Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.
We have recently shown that nitric oxide or authentic endothelium-derived relaxing factor generated in a biologic system reacts in the presence of specific protein thiols to form S-nitrosoprotein derivatives that have endothelium-derived relaxing factor-like properties. The single free cysteine of serum albumin, Cys-34, is particularly reactive toward nitrogen oxides (most likely nitrosonium ion) under physiologic conditions, primarily because of its anomalously low pK; given its abundance in plasma, where it accounts for approximately 0.5 mM thiol, we hypothesized that this plasma protein serves as a reservoir for nitric oxide produced by the endothelial cell. To test this hypothesis, we developed a methodology, which involves UV photolytic cleavage of the S--NO bond before reaction with ozone for chemiluminescence detection, with which to measure free nitric oxide, S-nitrosothiols, and S-nitrosoproteins in biologic systems. We found that human plasma contains approximately 7 microM S-nitrosothiols, of which 96% are S-nitrosoproteins, 82% of which is accounted for by S-nitroso-serum albumin. By contrast, plasma levels of free nitric oxide are only in the 3-nM range. In rabbits, plasma S-nitrosothiols are present at approximately 1 microM; 60 min after administration of NG-monomethyl-L-arginine at 50 mg/ml, a selective and potent inhibitor of nitric oxide synthetases, S-nitrosothiols decreased by approximately 40% (greater than 95% of which were accounted for by S-nitrosoproteins, and approximately 80% of which was S-nitroso-serum albumin); this decrease was accompanied by a concomitant increase in mean arterial blood pressure of 22%. These data suggest that naturally produced nitric oxide circulates in plasma primarily complexed in S-nitrosothiol species, principal among which is S-nitroso-serum albumin. This abundant, relatively long-lived adduct likely serves as a reservoir with which plasma levels of highly reactive, short-lived free nitric oxide can be regulated for the maintenance of vascular tone.


A combined RSA and FE study of the implanted proximal tibia: correlation of the post-operative mechanical environment with implant migration.
There is strong evidence to suggest that inducible displacements, migration and implant loosening are closely related to the initial mechanical environment of the implanted tibia. If this is true, then it should be possible to predict the likelihood of implant migration using patient-specific finite element models. Finite element models of the proximal implanted tibiae were analysed based on pre-operative quantitative computed tomography data of four patients entered into a radiographic migration study. These four patients were also part of an radiostereometric analysis (RSA) study. A variety of load cases were analysed and the risk of bone failure determined for a 2 mm layer of bone immediately beneath the tibial tray. The results were compared with the RSA data measured 1 year post-operatively for each patient. For each patient, an appropriate load case was selected based on patient weight and on the varus-valgus migrations observed in the migration study. The two patients with press-fit implants were predicted to have the highest risk of failure and were found to migrate the most. The two patients with bonded implants (one HA coated and one cemented) were found to have a low risk of failure and these implants migrated the least. This study suggests that the degree of implant migration is dependent on the initial mechanical environment and can be determined using patient-specific finite element analysis.


The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways.
Human fungal pathogens like Candida albicans respond to host immune surveillance by rapidly adapting their transcriptional programs. Chromatin assembly factors are involved in the regulation of stress genes by modulating the histone density at these loci. Here, we report a novel role for the chromatin assembly-associated histone acetyltransferase complex NuB4 in regulating oxidative stress resistance, antifungal drug tolerance and virulence in C. albicans. Strikingly, depletion of the NuB4 catalytic subunit, the histone acetyltransferase Hat1, markedly increases resistance to oxidative stress and tolerance to azole antifungals. Hydrogen peroxide resistance in cells lacking Hat1 results from higher induction rates of oxidative stress gene expression, accompanied by reduced histone density as well as subsequent increased RNA polymerase recruitment. Furthermore, hat1Δ/Δ cells, despite showing growth defects in vitro, display reduced susceptibility to reactive oxygen-mediated killing by innate immune cells. Thus, clearance from infected mice is delayed although cells lacking Hat1 are severely compromised in killing the host. Interestingly, increased oxidative stress resistance and azole tolerance are phenocopied by the loss of histone chaperone complexes CAF-1 and HIR, respectively, suggesting a central role for NuB4 in the delivery of histones destined for chromatin assembly via distinct pathways. Remarkably, the oxidative stress phenotype of hat1Δ/Δ cells is a species-specific trait only found in C. albicans and members of the CTG clade. The reduced azole susceptibility appears to be conserved in a wider range of fungi. Thus, our work demonstrates how highly conserved chromatin assembly pathways can acquire new functions in pathogenic fungi during coevolution with the host.


Social aspects in additive manufacturing of pharmaceutical products.
Additive manufacturing (AM) techniques, such as drug printing, represent a new engineering approach that can implement the concept of personalized medicine via on-demand manufacturing of dosage forms with individually adjusted doses. Implementation of AM principles, such as pharmacoprinting, will challenge the entire drug distribution chain and affect the society at different levels. Areas covered: This work summarizes the concept of personalized medicine and gives an overview of possibilities for monitoring patients' health. The most recent activities in the field of printing technologies for fabrication of dosage forms and 'polypills' with flexible doses and tailored release profiles are reviewed. Different scenarios for the drug distribution chain with the required adjustments in drug logistics, quality systems and environmental safety are discussed, as well as whether AM will be used for production of on-demand medicine. The impact of such changes in the distribution chain on regulation, healthcare professionals and patients are highlighted. Expert opinion: Drug manufacturing by traditional methods is well-established, but it lacks the possibility for on-demand personalized drug production. With the recent approval of the first printed medicine, society should be prepared for the changes that will follow the introduction of printed pharmaceuticals.


Stabilized Cyclic Peptides as Scavengers of Autoantibodies: Neutralization of Anticitrullinated Protein/Peptide Antibodies in Rheumatoid Arthritis.
The occurrence of autoantibodies is a hallmark of rheumatoid arthritis, specifically those autoantibodies targeting proteins containing the arginine-derived amino acid citrulline. There is strong evidence showing that the occurrence of anticitrullinated protein/peptide antibodies (ACPA) are involved in disease progression, and ACPA was recently shown to induce pain in animals. Here, we explore a novel concept useful for research, diagnostics, and possibly therapy of autoimmune diseases, namely, to directly target and neutralize autoantibodies using peptide binders. A high-affinity peptide-based scavenger of ACPA was developed by grafting a citrullinated epitope derived from human fibrinogen into a naturally occurring stable peptide scaffold. The best scavenger comprises the truncated epitope α-fibrinogen, [Cit573]fib(566-580), grafted into the scaffold sunflower trypsin inhibitor-1, SFTI-1. The final peptide demonstrates low nanomolar apparent affinity and superior stability.


Nocturnal enuresis in Turkey: prevalence and accompanying factors in different socioeconomic environments.
To study the prevalence of nocturnal enuresis and the impact of associated familial factors in Turkish children with a different socioeconomic status. A specific questionnaire was distributed to 3,000 parents of primary school children (6-12 years old). Of these children, 1,500 attended primary schools in Umraniye, a suburban region of Istanbul (group 1), and the other 1,500 children visited schools in Suadiye, a well-developed part of Istanbul (group 2). The first part of the survey investigated the familial conditions of the children (financial status, family history of enuresis, and family size). The second part of the questionnaire surveyed the demographic and physical characteristics of the children. The last part was designed to investigate the opinions and beliefs of the parents about nocturnal enuresis and treatment modalities. The prevalence rates of nocturnal enuresis and associated familial factors of these children from two different regions of Istanbul were compared. Of the 3,000 questionnaires distributed, 2,589 (86.3%) were returned and included in the final analysis. The mean age of group 1 and 2 children was 8.88 +/- 1.4 and 8.9 +/- 1.5 years, respectively (p > 0.05). The gender of the subjects was equally distributed (48.6% males and 51.4% females). Enuresis was present in 334 children (25.5%) of group 1 and in 205 children (16%) of group 2. Enuresis was significantly more common in group 1 (p < 0.01). The families consisted of 4.69 +/- 1.4 and 4.1 +/- 1.1 persons, respectively (p < 0.01). A yearly income of USD 7,000 was achieved in group 2 by 54%, in group 1 by only 0.7% (p < 0.01). Only 26 children of group 1 (7.8%) and 22 children of group 2 (10.8%) were noted to receive medical enuresis treatments, with no statistically significant difference between the groups (p > 0.01). The parents of the enuretic children from the suburban region of Istanbul were found to consider the condition a normal developmental entity. They believed that enuresis will resolve spontaneously and that no treatment is necessary. On the contrary, the parents of the enuretic children in the well-developed region of the city believed that enuresis is a psychological problem and that intensive psychological assistance is essential for the management. Our study indicates that the prevalence of nocturnal enuresis in Turkey is comparable to that reported in the literature. The parents consider that enuresis nocturna is not a fatal disorder, that the drugs used in the treatment may be harmful, and that no medical assistance is required. Trained health personnel and physicians should inform the parents about enuresis in order to prevent possible behavioral and self-esteem problems.


Light exerts multiple levels of influence on the Arabidopsis wound response.
Light plays important roles in modulating plant responses to attack by pests and pathogens. Here, we test the hypothesis that darkness modifies the response to wounding, and examine possible mechanisms for such an effect. We investigated changes in the Arabidopsis transcriptome following a light-dark transition and the response to wounding either in the light or in the dark. The transcriptional response to the light-dark transition strongly resembles responses associated with carbon depletion. The dark shift and wound responses acted largely independently, but more complex interactions were identified at a number of levels. Darkness attenuates the overall transcriptional response to wounding, and we identified genes and physiological processes, such as anthocyanin accumulation, that exhibit light-dependent wound responses. Transcriptional activation of light-dependent wound-induced genes requires a chloroplast-derived signal originating from photosynthetic electron transport. We also present evidence of a role for the circadian clock in modifying wound responses. Our results show that darkness impacts on the wound response at a number of levels, which may imply differences in induced herbivore defences during the day and night.


Collaboration of histoincompatible T and B lymphocytes using cells from tetraparental bone marrow chimeras.
T-B collaboration has been studied in a secondary response to sheep erythrocytes using either syngeneic or allogeneic T- and B-cell combinations. T cells prepared from tetraparental bone marrow chimeras (TBMC), carrying H-2 determinants of one parental strain only, cooperated with syngeneic, as well as with allogeneic B cells carrying the alloantigens to which the T cells had been tolerized in the chimeric environment. When TBMC-derived cells of a single H-2 specificity were transferred with a mixture of TBMC-derived B cells of both H-2 types of the parental strains, no preference for syngeneic cooperation was found. The data therefore suggest that the presence of differing H-2-complex determinants on the allogeneic T- and B-cell populations of the two different strain combinations tested do not interfere with T-B collaboration when the cell populations studied are mutually tolerant.


Observation of the side chain O-methylation of glutamic acid or aspartic acid containing model peptides by electrospray ionization-mass spectrometry.
O-methylation of the side chains of glutamic acid (E) and aspartic acid (D) residues is generally observed modification when an acidified methanol/water (MeOH/dH2O) mixture is used as a solvent system during sample preparation for proteomic research. This chemical modification may result misidentification with endogenous protein methylation; therefore, a special care should be taken during sample handling prior to mass spectrometric analysis. In the current study, we systematically examined the extent of E/D methylation and C-terminus carboxyl group of synthetic model peptides in terms of different incubation temperatures, storage times, and added acid types as well as its percentages. To monitor these effects, C-terminus amidated and free acid forms of synthetic model peptides comprised of E or D residue(s) have been analyzed by electrospray ionization-mass spectrometry (ESI-MS). Additionally, LC-MS/MS experiments were performed to confirm the formation of methylated peptide product. The results showed that the rate of methylation was increased as the temperature increases along with prolong incubation times. Moreover, the extent of methylation was remarkably high when formic acid (FA) used as a protonation agent instead of acetic acid (AA). In addition, it was found that the degree of methylation was significantly decreased by lowering acid percentages in ESI solution. More than one acidic residue containing model peptides have been also used to explore the extent of multiple methylation reaction. Lastly, the ethanol (EtOH) and isopropanol (iPrOH) have been substituted separately with MeOH in sample preparation step to investigate the extent of esterification reaction under the same experimental conditions. However, in the positive perspective of view, this method can be used as a simple, rapid and cheap method for methylation of acidic residues under normal laboratory conditions.


SABRE hyperpolarization enables high-sensitivity 1H and 13C benchtop NMR spectroscopy.
Benchtop NMR spectrometers operating with low magnetic fields of 1-2 T at sub-ppm resolution show great promise as analytical platforms that can be used outside the traditional laboratory environment for industrial process monitoring. One current limitation that reduces the uptake of benchtop NMR is associated with the detection fields' reduced sensitivity. Here we demonstrate how para-hydrogen (p-H2) based signal amplification by reversible exchange (SABRE), a simple to achieve hyperpolarization technique, enhances agent detectability within the environment of a benchtop (1 T) NMR spectrometer so that informative 1H and 13C NMR spectra can be readily recorded for low-concentration analytes. SABRE-derived 1H NMR signal enhancements of up to 17 000-fold, corresponding to 1H polarization levels of P = 5.9%, were achieved for 26 mM pyridine in d4-methanol in a matter of seconds. Comparable enhancement levels can be achieved in both deuterated and protio solvents but now the SABRE-enhanced analyte signals dominate due to the comparatively weak thermally-polarized solvent response. The SABRE approach also enables the acquisition of 13C NMR spectra of analytes at natural isotopic abundance in a single scan as evidenced by hyperpolarized 13C NMR spectra of tens of millimolar concentrations of 4-methylpyridine. Now the associated signal enhancement factors are up to 45 500 fold (P = 4.0%) and achieved in just 15 s. Integration of an automated SABRE polarization system with the benchtop NMR spectrometer framework produces renewable and reproducible NMR signal enhancements that can be exploited for the collection of multi-dimensional NMR spectra, exemplified here by a SABRE-enhanced 2D COSY NMR spectrum.


Radiation-induced sarcoma of the breast.
A small but growing number of radiation-induced sarcomas after breast-conserving surgery for carcinoma have been reported. Because breast-conserving surgery followed by irradiation is becoming increasingly popular, the potential for the emergence of these sarcomas is growing. Unfortunately, because of postirradiation changes in the affected breast, detection of a new lesion can be difficult, resulting in a delay in diagnosis. This case history describes a 48-year-old woman in whom a malignant fibrous histiocytoma was discovered 5 years after she had had a lumpectomy followed by radiation therapy for infiltrating ductal carcinoma. Although the exact mechanism of radiation-induced carcinogenesis is unclear, one theory is discussed. Also discussed are the histologic composition of the malignant fibrous histiocytoma, its latency period, and the best treatment modality for radiation-induced sarcomas.


Symptoms of psychosis in schizophrenia, schizoaffective disorder, and bipolar disorder: A comparison of African Americans and Caucasians in the Genomic Psychiatry Cohort.
Several studies have reported differences between African Americans and Caucasians in relative proportion of psychotic symptoms and disorders, but whether this reflects racial bias in the assessment of psychosis is unclear. The purpose of this study was to examine the distribution of psychotic symptoms and potential bias in symptoms assessed via semi-structured interview using a cohort of 3,389 African American and 5,692 Caucasian participants who were diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder. In this cohort, the diagnosis of schizophrenia was relatively more common, and the diagnosis of bipolar disorder and schizoaffective disorder-bipolar type was less relatively common, among African Americans than Caucasians. With regard to symptoms, relatively more African Americans than Caucasians endorsed hallucinations and delusions symptoms, and this pattern was striking among cases diagnosed with bipolar disorder and schizoaffective-bipolar disorder. In contrast, the relative endorsement of psychotic symptoms was more similar among cases diagnosed with schizophrenia and schizoaffective disorder-depressed type. Differential item function analysis revealed that African Americans with mild psychosis over-endorsed "hallucinations in any modality" and under-endorsed "widespread delusions" relative to Caucasians. Other symptoms did not show evidence of racial bias. Thus, racial bias in assessment of psychotic symptoms does not appear to explain differences in the proportion of symptoms between Caucasians and African Americans. Rather, this may reflect ascertainment bias, perhaps indicative of a disparity in access to services, or differential exposure to risk factors for psychosis by race. © 2015 Wiley Periodicals, Inc.


Drug scene roles and HIV risk.
Drug scenes (social and spatial drug-using and drug-selling environments) have complex role structures. Many drug injectors earn money or drugs as drug or syringe sellers, hit doctors (people who help others to inject) commercial sex workers, or in other roles. This paper aims to measure "role behaviors" of drug injectors; describe which drug injectors are more likely to engage in such role behaviors; and to determine whether roles are related to elements of HIV risk. Cross-sectional study of drug injectors. Bushwick, a section of Brooklyn, New York, a major location for injection drug use and drug sales. Seven hundred and sixty-seven street-recruited drug injectors. Participants were interviewed about their roles, behaviors, socio-demographics and risk networks; sera were collected and assayed for HIV and hepatitis B core antibody. Socio-demographic variables are related to role-holding in complex ways. Economic need is generally associated with engaging in drug-scene role behaviors. Holders of these roles are at greater behavioral and network risk for HIV and other blood-borne infections than are other drug injectors. They also engage in extensive communication with other drug users, including discussion of HIV risk reduction. Role behaviors can be measured in quantitative studies, and seem to be related to HIV risk. Role-holders may be strategic targets for risk-reduction campaigns. It seems feasible and advisable to measure drug scene role-holding in research on drug users.


Triggering receptor expressed on myeloid cells receptor family modulators: a patent review.
Triggering receptor expressed on myeloid cells (TREM) receptors and TREM-like transcript (TLT; or TREML) receptors of the immunoglobulin superfamily are known as key modulators of host immune responses. TREM-1 (CD354) and TREM-2 share the transmembrane adaptor DNAX-activation protein of 12 kDa (DAP12), but they possess separate stimulatory and inhibitory functional roles, especially in myeloid cells. This review covers findings related to TREMs and TLTs published in patent applications from their discovery in 2000 to the present. New roles for TREM-1, TREM-2, TLT-1 and TLT-2 in maladies ranging from acute and chronic inflammatory disorders to cardiovascular diseases and cancers are discussed. Putative endogenous ligands and novel synthetic peptide blockers are also discussed. So far, therapeutic use of activators/blockers specific for TREMs and TLTs has been limited to preclinical animal models. TREM-1 is an immediate therapeutic target for acute and chronic inflammatory conditions, especially sepsis. Certain mutations in DAP12 and TREM-2 manifest into a disorder named polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, and newly identified TREM-2 variants confer a significant increase in risk of developing Alzheimer's disease. This makes TREM-2 an attractive therapeutic target for neurodegenerative diseases.


Age-related differences in working memory deficits during nicotine withdrawal.
Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment-seeking smokers, and explored the moderating influence of age on abstinence-induced alterations in brain activity and performance. Sixty-three smokers participated in two blood oxygen level-dependent (BOLD) functional magnetic resonance imaging scans while performing a visual N-back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time and reduced BOLD signal change in the three a priori regions of interest: medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age × session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged ≥50 years compared with those <50 years old. These results suggest that abstinence effects on neurocognitive function may be more pronounced for younger smokers, and may indicate a new avenue for research exploring mechanisms underlying age differences in smoking cessation success.


Epigenetic changes: the missing link.
The association of rheumatoid arthritis (RA) with a number of genetic risk loci is well established; however, only part of the risk to develop the disease is based on genetics. Environmental factors significantly contribute to the pathogenesis. A gene-environment interaction for smoking and certain major histocompatibility complex (MHC) class II alleles has been shown to promote anti-citrullinated protein antibody (ACPA)-positive RA; however, the molecular mechanisms of interaction remain unclear. In contrast to the genetic background, epigenetic factors are responsive to external stimuli and can modulate gene expression. Therefore, epigenetic mechanisms may function as intermediaries between genetic risk alleles and environmental factors. In this review, epigenetic mechanisms are explained and the evidence for epigenetic changes relevant for the pathogenesis of RA and potential therapeutic applications are discussed.


Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes.
Fibroblast growth factor 23 (FGF23), elevated in chronic renal failure, increases atrial arrhythmogenesis and dysregulates calcium homeostasis. Late sodium currents (INa-Late) critically induces ectopic activity of pulmoanry vein (the most important atrial fibrillation trigger). This study was to investigate whether FGF23 activates the INa-Late leading to calcium dysregulation and increases PV arrhythmogenesis. Patch clamp, western blot, and confocal microscopy were used to evaluate the electrical activities, calcium homeostasis, and mitochondrial reactive oxygen species (ROS) in PV cardiomyocytes with or without FGF23 (0.1 or 1 ng/mL) incubation for 4~6 h. Compared to the control, FGF23 (1 ng/mL, but not 0.1 ng/mL)-treated PV cardiomyocytes had a faster beating rate. FGF23 (1 ng/mL)-treated PV cardiomyocytes had larger INa-Late, calcium transients, and mitochondrial ROS than controls. However, ranolazine (an inhibitor of INa-Late) attenuated FGF23 (1 ng/mL)-increased beating rates, calcium transients and mitochondrial ROS. FGF23 (1 ng/mL)-treated PV cardiomyocytes exhibited larger phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). Chelerythrine chloride (an inhibitor of protein kinase C) decreased INa-Late in FGF23 (1 ng/mL)-treated PV cardiomyocytes. However, KN93 (a selective CaMKII blocker) decreased INa-Late in control and FGF23 (1 ng/mL)-treated PV cardiomyocytes to a similar extent. In conclusion, FGF23 increased PV arrhythmogenesis through sodium and calcium dysregulation by acting protein kinase C signaling.


Film lessons: early cinema for historians of science.
Despite much excellent work over the years, the vast history of scientific filmmaking is still largely unknown. Historians of science have long been concerned with visual culture, communication and the public sphere on the one hand, and with expertise, knowledge production and experimental practice on the other. Scientists, we know, drew pictures, took photographs and made three-dimensional models. Rather like models, films could not be printed in journals until the digital era, and this limited their usefulness as evidence. But that did not stop researchers from making movies for projection at conferences as well as in lecture halls, museums and other public venues, not to mention for breaking down into individual frames for analysis. Historians of science are more likely to be found in the library, archive or museum than the darkened screening room, and much work is still needed to demonstrate the major effects of cinema on scientific knowledge. Film may have taken as long to change science as other areas of social life, but one can begin to glimpse important ways in which 'image machines' (cameras, projectors and the like) were beginning to mediate between backstage experimental work and more public demonstration even around 1900.


Persistent disabling breathlessness in chronic obstructive pulmonary disease.
To determine the prevalence, change in breathlessness status over time, and risk factors for disabling and persistent disabling breathlessness in relation to treatments in chronic obstructive pulmonary disease (COPD). Longitudinal analysis of data from the Swedish National Register of COPD with breathlessness measured using modified Medical Research Council (mMRC) scores at two subsequent visits. Prevalence of disabling breathlessness (mMRC ≥2 at baseline) and persistent disabling breathlessness (disabling breathlessness at baseline and follow-up) was investigated in relation to COPD treatment. Risk factors for disabling breathlessness, change from non-disabling to disabling breathlessness, and persistent disabling breathlessness were analyzed using multiple logistic regression. A total of 1,689 patients were included in the study with a median follow-up of 12 months (interquartile range: 4 months). Prevalence of disabling breathlessness was 54% at baseline. Persistent disabling breathlessness was present in 43% of patients despite treatment and in 74% of patients despite combined inhaled triple therapy and physiotherapy. Risk factors for disabling breathlessness or change to disabling breathlessness were higher age, lower lung function, frequent exacerbations, obesity, heart failure, depression, and hypoxic respiratory failure (all P<0.05). Persistent disabling breathlessness was associated with lower lung function and ischemic heart disease (all P<0.05). Disabling breathlessness is common in COPD despite treatment, which calls for improved symptomatic treatments and consideration of factors influencing disabling breathlessness. Factors influencing disabling breathlessness should be considered for COPD management.


Necrotic complications after nipple- and areola-sparing mastectomy.
The objective was to analyze the frequency and factors influencing necrotic complication in female patients undergoing nipple- and areola-sparing mastectomy. Nipple- and areola-sparing mastectomy has recently been shown to yield satisfactory results in a carefully selected group of breast cancer patients. The technique includes extensive undermining of the nipple-areola complex, which may result in an increased rate of necrotic complications. We report our early experience with necrotic changes after nipple- and areola-sparing mastectomy. The medical records of 38 patients undergoing nipple- and areola-sparing mastectomy were analyzed retrospectively. Mean age of the patient was 44.5 years (range 26-65). Necrotic complications occurred in 15.8% of patients and included: skin flap necrosis (1 case), partial nipple-areola complex necrosis (2 cases), and complete nipple-areola complex necrosis (3 cases). Two cases of capsular contraction were also recorded. Statistical analysis showed age below 45 years to be associated with a lower risk of necrotic complications (OR 4.51, P<0.05). The nipple- and areola-sparing mastectomy, although resulting in a relatively high frequency of necrotic complications, is a valuable surgical option for patients with small, peripheral tumors and for women undergoing prophylactic mastectomy. The procedure seems to be safer for women under 45 years of age.


Poverty identification for a pro-poor health insurance scheme in Tanzania: reliability and multi-level stakeholder perceptions.
Many low income countries have policies to exempt the poor from user charges in public facilities. Reliably identifying the poor is a challenge when implementing such policies. In Tanzania, a scorecard system was established in 2011, within a programme providing free national health insurance fund (NHIF) cards, to identify poor pregnant women and their families, based on eight components. Using a series of reliability tests on a 2012 dataset of 2,621 households in two districts, this study compares household poverty levels using the scorecard, a wealth index, and monthly consumption expenditures. We compared the distributions of the three wealth measures, and the consistency of household poverty classification using cross-tabulations and the Kappa statistic. We measured errors of inclusion and exclusion of the scorecard relative to the other methods. We also gathered perceptions of the scorecard criteria through qualitative interviews with stakeholders at multiple levels of the health system. The distribution of the scorecard was less skewed than other wealth measures and not truncated, but demonstrated clumping. There was a higher level of agreement between the scorecard and the wealth index than consumption expenditure. The scorecard identified a similar number of poor households as the "basic needs" poverty line based on monthly consumption expenditure, with only 45 % errors of inclusion. However, it failed to pick up half of those living below the "basic needs" poverty line as being poor. Stakeholders supported the inclusion of water sources, income, food security and disability measures but had reservations about other items on the scorecard. In choosing poverty identification strategies for programmes seeking to enhance health equity it's necessary to balance between community acceptability, local relevance and the need for such a strategy. It is important to ensure the strategy is efficient and less costly than alternatives in order to effectively reduce health disparities.


Stimulation of Na(+)-K(+)-ATPase by thyrotropin in cultured thyroid follicular cells.
Thyroid-stimulating hormone (TSH; thyrotropin) produces a pleiotropic response in the thyroid gland, accelerating nearly every aspect of metabolic turnover within the follicular epithelia. We examined the effects of TSH on expression of Na(+)-K(+)-ATPase in FRTL-5 cells, a cell line derived from rat thyroid. TSH (10 mU/ml) produced a nearly twofold increase in abundance of the mRNA encoding the catalytic alpha 1-subunit within 6 h of treatment. With the four mRNAs encoding the beta 1-subunit, TSH produced a striking increase in abundance, but this regulation was discoordinate, and some species increased more than others. Similar increases in mRNA abundance were elicited by activators of the adenosine 3',5'-cyclic monophosphate second messenger system. In contrast to the alpha 1- and beta 1-mRNAs, the abundance of the mRNA encoding the beta 2-subunit was unchanged with TSH after 6 h, indicating that the effects of thyrotropin were not universal or indiscriminate. Thyrotropin also caused a 76% increase in Na(+)-K(+)-ATPase activity and a 46% increase in pump-mediated transport after 48 h. These studies suggest that the changes in metabolic turnover initiated by TSH during hormone synthesis include upregulation of the N(+)-K+ pump.


The Resilience Questionnaire for Bipolar Disorder: Development and validation.
The goal of this research project was to develop a new questionnaire to assess resilience in Bipolar Disorder (BD), the Resilience Questionnaire for Bipolar Disorder (RBD). To examine its psychometric properties, a sample of 125 patients diagnosed with BD and a comparison sample of 107 people completed the new RBD and established measures of generic resilience and health-related outcomes. Exploratory factor analysis for the RBD yielded a 23-item 5-factor solution, and confirmatory factor analysis indicated adequate fit indices. Internal consistency, stability, concurrent validation and known-groups' validity were also supported. The RBD obtained higher responsiveness (6-month follow-up) than the generic resilience scale (BD sample). The RBD is a robust measure to monitor resilience in BD.


RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis.
Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P < 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.


Inter-clinic variation in the chances of natural conception of subfertile couples.
Are there differences between clinics in the chances of natural conception of couples? We found significant differences between clinics in the couples' natural conception chances, which could not be explained by differences in characteristics of the patients or the clinics. In pooled data from multiple centers the synthesis prediction model for natural conception was found to be valid, yet the outcome of interest (i.e. natural conception) might differ between centers. Possible differences between clinics in natural conception rates, as well as the validity of the prediction model in each individual clinic are addressed in this paper. A secondary data-analysis of a prospective cohort study among 3020 subfertile couples recruited in 38 clinics in the Netherlands between January 2002 and December 2004. Clinics with less than 20 couples were excluded from the analyses, resulting in 21 clinics with 2916 couples. Inclusion of 2916 subfertile couples who underwent a basic fertility work-up. Couples were excluded who had a fertility disorder (one or two-sided tubal pathology, ovulation disorder, total motile sperm count <3 × 10(6)). Included couples were counseled for expectant management for at least six months or followed until the first day of treatment. Follow-up began at the completion of the fertility work-up. Couples lost to follow-up were censored at the last day of contact. Kaplan-Meier survival curves and a log-rank statistic were estimated. Crude and adjusted hazard ratios were determined, adjusted for patient characteristics and the type of clinic (university hospitals with an assisted conception unit (ACU), non-university hospitals with an ACU and non-university hospitals without an ACU). Hazard ratios were also ascertained with empirical Bayes (EB) estimates. Validation of the prediction model per clinic was performed through calibration. We found significant differences between clinics in the chance of ongoing pregnancy (P < 0.001); even after adjustment for female age, duration of subfertility, percentage of progressive motile sperm, primary/secondary subfertility and post-coital test (P < 0.001). Adjusted hazard ratios and EB estimates ranged from 0.50 to 2.21 and 0.58 to 1.53, respectively. Among the 21 clinics, there were 4 university hospitals, 10 non-university hospitals with an ACU and 7 non-university hospitals without an ACU. In the multivariable analysis, the type of clinic was not significant (P = 0.11). Calibration gave an average intercept of -0.25 (95% range: -1.04-0.53) and average slope of 0.81 (95% range: 0.03-1.60). Six clinics had a negative intercept that differed significantly from zero and three clinics had a negative or positive slope that differed significantly from one. A more extensive model including more predictors could give less variation in the differences between the clinics. Variation in work-up protocol between clinics could also have played a role. In fertility prediction research the Cox proportional hazards regression is the most widely used statistical model, but as the underlying assumptions have rarely been evaluated, this model could lead to biased outcomes. Our findings suggest that the synthesis model to predict natural conception is useful overall in clinical practice but in a minority of clinics the model is not well calibrated. Updating the synthesis model to include a center-specific baseline chance might improve the synthesis model for certain clinics. The study (on which this secondary data-analysis was based) was supported by grant 945/12/002 from ZonMW, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands.


Combination effects of salvianolic acid B with low-dose celecoxib on inhibition of head and neck squamous cell carcinoma growth in vitro and in vivo.
Head and neck squamous cell carcinoma (HNSCC) development is closely associated with inflammation. Cyclooxygenase-2 (COX-2) is an important mediator of inflammation. Therefore, celecoxib, a selective inhibitor of COX-2, was hailed as a promising chemopreventive agent for HNSCC. Dose-dependent cardiac toxicity limits long-term use of celecoxib, but it seems likely that this may be diminished by lowering its dose. We found that salvianolic acid B (Sal-B), isolated from Salvia miltiorrhiza Bge, can effectively suppress COX-2 expression and induce apoptosis in a variety of cancer cell lines. In this study, we report that combination of Sal-B with low-dose celecoxib results in a more pronounced anticancer effect in HNSCC than either agent alone. The combination effects were assessed in four HNSCC cell lines (JHU-06, JHU-011, JHU-013, and JHU-022) by evaluating cell viability, proliferation, and tumor xenograft growth. Cell viability and proliferation were significantly inhibited by both the combined and single-agent treatments. However, the combination treatment significantly enhanced anticancer efficacy in JHU-013 and JHU-022 cell lines compared with the single treatment regimens. A half-dose of daily Sal-B (40 mg/kg/d) and celecoxib (2.5 mg/kg/d) significantly inhibited JHU-013 xenograft growth relative to mice treated with a full dose of Sal-B or celecoxib alone. The combination was associated with profound inhibition of COX-2 and enhanced induction of apoptosis. Taken together, these results strongly suggest that combination of Sal-B, a multifunctional anticancer agent, with low-dose celecoxib holds potential as a new preventive strategy in targeting inflammatory-associated tumor development.


Murine CD14 gene expression in vivo: extramyeloid synthesis and regulation by lipopolysaccharide.
A murine model system was used to study the distribution and regulation of CD14 gene expression in vivo. Western blot analysis failed to detect CD14 in plasma from untreated CB6 (BALB/c x C57Bl6) mice, but showed markedly increased levels of CD14 in plasma from mice treated with lipopolysaccharide (LPS). Plasma levels of CD14 increased in a time- and dose-dependent manner, reaching a maximum between 8 and 16 h. Northern blot analysis of total RNA extracted from mouse tissues revealed low, but significant, levels of CD14 mRNA in many tissues of untreated animals with the highest levels in uterus, adipose tissue, and lung. After intraperitoneal injection of LPS, induction of CD14 gene expression was detected in all organs examined with the extent of induction varying between organs. Induction of CD14 mRNA was both time and dose dependent. Maximum induction in the heart and lung was observed 2-4 h after injection of LPS, while liver and kidney showed maximal induction between 8 and 16 h. In situ hybridization showed that CD14 mRNA was expressed in myeloid cells in many tissues, and that expression in these cells was upregulated by LPS. Unexpectedly, CD14 mRNA was also detected in other cells within tissues, including epithelial cells, and expression in these cell types also was upregulated by LPS. Immunochemical analysis revealed that CD14 antigen colocalized to the cytoplasm of cells expressing CD14 mRNA. These studies demonstrate that CD14 gene expression is not restricted to myeloid cells, and that the level of expression of CD14 is influenced by exposure to LPS.


A complete collection of single-gene deletion mutants of Acinetobacter baylyi ADP1.
We have constructed a collection of single-gene deletion mutants for all dispensable genes of the soil bacterium Acinetobacter baylyi ADP1. A total of 2594 deletion mutants were obtained, whereas 499 (16%) were not, and are therefore candidate essential genes for life on minimal medium. This essentiality data set is 88% consistent with the Escherichia coli data set inferred from the Keio mutant collection profiled for growth on minimal medium, while 80% of the orthologous genes described as essential in Pseudomonas aeruginosa are also essential in ADP1. Several strategies were undertaken to investigate ADP1 metabolism by (1) searching for discrepancies between our essentiality data and current metabolic knowledge, (2) comparing this essentiality data set to those from other organisms, (3) systematic phenotyping of the mutant collection on a variety of carbon sources (quinate, 2-3 butanediol, glucose, etc.). This collection provides a new resource for the study of gene function by forward and reverse genetic approaches and constitutes a robust experimental data source for systems biology approaches.


The single-payer option: a reconsideration.
This article discusses some of the merits and demerits of the single-payer model of health care financing, with particular reference to the English National Health Service (NHS). Specifically, it is argued that the main merits are that the model can directly provide universal health care coverage, thus eradicating or at least alleviating market failure and equity concerns, and that it can achieve this with relatively low total health care expenditure in general and -- as compared to the commercial multiple insurance model -- low administrative costs in particular. A perceived demerit of the single-payer model is that it can lead to excessive health care rationing, particularly in terms of waiting times, although it is argued here that long waits are probably caused by insufficient funding rather than by the single-payer model per se. Moreover, rationing of one form or another occurs in all health care systems, and single-payer models may be the best option if the aim is to incorporate structured rationing such that an entire population is subject to the same rules and is thus treated equitably. A further perceived disadvantage of the single-payer model is that it offers limited choice, which is necessarily true with respect to choice of insurer, but choice of provider can be, and increasingly is, a feature of centrally tax-financed health care systems. No model of health care funding is perfect; trade-offs are inevitable. Whether the merits of the single-payer model are judged to outweigh the demerits will typically vary both across countries at any point in time and within a country over time.


Energy and standardized ileal amino Acid digestibilities of chinese distillers dried grains, produced from different regions and grains fed to growing pigs.
Two experiments were conducted to determine the digestibility of crude protein (CP), amino acids and energy in three Chinese corn distillers dried grains with solubles (DDGS), one rice DDGS, one American corn DDGS and one American high protein distillers dried grains (HP-DDG). In Exp. 1, the apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of CP and amino acids in the six samples were determined using cannulated barrows (initial BW: 43.3±1.7 kg). In Exp. 2, the digestible energy (DE) and metabolizable energy (ME) content of these six samples were determined using crossbred barrows (initial BW: 46.0±2.5 kg). The results of the two experiments indicated that Chinese corn DDGS is generally similar to American DDGS in chemical composition, digestibility of amino acids, DE and ME. However, Chinese DDGS had a lower Lys concentration (0.50% vs. 0.74%) and SID Lys (52.3% vs. 57.0%, p<0.01). The DE and ME values in Chinese corn DDGS were 3,427 and 3,306 kcal/kg, respectively. Rice DDGS had a similar DE and ME (3,363 and 3,228 kcal/kg) but higher Lys concentration (0.64% vs. 0.50%) to corn DDGS, while the SID of Lys was quite low (61.8%, p<0.01). HP-DDG had high value of SID of Lys, DE and ME (79.8%, 3,899 and 3,746 kcal/kg). In conclusion, except for a lower Lys concentrations and availability, the chemical composition, digestibility of amino acids, DE and ME values in Chinese corn DDGS are similar to American corn DDGS. Additionally, the rice DDGS had lower Lys content and digestible Lys values than that in corn DDGS. Thirdly, HP-DDG has higher levels of digestible amino acids and energy than DDGS.


Knowledge and practice of clinical ethics among healthcare providers in a government hospital, Chennai.
The growing public concern about the ethical conduct of healthcare professionals highlights the need to incorporate clinical ethics in medical education. This study examined the knowledge and practice of clinical ethics among healthcare providers in a government hospital in Chennai. A sample of 51 treating physicians and 58 other non-physician service providers from the hospital answered a self-administered, semi-structured questionnaire on their knowledge of and adherence to ethical principles, and the problems they faced related to healthcare ethics. More than 30% did not give a definition of healthcare ethics, and 40% did not name a single ethical principle. 51% stated that they witnessed ethical problems in their settings and named patient dissatisfaction, gender bias by provider, and not maintaining confidentiality. The responses of healthcare providers to various ethical scenarios are reported.


Spectral interference of frequency-shifted solitons in a photonic-crystal fiber.
Frequency-shifted solitons in a highly nonlinear photonic-crystal fiber (PCF) are shown to give rise to high-visibility interference fringes in PCF output spectra, indicating flat spectral phase profiles of individual solitons in the PCF output. This experimental finding, supported by numerical simulations, suggests a promising method of fiber-format pulse shaping and an attractive technology for few-cycle pulse synthesis through a coherent addition of frequency-shifted solitons generated in a highly nonlinear fiber.


Clinical assessment of postural stability following vestibular nerve section.
Little is known about the recovery of postural control in patients following acute vestibular loss. This paper reports on the results of moving-platform posturography to assess the recovery of postural stability in 24 patients following vestibular nerve section. Posturography was abnormal prior to surgery in 17% of the patients. Seven days following surgery, 44% of the patients demonstrated vestibular deficit patterns, while 56% of the patients had normal posturography. Posturography was normal in all patients 1 month following surgery. Abnormal posturography was subsequently noted in 21% of the patients between 3 and 20 months following surgery. Each of the patients with abnormal preoperative posturography subsequently demonstrated abnormal late postoperative posturography. These results suggest that perioperative posturography may be useful in the evaluation and counseling of patients considering ablative vestibular surgery.


Pneumocystis carinii pneumonia and respiratory failure in AIDS. Improved outcomes and increased use of intensive care units.
To determine whether the outcome of intensive care for patients with AIDS, Pneumocystis carinii pneumonia (PCP), and respiratory failure has changed, we studied patients admitted to the intensive care units an San Francisco General Hospital from 1981 to 1988. We compared the course of patients with PCP and respiratory failure admitted to the intensive care unit from 1986 to 1988 with a similar cohort hospitalized from 1981 to 1985. The hospital survival rate for the 35 patients in the 1986 to 1988 cohort was 40%, compared with 14% for the 42 patients in the 1981 to 1985 cohort (p less than 0.01). Age, episode of PCP, time since AIDS diagnosis, anti-PCP therapy, and important clinical variables were similar in both cohorts. Corticosteroids were used commonly in the recent era. Patients who received steroids had an in-hospital survival rate of 46%, compared with 22% for those who did not receive steroids (p = NS). In a stepwise logistic regression model, ICU care in the recent era and higher serum albumin at the time of ICU admission were the only variables significantly associated with survival. The hospital survival of patients with PCP and respiratory failure has improved. The improvement could not be explained by patient selection or by better anti-PCP therapy. The apparent beneficial effect of corticosteroids deserves further study. The improvement in ICU outcome was reflected in increased ICU utilization by patients with AIDS, PCP, and respiratory failure.


Otolaryngology fantastica: the ear, nose, and throat manifestations of Munchausen's syndrome.
Munchausen's syndrome (MS) is a form of severe, chronic, factitious disorder with physical symptoms. Some essential features define MS, such as recurrent, feigned, or simulated illness; peregrination (traveling or wandering); pseudologia fantastica; and drug abuse. Munchausen's syndrome by proxy (MSBP) classically involves a parent or other caregiver who inflicts injury or induces illness in a child. The aim of the present study was to summarize and study the main ear, nose, and throat (ENT) manifestations of MS and MSBP. A systematic literature review carried out in a tertiary university referral center. An appropriate string was run on PubMed to retrieve articles dealing with ENT manifestations of MS and MSBP. A double cross-check was performed on citations and full-text articles found using selected inclusion and exclusion criteria. In total, 24 articles were finally included in the study, describing 30 cases of MS or MSBP involving the ENT region; 15/30 (50%) cases involved the face, most often presenting as facial pain or facial swelling; and 7/30 (23.3%) cases presented with symptoms involving the ear. Six cases out of 30 (20%) were MSBP. MS and MSBP may present with symptoms involving the head and neck area, particularly the face and external ear canal. The ENT specialist should suspect MS in patients with strange and long-lasting symptoms, so as to avoid misdiagnosis and unnecessary treatments that waste time and money in the healthcare sector.


Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.
Somatic loss of wild-type alleles can produce disease traits such as neoplasia. Conversely, somatic loss of disease-causing mutations can revert phenotypes; however, these events are infrequently observed. Here we show that ichthyosis with confetti, a severe, sporadic skin disease in humans, is associated with thousands of revertant clones of normal skin that arise from loss of heterozygosity on chromosome 17q via mitotic recombination. This allowed us to map and identify disease-causing mutations in the gene encoding keratin 10 (KRT10); all result in frameshifts into the same alternative reading frame, producing an arginine-rich C-terminal peptide that redirects keratin 10 from the cytokeratin filament network to the nucleolus. The high frequency of somatic reversion in ichthyosis with confetti suggests that revertant stem cell clones are under strong positive selection and/or that the rate of mitotic recombination is elevated in individuals with this disorder.


A graphene oxide-based enzyme-free signal amplification platform for homogeneous DNA detection.
A graphene oxide (GO) based enzyme-free signal amplification platform for homogeneous DNA sensing is developed with simplicity and high sensitivity. In the absence of the target DNA, labeled hairpin probe 1 (H1) and probe 2 (H2) were adsorbed on the surface of GO, resulting in the fluorescence quenching of the dyes and minimizing the background fluorescence. The addition of the target DNA facilitated the formation of double-stranded DNA (dsDNA) between H1 and H2, causing the probes to separate from GO and release the target DNA through a strand displacement reaction. Meanwhile, the whole reaction started anew. This is an excellent isothermal signal amplification technique without the involvement of enzymes. By monitoring the change of the fluorescence intensity, the target DNA not only can be determined in buffer solution, but also can be detected in 1% serum solution spiked with a series of concentrations of the target DNA. In addition, the consumption amount of the probes in this method is lower than that in traditional molecular beacon methods.


Studies on the motility of the foraminifera. I. Ultrastructure of the reticulopodial network of Allogromia laticollaris (Arnold).
Allogromia laticollaris, a benthic marine foraminifer, extends numerous trunk filopodia that repeatedly branch, anastomose, and fuse again to form the reticulopodial network (RPN), within which an incessant streaming of cytoplasmic particles occurs. The motion of the particles is saltatory and bidirectional, even in the thinnest filopodia detected by optical microscopy. Fibrils are visible by differential interference microscopy, and the PRN displays positive birefringence in polarized light. These fibrils remain intact after lysis and extraction of the RPN in solutions that stabilize microtubules (MTs). Electron micrographs of thin sections through these lysed and stabilized cytoskeletal models reveal bundles of MTs. The RPNs of living Allogromia may be preserved by standard EM fixatives only after acclimatization to calcium-free seawater, in which the streaming is normal. The MTs in the RPN are typically arranged in bundles that generally lie parallel to the long axis of the trunk and branch filopodia. Stereo electron micrographs of whole-mount, fixed, and critical-point-dried organisms show that the complex pattern of MT deployment reflects the pattern of particle motion in both flattened and highly branched portions of the RPN. Cytoplasmic particles, some of which have a fuzzy coat, are closely associated with, and preferentially oriented along, either single MTs or MT bundles. Thin filaments (approximately 5 nm) are also observed within the network, lying parallel to and interdigitating with the MTs, and in flattened terminal areas of the filopodia. These filaments do not bind skeletal muscle myosin S1 under conditions that heavily decorate actin filaments in controls (human blood platelets), and are approximately 20% too thin to be identified ultrastructurally as F-actin.


Mortality and morbidity of stairlift injuries: Analysis of the UK TARN database.
To investigate the incidence and pattern of injury in patients with a diagnosis of a fall from a stairlift. Data was analysed from the Trauma Audit and Research Network (TARN) database from 2000 to 2018 for those recorded suffering stairlift related injuries between the ages of 40-100 years. Patient demographics, injury mechanism and pattern, mortality rate and height of fall were analysed. 1069 patients were identified in the initial search with 651 having an eligible mechanism of injury. The mean age was 82 (range 41.4-100.1) years. The most common site of injury was the limbs (49.2%) with the most severe injuries to the head (mean AIS 3.1). The mean ISS was 12.5 (Range 1-75). There was no relationship between height of fall and ISS (rs 0.054 p = 0.4). Individuals were 78% more likely to have an ISS score of 15 or more if they had a head injury, (OR: 0.12; 95% CI: 0.06-0.24) and 79% more likely to have sustained an injury to the thorax (OR: 0.21; 95% CI: 0.11-0.41). Injury to the head was 95% more likely in individuals with an ISS score greater than 25 points or more (OR: 0.05; 95% CI: 0.01-0.16) and 69% more likely for those who sustain injury to the thorax. Individuals with an ISS score of 25 points or more were 18 times more likely to have sustained injury getting off their stair lift compared to any other method of falling from their stair lift. Mortality was associated with injuries to the thorax in those aged 70 years or below, injuries to the face, spine and limb for those aged 71-85 years and with head injury in those over 85 years. The overall mortality rate was 15.7%. Falls from stairlifts commonly result in limb injuries and most severe injuries are sustained to the head. When patients fall getting off from astairlift, have injuries to their head or thorax they have a higher ISS. The overall mortality is 15.7%. Given the increasing use of stairlifts in our ageing population, strategies should be considered to make these safer.


Surface state engineering of molecule-molecule interactions.
Engineering the electronic structure of organics through interface manipulation, particularly the interface dipole and the barriers to charge carrier injection, is of essential importance to improve organic devices. This requires the meticulous fabrication of desired organic structures by precisely controlling the interactions between molecules. The well-known principles of organic coordination chemistry cannot be applied without proper consideration of extra molecular hybridization, charge transfer and dipole formation at the interfaces. Here we identify the interplay between energy level alignment, charge transfer, surface dipole and charge pillow effect and show how these effects collectively determine the net force between adsorbed porphyrin 2H-TPP on Cu(111). We show that the forces between supported porphyrins can be altered by controlling the amount of charge transferred across the interface accurately through the relative alignment of molecular electronic levels with respect to the Shockley surface state of the metal substrate, and hence govern the self-assembly of the molecules.


Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review.
Cerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult. To address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization. The FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.


Sociodemographic, psychological, and lifestyle characteristics are associated with a liking for salty and sweet tastes in French adults.
Various studies have shown that sensory liking influences dietary behavior and that individual characteristics are related to food intake and weight status, but little is known about individual profiles associated with salt and sweet liking. The aim of the present study was to investigate the association between a liking for salty and sweet tastes (i.e., a liking for foods rich in salt or sugar and preferred amounts of salt or sugar seasoning in foods) and sociodemographic, psychological, and lifestyle characteristics in a large sample. Individual factors and liking scores were collected by validated questionnaires from 37,181 French adults participating in the NutriNet-Santé study, a large web-based observational cohort launched in 2009 that studies relations between nutrition and health. The associations were assessed by multivariable multinomial logistic regression models adjusted for socioeconomic, anthropometric, and health variables. In both genders, with increasing age, individuals were more likely to have a high salt liking (men, OR: 1.24; 95% CI: 1.18, 1.30; women, OR: 1.14, 95% CI: 1.09, 1.19), whereas they were less likely to have a strong sweet liking (men, OR: 0.87; 95% CI: 0.83, 0.91; women, OR: 0.66; 95% CI: 0.64, 0.68). Current smokers (men, OR: 2.30; 95% CI: 1.90, 2.78; women, OR: 1.50; 95% CI: 1.36, 1.66) and heavy drinkers (men, OR: 2.92; 95% CI: 2.37, 3.58; women, OR: 2.57, 95% CI: 2.22, 2.98) were more likely to like salt than nonsmokers and alcohol abstainers. Regarding the sweet taste, women smokers were less likely to like sweets (OR: 0.80; 95% CI: 0.72, 0.89). Highly uncontrolled eaters [men, OR: 2.39; 95% CI: 2.04, 2.80; women, OR: 2.22; 95% CI: 1.99, 2.47) and highly emotional women (OR: 1.35; 95% CI: 1.18, 1.55) were more likely to have a high liking for sweets than slightly uncontrolled eaters and nonemotional eaters, whereas those with high cognitive restraint (men, OR: 0.39; 95% CI: 0.33, 0.46; women, OR: 0.55; 95% CI: 0.50, 0.60) and former weight-loss dieters (men, OR: 0.60; 95% CI: 0.52, 0.70; women, OR: 0.68; 95% CI: 0.62, 0.73) were less likely to have a strong sweet liking compared with those with low cognitive restraint and never-dieters. An unhealthy lifestyle that includes smoking and alcohol consumption may influence salt liking, and eating behavior may have an impact on sweet liking. Further research is needed to study the influence of individual factors and sensory liking on dietary intake and weight status. This study was registered at the European Clinical Trials Database as 2013-000929-31.


Plague outbreaks in prairie dog populations explained by percolation thresholds of alternate host abundance.
Highly lethal pathogens (e.g., hantaviruses, hendra virus, anthrax, or plague) pose unique public-health problems, because they seem to periodically flare into outbreaks before disappearing into long quiescent phases. A key element to their possible control and eradication is being able to understand where they persist in the latent phase and how to identify the conditions that result in sporadic epidemics or epizootics. In American grasslands, plague, caused by Yersinia pestis, exemplifies this quiescent-outbreak pattern, because it sporadically erupts in epizootics that decimate prairie dog (Cynomys ludovicianus) colonies, yet the causes of outbreaks and mechanisms for interepizootic persistence of this disease are poorly understood. Using field data on prairie community ecology, flea behavior, and plague-transmission biology, we find that plague can persist in prairie-dog colonies for prolonged periods, because host movement is highly spatially constrained. The abundance of an alternate host for disease vectors, the grasshopper mouse (Onychomys leucogaster), drives plague outbreaks by increasing the connectivity of the prairie dog hosts and therefore, permitting percolation of the disease throughout the primary host population. These results offer an alternative perspective on plague's ecology (i.e., disease transmission exacerbated by alternative hosts) and may have ramifications for plague dynamics in Asia and Africa, where a single main host has traditionally been considered to drive Yersinia ecology. Furthermore, abundance thresholds of alternate hosts may be a key phenomenon determining outbreaks of disease in many multihost-disease systems.


The association of health-related fitness with indicators of academic performance in Texas schools.
This study examined the associations between indicators of health-related physical fitness (cardiovascular fitness and body mass index) and academic performance (Texas Assessment of Knowledge and Skills). Partial correlations were generally stronger for cardiovascular fitness than body mass index and consistently stronger in the middle school grades. Mixed-model regression analyses revealed modest associations between fitness and academic achievement after controlling for potentially confounding variables. The effects of fitness on academic achievement were positive but small. A separate logistic regression analysis indicated that higher fitness rates increased the odds of schools achieving exemplary/recognized school status within the state. School fitness attainment is an indicator of higher performing schools. Direction of causality cannot be inferred due to the cross-sectional nature of the data.


Crucial role for neuronal nitric oxide synthase in early microcirculatory derangement and recipient survival following murine pancreas transplantation.
Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation. Tetrahydrobiopterin donor treatment has been shown to specifically attenuate these derangements following pancreas transplantation, and tetrahydrobiopterin-mediated protective effects to rely on its NOS-cofactor activity, rather than on its antioxidant capacity. However, the NOS-isoform mainly involved in this process has still to be defined. Using a murine pancreas transplantation model, grafts lacking one of the three NOS-isoforms were compared to grafts from wild-type controls. Donors were treated with either tetrahydrobiopterin or remained untreated. All grafts were subjected to 16 h cold ischemia time and transplanted into wild-type recipients. Following 4 h graft reperfusion, microcirculation was analysed by confocal intravital fluorescence microscopy. Recipient survival was monitored for 50 days. Transplantation of the pancreas from untreated wild-type donor mice resulted in microcirculatory damage of the transplanted graft and no recipient survived more than 72 h. Transplanting grafts from untreated donor mice lacking either endothelial or inducible NOS led to similar outcomes. In contrast, donor treatment with tetrahydrobiopterin prevented microcirculatory breakdown enabling long-term survival. Sole exception was transplantation of grafts from untreated donor mice lacking neuronal NOS. It resulted in intact microvascular structure and long-term recipient survival, either if donor mice were untreated or treated with tetrahydrobiopterin. We demonstrate for the first time the crucial involvement of neuronal NOS in early microcirculatory derangements following solid organ transplantation. In this model, protective effects of tetrahydrobiopterin are mediated by targeting this isoform.


Prediction and validation of total and regional fat mass by B-mode ultrasound in Japanese pre-pubertal children.
The present study was performed to develop regression-based prediction equations for fat mass by ultrasound in Japanese children and to investigate the validity of these equations. A total of 127 healthy Japanese pre-pubertal children aged 6-12 years were randomly separated into two groups: the model development group (fifty-four boys and forty-four girls) and the validation group (eighteen boys and eleven girls). Total body, trunk, arm and leg fat masses were initially determined by dual-energy X-ray absorptiometry (DXA, Delphi A-QDR whole-body scanner; Hologic, Inc., Bedford, MA, USA). Then, fat thickness was measured by B-mode ultrasound (5 MHz scanning head) at nine sites (arm: lateral forearm, anterior and posterior upper arm; trunk: abdomen and subscapular; leg: anterior and posterior thigh, anterior and posterior lower leg). Regression analyses were used to describe the relationships between the site-matched fat masses (total body, arm, trunk and leg) obtained by DXA and ultrasound in the development group. When these fat mass prediction equations were applied to the validation group, the measured total and regional fat mass was very similar to the predicted fat mass (mean difference calculated as predicted - measured fat mass ± 2 SD; total body 0·1 (SD 0·5) kg, arm 0·1 (SD 0·3) kg, trunk - 0·1 (SD 0·3) kg, leg 0·1 (SD 0·5) kg for boys; total body 0·5 (SD 1·3) kg, arm 0·0 (SD 0·3) kg, trunk 0·1 (SD 0·8) kg, leg 0·3 (SD 0·6) kg for girls), and the Bland-Altman analysis did not indicate a bias. These results suggest that ultrasound-derived prediction equations for boys and girls are useful for estimating total and regional fat mass.


Effect of wall-molecule interactions on electrokinetic transport of charged molecules in nanofluidic channels during FET flow control.
The interactions between charged molecules and channel surfaces are expected to significantly influence the electrokinetic transport of molecules and their separations in nanochannels. This study reports the effect of wall-molecule interactions on flow control of negatively charged Alexa 488 and positively charged Rhodamine B dye molecules in an array of nanochannels (100 nm wx 500 nm dx 14 mm l) embedded in fluidic field effect transistors (FETs). For FET flow control, a third electrical potential, known as a gate bias, is applied to the channel walls to manipulate their zeta-potential. Electroosmotic flow of charged dye molecules is accelerated or reversed according to the polarity and magnitude of the gate bias. During FET flow control, we monitor how the electrostatic interaction between charged dye molecules and channel walls affects the apparent velocity of molecules, using laser-scanning confocal fluorescence microscopy. We observe that the changes in flow speed and direction of negatively charged Alexa 488 is much more pronounced than that of positively charged Rhodamine B in response to the gate bias that causes either repulsive or attractive electrostatic interactions. This observation is supported by calculations of concentration-weighted velocity profiles of the two dye molecules during FET flow control. The velocity profile of negatively charged Alexa 488 is much more pronounced at the center of each nanochannel than near its walls since Alexa 488 molecules are repelled from negatively charged channel walls. This pronounced center velocity further responds to the gate bias, increasing the average velocity by as much as 23% when -30 V is applied to the gate (zeta-potential = -80.6 mV). In contrast, the velocity profile of positively charged Rhodamine B is dispersed over the entire channel width due to dye-wall attraction and adsorption. Our experimental observations and calculations support the hypothesis that valence-charge-dependent electrostatic interaction and its manipulation by the gate bias would enhance molecular separations of differentially charged molecules in nanofluidic FETs.


Left Ventricular Diastolic Function Studied with Magnetic Resonance Imaging: A Systematic Review of Techniques and Relation to Established Measures of Diastolic Function.
Purpose: In recent years, cardiac magnetic resonance (CMR) has been used to assess LV diastolic function. In this systematic review, studies were identified where CMR parameters had been evaluated in healthy and/or patient groups with proven diastolic dysfunction or known to develop heart failure with preserved ejection fraction. We aimed at describing the parameters most often used, thresholds where possible, and correlation to echocardiographic and invasive measurements. Methods and results: A systematic literature review was performed using the databases of PubMed, Embase, and Cochrane. In total, 3808 articles were screened, and 102 studies were included. Four main CMR techniques were identified: tagging; time/volume curves; mitral inflow quantification with velocity-encoded phase-contrast sequences; and feature tracking. Techniques were described and estimates were presented in tables. From published studies, peak change of torsion shear angle versus volume changes in early diastole (-dφ'/dV') (from tagging analysis), early peak filling rate indexed to LV end-diastolic volume <2.1 s-1 (from LV time-volume curve analysis), enlarged LA maximal volume >52 mL/m2, lowered LA total (<40%), and lowered LA passive emptying fractions (<16%) seem to be reliable measures of LV diastolic dysfunction. Feature tracking, especially of the atrium, shows promise but is still a novel technique. Conclusion: CMR techniques of LV untwisting and early filling and LA measures of poor emptying are promising for the diagnosis of LV filling impairment, but further research in long-term follow-up studies is needed to assess the ability for the parameters to predict patient related outcomes.


Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values.
The assumption that the assessment of forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) does not provide additional information in asthmatic children with normal FEV(1) percent predicted has not been adequately tested. We sought to determine whether the measurement of FEF(25-75) percent predicted offers advantages over FEV(1) percent predicted and FEV(1)/forced vital capacity (FVC) percent predicted for the evaluation of childhood asthma. This is a secondary analysis of data from the Pediatric Asthma Controller Trial and the Characterizing the Response to a Leukotriene Receptor Antagonist and Inhaled Corticosteroid trials. Pearson correlation coefficients, Pearson partial correlation coefficients, canonical correlations, and receiver operating characteristic (ROC) curves were constructed. Among 437 children with normal FEV(1) percent predicted, FEF(25-75) percent predicted, and FEV(1)/FVC percent predicted were (1) positively correlated with log(2) methacholine PC(20), (2) positively correlated with morning and evening peak expiratory flow percent predicted, and (3) negatively correlated with log(10) fraction of exhaled nitric oxide and bronchodilator responsiveness. Pearson partial correlations and canonical correlations indicated that FEF(25-75) percent predicted was better correlated with bronchodilator responsiveness and log(2) methacholine PC(20) than were FEV(1) percent predicted or FEV(1)/FVC percent predicted. In the ROC curve analysis, FEF(25-75) at 65% of predicted value had a 90% sensitivity and a 67% specificity for detecting a 20% increase in FEV(1) after albuterol inhalation. FEF(25-75) percent predicted was well correlated with bronchodilator responsiveness in asthmatic children with normal FEV(1). FEF(25-75) percent predicted should be evaluated in clinical studies of asthma in children and might be of use in predicting the presence of clinically relevant reversible airflow obstruction.


Rectal screening displays high negative predictive value for bloodstream infection with (ESBL-producing) Gram-negative bacteria in neonates with suspected sepsis in a low-resource setting neonatal care unit.
We analysed the concordance of rectal swab isolates and blood culture for Gram-negative bacteria (GNB) isolates in neonates with a suspicion of neonatal sepsis admitted to a neonatal care unit in Haiti. We matched pairs of blood and rectal samples taken on the date of suspected sepsis onset in the same neonate. We calculated the proportion of rectal isolates in concordance with the blood isolates by species and genus. We calculated the negative predictive value (NPV) for GNB and extended-spectrum β-lactamase (ESBL)-producing GNB for all rectal and blood isolate pairs in neonates with suspected sepsis. We identified 238 blood and rectal samples pairs, with 238 blood isolate results and 309 rectal isolate results. The overall concordance in genus and species between blood and rectal isolates was 22.3% [95% confidence interval (CI) 17.4-28.0%] and 20.6% (95% CI 16.0-26.2%), respectively. The highest concordance between blood and rectal isolates was observed for samples with no bacterial growth (65%), followed byKlebsiella pneumoniae (18%) and Klebsiella oxytoca (12%). The NPV of detecting GNB bacterial isolates in rectal samples compared with those in blood samples was 81.6% and the NPV for ESBL-positive GNB was 92.6%. The NPV of rectal swab GNB isolates was high in all patient groups and was even higher for ESBL-positive GNB. Clinicians can use the results from rectal swabs when taken simultaneously with blood samples during outbreaks to inform the (de-)escalation of antibiotic therapy in those neonates that have an ongoing sepsis profile.


Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity.
The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It has been suggested that this system of thermogenesis can provide a defense against obesity. To test this idea, we created a transgenic mouse in which the fat-specific aP2 gene promoter directed Ucp expression in white fat and provided for the constitutive expression of Ucp in brown fat. Transgenic mice showed both Ucp mRNA and immunoreactive UCP in white fat at 2-10% the level normally measured in brown fat. A reduction in subcutaneous fat of aP2-Ucp C57BL/6J mice was observed at 3 mo of age. When the transgene was expressed in Avy genetically obese mice reductions in total body weight and subcutaneous fat stores were observed. Female transgenic Avy mice at 13 mo of age weighed 35 grams, a weight indistinguishable from nontransgenic C57BL/6J mice. Gonadal fat showed an increase in a novel adipocyte derivative that did not accumulate lipids and that constituted approximately 80% of the mass of the tissue in Avy transgenic. A major effect of aP2-Ucp in brown fat was to reduce endogenous gene expression by as much as 95%. The results suggest that UCP synthesized from the aP2 gene promoter is thermogenically active and capable of reducing fat stores.


Cost of maternal health services in low and middle-income countries: protocol for a systematic review.
There is substantial evidence that maternal health services across the continuum of care are effective in reducing morbidities and mortalities associated with pregnancy and childbirth. There is also consensus regarding the need to invest in the delivery of these services towards the global goal of achieving Universal Health Coverage in low/middle-income countries (LMICs). However, there is limited evidence on the costs of providing these services. This protocol describes the methods and analytical framework to be used in conducting a systematic review of costs of providing maternal health services in LMICs. African Journal Online, CINAHL Plus, EconLit, Embase, Global Health Archive, Popline, PubMed and Scopus as well as grey literature databases will be searched for relevant articles which report primary cost data for maternal health service in LMICs published from January 2000 to June 2019. This search will be conducted without implementing any language restrictions. Two reviewers will independently search, screen and select articles that meet the inclusion criteria, with disagreements resolved by discussions with a third reviewer. Quality assessment of included articles will be conducted based on cost-focused criteria included in globally recommended checklists for economic evaluations. For comparability, where feasible, cost will be converted to international dollar equivalents using purchasing power parity conversion factors. Costs associated with providing each maternal health services will be systematically compared, using a subgroup analysis. Sensitivity analysis will also be conducted. Where heterogeneity is observed, a narrative synthesis will be used. Population contextual and intervention design characteristics that help achieve cost savings and improve efficiency of maternal health service provision in LMICs will be identified. Ethical approval is not required for this review. The plan for dissemination is to publish review findings in a peer-reviewed journal and present findings at high-level conferences that engage the most pertinent stakeholders. CRD42018114124.


Glucocorticosteroids for viral hepatitis C.
Hepatitis C virus may cause liver inflammation and fibrosis. It is not known whether glucocorticosteroids are beneficial or harmful for patients with hepatitis C infection. The objectives were to evaluate the beneficial and harmful effects of glucocorticosteroids for patients with acute or chronic hepatitis C infection with or without hepatitis C related autoimmune disorders. Searches of The Cochrane Hepato-Biliary Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of relevant articles and hand searches of relevant journals were performed in July 2003. Principal authors of clinical trials were approached. Randomised clinical trials dealing with glucocorticosteroids for viral hepatitis C - acute or chronic with or without autoimmune disorders. Data were extracted by one reviewer and validated by another. Further information was sought by correspondence with the principal investigator of the trial in case the relevant data were not published. Disagreements were solved by discussion before the meta-analysis. Eight trials randomised 384 patients with chronic hepatitis C to glucocorticosteroids plus interferon versus interferon plus placebo/no intervention, glucocorticosteroids versus interferon, or glucocorticosteroids versus placebo. Glucocorticosteroids treatment given as short pre-treatment followed by interferon or as long-term parallel treatment combined with interferon versus interferon monotherapy had no significant effect on mortality (no deaths occurred; 342 patients), virological response at six months follow-up (RR 0.85; 95% CI 0.52 to 1.38; 38 patients), or biochemical response at six months follow-up (RR 0.95; 95% CI 0.84 to 1.06; 307 patients). There was no significant difference in serious adverse events between combination therapy versus interferon monotherapy (RR 4.76; 95% CI 0.24 to 93.19; 342 patients). Glucocorticosteroids versus interferon had no significant effect on mortality (RR 2.33; 95% CI 0.27 to 17.80; 13 patients) or virological response at follow-up (RR 1.17; 95% CI 0.86 to 1.58; 13 patients). We found no trials on glucocorticosteroids for acute hepatitis C. There is insufficient evidence neither to confirm nor exclude both beneficial and harmful effects of glucocorticosteroids for chronic hepatitis C with or without autoimmune disorders. This Review is not able to rule out potential serious adverse effects of glucocorticosteroids. Therefore, this Review cannot establish whether glucocorticosteroids treatment can be safely administrated for indications requiring glucocorticosteroids without analysing for hepatitis C virus. The effect of glucocorticosteroids for acute hepatitis C has not been examined in randomised trials.


New tools for the quantitative assessment of prodrug delivery and neurotoxicity.
Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: (1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and (2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, ND(PXL), is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined ND(PXL) with a traceable beacon, ND(PB), yielding ND(PXL)-ND(PB) that functions as a theranostic compound. In vivo fluorescence FRET imaging of this theranostic platform was used to confirm localized delivery to tumors and to assess the efficiency of drug delivery to tumors, achieving 25-30% activation in the tumors of an immunocompetent mouse model of breast cancer. In this model, ND-drug exhibited anti-tumor efficacy comparable to nab-paclitaxel, a clinical formulation. In addition, we combined neurobehavioral metrics of nociception and sensorimotor performance of individual mice to develop a novel composite toxicity score that reveals and quantifies peripheral neurotoxicity, a debilitating long-term systemic toxicity of paclitaxel therapy. Importantly, mice treated with nab-paclitaxel developed changes in behavioral metrics with significantly higher toxicity scores indicative of peripheral neuropathy, while mice treated with ND(PXL) showed no significant changes in behavioral responses or toxicity score. Our ND formulation was designed to be readily adaptable to incorporate different drugs, imaging modalities and/or targeting motifs. This formulation has significant potential for preclinical and clinical tools across multiple disease states. The studies presented here report a novel toxicity score for assessing peripheral neuropathy and demonstrate that our targeted, theranostic NDs are safe and effective, providing localized tumor delivery of a chemotherapeutic and with reduced common neurotoxic side-effects.


CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells.
Compaction and looping of the ~2.5-Mb Igh locus during V(D)J rearrangement is essential to allow all V(H) genes to be brought in proximity with D(H)-J(H) segments to create a diverse antibody repertoire, but the proteins directly responsible for this are unknown. Because CCCTC-binding factor (CTCF) has been demonstrated to be involved in long-range chromosomal interactions, we hypothesized that CTCF may promote the contraction of the Igh locus. ChIP sequencing was performed on pro-B cells, revealing colocalization of CTCF and Rad21 binding at ~60 sites throughout the V(H) region and 2 other sites within the Igh locus. These numerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement. To test whether CTCF was involved in locus compaction, we used 3D-FISH to measure compaction in pro-B cells transduced with CTCF shRNA retroviruses. Reduction of CTCF binding resulted in a decrease in Igh locus compaction. Long-range interactions within the Igh locus were measured with the chromosomal conformation capture assay, revealing direct interactions between CTCF sites 5' of DFL16 and the 3' regulatory region, and also the intronic enhancer (Eμ), creating a D(H)-J(H)-Eμ-C(H) domain. Knockdown of CTCF also resulted in the increase of antisense transcription throughout the D(H) region and parts of the V(H) locus, suggesting a widespread regulatory role for CTCF. Together, our findings demonstrate that CTCF plays an important role in the 3D structure of the Igh locus and in the regulation of antisense germline transcription and that it contributes to the compaction of the Igh locus.


Adductor canal block in combination with posterior capsular infiltration on the pain control after TKA.
Adductor canal block (ACB) and local infiltration anesthesia (LIA) are both widely accepted techniques for postoperative pain control without quadriceps weakness after total knee arthroplasty (TKA). However, the above techniques are insufficient in efficacy or duration. The aim of our study was to address whether ACB plus posterior capsular infiltration (PCI) result in improved analgesia compared with ACB or LIA in patients underwent TKA during 48 h after operation. Sixty patients were included: ACB group (group A, ACB with 0.375% ropivacaine 30 ml, n = 20), ACB + PCI group (group B, ACB same as group A, PCI with 0.2% ropivacaine 50 ml, n = 20), LIA group (group C, local infiltration with 0.2% ropivacaine 100 ml, n = 20). VAS pain scores, rescue analgesic tramadol consumption, nausea and vomiting occurrence, and patient satisfaction were recorded at 4, 8, 24, and 48 h post-operation. Group B, versus group A, had lower pain scores (at rest and during mobilization) at 4 to 8 h post-operation (P < 0.017). As compared with group C, only at 24 h post-operation, group B had statistically decreased rest and active pain scores (p = 0.016 and 0.014, respectively). There were no statistical differences in total tramadol consumption and nausea and vomiting occurrence among the three groups. However, there was improved patient satisfaction in group B. Overall, as compared with ACB or LIA, ACB plus PCI appeared to provide more ideal analgesia and patient satisfaction in the first 24 h after operation.


Evaluation of the potential effects of ingredients added to cigarettes. Part 3: in vitro genotoxicity and cytotoxicity.
Cigarette mainstream smoke from blended cigarettes with and without the addition of ingredients was assayed for its cytotoxicity and genotoxicity. In total, 333 ingredients commonly used in cigarette manufacturing were assigned to three different groups. Each group of ingredients was added at a low and a high level to the test cigarettes. The mutagenicity of the particulate phase of the resulting cigarette smoke was assayed in the Salmonella plate incorporation (Ames) assay with tester strains TA98, TA100, TA102, TA1535 and TA1537. The cytotoxicity of the gas/vapor phase and the particulate phase was determined in the neutral red uptake assay with mouse embryo BALB/c 3T3 cells. Within the sensitivity and specificity of the test systems, the in vitro mutagenicity and cytotoxicity of the cigarette smoke were not increased by the addition of the ingredients.


Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers.
Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITEcomb for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8-42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7-8.9% even when treatment was started in middle age.


Rehabilitation in practice: Hemispatial neglect: approaches to rehabilitation.
This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee consistently demonstrates a knowledge of the pathophysiology of various specific impairments including cognitive dysfunction including perception' and 'management approaches for specific impairments including cognitive dysfunction including perception'. The article focuses on hemispatial neglect as a common and difficult to manage problem in clinical practice.