Reliability of Symptom-Based Diagnosis of Uncomplicated Cystitis.
Acute uncomplicated cystitis (AC) is common among women. Acute onset of specific typical symptoms may serve as reliable criteria for developing a cost-effective strategy to make an accurate diagnosis of AC. We aimed to evaluate the diagnostic values of most common symptoms and signs of AC depending on their presence and severity. The current trial was designed as a case-control study. Data derived from the Acute Cystitis Symptom Score (ACSS) database were analyzed. Diagnostic values of the symptoms and their severity were assessed via the calculations of the sensitivity and specificity, odds ratio, positive and negative likelihood ratios. The strength of associations was estimated by the coefficient of correlation (Pearson's R). Data from 819 female subjects (423 Patients, 396 controls) with the mean age of 37.1 ± 15.3 were analyzed. Highest diagnostic values for AC in this study belonged to dysuria, urgency, and frequency. Interestingly, complaints of vaginal discharge was not found to decrease the odds for having AC in the study population. The severity of the symptom is even more essential than just its presence for an accurate diagnosis. The ACSS is an accurate tool and may be recommended for clinical practice and studies for diagnosis of AC in women. Further studies and unification of terms are need.


Lactate and metabolic H+ transport and distribution after exercise in rainbow trout white muscle.
An isolated-perfused tail-trunk preparation was employed to study the influence of transmembrane pH gradient and membrane potential on the transport and distribution of L(+)-lactate (Lac), metabolic H+ (delta Hm+), and related parameters in rainbow trout white muscle after exhaustive exercise. One resting [arterial pH (pHa) approximately 7.9] and four postexercise treatments (pHa approximately 7.4, 7.9, 8.4, and, high K+, pHa approximately 7.9, partially depolarized by 15 mM K+) were examined. Variations in HCO3- concentration (2-18 mM) at a constant PCO2 approximately 2 Torr were used to alter pHa. The elevated intracellular Lac (approximately 50 mM) remained unchanged after 60 min of perfusion because of very low rates of lactate efflux and oxidation. H+, HCO3-, and Lac- distributions were all well out of electrochemical equilibrium. Total CO2 efflux was reduced at high extracellular pH (pHe); alterations in the net driving force on HCO3- may have overshadowed the influence of PCO2 gradients in driving total CO2 efflux. Lac efflux and delta Hm+ flux were completely uncoupled. delta Hm+ flux reacted to both acid-base and electrochemical gradients as delta Hm+ efflux dropped and even reversed when pHe decreased, whereas partial depolarization in conjunction with depressed intracellular pH resulted in elevated delta Hm+ efflux. Lac efflux did not respond to changes in pHe. Changes in Lac efflux corresponded more closely to changes in the Lac- concentration gradient than in the lactic acid gradient. This study provides circumstantial evidence for the involvement of electroneutral mechanisms (i.e., Lac(-)-H+ cotransport and/or Lac-/anion exchange) in lactate efflux, but does not eliminate the possibility of an active transport mechanism contributing to the retention of Lac.


Natural Infection of Canavalia ensiformis with Tobacco mosaic virus in Venezuela.
Jack bean (Canavalia ensiformis) is a valuable green manure and cover-crop species. In late summer of 2002, jack bean plants showing severe stunting, leaf mosaic, mottling, distortion, and general yellowing were observed in fields located in Maracay, Aragua State, Venezuela. Sap from symptomatic leaves was used to mechanically inoculate healthy jack bean, and field symptoms were successfully reproduced. Similar inoculations on Nicotiana tabacum var. Sansum resulted in mosaic symptoms and leaf distortion. Electron microscopic examination of leafdip preparations showed filamentous rods resembling those of a tobamovirus. Tobacco mosaic virus (TMV) was specifically identified with TMV-specific polyclonal antibody (PVAS-958, ATTC) in enzyme-linked immunosorbent assay. Sequence analysis of a coat protein gene (CP) fragment amplified using reverse transcription-polymerase chain reaction (RT-PCR) with primers TMV-CP-F and TMV-CP-R (1) from total RNA confirmed the diagnosis. Nucleotide and deduced amino acid sequences of a 450-bp region of the RT-PCR product were 96 to 99% and 98 to 100% identical, respectively, to the TMV CP gene in GenBank Accession Nos. J02415 and X68110. On the basis of foliar symptoms, incidence of TMV in jack bean was more than 50% in this experimental field. The source of infection is not known. Because TMV is reported to be seedborne in many other plant species, testing jack bean seed stocks for TMV infection could have important implications on the future control of the virus. To our knowledge, this is the first report of natural infection of jack bean by a tobamovirus. Reference: (1) N. J. Spence et al. Eur. J. Plant Pathol. 107:633, 2001.


A bibliometric analysis of natural language processing in medical research.
Natural language processing (NLP) has become an increasingly significant role in advancing medicine. Rich research achievements of NLP methods and applications for medical information processing are available. It is of great significance to conduct a deep analysis to understand the recent development of NLP-empowered medical research field. However, limited study examining the research status of this field could be found. Therefore, this study aims to quantitatively assess the academic output of NLP in medical research field. We conducted a bibliometric analysis on NLP-empowered medical research publications retrieved from PubMed in the period 2007-2016. The analysis focused on three aspects. Firstly, the literature distribution characteristics were obtained with a statistics analysis method. Secondly, a network analysis method was used to reveal scientific collaboration relations. Finally, thematic discovery and evolution was reflected using an affinity propagation clustering method. There were 1405 NLP-empowered medical research publications published during the 10 years with an average annual growth rate of 18.39%. 10 most productive publication sources together contributed more than 50% of the total publications. The USA had the highest number of publications. A moderately significant correlation between country's publications and GDP per capita was revealed. Denny, Joshua C was the most productive author. Mayo Clinic was the most productive affiliation. The annual co-affiliation and co-country rates reached 64.04% and 15.79% in 2016, respectively. 10 main great thematic areas were identified including Computational biology, Terminology mining, Information extraction, Text classification, Social medium as data source, Information retrieval, etc. CONCLUSIONS: A bibliometric analysis of NLP-empowered medical research publications for uncovering the recent research status is presented. The results can assist relevant researchers, especially newcomers in understanding the research development systematically, seeking scientific cooperation partners, optimizing research topic choices and monitoring new scientific or technological activities.


Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone. We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. NCT00094302.


The effect of keeping an end-product on intrinsic motivation.
According to literature in occupational therapy and psychology, intrinsic motivation is thought to be enhanced if people can keep the end-product of an activity. The purpose of this study was to examine the effect of keeping an end-product on intrinsic motivation. Fifty participants chose one of four activities (painting a ceramic vase, decorating cookies, stringing beads for a necklace, creating stationery) and performed two conditions (keep, no-keep) in counterbalanced order. Participants were timed in each condition and, after each condition, ranked their self-determination and competence, which are psychological needs underlying intrinsic motivation. Participants were interviewed at the end of the study to examine their experiences. Participants worked significantly longer on a chosen activity when the end-product could be kept and rated themselves significantly more self-determined and competent after performing the keep condition. However, further analysis revealed that these results depended on the activity chosen. The findings support that keeping an end-product can enhance performance of an activity. However, because results were not consistent across all activity choices, further research is needed to characterize the meaningfulness of particular activities.


Relationship between increased body iron stores, oxidative stress and insulin resistance in healthy men.
The aim of our cross-sectional study was to assess the relationships between body iron stores, oxidative stress, impaired insulin sensitivity and carotid atherosclerosis in a cohort of healthy men in primary prevention of cardiovascular disease. We examined 151 volunteers, aged 35- 60 years. Anthropometric parameters, markers of metabolic syndrome, insulin resistance, inflammatory markers, parameters of oxidative stress and intima-media thickness of common carotid artery were measured. Ferritin correlated positively with waist circumference, body mass index, impaired insulin sensitivity, plasma triglycerides and inversely with high-density lipoprotein cholesterol. We observed positive correlations between ferritin, oxidized lowdensity lipoprotein and advanced oxidation protein products after adjustment for age, waist circumference, body mass index and measured inflammatory markers (high-sensitivity C-reactive protein, fibrinogen, interleukin-6 and tumor necrosis factor-alpha). There were no significant associations between ferritin and intima-media thickness or markers of endothelial dysfunction. In a stepwise multiple regression analysis, triglycerides, waist circumference and elevated transaminases were independent determinants of the serum ferritin level. Our results provide evidence for a relationship between plasma ferritin and oxidative modification of lipids as well as proteins in vivo. Higher body iron stores may contribute to impaired insulin sensitivity through increased oxidative stress in a cohort of healthy men.


EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans.
Inhibitory molecules associated with myelin and the glial scar limit axon regeneration in the adult central nervous system (CNS), but the underlying signaling mechanisms of regeneration inhibition are not fully understood. Here, we show that suppressing the kinase function of the epidermal growth factor receptor (EGFR) blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promotes significant regeneration of injured optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after CNS injury.


Self-assembled supramolecular hetero-bimetallacycles for anticancer potency by intracellular release.
Two new tetracationic hetero-bimetallacycles, compounds 4 and 5, have been constructed from an N,N'-bis(4-(pyridin-4-ylethynyl)phenyl)pyridine-2,6-dicarboxamide ligand (1), and cis-blocked complexes [M(dppf)(OTf)2 ] (dppf=1,1'-bis(diphenylphosphino)ferrocene; OTf=trifluoromethanesulfonate; M=Pd (2), Pt (3)) in CH3 NO2 /CH2 Cl2 (1:1) solvent. Both complexes were isolated with adequate yields as triflate salts and were then characterized using (1) H, (13) C, and (31) P NMR spectroscopy, elemental analysis, UV/Vis spectroscopy, and high-resolution electrospray mass spectrometry (HR-ESMS). The molecular structure of 4 was determined by molecular mechanics force-field calculations. The cytotoxic effect of both new complexes were analyzed against T98G (brain tumor), KB (head and neck cancer), SNU-80 (thyroid cancer), and HEK-293 non-malignant cell lines. The cytotoxicity of complexes 4 and 5 were found to be considerably more effective against cancer cells than reference drug cisplatin. Annexin-V/PI staining, caspase-3/7 activity, and the reduction in mitochondrial membrane potential justify a significant level of apoptosis in complex-treated cells.


Adverse perinatal events, treatment gap, and positive family history linked to the high burden of active convulsive epilepsy in Uganda: A population-based study.
To determine the prevalence of active convulsive epilepsy (ACE) and describe the clinical characteristics and associated factors among a rural Ugandan population. The entire population in Iganga/Mayuge Health Demographic Surveillance Site (IM-HDSS) was screened using two questions about seizures during a door-to-door census exercise. Those who screened positive were assessed by a clinician to confirm diagnosis of epilepsy. A case control study with the patients diagnosed with ACE as the cases and age/sex-matched controls in a ratio of 1:1 was conducted. A total of 64,172 (92.8%) IM-HDSS residents, with a median age of 15.0 years (interquartile range [IQR]: 8.0-29.0), were screened for epilepsy. There were 152 confirmed ACE cases, with a prevalence of 10.3/1,000 (95% confidence interval [CI]: 9.5-11.1) adjusted for nonresponse and screening sensitivity. Prevalence declined with age, with the highest prevalence in the 0-5 years age group. In an analysis of n = 241 that included cases not identified in the survey, nearly 70% were unaware of their diagnosis. Seizures were mostly of focal onset in 193 (80%), with poor electroencephalogram (EEG) agreement with seizure semiology. Antiepileptic drug use was rare, noted in 21.2% (95% CI: 16.5-25.8), and 119 (49.3%) reported using traditional medicines. History of an abnormal antenatal period (adjusted odds ratio [aOR] 10.28; 95%CI 1.26-83.45; p = 0.029) and difficulties in feeding, crying, breathing in the perinatal period (aOR 10.07; 95%CI 1.24-81.97; p = 0.031) were associated with ACE in children. In adults a family history of epilepsy (aOR 4.38 95%CI 1.77-10.81; p = 0.001) was the only factor associated with ACE. There is a considerable burden of epilepsy, low awareness, and a large treatment gap in this population of rural sub-Saharan Africa. The identification of adverse perinatal events as a risk factor for developing epilepsy in children suggests that epilepsy burden may be decreased by improving obstetric and postnatal care.


Farmers' preferences for high-input agriculture supported by site-specific extension services: Evidence from a choice experiment in Nigeria.
Agricultural extension to improve yields of staple food crops and close the yield gap in Sub-Saharan Africa often entails general recommendations on soil fertility management that are distributed to farmers in a large growing area. Site-specific extension recommendations that are better tailored to the needs of individual farmers and fields, and enabled by digital technologies, could potentially bring about yield and productivity improvements. In this paper, we analyze farmers' preferences for high-input maize production supported by site-specific nutrient management recommendations provided by an ICT-based extension tool that is being developed for extension services in the maize belt of Nigeria. We use a choice experiment to provide ex-ante insights on the adoption potentials of site-specific extension services from the perspective of farmers. We control for attribute non-attendance and account for class as well as scale heterogeneity in preferences using different models, and find robust results. We find that farmers have strong preferences to switch from general to ICT-enabled site-specific soil fertility management recommendations which lend credence to the inclusion of digital technologies in agricultural extension. We find heterogeneity in preferences that is correlated with farmers' resource endowments and access to services. A first group of farmers are strong potential adopters; they are better-off, less sensitive to risk, and are more willing to invest in a high-input maize production system. A second group of farmers are weak potential adopters; they have lower incomes and fewer productive assets, are more sensitive to yield variability, and prefer less capital and labor intensive production techniques. Our empirical findings imply that improving the design of extension tools to enable provision of information on the riskiness of expected outcomes and flexibility in switching between low-risk and high-risk recommendations will help farmers to make better informed decisions, and thereby improve the uptake of extension advice and the efficiency of extension programs.


Triangular-range-intensity profile spatial-correlation method for 3D super-resolution range-gated imaging.
We present a triangular-range-intensity profile (RIP) spatial-correlation method for 3D range-gated imaging with a depth of super resolution. In this method, spatial sampling volumes with triangular-RIPs are established by matching laser-pulse width and sensor gate time, and then depth information collapsed in gate images can be reconstructed by spatial correlation of overlapped gate images corresponding to sampling volumes. Compared with super-resolution depth mapping under trapezoidal-RIPs, range accuracy and precision are improved, and a large range fluctuation due to noise disturbance is smoothed by noise suppression under triangular-RIPs. In this paper, a proof experiment is demonstrated with a range precision 2.5 times better than that obtained under trapezoidal-RIPs.


Serum, salivary and tissue proteomics for discovery of biomarkers for head and neck cancers.
Initial clinically oriented applications of emerging proteomic technologies that aim to identify biomarkers for head and neck squamous cell carcinoma diagnostics have yielded promising results. The development of new proteomic diagnostics remains critical for the early detection of head and neck squamous cell carcinoma at more treatable stages. Prognostic markers for disease recurrence and treatment sensitivities are also required. In this overview of current biomarker identification strategies for head and neck squamous cell carcinoma, different combinations of mass spectrometry platforms, laser capture microscopy and 2D gel electrophoresis procedures are summarized as applied to readily available clinical specimens (tissue, blood and saliva). Issues related to assay reproducibility, management of large data sets and future improvements in clinical proteomics are also addressed.


A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy.
Diabetes is a leading cause of peripheral neuropathy (diabetic peripheral neuropathy, DPN), and uncontrolled long-lasting hyperglycemia leads to severe complications. A major proportion of diabetics develop excruciating pain with a variable course. Mechanisms leading to painful DPN are not completely understood and treatment options limited. We hypothesized that epigenetic modulation at the level of microRNA (miRNA) expression triggered by metabolic imbalance and nerve damage regulates the course of pain development. We used clinically relevant preclinical models, genome-wide screening, in silico analyses, cellular assays, miRNA fluorescent in situ hybridization, in vivo molecular manipulations, and behavioral analyses in the current study. We identified miRNAs and their targets that critically impact on nociceptive hypersensitivity in painful DPN. Our analyses identify miR-33 and miR-380 expressed in nociceptive neurons as critical denominators of diabetic pain and miR-124-1 as a mediator of physiological nociception. Our comprehensive analyses on the putative mRNA targets for miR-33 or miR-124-1 identified a set of mRNAs that are regulated after miR-33 or miR-124-1 overexpression in dorsal root ganglia in vivo. Our results shed light on the regulation of DPN pathophysiology and implicate specific miRNAs as novel therapeutic targets for treating painful DPN.


Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis.
Dendritic cells (DCs) play a key role in critical illness and are depleted in spleens from septic patients and mice. To date, few studies have characterized the systemic effect of sepsis on DC populations in lymphoid tissues. We analyzed the phenotype of DCs and Th cells present in the local (mesenteric) and distant (inguinal and popliteal) lymph nodes of mice with induced polymicrobial sepsis (cecal ligation and puncture). Flow cytometry and immunohistochemical staining demonstrated that there was a significant local (mesenteric nodes) and partial systemic (inguinal, but not popliteal nodes) loss of DCs from lymph nodes in septic mice, and that this process was associated with increased apoptosis. This sepsis-induced loss of DCs occurred after CD3(+)CD4(+) T cell activation and loss in the lymph nodes, and the loss of DCs was not preceded by any sustained increase in their maturation status. In addition, there was no preferential loss of either mature/activated (MHCII(high)/CD86(high)) or immature (MHCII(low)/CD86(low)) DCs during sepsis. However, there was a preferential loss of CD8(+) DCs in the local and distant lymph nodes. The loss of DCs in lymphoid tissue, particularly CD8(+) lymphoid-derived DCs, may contribute to the alterations in acquired immune status that frequently accompany sepsis.


Computed high concentrations of low-density lipoprotein correlate with plaque locations in human coronary arteries.
Subendothelial accumulation of low-density lipoprotein (LDL) in arterial walls is an initiator of atherosclerotic plaque formation. We report here on the correlation between healthy state subendothelial LDL concentration distribution and sites of subsequent plaque formation in coronary arteries of patients with coronary artery disease (CAD). We acquired left (LCA) and right coronary artery (RCA) and atherosclerotic plaque geometries of 60 patients with CAD using dual-source computed tomography angiography. After virtually removing all plaques to obtain an approximation of the arteries' healthy state, we calculated LDL concentration in the artery walls as a function of local lumen-side shear stress. We found that maximum subendothelial LDL concentrations at plaque locations were, on average, 45% (RCA) and 187% (LCA) higher than the respective average subendothelial concentration. Our results demonstrate that locally elevated subendothelial LDL concentration correlates with subsequent plaque formation at the same location.


Understanding the use of respite services among informal carers.
To examine the use of respite services among carers of non-institutionalised individuals aged 15 and over with either profound or severe disabilities. Based on data collected from the Australian Survey of Disability, Ageing and Carers in 2003, the investigation evaluated the statistical significance of a number of carer and recipient characteristics on the likelihood of the use of respite services. Further analysis assisted in identifying the support most desired by the majority of carers (88.6%, n = 243 690) who have never used respite. The results revealed that social and cultural factors played a critical role in the receipt of respite services. Family relationships were important. Just under one-fifth of all primary carers most preferred more financial assistance in their role as caregiver. After controlling for confounding variables it was found that, compared with other forms of assistance, the desire for an improvement in the primary carers' own health was more likely among non-respite users. This may reflect the carers' preference to improve their own capacity to service the recipient rather than rely on others outside the household. Since the recipients under investigation typically possess core communication restrictions and highly individualised needs, it is speculated that carers perceive family members as better able to interpret and meet the sporadic and individualised care demands of recipients. Given the low usage of respite services among primary informal carers, policy makers and health organisations need to dispel the "one size fits all" approach to support services for households.


Methoxyflurane toxicity: historical determination and lessons for modern patient and occupational exposure.
Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane. Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library. Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear. Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation.


Erythrocyte adenosine triphosphate and 2,3-diphosphoglycerate after human renal transplantation: dissociation from hypophosphataemia.
1. Erythrocyte 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) were determined in normal individuals, uraemic patients on chronic haemodialysis and patients who underwent renal transplantation, and correlated with plasma phosphate and arterial blood pH. 2. Significant increases in the 2,3-DPG and ATP content were found in the uraemic patients and these persisted after transplantation in spite of marked hypophosphataemia. 3. No correlation was established with plasma phosphate for either of the compounds but 2,3-DPG had a significant correlation with arterial blood pH. 4. Normal values for ATP and 2,3-DPG were observed in post-transplant patients with normal haematological values. The high amounts of erythrocyte 2,3-DPG and ATP in the early post-transplant period are independent of the circulating concentration of inorganic phosphate, and might represent the response of erythrocyte glycolysis to changing arterial blood pH.


Human and methodological sources of variability in the measurement of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine.
Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (rp 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.


Measuring Depression in Adults With Burn Injury: A Systematic Review.
We conducted a systematic review of the literature to identify evidence to support the use of measures of depression for adults with burn injuries. Our goal was to be able to identify the most reliable, valid, and efficient means of identifying adults with symptoms of depression including major depressive disorder. We modified established guidelines for conducting systematic reviews by excluding measures that focused on distress or anxiety or only used depression as a predictor of interest. We also excluded studies that did not report psychometric data in their results. We identified a total of 213 articles that broadly addressed the topic of depression in burn injuries; of those, 56 that met the majority of the inclusion criteria and used depression as either the primary or the secondary outcome were reviewed. Nine studies that included report of some psychometric properties were reviewed. There have been no measures specifically developed to measure depression in those with burn injuries, and it is unclear if they are actually needed. Greater understanding of depression after burn injury can be gained by evaluating the existing general measures of depression and how they are used in the field of burn injury rehabilitation. The ultimate goal is to develop a set of recommendations for the standardization of how depressive symptomatology is assessed in this population. In this review, we highlight the deficiencies of validated measures of depression in the field of burn recovery and provide specific recommendations for both clinicians and researchers to advance our knowledge of depression following a burn injury, which will allow us to advance treatment.


Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy.
Although autonomic failure, parkinsonism, and cerebellar and pyramidal signs are well documented in multiple system atrophy, much less is known about the frequency and severity of involvement of the peripheral nervous system. The frequency and nature of peripheral nerve involvement has therefore been determined in 74 patients with multiple system atrophy using nerve conduction studies and skeletal muscle EMG. These findings were compared with those on sphincter EMG. Ninety per cent of the patients had an abnormal sphincter EMG, indicating denervation and reinnervation consistent with anterior horn cell loss in Onuf's nucleus, but only 40% had either abnormal nerve conduction studies (mixed sensorimotor axonal neuropathy in 17.5%) or abnormal skeletal muscle EMG (suggesting partial denervation in 22.5%). These data indicate a remarkable selective vulnerability of the anterior horn cells of Onuf's nucleus innervating external sphincter muscles relative to those supplying skeletal muscle in patients with multiple system atrophy. If this selective pattern of involvement can be explained it may be a clue to pathogenetic mechanisms in multiple system atrophy.


Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.


FOCUS Program: Treating Patients With Cancer and Family Caregivers as a Unit of Care.
Studies indicate that patients' and caregivers' responses to illness are interdependent; each person affects the other. Existing evidence reinforces the need to recognize family caregivers as equal recipients of care and support. This evidence-based pilot study evaluated the feasibility and preliminary efficacy of the nurse-guided, psychoeducational, family-based FOCUS program intervention at a local oncology outpatient clinic. 30 patient-caregiver dyads were recruited from a local oncology clinic. Intervention delivery occurred using home visits and telephone calls. Self-administered questionnaires were used to assess participants' self-efficacy, quality of life (QOL), and coping pre- and postintervention, and intervention satisfaction postintervention. Three tailored psychosocial education sessions were held during a 6- to 9-week period. Significant changes in outcomes were found, including increased self-efficacy in both patients and caregivers, higher QOL in caregivers, and decreased use of substances for coping in patients. There was a trend for patients' emotional well-being to improve over time; other aspects of QOL showed little change. There were no significant changes in caregivers' coping.


Characterization of the execution phase of apoptosis in vitro using extracts from condemned-phase cells.
Apoptotic cell death is characterized by a dramatic morphological transformation during which apparently healthy cells suddenly initiate a comprehensive program of motility changes and degradative activities that culminates in disassembly of the cell into membrane-enclosed vesicles. The mechanism of the cellular changes during this spectacular execution phase of apoptosis is just now yielding to biochemical analysis. In our laboratory, we have applied a novel in vitro system to the study of these events. In this system, nuclei isolated from healthy cells undergo the characteristic changes of apoptosis rapidly and synchronously. Using this system we have identified the first substrates for interleukin-1 beta-converting enzyme (ICE)-like proteinases during apoptotic execution. One of these, the nuclear enzyme poly (ADP-ribose) polymerase is cleaved very early in the apoptotic process. A second class of proteins, the nuclear lamins, is cleaved later in the pathway. Lamin cleavage requires a second ICE-related proteinase, and is essential for the complete dissolution of nuclei into apoptotic bodies. Studies with our cell-free extracts reveal that the various proteinases and nucleases that operate during the execution phase of apoptosis do so largely in independent parallel biochemical pathways. However, all of these pathways require the action of ICE-related proteinases for their initiation.


Migration and stress during reproduction govern telomere dynamics in a seabird.
Changes in telomere length are believed to reflect changes in physiological state and life expectancy in animals. However, much remains unknown about the determinants of telomere dynamics in wild populations, and specifically the influence of conditions during highly mobile life-history stages, for example migration. We tested whether telomere dynamics were associated with migratory behaviour and/or with stress during reproduction in free-living seabirds. We induced short-term stress during reproduction in chick-rearing, black-legged kittiwakes (Rissa tridactyla), tracked winter migration with geolocators and measured telomere length before and after winter migration. We found that time spent at wintering grounds correlated with reduced telomere loss, while stress during reproduction accelerated telomere shortening. Our results suggest that different life-history stages interact to influence telomere length, and that migratory patterns may be important determinants of variation in an individual's telomere dynamics.


The plasminogen activator inhibitor-1 (PAI-1) gene -844 A/G and -675 4G/5G promoter polymorphism significantly influences plasma PAI-1 levels in women with polycystic ovary syndrome.
Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with increased PAI-1 levels, have been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). We investigated a possible influence of the promoter polymorphism (-844 A/G and -675 4G/5G) in the PAI-1 gene on plasma PAI-1 levels in 126 PCOS patients and 97 healthy controls. Levels of total testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), fasting plasma glucose (FPG), fasting insulin, and PAI-1 were measured, and body mass index (BMI), waist-to-hip ratio (WHR), LH/FSH ratio, and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. PAI-1 -675 4G/5G and -844 A/G gene polymorphisms were also performed. Total testosterone, fasting insulin, and PAI-1 levels; BMI, LH/FSH, and HOMA-IR were significantly higher in PCOS patients than controls (P < 0.05). The odds ratio of 4G/4G genotype, 4G allele, and the combination genotype of 4G/4G and -844 A/A were 2.49 (95% confidence interval (CI), 1.4-4.44), 2.1 (95% CI, 1.43-3.08), and 2.9 (95% CI, 1.41-5.98), respectively, (P < 0.001). In the PCOS group, the PAI-1 level of the A/A was significantly higher than that of the A/G or G/G genotype, similarly was 4G/4G genotype compared with 4G/5G or 5G/5G genotype. The plasma PAI-1 levels of the combination of the PAI-1 -844 A/A and -675 4G/4G or 4G/5G genotypes, or the coadunation of 4G/4G and -844 non-G/G (A/A + A/G) genotypes were significantly high in PCOS women compared with controls. A trend to a positive interaction between PAI-1 -675 4G/5G and -844 A/G gene polymorphism may elevate plasma PAI-1 levels and hypofibrinolysis, which is probably an important hereditary risk factor in PCOS.


Molecular biology of light transduction by the Mammalian photoreceptor, rhodopsin.
Abstract Rhodopsin, the vertebrate photoreceptor, is a prototypic molecule in the largest family of G- protein coupled receptors (GPCR). Like all receptors of this family, it contains three distinct domains: the cytoplasmic (intracellular) domain that is involved in all the protein-protein interactions; the transmembrane (TM) domain where the signal transduction begins, by light- catalysed isomerization of 11-cis-retinal to all trans-retinal, and the intradiscal domain which appears to be involved in a specific tertiary structure. The main focus of this talk is to describe efforts to understand specific structure and function in each domain. The main findings to be presented are as follows: 1. Intradiscal domain contains a globular tertiary structure. A central feature is a disulfide bond (Cys110-Cys187) which is conserved in most of the known GPCR. 2. The correct folding in vivo requires the formation of the above disulfide bond. Misfolding resulting in non-retinal binding is frequently caused by Retinitis Pigmentosa (RP) point mutations in the intradiscal and the TM domain. 3. In vivo folding studies, using RP mutations in every one of the seven helices, have shown that the packing of the helices in the TM domain and folding to form the intradiscal tertiary structure are coupled. 4. Cysteine mutagenesis has been used systematically to study the tertiary structure and light-dependent changes throughout the cytoplasmic face by combination of biochemical and biophysical studies. In particular, EPR spectroscopy following spin labeling of selected double cysteine mutants has shown movements in helices, including tilting, following retinal isomerization. 5. Large scale expression of mutants has allowed application of both (19)F-NMR (solution) and MAS solid state NMR (in collaboration with Dr. Steve Smith's group, SUNY, Stony Brook). Results of current work are promising for detailed study of the conformational change. Finally, a unifying hypothesis, which is termed the central dogma in the GPCR field, will be proposed. This states that despite the enormous variation in "accessory" structural details, the principal mechanism of signal transduction starting with pertubation in the seven helical bundle is fundamentally the same in all GPCRs. Experiments to test helix movements, the first step in signal transduction following ligand binding in two adrenergic receptors are now feasible. The patterns of helix movements in them will be compared with the pattern demonstrated for rhodopsin and its mutants.


Representations of the texture of food in the primate orbitofrontal cortex: neurons responding to viscosity, grittiness, and capsaicin.
The primate orbitofrontal cortex (OFC) is a site of convergence from taste, olfactory, and somatosensory cortical areas. We describe a population of single neurons in the macaque OFC that responds to the texture of food in the mouth. Use of oral viscosity stimuli consisting of carboxymethylcellulose (CMC) in the range 1-10,000 centipoise showed that the responses of one subset of these neurons were related to stimulus viscosity. Some of the neurons had increasing responses to increasing viscosity, some had decreasing responses, and some neurons were tuned to a range of viscosities. These neurons are a different population to oral fat-sensitive neurons, in that their responses to fats (e.g., safflower oil), to silicone oil [(Si(CH3)2O)n], and to mineral oil (hydrocarbon) depended on the viscosity of these oils. Thus there is a dissociation between texture channels used to sense viscosity and fat. Some of these viscosity-sensitive single neurons were unimodal (somatosensory; 25%) and some received convergent taste inputs (75%). A second subpopulation of neurons responded to gritty texture (produced by microspheres suspended in CMC). A third subpopulation of neurons responded to capsaicin. These results provide evidence about the information channels used to represent the texture and flavor of food in a part of the brain important in appetitive responses to food and are relevant to understanding the physiological and pathophysiological processes related to food intake, food selection, and the effects of variety of food texture in combination with taste and other inputs that affect food intake.


PTLD Burkitt Lymphoma in a Patient with Remote Lymphomatoid Granulomatosis.
Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of solid organ transplantation. The majority of PTLD is of B-cell origin, and 90% are associated with the Epstein-Barr virus (EBV). Lymphomatoid granulomatosis (LG) is a rare, EBV-associated systemic angiodestructive lymphoproliferative disorder, which has rarely been described in patients with renal transplantation. We report the case of a patient with renal transplantation for SLE, who presented, 9 months after renal transplantation, an EBV-associated LG limited to the intracranial structures that recovered completely after adjustment of her immunosuppressive treatment. Nine years later, she developed a second PTLD disorder with central nervous system initial manifestation. Workup revealed an EBV-positive PTLD Burkitt lymphoma, widely disseminated in most organs. In summary, the reported patient presented two lymphoproliferative disorders (LG and Burkitt's lymphoma), both with initial neurological manifestation, at 9 years interval. With careful reduction of the immunosuppression after the first manifestation and with the use of chemotherapy combined with radiotherapy after the second manifestation, our patient showed complete disappearance of neurologic symptoms and she is clinically well with good kidney function. No recurrence has been observed by radiological imaging until now.


Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.
Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA. The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.


Linkage of early-onset familial breast cancer to chromosome 17q21.
Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally, susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region.


Urban-suburban differences in GP requests for lumbosacral spine radiographs in a primary healthcare centre in Malta.
Due to demographic changes, growing demands, technological developments and rising healthcare costs, analysis of resources in rural and urban primary care clinics is crucial. However, data on primary care provision in rural and suburban areas are lacking. Moreover, health inequities in small island communities tend to be reduced by social homogeneity and an almost indiscernible urban-rural difference. The aim of the study was to examine the urban-suburban differences in the indications for lumbosacral spine radiographs in a public primary healthcare centre in Malta. A list of all patients who underwent lumbosacral spine radiography in a public primary healthcare centre between January and June 2014 was obtained. The indications for lumbosacral spine radiographs were compared against the evidence-based indications posited by the America College of Radiology, the American Society of Spine Radiology, the Society for Pediatric Radiology and the Society of Skeletal Radiology in 2014. Differences between suburban and urban areas were analysed using the χ² test. Direct logistic regression was used to estimate the influences of different patients' characteristics and imaging indications in urban and suburban areas. The logistic regression model predicting the likelihood of different factors occurring with suburban patients as opposed to those residing in urban areas contained four independent variables (private/public sector, examination findings, osteoporosis, infection). The full model containing all predictors was statistically significant, c2 (4, N=1112) = 26.57, p≤0.001, indicating that the model was able to distinguish between patients residing in rural and urban areas. All four of the independent variables made a unique, statistically significant contribution to the model. The model as a whole explained between 2.4% (Cox and Snell R2) and 3.6% (Nagelkerke R2) of the variance in suburban/urban areas, and correctly classified 78.5% of cases. All four of the independent variables made a unique statistically significant contribution to the model. General practitioner (GP) requests for patients residing in suburban areas were more likely to be submitted from the private sector whereas urban GPs tended to include more examination findings. Requests by GPs for lumbosacral spine radiographs due to osteoporosis and infection tended to be more prevalent for urban patients. Such findings provide information for policymakers to improve equity in health care and resource allocations within the settings of urbanity and rurality.


Doing well by doing good. The relationship between formal volunteering and self-reported health and happiness.
In this paper, we examine whether engaging in voluntary work leads to greater well-being, as measured by self-reported health and happiness. Drawing on data from the USA, our estimates suggest that people who volunteer report better health and greater happiness than people who do not, a relationship that is not driven by socio-economic differences between volunteers and non-volunteers. We concentrate on voluntary labor for religious groups and organizations and using second stage least square regressions we find that religious volunteering has a positive, causal influence on self-reported happiness but not on self-reported health. We explore reasons that could account for the observed causal effect of volunteering on happiness. Findings indicate that low relative socio-economic status is associated with poor health both among those who volunteer and those who do not. Low status, however, is associated with unhappy states only among those who do not volunteer, while volunteers are equally likely to be happy whether they have high or low status. We propose that volunteering might contribute to happiness levels by increasing empathic emotions, shifting aspirations and by moving the salient reference group in subjective evaluations of relative positions from the relatively better-off to the relatively worse-off.


Regulation systems of protease and hemolysin production in Vibrio vulnificus.
Vibrio vulnificus, a gram-negative halophilic estuarine bacterium, is an opportunistic human pathogen that causes rapidly progressive fatal septicemia and necrotizing wound infection. This species also causes hemorrhagic septicemia called vibriosis in cultured eels. It has been proposed that a range of virulence factors play roles in pathogenesis during human and/or eel infection. Among these factors, a metalloprotease (V. vulnificus protease [VVP]) and a cytolytic toxin (V. vulnificus hemolysin [VVH]) are of significant importance. VVP elicits the characteristic edematous and hemorrhagic skin damage, whereas VVH exhibits powerful hemolytic and cytolytic activities and contributes to bacterial invasion from the intestine to the blood stream. In addition, a few V. vulnificus strains isolated from diseased eels have recently been found to produce a serine protease designated as V. vulnificus serine protease (VvsA) instead of VVP. Similarly to VVP, VvsA may possess various toxic activities such as collagenolytic, cytotoxic and edema-forming activity. In this review, regulation of V. vulnificus VVP, VVH and VvsA is clarified in terms of expression at the mRNA and protein levels. The explanation is given on the basis of the quorum sensing system, which is dependent on bacterial cell density. In addition, the roles of environmental factors and global regulators, such as histone-like nucleoid structuring protein, cyclic adeno monophosphate receptor protein, RpoS, HlyU, Fur, ToxRS, AphB and LeuO, in this regulation are outlined. The cumulative impact of these regulatory systems on the pathogenicity of V. vulnificus is here delineated.


Expression-invariant representations of faces.
Addressed here is the problem of constructing and analyzing expression-invariant representations of human faces. We demonstrate and justify experimentally a simple geometric model that allows to describe facial expressions as isometric deformations of the facial surface. The main step in the construction of expression-invariant representation of a face involves embedding of the facial intrinsic geometric structure into some low-dimensional space. We study the influence of the embedding space geometry and dimensionality choice on the representation accuracy and argue that compared to its Euclidean counterpart, spherical embedding leads to notably smaller metric distortions. We experimentally support our claim showing that a smaller embedding error leads to better recognition.


Potential cost savings attributable to influenza vaccination of school-aged children.
To analyze the costs and benefits of influenza vaccination of healthy school-aged children. The analysis was based on data from the literature. Total costs included direct medical costs for vaccination, physician visits, and treatment as well as indirect costs. Indirect costs were in the form of lost productivity when working parents stayed home to care for ill children or to take children to an office for vaccination. The total costs of vaccination strategies were compared with the total cost of not vaccinating. For the base case, the vaccine was assumed to have no effect on rates of otitis media. Two hypothetical scenarios were investigated 1) individual-initiated vaccination and 2) vaccination in a group-based setting. The former scenario required the child to be accompanied to a clinic by a parent during usual work hours. Vaccination resulted in a net savings per child vaccinated of $4 for individual-initiated vaccination and of $35 for group-based vaccination. The savings were caused primarily by averted indirect costs. Moderate increases in the cost of vaccination or reductions in the rate of influenza would eliminate the savings for individual-initiated vaccination but not for group-based vaccination. Alternatively, if influenza vaccination was effective in reducing rates of otitis media, the net savings from vaccination would be substantially higher than the base case. Vaccination of school-aged children against influenza could have substantial financial benefits to society, especially if performed in a group-based setting. influenza, cost-effectiveness, vaccination, children, cost.


Exciton-exciton annihilation and relaxation pathways in semiconducting carbon nanotubes.
We present a thorough analysis of one- and two-color transient absorption measurements performed on single- and double-walled semiconducting carbon nanotubes. By combining the currently existing models describing exciton-exciton annihilation-the coherent and the diffusion-limited ones-we are able to simultaneously reproduce excitation kinetics following both E11 and E22 pump conditions. Our simulations revealed the fundamental photophysical behavior of one-dimensional coherent excitons and non-trivial excitation relaxation pathways. In particular, we found that after non-linear annihilation a doubly-excited exciton relaxes directly to its E11 state bypassing the intermediate E22 manifold, so that after excitation resonant with the E11 transition, the E22 state remains unpopulated. A quantitative explanation for the observed much faster excitation kinetics probed at E22 manifold, comparing to those probed at the E11 band, is also provided.


No protective effect of acyclovir on HIV disease progression in a cohort of HSV-2-HIV-infected individuals.
The efficacy of anti-herpetic drugs in decreasing HIV disease progression has not been clarified. We studied a cohort of 126 HIV-positive individuals with known date of seroconversion who were HSV-2-seropositive to determine if progression to AIDS was influenced by treatment with acyclovir. In the multivariate analysis, being homosexual and low CD4 count were associated with a faster progression to AIDS, whereas treatment with acyclovir showed a 37.0% protective effect compared to those who did not receive it when antiretroviral treatment was not included in the model. When including antiretroviral therapy, the protective effect of acyclovir decreased to 9.0% and that of antiretroviral therapy was 43.0% for monotherapy and 36.0% for double therapy, suggesting that most of the protective effect of acyclovir in the previous model was due to antiretroviral therapy. In conclusion, treatment with acyclovir does not seem to prolong significantly survival to AIDS among HIV-positive individuals who are HSV-2-infected.


Interest of Youth Living With HIV in Long-Acting Antiretrovirals.
This study's primary objective was to characterize attitudes to long-acting antiretrovirals (LAARV), among youth aged 13-24 years living with perinatally acquired HIV and nonperinatally acquired HIV. Secondary objectives included: assessing whether those with detectable HIV RNA PCR viral load had higher enthusiasm for LAARV compared to those with suppressed viral load, and examining characteristics associated with LAARV enthusiasm. A cross-sectional survey of 303 youth living with HIV (YHIV) followed at 4 pediatric/adolescent HIV clinics in the United States was performed to determine interest in LAARV, using a modified survey instrument previously used in adults. Interest in LAARV across groups was compared. Poisson regression with robust variance was used to determine the impact of various characteristics on interest in LAARV. Overall, 88% of YHIV reported probable or definite willingness to use LAARV. The enthusiasm level was similar between youth with perinatally acquired HIV and nonperinatally acquired HIV (P = 0.93). Youth with HIV viral load >1000 copies per milliliter had significantly higher interest than youth with suppressed viral load [prevalence ratio 1.12 (95% confidence interval: 1.03 to 1.20); P = 0.005]. Female youth participants who had had past experience with implantable contraceptive methods had a significantly higher interest in LAARV (100% vs. 85.5%; P = 0.002). Proportion of respondents endorsing definite willingness to use was significantly higher with decreased injection frequency compared with increased injection frequency. YHIV at 4 urban US pediatric/adolescent HIV clinics had high levels of enthusiasm for LAARV. LAARV should be given high priority as a potentially viable treatment option to improve clinical outcomes in YHIV.


Is quadriceps endurance reduced in COPD?: a systematic review.
Although the aerobic profile of the quadriceps muscle is reduced in COPD, there is conflicting evidence regarding whether this leads to reduced quadriceps muscle endurance. We, therefore, performed a systematic review of studies comparing quadriceps endurance in individuals with COPD with that in healthy control subjects. Relevant studies were identified by searching six electronic databases (1946-2011). Full-text articles were obtained after two researchers independently reviewed the abstracts. The results were combined in a random effects meta-analysis, and metaregression models were fitted to assess the influence of the type of measurement. Data were extracted from 21 studies involving 728 individuals with COPD and 440 healthy control subjects. Quadriceps endurance was reduced in those with COPD compared with healthy control subjects (standardized mean difference, 1.16 [95% CI, 1.02-1.30]; P < .001) with a 44.5 s (4.5-84.5 s; P = .029) reduction in COPD (large effect size) when measured using a nonvolitional technique. The relationship between quadriceps endurance in those with COPD and control subjects did not differ when comparing nonvolitional and volitional techniques (P = .22) or when high- or low-intensity tasks (P = .44) were undertaken. Quadriceps endurance is reduced in individuals with COPD compared with healthy control subjects, independent of the type of task performed.


RNA Sequencing and Co-expressed Long Non-coding RNA in Modern and Wild Wheats.
There is an urgent need for the improvement of drought-tolerant bread and durum wheat. The huge and complex genome of bread wheat (BBAADD genome) stands as a vital obstruction for understanding the molecular mechanism underlying drought tolerance. However, tetraploid wheat (Triticum turgidum ssp., BBAA genome) is an ancestor of modern bread wheat and offers an important model for studying the drought response due to its less complex genome. Additionally, several wild relatives of tetraploid wheat have already shown a significant drought tolerance. We sequenced root transcriptome of three tetraploid wheat varieties with varying stress tolerance profiles, and built differential expression library of their transcripts under control and drought conditions. More than 5,000 differentially expressed transcripts were identified from each genotype. Functional characterization of transcripts specific to drought-tolerant genotype, revealed their association with osmolytes production and secondary metabolite pathways. Comparative analysis of differentially expressed genes and their non-coding RNA partners, long noncoding RNAs and microRNAs, provided valuable insight to gene expression regulation in response to drought stress. LncRNAs as well as coding transcripts share similar structural features in different tetraploid species; yet, lncRNAs slightly differ from coding transcripts. Several miRNA-lncRNA target pairs were detected as differentially expressed in drought stress. Overall, this study suggested an important pool of transcripts where their manipulations confer a better performance of wheat varieties under drought stress.


An algebra for the analysis of object encoding.
The encoding of the objects from the world around us is one of the major topics of cognitive psychology, yet the principles of object coding in the human brain remain unresolved. Beyond referring to the particular features commonly associated with objects, our ability to categorize and discuss objects in detailed linguistic propositions implies that we have access to generic concepts of each object category with well-specified boundaries between them. Consideration of the nature of generic object concepts reveals that they must have the structure of a probabilistic list array specifying the Bayesian prior on all possible features that the object can possess, together with mutual covariance matrices among the features. Generic object concepts must also be largely context independent for propositions to have communicable meaning. Although, there is good evidence for local feature processing in the occipital lobe and specific responses for a few basic object categories in the posterior temporal lobe, the encoding of the generic object concepts remains obscure. We analyze the conceptual underpinnings of the study of object encoding, draw some necessary clarifications in relation to its modality-specific and amodal aspects, and propose an analytic algebra with specific reference to functional Magnetic Resonance Imaging approaches to the issue of how generic (amodal) object concepts are encoded in the human brain.


Metabotropic receptor activation, desensitization and sequestration-I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation.
A mathematical account is given of the processes governing the time courses of calcium ions (Ca2+), inositol 1,4,5-trisphosphate (IP(3)) and phosphatidylinositol 4,5-bisphosphate (PIP(2)) in single cells following the application of external agonist to metabotropic receptors. A model is constructed that incorporates the regulation of metabotropic receptor activity, the G-protein cascade and the Ca2+ dynamics in the cytosol. It is subsequently used to reproduce observations on the extent of desensitization and sequestration of the P(2)Y(2) receptor following its activation by uridine triphosphate (UTP). The theory predicts the dependence on agonist concentration of the change in the number of receptors in the membrane as well as the time course of disappearance of receptors from the plasmalemma, upon exposure to agonist. In addition, the extent of activation and desensitization of the receptor, using the calcium transients in cells initiated by exposure to agonist, is also predicted. Model predictions show the significance of membrane PIP(2) depletion and resupply on the time course of IP(3) and Ca2+ levels. Results of the modelling also reveal the importance of receptor recycling and PIP(2) resupply for maintaining Ca2+ and IP(3) levels during sustained application of agonist.


Dorsal laminectomy for treatment of cervical vertebral stenotic myelopathy in an alpaca.
An 11-year-old male breeding alpaca was evaluated for a 2-day history of lowered head carriage and lethargy. On initial examination, the alpaca had signs of lethargy and lowered carriage of the head and neck, but no specific neurologic deficits. Medical management improved the clinical signs, but 8 months later, the alpaca developed acute, progressive general proprioceptive ataxia affecting all 4 limbs and was referred for further evaluation and treatment. Magnetic resonance imaging and CT identified disruption of the normal osseous architecture of C7 and T1. Medical management was attempted, but because of a lack of improvement, the patient underwent surgery 14 months after initial examination. A dorsal laminectomy of C7 and T1 via a dorsal midline approach was performed, and the spinous processes of both vertebrae were removed prior to removal of the overlying lamina. Free dorsal expansion of the spinal cord was ensured by resection of the ligamentum flavum. Six months after surgery, the alpaca had returned to successful breeding with 7 hembra bred in the first year after surgery, producing 6 crias, and 4 crias in the second year. The patient was eventually euthanized 28 months after surgery because of neurologic deterioration but was still ambulatory at that time. A good outcome with adequate alleviation of clinical signs and breeding soundness for > 2 years following dorsal laminectomy was achieved in this camelid patient. The surgical approach was similar to that in other species and was associated with mild postoperative morbidity. Veterinarians treating camelids should be aware of the initial clinical signs and treatment options for cervical vertebral stenotic myelopathy. In acute cases, the signs of reduced cervical mobility and pain on manipulation should prompt investigation including appropriate diagnostic imaging. Timely surgical intervention should be considered in patients that respond poorly to medical treatment to avoid irreversible spinal cord injury and optimize outcome.


Functional Bowel Disorders: A Roadmap to Guide the Next Generation of Research.
In June 2016, the National Institutes of Health hosted a workshop on functional bowel disorders (FBDs), particularly irritable bowel syndrome, with the objective of elucidating gaps in current knowledge and recommending strategies to address these gaps. The workshop aimed to provide a roadmap to help strategically guide research efforts during the next decade. Attendees were a diverse group of internationally recognized leaders in basic and clinical FBD research. This document summarizes the results of their deliberations, including the following general conclusions and recommendations. First, the high prevalence, economic burden, and impact on quality of life associated with FBDs necessitate an urgent need for improved understanding of FBDs. Second, preclinical discoveries are at a point that they can be realistically translated into novel diagnostic tests and treatments. Third, FBDs are broadly accepted as bidirectional disorders of the brain-gut axis, differentially affecting individuals throughout life. Research must integrate each component of the brain-gut axis and the influence of biological sex, early-life stressors, and genetic and epigenetic factors in individual patients. Fourth, research priorities to improve diagnostic and management paradigms include enhancement of the provider-patient relationship, longitudinal studies to identify risk and protective factors of FBDs, identification of biomarkers and endophenotypes in symptom severity and treatment response, and incorporation of emerging "-omics" discoveries. These paradigms can be applied by well-trained clinicians who are familiar with multimodal treatments. Fifth, essential components of a successful program will include the generation of a large, validated, broadly accessible database that is rigorously phenotyped; a parallel, linkable biorepository; dedicated resources to support peer-reviewed, hypothesis-driven research; access to dedicated bioinformatics expertise; and oversight by funding agencies to review priorities, progress, and potential synergies with relevant stakeholders.


Efficacy of digital cognitive behavioural therapy for symptoms of generalised anxiety disorder: a study protocol for a randomised controlled trial.
Generalised anxiety disorder (GAD) is a chronic and disabling condition with considerable personal and economic impact. Cognitive behavioural therapy (CBT) is a recommended psychological therapy for GAD; however, there are substantial barriers to accessing treatment. Digital CBT, in particular smartphone-delivered CBT, has the potential to improve accessibility and increase dissemination of CBT. Despite the emerging evidence of smartphone-based psychological interventions for reducing anxiety, effect size scores are typically smaller than in-person interventions, and there is a lack of research assessing the efficacy of smartphone-delivered digital interventions specifically for GAD. In the DeLTA trial (DigitaL Therapy for Anxiety), we plan to conduct a parallel-group superiority randomised controlled trial examining the efficacy of a novel smartphone-based digital CBT intervention for GAD compared to a waitlist control. We aim to recruit 242 adults (aged 18 years or above) with moderate-to-severe symptoms of GAD. This trial will be conducted entirely online and will involve assessments at baseline (week 0; immediately preceding randomisation), mid-intervention (week 3), post-intervention (week 6; primary end point) and follow-up (week 10). The primary objective is to evaluate the efficacy of the intervention on GAD symptom severity compared to a waitlist control at post-intervention. Secondary objectives are to examine between-group effects on GAD at follow-up, and to examine the following secondary outcomes at both post-intervention and follow-up: 1) worry; 2) depressive symptoms; 3) wellbeing; 4) quality of life; and 5) sleep difficulty. This trial will report findings on the initial efficacy of a novel digital CBT intervention for GAD. Results have the potential to contribute towards the evidence base for digital CBT for GAD and increase the dissemination of CBT. ISRCTN, ISRCTN12765810. Registered on 11 January 2019.


Hunter-gatherer postcranial robusticity relative to patterns of mobility, climatic adaptation, and selection for tissue economy.
Human skeletal robusticity is influenced by a number of factors, including habitual behavior, climate, and physique. Conflicting evidence as to the relative importance of these factors complicates our ability to interpret variation in robusticity in the past. It remains unclear how the pattern of robusticity in the skeleton relates to adaptive constraints on skeletal morphology. This study investigates variation in robusticity in claviculae, humeri, ulnae, femora, and tibiae among human foragers, relative to climate and habitual behavior. Cross-sectional geometric properties of the diaphyses are compared among hunter-gatherers from southern Africa (n = 83), the Andaman Islands (n = 32), Tierra del Fuego (n = 34), and the Great Lakes region (n = 15). The robusticity of both proximal and distal limb segments correlates negatively with climate and positively with patterns of terrestrial and marine mobility among these groups. However, the relative correspondence between robusticity and these factors varies throughout the body. In the lower limb, partial correlations between polar second moment of area (J(0.73)) and climate decrease from proximal to distal section locations, while this relationship increases from proximal to distal in the upper limb. Patterns of correlation between robusticity and mobility, either terrestrial or marine, generally increase from proximal to distal in the lower and upper limbs, respectively. This suggests that there may be a stronger relationship between observed patterns of diaphyseal hypertrophy and behavioral differences between populations in distal elements. Despite this trend, strength circularity indices at the femoral midshaft show the strongest correspondence with terrestrial mobility, particularly among males.


Nurses' views about tuberculosis patients' discharge plan at Moses Kotane in the North-West Province.
The purpose of this study was to explore and describe the opinions of nurses working with tuberculosis (TB) patients regarding hospital discharge plans at Moses Kotane in North-West, South Africa. A qualitative, exploratory and descriptive study was conducted with these nurses. The population involved registered nurses working with TB patients for more than two years. The population was purposely selected. Focus group interviews were conducted to collect data from this population. The research process was guided by the research question: What are the opinions of nurses working with TB patients regarding hospital discharge plans at Moses Kotane in the North-West Province? The group moderator guided the participants throughout the interviews in which the central research question was posed. Tesch's qualitative method of data analysis was used to analyse the data obtained. Subcategories and categories, and the following themes emerged during the data analysis: the need for education and involvement, the co-existence of TB and HIV/ Aids infections and the knowledge of continuous laboratory investigations. The participants discussed the suggestions and solutions for effective hospital discharge plans. The research findings could assist in the improvement of existing hospital discharge plans at Moses Kotane District. The results revealed both positive and negative opinions regarding discharge plans. The data were classified into themes, categories and subcategories. The participants' suggestions regarding discharge plans were addressed and discussed. Finally, recommendations were disseminated to concerned authorities.


Examining current or future trade-offs for biodiversity conservation in north-eastern Australia.
With the high rate of ecosystem change already occurring and predicted to occur in the coming decades, long-term conservation has to account not only for current biodiversity but also for the biodiversity patterns anticipated for the future. The trade-offs between prioritising future biodiversity at the expense of current priorities must be understood to guide current conservation planning, but have been largely unexplored. To fill this gap, we compared the performance of four conservation planning solutions involving 662 vertebrate species in the Wet Tropics Natural Resource Management Cluster Region in north-eastern Australia. Input species data for the four planning solutions were: 1) current distributions; 2) projected distributions for 2055; 3) projected distributions for 2085; and 4) current, 2055 and 2085 projected distributions, and the connectivity between each of the three time periods for each species. The four planning solutions were remarkably similar (up to 85% overlap), suggesting that modelling for either current or future scenarios is sufficient for conversation planning for this region, with little obvious trade-off. Our analyses also revealed that overall, species with small ranges occurring across steep elevation gradients and at higher elevations were more likely to be better represented in all solutions. Given that species with these characteristics are of high conservation significance, our results provide confidence that conservation planning focused on either current, near- or distant-future biodiversity will account for these species.


Thresholds for masking responses to light in three strains of retinally degenerate mice.
Mutant mice with retinal degeneration (rd/rd) were given 1-h pulses of light of varying brightness at times of the night when they would normally be active. The mutant mice showed a significantly greater inhibition of locomotor activity to light (negative masking) than wildtype controls. Lack of impairment, or even enhancement of negative masking suggests that this response may depend on sparing in retinally degenerate mice of the same receptor type that mediates clock resetting, because synchronization of the circadian system is known to be unimpaired in these mutants. With very dim light pulses, mutants did not change their activity, but wildtypes actually became more active (positive masking). Positive and negative masking appear to depend on different sensory and central processes.


Extracellular S100A4 induces smooth muscle cell phenotypic transition mediated by RAGE.
We identified S100A4 as a marker of rhomboid (R) smooth muscle cells (SMCs) in vitro (the synthetic phenotype, typical of intimal SMCs) in the porcine coronary artery and of intimal SMCs in vivo in both pigs and humans. S100A4 is an intracellular Ca²⁺ signaling protein and can be secreted; it has extracellular functions via the receptor for advanced glycation end products (RAGE). Our objective was to explore the role of S100A4 in SMC phenotypic change, a phenomenon characteristic of atherosclerotic plaque formation. Transfection of a human S100A4-containing plasmid in spindle-shaped (S) SMCs (devoid of S100A4) led to approximately 10% of S100A4-overexpressing SMCs, S100A4 release, and a transition towards a R-phenotype of the whole SMC population. Furthermore treatment of S-SMCs with S100A4-rich conditioned medium collected from S100A4-transfected S-SMCs induced a transition towards a R-phenotype, which was associated with decreased SMC differentiation markers and increased proliferation and migration by activating the urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). It yielded NF-κB activation in a RAGE-dependent manner. Blockade of extracellular S100A4 in R-SMCs with S100A4 neutralizing antibody induced a transition from R- to S-phenotype, decreased proliferative activity and upregulation of SMC differentiation markers. By contrast, silencing of S100A4 mRNA in R-SMCs did not change the level of extracellular S100A4 or SMC morphology in spite of decreased proliferative activity. Our results show that extracellular S100A4 plays a pivotal role in SMC phenotypic changes. It could be a new target to prevent SMC accumulation during atherosclerosis and restenosis. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.


The role of mediastinoscopy in the evaluation of thoracic disease and lung cancer.
Mediastinoscopy is a widely used technique in the diagnosis of mediastinal disease and the staging of bronchogenic carcinoma. Its efficacy in the preoperative staging of lung cancer is well-established, with a procedural sensitivity of greater than 90% and specificity of 100%. Mediastinoscopy can also establish the diagnosis in greater than 90% of mediastinal disease. We conducted a retrospective study of mediastinoscopy performed at our institution between 1998 and 2001 to evaluate the safety and efficacy of mediastinoscopy. We collected 100 consecutive mediastinoscopies performed in Thoracic Division of Taipei Veterans General Hospital between 1998 and 2001. The indications for mediastinoscopy included mediastinal mass or lymphadenopathy and the staging of lung cancer. Some patients had the undetermined lung mass with enlarged mediastinal lymph node. There were 69 men and 31 women aged from 13 to 87 (mean 60.9). Sixty-seven patients had mediastinoscopy for the staging of lung cancer, 29 patients for diagnosis of mediastinal mass or lymphadenopathy, and 4 patients for undetermined lung mass with mediastinal lymphadenopathy. Among the patients with mediastinal disease, sarcoidosis was diagnosed in 13 patients, and lymphoma in 5 patients. N2 or N3 nodal metastasis was revealed in 38 of 67 patients who had lung cancer. Fifteen patients with negative mediastinoscopy proceeded to thoracotomy for tumor resection. Seventeen patients received neoadjuvant chemotherapy followed by resection. There were three complications, all due to bleeding, and no mortality. Mediastinoscopy is a safe and effective procedure for the diagnosis of mediastinal disease and the staging of lung cancer. In cases of lung cancer, mediastinoscopy can provide more accurate evaluation of mediastinal lymph node metastasis than conventional diagnostic tools like computed scan or magnetic resonance image with low morbidity and mortality.


Neoplastic transformation in C3H 10T(1/2) cells after exposure to 835.62 MHz FDMA and 847.74 MHz CDMA radiations.
The effect of radiofrequency (RF) radiation in the cellular phone communication range (835.62 MHz frequency division multiple access, FDMA; 847.74 MHz code division multiple access, CDMA) on neoplastic transformation frequency was measured using the in vitro C3H 10T(1/2) cell transformation assay system. To determine if 835.62 MHz FDMA or 847.74 MHz CDMA radiations have any genotoxic effects that induce neoplastic transformation, C3H 10T(1/2) cells were exposed at 37 degrees C to either of the above radiations [each at a specific absorption rate (SAR) of 0.6 W/kg] or sham-exposed at the same time for 7 days. After the culture medium was changed, the cultures were transferred to incubators and refed with fresh growth medium every 7 days. After 42 days, the cells were fixed and stained with Giemsa, and transformed foci were scored. To determine if exposure to 835.62 MHz FDMA or 847.74 MHz CDMA radiation has any epigenetic effects that can promote neoplastic transformation, cells were first exposed to 4.5 Gy of X rays to induce the transformation process and then exposed to the above radiations (SAR = 0.6 W/kg) in temperature-controlled irradiators with weekly refeeding for 42 days. After both the 7-day RF exposure and the 42-day RF exposure after X irradiation, no statistically significant differences in the transformation frequencies were observed between incubator controls, the sham-exposed (maintained in irradiators without power to the antenna), and the 835.62 MHz FDMA or 847.74 MHz CDMA-exposed groups.


Comparing growth trajectories of risk behaviors from late adolescence through young adulthood: an accelerated design.
Risk behaviors such as substance use or deviance are often limited to the early stages of the life course. Whereas the onset of risk behavior is well studied, less is currently known about the decline and timing of cessation of risk behaviors of different domains during young adulthood. Prevalence and longitudinal developmental patterning of alcohol use, drinking to the point of drunkenness, smoking, cannabis use, deviance, and HIV-related sexual risk behavior were compared in a Swiss community sample (N = 2,843). Using a longitudinal cohort-sequential approach to link multiple assessments with 3 waves of data for each individual, the studied period spanned the ages of 16 to 29 years. Although smoking had a higher prevalence, both smoking and drinking up to the point of drunkenness followed an inverted U-shaped curve. Alcohol consumption was also best described by a quadratic model, though largely stable at a high level through the late 20s. Sexual risk behavior increased slowly from age 16 to age 22 and then remained largely stable. In contrast, cannabis use and deviance linearly declined from age 16 to age 29. Young men were at higher risk for all behaviors than were young women, but apart from deviance, patterning over time was similar for both sexes. Results about the timing of increase and decline as well as differences between risk behaviors may inform tailored prevention programs during the transition from late adolescence to adulthood.


MxiD, an outer membrane protein necessary for the secretion of the Shigella flexneri lpa invasins.
The invasive phenotype of Shigella flexneri is conferred by a 220 kb virulence plasmid, pWR100, that encodes both the lpa proteins, which are involved in the entry process, and factors which are required for the export and correct localization of the lpa proteins. We have characterized the mxiD gene, whose expression, like that of the ipa operon, is regulated by temperature. After inactivation of mxiD, the mutant strain was unable to invade HeLa cells and to provoke keratoconjunctivitis in guinea-pigs. Analysis of culture supernatants indicated that wild-type S. flexneri secretes about nine polypeptides and that secretion of several of these, including lpaA, lpaB, and lpaC, is abolished in the mxiD mutant. Examination of the membrane proteins of the wild-type and mxiD strains suggested that MxiD is an outer membrane protein. Amino acid sequence comparison revealed that MxiD is homologous to the YscC protein of Yersinia enterocolitica and to the C-terminal region of the PulD protein of Klebsiella pneumoniae. Both YscC and PulD are involved in extracellular protein secretion. These results indicate that MxiD is an essential component of the lpa secretion apparatus.


The relationship between pain-induced autonomic arousal and perceived duration.
Emotional distortions of the perceived duration of events are often explained in terms of increases and decreases in arousal. While this explanation is theoretically plausible, there is a lack of evidence for a direct relationship between physiological arousal and perceived duration. The aim of the current study was to investigate whether physiological arousal, defined by autonomic nervous system (ANS) activity is directly related to perceived duration. In two experiments we measured skin conductance level (SCL) and high frequency heart rate variability (HF HRV) during verbal estimation tasks. In Experiment 1, participants estimated the duration of electro-cutaneous stimuli previously rated as inducing no pain, low pain and high pain. High intensity stimuli were perceived as lasting for longer than low intensity stimuli, and these changes in duration estimation were associated with changes in ANS activity. In Experiment 2, participants estimated the duration of a neutral visual stimulus while experiencing different intensities of background thermal pain (no pain, low pain, and high pain), to determine whether task-irrelevant arousal also affects time perception. Duration estimations for the neutral stimulus did not increase with pain intensity despite significant increases in SCL. Furthermore, there was no association between ANS activity and time estimation in Experiment 2. These findings suggest that the relationship between physiological arousal and time perception is more complex than previously described. While physiological arousal can influence the perceived duration of events, it appears to have a greater capacity to do so when the to-be-timed stimulus is itself the source of arousal. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assessing the robustness of raingardens under climate change using SDSM and temporal downscaling.
Climate change is expected to lead to higher precipitation amounts and intensities causing an increase of the risk for flooding and combined sewer overflows in urban areas. To cope with these changes, water managers are requesting practical tools that can facilitate adaptive planning. This study was carried out to investigate how recent developments in downscaling techniques can be used to assess the effects of adaptive measures. A combined spatial-temporal downscaling methodology using the Statistical DownScaling Model-Decision Centric (SDSM-DC) and the Generalized Extreme Value distribution was applied to project future precipitation in the city of Bergen, Norway. A raingarden was considered a potential adaptive measure, and its performance was assessed using the RECARGA simulation tool. The benefits and limitations of using the proposed method have been demonstrated and compared to current design practices in Norway. Large differences in the raingarden's performance with respect to percentage overflow and lag-time reduction were found for varying projections. This highlights the need for working with a range of possible futures. Further, it was found that Ksat was the determining factor for peak-flow reduction and that different values of Ksat had different benefits. Engineering flexible solutions by combining measures holding different characteristics will induce robust adaptation.


Repositioning Chloride Transmembrane Transporters: Transport of Organic Ion Pairs.
Given the biological importance of organic cations, the facilitated transport of organic ion pairs could find many applications. Calix[6]arene tris(thio)ureas, which possess a cavity that can accommodate primary ammonium ions, can not only act as carriers for Cl- /NO3- antiport but can also perform the cotransport of PrNH3 Cl. Transport was monitored by fluorescence spectroscopy and the presence of the different species inside the vesicles was characterized by 1 H and 35 Cl NMR experiments involving shift reagents. The cotransport of PrNH3 Cl was also observed by receptors deprived of a cavity, but the presence of the cavity conveys an advantage, as the cotransport by calix[6]arenes was observed to be more efficient than the Cl- /NO3- antiport, which is not the case with receptors without a cavity. The role played by the cavity was further highlighted by the disappearance of this advantage when using a bulky ammonium ion, which cannot be complexed within the cavity.


Clinical implications of molecular neuropathology and biomarkers for malignant glioma.
Malignant gliomas are currently diagnosed based on morphological criteria and graded according to the World Health Organization classification of primary brain tumors. This algorithm of diagnosis and classification provides clinicians with an estimated prognosis of the natural course of the disease. It does not reflect the expected response to specific treatments beyond surgery (eg, radiotherapy or alkylating chemotherapy). Clinical experience has revealed that gliomas sharing similar histomorphological criteria might indeed have different clinical courses and exhibit highly heterogenous responses to treatments. This was very impressively demonstrated first for oligodendrogliomas. The presence or lack of combined deletions of the chromosomal segments 1p/19q was associated with different benefit from radiotherapy and chemotherapy. We review current molecular markers for malignant gliomas and discuss their current and future impact on clinical neuro-oncology.


Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy.
Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.


Physical activity, health benefits, and mortality risk.
A plethora of epidemiologic evidence from large studies supports unequivocally an inverse, independent, and graded association between volume of physical activity, health, and cardiovascular and overall mortality. This association is evident in apparently healthy individuals, patients with hypertension, type 2 diabetes mellitus, and cardiovascular disease, regardless of body weight. Moreover, the degree of risk associated with physical inactivity is similar to, and in some cases even stronger than, the more traditional cardiovascular risk factors. The exercise-induced health benefits are in part related to favorable modulations of cardiovascular risk factors observed by increased physical activity or structured exercise programs. Although the independent contribution of the exercise components, intensity, duration, and frequency to the reduction of mortality risk is not clear, it is well accepted that an exercise volume threshold defined at caloric expenditure of approximately 1,000 Kcal per week appears to be necessary for significant reduction in mortality risk. Further reductions in risk are observed with higher volumes of energy expenditure. Physical exertion is also associated with a relatively low and transient increase in risk for cardiac events. This risk is significantly higher for older and sedentary individuals. Therefore, such individuals should consult their physician prior to engaging in exercise."Walking is man's best medicine"Hippocrates.