Carpolobia lutea G. Don (Polygalaceae) Inhibits Inflammation and Oxidative Stress in an Acetic Acid Induced Model of Rat Colitis.
Carpolobia lutea G. Don (CL) is used in folk medicine for the treatment of inflammatory disorders. Effort in this study is to evaluate the beneficial effect of the aqueous-methanol extract of leaf of CL in a rat model of acetic acid induced colitis. Male Wistar rats were distributed into 6 groups of 7 rats each; non colitic, untreated colitic and colitic rats treated with graded doses of CL (100-800 mg/kg). Rats were pre-treated for 2 days before colitis induction and thereafter for 7 days post colitic induction. 24 h after the last treatment, animals were sacrificed and colonic inflammation was evaluated both macroscopically and biochemically. Macroscopic damage score, weight/length ratio, myeloperoxidase (MPO) activity and tumor necrotic factor alpha (TNF-α) levels, were significantly higher in untreated colitic rats in comparison with non colitic rats (P<0.05). Treatment with CL significantly reduced the macroscopic damage scores, neutrophil infiltration (MPO activity) and TNF-α level (P<0.05). In addition, C. lutea significantly prevented depletion of colonic GSH and (SOD) levels (P<0.05). It appears that the beneficial effect of methanol extract of C. lutea leaf observed in this study is dose dependent and is related to its antioxidant and anti-inflammatory activity.


High Prevalence of Spinal Magnetic Resonance Imaging Findings in Asymptomatic Young Adults (18-22 Yrs) Candidate to Air Force Flight.
Cross-sectional, retrospective, magnetic resonance (MR) imaging study, performed during cadets' selection procedures of the Italian Air Force Academy. To assess the prevalence of spinal MR imaging findings in asymptomatic young adults (18-22 yrs) candidate to Air Force Flight. Spinal MR imaging findings are frequently detected in asymptomatic subjects. Literature prevalence data come from studies that analyze different patient populations, in a wide age range and in different spinal tracts. Chronic degenerative disease of the vertebral column often occurs in pilots exposed to high flight acceleration forces, thus resulting crucial for Air Force Academy to exclude vertebral disease in cadets. Three hundred fifty asymptomatic young adults underwent a 3T MR examination of the entire spine. A structured radiological report was set up to classify and calculate the prevalence of spinal MR imaging findings. Two hundred seventy of 350 subjects (77%) presented spinal MR findings, while 80 of 350 candidates (23%) had no detectable MR imaging findings. One hundred six of 350 (30%) candidates had at least one disc desiccation and 47 of 350 (13%) presented at least one disc narrowing. Disc bulging was found in 176 of 350 (49%) cadets. Sixty-two of 350 (18%) subjects showed disc protrusion while 28 of 350 (8%) had disc extrusion. Forty-five of 350 (13%) candidates presented low grade intervertebral spondylosis and of these 12 had also facet joints spondylosis. Asymptomatic vertebral fractures were observed in 2 of 350 (<1%) cadets. A high rate of MR spinal imaging findings, similar to that of the adult population, was detected in our population of young asymptomatic subjects. Our results suggest that the process of aging spine, which is supposed to begin in the second decade of life, is morphologically appreciable in the immediate postadolescent period and this issue is of crucial importance when selecting military pilots. 4.


Impact of metric and sample size on determining malaria hotspot boundaries.
The spatial heterogeneity of malaria suggests that interventions may be targeted for maximum impact. It is unclear to what extent different metrics lead to consistent delineation of hotspot boundaries. Using data from a large community-based malaria survey in the western Kenyan highlands, we assessed the agreement between a model-based geostatistical (MBG) approach to detect hotspots using Plasmodium falciparum parasite prevalence and serological evidence for exposure. Malaria transmission was widespread and highly heterogeneous with one third of the total population living in hotspots regardless of metric tested. Moderate agreement (Kappa = 0.424) was observed between hotspots defined based on parasite prevalence by polymerase chain reaction (PCR)- and the prevalence of antibodies to two P. falciparum antigens (MSP-1, AMA-1). While numerous biologically plausible hotspots were identified, their detection strongly relied on the proportion of the population sampled. When only 3% of the population was sampled, no PCR derived hotspots were reliably detected and at least 21% of the population was needed for reliable results. Similar results were observed for hotspots of seroprevalence. Hotspot boundaries are driven by the malaria diagnostic and sample size used to inform the model. These findings warn against the simplistic use of spatial analysis on available data to target malaria interventions in areas where hotspot boundaries are uncertain.


The nocebo effect of drugs.
While the placebo effect has been studied for a long time, much less is known about its negative counterpart, named the nocebo effect. However, it may be of particular importance because of its impact on the treatment outcomes and public health. We conducted a review on the nocebo effect using PubMed and other databases up to July 2014. The nocebo effect refers by definition to the induction or the worsening of symptoms induced by sham or active therapies. Examples are numerous and concerns both clinical trials and daily practice. The underlying mechanisms are, on one hand, psychological (conditioning and negative expectations) and, on the other hand, neurobiological (role of cholecystokinin, endogenous opioids and dopamine). Nocebo effects can modulate the outcome of a given therapy in a negative way, as do placebo effects in a positive way. The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response. This raises the important issue of how physicians can at the same time obtain informed consent and minimize nocebo-related risks. Every physician has to deal with this apparent contradiction between primum non nocere and to deliver truthful information about risks. Meticulous identification of patients at risk, information techniques such as positive framing, contextualized informed consent, and even noninformation, is valuable.


π-π-Stacked Poly(ε-caprolactone)-b-poly(ethylene glycol) Micelles Loaded with a Photosensitizer for Photodynamic Therapy.
To improve the in vivo stability of poly(-caprolactone)-b-poly(ethylene glycol) (PCL-PEG)-based micelles and cargo retention by π-π stacking interactions, pendant aromatic rings were introduced by copolymerization of -caprolactone with benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (TMC-Bz). It was shown that the incorporation of aromatic rings yielded smaller micelles (18-30 nm) with better colloidal stability in PBS than micelles without aromatic groups. The circulation time of i.v. injected micelles containing multiple pendant aromatic groups was longer (t½-α: ~0.7 h; t½-β: 2.9 h) than that of micelles with a single terminal aromatic group (t½ < 0.3 h). In addition, the in vitro partitioning of the encapsulated photosensitizer (meta-tetra(hydroxyphenyl)chlorin, mTHPC) between micelles and human plasma was favored towards micelles for those that contained the pendant aromatic groups. However, this was not sufficient to fully retain mTHPC in the micelles in vivo, as indicated by similar biodistribution patterns of micellar mTHPC compared to free mTHPC, and unequal biodistribution patterns of mTHPC and the host micelles. Our study points out that more detailed in vitro methods are necessary to more reliably predict in vivo outcomes. Furthermore, additional measures beyond π-π stacking are needed to stably incorporate mTHPC in micelles in order to benefit from the use of micelles as targeted delivery systems.


Web-based electronic health records improve data completeness and reduce medical discrepancies in employee vaccination programs.
A Web-based electronic health record (EHR) system was compared with traditional paper-based documentation and vaccination tracking during the 2009 H1N1 influenza pandemic. In a cohort of 8,411 healthcare network employees, EHRs improved completeness of self-reported contraindication data and reduced medical discrepancies. Vaccination program quality and accuracy are enhanced by EHRs.


Complex Fluids and Hydraulic Fracturing.
Nearly 70 years old, hydraulic fracturing is a core technique for stimulating hydrocarbon production in a majority of oil and gas reservoirs. Complex fluids are implemented in nearly every step of the fracturing process, most significantly to generate and sustain fractures and transport and distribute proppant particles during and following fluid injection. An extremely wide range of complex fluids are used: naturally occurring polysaccharide and synthetic polymer solutions, aqueous physical and chemical gels, organic gels, micellar surfactant solutions, emulsions, and foams. These fluids are loaded over a wide range of concentrations with particles of varying sizes and aspect ratios and are subjected to extreme mechanical and environmental conditions. We describe the settings of hydraulic fracturing (framed by geology), fracturing mechanics and physics, and the critical role that non-Newtonian fluid dynamics and complex fluids play in the hydraulic fracturing process.


The aquaporin gene aqpX of Brucella abortus is induced in hyperosmotic conditions.
An aquaporin gene (aqpX) was previously detected in the pathogenic bacterium Brucella abortus. Earlier studies showed that AqpX mediated rapid and large water fluxes in both directions in response to sudden osmotic up- or downshifts. Here, to study the role and the expression of the aqpX gene in B. abortus, an aqpX null mutant was constructed using an aqpX : : lacZ gene fusion. This mutant showed no significant difference in growth rate compared to the wild-type strain when grown in rich and minimal media, demonstrating that disruption of the aqpX gene was not lethal for B. abortus. The role of the B. abortus AqpX water channel was investigated by exposing the cells to hypo- and hyperosmolar conditions. While in hyperosmolar environments the growth rate of the knockout mutant was not affected, in hypo-osmolar conditions this mutant showed reduced viability after 50 h of growth. beta-Galactosidase assays and RT-PCR revealed that aqpX gene expression and the amount of aqpX mRNA were markedly increased in hyperosmolar conditions. Moreover, B. abortus aqpX expression levels were enhanced during the mid-exponential phase of growth. These results indicated that the expression of aqpX was regulated during the growth curve and induced in hyperosmolar conditions. This report is believed to be the first example of the induction of a bacterial aquaporin in hypertonic conditions.


Antineoplastic effects of simvastatin in experimental breast cancer.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have proven therapeutic and preventive effects on cardiovascular diseases. Preclinical evidence demonstrates tumor-suppressive effects of statins in several human neoplasias, including breast cancer. In this study, antineoplastic effects of simvastatin in chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. The drug was dietary administered at two concentrations--18 mg/kg (SIMVA 18) and 180 mg/kg (SIMVA 180). Basic parameters of experimental carcinogenesis after long-term simvastatin treatment in animals were assessed. In the SIMVA 180 group, simvastatin significantly suppressed tumour frequency by 80.5% and tumour incidence by 58.5% in comparison to the controls. Higher dose simvastatin non-significantly decreased the mean tumor volume by 23.5%, as well as non-significantly lengthened the latency period by 14.5 days compared to the control animals. Simvastatin, administered at a lower dose did not change parameters of mammary carcinogenesis in comparison to the control group. Simvastatin in both treated groups significantly decreased serum levels of triacylglycerols and VLDL-cholesterol in comparison to the control animals. Compared to the controls, a significant increase in food intake by the animals was recorded in the SIMVA 18 and SIMVA 180 groups. No significant differences in the final body weight gain between the simvastatin-administered and the control group were found. This study represents the first report of simvastatin use in experimental mammary carcinogenesis in vivo.


Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus.
Micro-RNAs constitute a family of small noncoding ribonucleic acids that are posttranscriptional regulators of messenger RNA activity. Although micro-RNAs are known to be dynamically regulated during neural development, the role of micro-RNAs in brain aging and neurodegeneration is not known. This study examined micro-RNA abundance in the hippocampal region of fetal, adult and Alzheimer's disease brain. The data indicate that micro-RNAs encoding miR-9, miR-124a, miR-125b, miR-128, miR-132 and miR-219 are abundantly represented in fetal hippocampus, are differentially regulated in aged brain, and an alteration in specific micro-RNA complexity occurs in Alzheimer hippocampus. These data are consistent with the idea that altered micro-RNA-mediated processing of messenger RNA populations may contribute to atypical mRNA abundance and neural dysfunction in Alzheimer's disease brain.


Predictors of Increased Carotid Intima-Media Thickness in Youth With Type 1 Diabetes: The SEARCH CVD Study.
Youth with type 1 diabetes have worse cardiovascular (CV) risk factors and higher carotid intima-media thickness (IMT) than their peers without diabetes. Whether the burden of CV risk factors over time is associated with carotid IMT at follow-up in youth with type 1 diabetes is not known. Two hundred ninety-eight youth with type 1 diabetes (mean age 13.3 ± 2.9 years, 87.6% non-Hispanic white, 53.7% male) had two study visits 5 years apart. CV risk factors, including BMI, lipids, blood pressure, hemoglobin A(1c), and smoking status, were assessed at both visits, and carotid IMT was measured at follow-up using B-mode ultrasonography. Linear regression models with an area under the curve measurement that incorporated the baseline and follow-up CV risk factors were used to evaluate the relationship with carotid IMT at follow-up. All CV risk factors worsened significantly over time (except LDL cholesterol) (P < 0.05). From baseline to follow-up, the number of abnormal CV risk factors also increased (P < 0.05). Predictors of carotid IMT were older age, male sex, and higher BMI z score area under the curve (all P < 0.05). The CV risk factor burden increases over time in youth with type 1 diabetes. BMI z score was the only modifiable CV risk factor that predicted carotid IMT. This study highlights the critical need to better understand the risk factors that influence carotid IMT early in the course of type 1 diabetes.


A future for digital public goods for monitoring SDG indicators.
Digital public goods (DPGs), if implemented with effective policies, can facilitate the realization of the United Nations Sustainable Development Goals (SDGs). However, there are ongoing deliberations on how to define DPGs and assure that society can extract the maximum benefit from the growing number of digital resources. The International Research Center of Big Data for Sustainable Development Goals (CBAS) sees DPGs as an important mechanism to facilitate information-driven policy and decision-making processes for the SDGs. This article presents the results of a CBAS survey of 51 respondents from around the world spanning multiple scientific fields, who shared their expert opinions on DPGs and their thoughts about challenges related to their practical implementation in supporting the SDGs. Based on the survey results, the paper presents core principles in a proposed strategy, including establishment of international standards, adherence to open science and open data principles, and scalability in monitoring SDG indicators. A community-driven strategy to develop DPGs is proposed to accelerate DPG production in service of the SDGs while adhering to the core principles identified in the survey.


CoCr-enriched medium modulates integrin-based downstream signaling and requires a set of inflammatory genes reprograming in vitro.
Significant health concerns have been raised by the high levels of Cr and Co ions into whole blood as resulted of corrosion process released from biomedical implants, but very little is known about their biological behavior in governing cell metabolism. Thus, we prompted to address this issue by exploring the effects of CoCr enriched medium on both fibroblast and preosteoblast (pre-Ob) cells. First, we showed there is a significant difference in Co and Cr releasing dependent on engineered surface, it being even more released in dual acid-etching treating surface (named w/DAE) than the machined surfaces (named wo/DAE). Thereafter, we showed CoCr affects pre-osteoblast and fibroblast metabolism by dynamically modulating integrin-based downstream signaling (FAK, Src, Rac1, and Cofilin). Specifically on this matter, we have shown there is dynamic β1-integrin gene activation up 24 h in both preosteoblast and fibroblast. Our analysis showed also that both pre-Ob and fibroblast are important resource of proinflammatory cytokines when responding to CoCr enriched medium. In addition, survival-related signaling pathway was also affected interfering on survival and proliferating signal, mainly affecting CDK2, mapk-Erk and mapk-p38 phosphorylations, while AKT/PKB-related gene remained active. In addition, during cell adhesion PP2A (an important Ser/Thr phosphatase) was inactive in both cell lineages and it seems be a CoCr's molecular fingerprint, regulating specific metabolic pathways involved with cytoskeleton rearrangement. Altogether, our results showed for the first time CoCr affects cellular performance in vitro by modulating integrin activation-based downstream signaling and requiring a reprograming of inflammatory genes activations in vitro. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 839-849, 2018.


Heritability estimates associated with alternative definitions of mastitis and correlations with somatic cell score and yield.
The objectives of this study were to compare alternative mastitis definitions and to estimate genetic correlations of producer-recorded mastitis with somatic cell score (SCS) and yield. Cow health events and lactation records from June 2002 through October 2007 were provided by Dairy Records Management Systems (Raleigh, NC). First- through fifth-lactation records from cows calving between 20 and 120 mo of age and that calved in a herd-year with at least 1% of cows with a clinical mastitis event were retained. The edited data contained 118,516 lactation records and 1,072,741 test-day records of 64,893 cows. Mastitis occurrence (1 = at least one mastitis event during lactation or test-day interval, 0 = no mastitis events), number of mastitis events during lactation, SCS, and yield were analyzed with animal models (single trait) or sire-maternal grandsire models (multiple trait) in ASREML. Comparisons were made among models assuming a normal distribution, a binary distribution, or Poisson distribution (for total episodes). The overall incidence of clinical mastitis was 15.4%; and heritability estimates ranged from 0.73% (test-day interval mastitis with a linear model) to 11.07% (number of mastitis episodes with a Poisson model). Increased mastitis incidence was genetically correlated with higher SCS (range 0.66 to 0.88) and was generally correlated with higher yield (range -0.03 to 0.40), particularly during first lactation (0.04 to 0.40). Significant genetic variation exists for clinical mastitis; and health events recorded by producers could be used to generate genetic evaluations for cow health. Sires ranked similarly for daughter mastitis susceptibility regardless of how mastitis was defined; however, test-day interval mastitis and a total count of mastitis episodes per lactation allow a higher proportion of mastitis treatments to be included in the genetic analysis.


Defibrillation thresholds are increased by right-sided implantation of totally transvenous implantable cardioverter defibrillators.
Whether an ICD is placed via a left- or right-sided approach depends on venous access, the presence of a preexisting pacemaker, and other factors. Since the DFT is affected by lead position, which in turn is determined in part by the side of access, right-sided venous access could adversely affect DFTs. Furthermore, right-sided active can placement directs electric current toward the right hemithorax, which could further increase DFTs. This study sought to determine whether DFTs were increased by right-sided vascular access, and whether active can technology was beneficial or detrimental with right-sided ICD placement. Stepdown to failure DFTs were found in 290 patients receiving transvenous systems at the time of initial ICD implantation. Of these, 271 (93%) received left-sided systems and 19 (7%) received right-sided systems. The mean DFT in systems placed via left-sided vascular access was 11.3 +/- 5.3 J versus 17.0 +/- 4.9 J for right-sided implantation (P < 0.0001); right-sided DFTs were elevated for both active can and cold can systems. Right-sided active can devices had a lower DFT than right-sided cold can systems (15 +/- 4.1 J vs 19 +/- 4.8 J, P = 0.05). The right-sided implantation of implantable defibrillators results in significantly higher DFTs than the left-sided approach. This may be due to the less favorable distribution of the defibrillating field relative to the myocardium with the devices on the right. When right-sided implantation is clinically mandated, active can devices result in lower thresholds and should be used.


Characterization of a Root-Knot Nematode Population of Meloidogyne arenaria from Tupungato (Mendoza, Argentina).
Root-knot nematodes (Meloidogyne spp.) are polyphagous plant parasites of global importance. Successful host infection depends on the particular interaction between a specific nematode species and race and a specific plant species and cultivar. Accurate diagnosis of nematode species is relevant to effective agricultural management; and benefits further from understanding the variability within a single nematode species. Here, we described a population of M. arenaria race 2 from Mendoza (Argentina). This study represents the first morphometric, morphological, biochemical, reproductive, molecular, and host range characterization of a root-knot nematode species from Argentina. Even after gathering morphological and morphometric data of this population and partially sequencing its rRNA, an unequivocal taxonomic assignment could not be achieved. The most decisive data was provided by esterase phenotyping and molecular methods using SCARs. These results highlight the importance of taking a multidimensional approach for Meloidogyne spp. diagnosis. This study contributes to the understanding of the variability of morphological, reproductive and molecular traits of M. arenaria, and provides data on the identification of root-knot nematodes on tomato cultivars from Argentina.


Targeting of liposomal andrographolide to L. donovani-infected macrophages in vivo.
Despite the rapid development in medicinal and pharmaceutical technology, the targeting of drugs to phagocytic cells in macrophage-related diseases still remains a major unsolved problem. By using the mannosyl-fucosyl receptors on macrophages, attempts were made to target antileishmanial drugs encapsulated in mannosylated or fucosylated liposomes to treat experimental leishmaniasis in the hamster model. Mannosylated liposomes were found to be more potent in delivering antileishmanial drugs to phagocytic cells. Liposomes loaded with an indigenous drug, andrographolide, a labdane diterpenoid isolated from Indian medicinal plant Andrographis paniculata, were prepared and tested against experimental leishmaniasis in a hamster model. Mannosylated liposomes loaded with the drug were found to be most potent in reducing the parasitic burden in the spleen as well as in reducing the hepatic and renal toxicity. In addition, mannosylated drug-loaded liposome-treated animals showed a normal blood picture and splenic tissue histoarchitecture when compared with those treated with free drug or regular liposomal drug. Such a drug-vehicle formulation may be considered for clinical trials.


Rapid decline of anti-pneumococcal antibody levels in nephrotic children.
Nephrotic children are at increased risk for pneumococcal infections. Antibody responses to the currently recommended pneumococcal polysaccharide vaccine have been variable and maintenance of adequate antibody levels over time has not been well documented. In this study, we determined total IgG antibody levels against pneumococcal polysaccharides before and 1, 6, 12 and 36 months after 23-valent pneumococcal polysaccharide vaccine (PPV) administration in nine children with steroid-responsive nephrotic syndrome during remission while off corticosteroids. The baseline antibody levels were between 4 and 86 mg/l. Four weeks after vaccination, the titer increased at least twofold in all patients with a mean arithmetic value of 165.4 mg/l. At the 6th month, the levels decreased in six out of nine subjects to a mean of 94.6 mg/l. At the 36th month, the control antibody levels were below the baseline or below the early postvaccination values in four out of nine subjects. Only two patients had stable high concentrations through the study period. Our data show that nephrotic patients may not retain their antibody levels despite reasonably good initial responses to the pneumococcal vaccine and that susceptibility to infections may continue in vaccinated children.


Cutaneous Manifestations of Myeloid Neoplasms Exhibit Broad and Divergent Morphologic and Immunophenotypic Features but Share Ancestral Clonal Mutations With Bone Marrow.
In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.


[Xenotransplantation from the ethical viewpoint. An outline].
The duty to save and to preserve lives on one hand, and the scarcity of human donor organs on the other hand call for a search for new organ sources, including xenogenic ones. Xenotransplantation, however, is not only in need of medical research, but also of ethical analysis. The latter is not to be considered a substitute for moral intuition, but rather a foundation of it by way of a critical evaluation of the ethical principles and reasons involved. This basically demands an analysis of the legitimacy of the aims and of the acceptability of the means for xenotransplantation. It includes safeguarding informed consent; risk assessment and the protection of not only the recipient, but also others; the question of limitation of personal rights; allocation problems; and last but not least animal protection. The aim is to clarify the ethical status of xenotransplantation in general and the question of a moratorium regarding clinical trials due to unsolved problems of infectivity and immunosuppression in particular by way of an integrative approach to both scientific developments and ethical analysis.


Differentiating quadruplexes: binding preferences of a luminescent dinuclear ruthenium(II) complex with four-stranded DNA structures.
The interaction of luminescent dinuclear ruthenium(II) complexes containing the bridging ligand tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2'',3''-j]phenazine with several intramolecular and intermolecular quadruplex DNA structures has been explored. It was found that these interactions produced distinctly different luminescence signatures. Binding curves constructed from these optical changes reveal that binding affinities for the quadruplex structures vary by over two orders of magnitude. The differences in quadruplex binding affinity and optical signature are rationalized through a consideration of the structural features of the quadruplexes. In particular we conclude large blue shifted emission enhancements are only observed on binding to quadruplexes containing lateral loops that are at least three base pairs long.


Tree resin composition, collection behavior and selective filters shape chemical profiles of tropical bees (Apidae: Meliponini).
The diversity of species is striking, but can be far exceeded by the chemical diversity of compounds collected, produced or used by them. Here, we relate the specificity of plant-consumer interactions to chemical diversity applying a comparative network analysis to both levels. Chemical diversity was explored for interactions between tropical stingless bees and plant resins, which bees collect for nest construction and to deter predators and microbes. Resins also function as an environmental source for terpenes that serve as appeasement allomones and protection against predators when accumulated on the bees' body surfaces. To unravel the origin of the bees' complex chemical profiles, we investigated resin collection and the processing of resin-derived terpenes. We therefore analyzed chemical networks of tree resins, foraging networks of resin collecting bees, and their acquired chemical networks. We revealed that 113 terpenes in nests of six bee species and 83 on their body surfaces comprised a subset of the 1,117 compounds found in resins from seven tree species. Sesquiterpenes were the most variable class of terpenes. Albeit widely present in tree resins, they were only found on the body surface of some species, but entirely lacking in others. Moreover, whereas the nest profile of Tetragonula melanocephala contained sesquiterpenes, its surface profile did not. Stingless bees showed a generalized collecting behavior among resin sources, and only a hitherto undescribed species-specific "filtering" of resin-derived terpenes can explain the variation in chemical profiles of nests and body surfaces from different species. The tight relationship between bees and tree resins of a large variety of species elucidates why the bees' surfaces contain a much higher chemodiversity than other hymenopterans.


Pseudomonas osteomyelitis of the metatarsal sesamoid bones.
It is unusual for osteomyelitis of the sesamoid bones to occur after a puncture wound to the foot. When the puncture occurs through tennis shoes, the risk of Pseudomonas infection is increased. Pseudomonas was the causative organism in 7 of 22 cases reported in the literature. This report will explore the causes and natural history, as well as the treatment, of these infections. Initially, basic wound care principles should be adhered to when treating these wounds. Patient awareness and close follow-up is important to ensure complete healing. Treatment of this case involved intravenous antibiotics and medial sesamoidectomy. Foot deformities can occur with sesamoid osteomyelitis and sesamoid excision. Hallux valgus deformity was noted to occur with the osteomyelitis and worsen with sesamoid excision. Preservation of surrounding structures during excision is important to prevent deformity.


Prevalence of youth access to alcohol, guns, illegal drugs, or cigarettes in the home and association with health-risk behaviors.
PURPOSE: To describe the prevalence of access to alcohol, guns, drugs, or cigarettes in the home and its association with related health-risk behaviors among adolescents.METHODS: We analyzed cross-sectional data from the 1995 in-home survey of the National Longitudinal Study on Adolescent Health which used a nationally representative school-based sample (N = 6,504) of adolescents in grades 7-12. We used logistic regression analysis, adjusted for gender, race/ethnicity and age, to examine the associations between access to alcohol, guns, drugs, and cigarettes in the home and the practice of risk behaviors involving those variables.RESULTS: Overall, 1,817 (28%) adolescents reported having easy access to alcohol in the home, 1,616 (25%) had access to a gun, 189 (3%) had access to drugs, and 2,067 (32%) had access to cigarettes. Associations were found between easy home access to alcohol and drinking during the past 12 months (Adj. OR = 2.16, 95% CI = 1.89-2.47), ever being drunk at school (Adj. OR = 2.33, 95% CI = 1.85-2.95, and ever driving drunk (Adj. OR = 1.64, 95% CI = 1.29-2.09). Access to a gun at home was associated with carrying a gun to school (Adj. OR = 2.54, 95% CI = 1.40-4.64). Associations were also found between access to drugs and cigarettes in the home and ever using drugs and smoking regularly.CONCLUSIONS: Easy access to alcohol, guns, and cigarettes in the home is prevalent among adolescents and may increase involvement in risky behaviors. Limiting access therefore is important in order to reduce the occurrence of health-risk behaviors associated with substance use, deliquency and injury among adolescents.


Differences in in vivo muscle fascicle and tendinous tissue behavior between the ankle plantarflexors during running.
The primary human ankle plantarflexors, soleus (SO), medial gastrocnemius (MG), and lateral gastrocnemius (LG) are typically regarded as synergists and play a critical role in running. However, due to differences in muscle-tendon architecture and joint articulation, the muscle fascicles and tendinous tissue of the plantarflexors may exhibit differences in their behavior and interactions during running. We combined in vivo dynamic ultrasound measurements with inverse dynamics analyses to identify and explain differences in muscle fascicle, muscle-tendon unit, and tendinous tissue behavior of the primary ankle plantarflexors across a range of steady-state running speeds. Consistent with their role as a force generator, the muscle fascicles of the uniarticular SO shortened less rapidly than the fascicles of the MG during early stance. Furthermore, the MG and LG exhibited delays in tendon recoil during the stance phase, reflecting their ability to transfer power and work between the knee and ankle via tendon stretch and storage of elastic strain energy. Our findings add to the growing body of evidence surrounding the distinct mechanistic functions of uni- and biarticular muscles during dynamic movements.


[Gram-negative virulent bacterial lipopolysaccharide: role in infection and immunity].
The paper discusses the data available in the literature on the studies on lipopolysaccharides (LPS) of bacteria which show their different virulence. A comparative study of the chemical composition and structure of LPS of the bacteria fails to detect any great difference, but they differ in their biological, especially immunobiological properties. It is suggested that the differences are associated with LPS conformation, chiefly its lipid moiety and ion-coordinating processes and free radical reactions are involved in the conformation. Examining just these phenomena may made advances in further studies of virulent bacterial LPS and possibilities of its use while designing new-generation vaccines.


Identification of Patients for Adjuvant Therapy After Resection of Carcinoma of the Extrahepatic Bile Ducts: A Propensity Score-Matched Analysis.
Resectability rates for extrahepatic cholangiocarcinoma have increased over time, but long-term survival after resection alone with curative intent remains poor. Recent series suggest improved survival with adjuvant therapy. Patient subsets benefiting most from adjuvant therapy have not been clearly defined. Patients with extrahepatic cholangiocarcinoma who underwent resection with curative intent and received adjuvant therapy (chemotherapy ± radiotherapy) or surgery alone (SA) were identified in the U.S. National Cancer Data Base (2004-2014). Cox regression identified covariates associated with overall survival (OS). Adjuvant therapy and SA cohorts were matched (1:1) by propensity scores based on the survival hazard in Cox modeling. Overall survival was compared by Kaplan-Meier estimates. Of 4872 patients, adjuvant chemotherapy was used frequently for 2416 (49.6%), often in conjunction with radiotherapy (RT) (n = 1555, 64.4%). Adjuvant chemotherapy with or without RT was used increasingly for cases with higher T classification [reference: T1-2; T3: 1.36; 95% confidence interval (CI), 1.19-1.55; T4: 1.77; 95% CI 1.38-2.26], nodal positivity [odds ratio (OR), 1.26; 95% CI 1.01-1.56], lymphovascular invasion (OR 1.21; 95% CI 1.01-1.46), or margin-positive resection (OR 1.85; 95% CI 1.61-2.12), and was associated with significant improvements in OS for each high-risk subset in the propensity score-matched cohort. Adjuvant therapy was associated with improved median OS for hilar tumors (40.0 vs 30.6 months; p = 0.025) but not distal tumors (33.0 vs 30.3 months; p = 0.123). Chemoradiotherapy was associated with superior outcomes compared with chemotherapy alone in the subset of margin-positive resection [hazard ratio (HR), 0.63; 95% CI 0.42-0.94]. Adjuvant multimodality therapy is associated with improved survival for patients with resected extrahepatic cholangiocarcinoma and high-risk features.


Extracorporeal shock wave lithotripsy monotherapy of 'stoned' internal ureteral stent in children. Case report.
A case of ESWL treatment, as monotherapy, of a 'stoned' ureteral stent in a 12-year-old boy was described. Two years previously, the patient had pyelolithotomy with staghorn stone removal, and double-J stent was left indwelling intraoperatively. The patient was lost for follow-up for 2 years, when he had multiple stone formation adherent to the whole length of the stent. Four ESWL sessions were required before the stent was freed for removal.


Long-term dynamics of bluetongue virus in wild ruminants: relationship with outbreaks in livestock in Spain, 2006-2011.
Wild and domestic ruminants are susceptible to Bluetongue virus (BTV) infection. Three BTV serotypes (BTV-4, BTV-1 and BTV-8) have been detected in Spain in the last decade. Even though control strategies have been applied to livestock, BTV circulation has been frequently detected in wild ruminant populations in Spain. The aim of the present study is to assess the role for wild ruminants in maintaining BTV after the vaccination programs in livestock in mainland Spain. A total of 931 out 1,914 (48.6%) serum samples, collected from eight different wild ruminant species between 2006 and 2011, were BTV positive by ELISA. In order to detect specific antibodies against BTV-1, BTV-4 and BTV-8, positive sera were also tested by serumneutralisation test (SNT). From the ELISA positive samples that could be tested by SNT (687 out of 931), 292 (42.5%) showed neutralising antibodies against one or two BTV serotypes. For each BTV serotype, the number of outbreaks in livestock (11,857 outbreaks in total) was modelled with pure autoregressive models and the resulting smoothed values, representing the predicted number of BTV outbreaks in livestock at municipality level, were positively correlated with BTV persistence in wild species. The strength of this relationship significantly decreased as red deer (Cervus elaphus) population abundance increased. In addition, BTV RNA was detected by real time RT-PCR in 32 out of 311 (10.3%) spleen samples from seropositive animals. Although BT outbreaks in livestock have decreased substantially after vaccination campaigns, our results indicated that wild ruminants have been exposed to BTV in territories where outbreaks in domestic animals occurred. The detection of BTV RNA and spatial association between BT outbreaks in livestock and BTV rates in red deer are consistent with the hypothesis of virus circulation and BTV maintenance within Iberian wild ruminant populations.


Vascular trauma associated with fractures and dislocations.
Vascular trauma occurs relatively infrequently in association with general orthopedic trauma but may be seen more often in injuries involving joint dislocations and areas in which vascular structures are tethered at the fracture site. The mechanisms of vascular trauma are identified, and the general principles in managing these injuries, including the operative approach to the injury itself and the options in repairing both arterial and venous injuries, are discussed. The role of fasciotomy and primary amputation are also reviewed. Several specific injuries, including pelvic fracture, knee dislocation, shoulder and upper limb injuries, complex tibial fractures, and iatrogenic injuries, are examined from diagnostic and management perspectives. Despite an ongoing evolution in the diagnosis and management of these often challenging injuries, the essential requirements for a good clinical outcome remain early recognition of the dysvascular limb and rapid institution of therapy.


Mortality patterns of rock and slag mineral wool production workers: an epidemiological and environmental study.
An epidemiological and environmental study of rock and slag mineral wool production workers was undertaken at a plant that has been in operation since the early 1900s. Size characteristics of fibres produced by each process at the plant and data from industrial hygiene surveys were used to evaluate current and past exposures. These data suggest that the average historical airborne fibre concentration probably did not exceed 2.5 fibres/cc before 1935 and 1.0 fibre/cc after 1935. A retrospective cohort mortality study was designed to assess mortality patterns. Detailed occupational histories were compiled on all plant employees. All jobs in the plant were assigned to one of eight potential exposure categories to assess the extent and severity of mineral wool exposure and the effect of other significant exposures on employee mortality. Findings included an increase in the number of deaths due to cancer of the digestive system and non-malignant respiratory disease among workers who had over 20 years' exposure to mineral wool or who had survived 20 years since their first exposure to mineral wool. These findings are not inconsistent with those of Enterline's (Symposium on Biological Effects of Mineral Fibres, Lyon, France, September 1979) in the Thermal Insulation Manufacturers' Association's mortality study of men employed in four mineral wool plants.


MTF evaluation of a phosphor-coated CCD for x-ray imaging.
A novel digital x-ray detector has been assembled. The imaging system is based on a phosphor-coated charge-coupled device (CCD) obtained by direct deposition of a gadolinium oxysulphide scintillator onto the detector surface. The modulation transfer function has been measured along the two directions of the digital coordinates with the narrow slit technique. A resolution limit of about 20 line pairs per mm has been obtained for both directions. The high spatial resolution currently demanded in mammography can be achieved with this imaging system.


Rabies and rabies control in striped skunks (Mephitis mephitis) in three prairie regions of western North America.
The number and geographic distribution of rabies cases in striped skunks (Mephitis mephitis) from Saskatchewan (n = 2,506 cases), Montana (n = 1,142), and Alberta (n = 199) since 1963 were reviewed. In Saskatchewan the number of cases increased steadily for 5 yr and then fluctuated consistently in a 4 yr cyclic pattern. Similarly an initial sweep across the province was followed by a cyclic pattern of geographic expansion (3 to 4 yr) and reduction (1 to 2 yr). No organized control efforts were conducted in Saskatchewan. Similar cyclic pattern were not seen in data from Montana or Alberta. In the latter areas, the number and distribution of rabies cases in skunks appeared to reflect efforts to reduce the population of skunks. An integrated program of skunk removal using poison and live-traps in association with research and public education successfully contributed to limiting the spread and establishment of rabies in striped skunks within prairie habitats. Rabies did not persist in skunks in other habitats.


Oncogene expression in reticuloendotheliosis virus-transformed lymphoid cell lines and avian tissues.
The genome of reticuloendotheliosis virus (REV-T) contains a unique oncogene, designated v-rel, which is inserted into the env region. Employing a cloned rel DNA probe, a single 2.9- to 3.0-kilobase v-rel mRNA was identified in poly(A)+ RNA from REV-T-transformed lymphoid cell lines. A 4.0-kilobase rel-specific transcript corresponding to the cellular homolog of the v-rel oncogene was identified in MSB-1 cells, a herpesvirus-transformed lymphoid cell line. Cytodot hybridization was used to quantitate the levels of rel, c-rel, c-myc, c-myb, c-abl, c-fms, c-Ha-ras, c-Ki-ras, c-src, c-yes, c-mos, and c-sis mRNA in REV-T-transformed cells. The levels of rel transcription in REV-T-transformed cells were elevated only two to eightfold over levels found in the transformed immature avian lymphoid cell line MSB-1. The relatively modest levels of rel transcription in REV-T-transformed cells and the significant differences between the lengths of the v-rel and c-rel mRNA suggest that REV-T transformation is the result of the production of an altered rel protein. The c-rel proto-oncogene is expressed in all avian hematopoietic tissues but is not expressed at significant levels in brain and muscle. The transcription of other proto-oncogenes is not enhanced in REV-T-transformed lymphoid cell lines.


Evaluating the Cost and Utility of Mandating Schools to Stock Epinephrine Auto-injectors.
The Michigan Legislature mandated that all public schools stock epinephrine auto-injectors (EAIs). A minimal amount is known regarding the incremental value of EAIs in schools. Our primary objective was to describe the frequency of administration of epinephrine for EMS patients with acute allergic reactions in public schools. Our secondary objective was to estimate the cost of mandating public schools to stock EAIs. We performed a retrospective cohort study of EMS cases with an impression of allergic reaction and who received epinephrine recorded in the 2014 Michigan EMS Information System (MI-EMSIS). We abstracted patient demographics, incident location by address to identify public schools, source of epinephrine given, and suspected allergen if known. We calculated advanced life support (ALS) response times to assess temporal impact of school EAIs in communities with ALS systems. We estimated the unsubsidized annual procurement cost of this mandate for Michigan public schools (N = 4,039), using range of costs for the required 2 EAIs (adult and pediatric) as estimated by the legislature ($140/each) and recently reported costs for commercial sources ($1,200). Training costs were not included. Descriptive statistics are reported. During this period, there were 1,550,009 EMS cases in the state with 631 receiving non-cardiac arrest epinephrine for presumed anaphylaxis, of which 23 cases were in public schools. Reported allergens were most often food 12 (51.2%), insect stings 4(22.2%) or unknown 7(30.4%). Among these patients, the source for epinephrine used was from the student, 7 (30.4%), EMS 7 (30.4%), school 7(30.4%), and unknown 2(8.7%). A majority (21, 91.3%) of the public school cases occurred in communities with ALS systems and ALS response was relatively rapid (median response 6 minutes, 90 percentile, 13 minutes). The unsubsidized annual cost of Michigan public schools to stock EAIs ranges from $565,460 to $4,846,800. In this study, few public school patients received epinephrine for anaphylaxis and the vast majority occurred in communities with rapid ALS response. The direct annual supply cost of the school EAI mandate is substantial.


The effectiveness of the comprehensive coping strategy program on clinical outcomes in breast cancer autologous bone marrow transplantation.
Patients with breast cancer who undergo autologous bone marrow/peripheral blood stem cell transplantation (ABMT) cope not only with a life-threatening medical treatment, but also with multiple, interrelated symptoms including pain, fatigue, psychological distress, and nausea. The purpose of this study was to determine, in a randomized controlled clinical trial, whether a comprehensive coping strategy program (CCSP) was effective in significantly reducing pain, fatigue, psychological distress, and nausea in patients with breast cancer who underwent ABMT. The CCSP was composed of preparatory information, cognitive restructuring, and relaxation with guided imagery. Randomization placed 52 patients in the CCSP treatment group and 58 patients in the control group. The CCSP was found to be effective in significantly reducing nausea as well as nausea combined with fatigue 7 days after the ABMT when the side effects of treatment were most severe. These results are important given the high incidence of nausea and fatigue in the ABMT population. The CCSP-treated group experienced mild anxiety as compared with the control group who reported moderate anxiety. The greatest effectiveness of CCSP may correspond to the time of the greatest morbidity for patients with breast cancer who have undergone ABM.


Probiotics for gastrointestinal disorders.
In recent years, interest has increased in the use of probiotics (orally administered micro-organisms) to treat people with a wide range of health problems. In the UK, probiotic preparations are classified as foods or food supplements so, unlike for medicines, there are no regulations to prevent their manufacturers from making non-specific promotional health claims, such as "Gives your patients a boost". Here we focus on the use of probiotics to treat people with gastrointestinal disorders. In a future issue, we will consider their use in atopic disease.


Morphologic aspect of the placenta in young and adult pregnant rats bearing Walker 256 carcinoma.
In the present study we investigated the influence of Walker 256 tumor growth on the modification of placental morphology and on fetal development in young and adult pregnant rats. After mating, female rats were divided into six groups: young control pregnant (Y), young pregnant with tumor (Yw), young pregnant injected with ascitic fluid (Ya), adult control pregnant (A), adult pregnant with tumor (Aw), and adult pregnant injected with ascitic fluid (Aa). Rats from tumor-bearing groups (Yw and Aw) were injected with 2.5 x 10(6) viable tumor cells into the right flank. Rats from Ya and Aa groups received daily inoculations of ascitic fluid (2.0 ml, i.p.) obtained from tumor-bearing rats without tumor cells. After 21 days, all animals were killed and the placentas were weighed and fixed with paraformaldehyde for histological analysis. Compared with control groups (Y and A), both tumor-bearing groups (Yw and Aw) presented the following changes: i) hemorrhage in the decidua and in the trophoblast giant cell layer; ii) disarrangement of the spongy zone, iii) restricted delimitation of the maternal and fetal blood vessels in the placental labyrinth; iv) hemorrhage and edema in the placental labyrinth. Similar results were observed in the placenta of groups injected with ascitic fluid (Ya and Aa). These results indicate that tumor development during pregnancy can have deleterious effects on placenta and fetus. These observations extend our previous data of extensive fetal reabsorption in both pregnant tumor-bearing and ascitic fluid-injected animals. These changes in placental morphology may be related to the synthesis and release of some factors by the tumor and the host cells, which could act directly or indirectly on placental tissue.


Information content based model for the topological properties of the gene regulatory network of Escherichia coli.
Gene regulatory networks (GRN) are being studied with increasingly precise quantitative tools and can provide a testing ground for ideas regarding the emergence and evolution of complex biological networks. We analyze the global statistical properties of the transcriptional regulatory network of the prokaryote Escherichia coli, identifying each operon with a node of the network. We propose a null model for this network using the content-based approach applied earlier to the eukaryote Saccharomyces cerevisiae (Balcan et al., 2007). Random sequences that represent promoter regions and binding sequences are associated with the nodes. The length distributions of these sequences are extracted from the relevant databases. The network is constructed by testing for the occurrence of binding sequences within the promoter regions. The ensemble of emergent networks yields an exponentially decaying in-degree distribution and a putative power law dependence for the out-degree distribution with a flat tail, in agreement with the data. The clustering coefficient, degree-degree correlation, rich club coefficient and k-core visualization all agree qualitatively with the empirical network to an extent not yet achieved by any other computational model, to our knowledge. The significant statistical differences can point the way to further research into non-adaptive and adaptive processes in the evolution of the E. coli GRN.


Identification of domains in the simian immunodeficiency virus matrix protein essential for assembly and envelope glycoprotein incorporation.
The matrix domain (MA) of the simian immunodeficiency virus (SIV) is encoded by the amino-terminal region of the Gag polyprotein precursor and is the component of the viral capsid that lines the inner surface of the virus envelope. To define domains of the SIV MA protein that are involved in virus morphogenesis, deletion and substitution mutations were introduced in this protein in the context of a gag-protease construct and expressed in the vaccinia virus vector system. The MA mutants were characterized with respect to synthesis and processing of the Gag precursor, assembly and release of virus-like particles, and incorporation of the envelope (Env) glycoprotein into particles. We have identified two regions of the SIV MA which are critical for particle formation. Both domains are located in a central hydrophobic alpha-helix of the SIV MA, according to data on the structure of this protein. In addition, we have characterized a domain whose mutation impairs the incorporation of SIV Env glycoproteins with long transmembrane cytoplasmic tails into particles. Interestingly, these mutant particles retained the ability to associate with SIV Env proteins with short cytoplasmic tails.


Carbon monoxide and the embryo.
Mammals are homeotherms and expend considerable energy maintaining their body temperatures. The temperature of a mammalian embryo on the other hand is maintained by the mother and the embryo can devote its metabolic energy to growth and development. The mammalian embryo is acting as a poikilotherm and its energy needs are thus considerably less than if it were a comparably sized homeotherm. The energy requirements of the preimplantation rat embryo are generated by anaerobic metabolism. As it grows, aerobic metabolism develops. In culture, the addition of carbon monoxide to the perfusing gas for early rat embryos has a much smaller effect than decreasing the oxygen concentration. Carbon monoxide appears to be a relatively mild toxicant until the embryo is much larger, is depending much more on transport of oxygen by red blood cells, and the fraction of required metabolic energy produced by anaerobic metabolism has become quite small. The effect from smoking during gestation may be either by the concomitant reduction in food intake or a more direct toxic effect from some components in the smoke. Carbon monoxide does not seem to be the culprit. The possible mitigating effect of a compensatory increase in fetal hematocrit in response to any hypoxia must also be considered. Humans have no yolk sac placenta as rodents do, but if the switch from anaerobic to aerobic metabolism is correlated with the stage of development, then carbon monoxide exposure should not represent any significant risk to the human embryo until later in gestation.


A control system approach for evaluating somatosensory activation by laser-Doppler flowmetry in the rat cortex.
Coupling between functional cortical activity and blood flow is a regulatory principle that adjusts the supply of substrates to the metabolic needs of the tissue. The flow response is usually expressed as the maximum increase over baseline; control system analysis allows the description of the entire time course and the main dynamic features of the regulative principle. In chloralose-anesthetized rats, forepaws were stimulated by trains of electric pulses of 0.3 or 5 ms duration. Blood flow was recorded in the contralateral somatosensory cortex by laser-Doppler flowmetry and correlated with the amplitude of primary somatosensory evoked potentials (SEP). Changes were analyzed by a control system approach. Pulses of 0.3 or 5 ms evoked SEPs of similar amplitude, whereas flow responses differed: 0.3 ms pulses led to a peak and plateau characteristic, 5 ms pulses evoked a plateau characteristic. The flow response evoked by 0.3 ms pulses can be modeled mathematically by an initial feedforward regulative principle followed after some delay by feedback controlled flow stabilization, whereas 5 ms pulses lack the feedforward component. The absence of an electrophysiological difference points to a dissociation between electrophysiological and hemodynamic responses and may be of importance for the understanding of flow coupling.


Control of the collapse distance in atmospheric propagation.
We show experimentally for ultrashort laser pulses propagating in air, that the collapse/filamentation distance of intense laser pulses in the atmosphere can be extended and controlled with a simple double-lens setup. We derive a simple formula for the filamentation distance, and confirm its agreement with the experimental results. We also observe that delaying the onset of filamentation increases the filament length.


[Ethical dilemmas for end-of-life decisions in the perinatal period].
According to several recent surveys, around 50% of the deaths occurring nowadays in French neonatal intensive care units result from a medical decision. This has led French neonatologists to set up guidelines for end-of-life decisions and practice in the perinatal period, which are presented in this paper. It covers definitions, clinical situations, ethical principles, obligations of the medical and nursing staff.


Trunk Muscle EMG During Intermediate Pilates Mat Exercises in Beginner Healthy and Chronic Low Back Pain Individuals.
The purpose of this study was to compare the electromyographic pattern of core muscles during intermediate Pilates mat exercises between healthy people and those with low back pain. We evaluated healthy participants (n = 19; mean ± standard deviation [SD]: age 28 ± 8 years, body mass 65 ± 10 kg, height 160.0 ± 9.1 cm) and a low back pain group (n = 13; mean ± SD: age 30 ± 9 years, body mass 67 ± 12 kg, height 170.0 ± 6.6 cm). Electromyographic analysis assessed the multifidus, external oblique, internal oblique, and rectus abdominis muscles during classical Pilates exercises (single leg stretch, criss-cross, and dead bug). We calculated the root mean square normalized by maximum voluntary contraction, and the time of peak activation was provided by a linear envelope and normalized by the total movement cycle. The criss-cross exercise presented the highest values of root mean square for trunk flexors (rectus abdominis and oblique) compared with the other exercises, followed by the single leg stretch and the dead bug, which had similar muscle activation. The single leg stretch presented more activation of the rectus abdominis and oblique, whereas the criss-cross and dead bug created more activation of the oblique compared with the multifidus and rectus. The Pilates exercises presented different muscle recruitment patterns, and allowed the activation of the lumbopelvic stabilizing muscles even in the first session for healthy individuals and those with chronic low back pain.


Critical Care Management of Anti-N-Methyl-D-Aspartate Receptor Encephalitis.
Anti-N-methyl-D-aspartate receptor encephalitis is considered an immune-mediated form of encephalitis with paraneoplastic and nonparaneoplastic forms. Delay in recognition is common and patients typically present to the ICU without a diagnosis or with complications following a delayed diagnosis. The aim of this review is to provide a focused overview for the ICU clinician regarding presentation, diagnosis, and critical care management. PubMed database search with manual review of articles involving anti-N-methyl-D-aspartate receptor encephalitis. Anti-N-methyl-D-aspartate receptor encephalitis is increasingly encountered in the ICU. The cascade of events initiating anti-N-methyl-D-aspartate receptor antibody formation may involve an infectious trigger particularly in the setting of teratoma. Following a prodrome, most patients develop psychiatric symptoms followed by movement disorder. Classical, psychiatric, and catatonic phenotypes may be distinguished based on the presence and severity of symptoms. Early immunotherapy and low initial cerebrospinal fluid inflammation are independent predictors of positive outcomes in ICU patients. Concomitant organ failure, status epilepticus, and the identification of a tumor did not influence outcome in critically ill patients. Supportive care in the ICU includes management of various manifestations of dyskinesia, status epilepticus, autonomic disorders, and the need for general sedation. Common treatment strategies and limitations are discussed including the emerging role of bortezomib. Intensivists should be familiar with the presentation and management of anti-N-methyl-D-aspartate receptor encephalitis. Early diagnosis and immediate implementation of steroids, immunoglobulins, and/or plasmapheresis and immune therapy are associated with a good neurologic outcome although response may be delayed. The selection and timing of second-line immune therapy requires further study.


The role of computed tomography in the preoperative assessment of gastrointestinal causes of acute abdomen in elderly patients.
Gastro-intestinal disorders in older patients is a medical emergency that requires immediate medical care. Chances of recovery improve with an early diagnosis and treatment. It might be caused by a number of different diseases, including perforations by foreign bodies, colon cancer, diverticulitis, ischemia. CT is often the initial modality used to assess patients with acute abdomen, the radiologist may be the first to suggest such a diagnosis. Computed tomography allows to identify the site of gastrointestinal perforations, of ischemia and to determine the most predictive signs in this diagnosis. The purpose of this study was to assess the diagnostic performance of CT gastrointestinal emergency of elderly patients with nontraumatic acute abdominal pain. The cases of 126 consecutively registered patients 65 years old or older presenting to the emergency department with acute abdominal pain and who underwent CT were retrospectively reviewed by two radiologists. Diagnostic accuracy was calculated according to the level of correctly classified cases in both the entire cohort and a surgical subgroup and was compared between readings. Agreement between each reading and the reference diagnosis and interobserver agreement were assessed with kappa statistics. In both the entire cohort (87.5% vs 85.3%, p = 0.07) and the surgical group (94% vs 91%, p = 0.15), there was no significant difference in CT accuracy between diagnoses made by the radiologist. Agreement between the CT diagnosis and the final diagnosis was excellent. In the care of elderly patients, CT is accurate for diagnosing the cause of acute abdominal pain, particularly when it is of gastrointestinal surgical origin. Thus CT interpretation should not be delayed until complete clinicobiologic data are available, and the images should be quickly transmitted to the emergency physician so that appropriate therapy can be begun.


Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage.
The differentiation potential of stem cells is determined by the ability of these cells to establish and maintain developmentally regulated gene expression programs that are specific to different lineages. Although transcriptionally potentiated epigenetic states of genes have been described for haematopoietic progenitors, the developmental stage at which the formation of lineage-specific gene expression domains is initiated remains unclear. In this study, we show that an intergenic cis-acting element in the mouse lambda5-VpreB1 locus is marked by histone H3 acetylation and histone H3 lysine 4 methylation at a discrete site in embryonic stem (ES) cells. The epigenetic modifications spread from this site toward the VpreB1 and lambda5 genes at later stages of B-cell development, and a large, active chromatin domain is established in pre-B cells when the genes are fully expressed. In early B-cell progenitors, the binding of haematopoietic factor PU.1 coincides with the expansion of the marked region, and the region becomes a center for the recruitment of general transcription factors and RNA polymerase II. In pre-B cells, E2A also binds to the locus, and general transcription factors are distributed across the active domain, including the gene promoters and the intergenic region. These results suggest that localized epigenetic marking is important for establishing the transcriptional competence of the lambda5 and VpreB1 genes as early as the pluripotent ES cell stage.


Measurement of glomerular filtration rate by low-dose iopromide plasma clearance.
Glomerular filtration rate (GFR) can be measured by iopromide plasma clearance. As an injection of 120 ml nonionic contrast medium is expensive and especially in patients with nephropathy potentially nephrotoxic, we investigated whether iopromide plasma clearance could be measured using a tenth of that dose as 'low-dose' clearance. Fifty adult patients scheduled for CT were recruited. Iopromide 300 mg I/ml was used for GFR measurement. Prior to CT, low-dose clearance was measured by injecting 12 ml iopromide per 75 kg b.w. At 3, 4 and 5 h after injection, plasma samples were obtained and the iodine concentration was measured by X-ray fluorescence analysis. Immediately after the last blood sample, CT was again performed following injection of 120 ml iopromide per 75 kg b.w. A further 3 plasma samples were then obtained 3, 4, and 5 h after CT and used for the determination of high-dose clearance. Low-dose clearance ranged from 20 ml/min to 141 ml/min (mean 78.3 ml/min). High-dose and low-dose clearance correlated excellently, with clearance (high-dose) = 1.4 + 0.994 clearance (low-dose); the correlation coefficient was r = 0.944, the standard deviation SDxy= 9.3 ml/min. Plasma clearance of iopromide is dose-independent on use of iodine amounts of 3.6 g and 36 g I/75 kg b.w. The GFR can be determined by high-dose and low-dose iopromide plasma clearance with identical accuracy.


Reversible modification of rat liver glutathione S-transferase 3-3 with 1-chloro-2,4-dinitrobenzene: specific labelling of Tyr-115.
Rat liver glutathione S-transferase 3-3 (GST, EC 126.96.36.199), a triple mutant with all three cysteine residues replaced with serine (CallS) and a quadruple mutant with a Tyr-115 to phenylalanine substitution on CallS (CallSY115F) were overexpressed in Escherichia coli under the control of a phoA promoter. Using this system, we obtained over 35 mg of fully active pure protein/litre of cell medium. GST 3-3 and CallS mutant were modified with 1-chloro-2,4-dinitrobenzene (CDNB), a model substrate for the enzyme, in the absence of GSH. Dinitrophenol, but not S-methylglutathione, inhibits this process. The dinitrophenyl groups are readily removed from the enzyme with GSH, but much more slowly with dithiothreitol. Results from peptide mapping and amino acid sequence analyses indicate that CDNB modifies the cysteine residues and Tyr-115 on wild-type GST 3-3, but only Tyr-115 on CallS. In addition, CDNB cannot modify the CallSY115F mutant. We propose that Tyr-115 is located at or near the H-site of GST 3-3.


Trends in socioeconomic inequalities in stunting prevalence in Latin America and the Caribbean countries: differences between quintiles and deciles.
With the adoption of the Sustainable Development Goals (SDGs), there is a renewed commitment of tackling the varied challenges of undernutrition, particularly stunting (SDG 2.2). Health equity is also a priority in the SDG agenda and there is an urgent need for disaggregated analyses to identify disadvantaged subgroups. We compared time trends in socioeconomic inequalities obtained through stratification by wealth quintiles and deciles for stunting prevalence. We used 37 representative Demographic and Health Surveys and Multiple Indicator Cluster surveys from nine Latin American and Caribbean (LAC) countries conducted between 1996 and 2016. Stunting in children under-5 years was assessed according to the 2006 WHO Child Growth Standards and stratified by wealth quintiles and deciles. Within-country socioeconomic inequalities were measured through concentration index (CIX) and slope index of inequality (SII). We used variance-weighted least squares regression to estimate annual changes. Eight out of nine countries showed a statistical evidence of reduction in stunting prevalence over time. Differences between extreme deciles were larger than between quintiles in most of countries and at every point in time. However, when using summary measures of inequality, there were no differences in the estimates of SII with the use of deciles and quintiles. In absolute terms, there was a reduction in socioeconomic inequalities in Peru, Honduras, Dominican Republic, Belize, Suriname and Colombia. In relative terms, there was an increase in socioeconomic inequalities in Peru, Bolivia, Haiti, Honduras and Guatemala. LAC countries have made substantial progress in terms of reducing stunting,. Nevertheless, renewed actions are needed to improve equity. Particularly in those countries were absolute and relative inequalities did not change over time such Bolivia and Guatemala. Finer breakdowns in wealth distribution are expected to elucidate more differences between subgroups; however, this approach is relevant to cast light on those subgroups that are still lagging behind within populations and inform equity-oriented health programs and practices.


Phyloecology of nitrate ammonifiers and their importance relative to denitrifiers in global terrestrial biomes.
Nitrate ammonification is important for soil nitrogen retention. However, the ecology of ammonifiers and their prevalence compared with denitrifiers, being competitors for nitrate, are overlooked. Here, we screen 1 million genomes for nrfA and onr, encoding ammonifier nitrite reductases. About 40% of ammonifier assemblies carry at least one denitrification gene and show higher potential for nitrous oxide production than consumption. We then use a phylogeny-based approach to recruit gene fragments of nrfA, onr and denitrification nitrite reductase genes (nirK, nirS) in 1861 global terrestrial metagenomes. nrfA outnumbers the nearly negligible onr counts in all biomes, but denitrification genes dominate, except in tundra. Random forest modelling teases apart the influence of the soil C/N on nrfA-ammonifier vs denitrifier abundance, showing an effect of nitrate rather than carbon content. This study demonstrates the multiple roles nitrate ammonifiers play in nitrogen cycling and identifies factors ultimately controlling the fate of soil nitrate.


Expansive suboccipital cranioplasty for the treatment of syringomyelia associated with Chiari malformation.
In order to treat syringomyelia associated with adult type Chiari malformation, the authors developed a method of expansive suboccipital cranioplasty (ESC) that involves enlarging the small posterior fossa to obtain a sufficient flow of cerebrospinal fluid (CSF). The relative effectiveness of ESC with the obex plugged and not plugged was also examined, as well as other factors influencing the operative results. Twenty patients without arachnoid adhesion at the major cistern underwent ESC without opening the arachnoid membrane at the major cistern. After surgery, all improved with no recurrence and CSF flow study using magnetic resonance (MR) imaging showed significant improvement of the flow at the major cistern. Another 20 patients without arachnoid adhesion also underwent ESC but with obex plugging. Sixteen improved and one displayed only temporary improvement with recurrent syringomyelia due to postoperative arachnoid adhesions. The remaining three showed no change in spite of shrinkage of the syrinx on postoperative MR imaging. These three patients had displayed pre-operative symptoms over an approximately 10-year period involving almost the entire axial plain of the spinal cord, and presented a large syrinx before surgery. In 4 patients with arachnoid adhesions, all required intra-arachnoid procedures in addition to ESC. Intra-arachnoid procedures are not necessary to facilitate restoration of CSF flow in patients without arachnoid adhesions, because ESC can release the CSF flow blockage in the major cistern even without plugging of the obex. An associated arachnoid adhesion at the major cistern or a long-standing syringomyelia with irreversible damage of the spinal cord results in a poor operative prognosis. When posterior fossa surgery fails, insufficient decompression or postoperative arachnoid adhesions at the major cistern as the cause of treatment's failure should be evaluated by CSF flow studies using phase contrast MR imaging.


Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons.
Specific families of transcription factors mediate events in the sequential maturation of distinct neuronal phenotypes. Members of one such family, the class IV POU domain transcription factor Brn-3.0, and two highly related factors Brn-3.1 and Brn-3.2, are differentially expressed in the developing and mature mammalian nervous system. The expression pattern of Brn-3.0 suggested that it has an important role in the development of sensory ganglia, as well as red nucleus, inferior olive, and nucleus ambiguus. Analysis of mice null for the Brn-3.0 locus shows that Brn-3.0 is required for the survival of subpopulations of proprioceptive, mechanoreceptive and nociceptive sensory neurons, where deletion of the gene affects neurotrophin and neurotrophin-receptor gene expression. Deletion of Brn-3.0 also alters either differentiation, migration or survival of specific central neuronal populations.


Relative safety profiles of high dose statin regimens.
Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.


Sexual Behavior and Network Characteristics and Their Association with Bacterial Sexually Transmitted Infections among Black Men Who Have Sex with Men in the United States.
Black men who have sex with men (MSM) have a high prevalence of bacterial sexually transmitted infections (STIs), and individual risk behavior does not fully explain the higher prevalence when compared with other MSM. Using the social-ecological framework, we evaluated individual, social and sexual network, and structural factors and their association with prevalent STIs among Black MSM. The HIV Prevention Trials Network 061 was a multi-site cohort study designed to determine the feasibility and acceptability of a multi-component intervention for Black MSM in six US cities. Baseline assessments included demographics, risk behavior, and social and sexual network questions collected information about the size, nature and connectedness of their sexual network. Logistic regression was used to estimate the odds of having any prevalent sexually transmitted infection (gonorrhea, chlamydia, or syphilis). A total of 1,553 Black MSM were enrolled in this study. In multivariate analysis, older age (aOR = 0.57; 95% CI 0.49-0.66, p<0.001) was associated with a lower odds of having a prevalent STI. Compared with reporting one male sexual partner, having 2-3 partners (aOR = 1.74; 95% CI 1.08-2.81, p<0.024) or more than 4 partners (aOR = 2.29; 95% CI 1.43-3.66, p<0.001) was associated with prevalent STIs. Having both Black and non-Black sexual partners (aOR = 0.67; 95% CI 0.45-0.99, p = 0.042) was the only sexual network factor associated with prevalent STIs. Age and the number and racial composition of sexual partners were associated with prevalent STIs among Black MSM, while other sexual network factors were not. Further studies are needed to evaluate the effects of the individual, network, and structural factors on prevalent STIs among Black MSM to inform combination interventions to reduce STIs among these men.


Using a word association task to investigate semantic depth in swedish-speaking children with developmental language disorder.
We examined word associations in Swedish children with Developmental Language Disorder (DLD) compared to their typically developing (TD) peers. Furthermore, the study aimed to explore the dimensions of vocabulary knowledge (breadth, depth, and fluency) in these children. Fifty children (15 DLD and 35 TD) participated in the study, aged six to nine years. This age span is commonly associated with substantial lexical reorganisation, by some referred to as the syntagmatic-paradigmatic shift. Fifty items from the Kent-Rosanoff list were used to elicit word associations (say the first word that comes to mind). Word associations were coded as paradigmatic (lion-tiger), syntagmatic (chair-sit), phonological (moon-poon), and other/no answer (foot-hello/bed- -). A semantic depth score (paradigmatic and syntagmatic associations) was calculated and analysed. The children with DLD showed significantly lower semantic depth scores than their TD peers, in line with previous research in English-speaking children. However, the vocabulary dimensions were uniformly affected for the DLD group, contradicting previous findings of semantic depth as a particular area of weakness in this group.


Fludrocortisone Is Associated With a Higher Risk of All-Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension.
Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α-1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety. We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995-2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all-cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person-years, respectively (adjusted incidence-rate ratio 1.20, 95% confidence interval, 1.02-1.40). The respective rates of heart failure-related hospitalization were 76 and 84 per 1000 person-years (adjusted incidence-rate ratio: 1.33, 95% confidence interval, 0.79-2.56). Among patients with a history of congestive heart failure, the rates of all-cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person-years (adjusted incidence-rate ratio: 1.42, 95% confidence interval, 1.07-1.90), and the respective rates of heart failure exacerbation-related hospitalizations were 297 and 263 per 1000 person-years (adjusted incidence-rate ratio: 1.48, 95% confidence interval, 0.69-3.16). Compared with users of midodrine, users of fludrocortisone had higher rates of all-cause hospitalizations, especially among patients with congestive heart failure.


Solution-Based One-Step Preparation of Three-Dimensional Self-Assembled Octadecyl Silica Nanosquare Plate and Microlamella Structures for Superhydrophobic and Icephobic Surfaces.
Icephobic surfaces have gained immense attention owing to their significant roles in decreasing the energy consumption of refrigerators and in improving safety issues by preventing the formation of ice on them. Superhydrophobic surfaces incorporating micro- or nanoscale roughness and hydrophobic functional groups have been shown to prevent ice accumulation. Herein, we report a simple, low-cost, and solution-based one-step process for the production of superhydrophobic surfaces with three-dimensional (3D) self-assembled structures. The controlled hydrolysis and polycondensation of n-octadecyltrichlorosilane (OTS-Cl) in an acetone solution produced a highly uniform superhydrophobic surface on various substrates such as glass, metals, and polymers without the limitation of the surface curvature structure. The as-prepared 3D self-assembled surface exhibited a very high contact angle of 161.7° and a low contact hysteresis of 1.47°. The solvent type, H2O content in acetone, and carbon chain length of the silane compound were critical in the formation of self-assembled nanostructures. The thickness of the superhydrophobic 3D self-assembled structure could be varied by controlling the surface properties of the glass substrate. In addition, a novel octadecyl silica nanosquare plate structure was formed as an intermediate for the microlamella structure. The water drop impact experiments on the 3D self-assembled superhydrophobic glass substrates at low temperatures (T < -25 °C) showed that the as-prepared superhydrophobic glass possessed a high impalement threshold for water contact, resulting in excellent and stable icephobic properties. The preparation method proposed in this study is scalable and can be used on a flat glass surface or in a glass vial inside a glass tube. Moreover, it can be applied to various substrates such as metals and polyurethane surfaces with curvature. Therefore, the solution-based self-assembly method proposed in this study is a promising approach to produce superhydrophobic and icephobic surfaces on a wide range of substrates regardless of their structure and properties.


Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex.
Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the hydrolysis of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype, dysostosis multiplex, mental retardation and hepatosplenomegaly (sialidosis type II). We have analyzed the genomic DNA from nine sialidosis patients of multiple ethnic origin in order to find mutations responsible for the enzyme deficiency. The activity of the identified variants was studied by transgenic expression. One patient had a frameshift mutation (G623delG deletion), which introduced a stop codon, truncating 113 amino acids. All others had missense mutations: G679G-->A (Gly227Arg), C893C-->T (Ala298Val), G203G-->T (Gly68Val), A544A-->G (Ser182Gly) C808C-->T (Leu270Phe) and G982G-->A (Gly328Ser). We have modeled the three-dimensional structure of sialidase based on the atomic coordinates of the homologous bacterial sialidases, located the positions of mutations and estimated their potential effect. This analysis showed that five mutations are clustered in one region on the surface of the sialidase molecule. These mutations dramatically reduce the enzyme activity and cause a rapid intralysosomal degradation of the expressed protein. We hypothesize that this region may be involved in the interface of sialidase binding with lysosomal cathepsin A and/or beta-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.


Imipramine as a discriminative stimulus.
The tricyclic antidepressant imipramine was established as a discriminative stimulus in pigeons at two doses (3.0 or 5.6 mg/kg). Because imipramine has multiple effects on different neurotransmitter systems, a range of compounds from several pharmacological classes were tested for substitution. The tricyclic antidepressants desipramine, amitriptyline and doxepin, all of which block serotonin (5-HT) and norepinephrine (NE) reuptake, resulted in imipramine-key responding. The psychomotor stimulants cocaine and d-amphetamine also occasioned responding on the imipramine key, as did the NE reuptake inhibitor tomoxetine; nomifensine, which blocks the reuptake of both NE and dopamine (DA), also resulted in responding on the key correlated with imipramine injections. Bupropion, a DA reuptake inhibitor, resulted in drug key responding but substitution did not occur with another DA uptake inhibitor GBR 12909. The alpha-2 agonist clonidine, the 5-HT2 antagonist ritanserin or the 5-HT reuptake inhibitor fluoxetine also did not occasion drug-key responding. Drug-appropriate responding occurred in pigeons trained at the lower dose of imipramine with the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide and gepirone; partial substitution occurred in pigeons trained with the higher dose of imipramine. Substitution for the imipramine stimulus by gepirone, an antidepressant with actions mediated by the 5-HT1A receptor, as well as with 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, suggests that imipramine may have effects at this receptor site and confirms reports that compounds active at this receptor may have antidepressant activity. This appears to be the first report of the successful, long-term establishment of imipramine as a discriminative stimulus without the development of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of quorum sensing-deficient clinical isolates of Pseudomonas aeruginosa.
Pseudomonas aeruginosa produces multiple virulence factors and causes different types of infections. Previous clinical studies identified P. aeruginosa isolates that lack individual virulence factors. However, the impact of losing several virulence factors simultaneously on the in vivo virulence of P. aeruginosa is not completely understood. The P. aeruginosa cell-to-cell communication system, or quorum sensing (QS), controls the production of several virulence factors. Animal studies using constructed QS mutants indicated that loss of the QS system severely impacts the virulence of P. aeruginosa. In this study, we tried to determine if deficiency within the QS system compromises the ability of P. aeruginosa to establish infections in humans. We have identified five QS-deficient strains through screening 200 isolates from patients with urinary tract, lower respiratory tract and wound infections. These strains lacked LasB and LasA activities and produced either no or very low levels of the autoinducers N-(3-oxododecanoyl) homoserine lactone and N-butyryl homoserine lactone. PCR analysis revealed that three isolates contained all four QS genes (lasI, lasR, rhlI and rhlR) while two isolates lacked both the lasR and rhlR genes. We also examined the five isolates for other virulence factors. The isolates produced variable levels of exotoxin A and, with one exception, were deficient in pyocyanin production. One isolate produced the type III secretion system (TTSS) effector proteins ExoS and ExoT, two isolates produced ExoT only and two isolates produced no TTSS proteins. The isolates produced weak to moderate biofilms on abiotic surfaces. Analysis of the patients' data revealed that two of the isolates represented a single strain that was isolated twice from the same patient within a 1 month interval. One QS-deficient clinical isolate (CI-1) lacked all tested virulence factors and produced a weak biofilm. These results suggest that naturally occurring QS-deficient strains of P. aeruginosa do occur and are capable of causing infections; and, that besides the known virulence factors, additional factors may contribute to the ability of certain strains such as CI-1 to establish an infection.


Simultaneous Endo-Epicardial Mapping of the Human Right Atrium: Unraveling Atrial Excitation.
Background The significance of endo-epicardial asynchrony (EEA) and atrial conduction block (CB), which play an important role in the pathophysiology of atrial fibrillation (AF) during sinus rhythm is poorly understood. The aim of our study was therefore to examine 3-dimensional activation of the human right atrium (RA). Methods and Results Eighty patients (79% men, 39% history of AF) underwent simultaneous endo-epicardial sinus rhythm mapping of the inferior, middle and superior RA. Areas of CB were defined as conduction delays of ≥12 ms, EEA as activation time differences of opposite electrodes of ≥15 ms and transmural CB as CB at similar endo-epicardial sites. CB was more pronounced at the endocardium (all locations P<0.025). Amount, extensiveness and severity of CB was higher at the superior RA. Transmural CB at the inferior RA was associated with a higher incidence of post-operative AF (P=0.03). EEA occurred up to 84 ms and was more pronounced at the superior RA (superior: 27 ms [interquartile range, 18.3-39.3], versus mid-RA: 20.3 ms [interquartile range, 0-29.9], and inferior RA: 0 ms [interquartile range, 0-21], P<0.001). Hypertension (P=0.009), diabetes mellitus (P=0.018), and hypercholesterolemia (P=0.015) were associated with a higher degree of EEA. CB (P=0.007) and EEA (P=0.037) were more pronounced in patients with a history of persistent AF compared with patients without AF history. Conclusions This study provides important insights into complex atrial endo-epicardial excitation. Significant differences in conduction disorders between the endo- and epicardium and a significant degree of EEA are already present during sinus rhythm and are more pronounced in patients with cardiovascular risk factors or a history of persistent AF.


Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer.
To investigate whether hyaluronan (HA) and CD44 (hereinafter HA-CD44) promotes head and neck squamous cell carcinoma (HNSCC) chemotherapy resistance and whether HA-CD44 promotes epidermal growth factor receptor (EGFR)-mediated oncogenic signaling to alter chemotherapy sensitivity in HNSCC. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, is a ligand for the transmembrane receptor CD44, which acts through multiple signaling pathways to influence cellular behavior. We recently determined that HA-CD44 promotes phospholipase C-mediated calcium signaling and cisplatin resistance in HNSCC. Cell line study. Tumor cell growth with various chemotherapeutic drugs (methotrexate, doxorubicin hydrochloride, adriamycin, and cisplatin) was measured in the presence or absence of HA and other inhibitors of the EGFR-mediated signaling pathway. Immunoblotting was used to study EGFR signaling. Migration assays provided one measure of tumor progression. The addition of HA, but not HA plus anti-CD44 antibody, resulted in a 2-fold reduced ability of methotrexate and an 8-fold reduced ability of adriamycin to cause HNSCC cell death. Immunoblotting studies demonstrated that HA can promote an association between CD44 and EGFR as well as CD44-dependent activation of EGFR-mediated signaling. Migration assays demonstrated that HA-CD44 can promote tumor migration with EGFR signaling. The presence of AG1478, an EGFR inhibitor, and U0126, an extracellular signal-regulated kinase inhibitor, inhibited HA-mediated tumor growth, migration, and chemotherapy resistance. Our results indicate that HA promotes CD44/EGFR interaction, EGFR-mediated oncogenic signaling, and chemotherapy resistance in HNSCC. Perturbation of HA-CD44-mediated signaling may be a promising and novel strategy to treat HNSCC.


Immigration and the regional demographics of the elderly population in the United States.
This research examined the impacts of past international and interregional migration flows on regional elderly population growth and distribution patterns. The authors used 1960, 1970, 1980, and 1990 Census data and multiregional demographic models to analyze changes in the sources of regional elderly population growth rates, age compositions, and spatial distributions over time. Past elderly interregional migration patterns have exhibited considerable stability and have contributed less than aging-in-place in shaping regional elderly population geographies. Also the effects of immigration on elderly dependency ratios have been very modest. Little evidence exists of any significant breaks with past trends in internal elderly migration patterns. Reconstruction of elderly population changes between 1950 and 1990 reveals that the driving force behind the changes was net aging-in-place and not net migration. Finally, analysis of the possible population rejuvenating effects of immigration suggests that although its impact has contributed to lower elderly-to-worker dependency ratios, its level over the past decades has been insufficient to counteract the much stronger countervailing impact of population aging.


Percutaneous nephrolithotomy in patients with solitary kidney.
The aim of this study was to evaluate percutaneous nephrolithotomy (PCNL) in the patients with solitary kidneys. Between 1995 and 2005, we had 11 patients with a solitary kidney and kidney calculi who underwent PCNL at our center. Tubeless and standard PCNLs were performed in 3 and 7 patients. In 1 patient, we could not achieve access to the system due to the stricture of the infundibulum. The calculi were extracted or fragmented successfully in 10 patients. In 2 patients with residual calculi, a double-J catheter was inserted and extracorporeal shock wave lithotripsy (SWL) was performed. Retroperitoneal hematoma was detected in 3 cases by ultrasonography 1 week after the procedure, which was treated conservatively. Also, fever occurred in 3 patients after the procedure which was treated successfully. The patients were discharged on the 3rd and 4th postoperative days. Although PCNL is accompanied by the risk of complications such as severe bleeding that may result in kidney loss in patients with a solitary kidney, the rate of success and complications seem to be similar to the other patients if careful operation and correct selection of candidates are done. Therefore, we recommend cautious performance of PCNL in patients with solitary kidneys.