The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion.
A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO(3)) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pK(a). This indicates that NaHCO(3), with a pK(a) of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pK(a) of approximately 7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion.


MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with microRNA‑132 in rats with depression.
Major depressive disorder (MDD) is a considerable public health concern, which affects patients worldwide. MDD is associated with psychosocial impairment, poor quality of life, and significant disability, morbidity and mortality. Stress is a major factor in depression, which impairs the structural and functional plasticity of the hippocampus. Previous studies have demonstrated that chronic unpredictable mild stress is able to downregulate the expression of brain‑derived neurotrophic factor (BDNF) and methyl‑CpG‑binding protein 2 (MeCP2), and alter the expression levels of certain microRNAs (miR). The aim of the present study was to investigate the regulatory association between BDNF, MeCP2 and miR-132 in an animal model of chronic stress‑induced depression. ELISA, western blot and qPCR were used to detect the expression levels of BDNF, MeCP2 and miR-132 in the peripheral blood samples of patients with MDD and in the hippocampi of depressed animals. In addition, a dual luciferase reporter gene system was used to determine whether miR-132 directly targets BDNF or MeCP2. The present study demonstrated that, as compared with normal subjects, miR‑132 expression was increased in the peripheral blood samples of patients with MDD, whereas the expression of MeCP2 and BDNF was decreased; thus, the expression levels of MeCP2 and BDNF were negatively correlated with those of miR‑132. In addition, in an animal model of chronic stress‑induced depression, increased expression levels of miR‑132, and decreased levels of MeCP2 and BDNF were detected in the hippocampi. Furthermore, knockdown of MeCP2 expression in primary hippocampal neurons increased the expression of miR‑132 and decreased the expression levels of BDNF. The results of the present study demonstrated that miR‑132 may directly target MeCP2, but not BDNF, and control its expression at the transcriptional and translational level. miR‑132 was also shown to negatively regulate BDNF expression. The reduced expression levels of BDNF, as induced by MeCP2 knockdown, were enhanced by miR‑132 mimics, and were rescued by miR‑132 inhibitors. These results suggested that homeostatic interactions between MeCP2 and miR‑132 may regulate hippocampal BDNF levels, which may have a role in the pathogenesis of MDD.


Acute and long-term results after intra-arterial thrombolysis of occluded lower extremity bypass grafts using recombinant tissue plasminogen activator for acute limb-threatening ischemia.
Occlusion of lower extremity vascular bypass grafts results in acute limb-threatening ischemia. The underlying cause of graft failure generally is distal anastomosis stenosis, and relief of culprit stenosis is a required to maintain long-term patency. Of the three thrombolytic agents used for prolonged infusion to accomplish fibrinolysis, streptokinase was the first to be used and is limited owing to the antigenicity that precludes repeated use. Urokinase had been the mainstay of thrombolytic therapy until it was withdrawn by the U.S. Food and Drug Administration in 1999 because of the potential of transmission of infectious agents during its manufacturing process. Recombinant tissue plasminogen activator (rt-PA) has not been studied adequately to assess safety and efficacy, and there are no standardized dosing guidelines. We report our experience with six patients presenting with acute limb-threatening ischemia attributable to thrombosis of synthetic lower extremity bypass grafts. After thrombolysis using rt-PA (mean bolus dose, 12.2 +/- 3.6 mg; range, 6-15 mg administered over 5 minutes followed by infusion at 2 mg/h for 15.6 +/- 6.4 hours; total dose, 51 +/- 16 mg), successful thrombolysis was achieved in 84% of the patients. The primary patency rate was 75% and the secondary patency rate 100% at 16 weeks. One patient underwent amputation owing to unsuccessful thrombolysis. No major bleeding or vascular complications occurred. We conclude that intra-arterial thrombolysis using rt-PA is a safe and effective therapy for patients with thrombotic occlusion of synthetic lower extremity bypass grafts presenting with acute limb-threatening ischemia and allows a high rate of secondary patency, avoiding amputation.


Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles.
EDA splice isoforms EDA-A1 and EDA-A2 belong to the TNF ligand family and regulate skin appendage formation by activating NF-kappa B- and JNK- promoted transcription. To analyze their action further, we conditionally expressed the isoforms as tetracycline ('Tet')-regulated transgenes in Tabby (EDA-negative) and wild-type mice. Expression of only the mEDA-A1 transgene had two types of effects during embryogenesis: (1) determinative effects on sweat glands and hair follicles. In Tabby mice, one type of hair follicle ('guard hair') was restored, whereas a second type, the dominant undercoat hair follicle ('zigzag') was not; furthermore, the transgene sharply suppressed zigzag hair formation in wild-type mice, with the overall numbers of back hair follicles remaining the same; and (2) trophic effects on sebaceous and Meibomian glands. Marked hyperplasia resulted from expansion of the sebocyte-producing zone in sebaceous glands, with particularly high expression of the transgene and the replication marker PCNA, and correspondingly high production of sebum. The phenotypic effects of mEDA-A1 on sebaceous glands, but not on hair follicles, were reversed when the gene was repressed in adult animals. The results thus reveal both initiating and trophic isoform-specific effects of the EDA gene, and suggest a possible balance of isoform interactions in skin appendage formation.


Patterns of dietary intake and psychological distress in older Australians: benefits not just from a Mediterranean diet.
Anxiety and depression contribute to morbidity in elderly adults and may be associated with diet. We investigated the association between diet and psychological distress as a marker for depression. Dietary patterns were defined by factor analysis or the Mediterranean Diet Score (MDS); depression and anxiety were assessed 12 years later. A total of 8,660 generally healthy men and women born in Australia and aged 50-69 years from the Melbourne Collaborative Cohort Study were included. At baseline (1990-1994), diet (food frequency questionnaire), education, Socio-Economic Indexes for Areas (SEIFA) - Index of Relative Socio-economic Disadvantage, medication use, social engagement, physical activity, smoking status, alcohol use, and health conditions were assessed; at follow-up (2003-2007), psychological distress was assessed using the Kessler Psychological Distress Scale (K10). Logistic regression was used to identify associations between diet and a K10 score ≥20, indicative of psychological distress. The MDS was inversely associated with psychological distress, with the odds ratio in the top-scoring group relative to the lowest scoring group being 0.72 (95% confidence interval = 0.54-0.95). Stronger adherence to a traditional Australian-style eating pattern was also associated with a lower K10 score at follow-up, with the odds ratio for having a K10 score indicative of psychological distress for the top 20% of adherence to this pattern relative to the lowest being 0.61 (95% confidence interval = 0.40-0.91). A Mediterranean-style diet was associated with less psychological distress, possibly through provision of a healthy nutrient profile. The Australian dietary pattern, which included some foods high in fat and sugar content along with whole foods, also showed a weak inverse association. Adherence to this pattern may reflect a feeling of belonging to the community associated with less psychological distress.


Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis.
We conducted a meta-analysis of studies comparing the presence of Chlamydia pneumoniae (Cpn) between multiple sclerosis (MS) patients and other neurological diseases patients or healthy controls. We identified 26 studies with 1332 MS patients and 1464 controls. Using random-effects methods, MS patients were found more likely to have detectable levels of Cpn DNA (OR = 3.216; 95% CI: 1.204, 8.585) in their cerebrospinal fluid, and intrathecally synthesized immunoglobulins (OR = 3.842; 95% CI: 1.317, 11.212), compared to other patients with neurological diseases. There is no evidence for increased levels of serum immunoglobulins (OR = 1.068; 95% CI: 0.745, 1.530), even though this result is confounded by the presence of studies using normal subjects as controls. Similarly, there is no evidence for association of immunoglobulins against Cpn in the cerebrospinal fluid (OR = 3.815; 95% CI: 0.715, 20.369). Up to 59.7% of the between-studies variability could be explained by the inappropriate matching of cases and controls for gender. In random-effects meta-regressions, adjusting for the confounding effect of gender differences results in stronger and statistically significant associations of MS with detectable levels of Cpn DNA, intrathecally synthesized immunoglobulins and immunoglobulins in the cerebrospinal fluid. Even though the presence of Cpn is clearly more likely in MS patients, these findings are insufficient to establish an etiologic relation.


Self-guided internet-based and mobile-based stress management for employees: results of a randomised controlled trial.
This randomised controlled trial (RCT) aimed to evaluate the efficacy of a self-guided internet-based stress management intervention (iSMI) for employees compared to a 6-month wait-list control group (WLC) with full access for both groups to treatment as usual. A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale, PSS-10 ≥22) was randomly assigned to either the iSMI or to the WLC. The iSMI consisted of seven sessions and one booster session including problem-solving and emotion regulation techniques. Self-report data were assessed at baseline, at 7 weeks and at 6 months following randomisation. The primary outcome was perceived stress (PSS-10). The secondary outcomes included other relevant mental-related and work-related health outcomes. Data were analysed based on intention-to-treat principles. The iSMI participants showed a significantly higher reduction in perceived stress from baseline to post-treatment at 7 weeks (d=0.96, 95% CI 0.70 to 1.21) and to the 6-month follow-up (d=0.65, 95% CI 0.40 to 0.89) compared to the WLC. Significant differences with small to moderate effect sizes were also found for depression, anxiety, emotional exhaustion, sleeping problems, worrying, mental health-related quality of life, psychological detachment, emotion regulation skills and presenteeism, in favour of the experimental group. At the 6 -month follow-up, all outcomes remained significantly better for the experimental group with the exception of work engagement, physical health-related quality of life and absenteeism, which were not found to significantly differ between the iSMI and WLC groups. The iSMI investigated in this study was found to be effective in reducing typical mental-related and work-related health symptoms of stressed employees. Internet-based self-guided interventions could be an acceptable, effective and potentially cost-effective approach to reduce the negative consequences associated with work-related stress.


Nonbehavioral selection for pawns, mutants of Paramecium aurelia with decreased excitability.
The reversal response in Paramecium aurelia is mediated by calcium which carries the inward current during excitation. Electrophysiological studies indicate that strontium and barium can also carry the inward current. Exposure to high concentrations of barium rapidly paralyzes and later kills wild-type paramecia. Following mutagenesis with nitrosoguanidine, seven mutants which continued to swim in the ;high-barium' solution were selected. All of the mutants show decreased reversal behavior, with phenotypes ranging from extremely non-reversing (;extreme' pawns) to nearly wild-type reversal behavior (;partial' pawns). The mutations fall into three complementation groups, identical to the pwA, pwB, and pwC genes of Kunget al. (1975). All of the pwA and pwB mutants withstand longer exposure to barium, the pwB mutants surviving longer than the pwA mutants. Among mutants of each gene, survival is correlated with loss of reversal behavior. Double mutants (A-B, A-C, B-C), identified in the exautogamous progeny of crosses between ;partial' mutants, exhibited a more extreme non-reversing phenotype than either of their single-mutant (;partial' pawn) parents.---Inability to reverse could be expected from an alteration in the calcium-activated reversal mechanism or in excitation. A normal calcium-activated structure was demonstrated in all pawns by chlorpromazine treatment. In a separate report (Schein, Bennett and Katz 1976) the results of electrophysiological investigations directly demonstrate decreased excitability in all of the mutants, a decrease due to an altered calcium activation. The studies of the genetics, the survival in barium and the electro-physiology of the pawns demonstrate that the pwA and pwB genes have different effects on calcium activation.


CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer.
The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


MALDI-TOF mass spectrometry for sub-typing of Streptococcus pneumoniae.
Serotyping of Streptococcus pneumoniae is important for monitoring of vaccine impact. Unfortunately, conventional and molecular serotyping is expensive and technically demanding. This study aimed to determine the ability of matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) mass spectrometry to discriminate between pneumococcal serotypes and genotypes (defined by global pneumococcal sequence cluster, GPSC). In this study, MALDI-TOF mass spectra were generated for a diverse panel of whole genome sequenced pneumococcal isolates using the bioMerieux VITEK MS in clinical diagnostic (IVD) mode. Discriminatory mass peaks were identified and hierarchical clustering was performed to visually assess discriminatory ability. Random forest and classification and regression tree (CART) algorithms were used to formally determine how well serotypes and genotypes were identified by MALDI-TOF mass spectrum. One hundred and ninety-nine pneumococci, comprising 16 serotypes and non-typeable isolates from 46 GPSC, were analysed. In the primary experiment, hierarchical clustering revealed poor congruence between MALDI-TOF mass spectrum and serotype. The correct serotype was identified from MALDI-TOF mass spectrum in just 14.6% (random forest) or 35.4% (CART) of 130 isolates. Restricting the dataset to the nine dominant GPSC (61 isolates / 13 serotypes), discriminatory ability improved slightly: the correct serotype was identified in 21.3% (random forest) and 41.0% (CART). Finally, analysis of 69 isolates of three dominant serotype-genotype pairs (6B-GPSC1, 19F-GPSC23, 23F-GPSC624) resulted in the correct serotype identification in 81.1% (random forest) and 94.2% (CART) of isolates. This work suggests that MALDI-TOF is not a useful technique for determination of pneumococcal serotype. MALDI-TOF mass spectra appear more associated with isolate genotype, which may still have utility for future pneumococcal surveillance activities.


A Computationally Efficient Visual Saliency Algorithm Suitable for an Analog CMOS Implementation.
Computer vision algorithms are often limited in their application by the large amount of data that must be processed. Mammalian vision systems mitigate this high bandwidth requirement by prioritizing certain regions of the visual field with neural circuits that select the most salient regions. This work introduces a novel and computationally efficient visual saliency algorithm for performing this neuromorphic attention-based data reduction. The proposed algorithm has the added advantage that it is compatible with an analog CMOS design while still achieving comparable performance to existing state-of-the-art saliency algorithms. This compatibility allows for direct integration with the analog-to-digital conversion circuitry present in CMOS image sensors. This integration leads to power savings in the converter by quantizing only the salient pixels. Further system-level power savings are gained by reducing the amount of data that must be transmitted and processed in the digital domain. The analog CMOS compatible formulation relies on a pulse width (i.e., time mode) encoding of the pixel data that is compatible with pulse-mode imagers and slope based converters often used in imager designs. This letter begins by discussing this time-mode encoding for implementing neuromorphic architectures. Next, the proposed algorithm is derived. Hardware-oriented optimizations and modifications to this algorithm are proposed and discussed. Next, a metric for quantifying saliency accuracy is proposed, and simulation results of this metric are presented. Finally, an analog synthesis approach for a time-mode architecture is outlined, and postsynthesis transistor-level simulations that demonstrate functionality of an implementation in a modern CMOS process are discussed.


ZZ domain of CBP: an unusual zinc finger fold in a protein interaction module.
CREB-binding protein (CBP) is a large, multi-domain protein that provides a multitude of binding sites for transcriptional coactivators. The site of interaction of the tumor suppressor p53 and the oncoprotein E1A with CBP/p300 has been identified with the third cysteine-histidine-rich (CH3) domain, which incorporates two zinc-binding motifs, ZZ and TAZ2. We show that these two domains fold independently and do not interact in solution. Our experiments demonstrate conclusively that the interaction of p53 and E1A with the CH3 domain resides exclusively in the TAZ2 domain, with no contribution from the ZZ domain. We report also the three-dimensional solution structure of the ZZ domain of murine CBP. The 52 residue ZZ domain contains two twisted antiparallel beta-sheets and a short alpha-helix, and binds two zinc ions. The identity of the zinc coordinating ligands was resolved unambiguously using NMR spectroscopy of the ZZ domain substituted with (113)Cd. One zinc ion is coordinated tetrahedrally via two CXXC motifs to four cysteine side-chains, and the second zinc ion is coordinated tetrahedrally by a third CXXC motif, together with an unusual HXH motif coordinating via the N(epsilon2) atom of His40 and the N(delta1) atom of His-42. The first zinc cluster of the ZZ domain is strictly conserved, whereas the second zinc cluster shows variability in the position of the two histidine residues, reflecting the wide variety of molecules that incorporate ZZ domains. The structure of the ZZ domain shows that it belongs to the family of cross-brace zinc finger motifs that include the PHD, RING, and FYVE domains; however, its biological function is unclear. Mapping of the positions of conserved residues onto the calculated structures reveals a face containing exposed aromatic and hydrophobic side-chains, while the opposite face contains a series of conserved charged or hydrophilic groups. These homologies suggest that the ZZ domain is involved in ligand binding or molecular scaffolding, with specificity provided by the variability of the sequence that contains the helix in the murine CPB ZZ domain structure.


Expression of Middle-Component RNA of Cowpea Mosaic Virus: In Vitro Generation of a Precursor to Both Capsid Proteins by a Bottom-Component RNA-Encoded Protease from Infected Cells.
The expression of the middle-component (M) RNA of cowpea mosaic virus was studied by means of in vitro translation. In both the wheat germ extract and the rabbit reticulocyte lysate, M RNA was translated into two overlapping polypeptides of 95 and 105 kilodaltons. Incubation of these polypeptides with 30,000 x g supernatant fractions from cowpea mesophyll protoplasts inoculated with complete virus or with separate bottom (B) components alone resulted in extensive processing, yielding polypeptides of 60, 58, 48, and 47 kilodaltons. Similar proteolytic activity was found associated with the in vitro translation products from the bottom-component RNA, demonstrating that the protease present in infected cells is encoded by B RNA. Using antisera raised against the separate capsid proteins VP23 and VP37, it was shown that the 60-kilodalton cleavage product is the precursor to both capsid proteins. Cleavage of nascent 95- and 105- kilodalton polypeptides by the in vivo protease demonstrated that this capsid protein precursor is located C terminally within both polypeptides and that the synthesis of these two overlapping polypeptides is the result of two initiation sites on middle-component RNA. In addition, a second virus-induced proteolytic activity, capable of releasing VP23 from the 95- and 105-kilodalton polypeptides, was detected in leaves of infected plants, but not in infected mesophyll protoplasts. A model for the expression of the middle-component RNA is presented.


Lack of correlation between DNA strand breakage and p53 protein levels in human fibroblast strains exposed to ultraviolet lights.
The contribution of DNA strand breaks accumulating in the course of nucleotide excision repair to upregulation of the p53 tumor suppressor protein was investigated in human dermal fibroblast strains after treatment with 254 nm ultraviolet (UV) light. For this purpose, fibroblast cultures were exposed to UV and incubated for 3 h in the presence or absence of l-beta-D-arabinofuranosylcytosine (araC) and/or hydroxyurea (HU), and then assayed for DNA strand breakage and p53 protein levels. As expected from previous studies, incubation of normal and ataxia telangiectasia (AT) fibroblasts with araC and HU after UV irradiation resulted in an accumulation of DNA strand breaks. Such araC/HU-accumulated strand breaks (reflecting nonligated repair-incision events) following UV irradiation were not detected in xeroderma pigmentosum (XP) fibroblast strains belonging to complementation groups A and G. Western blot analysis revealed that normal fibroblasts exhibited little upregulation of p53 (approximately 1.2-fold) when incubated without araC after 5 J/m2 irradiation, but showed significant (three-fold) upregulation of p53 when incubated with araC after irradiation. AraC is known to inhibit nucleotide excision repair at both the damage removal and repair resynthesis steps. Therefore, the potentiation of UV-induced upregulation of p53 evoked by araC in normal cells may be a consequence of either persistent bulky DNA lesions or persistent incision-associated DNA strand breaks. To distinguish between these two possibilities, we determined p53 induction in AT fibroblasts (which do not upregulate p53 in response to DNA strand breakage) and in XP fibroblasts (which do not exhibit incision-associated breaks after UV irradiation). The p53 response after treatment with 5 J/m2 UV and incubation with araC was similar in AT, XPA, XPG and normal fibroblasts. In addition, exposure of XPA and XPG fibroblasts to UV (5, 10 or 20 J/m2) followed by incubation without araC resulted in a strong upregulation of p53. We further demonstrated that HU, an inhibitor of replicative DNA synthesis (but not of nucleotide excision repair), had no significant impact on p53 protein levels in UV irradiated and unirradiated human fibroblasts. We conclude that upregulation of p53 at early times after exposure of diploid human fibroblasts to UV light is triggered by persistent bulky DNA lesions, and that incision-associated DNA strand breaks accumulating in the course of nucleotide excision repair and breaks arising as a result of inhibition of DNA replication contribute little (if anything) to upregulation of p53.


Effects of thiazide diuretic therapy on bone mass, fractures, and falls. The Study of Osteoporotic Fractures Research Group.
To determine the relation between the use of thiazide diuretics and bone mass, fractures, and falls in older women. Cross-sectional study of thiazide diuretics, bone mass, and prevalent vertebral deformities; cohort analysis of thiazide diuretics and nonspinal fractures and falls. Four clinical centers located in Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania. A total of 9704 ambulatory, nonblack women who were 65 years or older. Information on thiazide use, demographic data, medical history, and anthropometric measurements were obtained by questionnaire, interview, and examination. Appendicular bone mass was measured by single-photon absorptiometry. Incident falls and fractures were ascertained every 4 months. Women using thiazide diuretics for more than 10 years had significantly higher bone mass than women who had never used thiazide diuretics (for example, 0.381 g/cm2 compared with 0.355 g/cm2 for the distal radius [P < 0.001]). Current users of thiazide diuretics had an incidence of falls (relative risk, 1.06; 95% CI, 0.90 to 1.25) that was similar to that of those who had never used these drugs. After adjusting for age, body weight, functional status, total calcium intake, duration of estrogen replacement therapy, and self-reported health status, we found that current users of thiazide diuretics who had taken these drugs for more than 10 years had a risk for nonspinal (relative risk, 0.99; CI, 0.81 to 1.20) and osteoporotic (relative risk, 0.98; CI, 0.79 to 1.22) fractures that was similar to that of women who had never used thiazides; however, thiazide users did have a lower risk for fractures of the hip (relative risk, 0.63; CI, 0.34 to 1.16) and wrist (relative risk, 0.66; CI, 0.40 to 1.08), neither of which was significant. Thiazide diuretics have no effect on a women's risk for falling or for experiencing nonspinal fractures. The trend toward a lower risk for hip and wrist fractures is consistent with findings in previous cohort studies but may reflect selection factors for the use of thiazide diuretics. A randomized trial is needed to determine the effect ot thiazide diuretics on the incidence of fractures.


Paced breathing in roller-ski skating: effects on metabolic rate and poling forces.
This study aimed (1) to determine whether paced breathing (synchronization of the expiration phase with poling time) would reduce the metabolic rate and dictate a lower rate of perceived exertion (RPE) than does spontaneous breathing and (2) to analyze the effects of paced breathing on poling forces and stride-mechanics organization during roller-ski skating exercises. Thirteen well-trained cross-country skiers performed 8 submaximal roller-skiing exercises on a motorized driven treadmill with 4 modes of skiing (2 skating techniques, V2 and V2A, at 2 exercise intensities) by using 2 patterns of breathing (unconscious vs conscious). Poling forces and stride-mechanics organization were measured with a transducer mounted in ski poles. Oxygen uptake (VO2) was continuously collected. After each bout of exercise RPE was assessed by the subject. No difference was observed for VO2 between spontaneous and paced breathing conditions, although RPE was lower with paced breathing (P < .05). Upper-limb cycle time and recovery time were significantly (P < .05) increased by paced breathing during V2A regardless of the exercise intensity, but no changes for poling time were observed. A slight trend of increased peak force with paced breathing was observed (P = .055). The lack of a marked effect of paced breathing on VO2 and some biomechanical variables could be explained by the extensive experience of our subjects in cross-country skiing.


Exposing the exposures responsible for type 2 diabetes and obesity.
The rising prevalences of type 2 diabetes and obesity constitute major threats to human health globally. Powerful social and economic factors influence the distribution of these diseases among and within populations. These factors act on a substrate of individual predisposition derived from the composite effects of inherited DNA variation and a range of environmental exposures experienced throughout the life course. Although "Western" lifestyle represents a convenient catch-all culprit for such exposures, effective treatment and prevention will be informed by characterization of the most critical, causal environmental factors. In this Review, we examine how burgeoning understanding of the genetic basis of type 2 diabetes and obesity can highlight nongenetic exposures that drive development of these conditions.


Examination of tourists' willingness to pay under different conservation scenarios; Evidence from reef manta ray snorkeling in Fiji.
Wildlife-focused tourism is often considered as having the potential to play an integral part of threatened species conservation efforts, particularly through financial support. We focused on the direct financing of conservation by investigating tourists' willingness to pay to snorkel with reef manta rays (Mobula alfredi) at Barefoot Manta, an ecotourism resort in the Yasawa group of islands in Fiji. Our results indicate that 82.4% of people surveyed would be willing to pay a mean value of ~ USD $9.2 (SE 0.9) more than the current cost, a 28% increase. Also, 89% of people surveyed would be willing to pay a mean value of ~ USD $10.2 (SE 0.9) more for a hypothetical scenario where they would snorkel with 50% fewer people, a 31% increase. We also investigated tourists' willingness to make voluntary donations to the local community above an existing payment of ~ USD $10 that is built into the current snorkel payment of ~ USD $32.5. On average, 91.3% of the tourists interviewed were willing to donate additional funds with an average additional donation of ~ USD $8.6 (SE 0.5) to the community to pay for educational and environmental support, an 86% increase. There were few significant relationships between willingness to pay and demographic factors (including age, income, nationality, education, and others), suggesting that willingness to pay was widely held by the tourist population staying at Barefoot Manta Resort. Together, these results indicate that wildlife-based nature tourism could represent a potential, but not unlimited, income source to fund conservation in the Yasawa group, Fiji islands, and that conservation can arise from partnerships between local communities and the tourism sector.


Cyclic adenosine monophosphate in bacteria.
Both cyclic AMP and a specific inducer acting in concert are required for the synthesis of many inducible enzymes in E. coli. Little enzyme is made in the absence of either. In contrast to the specific inducers which stimulate the synthesis only of the proteins required for their metabolism, cyclic AMP controls the synthesis of many proteins. Glucose and certain other carbohydrates decrease the differential rate of synthesis of inducible enzymes by lowering cyclic AMP concentrations. In the lac operon, cyclic AMP acts at the promoter site to facilitate initiation of transcription. This action requires another protein, the cyclic AMP receptor protein. The nucleotide stimulates tryptophanase synthesis at a translational level. The action of cyclic AMP in E. coli may serve as a model to understand its action on transcriptional and translational processes in eukaryotes.


Production of 3-hydroxypropionic acid from glycerol by recombinant Klebsiella pneumoniae ΔdhaTΔyqhD which can produce vitamin B₁₂ naturally.
3-Hydroxypropionic acid (3-HP) is an important platform chemical that can be used to synthesize a range of chemical compounds. A previous study demonstrated that recombinant Escherichia coli stains can produce 3-HP from glycerol in the presence of vitamin B₁₂ (coenzyme B₁₂), when overexpressed with a coenzyme B₁₂-dependent glycerol dehydratase (DhaB) and an aldehyde dehydrogenase. The present study examined the production of 3-HP in recombinant Klebsiella pneumoniae strains, which naturally synthesizes vitamin B₁₂ and does not require supplementation of the expensive vitamin. The NAD⁺-dependent gamma-glutamyl-gamma-aminobutyraldehyde dehydrogenase (PuuC) of K. pneumoniae alone or with its DhaB was overexpressed homologously, and two major oxidoreductases, DhaT and YqhD, were disrupted. Without vitamin B₁₂ addition, the recombinant K. pneumoniae ΔdhaTΔyqhD overexpressing PuuC could produce ∼3.8 g/L 3-HP in 12 h of flask culture. However, this was possible only under the appropriate aeration conditions; 1,3-propanediol (1,3-PDO) (instead of 3-HP) was mainly produced when aeration was insufficient, whereas a very small amount of both 3-HP and 1,3-PDO were produced when aeration was too high. The production of a small amount of 3-HP under improper aeration conditions was attributed to either slow NAD⁺ regeneration (under low aeration) or reduced vitamin B₁₂ synthesis (under high aeration). In a glycerol fed-batch bioreactor experiment under a constant DO of 5%, the strain, K. pneumoniae ΔdhaTΔyqhD, overexpressing both PuuC and DhaB could produce >28 g/L 3-HP in 48 h with a yield of >40% on glycerol. Only small amount of 3-HP was produced when cultivation was carried out at a constant aeration of 1 vvm or constant 10% DO. These results show that K. pneumoniae is potentially useful for the production of 3-HP in an economical culture medium that does not require vitamin B₁₂. The results also suggest that the aeration conditions should be optimized carefully for the efficient production of 3-HP while using this strain.


1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: synthesis and biological evaluation.
A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 μM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.


Optimization of a Quantitative Micro-neutralization Assay.
The micro-neutralization (MN) assay is a standard technique for measuring the infectivity of the influenza virus and the inhibition of virus replication. In this study, we present the protocol of an imaging-based MN assay to quantify the true antigenic relationships between viruses. Unlike typical plaque reduction assays that rely on visible plaques, this assay quantitates the entire infected cell population of each well. The protocol matches the virus type or subtype with the selection of cell lines to achieve maximum infectivity, which enhances sample contrast during imaging and image processing. The introduction of quantitative titration defines the amount of input viruses of neutralization and enables the results from different experiments to be comparable. The imaging setup with a flatbed scanner and free downloadable software makes the approach high throughput, cost effective, user friendly, and easy to deploy in most laboratories. Our study demonstrates that the improved MN assay works well with the current circulating influenza A(H1N1)pdm09, A(H3N2), and B viruses, without being significantly influenced by amino acid substitutions in the neuraminidase (NA) of A(H3N2) viruses. It is particularly useful for the characterization of viruses that either grow to low HA titer and/or undergo an abortive infection resulting in an inability to form plaques in cultured cells.


Safety and efficacy of hydroxypropyl cellulose for all animal species.
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on hydroxypropyl cellulose as a feed additive for all animal species. Hydroxypropyl cellulose is intended for use as a technological additive (functional groups: emulsifier, stabiliser and thickener) in premixtures and feedingstuffs for all animal species with no minimum and maximum content. A proper identification and characterisation of hydroxypropyl cellulose as required for a feed additive is not available and the occurrence of potential toxic impurities cannot be assessed. The following conclusions apply only to hydroxypropyl cellulose meeting the food additive specifications. The FEEDAP Panel concluded that hydroxypropyl cellulose is considered safe for all animal species. The use of hydroxypropyl cellulose in animal nutrition is of no concern for consumer safety. In the absence of data, the FEEDAP Panel was not in the position to conclude on the safety of hydroxypropyl cellulose for the user. The use of hydroxypropyl cellulose as a feed additive is considered safe for the environment. The additive is considered to be efficacious in feedingstuffs for all animal species.


Effect of particle asphericity on single-scattering parameters: comparison between Platonic solids and spheres.
The single-scattering properties of the Platonic shapes, namely, the tetrahedron, hexahedron, octahedron, dodecahedron, and icosahedron, are investigated by use of the finite-difference time-domain method. These Platonic shapes have different extents of asphericity in terms of the ratios of their volumes (or surface areas) to those of their circumscribed spheres. We present the errors associated with four types of spherical equivalence that are defined on the basis of (a) the particle's geometric dimension (b) equal surface area (A), (c) equal volume (V), and (d) equal-volume-to-surface-area ratio (V/A). Numerical results show that the derivations of the scattering properties of a nonspherical particle from its spherical counterpart depend on the definition of spherical equivalence. For instance, when the Platonic and spherical particles have the same geometric dimension, the phase function for a dodecahedron is more similar than that for an icosahedron to the spherical result even though an icosahedron has more faces than a dodecahedron. However, when the nonspherical and spherical particles have the same volume, the phase function of the icosahedral particle essentially converges to the phase function of the sphere, whereas the result for the dodecahedron is quite different from its spherical counterpart. Furthermore, the present scattering calculation shows that the approximation of a Platonic solid with a sphere based on V/A leads to larger errors than the spherical equivalence based on either volume or projected area.


Affect and exertion during incremental physical exercise: Examining changes using automated facial action analysis and experiential self-report.
Recent research indicates that affective responses during exercise are an important determinant of future exercise and physical activity. Thus far these responses have been measured with standardized self-report scales, but this study used biometric software for automated facial action analysis to analyze the changes that occur during physical exercise. A sample of 132 young, healthy individuals performed an incremental test on a cycle ergometer. During that test the participants' faces were video-recorded and the changes were algorithmically analyzed at frame rate (30 fps). Perceived exertion and affective valence were measured every two minutes with established psychometric scales. Taking into account anticipated inter-individual variability, multilevel regression analysis was used to model how affective valence and ratings of perceived exertion (RPE) covaried with movement in 20 facial action areas. We found the expected quadratic decline in self-reported affective valence (more negative) as exercise intensity increased. Repeated measures correlation showed that the facial action mouth open was linked to changes in (highly intercorrelated) affective valence and RPE. Multilevel trend analyses were calculated to investigate whether facial actions were typically linked to either affective valence or RPE. These analyses showed that mouth open and jaw drop predicted RPE, whereas (additional) nose wrinkle was indicative for the decline in affective valence. Our results contribute to the view that negative affect, escalating with increasing exercise intensity, may be the body's essential warning signal that physiological overload is imminent. We conclude that automated facial action analysis provides new options for researchers investigating feelings during exercise. In addition, our findings offer physical educators and coaches a new way of monitoring the affective state of exercisers, without interrupting and asking them.


Organization of suppression in receptive fields of neurons in cat visual cortex.
1. The response to an optimally oriented stimulus of both simple and complex cells in the cat's striate visual cortex (area 17) can be suppressed by the superposition of an orthogonally oriented drifting grating. This effect is referred to as cross-orientation suppression. We have examined the spatial organization and tuning characteristics of this suppressive effect with the use of extracellular recording techniques. 2. For a total of 75 neurons, we have measured the size of each cell's excitatory receptive field by use of rectangular patches of drifting sinusoidal gratings presented at the optimal orientation and spatial frequency. The length and width of these grating patches are varied independently. Receptive-field length and width are determined from the dimensions of the smallest grating patch required to elicit a maximal response. 3. The extent of the area from which cross-orientation suppression originates has been measured in an analogous manner. Each neuron is excited by a patch of drifting grating the same size as the receptive field. The response to this stimulus is modulated by a superimposed patch of grating having an orthogonal orientation. After selecting the spatial frequency that produces maximal suppression, the response of each cell is examined as a function of the length and width of the orthogonal (suppressive) grating patch. Results from 29 cells show that the dimensions of the orthogonal grating patch required to elicit maximal suppression are similar to, or smaller than, the dimensions of the excitatory receptive field. Thus cross-orientation suppression originates from within the receptive field. 4. For some cells the spatial frequency tuning of the suppressive effect is much broader than the spatial frequency tuning for excitation. In these cases it is possible to find a spatial frequency that produces suppression but not excitation. With the use of a suppressive stimulus having this spatial frequency, we examined the strength of suppression as a function of orientation for 11 cells. These tests show that suppression occurs at all orientations, including the preferred orientation for excitation. In some cases, suppression is somewhat stronger at the preferred orientation for excitation than at any other orientation. 5. For 12 cells we varied the relative spatial phase between the optimally oriented and orthogonal gratings. In all cases the magnitude of suppression is largely independent of the relative spatial phase. 6. For three binocular cells we examined whether the suppressive effect of a grating oriented orthogonal to the optimum could be mediated dichoptically.(ABSTRACT TRUNCATED AT 400 WORDS)


A new method for choosing the computational cell in stochastic reaction-diffusion systems.
How to choose the computational compartment or cell size for the stochastic simulation of a reaction-diffusion system is still an open problem, and a number of criteria have been suggested. A generalized measure of the noise for finite-dimensional systems based on the largest eigenvalue of the covariance matrix of the number of molecules of all species has been suggested as a measure of the overall fluctuations in a multivariate system, and we apply it here to a discretized reaction-diffusion system. We show that for a broad class of first-order reaction networks this measure converges to the square root of the reciprocal of the smallest mean species number in a compartment at the steady state. We show that a suitably re-normalized measure stabilizes as the volume of a cell approaches zero, which leads to a criterion for the maximum volume of the compartments in a computational grid. We then derive a new criterion based on the sensitivity of the entire network, not just of the fastest step, that predicts a grid size that assures that the concentrations of all species converge to a spatially-uniform solution. This criterion applies for all orders of reactions and for reaction rate functions derived from singular perturbation or other reduction methods, and encompasses both diffusing and non-diffusing species. We show that this predicts the maximal allowable volume found in a linear problem, and we illustrate our results with an example motivated by anterior-posterior pattern formation in Drosophila, and with several other examples.


Role of risk stratification and genetics in sudden cardiac death.
Sudden cardiac death (SCD) is a major public health issue due to its increasing incidence in the general population and the difficulty in identifying high-risk individuals. Nearly 300 000 - 350 000 patients in the United States and 4-5 million patients in the world die annually from SCD. Coronary artery disease and advanced heart failure are the main etiology for SCD. Ischemia of any cause precipitates lethal arrhythmias, and ventricular tachycardia and ventricular fibrillation are the most common lethal arrhythmias precipitating SCD. Pulseless electrical activity, bradyarrhythmia, and electromechanical dissociation also result in SCD. Most SCDs occur outside of the hospital setting, so it is difficult to estimate the public burden, which results in overestimating the incidence of SCD. The insufficiency and limited predictive value of various indicators and criteria for SCD result in the increasing incidence. As a result, there is a need to develop better risk stratification criteria and find modifiable variables to decrease the incidence. Primary and secondary prevention and treatment of SCD need further research. This critical review is focused on the etiology, risk factors, prognostic factors, and importance of risk stratification of SCD.


Drug-induced liver disease--a review of 14 cases.
The clinical and pathological features of 14 cases of acute drug-induced liver disease (DILD) were analyzed using the French group method for drug reaction assessment. Among them, 8 were of the cytotoxic type, 4 were of the cholestatic type and 2 were of the mixed type. Serum alkaline phosphatase (ALP) levels of the cytotoxic type DILD were all < 1.8 times the normal value, while those of the cholestatic type DILD > 1.8 times (P < 0.05). The alanine aminotransaminase and aspartate aminotransaminase (ALT and AST) levels of the cholestatic type were all < 13.1 times the normal value, while those of the cytotoxic type varied from 2.2 to 118 times the normal value. We found that steatosis was the major feature in the cytotoxic type with ALT and AST < 2.5 times the normal value. Piecemeal necrosis was noted only in all the cases with ALT and AST > 20 times the normal value. In the cholestatic type, the pathological features of the oral contraceptive-related DILD showed mainly cholestasis, whereas chlorpromazine-related DILD revealed additional portal inflammation. Meticulous taking of patient history and clinical assessment are mandatory for the diagnosis of DILD. The ALP levels were helpful in distinguishing different types of DILD. There are some correlations between biochemical changes and pathological features, and both are helpful in distinguishing different etiologies of DILD when the inciting drug is in doubt.


Functional variability of the Lr34 durable resistance gene in transgenic wheat.
Breeding for durable disease resistance is challenging, yet essential to improve crops for sustainable agriculture. The wheat Lr34 gene is one of the few cloned, durable resistance genes in plants. It encodes an ATP binding cassette transporter and has been a source of resistance against biotrophic pathogens, such as leaf rust (Puccinina triticina), for over 100 years. As endogenous Lr34 confers quantitative resistance, we wanted to determine the effects of transgenic Lr34 with specific reference to how expression levels affect resistance. Transgenic Lr34 wheat lines were made in two different, susceptible genetic backgrounds. We found that the introduction of the Lr34 resistance allele was sufficient to provide comparable levels of leaf rust resistance as the endogenous Lr34 gene. As with the endogenous gene, we observed resistance in seedlings after cold treatment and in flag leaves of adult plants, as well as Lr34-associated leaf tip necrosis. The transgene-based Lr34 resistance did not involve a hypersensitive response, altered callose deposition or up-regulation of PR genes. Higher expression levels compared to endogenous Lr34 were observed in the transgenic lines both at seedling as well as adult stage and some improvement of resistance was seen in the flag leaf. Interestingly, in one genetic background the transgenic Lr34-based resistance resulted in improved seedling resistance without cold treatment. These data indicate that functional variability in Lr34-based resistance can be created using a transgenic approach.


Urodynamic analysis of voiding dysfunction in orthotopic ileal neobladder.
We examined the urodynamics, particularly voiding dysfunction, in patients with a neobladder. Free uroflowmetry, pressure-flow study, and voiding cystourethrography were performed in 22 patients (mean age 65 years) at a mean of 21 months after ileal neobladder substitution. The results of free uroflowmetry were used to divide patients into two groups: the good voiders and the poor. Daytime continence was achieved in all patients, while 10 (45%) had nighttime continence. To void 250 ml urine the good voiders strained 2 +/- 1.5 times, and the poor voiders 6 +/- 5 times. The neobladder neck was at the most caudal portion of the reservoir in good voiders, and there was wide funneling. In the group with poor emptying ability, the outlet was not located at the most dependent position. The principal factors for ensuring good voiding function in neobladder patients are the ability to perform effective straining and the location of the neobladder neck.


Characterization of modular bacteriophage endolysins from Myoviridae phages OBP, 201φ2-1 and PVP-SE1.
Peptidoglycan lytic enzymes (endolysins) induce bacterial host cell lysis in the late phase of the lytic bacteriophage replication cycle. Endolysins OBPgp279 (from Pseudomonas fluorescens phage OBP), PVP-SE1gp146 (Salmonella enterica serovar Enteritidis phage PVP-SE1) and 201φ2-1gp229 (Pseudomonas chlororaphis phage 201φ2-1) all possess a modular structure with an N-terminal cell wall binding domain and a C-terminal catalytic domain, a unique property for endolysins with a Gram-negative background. All three modular endolysins showed strong muralytic activity on the peptidoglycan of a broad range of Gram-negative bacteria, partly due to the presence of the cell wall binding domain. In the case of PVP-SE1gp146, this domain shows a binding affinity for Salmonella peptidoglycan that falls within the range of typical cell adhesion molecules (K(aff) = 1.26 × 10(6) M(-1)). Remarkably, PVP-SE1gp146 turns out to be thermoresistant up to temperatures of 90 °C, making it a potential candidate as antibacterial component in hurdle technology for food preservation. OBPgp279, on the other hand, is suggested to intrinsically destabilize the outer membrane of Pseudomonas species, thereby gaining access to their peptidoglycan and exerts an antibacterial activity of 1 logarithmic unit reduction. Addition of 0.5 mM EDTA significantly increases the antibacterial activity of the three modular endolysins up to 2-3 logarithmic units reduction. This research work offers perspectives towards elucidation of the structural differences explaining the unique biochemical and antibacterial properties of OBPgp279, PVP-SE1gp146 and 201φ2-1gp229. Furthermore, these endolysins extensively enlarge the pool of potential antibacterial compounds used against multi-drug resistant Gram-negative bacterial infections.


Psoriasis and associated variables in classification and outcome of juvenile idiopathic arthritis - an eight-year follow-up study.
To study the impact of psoriasis and features associated with psoriasis on classification and outcome in a population-based follow-up cohort of children with juvenile idiopathic arthritis (JIA). In all, 440 children with JIA were followed for a median of 8 years in a prospective Nordic population-based cohort study. Data for remission was available for 427 of these children. The presence of psoriasis, psoriasis-like rash, dactylitis, nail pitting, enthesitis, tenosynovitis and heredity was assessed in relation to ILAR classification and remission. Clinical findings associated with psoriasis developed consecutively during the 8-year period. Six of 14 children with psoriasis were not classified as juvenile psoriatic arthritis according to the ILAR criteria at 8 year follow-up. Dactylitis was more common in children with early onset of JIA. After 8 years we found a cumulative median number of eleven arthritic joints in children with psoriasis or psoriasis-like rash compared with six in the rest of the cohort (p = 0.02). Also, the chance for not being in remission after 8 years increased significantly in patients with psoriasis, psoriasis-like rash or at least two of: 1) first-degree heredity for psoriasis or psoriatic arthritis, 2) dactylitis or 3) nail pitting, compared with the rest of the group (OR 3.32, p = 0.010). Our results indicate a more severe disease over time in psoriasis-associated JIA, as features of psoriasis develop during the disease course. This group is a major challenge to encompass in a future JIA classification in order to facilitate early tailored treatment.


MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity.
Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.


Pilots of oncology health care: a concept analysis of the patient navigator role.
To summarize the current scientific literature pertaining to the role of the patient navigator in oncology using the concept analysis framework developed by Walker and Avant. Published research articles, clinical articles, and Internet sources on patient navigator roles and programs. Literature was obtained from CINAHL, PubMed, PsycINFO, the Cochrane Library, and Google Scholar, incorporating reports in English from 1990-2008. Patient navigation has received a plethora of attention as healthcare programs strive to streamline care and address current gaps in service delivery. The literature revealed that the role of the patient navigator remains context-specific and has been filled by a variety of individuals, including nurses, social workers, peer supporters, and lay individuals. The role of a patient navigator includes removing barriers to care, improving patient outcomes, and ameliorating the overall quality of healthcare delivery. By examining the role of the patient navigator depicted in the scientific literature, nurses can gain insight into not only the features of navigation but also the current systematic gaps that call for navigation services. This article examines the numerous functions of a patient navigator and exemplifies the significance of the role in various domains.


Shortening of the bleeding time in rabbits by hydrocortisone caused by inhibition of prostacyclin generation by the vessel wall.
The effect of hydrocortisone on thrombocytopenic bleeding has been studied in rabbits using a jugular vein bleeding-time technique and a microvascular bleeding-time technique. An inverse relationship was found between the bleeding time and platelet count with both techniques in rabbits made thrombocytopenic by either X-irradiation or injection of heterologous platelet antiserum. Hydrocortisone shortened both bleeding times in thrombocytopenic animals when given in single large doses intravenously (25-100 mg/kg), in daily doses (6 mg/kg) intramuscularly, and shortened the jugular bleeding time when applied to the outside of the jugular vein or instilled intraluminally into the vein. This effect was also noted in normal animals. The effect on thrombocytopenic bleeding was dose related. When given daily, the effect was greater when hydrocortisone was given for 10 d than for 5 d. Both indomethacin and tranylcypromine also reduced the jugular vein bleeding time when instilled intraluminally into the jugular vein, whereas exogenously provided arachidonic acid reversed the effect of hydrocortisone but did not reverse the effect of indomethacin or tranylcypromine. Exogenously provided linoleic acid did not have any effect. Perfusion of the vessel segment with prostacyclin (PGI(2)) reversed the effect of intraluminally administered hydrocortisone, indomethacin, and tranylcypromine. Similarly, hydrocortisone, indomethacin, and tranylcypromine all reduced the rate of loss of fluid from a standard wound in isolated vessels emptied of blood and perfused with saline under constant pressure. PGI(2) reversed the action of these three agents, however, arachidonic acid reversed only the effect of hydrocortisone and did not reverse the effect of indomethacin and tranylcypromine. The generation of PGI(2)-like material and 6-keto-prostaglandinF(1) alpha from jugular vein strips was prevented by prior exposure of the animals or vessel wall to hydrocortisone. These results are compatible with the hypothesis that the vessel wall releases smooth muscle-relaxing prostaglandins when injured and that inhibition of prostaglandin formation by hydrocortisone enhances hemostasis by allowing vasoconstriction to be maintained.


Nanoformulation properties, characterization, and behavior in complex biological matrices: Challenges and opportunities for brain-targeted drug delivery applications and enhanced translational potential.
Nanocarriers (synthetic/cell-based have attracted enormous interest for various therapeutic indications, including neurodegenerative disorders. A broader understanding of the impact of nanomedicines design is now required to enhance their translational potential. Nanoformulations in vivo journey is significantly affected by their physicochemical properties including the size, shape, hydrophobicity, elasticity, and surface charge/chemistry/morphology, which play a role as an interface with the biological environment. Understanding protein corona formation is crucial in characterizing nanocarriers and evaluating their interactions with biological systems. In this review, the types and properties of the brain-targeted nanocarriers are discussed. The biological factors and nanocarriers properties affecting their in vivo behavior are elaborated. The compositional description of cell culture and biological matrices, including proteins potentially relevant to protein corona built-up on nanoformulation especially for brain administration, is provided. Analytical techniques of characterizing nanocarriers in complex matrices, their advantages, limitations, and implementation challenges in industrial GMP environment are discussed. The uses of orthogonal complementary characterization approaches of nanocarriers are also covered.


Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.
The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.


Fully-Non-Contact Masking-Based Holography Inspection on Dimensionally Responsive Artwork Materials.
Environmental control in galleries and museums is a necessity and is informed by the knowledge of ongoing processes of deterioration which can threaten the integrity and stability of artworks. Invisible dimensional changes in many works of art occur following environmental fluctuations as materials respond to the changes in humidity and temperature. The constant influence of dimensional changes usually remains invisible until displacement generates visible deterioration and irreversible damage. This paper exploits fully non contact coherent interferometry in a sequential masking procedure for visualising and studying surface deformation which is the direct effect of dimensional alterations induced by humidity changes. Surface deformation during dimensional displacements of constituent materials may occur on any artwork within an unstable environment. In this context, the presented research study explores the diagnostic potential of fully non contact sensors for the direct structural assessment of environmental effects as they occur in real time on works of art. The method is employed to characterise material responses, complementing and improving understanding of material behaviour in unstable environments.


Identification of microplastic in effluents of waste water treatment plants using focal plane array-based micro-Fourier-transform infrared imaging.
The global presence of microplastic (MP) in aquatic ecosystems has been shown by various studies. However, neither MP concentrations nor their sources or sinks are completely known. Waste water treatment plants (WWTPs) are considered as significant point sources discharging MP to the environment. This study investigated MP in the effluents of 12 WWTPs in Lower Saxony, Germany. Samples were purified by a plastic-preserving enzymatic-oxidative procedure and subsequent density separation using a zinc chloride solution. For analysis, attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FT-IR) and focal plane array (FPA)-based transmission micro-FT-IR imaging were applied. This allowed the identification of polymers of all MP down to a size of 20 μm. In all effluents MP was found with quantities ranging from 0 to 5 × 101 m-3 MP > 500 μm and 1 × 101 to 9 × 103 m-3 MP < 500 μm. By far, polyethylene was the most frequent polymer type in both size classes. Quantities of synthetic fibres ranged from 9 × 101 to 1 × 103 m-3 and were predominantly made of polyester. Considering the annual effluxes of tested WWTPs, total discharges of 9 × 107 to 4 × 109 MP particles and fibres per WWTP could be expected. Interestingly, one tertiary WWTP had an additionally installed post-filtration that reduced the total MP discharge by 97%. Furthermore, the sewage sludge of six WWTPs was examined and the existence of MP, predominantly polyethylene, revealed. Our findings suggest that WWTPs could be a sink but also a source of MP and thus can be considered to play an important role for environmental MP pollution.


Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study.
Chronic liver disease (CLD) is a major cause of mortality and morbidity worldwide. The aim of this study was to assess the overall and liver-related mortality and their predictors in patients with CLD using population data. The Third National Health and Nutrition Examination Survey (NHANES III) and linked mortality data were utilised. Participants from NHANES III (1988-1994) and their mortality status were updated by the Center for Disease Control (CDC) as of 31 December 2006. In this study, the aetiology of CLD was based on available serological tests and clinical data. Each diagnostic cohort was compared with a cohort without liver disease using stratum-specific χ(2). The Cox proportional hazard model was used for analysis, and HRs adjusted for all major confounders; overall mortality and cause-specific mortality were calculated for each type of liver disease. All analyses were run using SAS-callable SUDAAN 10.0 functions using remote access to the CDC Research Data Center server with restricted use linked mortality data. The study cohort included 15 866 NHANES III participants with complete clinical, demographic, laboratory and mortality follow-up data. Of these, 235 subjects had alcohol-related liver disease (ALD), 66 had chronic hepatitis B (CH-B), 264 had chronic hepatitis C (CH-C), 991 were presumed to have non-alcoholic fatty liver disease (NAFLD) and 505 had other liver disease. Additionally, 13 004 subjects without evidence of liver disease served as controls. The analysis shows that type II diabetes (DM) and/or insulin resistance (IR) are independent predictors of overall mortality in CH-B, NAFLD and ALD (p <0.05). Additionally, DM, IR, obesity and metabolic syndrome could be independent predictors of liver-related mortality in CH-C, NAFLD and ALD. Components of metabolic syndrome are associated with overall and liver-related mortality in subjects with CLD.


The genetic heritage of the earliest settlers persists both in Indian tribal and caste populations.
Two tribal groups from southern India--the Chenchus and Koyas--were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools.


The Effect of Stopping Smoking on Disease Activity in Rheumatoid Arthritis (RA). Data from BARFOT, a Multicenter Study of Early RA.
We studied the effect of stopping smoking on disease activity in patients with RA. Between 1992 and 2005, 2,800 adult patients were included in the BARFOT early RA study in Sweden. Disease Activity Score 28 joints (DAS28), C-reactive protein (CRP), Health Assessment Questionnaire (HAQ), rheumatoid factor (RF), anti-CCP, general health and pain visual analog scales (VAS), EULAR response and treatment were registered at inclusion and at follow-up 2, 5 and 8 years. In 2010, a self-completion postal questionnaire was sent to 2,102 patients, enquiring about lifestyle factors, including cessation of smoking. A total of 1,460 adult RA patients with disease duration ≤2 years were included in this study. Seventeen percent smoked in 2010. In total, 127 patients stopped smoking after inclusion in the study. Smoking cessation after inclusion in the study was negatively associated with EULAR good outcome at 8 years (OR 0.44, 95% CI 0.22-0.86, p=0.02), controlled for age, disease duration, sex, socioeconomic class, smoking status, RF, and DAS28 at inclusion. Seventeen percent of the RA patients smoked in 2010 in this large Swedish RA cohort. Stopping smoking after onset of RA did not change the poor prognosis of smokers with RA, but all RA patients need to stop smoking because of the high risk of cardiovascular mortality and morbidity and the association of smoking with vasculitis and noduli in RA.


Development and evaluation of global child health educational modules.
To determine if a standardized global child health (GCH) modular course for pediatric residents leads to satisfaction, learning, and behavior change. Four 1-hour interactive GCH modules were developed addressing priority GCH topics. "Site champions" from 4 Canadian institutions delivered modules to pediatric residents from their respective programs during academic half-days. A pre-post, mixed methods evaluation incorporated satisfaction surveys, multiple-choice knowledge tests, and focus group discussions involving residents and satisfaction surveys from program directors. A total of 125 trainees participated in ≥1 module. Satisfaction levels were high. Focus group participants reported high satisfaction with the concepts taught and the dynamic, participatory approach used, which incorporated multimedia resources. Mean scores on knowledge tests increased significantly postintervention for 3 of the 4 modules (P < .001), and residents cited increases in their practical knowledge, global health awareness, and motivation to learn about global health. Program directors unanimously agreed that the modules were relevant, interesting, and could be integrated within existing formal training time. A relatively short, participatory, foundational GCH modular curriculum facilitated knowledge acquisition and attitude change. It could be scaled up and serve as a model for other standardized North American curricula.


Impact of Long Non-Coding RNA HOTAIR Genetic Variants on the Susceptibility and Clinicopathologic Characteristics of Patients with Urothelial Cell Carcinoma.
Increasing evidence shows that dysregulated expression of long non-coding (lnc)RNAs can serve as diagnostic or prognostic markers in urothelial cell carcinoma (UCC), the most common pathological type of bladder cancer. lncRNA HOX transcript antisense RNA (HOTAIR) was shown to promote tumor progression and be associated with a poor prognosis in multiple cancers including bladder cancer. Polymorphisms of HOTAIR were recently linked to a predisposition for diverse malignancies. Herein we conducted a case-control study to evaluate whether genetic polymorphisms of HOTAIR were associated with UCC risk and clinicopathologic characteristics. Four loci (rs920778 T>C, rs1899663 G>T, rs4759314 A>G, and rs12427129, C>T) of HOTAIR were genotyped by a TaqMan allelic discrimination method in 431 cases and 862 controls. We found that female patients who carried AG + GG genotype of rs4759314 were associated with an increased UCC risk after controlling for age and tobacco consumption (adjusted odds ratio (AOR) = 1.92, 95% confidence interval (CI): 1.01⁻3.64, p = 0.047) and a lower overall survival rate (p = 0.008). Moreover, patients with a smoking habit or younger age (≤65 years), who had at least one T allele of HOTAIR rs12427129 were at a higher risk of developing advance tumor T satge (p = 0.046), compared to those patients with CC homozygotes. In contrast, rs920778 C allele carriers were negatively correlated with the development of lymph node metastasis (OR = 0.51, 95% CI: 0.28⁻0.94, p = 0.031). Further analyses of clinical datasets revealed correlations of the expression of HOTAIR with tumor metastasis and a poor survival rate in patients with UCC. Our results verified the diverse impacts of HOTAIR variants on UCC susceptibility and clinicopathologic characteristics.


High order kinoforms as a broadband achromatic diffractive optics for terahertz beams.
We discuss thin optical structures that allow chromatic aberrations to be avoided in the THz domain. The paper contains the theoretical considerations, computer modeling and experimental evaluation of the high order kinoform diffractive elements in the THz range. According to the obtained results application of the high order kinoforms enables broadband operation in the THz range.


The receptor for the subgroup A avian leukosis-sarcoma viruses binds to subgroup A but not to subgroup C envelope glycoprotein.
The putative subgroup A avian leukosis-sarcoma virus (ALSV) receptor (Tva) was recently cloned by gene transfer (P. Bates, J. A. Young, and H. E. Varmus, Cell 74:1043-1051, 1993; J. A. T. Young, P. Bates, and H. E. Varmus, J. Virol. 67:1811-1816, 1993). Susceptibility to infection by subgroup A ALSV is conferred on cells upon transfection with cDNAs encoding tva. The hypothesis that tva encodes a specific receptor for subgroup A ALSV predicts that the Tva protein should bind to subgroup A, but not to subgroup C, envelope glycoprotein. In this study, we examined this prediction by using several biochemical assays. We established stable NIH 3T3 cell lines expressing either Tva, the subgroup A envelope glycoprotein (Env-A), or the subgroup C envelop glycoprotein (Env-C) and used them in conjunction with soluble forms of these molecules to demonstrate specific binding. When cell lysates containing Tva were mixed with lysates of either Env-A or Env-C, an immunoprecipitable complex formed between Tva and Env-A but not between Tva and Env-C. A soluble, oligomeric form, of Env-A, not Env-C, binds to cells expressing Tva. Reciprocally, a secreted form of Tva can bind to cells expressing Env-A but not to cells expressing Env-C. A specific and stable complex formed between soluble Env-A and secreted Tva as demonstrated by sucrose density gradient centrifugation. Thus, by three kinds of assays, Tva appears to bind specifically to Env-A, which is consistent with genetic evidence that it serves as the cell surface receptor of subgroup A ALSV and the main determinant of subgroup specificity.


Adaptive Deep Brain Stimulation for Movement Disorders: The Long Road to Clinical Therapy.
Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of-principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Three-dimensional imaging utilizing energy discrimination. II.
A new algorithm for three-dimensional image reconstruction in nuclear medicine in which scattered radiation rather than multiple projected images is used for determination of the source depth within the body is proposed. Images taken from numerous energy windows are combined for the reconstruction of the source distribution in the body. In the first paper of this series Gunter et al. [IEEE Trans. Nucl. Sci. 37, 1300 (1990)] examined simple linear algorithms for recovering source depth information from scattered radiation. These linear algorithms were unsuccessful because the scattering process produces little signal in the low-energy images at high spatial frequencies. As a result, the reconstructed source distributions exhibited nodal patterns and blurring. The scattering kernel that was measured and reported in the first paper is now examined more carefully. The singular-value decomposition of the kernel matrices is used to break the reconstruction problem into distinct channels that relate energy spectra to source depth distributions. Based on this analysis, a new nonlinear reconstruction algorithm that avoids the earlier problems is proposed. The new algorithm does not degrade spatial resolution in the imaging plane and provides depth resolution with a standard deviation of 4 cm for point sources without requiring any camera motion. The algorithm also provides significant attenuation correction and, therefore, improved quantitation of the source distribution.


Identification of a possible proteomic biomarker in Parkinson's disease: discovery and replication in blood, brain and cerebrospinal fluid.
Biomarkers to aid diagnosis and delineate the progression of Parkinson's disease are vital for targeting treatment in the early phases of the disease. Here, we aim to discover a multi-protein panel representative of Parkinson's and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. We used aptamer-based technology (SomaLogic®) to measure proteins in 1599 serum samples, 85 cerebrospinal fluid samples and 37 brain tissue samples collected from two observational longitudinal cohorts (the Oxford Parkinson's Disease Centre and Tracking Parkinson's) and the Parkinson's Disease Brain Bank, respectively. Random forest machine learning was performed to discover new proteins related to disease status and generate multi-protein expression signatures with potential novel biomarkers. Differential regulation analysis and pathway analysis were performed to identify functional and mechanistic disease associations. The most consistent diagnostic classifier signature was tested across modalities [cerebrospinal fluid (area under curve) = 0.74, P = 0.0009; brain area under curve = 0.75, P = 0.006; serum area under curve = 0.66, P = 0.0002]. Focusing on serum samples and using only those with severe disease compared with controls increased the area under curve to 0.72 (P = 1.0 × 10-4). In the validation data set, we showed that the same classifiers were significantly related to disease status (P < 0.001). Differential expression analysis and weighted gene correlation network analysis highlighted key proteins and pathways with known relationships to Parkinson's. Proteins from the complement and coagulation cascades suggest a disease relationship to immune response. The combined analytical approaches in a relatively large number of samples, across tissue types, with replication and validation, provide mechanistic insights into the disease as well as nominate a protein signature classifier that deserves further biomarker evaluation.


Local cone-beam tomography image reconstruction on chords.
We develop reconstruction algorithms for local cone-beam tomography for use with generalized scanning trajectories. The algorithms are grounded theoretically in a recently developed chord-based theory for exact image reconstruction and principles of lambda tomography. Being chord based, they are distinct mathematically and conceptually from conventional local tomography reconstruction algorithms. The salient feature of our algorithms is that they permit reconstruction of discontinuities in the profiles of the object function along chords. By consideration of all possible chords, a 3D image that describes the locations of object discontinuities can be reconstructed. Results from microlocal analysis are applied for understanding the object features that can be reconstructed stably by use of the algorithms. A computer-simulation study is conducted to demonstrate the algorithms and compare their performance with an existing algorithm.


Female subfertility.
With an average monthly fecundity rate of only 20%, human beings are not fertile mammals. 10-15% of couples have difficulties conceiving, or conceiving the number of children they want, and seek specialist fertility care at least once during their reproductive lifetime. Dependent on the two main factors that determine subfertility, duration of childlessness and age of the woman, three questions need to be addressed before treatment is offered. Is it time to start the routine fertility investigation?--ie, has sufficient exposure to the chance of conception taken place? Are cost-effective, safe, and reliable treatments available for the disorder diagnosed? And, should the couple be referred straightaway for assisted reproduction?


Subjective age and sleep in middle-aged and older adults.
Chronological age is commonly used to explain change in sleep. The present study examines whether subjective age is associated with change in sleep difficulties across middle adulthood and old age. Participants were drawn from the second (2004-2005) and third (2013-2014) waves of the Midlife in the United States Survey (MIDUS, N = 2350; Mean Age: 55.54 years), the 2008 and 2014 waves of the Health and Retirement Study (HRS, N = 4066; Mean Age: 67.59 years) and the first (2011) and fourth (2014) waves of the National Health and Aging Trends Survey (NHATS, N = 3541; Mean Age: 76.46). In each sample, subjective age, sleep difficulties, depressive symptoms, anxiety and chronic conditions were assessed at baseline. Sleep difficulties was assessed again at follow-up. Sleep difficulties. An older subjective age at baseline was related to an increase in sleep difficulties over time in the three samples, and was mediated, in part, through more depressive symptoms, anxiety and chronic conditions. Feeling older was associated with an increased likelihood of major sleeping difficulties at follow-up in the three samples. Subjective age is a salient marker of individuals' at risk for poor sleep quality, beyond chronological age.


Group III and IV muscle afferent discharge patterns after repeated lengthening and shortening actions.
The purpose of this study was to test the hypothesis that group III and IV muscle afferent activity would differ after concentric- and eccentric-type fatiguing tasks. Tibialis anterior afferent activities from adult rats were measured in three conditions: before and after a rest period (C), and after concentric (CC) or eccentric (EC) exercise. Specific activators were used to elicit increases in afferent discharge rates, i.e., electrically induced fatigue (EIF), or potassium chloride (KCl) and lactic acid (LA) injections. After the rest period (POST-condition), the control group displayed a pattern of response to stimuli similar to that obtained in baseline condition (PRE-condition). However, responses were significantly different in the exercise groups: afferent responses were blunted in the CC group and were almost suppressed in the EC group. These results demonstrate that the type of muscular contraction involved in the fatiguing task can affect group III and IV afferent fiber activity differently and, potentially, can differentially affect the regulation of central motor command.


On the neural basis of sensory weighting: Alpha, beta and gamma modulations during complex movements.
Previous studies have revealed that visual and somatosensory information is processed as a function of its relevance during movement execution. We thus performed spectral decompositions of ongoing neural activities within the somatosensory and visual areas while human participants performed a complex visuomotor task. In this task, participants followed the outline of irregular polygons with a pen-controlled cursor. At unpredictable times, the motion of the cursor deviated 120° with respect to the actual pen position creating an incongruence between visual and somatosensory inputs, thus increasing the importance of visual feedback to control the movement as suggested in previous studies. We found that alpha and beta power significantly decreased in the visual cortex during sensory incongruence when compared to unperturbed conditions. This result is in line with an increased gain of visual inputs during sensory incongruence. In parallel, we also found a simultaneous decrease of gamma and beta power in sensorimotor areas which has not been reported previously. The gamma desynchronization suggests a reduced integration of somatosensory inputs for controlling movements with sensory incongruence while beta ERD could be more specifically linked to sensorimotor adaptation processes.


Glucose Transporter-1 (GLUT-1) Expression is Associated with Tumor Size and Poor Prognosis in Locally Advanced Gastric Cancer.
BACKGROUND The clinicopathological parameters associated with glucose transporter-1 (GLUT-1) expression in advanced gastric cancer are still controversial. This study aimed to determine the clinicopathological parameters and prognosis associated with GLUT-1 expression in advanced gastric cancer. MATERIAL AND METHODS The GLUT-1 expression level of 234 consecutive gastric cancer samples was detected by immunohistochemical staining and evaluated by semiquantitative analysis. The clinicopathological data and expression level of GLUT-1 of enrolled patients were retrospectively analyzed with univariate and multivariate analyses. RESULTS Tumor size, depth of invasion, and Lauren classification were independent factors related to GLUT-1 expression (P<0.05). Within advanced gastric cancer, tumor size and Lauren type were independent factors associated with GLUT-1 (P=0.011, P<0.001, respectively). The mean survival time of GLUT-1-positive patients with stage M0 advanced gastric cancer who had undergone radical gastrectomy was shorter than that of GLUT-1-negative patients (61.26±6.12 versus 80.88±7.38, P=0.044). GLUT-1 was an independent prognosis factor in locally advanced gastric cancer patients who had undergone radical gastrectomy (hazard ratio [HR] 1.769, P=0.046). The mean survival time of adjuvant chemotherapy was significantly better than no adjuvant chemotherapy in the GLUT-1-positive group (71.10±6.88 versus 24.65±8.69, P<0.001) and in the GLUT-1 negative group (87.48±7.99 versus 49.39±11.71, P<0.001). CONCLUSIONS Tumor size and Lauren type independently affected GLUT-1 expression in advanced gastric cancer. GLUT-1 was not only related to poor prognosis but also predicted to be a metabolic biomarker for intestinal type in locally advanced gastric cancer. The relationship among GLUT-1, hepatic metastasis and chemotherapy regimens, and mechanism of chemotherapy responses related to GLUT-1 should be further investigated.


Free prostate-specific antigen provides more precise data on benign prostate volume than total prostate-specific antigen in korean population.
To investigate the efficacy of total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) for the estimation of prostate volume (PV) in pathologically-proven benign prostatic hyperplasia (BPH) patients. From January 2010 to March 2013, 165 Korean men with a PSA less than 10 ng/mL who were diagnosed without prostate cancer by prostate biopsy were enrolled. Patients were classified into three age groups: ≤60, 61-70, and >70 years old. The results were organized to estimate and compare the ability of serum tPSA and fPSA to assess the PV. Enrolled patients had a median age of 63.5 years (44 to 80), a median tPSA of 5.72 ng/mL, a median fPSA of 0.98 ng/mL and a median PV of 53.68 mL, respectively. Among the associations between tPSA, fPSA, age, and PV, the highest correlation was verified between fPSA and PV (r=0.377, P<0.0001); the correlation coefficient between tPSA and PV was much lower (r=0.262, P<0.001). All stratified age cohorts showed the same findings. The ROC curves (for PV greater than 30, 40, and 50 mL) showed that fPSA (area under the curve [AUC]=0.781, 0.718, and 0.700) outperformed tPSA (AUC=0.657, 0.583, and 0.67) in its ability to predict clinically significant PV enlargement. Both tPSA and fPSA significantly correlated with PV in Korean men, while the correlation efficiency between fPSA and PV was more powerful. fPSA may be a useful tool in making therapeutic decisions and follow-up management in BPH patients.


Children of the mentally ill: a qualitative focus group approach.
Children of the mentally ill constitute a group neglected by mental health care providers. Increased rates of psychopathology, impaired attention processes, disturbances in interpersonal relationships, and reduced overall adaptive functioning are reported as significant outcomes for offspring of parents with a mood disorder. While epidemiological studies underscoring the risks from a hereditary standpoint are many, there are few studies examining the subjective experience of living with a depressed parent. Findings from this pilot study elucidate the subjective experience of preadolescents/adolescents living with an affectively ill parent, applying a qualitative focus group design. Videotaped sessions were analysed using methods consistent with qualitative research. 'Struggle to understand the illness', 'managing the illness', 'recognizing the signs', and 'impact of parent's hospitalization' emerged as central themes, capturing the essence of participants' experiences. The first two themes were further divided into subthemes. Findings illuminate the need to broaden nursing interventions and research, to include family perspectives, particularly when parental mental illness is a factor.


Measurement of transparent plates with wavelength-tuned phase-shifting interferometry.
A wavelength-tuned Fizeau interferometer is applied to the problem of flatness testing of transparent plates. When the plate is positioned at a specific distance from the reference surface and an integer-math 13-frame phase-shifting algorithm is applied, the system directly filters out unwanted interference arising from backsurface reflections. The resulting front-surface profile exhibits less than 2 nm of residual error attributable to spurious reflections from within the plate.


Using electrical and optical tweezers to facilitate studies of molecular motors.
Dielectrophoresis was used to stretch and suspend actin filaments across a trench etched between two electrodes patterned on a glass slide. Optical tweezers were used to bring a motor protein-coated bead into close proximity to a pre-selected, suspended actin filament, facilitating the attachment of the myosin-coated bead to the filament. The clearance beneath the filament allowed the bead to move freely along and around its filamentous track, unhindered by solid surfaces. Using defocused images, the three-dimensional position of the bead was tracked as a function of time to obtain its trajectory. Experiments were carried out with myosin V and myosin X. Both motor proteins followed left-handed helical paths with the myosin X motor exhibiting a shorter pitch than the myosin V. The combined use of electrostatic and optical tweezers facilitates the preparation of motility assays with suspended tracks. Variants of this technique will enable higher complexity experiments in vitro to better understand the behavior of motors in cells.