Osteitis pubis: a review.
Osteitis pubis is a painful, noninfectious inflammatory condition that involves the pubic bone, symphysis, and surrounding structures. Initially associated with urologic procedures, osteitis pubis has been described as a complication of various obstetrical and gynecological procedures including vaginal deliveries. An incidence of approximately 2 to 3 percent has been observed after the Marshall-Marchetti-Krantz urethropexy. Although the pathogenesis of osteitis pubis is not clear, periosteal trauma seems to be an important initiating event. Pain is the primary symptom associated typically with difficulty in ambulation and the characteristic "waddling gait." A low grade fever, elevated sedimentation rate, and mild leukocytosis may be observed. Radiographic findings which include reactive sclerosis, rarefaction, and osteolytic changes lag behind the symptoms by about 4 weeks. The major differential diagnosis is osteomyelitis; however, the self-limiting nature and its response to nonantibiotic therapy indicates that osteitis pubis is a separate clinical entity. Treatment is directed at the associated inflammation with most minor cases responding to antiinflammatory agents and bedrest. Other more recalcitrant cases require more involved therapy including systemic steroids and rarely surgical resection. The diagnosis of osteitis pubis should be considered when pelvic pain is present in association with potential trauma to the symphysis pubis. Also, with more women participating in sporting activities patients may present to the physician with osteitis pubis related to athletic injury.


Detection of small surface defects of nontransparent scattering materials by using dynamic speckles.
We present a novel method for small surface defect detection based on the spatially filtered dynamic speckles. This method possesses high fidelity and versatility. Factors defining resolution of the proposed method is estimated and it is shown that resolution depends solely on the geometrical parameters of the optical system. Experimental results demonstrate feasibility of the proposed method for surface defect detection and are in good agreement with the theoretical estimations. A prototype for online detection of the defects with diameter of 400 µm is presented. Ways to improve prototype performance and the method resolution are discussed.


Comparative Genomics Analysis of a New Exiguobacterium Strain from Salar de Huasco Reveals a Repertoire of Stress-Related Genes and Arsenic Resistance.
The Atacama Desert hosts diverse ecosystems including salt flats and shallow Andean lakes. Several heavy metals are found in the Atacama Desert, and microorganisms growing in this environment show varying levels of resistance/tolerance to copper, tellurium, and arsenic, among others. Herein, we report the genome sequence and comparative genomic analysis of a new Exiguobacterium strain, sp. SH31, isolated from an altiplanic shallow athalassohaline lake. Exiguobacterium sp. SH31 belongs to the phylogenetic Group II and its closest relative is Exiguobacterium sp. S17, isolated from the Argentinian Altiplano (95% average nucleotide identity). Strain SH31 encodes a wide repertoire of proteins required for cadmium, copper, mercury, tellurium, chromium, and arsenic resistance. Of the 34 Exiguobacterium genomes that were inspected, only isolates SH31 and S17 encode the arsenic efflux pump Acr3. Strain SH31 was able to grow in up to 10 mM arsenite and 100 mM arsenate, indicating that it is arsenic resistant. Further, expression of the ars operon and acr3 was strongly induced in response to both toxics, suggesting that the arsenic efflux pump Acr3 mediates arsenic resistance in Exiguobacterium sp. SH31.


Improved parenchymal liver enhancement with extended delay on Gd-EOB-DTPA-enhanced MRI in patients with parenchymal liver disease: associated clinical and imaging factors.
To establish the effect of prolonged hepatobiliary phase (HBP) delay time on hepatic enhancement in patients with parenchymal liver disease (PLD). Gadoxetate disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) examinations with HBP were obtained after 20- (HBP-20) and 30-minute (HBP-30) delays in patients with PLD. For each patient, the Model for End-Stage Liver Disease (MELD) score, total and direct bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), prothrombin time (PT), and partial thromboplastin time (PTT) were recorded. Signal intensities of the liver, main portal vein, and spleen on pre-contrast, HBP-20, and HBP-30 were documented. Signal intensities were used to calculate liver relative enhancement (LRE), liver-spleen index (LSI), and liver-portal vein index (LPI) for HBP-20 and HBP-30. Improved hepatic enhancement was considered if two or more indices were higher on HBP-30 than HBP-20. A logistic regression model was constructed with improved hepatic enhancement as the outcome. One hundred and twenty-nine patients underwent 142 MRIs. Mean LRE, LSI, and LPI each increased from HBP-20 to HBP-30 (p = 0.004, p < 0.001, and p < 0.001, respectively). Seventy-two point five percent of cases demonstrated improved hepatic enhancement. The odds ratios for improved hepatic enhancement were 0.85 for MELD score (p = 0.02) and 3.2 for the 3 T scanner (p = 0.02), adjusted for age and sex. Increasing HBP delay to 30 minutes improves hepatic enhancement in patients with PLD, particularly if using a 3 T scanner. This effect is attenuated with higher MELD scores.


Emergence of complex computational structures from chaotic neural networks through reward-modulated Hebbian learning.
This paper addresses the question how generic microcircuits of neurons in different parts of the cortex can attain and maintain different computational specializations. We show that if stochastic variations in the dynamics of local microcircuits are correlated with signals related to functional improvements of the brain (e.g. in the control of behavior), the computational operation of these microcircuits can become optimized for specific tasks such as the generation of specific periodic signals and task-dependent routing of information. Furthermore, we show that working memory can autonomously emerge through reward-modulated Hebbian learning, if needed for specific tasks. Altogether, our results suggest that reward-modulated synaptic plasticity can not only optimize the network parameters for specific computational tasks, but also initiate a functional rewiring that re-programs microcircuits, thereby generating diverse computational functions in different generic cortical microcircuits. On a more general level, this work provides a new perspective for a standard model for computations in generic cortical microcircuits (liquid computing model). It shows that the arguably most problematic assumption of this model, the postulate of a teacher that trains neural readouts through supervised learning, can be eliminated. We show that generic networks of neurons can learn numerous biologically relevant computations through trial and error.


Ultrafast dynamics of massive dirac fermions in bilayer graphene.
Bilayer graphene is a highly promising material for electronic and optoelectronic applications since it is supporting massive Dirac fermions with a tunable band gap. However, no consistent picture of the gap's effect on the optical and transport behavior has emerged so far, and it has been proposed that the insulating nature of the gap could be compromised by unavoidable structural defects, by topological in-gap states, or that the electronic structure could be altogether changed by many-body effects. Here, we directly follow the excited carriers in bilayer graphene on a femtosecond time scale, using ultrafast time- and angle-resolved photoemission. We find a behavior consistent with a single-particle band gap. Compared to monolayer graphene, the existence of this band gap leads to an increased carrier lifetime in the minimum of the lowest conduction band. This is in sharp contrast to the second substate of the conduction band, in which the excited electrons decay through fast, phonon-assisted interband transitions.


BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis.
The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.


Alterations in connective tissue metabolism in stress incontinence and prolapse.
We describe current knowledge about collagen/elastin and extracellular matrix metabolism in the genitourinary tract with special emphasis on stress urinary incontinence. We also explored the influence of genetics and reproductive hormones on extracellular matrix metabolism. We performed a MEDLINE® search from 1995 to February 2011 using the key words stress urinary incontinence, pelvic organ prolapse, extracellular matrix, collagen, elastin, matrix metalloproteinase, collagenase, tissue inhibitors of matrix metalloproteinase, elastin metabolism, elastase, connective tissue, supportive tissue, mechanical stress, biomechanical properties, selective estrogen receptor modulators, transforming growth factor-β and wound healing. The literature searched produced data on 4 areas of significance for extracellular matrix metabolism in patients with stress urinary incontinence and prolapse, including collagen, elastin and transforming growth factor-β. Data on collagen metabolism continue to support the hypothesis of increased turnover involving matrix metalloproteinases and serine proteases in pelvic tissues of affected individuals. Elastin metabolism studies suggest increased degradation but also abnormal elastin fiber synthesis. Epidemiological data indicate a genetic predisposition to abnormal extracellular matrix in affected individuals while human tissue and animal models reveal differential expression of candidate genes involved in structural proteins. Transforming growth factor-β pathways have been documented to be involved in stress urinary incontinence in human tissues and animal models. Finally, these extracellular matrix metabolisms are modulated by reproductive hormones and selective estrogen receptor modulators. Pelvic tissue from women with stress urinary incontinence and pelvic organ prolapse show a genetic predisposition to abnormal extracellular matrix remodeling, which is modulated by reproductive hormones, trauma, mechanical stress load and aging. This progressive remodeling contributes to stress urinary incontinence/pelvic organ prolapse by altering normal tissue architecture and mechanical properties.


Relationship between intracranial hemodynamics and microdialysis markers of energy metabolism and glutamate-glutamine turnover in patients with subarachnoid hemorrhage. Clinical article.
The aim of this study was to explore the relationship between hemodynamics (intracranial and systemic) and brain tissue energy metabolism, and between hemodynamics and glutamate (Glt)-glutamine (Gln) cycle activity. Brain interstitial levels of lactate, pyruvate, Glt, and Gln were prospectively monitored in the neurointensive care unit for more than 3600 hours using intracerebral microdialysis in 33 patients with subarachnoid hemorrhage (SAH). Intracranial pressure (ICP), mean arterial blood pressure, and cerebral perfusion pressure (CPP) were recorded using a digitalized system. Interstitial Gln and pyruvate correlated with CPP (r = 0.25 and 0.24, respectively). Intracranial pressure negatively correlated with Gln (r = -0.29) and the Gln/Glt ratio (r = -0.40). Levels of Gln and pyruvate and the Gln/Glt ratio were higher and levels of Glt and lactate and the lactate/pyruvate ratio were lower during periods of decreased ICP (<or= 10 mm Hg) as compared with values in periods of elevated ICP (> 10 mm Hg). In 3 patients, a poor clinical condition was attributed to high ICP levels (range 15-25 mm Hg). When CSF drainage was increased and the ICP was lowered to 10 mm Hg, there was an instantaneous sharp increase in interstitial Glt and pyruvate in these 3 patients. Increasing interstitial Gln and pyruvate levels appear to be favorable signs associated with improved CPP and low ICP. The authors suggest that this pattern indicates an energy metabolic situation allowing augmented astrocytic energy metabolism with accelerated Glt uptake and Gln synthesis. Moreover, their data raised the question of whether patients with SAH and moderately elevated ICP (15-20 mm Hg) would benefit from CSF drainage at lower pressure levels than what is usually indicated in current clinical protocols.


Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation.
Rapidly proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks. This phenomenon is exemplified in certain malignant conditions such as cancer but also during embryonic development when cells rely heavily on glycolytic metabolism to exploit its metabolic intermediates for biosynthetic processes. How cells reshape their metabolism is not fully understood. Here we report that loss of cathepsin L (Cts L) is associated with a fast proliferation rate and enhanced glycolytic metabolism that depend on lactate dehydrogenase A (LDHA) activity. Using mass spectrometry analysis of cells treated with a pan cathepsin inhibitor, we observed an increased abundance of proteins involved in central carbon metabolism. Further inspection of putative Cts L targets revealed an enrichment for glycolytic metabolism that was independently confirmed by metabolomic and biochemical analyses. Moreover, proteomic analysis of Cts L-knockout cells identified LDHA overexpression that was demonstrated to be a key metabolic junction in these cells. Lastly, we show that Cts L inhibition led to increased LDHA protein expression, suggesting a causal relationship between LDHA expression and function. In conclusion, we propose that Cts L regulates this metabolic circuit to keep cell division under control, suggesting the therapeutic potential of targeting this protein and its networks in cancer.


Gut microbiota composition correlates with diet and health in the elderly.
Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.


A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain.
Dysfunction of glucose transporter 1 (GLUT1) proteins causes infantile epilepsy, which is designated as a GLUT1 deficiency syndrome (GLUT1DS; OMIM #606777). Patients with GLUT1DS display varied clinical phenotypes, such as infantile seizures, ataxia, severe mental retardation with learning disabilities, delayed development, hypoglycorrhachia, and other varied symptoms. Glut1Rgsc200 mutant mice mutagenized with N-ethyl-N-nitrosourea (ENU) carry a missense mutation in the Glut1 gene that results in amino acid substitution at the 324th residue of the GLUT1 protein. In this study, these mutants exhibited various phenotypes, including embryonic lethality of homozygotes, a decreased cerebrospinal-fluid glucose value, deficits in contextual learning, a reduction in body size, seizure-like behavior and abnormal electroencephalogram (EEG) patterns. During EEG recording, the abnormality occurred spontaneously, whereas the seizure-like phenotypes were not observed at the same time. In sleep-wake analysis using EEG recording, heterozygotes exhibited a longer duration of wake times and shorter duration of non-rapid eye movement (NREM) sleep time. The shortened period of NREM sleep and prolonged duration of the wake period may resemble the sleep disturbances commonly observed in patients with GLUT1DS and other epilepsy disorders. Interestingly, an in vivo kinetic analysis of glucose utilization by positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose imaging revealed that glucose transportation was reduced, whereas hexokinase activity and glucose metabolism were enhanced. These results indicate that a Glut1Rgsc200 mutant is a useful tool for elucidating the molecular mechanisms of GLUT1DS.This article has an associated First Person interview with the joint first authors of the paper.


Clueless, a conserved Drosophila gene required for mitochondrial subcellular localization, interacts genetically with parkin.
Parkinson's disease has been linked to altered mitochondrial function. Mutations in parkin (park), the Drosophila ortholog of a human gene that is responsible for many familial cases of Parkinson's disease, shorten life span, abolish fertility and disrupt mitochondrial structure. However, the role played by Park in mitochondrial function remains unclear. Here, we describe a novel Drosophila gene, clueless (clu), which encodes a highly conserved tetratricopeptide repeat protein that is related closely to the CluA protein of Dictyostelium, Clu1 of Saccharomyces cerevisiae and to similar proteins in diverse metazoan eukaryotes from Arabidopsis to humans. Like its orthologs, loss of Drosophila clu causes mitochondria to cluster within cells. We find that strong clu mutations resemble park mutations in their effects on mitochondrial function and that the two genes interact genetically. Conversely, mitochondria in park homozygotes become highly clustered. We propose that Clu functions in a novel pathway that positions mitochondria within the cell based on their physiological state. Disruption of the Clu pathway may enhance oxidative damage, alter gene expression, cause mitochondria to cluster at microtubule plus ends, and lead eventually to mitochondrial failure.


The effect of 5-fluorocytosine on the blastospores and hyphae of Candida albicans.
In Candida albicans the continued increase in dry weight, in cell volume and in hyphal length during 5FC treatment is mainly due to increased amount of carbohydrate despite the decreased amounts of nucleic acids. Incorporation studies with 32PO4 (for RNA) in C. albicans and with 3H-thymidine-monophosphate (for DNA) in a thymidine-utilising strain of Saccharomyces cerevisiae have shown that the decreased amounts of nucleic acids were due to an inhibition of synthesis of RNA and DNA by 5FC. Nuclear-staining techniques on the hyphal phase of C. albicans showed that 5FC inhibits nuclear division. The changes in amounts of protein during 5FC treatment do not wholly explain the changes in cell size although 14C-histidine incorporation experiments showed that protein synthesis continued in the presence of 5FC. 14C-glucose incorporation in the presence of 5FC showed an initial accelerated synthesis of carbohydrate with a maintained level of synthesis after 16 h. This abnormal pattern of synthesis correlates with the increase in amount of carbohydrate and in cell size and hyphal elongation. 5FC inhibits DNA synthesis, and all manifestations of unbalanced growth that culminate in the cell volume changes appear to be a consequence of that inhibition.


Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.
Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer's threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.


Screening for celiac disease in children with recurrent abdominal pain.
The clinical presentation of celiac disease--a life-long gluten intolerance--may be characterized by chronic abdominal pain. The objective of this study was to determine if children with recurrent abdominal pain had a higher prevalence of antiendomysial antibodies (a serologic marker of celiac disease) compared with healthy children. Children with recurrent abdominal pain and healthy control participants were recruited from the offices of community pediatricians. Serum samples were drawn and antiendomysial antibodies were measured in both groups. Demographic data included age, gender, height, and weight. A total of 200 children were recruited, of whom 173 (87%) had serum samples drawn. Of these, 92 were children with recurrent abdominal pain and 81 were control participants. Only 2 of the 173 samples (1.2%) were positive for antiendomysial antibody. The frequency of antiendomysial antibody positivity in children with recurrent abdominal pain was 1 in 92 (1%; 95% confidence interval, 0-6%) compared with 1 in 81 (1%; 95% confidence interval, 0-7%) in control participants. This community-based case-control study found no association between recurrent abdominal pain and the prevalence of antiendomysial antibody. Therefore, these data do not support screening for celiac disease in the child with classic recurrent abdominal pain in the primary care setting.


The role of arginine and arginine-metabolizing enzymes during Giardia - host cell interactions in vitro.
Arginine is a conditionally essential amino acid important in growing individuals and under non-homeostatic conditions/disease. Many pathogens interfere with arginine-utilization in host cells, especially nitric oxide (NO) production, by changing the expression of host enzymes involved in arginine metabolism. Here we used human intestinal epithelial cells (IEC) and three different isolates of the protozoan parasite Giardia intestinalis to investigate the role of arginine and arginine-metabolizing enzymes during intestinal protozoan infections. RNA expression analyses of major arginine-metabolizing enzymes revealed the arginine-utilizing pathways in human IECs (differentiated Caco-2 cells) grown in vitro. Most genes were constant or down-regulated (e.g. arginase 1 and 2) upon interaction with Giardia, whereas inducible NO synthase (iNOS) and ornithine decarboxylase (ODC) were up-regulated within 6 h of infection. Giardia was shown to suppress cytokine-induced iNOS expression, thus the parasite has both iNOS inducing and suppressive activities. Giardial arginine consumption suppresses NO production and the NO-degrading parasite protein flavohemoglobin is up-regulated in response to host NO. In addition, the secreted, arginine-consuming giardial enzyme arginine deiminase (GiADI) actively reduces T-cell proliferation in vitro. Interestingly, the effects on NO production and T cell proliferation could be reversed by addition of external arginine or citrulline. Giardia affects the host's arginine metabolism on many different levels. Many of the effects can be reversed by addition of arginine or citrulline, which could be a beneficial supplement in oral rehydration therapy.


Long-term health effects of neutering dogs: comparison of Labrador Retrievers with Golden Retrievers.
Our recent study on the effects of neutering (including spaying) in Golden Retrievers in markedly increasing the incidence of two joint disorders and three cancers prompted this study and a comparison of Golden and Labrador Retrievers. Veterinary hospital records were examined over a 13-year period for the effects of neutering during specified age ranges: before 6 mo., and during 6-11 mo., year 1 or years 2 through 8. The joint disorders examined were hip dysplasia, cranial cruciate ligament tear and elbow dysplasia. The cancers examined were lymphosarcoma, hemangiosarcoma, mast cell tumor, and mammary cancer. The results for the Golden Retriever were similar to the previous study, but there were notable differences between breeds. In Labrador Retrievers, where about 5 percent of gonadally intact males and females had one or more joint disorders, neutering at <6 mo. doubled the incidence of one or more joint disorders in both sexes. In male and female Golden Retrievers, with the same 5 percent rate of joint disorders in intact dogs, neutering at <6 mo. increased the incidence of a joint disorder to 4-5 times that of intact dogs. The incidence of one or more cancers in female Labrador Retrievers increased slightly above the 3 percent level of intact females with neutering. In contrast, in female Golden Retrievers, with the same 3 percent rate of one or more cancers in intact females, neutering at all periods through 8 years of age increased the rate of at least one of the cancers by 3-4 times. In male Golden and Labrador Retrievers neutering had relatively minor effects in increasing the occurrence of cancers. Comparisons of cancers in the two breeds suggest that the occurrence of cancers in female Golden Retrievers is a reflection of particular vulnerability to gonadal hormone removal.


Health-related quality of life 10 years after intracranial aneurysm rupture: a retrospective cohort study using EQ-5D.
Experiencing an aneurysmal subarachnoid hemorrhage (SAH) could affect health-related quality of life (HRQoL) several years after the onset. Long-term studies are scarce, and there is a lack of knowledge of whether HRQoL is affected > 5 years after the onset and, if so, in what dimensions. In the general population, HRQoL decreases with age and with the occurrence of a disease and differs between sexes. Factors that may influence HRQoL after aneurysmal SAH include neurological outcome, perceived recovery, aneurysm treatment, and family support. To measure HRQoL and to explore factors affecting HRQoL 10 years after aneurysmal SAH. A consecutive sample of all patients admitted for intracranial aneurysm rupture at a neurosurgical clinic in Stockholm (n = 217, 79.5% of eligible) were followed up from 2007 to 2008, approximately 10 years after aneurysm rupture. HRQoL was measured with EQ-5D, and the results were compared with a general population sample from the Stockholm Public Health Survey 2006 matched by age and sex. Compared with the general population, the aneurysm sample reported significantly more problems in 4 of 5 EQ-5D dimensions-mobility, self-care, usual activities, and anxiety/depression-and had significantly lower EQ-5Dindex and EQ visual analog scale values. Within the aneurysm sample, HRQoL was most affected in respondents with worse Glasgow outcome scale values at hospital discharge, respondents with comorbidities, and respondents with low perceived recovery. Aneurysmal SAH affects HRQoL to a large extent, even 10 years after the onset, indicating a need for long-term follow-up and support after the onset.


The Influence of a Nanopatterned Scaffold that Mimics Abnormal Renal Mesangial Matrix on Mesangial Cell Behavior.
The alteration of mesangial matrix (MM) components in mesangium, such as type IV collagen (COL4) and type I collagen (COL1), is commonly found in progressive glomerular disease. Mesangial cells (MCs) responding to altered MM, show critical changes in cell function. This suggests that the diseased MM structure could play an important role in MC behavior. To investigate how MC behavior is influenced by the diseased MM 3D nanostructure, we fabricated the titanium dioxide (TiO2)-based nanopatterns that mimic diseased MM nanostructures. Immortalized mouse MCs were used to assess the influence of disease-mimic nanopatterns on cell functions, and were compared with a normal-mimic nanopattern. The results showed that the disease-mimic nanopattern induced disease-like behavior, including increased proliferation, excessive production of abnormal MM components (COL1 and fibronectin) and decreased normal MM components (COL4 and laminin α1). In contrast, the normal-mimic nanopattern actually resulted in cells displaying normal proliferation and the production of normal MM components. In addition, increased expressions of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and integrin α5β1 were detected in cells grown on the disease-mimic nanopattern. These results indicated that the disease-mimic nanopattern induced disease-like cell behavior. These findings will help further establish a disease model that mimics abnormal MM nanostructures and also to elucidate the molecular mechanisms underlying glomerular disease.


The effect of exercise on depressive symptoms in multiple sclerosis based on a meta-analysis and critical review of the literature.
The purpose of this study was to perform a systematic review of the literature on the effects of exercise on depressive symptoms in patients with multiple sclerosis (MS), as well as to apply meta-analytical procedures to the results. A systematic search covering eight databases was conducted. The included studies were randomized controlled trials applied to people with definite MS who completed a structured exercise intervention which were compared to any comparator, including other forms of exercise. The outcomes included a primary measure of depression/depressive symptoms or an instrument with a clearly defined depression subscale. Fifteen randomized controlled trial studies were identified including a total of 331 exercising subjects and 260 controls. The average Physiotherapy Evidence Database (PEDro) score was 5.6 ± 1.3 points. Only one study applied depressive symptoms as the primary outcome. Four studies showed positive effects of exercise on depressive symptoms. An in-depth analysis of the studies revealed that the baseline level of depressive symptoms, patient disability level, choice of depression instrument and exercise intensity may influence the results. The meta-analysis included 12 studies reflecting a total of 476 subjects. The standardized mean difference across studies was g = -0.37, 95% confidence interval (-0.56; -0.17), and the null hypothesis of homogeneity within the sample could not be rejected (Q = 12.05, df = 11, P = 0.36). Exercise may be a potential treatment to prevent or reduce depressive symptoms in individuals with MS, but existing studies do not allow solid conclusions. Future well-designed studies evaluating the effects of exercise on depressive symptoms and major depression disorder in MS are highly warranted.


Replication of UV-irradiated single-stranded DNA by DNA polymerase III holoenzyme of Escherichia coli: evidence for bypass of pyrimidine photodimers.
Replication of UV-irradiated circular single-stranded phage M13 DNA by Escherichia coli RNA polymerase (EC 18.104.22.168) and DNA polymerase III holoenzyme (EC 188.8.131.52) in the presence of single-stranded DNA binding protein yielded full-length as well as partially replicated products. A similar result was obtained with phage G4 DNA primed with E. coli DNA primase, and phage phi X174 DNA primed with a synthetic oligonucleotide. The fraction of full-length DNA was several orders of magnitude higher than predicted if pyrimidine photodimers were to constitute absolute blocks to DNA replication. Recent models have suggested that pyrimidine photodimers are absolute blocks to DNA replication and that SOS-induced proteins are required to allow their bypass. Our results demonstrate that, under in vitro replication conditions, E. coli DNA polymerase III holoenzyme can insert nucleotides opposite pyrimidine dimers to a significant extent, even in the absence of SOS-induced proteins.


Chemical Defense Against Different Marine Herbivores: Are Amphipods Insect Equivalents?
The Structurally similar diterpenoid alcohols pachydictyol-A and dictyol-E are produced by the brown seaweed Dictyota dichotoma. This seaweed and several related species that also produce these compounds are known to be relatively low preference foods for tropical fishes and urchins. We evaluated the effect of various concentrations of these compounds on feeding by the three common types of herbivores that co-occur with Dictyota in coastal North Carolina. Fish (Diplodus holbrooki), sea urchins (Arbacia punctulata), and a mixed species group of gammarid amphipods were offered pieces of the palatable seaweed Gracilaria tikvahiae coated with either (1) dictyol-E or pachydictyol-A dissolved in diethyl ether or (2) diethyl ether alone. Dictyol-E significantly reduced consumption by fish and urchins at concentrations of 0.5 and 1.0% of algal dry mass, but had no effect on amphipod grazing. Pachydictyol-A significantly reduced fish grazing at the relatively high concentrations of 1.0 and 1.3% of plant dry mass; at 0.5% it tended to decrease grazing, but the effect was not significant (P = .07). Pachydictyol-A had no effect on urchin grazing and significantly increased amphipod grazing. When Pachydictyol-A was fed to fish as 1.0% of food dry mass, their growth rate was reduced by a significant 48%. In feeding preference experiments with several seaweeds, Dictyota ranks low for fish and urchins but high for amphipods. This is consistent with the hypothesis that the secondary metabolites produced by Dictyota play a major role in determining its susceptibility to herbivores. The ability of amphipods to circumvent the chemical defenses (Dictyota, and the fact that the two species of algae most readily consumed by amphipods (Codium and Dictyota) were the two species least readily consumed by fish, suggest that predation and herbivory by fishes may be major factors selecting for amphipods that can live on, and eat, seaweeds that are unpalatable to fishes. Amphipods that fed on Dictyota did not appear to sequester the Dictyota metabolites; when exposed to fish predation, Dictyota-fed amphipods were eaten as readily as amphipods that had fed on an alga with no defensive chemistry. Tubicolous amphipods and other small marine herbivores that may spend significant portions of their lives on only a few plants my be under very different evolutionary constraints than the larger, more mobile herbivores that commonly moved between many plants. Several characteristics of these smaller, less mobile, and much less studied, marine herbivores suggest that they may be ecologically similar to terrestrial insects and may play a large, but presently unappreciated, role in structuring marine plant communities.


Influences of ammonia contamination on leaching from air-pollution-control residues.
Application of selective non-catalytic reduction systems at municipal solid waste incinerators (MSWIs) often involves over-stoichiometric injection of ammonia into flue gases. Un-reacted ammonia may be deposited on fly ash particles and can ultimately influence the leaching behaviour of air-pollution-control (APC) residues. Batch tests were conducted to investigate the impacts of ammonia levels on leaching of a range of metals (sodium, potassium, calcium, aluminium, chromium, iron, lead, cadmium, copper, nickel and zinc), as well as chloride and dissolved organic carbon (DOC). Specific conductivity was also identified to reflect the soluble components. The results showed that with ammonia concentrations rising from a background level of 4 to 26,400 mg l(-1), the specific conductivity increased by 2-7 times as pH varied from alkaline to acidic values. DOC release was also significantly enhanced with high ammonia levels of 1400 mg l(-1) or higher at pH > 9; however at these high ammonia concentrations, the role of DOC in cadmium, copper, nickel and zinc leaching was negligible. Based on the experimental data, chloride, sodium and potassium were leached at high concentrations regardless of pH and ammonia concentrations. For aluminium, chromium, iron and lead, ammonia had little impact on their leaching behaviour. With respect to cadmium, copper, nickel and zinc, high ammonia concentrations significantly increased leaching in the pH range of 8-12 due to the formation of metal-ammonia complexes, which was also proved in the speciation calculations. However, the overall results suggest that typical levels of ammonia injection in MSWIs are not likely to affect metal leaching from APC residues.


Effect of advanced oxidation processes on the micropollutants and the effluent organic matter contained in municipal wastewater previously treated by three different secondary methods.
In this study, wastewater from the output of three different secondary treatment facilities (Activated Sludge, Moving Bed Bioreactor and Coagulation-Flocculation) present in the municipal wastewater treatment plant of Vidy, Lausanne (Switzerland), was further treated with various oxidation processes (UV, UV/H2O2, solar irradiation, Fenton, solar photo-Fenton), at laboratory scale. For this assessment, 6 organic micropollutants in agreement with the new environmental legislation requirements in Switzerland were selected (Carbamazepine, Clarithromycin, Diclofenac, Metoprolol, Benzotriazole, Mecoprop) and monitored throughout the treatment. Also, the overall removal of the organic load was assessed. After each secondary treatment, the efficiency of the AOPs increased in the following order: Coagulation-Flocculation < Activated Sludge < Moving Bed Bioreactor, in almost all cases. From the different combinations tested, municipal wastewater subjected to biological treatment followed by UV/H2O2 resulted in the highest elimination levels. Wastewater previously treated by physicochemical treatment demonstrated considerably inhibited micropollutant degradation rates. The degradation kinetics were determined, yielding: k (UV) < k (UV/H2O2) and k (Fenton) < k (solar irradiation) < k (photo-Fenton). Finally, the evolution of global pollution parameters (COD & TOC elimination) was followed and the degradation pathways for the effluent organic matter are discussed.


The Drosophila L1CAM homolog Neuroglian signals through distinct pathways to control different aspects of mushroom body axon development.
The spatiotemporal integration of adhesion and signaling during neuritogenesis is an important prerequisite for the establishment of neuronal networks in the developing brain. In this study, we describe the role of the L1-type CAM Neuroglian protein (NRG) in different steps of Drosophila mushroom body (MB) neuron axonogenesis. Selective axon bundling in the peduncle requires both the extracellular and the intracellular domain of NRG. We uncover a novel role for the ZO-1 homolog Polychaetoid (PYD) in axon branching and in sister branch outgrowth and guidance downstream of the neuron-specific isoform NRG-180. Furthermore, genetic analyses show that the role of NRG in different aspects of MB axonal development not only involves PYD, but also TRIO, SEMA-1A and RAC1.


A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis.
Polyketide synthases assemble diverse natural products with numerous important applications. The thioester intermediates in polyketide assembly are covalently tethered to acyl carrier protein domains of the synthase. Several mechanisms for polyketide chain release are known, contributing to natural product structural diversification. Here, we report a dual transacylation mechanism for chain release from the enacyloxin polyketide synthase, which assembles an antibiotic with promising activity against Acinetobacter baumannii. A non-elongating ketosynthase domain transfers the polyketide chain from the final acyl carrier protein domain of the synthase to a separate carrier protein, and a non-ribosomal peptide synthetase condensation domain condenses it with (1S,3R,4S)-3,4-dihydroxycyclohexane carboxylic acid. Molecular dissection of this process reveals that non-elongating ketosynthase domain-mediated transacylation circumvents the inability of the condensation domain to recognize the acyl carrier protein domain. Several 3,4-dihydroxycyclohexane carboxylic acid analogues can be employed for chain release, suggesting a promising strategy for producing enacyloxin analogues.


Reticulate evolutionary history of a complex group of grasses: phylogeny of Elymus StStHH allotetraploids based on three nuclear genes.
Elymus (Poaceae) is a large genus of polyploid species in the wheat tribe Triticeae. It is polyphyletic, exhibiting many distinct allopolyploid genome combinations, and its history might be further complicated by introgression and lineage sorting. We focus on a subset of Elymus species with a tetraploid genome complement derived from Pseudoroegneria (genome St) and Hordeum (H). We confirm the species' allopolyploidy, identify possible genome donors, and pinpoint instances of apparent introgression or incomplete lineage sorting. We sequenced portions of three unlinked nuclear genes-phosphoenolpyruvate carboxylase, beta-amylase, and granule-bound starch synthase I-from 27 individuals, representing 14 Eurasian and North American StStHHElymus species. Elymus sequences were combined with existing data from monogenomic representatives of the tribe, and gene trees were estimated separately for each data set using maximum likelihood. Trees were examined for evidence of allopolyploidy and additional reticulate patterns. All trees confirm the StStHH genome configuration of the Elymus species. They suggest that the StStHH group originated in North America, and do not support separate North American and European origins. Our results point to North American Pseudoroegneria and Hordeum species as potential genome donors to Elymus. Diploid P. spicata is a prospective St-genome donor, though conflict among trees involving P. spicata and the Eurasian P. strigosa suggests either introgression of GBSSI sequences from P. strigosa into North American Elymus and Pseudoroegneria, or incomplete lineage sorting of ancestral GBSSI polymorphism. Diploid H. californicum and/or allotetraploid H. jubatum are possible H-genome donors; direct involvement of an allotetraploid Hordeum species would simultaneously introduce two distinct H genomes to Elymus, consistent with some of the relationships among H-genome sequences in Hordeum and Elymus. Comparisons among molecular phylogenetic trees confirm allopolyploidy, identify potential genome donors, and highlight cases of apparent introgression or incomplete lineage sorting. The complicated history of this group emphasizes an inherent problem with interpreting conflicts among bifurcating trees-identifying introgression and determining its direction depend on which tree is chosen as a starting point of comparison. In spite of difficulties with interpretation, differences among gene trees allow us to identify reticulate species and develop hypotheses about underlying evolutionary processes.


Does breastfeeding protect against substantiated child abuse and neglect? A 15-year cohort study.
We explored whether breastfeeding was protective against maternally perpetrated child maltreatment. A total of 7223 Australian mother-infant pairs were monitored prospectively over 15 years. In 6621 (91.7%) cases, the duration of breastfeeding was analyzed with respect to child maltreatment (including neglect, physical abuse, and emotional abuse), on the basis of substantiated child protection agency reports. Multinomial logistic regression was used to compare no maltreatment with nonmaternal and maternally perpetrated maltreatment and to adjust for confounding in 5890 cases with complete data (81.5%). Potential confounders included sociodemographic factors, pregnancy wantedness, substance abuse during pregnancy, postpartum employment, attitudes regarding infant caregiving, and symptoms of anxiety or depression. Of 512 children with substantiated maltreatment reports, >60% experienced > or =1 episode of maternally perpetrated abuse or neglect (4.3% of the cohort). The odds ratio for maternal maltreatment increased as breastfeeding duration decreased, with the odds of maternal maltreatment for nonbreastfed children being 4.8 times the odds for children breastfed for > or =4 months. After adjustment for confounding, the odds for nonbreastfed infants remained 2.6 times higher, with no association seen between breastfeeding and nonmaternal maltreatment. Maternal neglect was the only maltreatment subtype associated independently with breastfeeding duration. Among other factors, breastfeeding may help to protect against maternally perpetrated child maltreatment, particularly child neglect.


Genetic Diversity in Bradyrhizobium japonicum Serogroup 123 and Its Relation to Genotype-Specific Nodulation of Soybean.
The genetic diversity among 20 field isolates of Bradyrhizobium japonicum serogroup 123 was examined by using restriction endonuclease digestions, one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis of total cell proteins, Southern hybridization analysis of nif and nod genes, and intrinsic antibiotic resistance profiles. All of the isolates were previously separated into three broad nodulation classes (low, medium, and high) based on their ability to form symbioses with specific soybean genotypes. Results of our studies indicate that there is a relationship between these three genotype-specific nodulation classes and groupings that have been made based on genomic DNA digestion patterns, sodium dodecyl sulfate-protein profiles, and Southern hybridizations to a nifHD gene probe. Intrinsic antibiotic resistance profiles and nodAB gene hybridizations were not useful in determining interrelationships between isolates and nodulation classes. Southern hybridizations revealed that two of the isolates had reiterated nod genes; however, there was no correlation between the presence of extra nodAB genes and the nodulation classes or symbiotic performance on permissive soybean genotypes. Hybridizations with the nif gene probe indicated that there is a relationship among serogroup, nodulation class, and the physical organization of the genome.


Development of a Novel Loop-Mediated Isothermal Amplification Method for the Rapid Detection of Monkeypox Virus Infections.
A recent outbreak of monkeypox virus (mpox) has prompted researchers to explore diagnostics as a means of impeding transmission and further spread. Rapid, sensitive, and specific methods are crucial for accurately diagnosing mpox infections. Here, we developed a loop-mediated isothermal amplification (LAMP) assay for the specific detection of mpox. The primer sets were designed to target regions in and around the N4R gene, and results showed a detection limit of 2 × 100 DNA copies, which is comparable to the gold-standard qPCR method currently used to detect mpox. Particularly, the assay provides results visible to the naked eye within 30 min. This test specifically detects mpox DNA with no cross-reactivity to related DNA viruses including Varicella Zoster Virus (VZV), Hepatitis B virus (HBV), Vaccinia virus (VACV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human papillomavirus-16 (HPV-16) and Human papillomavirus-18 (HPV-18). Furthermore, the LAMP assay has been evaluated using clinical samples from laboratory-confirmed mpox patients and found to be consistent with the qPCR results. Our results show that this single-tube LAMP method can contribute to diagnosis of suspected mpox infections in the field and clinic, especially in regions with limited laboratory resources.


Effect of combined bifidobacteria supplementation and resistance training on cognitive function, body composition and bowel habits of healthy elderly subjects.
Physical exercise exerts favourable effects on brain health and quality of life of the elderly; some of these positive health effects are induced by the modulation of microbiota composition. We therefore conducted a randomised, double blind, placebo-controlled trial that assessed whether a combination of Bifidobacterium spp. supplementation and moderate resistance training improved the cognitive function and other health-related parameters in healthy elderly subjects. Over a 12-week period, 38 participants (66-78 years) underwent resistance training and were assigned to the probiotic Bifidobacterium supplementation (n=20; 1.25×1010 cfu each of Bifidobacterium longum subsp. longum BB536, B. longum subsp. infantis M-63, Bifidobacterium breve M-16V and B. breve B-3) or the placebo (n=18) group. At baseline and at 12 weeks, we assessed the cognitive function, using the Japanese version of the Montreal Cognitive Assessment instrument (MoCA-J); modified flanker task scores; depression-anxiety scores; body composition; and bowel habits. At 12 weeks, the MoCA-J scores showed a significant increase in both the groups, while the flanker task scores of the probiotic group increased more significantly than those of the placebo group (0.35±0.9 vs -0.29±1.1, P=0.056). Only the probiotic group showed a significant decrease in the depression-anxiety scores (5.2±6.3 to 3.4±5.5, P=0.012) and body mass index (24.0±2.8 to 23.5±2.8 kg/m2, P<0.001), with a significant increase in the defecation frequency (5.3±2.3 to 6.4±2.3 times/5 days, P=0.023) at 12 weeks. Thus, in healthy elderly subjects, combined probiotic bifidobacteria supplementation and moderate resistance training may improve the mental condition, body weight and bowel movement frequency.


Detection of the TNFSF members BAFF, APRIL, TWEAK and their receptors in normal kidney and renal cell carcinomas.
In advanced renal cell carcinoma (RCC), surgery combined with systemic chemotherapy and immunotherapy have had limited effectiveness. Therapeutic modalities targeting VEGF, PDGF, and c-kit using tyrosine kinase inhibitors and m-TOR using specific biologic factors are in development. Therapeutic approaches targeting TNF-alpha have shown limited efficacy, while anti-TRAIL (TNFSF10) antibodies have shown enhanced activity. The presence and potential significance of other members of the TNFSF has not been investigated. Here, we assayed the TNFSF members APRIL, BAFF, TWEAK and their receptors (BCMA, TACI, BAFFR, Fn14) in 86 conventional type clear cell RCC, using immunohistochemistry and correlated our findings with histological data and, in a limited series, follow-up of patients. We observed a differential expression of these TNFSF ligands and receptors in cancerous and non-cancerous structures. BAFF was found in all RCC; APRIL expression is associated with an aggressive phenotype, correlating negatively with patients' disease-free survival, while TWEAK and its receptor Fn14 are heterogeneously expressed, correlating negatively with the grade and survival of RCC patients. This is the first study, presenting together the TNFSF members APRIL, BAFF, TWEAK and their receptors in different areas of normal renal tissue and RCC, suggesting a potential role of these TNFSF members in renal tumor biology.


Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2.
Sildenafil (Viagra), the first approved and widely used oral drug for the treatment of erectile dysfunction, was occasionally associated with life-threatening ventricular arrhythmias in patients. Since inward rectifier potassium current (I K1) may considerably contribute to this arrhythmogenesis, we investigated the effect of sildenafil on the human Kir2.1 and Kir2.2, the prevailing subunits forming the ventricular I K1 channels. Experiments were performed by the whole-cell patch clamp technique at 37°C using Chinese hamster ovary cells transiently expressing the human Kir2.1 and Kir2.2 channels. Changes of both the inward and outward current components (at -110 and -50 mV, respectively) were tested to be able to consider the physiological relevance of the sildenafil effect (changes at -110 and -50 mV did not significantly differ, results at -50 mV are listed below). A significant Kir2.1 inhibition was observed at all applied sildenafil concentrations (16.1% ± 3.7%, 20.0% ± 2.6%, and 15.0% ± 3.0% at 0.1, 1, and 10 μM, respectively). The inhibitory effect of 0.1 μM sildenafil was potentiated by the presence of a low concentration of Ba2+ (0.1 μM) which induced only a slight Kir2.1 inhibition by 5.95% ± 0.75% alone (the combined effect was 35.5% ± 3.4%). The subtherapeutic and therapeutic sildenafil concentrations (0.1 and 1 μM) caused a dual effect on Kir2.2 channels whereas a significant Kir2.2 activation was observed at the supratherapeutic sildenafil concentration (10 μM: 34.1% ± 5.6%). All effects were fully reversible. This is the first study demonstrating that sildenafil at clinically relevant concentrations inhibits both the inward and outward current components of the main human ventricular I K1 subunit Kir2.1. This inhibitory effect was significantly potentiated by a low concentration of environmental contaminant Ba2+ in agreement with recently reported data on rat ventricular I K1 which additionally showed a significant repolarization delay. Considering the similar subunit composition of the human and rat ventricular I K1 channels, the observed effects might contribute to sildenafil-associated arrhythmogenesis in clinical practice.


Sympathetic and periodic vagal influences on antegrade and retrograde conduction through the canine atrioventricular node.
Concurrent stimulation of the parasympathetic and sympathetic branches of the autonomic nervous system causes a diminished sympathetic response at high levels of vagal activity. This "accentuated antagonism" has been demonstrated for cardiac chronotropic, inotropic, and dromotropic responses. The effect on conduction was demonstrated with tonic stimulation of the vagus nerve. However, normally the vagus nerve fires periodically at certain times in the cardiac cycle. Thus, we have studied whether a similar interaction exists in the modulation of atrioventricular condition when short bursts of vagal stimulation were placed in various portions of the cardiac cycle. Anesthetized open-chest mongrel dogs were instrumented for stimulation of the cervical vagi and stellate ganglia when the heart was paced. We determined the relationship between cardiac cycle length, direction of action potential propagation, and levels of sympathetic and vagal activation and their effects on atrioventricular conduction times. All of the factors investigated, namely levels of vagal and stellate stimulation, pacing intervals, and direction of propagation of action potentials, affected atrioventricular conduction times. Furthermore, the vagal effect was greater at short cardiac cycle lengths. When bursts of vagal stimulation were timed to result in maximal or minimal prolongation of atrioventricular conduction, no significant effects of sympathetic-parasympathetic interaction on atrioventricular conduction times were apparent. However, an analysis of the differences in prolongation of atrioventricular conduction with periodic vagal stimulation revealed that a significant sympathetic-vagal interaction existed for these differences. Thus, autonomic neurotransmitters differentially affect cardiac conduction times depending on time of application of the stimulus.


Intradiscal pressure changes with dynamic pedicle screw systems.
In vitro study using porcine spines instrumented with pedicle screw and rod fixation. To determine the intradiscal pressure (IDP) changes with the use of dynamic and rigid pedicle screw systems in simulated spinal fusion. The intervertebral discs are prone to injury under conditions of altered IDP. The effects of instrumentation with dynamic pedicle screw systems on IDP have not been clearly delineated. A 2-level posterior instrumentation was applied to fresh porcine spinal segments (n=16). Dynamic and rigid pedicle screw constructs along with uninstrumented (n=6) spinal segments as controls were tested. The spinal segments were subjected to 24,000 cycles of flexion compression loading at 5 Hz. IDP within the instrumented (L2-L3 and L3-L4) and adjacent (L1-L2 and L4-L5) discs were measured using a pressure transducer needle. Results were recorded at 6000 cycle intervals. Instrumentation increased IDP. Within the instrumented levels, the greatest increase in IDP was found at the L2-L3 disc. Here, after 24,000 loading cycles, IDP for spines instrumented with mobile screws was 6.8 times higher than that of uninstrumented spines whereas for rigid screws the factor was 9.1. For the L3-L4 cases, the presence of instrumentation increased IDP by factors of 1.7 and 2.7 for mobile and rigid screws, respectively. In the uninstrumented levels, IDP at L1-L2 and L4-L5 was lower with mobile screws. These were statistically significant at for L1-L2 (24,000 cycles, P=0.008) and L4-L5 level (12,000, 18,000, and 24,000 cycles, P<0.04 in all cases). Of the 2 types, mobile screws produced the least increase in IDP. This feature might be beneficial for the fusion process while at the same time prevent secondary pathology such as premature disc degeneration and facet joint pathology due to excessive disc pressures.


The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro.
Combretastatin A-4-phosphate (CA-4-P) is a microtubule depolymerising agent currently in clinical trial as a tumour vascular-targeting agent. In vivo, CA-4-P causes rapid shutdown of tumour blood flow (within minutes) and a significant neutrophil infiltration at later times. Using an in vitro flow-cell assay, we investigated neutrophil-endothelial cell interactions and associated mechanisms, following endothelial cell exposure to CA-4-P. Cellular adhesion molecule (CAM) expression was examined using immunoblotting and immunofluorescence, and the role of CAM in neutrophil recruitment was investigated using specific blocking antibodies. Exposure of HUVEC to CA-4-P, resulted in significant neutrophil recruitment, and increased expression of endothelial CAM. Results of antibody studies demonstrated that endothelial CAM expression induced by CA-4-P is responsible for the observed neutrophil recruitment. This study demonstrated that the tumour vascular targeting agent, CA-4-P, directly induces endothelial CAM expression and subsequent neutrophil recruitment. In vivo, neutrophil infiltration probably contributes to CA-4-P-induced tumour cell kill. Therefore, increasing neutrophil recruitment into tumours may have potential for optimising vascular-targeted strategies for cancer therapy.


Neonicotinoid resistance in rice brown planthopper, Nilaparvata lugens.
Rice brown planthopper, Nilaparvata lugens Stål, is a primary insect pest of cultivated rice, and effective control is essential for economical crop production. Resistance to neonicotinoid insecticides, in particular imidacloprid, has been reported as an increasing constraint in recent years. In order to investigate the extent of resistance, 24 samples of N. lugens were collected from China, India, Indonesia, Malaysia, Thailand and Vietnam during 2005 and 2006. Their responses to two diagnostic doses of imidacloprid (corresponding approximately to the LC(95) and 5 x LC(95) of a susceptible strain) were examined. Ten of the 12 samples collected during 2005 were found to be susceptible to imidacloprid, but two late-season samples from India showed reduced mortality at both diagnostic doses. All 13 strains collected in 2006 showed reduced mortality at both doses when compared with the susceptible strain. Dose-response lines showed resistance in one of the most resistant field strains to be approximately 100-fold compared with the susceptible standard. The data demonstrate the development and spread of neonicotinoid resistance in N. lugens in Asia and support reports of reduced field efficacy of imidacloprid.


CAl4X (X=Si,Ge): molecules with simultaneous planar tetracoordinate carbon, aluminum, and silicon/germanium.
The authors report the first theoretical study on the hexa-atomic molecules CAl(4)X (X=Si,Ge) at the B3LYP/6-311++G(2d), MP2/6-311++G(2d), and CCSD(T)/6-311++G(3df) (single point) levels. Three low-lying isomers (within 2.0 kcal/mol) can be formally viewed as constructed by one Al+ interacting with the planar CAl3X- at the side Al-X bond (X-1), side Al-Al bond (X-2), and central C atom (X-3). The isomers X-1 and X-2 both have planar structures that include the planar tetracoordinate carbon, aluminum, and silicon/germanium, while the three-dimensional isomer X-3 has the pentacoordinate carbon. The planarity of X-1 and X-2 is ascribed to the ligand five-center two-electron bonding molecular orbital, similar to the orbital responsible for the planarity of CAl3X- (X=Si,Ge). Kinetically, the two planar structures X-1 and X-2 can be easily interconverted to each other via the intermediate X-3, indicative of their coexistence. Of particular interest, isomer X-1 represents the first example that simultaneously contains three types of planar centers in a single molecule, to the best of our knowledge. The three low-lying and structurally interesting isomers X-1, X-2, and X-3 await future experimental verification. The present results could enrich the planar chemistry.


Geminate charge recombination in polymer/fullerene bulk heterojunction films and implications for solar cell function.
We have studied the influence of three different fullerene derivatives on the charge generation and recombination dynamics of polymer/fullerene bulk heterojunction (BHJ) solar cell blends. Charge generation in APFO3/[70]PCBM and APFO3/[60]PCBM is very similar and somewhat slower than charge generation in APFO3/[70]BTPF. This difference qualitatively matches the trend in free energy change of electron transfer estimated from the LUMO energies of the polymer and fullerene derivatives. The first order (geminate) charge recombination rate is significantly different for the three fullerene derivatives studied and increases in the order APFO3/[70]PCBM < APFO3/[60]PCBM < APFO3/[70]BTPF. The variation in electron transfer rate cannot be explained from the LUMO energies of the fullerene derivatives and single-step electron transfer in the Marcus inverted region and simple considerations of expected trends for the reorganization energy and free energy change. Instead we suggest that geminate charge recombination occurs from a state where electrons and holes have separated to different distances in the various materials because of an initially high charge mobility, different for different materials. In a BHJ thin film this charge separation distance is not sufficient to overcome the electrostatic attraction between electrons and holes and geminate recombination occurs on the nanosecond to hundreds of nanoseconds time scale. In a BHJ solar cell, we suggest that the internal electric field in combination with polarization effects and the dynamic nature of polarons are key features to overcome electron-hole interactions to form free extractable charges.


Fruit and Vegetable Consumption and the Incidence of Hypertension in Three Prospective Cohort Studies.
Increased fruit and vegetable intake lowers blood pressure in short-term interventional studies. However, data on the association of long-term intake of fruits and vegetables with hypertension risk are scarce. We prospectively examined the independent association of whole fruit (excluding juices) and vegetable intake, as well as the change in consumption of whole fruits and vegetables, with incident hypertension in 3 large longitudinal cohort studies: Nurses' Health Study (n=62 175), Nurses' Health Study II (n=88 475), and Health Professionals Follow-up Study (n=36 803). We calculated hazard ratios and 95% confidence intervals for fruit and vegetable consumption while controlling for hypertension risk factors. Compared with participants whose consumption was ≤4 servings/week, the pooled hazard ratios among those whose intake was ≥4 servings/day were 0.92(0.87-0.97) for total whole fruit intake and 0.95(0.86-1.04) for total vegetable intake. Similarly, compared with participants who did not increase their fruit or vegetable consumption, the pooled hazard ratios for those whose intake increased by ≥7 servings/week were 0.94(0.90-0.97) for total whole fruit intake and 0.98(0.94-1.01) for total vegetable. Analyses of individual fruits and vegetables yielded different results. Consumption levels of ≥4 servings/week (as opposed to <1 serving/month) of broccoli, carrots, tofu or soybeans, raisins, and apples was associated with lower hypertension risk. In conclusion, our results suggest that greater long-term intake and increased consumption of whole fruits may reduce the risk of developing hypertension.


Wall enhancement, edema, and hydrocephalus after endovascular coil occlusion of intradural cerebral aneurysms.
Symptomatic local inflammation, aseptic meningitis, and hydrocephalus are reported in a group of patients treated with second generation/modified platinum coils. The purpose of this study was to define the frequency and determinants of magnetic resonance (MR) imaging findings of aneurysm wall enhancement, perianeurysmal edema, and hydrocephalus in a cohort of coil-embolized intradural cerebral aneurysms treated with bare platinum or modified platinum coils (Matrix or HydroCoils). The authors retrospectively reviewed 359 Gd-enhanced MR follow-up studies of 181 treated aneurysms (125 ruptured) for mural enhancement. Univariate and multivariate logistic regression analyses were used to define mural enhancement associations with demographic, clinical, angiographic, treatment, and follow-up data. Embolization-related edema and hydrocephalus were defined in 95 MR imaging studies of 56 unruptured aneurysms. Asymptomatic wall enhancement was observed in lesions treated with all coil types, occurring in 21 (18.6%) of 113 bare platinum coil-treated aneurysms. Independent associations were HydroCoil treatment (odds ratio [OR] 9.75, 95% confidence interval [CI] 3.45-30.75) and increasing aneurysm size (OR 3.58, 95% CI 1.99-6.95). Five (8.9%) unruptured aneurysms had asymptomatic de novo edema, and 3 (5.3%) demonstrated hydrocephalus; all had been treated with HydroCoils. Hydrocephalus presentation was delayed (8-31 months) and symptomatic in 2 patients. Asymptomatic aneurysm wall enhancement occurred in 18.6% of embolizations performed with bare platinum coils, and probably represents a normal healing response. Perimural edema and hydrocephalus were observed only in patients treated with HydroCoils, but have been reported in patients treated with other modified platinum coils. These symptoms appear to represent an exaggerated inflammatory response during aneurysm healing. Increased vigilance for delayed hydrocephalus is required. Judicious clinical use of modified platinum coils is warranted until results of randomized trials are published.


fNIRS-based evaluation of the impact of SARS-CoV-2 infection central auditory processing.
Coronavirus disease-2019 due to SARS-CoV-2 infection has been associated with neurological and neuropsychiatric illnesses as well as auditory system problems. In this study, we aimed to evaluate the impact of SARS-CoV-2 infection on the central auditory system by assessing the hemodynamic activation changes using functional near-infrared spectroscopy (fNIRS). Three participants who had SARS-CoV-2 infection (study group) and four participants who had no SARS-CoV-2 infection (control group) were included in the study. During the auditory oddball task in which two different frequencies of tonal stimulation were presented at 80 dB HL, the participants were asked to pay attention to the rare tonal stimulation and mentally count these target stimuli throughout the task. During this task, oxygenated hemodynamic response functions were evaluated with fNIRS. Significantly increased oxygenated hemodynamic responses were observed in both groups during the task (p < .05), which was significantly higher in the study group (p < .05). Significantly more HbO activation was observed in the vmPFC, superior temporal gyrus, and medial temporal gyrus in the study group compared to controls (p < .05). Significantly higher hemodynamic activation was observed in the right hemisphere in both groups, which was significantly higher in the study group (p < .05). SARS-CoV-2 infections may impact on central auditory processing or auditory attention due to changes in oxyhemoglobin levels in the frontal and temporal brain regions. It seems that SARS-CoV-2 infection is associated with an additional load on neural activity, and difficulties in focusing in auditory attention, following speech and hearing in noise as well as increased effort to perceive auditory cues.


Bisphosphonate-related osteonecrosis of the jaws: analysis of a case series at a dental school.
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is an adverse effect of drugs used to treat bone metabolism diseases, such as osteoporosis and bone metastases. The present study retrospectively evaluated the clinical characteristics and evolution of BRONJ cases that were diagnosed and treated at a dental school from 2004 to 2011. During that period, 13 patients met the criteria of the study among a population of 2,342 patients with oral lesions. Of the 13 patients, 12 were females. Ten were intravenous bisphosphonate users, and nine had breast cancer as the primary disease. Eight mandibular cases were observed. Eight patients interrupted the use of the bisphosphonates temporarily during the treatment. Surgical treatment was conducted in 10 patients, which was associated with platelet-rich plasma in six cases, which led to a regression to Stage I in 50% of these and cure in 33.3%. Of the total sample, four (30.8%) cases were cured, six (46.1%) regressed to Stage I, and three (23.1%) remained in Stage II after treatment. Dental rehabilitation occurred in seven patients. Dissemination of knowledge among professionals is essential for prevention and early diagnosis of BRONJ. Dental schools must act as reference centers and participate in the multidisciplinary care of bisphosphonate users.


Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial.
After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11). After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Sanofi and Regeneron Pharmaceuticals.


Do Arctic breeding geese track or overtake a green wave during spring migration?
Geese breeding in the Arctic have to do so in a short time-window while having sufficient body reserves. Hence, arrival time and body condition upon arrival largely influence breeding success. The green wave hypothesis posits that geese track a successively delayed spring flush of plant development on the way to their breeding sites. The green wave has been interpreted as representing either the onset of spring or the peak in nutrient biomass. However, geese tend to adopt a partial capital breeding strategy and might overtake the green wave to accomplish a timely arrival on the breeding site. To test the green wave hypothesis, we link the satellite-derived onset of spring and peak in nutrient biomass with the stopover schedule of individual Barnacle Geese. We find that geese track neither the onset of spring nor the peak in nutrient biomass. Rather, they arrive at the southernmost stopover site around the peak in nutrient biomass, and gradually overtake the green wave to match their arrival at the breeding site with the local onset of spring, thereby ensuring gosling benefit from the peak in nutrient biomass. Our approach for estimating plant development stages is critical in testing the migration strategies of migratory herbivores.


Bioinspired hydrogel surfaces to augment corneal endothelial cell monolayer formation.
Corneal endothelial cells (CECs) have limited proliferation ability leading to corneal endothelium (CE) dysfunction and eventually vision loss when cell number decreases below a critical level. Although transplantation is the main treatment method, donor shortage problem is a major bottleneck. The transplantation of in vitro developed endothelial cells with desirable density is a promising idea. Designing cell substrates that mimic the native CE microenvironment is a substantial step to achieve this goal. In the presented study, we prepared polyacrylamide (PA) cell substrates that have a microfabricated topography inspired by the dimensions of CECs. Hydrogel surfaces were prepared via two different designs with small and large patterns. Small patterned hydrogels have physiologically relevant hexagon densities (∼2000 hexagons/mm2 ), whereas large patterned hydrogels have sparsely populated hexagons (∼400 hexagons/mm2 ). These substrates have similar elastic modulus of native Descemet's membrane (DM; ∼50 kPa) and were modified with Collagen IV (Col IV) to have biochemical content similar to native DM. The behavior of bovine corneal endothelial cells on these substrates was investigated and results show that cell proliferation on small patterned substrates was significantly (p = 0.0004) higher than the large patterned substrates. Small patterned substrates enabled a more densely populated cell monolayer compared to other groups (p = 0.001 vs. flat and p < 0.0001 vs. large patterned substrates). These results suggest that generating bioinspired surface topographies augments the formation of CE monolayers with the desired cell density, addressing the in vitro development of CE layers.


"It's not a time spent issue, it's a 'what have you spent your time doing?' issue…" A qualitative study of UK patient opinions and expectations for implementation of Point of Care Tests for sexually transmitted infections and antimicrobial resistance.
Sexually transmitted infections (STIs) continue to be a major public health concern in the United Kingdom (UK). Epidemiological models have shown that narrowing the time between STI diagnosis and treatment may reduce the population burden of infection, and rapid, accurate point-of-care tests (POCTs) have potential for increasing correct treatment and mitigating the spread of antimicrobial resistance (AMR). We developed the Precise social science programme to incorporate clinician and patient opinions on potential designs and implementation of new POCTs for multiple STIs and AMR detection. We conducted qualitative research, consisting of informal interviews with clinicians and semi-structured in-depth interviews with patients, in six sexual health clinics in the UK. Interviews with clinicians focused on how the new POCTs would likely be implemented into clinical care; these new clinical pathways were then posed to patients in in-depth interviews. Patient interviews showed acceptability of POCTs, however, willingness to wait in clinic for test results depended on the context of patients' sexual healthcare seeking. Patients reporting frequent healthcare visits often based their expectations and opinions of services and POCTs on previous visits. Patients' suggestions for implementation of POCTs included provision of information on service changes and targeting tests to patients concerned they are infected. Our data suggests that patients may accept new POCT pathways if they are given information on these changes prior to attending services and to consider implementing POCTs among patients who are anxious about their infection status and/or who are experiencing symptoms.


Heteropathogenic virulence and phylogeny reveal phased pathogenic metamorphosis in Escherichia coli O2:H6.
Extraintestinal pathogenic and intestinal pathogenic (diarrheagenic) Escherichia coli differ phylogenetically and by virulence profiles. Classic theory teaches simple linear descent in this species, where non-pathogens acquire virulence traits and emerge as pathogens. However, diarrheagenic Shiga toxin-producing E. coli (STEC) O2:H6 not only possess and express virulence factors associated with diarrheagenic and uropathogenic E. coli but also cause diarrhea and urinary tract infections. These organisms are phylogenetically positioned between members of an intestinal pathogenic group (STEC) and extraintestinal pathogenic E. coli. STEC O2:H6 is, therefore, a 'heteropathogen,' and the first such hybrid virulent E. coli identified. The phylogeny of these E. coli and the repertoire of virulence traits they possess compel consideration of an alternate view of pathogen emergence, whereby one pathogroup of E. coli undergoes phased metamorphosis into another. By understanding the evolutionary mechanisms of bacterial pathogens, rational strategies for counteracting their detrimental effects on humans can be developed.


Pectin methylesterase is induced in Arabidopsis upon infection and is necessary for a successful colonization by necrotrophic pathogens.
The ability of bacterial or fungal necrotrophs to produce enzymes capable of degrading pectin is often related to a successful initiation of the infective process. Pectin is synthesized in a highly methylesterified form and is subsequently de-esterified in muro by pectin methylesterase. De-esterification makes pectin more susceptible to the degradation by pectic enzymes such as endopolygalacturonases (endoPG) and pectate lyases secreted by necrotrophic pathogens during the first stages of infection. We show that, upon infection, Pectobacterium carotovorum and Botrytis cinerea induce in Arabidopsis a rapid expression of AtPME3 that acts as a susceptibility factor and is required for the initial colonization of the host tissue.


Human Rights, Humanitarianism, and State Violence: Medical Documentation of Torture in Turkey.
State authorities invested in developing official expert discourses and practices to deny torture in post-1980 coup d'état Turkey. Documentation of torture was therefore crucial for the incipient human rights movement there in the 1980s. Human rights physicians used their expertise not only to treat torture victims but also to document torture and eventually found the Human Rights Foundation of Turkey (HRFT) in 1990. Drawing on an ethnographic and archival research at the HRFT, this article examines the genealogy of anti-torture struggles in Turkey and argues that locally mediated intimacies and/or hostilities between victims of state violence, human rights physicians, and official forensics reveal the limitations of certain universal humanitarian and human rights principles. It also shows that locally mediated long-term humanitarian encounters around the question of political violence challenge forensic denial of violence and remake the legitimate levels of state violence.


Ego-syntonic object manipulation: the formation of a submissive relationship.
Denial, acting on both the inner and external world, relies on further defence mechanisms in the form of object manipulations aimed at changing reality to make it fit the denying person's inner needs. If the object's ego is not strong enough to resist these manipulations, it is pressured into a submissive relationship. By means of seduction or its opposite, intimidation and the use of threats, the object is made to believe the content of the denying persons's inner or external world. The result is a mutually intrusive and reciprocal relationship in which the roles of victim and perpetrator alternate. This is the case when children are not allowed to acquire their own experiences during the process of transition from symbiosis to separation. Constant exposure to irritation leads to a regression of the ego, to the illusion that everything is possible in the 'we'. Object relations in adult life are then based on a parasitic need for the object in order to realize inner goals. In analysis this is manifested as symbiotic omnipotence, posing a 'serious stumbling block' to the analytic process, which may take the form of an 'as-if' analysis.


Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release.
Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.


Assessment of concordance between fresh-frozen and formalin-fixed paraffin embedded tumor DNA methylation using a targeted sequencing approach.
DNA methylation is altered in many types of disease, including metastatic colorectal cancer. However, the methylome has not yet been fully described in archival formalin-fixed paraffin embedded (FFPE) samples in the context of matched fresh-frozen (FF) tumor material at base-pair resolution using a targeted approach. Using next-generation sequencing, we investigated three pairs of matched FFPE and FF samples to determine the extent of their similarity. We identified a 'bowing' pattern specific to FFPE samples categorized by a lower CG proportion at the start of sequence reads. We have found no evidence that this affected methylation calling, nor concordance of results. We also found no significant increase in deamination, measured by C>T transitions, previously considered a result of crosslinking DNA by formalin fixation and a barrier to the use of FFPE in methylation studies. The methods used in this study have shown sensitivity of between 60-70% based on positions also methylated in colorectal cancer cell lines. We demonstrate that FFPE material is a useful source of tumor material for methylation studies using targeted sequencing.


Autologous CD34+ Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study.
An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34+ stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34+ stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 105 CD34/kg body weight), and high dose (5 × 105 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III-IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34+ cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34+ cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.


How can we battle the scourge of diarrhea? 2003 McKenna Memorial Lecture.
Diarrheal diseases exact a considerable toll of morbidity and mortality worldwide, including in developed countries where the incidence of foodborne illness, in particular, may be increasing. This article summarizes the current understanding of the basis of diarrheal illness, focusing particularly on intracellular signaling mechanisms that limit the extent of intestinal epithelial chloride secretion, which may offer new targets for antidiarrheal therapies. Recent information regarding the mechanisms whereby invasive bacteria cause diarrhea is also reviewed along with effects of beneficial bacteria (so-called probiotics) in limiting dysfunction associated with enteric infections. Finally, the author provides some speculations as to the possible benefits to the host of mounting a diarrheal response to an offending pathogen, and possible consequences of the failure of this primitive host defense mechanism.


Continuous clindamycin infusion, an innovative approach to treating bone and joint infections.
The feasibility, safety, and efficacy of prolonged, continuous, intravenous clindamycin therapy were retrospectively evaluated for 70 patients treated for bone and joint infections, 40% of whom were treated as outpatients. The median treatment duration was 40 days, the median daily clindamycin dose was 2,400 mg, and three moderate-grade adverse events occurred. The median serum clindamycin concentrations on days 3 to 14 and days 8 to 28 were 5 and 6.2 mg/liter, respectively; the median concentration was significantly lower (P < 0.02) in patients treated with rifampin (5.3 mg/liter) than in those not treated with rifampin (8.9 mg/liter). Among 53 patients with a median follow-up of 30 months (range, 24 to 53 months), 49 (92%) were considered cured (1 patient had a relapse, and 3 patients had reinfections).


Significant Phonon Drag Enables High Power Factor in the AlGaN/GaN Two-Dimensional Electron Gas.
In typical thermoelectric energy harvesters and sensors, the Seebeck effect is caused by diffusion of electrons or holes in a temperature gradient. However, the Seebeck effect can also have a phonon drag component, due to momentum exchange between charge carriers and lattice phonons, which is more difficult to quantify. Here, we present the first study of phonon drag in the AlGaN/GaN two-dimensional electron gas (2DEG). We find that phonon drag does not contribute significantly to the thermoelectric behavior of devices with ∼100 nm GaN thickness, which suppresses the phonon mean free path. However, when the thickness is increased to ∼1.2 μm, up to 32% (88%) of the Seebeck coefficient at 300 K (50 K) can be attributed to the drag component. In turn, the phonon drag enables state-of-the-art thermoelectric power factor in the thicker GaN film, up to ∼40 mW m-1 K-2 at 50 K. By measuring the thermal conductivity of these AlGaN/GaN films, we show that the magnitude of the phonon drag can increase even when the thermal conductivity decreases. Decoupling of thermal conductivity and Seebeck coefficient could enable important advancements in thermoelectric power conversion with devices based on 2DEGs.


The hazards of death by smoking in middle-aged women.
Recent studies have found that the risk of death continues to increase among female smokers, as compared with women who have never smoked. We wanted to examine the effect of smoking on all-cause and cause-specific mortality and calculate the corresponding population attributable fraction (PAF) of mortality in the Norwegian women and cancer study; a nationally representative prospective cohort study. We followed 85,320 women, aged 31–70 years, who completed a questionnaire in 1991–1997, through linkages to national registries through December 2008. Questionnaire data included information on lifestyle factors, including lifetime history of smoking. Poisson regression models were fitted to estimate relative risks (RRs) with 95 % confidence intervals (CIs) adjusting for age, birth cohort, education, postmenopausal status, alcohol consumption and body mass index, all at enrollment. During a mean follow-up time of 14 years 2,842 deaths occurred. Compared with that of never smokers, current smokers had a mortality rate that was double (RR = 2.34; 95 % CI 2.13–2.62) from deaths overall, triple (RR = 3.30; 95 % CI 2.21–4.82) from cerebrovascular disease and myocardial infarction (RR = 3.65; 95 % CI 2.18–6.15), 12 times (RR = 12.16; 95 % CI 7.80–19.00) from lung cancer and seventeen times (RR = 17.00; 95 % CI 5.90–48.78) from chronic obstructive pulmonary diseases. The PAF of mortality due to smoking was 34 % (CI 30–39). In summary, one in three deaths among middle aged women in Norway could have been prevented if the women did not smoke. More middle-aged women, than ever before, are dying prematurely due to smoking in Norway.


Surveyed opinion of American trauma, orthopedic, and thoracic surgeons on rib and sternal fracture repair.
Rib and sternal fracture repair are controversial. The opinion of surgeons regarding those patients who would benefit from repair is unknown. Members of the Eastern Association for the Surgery of Trauma, the Orthopedic Trauma Association, and thoracic surgeons (THS) affiliated with teaching hospitals in the United States were recruited to complete an electronic survey regarding rib and sternal fracture repair. Two hundred thirty-eight trauma surgeons (TRS), 97 orthopedic trauma surgeons (OTS), and 70 THS completed the survey. Eighty-two percent of TRS, 66% of OTS, and 71% of THS thought that rib fracture repair was indicated in selected patients. A greater proportion of surgeons thought that sternal fracture repair was indicated in selected patients (89% of TRS, 85% of OTS, and 95% of THS). Chest wall defect/pulmonary hernia (58%) and sternal fracture nonunion (>6 weeks) (68%) were the only two indications accepted by a majority of respondents. Twenty-six percent of surgeons reported that they had performed or assisted on a chest wall fracture repair, whereas 22% of surgeons were familiar with published randomized trials of the surgical repair of flail chest. Of surgeons who thought rib fracture or sternal fracture repair was rarely, if ever, indicated, 91% and 95%, respectively, specified that a randomized trial confirming efficacy would be necessary to change their negative opinion. A majority of surveyed surgeons reported that rib and sternal fracture repair is indicated in selected patients; however, a much smaller proportion indicated that they had performed the procedures. The published literature on surgical repair is sparse and unfamiliar to most surgeons. Barriers to surgical repair of rib and sternal fracture include a lack of expertise among TRS, lack of research of optimal techniques, and a dearth of randomized trials.