A, E57A>Y195A, Y196A. The genes encoding the mutant FbpA were introduced into H. influenzae and the resulting strains varied in the level of ferric citrate required to support growth on iron-limited medium, suggesting a rank order for metal-binding affinities under physiological conditions comparable with the competitive binding assay at pH 6.5 (wild-type=Q58L>H9Q>H9A, E57A>Y195A, Y196A). Growth dependence on human transferrin was only obtained with cells expressing wild-type, Q58L or H9Q FbpAs, proteins with stability constants derived from the competition assay >2.0x10(18) M(-1). These results suggest that a relatively high affinity of iron binding by FbpA is required for removal of iron from transferrin and its transport across the outer membrane.


Modified periinsular hemispherotomy: operative anatomy and technical nuances.
Surgical options for pediatric patients with marked dysfunction of a single epileptogenic hemisphere have evolved over time. Complications resulting from highly resective operations such as anatomical hemispherectomy, including superficial siderosis and secondary hydrocephalus, have led to the development of less resective and more disconnective functional hemispherectomy. Functional hemispherectomy has recently given rise to hemispherotomy, the least resective operation primarily aimed at disconnecting the abnormal hemisphere. Hemispherotomy is effective in decreasing seizure frequency and most likely decreases the risk of postoperative complications when compared with its predecessors. Hemispherotomy is a technically challenging operation that requires a thorough understanding of 3D cerebral anatomy to ensure adequate hemispheric disconnection without placing important structures at risk. The details of germane operative anatomy are not currently available because of the difficulty in exposing this operative anatomy adequately in cadavers to prepare detailed instructive illustrations. Using 3D graphic models, the authors have prepared 2D overlay illustrations to discuss the relevant operative nuances for a modified form of this procedure. Through hemispherotomy, experienced surgeons can effectively treat patients with unilateral epileptogenic hemisphere dysfunction while limiting potential complications.


Obesity and other health determinants across Europe: the EURALIM project.
EURALIM (EURope ALIMentation), a European collaborative study, aimed to determine and describe the extent to which European data on risk factor distributions from different populations could be pooled and harmonised in a common database for international comparisons. Seven independent population-based surveys from six European countries (France, Italy, Northern Ireland/United Kingdom, Spain, Switzerland, the Netherlands). Data for 18 381 women and 12 908 men aged 40-59 were pooled in a common database. Central statistical analyses on major cardiovascular risk factors were conducted with careful consideration of methodological issues, including differences in study designs, data assessment tools, and analytic techniques used. Because of the detected variability among methods used, direct comparisons of risk factor distributions and prevalences between studies were problematic. None the less, comparisons of within population contrasts by sex, age group, and other health determinants were considered to be meaningful and apt, as illustrated here for obesity. Results were targeted and disseminated to both the general public and public health professionals and framed in the context of a European information campaign. International and national comparisons between existing locally run studies are feasible and useful, but harmonisation methods need improvement. Development of an international risk factor surveillance programme based on decentralised data collection is warranted. In the meantime, risk factor contrasts across populations can be used as a basis for targeting needed public health intervention programmes.