Atrial natriuretic peptide regulates Ca channel in early developmental cardiomyocytes.
Cardiomyocytes derived from murine embryonic stem (ES) cells possess various membrane currents and signaling cascades link to that of embryonic hearts. The role of atrial natriuretic peptide (ANP) in regulation of membrane potentials and Ca(2+) currents has not been investigated in developmental cardiomyocytes. We investigated the role of ANP in regulating L-type Ca(2+) channel current (I(CaL)) in different developmental stages of cardiomyocytes derived from ES cells. ANP decreased the frequency of action potentials (APs) in early developmental stage (EDS) cardiomyocytes, embryonic bodies (EB) as well as whole embryo hearts. ANP exerted an inhibitory effect on basal I(CaL) in about 70% EDS cardiomyocytes tested but only in about 30% late developmental stage (LDS) cells. However, after stimulation of I(CaL) by isoproterenol (ISO) in LDS cells, ANP inhibited the response in about 70% cells. The depression of I(CaL) induced by ANP was not affected by either Nomega, Nitro-L-Arginine methyl ester (L-NAME), a nitric oxide synthetase (NOS) inhibitor, or KT5823, a cGMP-dependent protein kinase (PKG) selective inhibitor, in either EDS and LDS cells; whereas depression of I(CaL) by ANP was entirely abolished by erythro-9-(2-Hydroxy-3-nonyl) adenine (EHNA), a selective inhibitor of type 2 phosphodiesterase(PDE2) in most cells tested. CONCLUSION/SIGNIFICANCES: Taken together, these results indicate that ANP induced depression of action potentials and I(CaL) is due to activation of particulate guanylyl cyclase (GC), cGMP production and cGMP-activation of PDE2 mediated depression of adenosine 3', 5'-cyclic monophophate (cAMP)-cAMP-dependent protein kinase (PKA) in early cardiomyogenesis.


A Three-year Audit of Dental Services at Primary Health Care Facilities in Gauteng, South Africa: 2017 to 2019.
The aim of this study was to determine the types and trends of dental services offered over 3 months (April, May, and June) every year from 2017 till 2019 at all full-time primary oral health care facilities (POHCFs) in Gauteng Province, South Africa. This was a record-based retrospective study. Data were collected from April, May, and June in 2017, 2018, and 2019, from all full-time POHCFs in Gauteng. The data were obtained from the attendance registers at each facility and included the number of patients and personnel and the type and number of procedures performed. A total of 90 POHCFs were included. The number of clinicians remained stable, whereas the mean number of patients per month increased from 587 (2017) to 654 (2019). This resulted in an increase in the mean monthly patient-to-clinician ratio from 376 (2017) to 428 (2019). On average, 459 extractions, 64 restorations, and 43 fissure sealants were performed monthly per district. Clinicians treated on average 19 patients per day and on average 15 extractions for every restoration. The mean operator-to-dental assistant ratio was 1.3:1. Although there were differences in the types of services rendered and the workloads of clinicians across the province, a significant increase was observed in the number of patients over the study period. The most common services rendered were extractions and the extraction-to-restoration ratio was fairly high. Managers need to carry out regular audits to ensure that the facilities are operating optimally.


Pyrophosphate analogues as inhibitors of herpes simplex virus type 1 DNA polymerase.
Twenty nine pyrophosphate analogues have been tested for their ability to inhibit herpes simplex virus type 1 (HSV-1) DNA polymerase activity. The structural requirements for active inhibitors and their mechanism of action have been investigated. Active compounds had two negatively charged groups at close proximity. The most active compounds contained free phosphono and/or carboxyl groups. Apart from phosphonoformate and phosphonoacetate, which were strong inhibitors, some other analogues, 2-phosphonopropionate, 2-phenylphosphonoacetate, oxalate, carbonyldiphosphate, methanehydroxy-diphosphonate and hypophosphate also inhibited the HSV-1 DNA polymerase activity. With the exception of hypophosphate the tested compounds inhibited the activity of calf thymus DNA polymerase alpha to a lesser extent than the activity of the HSV-1 DNA polymerase. All inhibitors gave linear uncompetitive inhibition of HSV-1 DNA polymerase with activated DNA as variable substrate. With the four deoxynucleoside triphosphates as variable substrates all inhibitors except hypophosphate gave linear non-competitive inhibition patterns. Hypophosphate caused a more competitive type of inhibition. The inhibition constants for the active compounds have been determined. Phosphonoformate, phosphonoacetate, methanehydroxydiphosphonate and hypophosphate also inhibited HSV-1 plaque formation in cell culture.


Antigen-driven differentiation of naive Ig-transgenic B cells in vitro.
We have established a culture system in which naive B cells bearing a transgenic, chicken OVA (cOVA)-specific Ig differentiate to plasma cells in vitro after interaction with cOVA plus cOVA-specific helper T cells. B cell-enriched populations from Ig-transgenic mice, but not from nontransgenic mice, proliferated after presenting nanomolar concentrations of cross-linked cOVA to DO11.10 (cOVA plus IAd-specific) T cells. After 6 to 9 days of culture with Ag and specific T cells, the B cells acquired a plasma cell phenotype and secreted the transgene-derived Ig at high levels. Engagement of B cell surface Ig was not essential for primary B cell differentiation. Differentiating B cells enlarged, clustered, and acquired two plasma cell markers, Syndecan and CD43. B cell CD45 isoform expression changed: the B220 isoform was lost in a T cell-dependent manner, whereas the CD45RB isoform was gained in a T-independent manner. Although unstimulated B cells survived less than 72 h in vitro, those in Ag-stimulated cultures showed reduced early death, a surge of proliferation at 3 to 5 days, and increased death late in the culture. Using a large population of naive B cells of defined antigenic specificity permits us to study a primary immune response to an Ag, rather than to less physiologic polyclonal stimuli. Because all steps of differentiation occurred in vitro, they are easily accessible for study. This coculture system provides an opportunity to observe Ag-specific T cell-B cell collaboration.


Morphology and putative function of the colon and cloaca of marine and freshwater snakes.
Among tetrapods, evidence for postrenal modification of the urine by the distal digestive tract (including the colon and cloaca) is highly variable. Birds and bladderless reptiles are of interest because the colon and cloaca represent the only sites from which water and ions can be reclaimed from the urine secreted by the kidney. For animals occupying desiccating environments (e.g., deserts and marine environments), postrenal modification of the urine may directly contribute to the maintenance of hypo-osmotic body fluids. We compared the morphology and distribution of key proteins in the colon, cloaca, and urogenital ducts of watersnakes from marine (Nerodia clarkii clarkii) and freshwater (Nerodia fasciata) habitats. Specifically, we examined the epithelia of each tissue for evidence of mucus production by examining the distribution of mucopolysaccharides, and for evidence of water/ion regulation by examining the distribution of Na(+) /K(+) -ATPase (NKA), Na(+) /K(+) /Cl(-) cotransporter (NKCC), and aquaporin 3 (AQP3). NKCC localized to the basolateral epithelium of the colon, urodeal sphincter, and proctodeum, consistent with a role in secretion of Na(+), Cl(-) , and K(+) from the tissue, but NKA was not detected in the colon or any compartment of the cloaca. Interestingly, NKA was detected in the basolateral epithelium of the ureters, suggesting the urothelium may play a role in active ion transport. AQP3 was detected in the ureters and coprodeal complex, consistent with a role in urinary and fecal dehydration or, potentially, in the production of the watery component of the mucus secreted by the coprodeal complex. Since no differences in general cloacal morphology, production of mucus, or the distribution of ion transporters/water channels were detected between the two species, cloacal osmoregulation may either be regulated by proteins not examined in this study or may not be responsible for the differential success of N. c. clarkii and N. fasciata in marine habitats.


Effect of SO2 and steam on CO2 capture performance of biomass-templated calcium aluminate pellets.
Four types of synthetic sorbents were developed for high-temperature post-combustion calcium looping CO2 capture using Longcal limestone. Pellets were prepared with: lime and cement (LC); lime and flour (LF); lime, cement and flour (LCF); and lime, cement and flour doped with seawater (LCFSW). Flour was used as a templating material. All samples underwent 20 cycles in a TGA under two different calcination conditions. Moreover, the prepared sorbents were tested for 10 carbonation/calcination cycles in a 68 mm-internal-diameter bubbling fluidized bed (BFB) in three environments: with no sulphur and no steam; in the presence of sulphur; and with steam. When compared to limestone, all the synthetic sorbents exhibited enhanced CO2 capture performance in the BFB experiments, with the exception of the sample doped with seawater. In the BFB tests, the addition of cement binder during the pelletisation process resulted in the increase of CO2 capture capacity from 0.08 g CO2 per g sorbent (LF) to 0.15 g CO2 per g sorbent (LCF) by the 10th cycle. The CO2 uptake in the presence of SO2 dramatically declined by the 10th cycle; for example, from 0.22 g CO2 per g sorbent to 0.05 g CO2 per g sorbent in the case of the untemplated material (LC). However, as expected all samples showed improved performance in the presence of steam, and the decay of reactivity during the cycles was less pronounced. Nevertheless, in the BFB environment, the templated pellets showed poorer CO2 capture performance. This is presumably because of material loss due to attrition under the FB conditions. By contrast, the templated materials performed better than untemplated materials under TGA conditions. This indicates that the reduction of attrition is critical when employing templated materials in realistic systems with FB reactors.


Simultaneous detection and genotyping of "Norwalk-like viruses" by oligonucleotide array in a reverse line blot hybridization format.
"Norwalk-like viruses" (NLVs) are the most common cause of outbreaks of nonbacterial gastroenteritis worldwide. To date, the method most widely used for typing of NLV strains is sequencing and subsequent phylogenetic analysis of reverse transcription (RT)-PCR products, which has revealed the existence of stable distinct lineages (genotypes). This typing method is rather costly, not routinely used in clinical laboratories, and not very suitable for the analysis of large numbers of samples. Therefore, we have developed a rapid and simple method for genotyping of NLVs. The method, designated reverse line blot hybridization, is based on the nucleotide divergence of a region of the gene for RNA polymerase which can be used to classify NLVs into genotypes. NLV RNA was amplified by RT-PCR and then hybridized to 18 different membrane-bound oligonucleotides that were able to discriminate among 13 NLV genotypes. Application of the method to a panel of 132 positive stool samples from 34 outbreaks and 20 sporadic cases of gastroenteritis collected in a 6-year period (1994 to 1999) resulted in successful genotyping of 124 samples (94%), as confirmed by phylogenetic analysis. The nucleotide sequences of the remaning eight strains (6%) from three outbreaks did not cluster with the known NLV genotypes. Phylogenetic analysis of the complete and partial open reading frame 2 (capsid gene) sequences of these strains revealed the existence of one novel genotype (Alphatron) and one potentially novel genotype (Amsterdam). This novel method, which allows simultaneous detection and genotyping of NLVs, is useful in the diagnosis and typing of NLVs obtained from outbreaks and in large-scale epidemiological studies.


How much are we exposed to alcohol in electronic media? Development of the Alcoholic Beverage Identification Deep Learning Algorithm (ABIDLA).
Evidence demonstrates that seeing alcoholic beverages in electronic media increases alcohol initiation and frequent and excessive drinking, particularly among young people. To efficiently assess this exposure, the aim was to develop the Alcoholic Beverage Identification Deep Learning Algorithm (ABIDLA) to automatically identify beer, wine and champagne/sparkling wine from images. Using a specifically developed software, three coders annotated 57,186 images downloaded from Google. Supplemented by 10,000 images from ImageNet, images were split randomly into training data (70 %), validation data (10 %) and testing data (20 %). For retest reliability, a fourth coder re-annotated a random subset of 2004 images. Algorithms were trained using two state-of-the-art convolutional neural networks, Resnet (with different depths) and Densenet-121. With a correct classification (accuracy) of 73.75 % when using six beverage categories (beer glass, beer bottle, beer can, wine, champagne, and other images), 84.09 % with three (beer, wine/champagne, others) and 85.22 % with two (beer/wine/champagne, others), Densenet-121 slightly outperformed all Resnet models. The highest accuracy was obtained for wine (78.91 %) followed by beer can (77.43 %) and beer cup (73.56 %). Interrater reliability was almost perfect between the coders and the expert (Kappa = .903) and substantial between Densenet-121 and the coders (Kappa = .681). Free from any response or coding burden and with a relatively high accuracy, the ABIDLA offers the possibility to screen all kinds of electronic media for images of alcohol. Providing more comprehensive evidence on exposure to alcoholic beverages is important because exposure instigates alcohol initiation and frequent and excessive drinking.


Photodissociation of van der Waals complexes of iodine X-I2 (X = I2, C2H4) via charge-transfer state: A velocity map imaging investigation.
The photodissociation of van der Waals complexes of iodine X-I2 (X = I2, C2H4) excited via Charge-Transfer (CT) band has been studied with the velocity map imaging technique. Photodissociation of both complexes gives rise to translationally "hot" molecular iodine I2 via channels differing by kinetic energy and angular distribution of the recoil directions. These measured characteristics together with the analysis of the model potential energy surface for these complexes allow us to infer the back-electron-transfer (BET) in the CT state to be a source of observed photodissociation channels and to make conclusions on the location of conical intersections where the BET process takes place. The BET process is concluded to provide an I2 molecule in the electronic ground state with moderate vibrational excitation as well as X molecule in the electronic excited state. In the case of X = I2, the BET process converts anion I2- of the CT state into the neutral I2 in the repulsive excited electronic state which then dissociates promptly giving rise to a pair of I atoms in the fine states 2P1/2. In the case of C2H4-I2, the C2H4 molecules appear in the triplet T1 electronic state. Conical intersection for corresponding BET process becomes energetically accessible after partial twisting of C2H4+ frame in the excited CT state of complex. The C2H4(T)-I2 complex gives rise to triplet ethylene as well as singlet ethylene via the T-S conversion.


Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha.
Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.


[The hospital discharge for the family of the coronary artery disease patient].
Fourteen families of coronary artery disease patients were interviewed to describe their perspectives concerning the cardiac disease and hospital discharge. Ten patients had been hospitalized for clinical treatment, and for surgical treatment. The case study method was selected, and the analysis process resulted in the following categories: the disease as a problem, the heart meaning everything and, their coming back home after hospital discharge. We concluded that the heart is the core of the emotions for the relatives and, when the patients return home, there is a concern about keeping them away from potentially damaging emotions that might trigger a new ischemic event.


Demethylbellidifolin preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level.
The present study examined the anti-oxidation and protective effects of demethylbellidifolin (DMB), a xanthone compound extracted from swertia davidi Franch, on endothelium. The relationship between the protective effects of DMB on endothelium and the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, was also determined in the present study. DMB significantly inhibited Cu(2+)-induced low-density lipoprotein (LDL) oxidation and scavenged DPPH radicals. DMB significantly attenuated the inhibition of endothelium-dependent vasodilator responses, induced by lysophosphatidycholine (LPC) in vitro and LDL in vivo, and increased release of lactate dehydrogenase induced by LDL in cultured endothelial cells. DMB significantly attenuated the increased concentration of malondialdehyde and ADMA, and the decreased level of nitric oxide induced by LDL in vivo and in cultured endothelial cells. DMB also significantly reduced the decreased activity of dimethylarginine dimethylaminohydrolase (DDAH) induced by LDL in cultured endothelial cells. In summary, the present results suggest that DMB protects endothelial damage induced by LPC in vitro and LDL in vivo or in endothelial cells, and the protective effect of DMB on the endothelium is related to reduction of ADMA concentration via an increase of DDAH activity by inhibition of lipid peroxidation.


Neuropsychiatric disorders and risk factors in carbon monoxide intoxication.
Neuropsychiatric sequelae may be observed in the late phases of carbon monoxide (CO) intoxication. Establishing a link between CO-related neuropsychiatric disorders and associated risk factors may decrease morbidity and mortality by means of appropriate treatment and counseling. The aim of the present study was to determine the relationship between neuropsychiatric outcomes of CO intoxication and demographic and clinical variables. Thirty patients who presented with CO intoxication and had no known neuropsychiatric disease, and 30 healthy controls were included. Physical examinations and laboratory tests were performed. Following the 1st therapy, they underwent mental and psychiatric tests 5 times (the time of discharge, during the 1st week, and during the 1st, 3rd, and 6th months). They underwent cerebral magnetic resonance imaging (MRI) at the end of the 1st month. They were evaluated by cognitive function tests at the 6th month. Lesions relevant to CO intoxication were detected in 46.7% of the patients via cranial computed tomography and in 13.3% via MRI. Evaluation of psychiatric tests revealed a clear decrease in cognitive functions, such as immediate memory, learning, reaching the criterion, spontaneous recall, attention, visual memory, and logical memory. It was found that the patients had anxiety within the 1st month, and the frequency of anxiety reached to the value of the control group by the end of the 6th month. In conclusion, we suggested that CO intoxication might lead to neuropsychiatric disorders. Our results emphasized that in addition to standard treatment, neuropsychiatric evaluation should also be performed in patients with CO intoxication.


Quality of life, health outcomes, and identity for patients with prostate cancer in five different treatment groups.
To describe how different treatments for prostate cancer affect health-related quality of life (QOL), health status, and masculinity. Longitudinal survey design with descriptive, correlational, and comparative elements. A tertiary medical center and associated clinics in a suburban community in the Southwestern United States. 185 men with localized prostate cancer were enrolled from five treatment groups: watchful waiting (n = 30), surgery (n = 59), conventional radiation (n = 25), proton-beam radiation (n = 24), and a combination of conventional radiation and proton-beam radiation or mixed-beam radiation (n = 47). At six months, 163 remained on the study; at 12 months, 154 remained: and at 18 months, 153 remained. The average age was 68 years, and 82% of the men were white. Men were enrolled at treatment and given a questionnaire with a self-addressed, stamped envelope for return. Questionnaires were mailed again at 6, 12, and 18 months. Health-related QOL health status, prostate treatment-specific symptoms, and sex-role identity. No overall difference in health-related QOL or health status was found, but post-hoc analysis revealed specific differences. The differences existed in sexual functioning and gastrointestinal treatment-specific symptoms. No relationship existed between masculinity and health-related QOL. Health-related QOL and health status are similar regardless of type of treatment. Radiation tends to produce more gastrointestinal symptoms, and surgery tends to produce more sexual functioning symptoms. Watchful waiting is associated with poorer general health. Nurses can provide specific treatment-related information to men who are faced with making treatment decisions for prostate cancer and, in consultation with the healthcare team, can select a treatment best sulted to them.


Microarray and gene-clustering analysis.
Human mast cells are capable of secreting a plethora of inflammatory mediators and cytokines that may play a pivotal role in innate immune and inflammatory responses. Activation of mast cells by antigen and immunoglobulin E (IgE) results in signaling, gene expression, and expression of inflammatory mediators. Although a variety of techniques have been used to evaluate mast cell biology, recent advances in molecular techniques have provided unprecedented tools to study these cells. The complimentary deoxyribonucleic acid (DNA) oligonucleotide microarray, or DNA-chip technology, allows simultaneous monitoring of gene expression, provides a format for identifying genes as well as changes in their activity on a whole genome scale, and potentially offers a global view of pathophysiologic changes. This chapter reviews the use of DNA-chip technology in studying the expression of genes (transcriptional profiling) in activated human mast cells obtained from cultured cord blood-derived mononuclear cells and comments on the use of bioinformatics on analysis of gene expression. The most powerful applications of transcriptional profiling involve identification of the common patterns of gene expression across many experiments using various gene-clustering analyses. Several techniques have been used for the analysis of gene-expression data including hierarchical clustering and self-organizing maps. In this chapter, a general laboratory protocol for array analysis currently being used in our laboratory and the use of bioinformatics is discussed. Although the focus is on Affymetrix oligonucleotide arrays, the techniques described are generally applicable to expression data generated using other array formats.


Delayed toxicity following acute ingestion of valpromide.
As valpromide is a prodrug of valproic acid (valproate), the clinical presentation of overdoses with either valpromide or valproate sodium is generally considered similar. Whereas plasma peak levels and signs of central nervous system depression occur within a few hours after the acute ingestion of regular-release forms of valproate sodium, delayed toxicity and time to peak levels following valpromide ingestion can be seen as shown by the three reported cases. They were initially considered as mild because patients presented with no or only moderate symptoms and serum valproate levels were below or at therapeutic levels on admission more than 3 hours post-ingestion in two of the three patients. Serum valproate levels were not monitored until marked deterioration more than 10 hours after ingestion. At the time of deterioration, serum valproate was at toxic level in the three reported cases. Therefore, large intake of valpromide should be closely monitored because no or moderate symptoms together with low plasma levels in the first few hours after ingestion do not exclude a subsequent severe intoxication. Despite the usual favourable outcome and the poor correlation between plasma levels and toxic symptoms, patients should not be discharged until plasma levels are documented to remain at low levels for at least 10 hours after the ingestion of valpromide and the patient asymptomatic.


Human monocytes and macrophages express substance P and neurokinin-1 receptor.
We present data demonstrating the gene expression of substance P and its receptor in human peripheral blood-isolated monocytes and macrophages. Using the RT-PCR assay, preprotachykinin-A (substance P) mRNA is detected in human peripheral blood-isolated monocytes and macrophages. Among the alpha, beta, and gamma transcripts of the substance P gene, only the beta and gamma transcripts are detectable in these cells. By Southern blot assay these RT-PCR-amplified transcripts are recognized using a specific substance P probe. Sequence analysis of the RT-PCR products from both monocytes and macrophages also confirmed the structure of these transcripts, which are identical to those found in human neuronal cells. At the protein level, both human monocytes and macrophages produced endogenous substance P as determined by an enzyme immunoassay. Capsaicin, a vanillyl fatty acid amide (ingredient of hot pepper), released substance P from both human monocytes and macrophages. In addition, using nested RT-PCR analysis, we identified the presence of mRNA for neurokinin-1 receptor (the receptor for substance P) in human peripheral blood-isolated monocytes and macrophages, which was confirmed by DNA sequencing analysis. The demonstration that human monocytes and macrophages express substance P and its receptor support the notion that substance P is biologically involved in regulating the functions of these cells in an autocrine fashion.


Fine-scale mapping of quantitative trait loci using historical recombinations.
With increasing popularity of QTL mapping in economically important animals and experimental species, the need for statistical methodology for fine-scale QTL mapping becomes increasingly urgent. The ability to disentangle several linked QTL depends on the number of recombination events. An obvious approach to increase the recombination events is to increase sample size, but this approach is often constrained by resources. Moreover, increasing the sample size beyond a certain point will not further reduce the length of confidence interval for QTL map locations. The alternative approach is to use historical recombinations. We use analytical methods to examine the properties of fine QTL mapping using historical recombinations that are accumulated through repeated intercrossing from an F2 population. We demonstrate that, using the historical recombinations, both simple and multiple regression models can reduce significantly the lengths of support intervals for estimated QTL map locations and the variances of estimated QTL map locations. We also demonstrate that, while the simple regression model using historical recombinations does not reduce the variances of the estimated additive and dominant effects, the multiple regression model does. We further determine the power and threshold values for both the simple and multiple regression models. In addition, we calculate the Kullback-Leibler distance and Fisher information for the simple regression model, in the hope to further understand the advantages and disadvantages of using historical recombinations relative to F2 data.


Pulse radiolysis study on the reactivity of NO3˙ radical toward uranous(iv), hydrazinium nitrate and hydroxyl ammonium nitrate at room temperature and at 45 °C.
Concentrated nitric acid solutions subjected to radiation produce radicals of extreme importance in the reprocessing of spent nuclear fuel. Knowledge of the different rate constants of the reactions involved in this chemistry is needed to improve the efficiency of the process and to define safe operating practices. Pulse radiolysis measurements are performed to find the rate constant of the reaction between NO3˙ radicals and U(iv) in highly concentrated nitrate solution. The optimal stabilization conditions toward thermal oxidation are defined for the considered solutions at room temperature and at 45 °C by adding anti-nitrous agents such as hydrazinium nitrate (HN) and hydroxyl ammonium nitrate (HAN). The decay of the NO3˙ radical is monitored and its reaction rates with HN, HAN and U(iv) are found to be 1.3 × 105, 1.5 × 107 and 1.6 × 106 M-1 s-1 at room temperature. The latter value is more than 10 times lower than the one currently used in numerical codes for simulation of the long-term radiolytic degradation associated with the reprocessing and storage of spent nuclear waste. At 45 °C, conditions similar to the reprocessing of spent fuel, the values of the rate constants of NO3˙ radical toward HN, HAN and U(iv) increase and are found to be 2.6 × 105, 2.9 × 107 and 9.3 × 106 M-1 s-1.


In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.
Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular electrophysiology, calcium dynamics, and active contraction. The most recent models of human ventricular electrophysiology, excitation-contraction coupling, and active contraction were integrated, and the coupled models were calibrated using human experimental data. Simulations were then conducted using the coupled models to quantify the effects of electro-mechanical coupling and drug exposure on electrophysiology and force generation in virtual human ventricular cardiomyocytes and tissue. The resulting calibrated human electro-mechanical models yielded active tension, action potential, and calcium transient metrics that are in agreement with experiments for endocardial, epicardial, and mid-myocardial human samples. Simulation results correctly predicted the inotropic response of different multichannel action reference compounds and demonstrated that the electro-mechanical coupling improves the robustness of repolarisation under drug exposure compared to electrophysiology-only models. They also generated additional evidence to explain the partial mismatch between in-silico and in-vitro experiments on drug-induced electrophysiology changes. The human calibrated and evaluated modelling and simulation framework constructed in this study opens new avenues for future investigations into the complex interplay between the electrical and mechanical cardiac substrates, its modulation by pharmacological action, and its translation to tissue and organ models of cardiac patho-physiology.


Not Breathing Easy: "Disarticulated Homework" in Asthma Management.
Recent health policy in the United States encourages an outsourcing of labor from professional practice into domestic spaces, where in theory, medical professionals supply the training, technologies, and guidance needed to discharge responsibility for care to patients or caregivers. Mattingly et al. (2011) term this labor "chronic homework," describing the relationship between the assigning and undertaking of medical care at the borders of professional and domestic domains. This is a system predicated on relationships between professional and caregiver. However, in our research with families and providers in two U.S. sites, we observed a "disarticulation" of asthma care from professional medicine. Caregivers may undertake routine asthma management with little physician oversight, transforming chronic homework into what we term "disarticulated homework." We argue that expanding the concept of chronic homework to theorize disarticulation processes can help elucidate how health disparities are reproduced in the gap between medical systems and domestic life. [asthma, self-management, caregiving pharmaceuticalization, health disparities].


Finite element investigation of the loading rate effect on the spinal load-sharing changes under impact conditions.
Sudden deceleration and frontal/rear impact configurations involve rapid movements that can cause spinal injuries. This study aimed to investigate the rotation rate effect on the L2-L3 motion segment load-sharing and to identify which spinal structure is at risk of failure and at what rotation velocity the failure may initiate? Five degrees of sagittal rotations at different rates were applied in a detailed finite-element model to analyze the responses of the soft tissues and the bony structures until possible fractures. The structural response was markedly different under the highest velocity that caused high peaks of stresses in the segment compared to the intermediate and low velocities. Under flexion, the stress was concentrated at the upper pedicle region of L2 and fractures were firstly initiated in this region and then in the lower endplate of L2. Under extension, maximum stress was located in the lower pedicle region of L2 and fractures started in the left facet joint, then they expanded in the lower endplate and in the pedicle region of L2. No rupture has resulted at the lower or intermediate velocities. The intradiscal pressure was higher under flexion and decreased when the endplate was fractured, while the contact forces were greater under extension and decreased when the facet surface was cracked. The highest ligaments stresses were obtained under flexion and did not reach the rupture values. The endplate, pedicle and facet surface represented the potential sites of bone fracture. Results showed that spinal injuries can result at sagittal rotation velocity exceeding 0.5 degrees /ms.


Dynamic response in the larval geoduck (Panopea generosa) proteome to elevated pCO2.
Pacific geoducks (Panopea generosa) are clams found along the northeast Pacific coast where they are important components of coastal and estuarine ecosystems and a major aquaculture product. The Pacific coastline, however, is also experiencing rapidly changing ocean habitat, including significant reductions in pH. To better understand the physiological impact of ocean acidification on geoduck clams, we characterized for the first time the proteomic profile of this bivalve during larval development and compared it to that of larvae exposed to low pH conditions. Geoduck larvae were reared at pH 7.5 (ambient) or pH 7.1 in a commercial shellfish hatchery from day 6 to day 19 postfertilization and sampled at six time points for an in-depth proteomics analysis using high-resolution data-dependent analysis. Larvae reared at low pH were smaller than those reared at ambient pH, especially in the prodissoconch II phase of development, and displayed a delay in their competency for settlement. Proteomic profiles revealed that metabolic, cell cycle, and protein turnover pathways differed between the two pH and suggested that differing phenotypic outcomes between pH 7.5 and 7.1 are likely due to environmental disruptions to the timing of physiological events. In summary, ocean acidification results in elevated energetic demand on geoduck larvae, resulting in delayed development and disruptions to normal molecular developmental pathways, such as carbohydrate metabolism, cell growth, and protein synthesis.


Less invasive spinal deformity surgery: the impact of the learning curve at tertiary spine care centers.
The past decade has seen major advances in techniques for treating more complex spinal disorders using minimally invasive surgery (MIS). While appealing from the standpoint of patient perioperative outcomes, a major impediment to adoption has been the significant learning curve in utilizing MIS techniques. Data were retrospectively analyzed from a multicenter series of adult spinal deformity surgeries treated at eight tertiary spine care centers in the period from 2008 to 2015. All patients had undergone a less invasive or hybrid approach for a deformity correction satisfying the following inclusion criteria at baseline: coronal Cobb angle ≥ 20°, sagittal vertical axis (SVA) > 5 cm, or pelvic tilt > 20°. Analyzed data included baseline demographic details, severity of deformity, surgical metrics, clinical outcomes (numeric rating scale [NRS] score and Oswestry Disability Index [ODI]), radiographic outcomes, and complications. A minimum follow-up of 2 years was required for study inclusion. Across the 8-year study period, among 222 patients, there was a trend toward treating increasingly morbid patients, with the mean age increasing from 50.7 to 62.4 years (p = 0.013) and the BMI increasing from 25.5 to 31.4 kg/m2 (p = 0.12). There was no statistical difference in the severity of coronal and sagittal deformity treated over the study period. With regard to radiographic changes following surgery, there was an increasing emphasis on sagittal correction and, conversely, less coronal correction. There was no statistically significant difference in clinical outcomes over the 8-year period, and meaningful improvements were seen in all years (ODI range of improvement: 15.0-26.9). Neither were there statistically significant differences in major complications; however, minor complications were seen less often as the surgeons gained experience (p = 0.064). Operative time was decreased on average by 47% over the 8-year period.Trends in surgical practice were seen as well. Total fusion construct length was unchanged until the last year when there was a marked decrease in conjunction with a decrease in interbody levels treated (p = 0.004) while obtaining a higher degree of sagittal correction, suggesting more selective but powerful interbody reduction methods as reflected by an increase in the lateral and anterior column resection techniques being utilized. The use of minimally invasive methods for adult spinal deformity surgery has evolved over the past decade. Experienced surgeons are treating older and more morbid patients with similar outcomes. A reliance on selective, more powerful interbody approaches is increasing as well.


Development and Validation of a Brief Hospital-Based Ambulatory Patient Experience Survey Tool.
Recognition of the value of the patient perspective on services has led healthcare organizations to measure patient care experiences. A brief, generic and psychometrically sound scale to measure patient experiences in ambulatory/outpatient settings in Canada would be useful and is currently lacking. The purpose of this study was to develop and validate an English-language hospital-based ambulatory patient experience survey tool in a Canadian context. Based on a review of more than 20 instruments measuring experiences predominately in non-acute care settings, we initially selected 27 items to be included in the questionnaire, addressing quality dimensions of access, communication, continuity and coordination, shared decision making, emotional support, trust/confidence, privacy, patient-reported impact and physical environment. The survey instrument was subsequently tested among 1,219 ambulatory patients, and its psychometric properties were assessed. A final questionnaire was produced with 14 items and two emerging subscales: Patient-Provider Communication and Overall Quality of Experience, as determined by a factor analysis. The items within the scale showed high construct validity. Reliability was also excellent for the instrument. The applicability of this tool in supporting quality improvement initiatives is discussed.


Occurrence of patulin in organic and conventional apple-based food marketed in Catalonia and exposure assessment.
In the last years, consumption of organic foods has become increasingly popular. Nevertheless, safety of organic foods is still unclear, and needs to be thoroughly evaluated. Patulin is a mycotoxin mainly present in rotten apples and apple-based products. The aim of this study is to analyse the content of patulin in apple juices and purees derived from organic and conventional production systems, in order to assess the risk to consumers, particularly in children. A total of 93 apple-based products marketed in Catalonia were analysed, 49 of which were derived from conventional and 44 from organic farming. The results showed higher incidence of positive samples and higher concentration of patulin in organic apple purees when comparing with conventional ones. In the case of juices, significant differences were found between conventional and organic samples, but applying a multivariate analysis the type of agriculture did not seem to have a relevant contribution to patulin occurrence, being cloudiness the main factor involved. The estimated daily intake of patulin for infants and young children (0-3 years old), children (4-18 years old) and adults (19-66 years old), were below the provisional maximum tolerable daily intake (PMTDI) of 0.4 μg/kg bw in all scenarios considered.


Soil processes drive seasonal variation in retention of 15N tracers in a deciduous forest catchment.
Seasonal patterns of stream nitrate concentration have long been interpreted as demonstrating the central role of plant uptake in regulating stream nitrogen loss from forested catchments. Soil processes are rarely considered as important drivers of these patterns. We examined seasonal variation in N retention in a deciduous forest using three whole-ecosystem 15N tracer additions: in late April (post-snowmelt, pre-leaf-out), late July (mid-growing- season), and late October (end of leaf-fall). We expected that plant 15N uptake would peak in late spring and midsummer, that immobilization in surface litter and soil would peak the following autumn leaf-fall, and that leaching losses would vary inversely with 15N retention. Similar to most other 15N tracer studies, we found that litter and soils dominated ecosystem retention of added 15N. However, 15N recovery in detrital pools varied tremendously by season, with > 90% retention in spring and autumn and sharply reduced 15N retention in late summer. During spring, over half of the 15N retained in soil occurred within one day in the heavy (mineral-associated) soil fraction. During summer, a large decrease in 15N retention one week after addition coincided with increased losses of 15NO3- to soil leachate and seasonal increases in soil and stream NO3- concentrations, although leaching accounted for only a small fraction of the lost 15N (< 0.2%). Uptake of 15N into roots did not vary by season and accounted for < 4% of each tracer addition. Denitrification or other processes that lead to N gas loss may have consumed the rest. These measurements of 15N movement provide strong evidence for the dominant role of soil processes in regulating seasonal N retention and losses in this catchment and perhaps others with similar soils.


Performance of angiographic, electrocardiographic and MRI methods to assess the area at risk in acute myocardial infarction.
Objective Validation of methods to assess the area at risk (AAR) in patients with ST elevation myocardial infarction is limited. A study was undertaken to test different AAR methods using established physiological concepts to provide a reference standard. Main outcome measured In 78 reperfused patients with first ST elevation myocardial infarction, AAR was measured by electrocardiographic (Aldrich), angiographic (Bypass Angioplasty Revascularization Investigation (BARI), APPROACH) and cardiovascular magnetic resonance methods (T2-weighted hyperintensity and delayed enhanced endocardial surface area (ESA)). The following established physiological concepts were used to evaluate the AAR METHODS: (1) AAR size is always ≥ infarct size (IS); (2) in transmural infarcts AAR size=IS; (3) correlation between AAR size and IS increases as infarct transmurality increases; and (4) myocardial salvage ((AAR-IS)/AAR×100) is inversely related to infarct transmurality. Results Overall, 65%, 87%, 76%, 87% and 97% of patients using the Aldrich, BARI, APPROACH, T2-weighted hyperintensity and ESA methods obeyed the concept that AAR size is ≥IS. In patients with transmural infarcts (n=22), Bland-Altman analysis showed poor agreement (wide 95% limits of agreement) between AAR size and IS for the BARI, Aldrich and APPROACH methods (95% CI -22.9 to 29.6, 95% CI -28.3 to 21.3 and 95% CI -16.9 to 20.0, respectively) and better agreement for T2-weighted hyperintensity and ESA (95% CI -6.9 to 16.6 and 95% CI -4.3 to 18.0, respectively). Increasing correlation between AAR size and IS with increasing infarct transmurality was observed for the APPROACH, T2-weighted hyperintensity and ESA methods, with ESA having the highest correlation (r=0.93, p<0.001). The percentage of patients within a narrow margin (±30%) of the inverse line of identity between salvage extent and infarct transmurality was 56%, 76%, 65%, 77% and 92% for the Aldrich, BARI, APPROACH, T2-weighted hyperintensity and ESA methods, respectively, where higher percentages represent better concordance with the concept that the extent of salvage should be inversely related to infarct transmurality. Conclusions For measuring AAR, cardiovascular magnetic resonance methods are better than angiographic methods, which are better than electrocardiographic methods. Overall, ESA performed best for measuring AAR in vivo.


Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood.
Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45-75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = -2.77, 95% CI: -4.33, -1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = -2.02, 95% CI: -3.55, -0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.


The accuracy of the Zinc Taste Test method.
Diminished taste acuity (hypogeusia) has been linked to zinc deficiency in humans and animals. This phenomenon has been exploited in the Zinc Taste Test (ZTT), a taste acuity test commonly employed by Australian naturopaths. However, its validity has not yet been firmly established. A systematic search of several key databases was conducted. Only studies in which there were full reports of clinical trials comparing the ZTT to at least one other zinc test within the same sample population were included. Three (3) studies matched the criteria for inclusion. Study I compared the ZTT with sweat zinc in patients with food intolerance, reporting moderate correlation. Study II recruited pregnant women using the ZTT and serum zinc to assess zinc status, with above 70% congruence between the two tests at the start of the trial and 100% congruence at the end. Study III also recruited pregnant women at three stages during gestation, assessing ZTT and leukocyte zinc initially, later adding dietary zinc intake and at delivery cord blood zinc. No significant correlation was found between the results of these different methods; however, statistically significant differences in the ZTT responders (tasters and nontasters) were found for pregnancy outcomes. The methodology of the three studies is critically discussed. Although depletion of zinc leads to decreased taste acuity, it does not explain all cases of hypogeusia. Various other influences on taste perception are discussed in relation to the validity of the ZTT. Stringent exclusion criteria are therefore mandatory to increase specificity. Large variations from the original test design have been identified. The laboratory assays of zinc in these studies are also lacking sensitivity to accurately assess zinc status. To date, there are no tests that are both sensitive and specific that accurately assess marginal zinc status in humans. The ZTT, albeit widely used, does not fill this void, and further research is needed.


Effect of a synthetic link N peptide nanofiber scaffold on the matrix deposition of aggrecan and type II collagen in rabbit notochordal cells.
Self-assembling peptide nanofiber scaffolds have been studied extensively as biological materials for 3-dimensional cell culture and repairing tissue defects in animals. However, few studies have applied peptide nanofiber scaffolds in the tissue engineering of intervertebral discs (IVDs). In this study, a novel functionalized peptide scaffold was specifically designed for IVD tissue engineering, and notochordal cells (NCs) as an alternative cell source for IVD degeneration were selected to investigate the bioactive scaffold material. The novel RADA16-Link N self-assembling peptide scaffold material was designed by direct coupling to a bioactive motif link N. The link N nanofiber scaffold (LN-NS) material was obtained by mixing pure RADA16-I and RADA16-Link N (1:1) designer peptide solutions. Although live/dead cell assays showed that LN-NS and RADA16-I scaffold materials were both biocompatible with NCs, the LN-NS material significantly promoted NC adhesion compared with that of the pure RADA16-I SAP scaffold material. The depositions of aggrecan and type II collagen, which are significant markers for IVD cells, were remarkably increased. Furthermore, the results indicated that the link N motif, the matrix analog of the nucleus pulposus, significantly promoted the accumulation of other extracellular matrices in vitro. We conclude that the novel LN-NS material is a promising biological scaffold material, and may have a broad range of applications in IVD tissue engineering.


Volumetric cortical loss in sporadic and familial amyotrophic lateral sclerosis.
Patients homozygous for the D90A mutation of the SOD1 gene (homD90A) demonstrate markedly slower progression of disease than those patients with sporadic ALS (SALS). PET studies have demonstrated a different cortical vulnerability in the two groups, reflected also in neurophysiological studies showing reduced cortical excitability in homD90A. Voxel-based morphometric analysis of magnetic resonance images (MRIs) enables the detection of regional differences in grey matter volume, and can be used to localize cortical atrophy in vivo. In this study, segmented, spatially normalized, modulated and smoothed grey matter portions of the MRIs from 23 SALS and seven homD90A patients with similar disability, were compared with those from 28 healthy control subjects. The SALS group showed bilateral areas of atrophy mainly confined to motor and pre-motor cortices. Cortical changes in the homD90A group were more pronounced within the frontal lobes when both were compared with healthy controls. This study provides further evidence for a different pattern of cortical neuronal vulnerability in homD90A versus SALS patients that may provide insight as to their slower rate of disease progression.


Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases.
The exchange of nuclear genetic material between oocytes and embryos offers a novel reproductive option for the prevention of inherited mitochondrial diseases. Mitochondrial dysfunction has been recognized as a significant cause of a number of serious multiorgan diseases. Tissues with a high metabolic demand, such as brain, heart, muscle, and central nervous system, are often affected. Mitochondrial disease can be due to mutations in mitochondrial DNA or in nuclear genes involved in mitochondrial function. There is no curative treatment for patients with mitochondrial disease. Given the lack of treatments and the limitations of prenatal and preimplantation diagnosis, attention has focused on prevention of transmission of mitochondrial disease through germline gene replacement therapy. Because mitochondrial DNA is strictly maternally inherited, two approaches have been proposed. In the first, the nuclear genome from the pronuclear stage zygote of an affected woman is transferred to an enucleated donor zygote. A second technique involves transfer of the metaphase II spindle from the unfertilized oocyte of an affected woman to an enucleated donor oocyte. Our group recently reported successful spindle transfer between human oocytes, resulting in blastocyst development and embryonic stem cell derivation, with very low levels of heteroplasmy. In this review we summarize these novel assisted reproductive techniques and their use to prevent transmission of mitochondrial disorders. The promises and challenges are discussed, focusing on their potential clinical application.


Cerebral air embolism after arthrography of the ankle.
The accidental migration of air from the venous circulation into the systemic arterial circulation is called paradoxical air embolism. This is a potential disastrous complication after diagnostic and surgical procedures. Arthrography has been a useful technique in joint imaging for the past decades. Paradoxical cerebral air embolism is a very rare complication, only a few cases have been reported after arthrography of the hip in children. Here, we describe a patient with progressive encephalopathy after computer tomography (CT) arthrography of the ankle. We describe a 64-year-old male who underwent CT-arthrography of the left ankle, after the intra-articular injection of 20 ml of air he experienced progressive neurologic and hemodynamic deterioration. A brain CT showed a small amount of air in a right frontal sulcus. Hyperbaric oxygen therapy (HBO) was initiated after a delay of 16 hours and resulted in a complete recovery. A transesophageal echocardiography confirmed the presence of a right-left shunt. This case of paradoxical air embolism with severe neurological manifestations after arthrography of the ankle, emphasizes that air embolism should be considered in all patients with neurologic and/or hemodynamic deterioration after the injection of intra articular air. Furthermore a delay of more then 6 hours is no reason to withhold HBO in these patients.


Gains, losses, and amplification of genomic material in rhabdomyosarcoma analyzed by comparative genomic hybridization.
In this study, 10 embryonal and 14 alveolar rhabdomyosarcoma (RMS) tumor samples, including 4 cell lines derived from tumors of the alveolar subtype, were analyzed by comparative genomic hybridization. In the embryonal tumors, the gain of whole or most of various chromosomes, notably chromosomes 2 (60% of cases), 13 (60%), 12 (60%), 8 (60%), 7 (50%), 17 (40%), 18 (40%), and 19 (40%), and the loss of chromosomes 16 (40%), 10 (30%), 15 (20%), and 14 (20%) were found. One case showed evidence of genomic amplification at 12q13-15. In contrast, the alveolar tumors and cell lines showed consistent evidence of genomic amplification, with multiple amplicons in some cases. The amplicons were localized to l2q13-15 (50%), 2p24 (36%), 13q14 (14%), l3q32 (14%), 1q36 (14%), 1q21 (7%), and 8q13-21 (7%). Four cases had additional copies of chromosome 17 or l7q. These changes were in addition to the presence of fusion gene transcripts that are associated with translocations specific to alveolar RMS. The results show that distinct patterns of primarily gains of specific chromosomal material are associated with the embryonal subtype of RMS, and that genomic amplification seems to play an important role in the alveolar subtype. Notably, these distinct changes predominantly involved chromosomes 2, 12, and 13 in both subtypes.


The response of living cells to very weak electric fields: the thermal noise limit.
A physical model in which cells are considered as possible detectors of very weak periodic electric fields yields a general relation between cell size and both thermally induced fluctuations in membrane potential and the maximum change in membrane potential caused by an applied field. The simplest version of the model provides a broad-band estimate of the smallest applied electric field to which membrane macromolecules can directly respond (about 10(-3) volt per centimeter). Much smaller fields (10(-6) volt per centimeter) can be detected if there is a response in only a narrow band of frequencies or if signal averaging occurs through field-induced variation in the catalytic activity of membrane-associated enzymes. Both extensions of the simplest version remove the apparent violation of the thermal noise limit found in some experiments.


Prevalence and Etiological Profile of Short Stature among School Children in a South Indian Population.
Short stature (SS) is a common pediatric problem and it might be the first sign of underlying illness. Studies documenting the burden and etiological profile of SS are scarce from India and are mostly limited to data obtained from referral centers. Due to the lack of large-scale, community-based studies utilizing a standard protocol, the present study aimed to assess the prevalence and etiological profile of SS in school children of a South Indian district. In this cross-sectional study, children aged 4-16 years from 23 schools in Madurai district, Tamil Nadu, underwent anthropometric measurements and height was plotted in Khadilkar et al. growth chart. The cause of SS was assessed using clinical and laboratory evaluations in assigned children with a height less than third centile. A total of 15644 children belonging to 23 schools were evaluated, and 448 (2.86%) children had SS. Etiological evaluation was further performed in 87 randomly assigned children, and it is identified that familial SS or constitutional delay in growth was the most common cause of SS in the study population (66.67%). Hypothyroidism and growth hormone deficiency were the two most common pathological causes of SS seen in 12 (13.79%) and 8 (9.20%) children, respectively. Malnutrition was the cause of SS in 6 (6.9%) children and cardiac disorders, psychogenic SS, and skeletal dysplasia were other identified causes of SS in the study. The overall prevalence of SS in school children was 2.86% and familial SS or constitutional delay in growth was the most common cause of SS. As a significant percentage of children with SS had correctable causes, monitoring growth with a standard growth chart should be mandatory in all schools.


Chromosomal control of glutenin subunits in aneuploid lines of wheat: analysis by reversed-phase high-performance liquid chromatography.
Glutenin subunits from nullisomic-tetrasomic and ditelocentric lines of the hexaploid wheat variety 'Chinese Spring' (CS) and from substitution lines of the durum wheat variety 'Langdon' were fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) at 70 °C using a gradient of acetonitrile in the presence of 0.1% trifluoroacetic acid. Nineteen subunits were detected in CS. The presence and amounts of four early-eluted subunits were found, through aneuploid analysis, to be controlled by the long arms of chromosomes 1D (1DL) (peaks 1-2) and 1B (1BL) (peaks 3-4). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that these four subunits are the high molecular weight subunits of glutenin, which elute in the order 1Dy, 1Dx, 1By, and 1Bx. Similar amounts of 1DL subunits were present (6.3 and 8.8% of total glutenin), but 1BL subunits differed more in abundance (5.4 and 9.5%, respectively). Results indicate that most late-eluting CS glutenin subunits were coded by structural genes on the short arms of homoeologous group 1 chromosomes: 6 by 1DS, 5 by 1AS, and 4 by 1BS. Glutenin of tetraploid 'Langdon' durum wheat separated into nine major subunits: 6 were coded by genes on 1B chromosomes, and 3 on 1A chromosomes. Gene locations for glutenin subunits in the tetraploid durum varieties 'Edmore' and 'Kharkovskaya-5' are also given. These results should make RP-HPLC a powerful tool for qualitative and quantitative genetic studies of wheat glutenin.


Life satisfaction set point: stability and change.
Using data from 17 years of a large and nationally representative panel study from Germany, the authors examined whether there is a set point for life satisfaction (LS)--stability across time, even though it can be perturbed for short periods by life events. The authors found that 24% of respondents changed significantly in LS from the first 5 years to the last 5 years and that stability declined as the period between measurements increased. Average LS in the first 5 years correlated .51 with the 5-year average of LS during the last 5 years. Height, weight, body mass index, systolic and diastolic blood pressure, and personality traits were all more stable than LS, whereas income was about as stable as LS. Almost 9% of the sample changed an average of 3 or more points on a 10-point scale from the first 5 to last 5 years of the study.


Activity-dependent signaling mechanisms regulating adult hippocampal neural stem cells and their progeny.
Adult neural stem cells (NSCs) reside in a restricted microenvironment, where their development is controlled by subtle and presently underexplored cues. This raises a significant question: what instructions must be provided by this supporting niche to regulate NSC development and functions? Signaling from the niche is proposed to control many aspects of NSC behavior, including balancing the quiescence and proliferation of NSCs, determining the cell division mode (symmetric versus asymmetric), and preventing premature depletion of stem cells to maintain neurogenesis throughout life. Interactions between neurogenic niches and NSCs also govern the homeostatic regulation of adult neurogenesis under diverse physiological, environmental, and pathological conditions. An important implication from revisiting many previously-identifi ed regulatory factors is that most of them (e.g., the antidepressant fluoxetine and exercise) affect gross neurogenesis by acting downstream of NSCs at the level of intermediate progenitors and neuroblasts, while leaving the NSC pool unaffected. Therefore, it is critically important to address how various niche components, signaling pathways, and environmental stimuli differentially regulate distinct stages of adult neurogenesis.


Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease.
Amyloid plaques in Alzheimer's disease contain beta-amyloid, encoded by portions of exons 16 and 17 of the amyloid precursor protein. The specific association of rare amyloid precursor protein mutations with some kindreds with early-onset familial Alzheimer's disease suggests that specific abnormalities in amyloid precursor protein may contribute to the pathogenesis of Alzheimer's disease. Until now, there has been no evidence suggesting that amyloid precursor protein mutations could be involved in late-onset or sporadic Alzheimer's disease. We used reverse transcription-polymerase chain reaction, denaturing gradient gel electrophoresis, and direct DNA sequencing to analyze amyloid precursor protein exons 16 and 17 from postmortem cerebellar samples from patients with histologically confirmed Alzheimer's disease and control subjects. We found a novel point mutation, substitution of cytosine for guanine, at nucleotide 2119 (amyloid precursor protein 770 messenger RNA transcript) in a patient with late-onset Alzheimer's disease. This substitution deletes a BglII site and substitutes aspartate for glutamine at codon 665. Denaturing gradient gel electrophoresis analysis showed that this mutation was absent in 40 control subjects and 127 dementia patients. Whether this mutation is a rare but normal variant or contributes to the development of Alzheimer's disease is not known. The BglII restriction fragment length polymorphism enables investigators to determine the frequency of this polymorphism in normal subjects and Alzheimer's disease patients.


Partnerships to Improve Oral Hygiene Practices: Two Complementary Approaches.
The omission of oral care is linked to increased nurse workload and may contribute to serious patient infection and growing healthcare costs. Therefore, ineffective oral care comprises a significant patient safety issue across healthcare settings internationally. As studies have demonstrated a positive relationship between Nurs Leadersh (Tor Ont) and improved patient outcomes, it is imperative that leaders seek effective approaches to facilitate contextual exploration of barriers and facilitators for resolution of oral care delivery problems. One approach to improved processes of oral care is the creative engagement of front-line clinicians in the problems they confront in everyday practice. By drawing upon the role and process of facilitation, we outline two projects, located in Australia and Canada, that engaged front-line nurses, health leaders, and researchers as partners to identify a path to improved oral care delivery. In this paper, we summarize key learnings for nursing leaders about strategies to facilitate delivery of fundamental oral care. We found that facilitation, contextual knowledge and academic-clinician partnerships were essential to the detection and evaluation of oral care delivery problems and the identification of priorities for practice improvement. As collaboration is imperative for sustainable innovation, we summarize strategies of effective leadership for improving oral care delivery.


Elliptic Flow of Electrons from Beauty-Hadron Decays in Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV.
The elliptic flow of electrons from beauty hadron decays at midrapidity (|y|<0.8) is measured in Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV with the ALICE detector at the LHC. The azimuthal distribution of the particles produced in the collisions can be parametrized with a Fourier expansion, in which the second harmonic coefficient represents the elliptic flow, v_{2}. The v_{2} coefficient of electrons from beauty hadron decays is measured for the first time in the transverse momentum (p_{T}) range 1.3-6 GeV/c in the centrality class 30%-50%. The measurement of electrons from beauty-hadron decays exploits their larger mean proper decay length cτ≈500 μm compared to that of charm hadrons and most of the other background sources. The v_{2} of electrons from beauty hadron decays at midrapidity is found to be positive with a significance of 3.75 σ. The results provide insights into the degree of thermalization of beauty quarks in the medium. A model assuming full thermalization of beauty quarks is strongly disfavored by the measurement at high p_{T}, but is in agreement with the results at low p_{T}. Transport models including substantial interactions of beauty quarks with an expanding strongly interacting medium describe the measurement within uncertainties.


Tensiomyographic Assessment of Muscle Contractile Properties in 9- to 14-Year Old Children.
While there are numerous data on the skeletal muscle fiber type composition in adults, little is known about the changes in fiber type composition and contractile properties during maturational growth in children. Using noninvasive tensiomyography, we measured contraction time (Tc), an indirect estimate of the myosin heavy chain I (MHC-I) proportion, to assess the longitudinal changes of the biceps brachii (BB), biceps femois (BF), vastus lateralis (VL), and erector spinae (ES) muscles in 53 boys and 54 girls. The children were 9 years at the start of the study and returned for 5 follow-up measurements until the age of 14 years. The ES has the shortest and the BF has the longest Tc. The VL and ES of boys have shorter Tc than those of girls. When applying the relationship between proportion of MHC-I and Tc established in adults to children's TMG data, we found a slow-to-fast transition in the VL between, at least, the ages of 6 to 10 years, when it stabilized to adult proportions. Regular participation in sports was associated with a faster BF, but not in the VL. Our data represents a first non-invasive indication of the developmental changes in muscle fiber type composition in children.


Size-contrast illusions deceive the eye but not the hand.
When we reach out to pick up an object, not only do we direct our moving limb towards the location of the object, but the opening between our fingers and thumb is scaled in flight to the object's size. Evidence obtained from patients with neurological disorders has shown that the visual processing underlying the calibration of grip aperture and other movement parameters during grasping is mediated by visual mechanisms located in the cerebral cortex that are quite distinct from those underlying the experiential perception of object size and other object features. Under appropriate conditions, such dissociations can also be observed in individuals with normal vision. Here we present evidence that the calibration of grasp is quite refractory to pictorial illusions that have large effects on perceptual judgements of size. We used a variation of the familiar 'Titchener circles' illusion in which two target circles of equal size, each surrounded by a circular array of either smaller or larger circles, are presented side by side. Subjects typically report that the target circle surrounded by the array of smaller circles appears to be larger than the target surrounded by larger circles. In our test, two thin 'pokerchip' discs were used as the target circles. The relative size of the two discs was randomly varied so that on some trials the discs appeared perceptually different but were physically equivalent in size, and on other trials they were physically different but appeared perceptually equivalent. The perceptual judgements made by the 14 subjects in our experiment were strongly affected by this size-contrast illusion. However, when asked to pick up a disc, the scaling of the subjects grip aperture (measured opto-electronically before contact with the disc) was largely determined by the true size of the target disc and not its illusory size. It would seem that the automatic and metrically accurate calibrations required for skilled actions are mediated by visual processes that are separate from those mediating our conscious experiential perception. Earlier studies on patients with neurological deficits suggest that these two types of processing may depend on quite separate, but interacting, visual pathways in the cerebral cortex.


A perspective on the role of fugacity and activity for evaluating the PBT properties of organic chemicals and providing a multi-media synoptic indicator of environmental contamination.
The hazard and risk from organic chemicals present in the environment are routinely evaluated using P (persistence), B (bioaccumulation) and T (toxicity) criteria. We present a perspective on how models based on the equilibrium criteria of fugacity and chemical activity can contribute to all three evaluations, thus providing a consistent and seamless assessment process. Persistence and its closely related, but fundamentally different property, chemical residence time can be determined from degradation half-lives (typically obtained from monitoring data) and multi-media mass balance models describing chemical fate and transport in real or evaluative environments. Bioaccumulation is driven by equilibrium partitioning processes that can be estimated from fugacity models treating uptake by respiration and diet in single organisms and in food webs, most commonly for aquatic systems for which confirmatory monitoring data can be obtained. Biomagnification is readily evaluated both experimentally and as a fugacity (or activity) increase from prey to predator. Toxicokinetic evaluations of chemical uptake and disposition in a variety of organisms, including humans, can be obtained using fugacity- and physiologically-based pharmacokinetic models. Toxicodynamic processes of chemical interactions with organisms leading to adverse toxic outcomes are less obviously amenable to fugacity assessment with the notable exception of baseline toxicity (narcosis), the most common mode of action of commercial chemicals. It is shown that a range of fugacities can be defined and correlated for specific species thus enabling direct comparison of fugacities estimated or monitored in the environment with fugacities resulting in baseline toxicity. Finally, it is shown that fugacity and activity can serve as multi-media metrics of chemical contamination in ecosystems, thus enabling identification of specific regions and species at greatest risk in a pictorial format that is readily understandable to scientific and regulatory communities and to the general public.


X-ray phase contrast imaging of the bone-cartilage interface.
Synovial joints articulate in a lubricating environment, the system providing for smooth articulation. The articular cartilage overlying the bone consists of a network of collagen fibres. This network is essential to cartilage integrity, suffering damage in degenerative joint disease such as osteoarthritis. At Surrey and also in work conducted by this group at the Paul Scherrer Institute (PSI) synchrotron site we have been applying a number of techniques to study the bone-cartilage interface and of changes occurring in this with disease. One of the techniques attracting particular interest is X-ray phase contrast imaging, yielding information on anatomical features that manifest from the large scale organisation of collagen and the mineralised phase contained within the collagen fibres in the deep cartilage zone. This work briefly reviews some of the basic supporting physics of X-ray phase contrast imaging and then shows example images of the articular surface and subchondral bone and other supporting results obtained to-date. Present results have been obtained on sections of bone not displaying evidence of an osteoarthritic lesion and can be used as a baseline against which diseased bone can be compared.


Characteristics of social phobia among persons with essential tremor.
Social phobia symptoms have been reported to be common among patients with essential tremor, but characteristics of this comorbidity have not been systematically described. Cases with essential tremor (N = 94) and controls without essential tremor (N = 85), ascertained from movement disorder clinic and community samples, were evaluated for social phobia symptoms (using the social phobia module of the Structured Clinical Interview for DSM-IV Axis I Disorders and the Liebowitz Social Anxiety Scale), characteristics of tremor, and associated disability (via videotaped examination, performance test, and disability questionnaire). Lifetime combined prevalence of primary social phobia and clinically significant social phobia symptoms occurring secondary to essential tremor was 32.7% (16/49) among essential tremor patients in the clinic sample. Essential tremor cases with secondary social phobia symptoms reported a markedly later age at onset of clinically significant social phobia symptoms than essential tremor cases with primary social phobia (51.0 vs. 8.8 years). Cases with secondary social phobia also reported greater fear and avoidance of eating, drinking, and writing in public than essential tremor cases with primary social phobia and control subjects with social phobia. Essential tremor cases with secondary social phobia symptoms also demonstrated more severe tremor and tremor-related disability than essential tremor cases with primary social phobia and essential tremor cases without social phobia. Among all essential tremor cases, severity of social phobia symptoms and tremor independently contributed to disability. Social phobia appears to occur in a substantial minority of essential tremor patients, and severity of social phobia symptoms is associated with disability, independent of tremor severity. Persons with social phobia symptoms secondary to essential tremor evidence clinical characteristics that differ from those of persons with primary social phobia. Further research is needed to determine the efficacy of treatment of social phobia in essential tremor patients with significant social phobia symptoms.


Insecure attachment during infancy predicts greater amygdala volumes in early adulthood.
The quality of the early environment is hypothesized to be an influence on morphological development in key neural areas related to affective responding, but direct evidence to support this possibility is limited. In a 22-year longitudinal study, we examined hippocampal and amygdala volumes in adulthood in relation to early infant attachment status, an important indicator of the quality of the early caregiving environment. Participants (N = 59) were derived from a prospective longitudinal study of the impact of maternal postnatal depression on child development. Infant attachment status (35 Secure; 24 Insecure) was observed at 18 months of age, and MRI assessments were completed at 22 years [corrected]. In line with hypotheses, insecure versus secure infant attachment status was associated with larger amygdala volumes in young adults, an effect that was not accounted for by maternal depression history. We did not find early infant attachment status to predict hippocampal volumes. Common variations in the quality of early environment are associated with gross alterations in amygdala morphology in the adult brain. Further research is required to establish the neural changes that underpin the volumetric differences reported here, and any functional implications.


Neurological assessment and its relationship to CSF biomarkers in amateur boxers.
Mild traumatic brain injury (TBI) or concussion is common in many sports. Today, neuropsychological evaluation is recommended in the monitoring of a concussion and in return-to-play considerations. To investigate the sensitivity of neuropsychological assessment, we tested amateur boxers post bout and compared with controls. Further the relationship between neuropsychological test results and brain injury biomarkers in the cerebrospinal fluid (CSF) were investigated. Thirty amateur boxers on high elite level with a minimum of 45 bouts and 25 non-boxing matched controls were included. Memory tests (Rey Osterrieth Complex Figure, Listening Span, Digit Span, Controlled Word Association Test, and computerized testing of episodic memory), tests of processing speed and executive functions (Trail Making, Reaction Time, and Finger Tapping) were performed and related to previously published CSF biomarker results for the axonal injury marker neurofilament light (NFL). The neurological assessment showed no significant differences between boxers and controls, although elevated CSF NFL, as a sign of axonal injury, was detected in about 80% of the boxers 1-6 days post bout. The investigation of the relationship between neuropsychological evaluation and CSF NFL concentrations revealed that boxers with persisting NFL concentration elevation after at least 14 days resting time post bout, had a significantly poorer performance on Trail Making A (p = 0.041) and Simple Reaction Time (p = 0.042) compared to other boxers. This is the first study showing traumatic axonal brain injury can be present without measureable cognitive impairment. The repetitive, subconcussive head trauma in amateur boxing causes axonal injury that can be detected with analysis of CSF NFL, but is not sufficient to produce impairment in memory tests, tests of processing speed, or executive functions. The association of prolonged CSF NFL increase in boxers with impairment of processing speed is an interesting observation, which needs to be verified in larger studies.


Twin studies and the etiology of eating disorders.
To evaluate the major twin studies of eating disorders in order to consider the empirical standing of the suggestion that these disorders, notably bulimia nervosa, are largely genetically determined. Examination of the relevant twin studies and the methods used. The findings of the twin studies are inconsistent and difficult to interpret, with estimates for the heritability of liability to bulimia nervosa ranging from 0% to 83%, and from 0% to 70% for anorexia nervosa. Methodological reasons for this variability include issues of definition of phenotype, diagnostic reliability, violation of the equal environments assumption, and small sample sizes. Many of these issues also apply to twin studies of other psychiatric disorders. The heritability of eating disorders remains unknown. A broad view on the etiology of eating disorders should be maintained, with a focus on environmental mechanisms and gene-environment interactions, as well as continuing genetic studies.


Screening for Diabetic Retinopathy with a Nonmydriatic Ultra-Wide-Field Retina Camera by Family Medicine Physicians.
Diabetic retinopathy (DR) is the leading cause of blindness among working-aged adults aged 20 to 74 years. Despite professional association guidelines that recommend yearly screening for DR, only about 60% of Americans with diabetes mellitus (DM) receive annual examinations. The purpose of this 2-phase study was to determine the ability of family medicine (FM) physicians to accurately interpret retinal images of patients with DM. Five FM physicians received a 1-hour lecture on DR by a retinal specialist after which the physicians were shown 30 ultrawide-field retina images and asked to determine whether the images contained signs of DR (phase 1). Patients with DM who had not received an eye examination within the past year underwent nonmydriatic retinal photography in a FM clinic (phase 2). The 5 FM physicians were asked to evaluate the images for signs of DR and the images were simultaneously sent to a retinal specialist for independent interpretation. The diagnoses of the FM physicians and retina specialist were compared. Patients were informed of their results and were asked to complete a brief telephone survey regarding their experience with the screening process. Thirty retina images, 5 with DR and 25 without DR, were included in the postlecture assessment. Each of the 30 images was reviewed by all 5 FM physicians. Of the 5 images with DR, 3 were correctly diagnosed by all 5 FM physicians, 1 was correctly diagnosed by 4, and 1 was accurately diagnosed by 3. Overall accuracy for the 5 FM physicians was 100%, 100%, 100%, 97%, and 87%. Among the 34 patients included in phase 2, 3 (8%) were diagnosed with DR by the retinal specialist but 8 (24%) were diagnosed with DR by the FM physicians. Of the 3 patients with DR confirmed by the retinal specialist, only 1 was detected by the FM physicians (sensitivity, 33%; 95% CI, 1% to 91%). Of the 31 patients without DR as determined by the retinal specialist, 24 were accurately diagnosed by the FM physicians (specificity, 77%; 95% CI, 59% to 90%). The screening procedure was considered easy/efficient by 28 of 31 (90%) respondents. To improve early detection of DR new screening methods should be considered. FM physicians were able to accurately identify DR on postlecture images but were not as accurate when evaluating images taken from patients in the FM clinic. Patients found the screening process to be easy and efficient. This study was limited by the small sample size, particularly the limited number of DR cases. Future studies that include cases with a wide variation of DR severity are needed to determine the accuracy of FM physicians at detecting DR in a clinical setting.


Feature extraction using recursive cluster-based linear discriminant with application to face recognition.
A novel recursive procedure for extracting discriminant features, termed recursive cluster-based linear discriminant (RCLD), is proposed in this paper. Compared to the traditional Fisher linear discriminant (FLD) and its variations, RCLD has a number of advantages. First of all, it relaxes the constraint on the total number of features that can be extracted. Second, it fully exploits all information available for discrimination. In addition, RCLD is able to cope with multimodal distributions, which overcomes an inherent problem of conventional FLDs, which assumes uni-modal class distributions. Extensive experiments have been carried out on various types of face recognition problems for Yale, Olivetti Research Laboratory, and JAFFE databases to evaluate and compare the performance of the proposed algorithm with other feature extraction methods. The resulting improvement of performances by the new feature extraction scheme is significant.


Using functional genomics to study PINK1 and metabolic physiology.
Genome sequencing projects have provided the substrate for an unimaginable number of biological experiments. Further, genomic technologies such as microarrays and quantitative and exquisitely sensitive techniques such as real-time quantitative polymerase chain reaction have made it possible to reliably generate millions of data points per experiment. The data can be high quality and yield entirely new insights into how gene expression is coordinated under complex physiological situations. It can also be that the data and interpretation are meaningless because of a lack of physiological context or experimental control. Thus, functional genomics is now being applied to study metabolic physiology with varying degrees of success. From the genome sequencing projects we also have the information needed to design chemical tools that can knock down a gene transcript, even distinguishing between splice variants in mammalian cells. Use of such technologies, inspired by nature's endogenous RNAi mechanism-microRNA targeting, comes with significant caveats. While the discipline of Pharmacology taught us last century that inhibitor action specificity is dependent on the concentration used, these experiences have been ignored by users of siRNA technologies. What we provide in this chapter is some considerations and observations from functional genomic studies. We are largely concerned with the phase that follows a microarray study, where a candidate gene is selected for manipulation in a system that is considered to be simpler than the in vivo mammalian tissue and thus the methods discussed largely apply to this cell biology phase. We apologize for not referring to all relevant publications and for any technical considerations we have also failed to factor into our discussion.


A Methodological Framework to Estimate the Site Fidelity of Tagged Animals Using Passive Acoustic Telemetry.
The rapid expansion of the use of passive acoustic telemetry technologies has facilitated unprecedented opportunities for studying the behavior of marine organisms in their natural environment. This technological advance would greatly benefit from the parallel development of dedicated methodologies accounting for the variety of timescales involved in the remote detection of tagged animals related to instrumental, environmental and behavioral events. In this paper we propose a methodological framework for estimating the site fidelity ("residence times") of acoustic tagged animals at different timescales, based on the survival analysis of continuous residence times recorded at multiple receivers. Our approach is validated through modeling and applied on two distinct datasets obtained from a small coastal pelagic species (bigeye scad, Selar crumenophthalmus) and a large, offshore pelagic species (yellowfin tuna, Thunnus albacares), which show very distinct spatial scales of behavior. The methodological framework proposed herein allows estimating the most appropriate temporal scale for processing passive acoustic telemetry data depending on the scientific question of interest. Our method provides residence times free of the bias inherent to environmental and instrumental noise that can be used to study the small scale behavior of acoustic tagged animals. At larger timescales, it can effectively identify residence times that encompass the diel behavioral excursions of fish out of the acoustic detection range. This study provides a systematic framework for the analysis of passive acoustic telemetry data that can be employed for the comparative study of different species and study sites. The same methodology can be used each time discrete records of animal detections of any nature are employed for estimating the site fidelity of an animal at different timescales.


An emerging consensus on aquaporin translocation as a regulatory mechanism.
Water passes through cell membranes relatively slowly by diffusion. In order to maintain water homeostasis, the rapid and specific regulation of cellular water flow is mediated by the aquaporin (AQP) family of membrane protein water channels. The wide range of tissues that are known to express AQPs is reflected by their involvement in many physiological processes and diseases; thirteen human AQPs have been identified to date and the majority are highly specific for water while others show selectivity for water, glycerol and other small solutes. Receptor mediated translocation, via hormone activation, is an established method of AQP regulation, especially for AQP2. There is now an emerging consensus that the rapid and reversible translocation of other AQPs from intracellular vesicles to the plasma membrane, triggered by a range of stimuli, confers altered membrane permeability thereby acting as a regulatory mechanism. This review examines the molecular components that may enable such AQP regulation; these include cytoskeletal proteins, kinases, calcium and retention or localization signals. Current knowledge on the dynamic regulation of sub-cellular AQP translocation in response to a specific trigger is explored in the context of the regulation of cellular water flow.


Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer.
We sought to evaluate predictors of overall survival following progression after systemic chemotherapy in men with metastatic castration-resistant prostate cancer. For our study population, we used the TAX327 multicenter randomized phase III trial comparing administration of docetaxel and prednisone every 3 weeks, weekly administration of docetaxel and prednisone, and administration of mitoxantrone and prednisone every 3 weeks. Progression was defined as the earliest of prostate-specific antigen (PSA), tumor, or pain progression. We analyzed predictors of postprogression survival according to both prechemotherapy and postchemotherapy variables with adjustment for potential confounders. Among 1,006 men, 640 had evaluable information on protocol-defined progression leading to further therapy. Median postprogression survival was 14.5 months. In the multivariable analysis, several pretreatment factors were associated with postprogression survival: pain, performance status, alkaline phosphatase, number of sites of metastatic disease, liver metastases, hemoglobin, PSA, and time since diagnosis. In addition, we found that the number of progression factors (PSA, pain, and tumor size), the duration of first-line chemotherapy, and whether progression occurred during chemotherapy independently predicted postprogression survival. We found evidence for the benefit of continuation of chemotherapy beyond progression only for men who had isolated worsening of pain. A nomogram was constructed and internally validated with a concordance index of 0.70. An internally validated model to predict postchemotherapy survival was developed. Evaluation of men in the postdocetaxel setting should consider the type of progression, duration of therapy, and known pretreatment prognostic factors. Definitions of progression in castration-resistant prostate cancer that include pain should also consider composite measures of tumor or PSA progression. External validation is planned.


Measurement of humic and fulvic acid concentrations and dissolution properties by a rapid batch procedure.
Although humic substances (HS) strongly facilitate the transport of metals and hydrophobic organic contaminants in environmental systems, their measurement is hampered by the time-consuming nature of currently available methods for their isolation and purification. We present and apply a new rapid batch method to measure humic (HA) and fulvic (FA) acid concentrations and dissolution properties in both solid and aqueous samples. The method is compared with the conventional procedures and is shown to substantially facilitate HS concentration measurements, particularly for applications such as geochemical modeling where HS purification is not required. The new method can be performed within 1.5-4 h per sample and multiple samples can be processed simultaneously, while the conventional procedures typically require approximately 40 h for a single sample. In addition, specific dissolution properties of HS are identified and are consistent with recent views on the molecular structure of HS that emphasize molecular interactions of smaller entities over distinct macromolecular components. Because the principles of the new method are essentially the same as those of generally accepted conventional procedures, the identified HA and FA properties are of general importance for the interpretation of the environmental occurrence and behavior of HS.


An overview on dry eye treatment: approaches for cyclosporin a delivery.
Dry eye syndrome (DES, Keratoconjunctivitis sicca) is a common disorder of the tear film caused by decreased tear production or increased evaporation. Changes in tear composition also promote inflammation on the ocular surface by various mechanisms. Artificial tear drops, tear retention treatment, stimulation of tear secretion, or anti-inflammatory drugs may be used for dry eye treatment according to the severity of the disease. For untreated patients, the risk of ocular infection increases at considerable level and clinical course of the disease may proceed up to infection, corneal ulcer, and blindness. Artificial tears and/or punctual occlusions are used for tear replacement or preservation. New treatment approaches are designed to modify the underlying disease process. For the treatment of severe dry eye disease, cyclosporin A (CsA), the first one of the new generation immunomodulatory drugs, which has an anti-inflammatory effect, is frequently used. CsA has immunosuppressive effects following systemic application. Following local administration of CsA, it is expected to obtain effective drug concentration at the target area and to avoid the various side effects associated with systemic delivery. Microspheres, implants, and liposomes have been developed for administration of CsA subconjunctivally in order to enhance its efficiency.


The Salmonella Specific, σE-Regulated, STM1250 and AgsA, Function With the sHsps IbpA and IbpB, to Counter Oxidative Stress and Survive Macrophage Killing.
The host presents an array of environments which induce bacterial stress including changes in pH, antimicrobial compounds and reactive oxygen species. The bacterial envelope sits at the interface between the intracellular and extracellular environment and its maintenance is essential for Salmonella cell viability under a range of conditions, including during infection. In this study, we aimed to understand the contribution of the σH- and σE-regulated small heat shock proteins IbpA, IbpB, and AgsA and the putative σE-regulated stress response protein STM1250 to the Salmonella envelope stress response. Due to shared sequence identity, regulatory overlap, and the specificity of STM1250 and AgsA to Salmonella sp., we hypothesized that functional overlap exists between these four stress response proteins, which might afford a selective advantage during Salmonella exposure to stress. We present here new roles for three small heat shock proteins and a putative stress response protein in Salmonella that are not limited to heat shock. We have shown that, compared to WT, a quadruple mutant is significantly more sensitive to hydrogen peroxide, has a lower minimum bactericidal concentration to the cationic antimicrobial peptide polymyxin B, and is attenuated in macrophages.