History of federal legislation for persons with disabilities.
This paper discusses federal legislation relating to persons with disabilities and it divides into 13 areas. Several areas of legislation, such as education and basic education, have a long history beginning with World War I. Laws related to other areas, such as federal support for developing technology, have been adopted only within the past 5 years. The Americans With Disabilities Act of 1990 (ADA) (Public Law 101-336), which guarantees civil rights to Americans with disabilities, has five titles, and each is summarized. Although the ADA provides for Americans with disabilities to be included in American society, it has some major limitations, including the lack of an affirmative action requirement and of provisions for the education and training of persons with disabilities so that they can qualify for employment. Several of the federal laws related to persons with disabilities have affected the field of occupational therapy either favorably or adversely. The conclusion is drawn that occupational therapists need to be alert to pending legislation to promote the role of occupational therapy in serving persons with disabilities.


MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.
Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity.


PI3K/Akt and MAPK pathways evoke activation of FoxO transcription factor to undergo neuronal apoptosis in brain of the silkworm Bombyx mori (Lepidoptera: Bombycidae).
The Forkhead box O (FoxO) transcription factors, including FoxO1, FoxO3a, FoxO4, and FoxO6, are implicated in the regulation of cell apoptosis and survival. Here, we examined the role of FoxO transcription factors and the involvement of the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways in neuronal apoptosis in the brain of the silkworm Bombyx mori following starvation. Starvation inhibited cell proliferation and induced apoptosis through caspase-3 activation. The level of phosphorylated kinase Akt increased when the animals ceased feeding. Starvation conditions reduced extracellular-signal-regulated kinase phosphorylation but increased both c-Jun N-terminal kinase and p38 (MAPK) phosphorylation. FoxO1 and FoxO3a were simultaneously localized in the nuclei. These results provide new insights into the process of apoptosis of brain neurons through the involvement of FoxO transcription factors following starvation of insect species.


One- and two-center physical space partitioning of the energy in the density functional theory.
A conceptually new approach is introduced for the decomposition of the molecular energy calculated at the density functional theory level of theory into sum of one- and two-atomic energy components, and is realized in the "fuzzy atoms" framework. (Fuzzy atoms mean that the three-dimensional physical space is divided into atomic regions having no sharp boundaries but exhibiting a continuous transition from one to another.) The new scheme uses the new concept of "bond order density" to calculate the diatomic exchange energy components and gives them unexpectedly close to the values calculated by the exact (Hartree-Fock) exchange for the same Kohn-Sham orbitals.


Xenohybrid Bone Graft Containing Intrinsically Disordered Proteins Shows Enhanced In Vitro Bone Formation.
Bone defects are a significant health problem worldwide, as bone is the second-most transplanted tissue after blood. Although a myriad of bone grafts (BGs) have been used to treat bone repairs, none of them possesses all the desirable characteristics. An approach to improve BGs is to add bio-active components, however often difficult as BG production may disrupt the biological activities of such molecules. Here, we present a composite xenohybrid BG, SmartBonePep, with a type of biomolecule inspired by intrinsically disordered proteins (IDPs). These synthetic peptides (named P2 and P6) are physically entrapped into the polymer matrix of the composite BG. The effects of SmartBonePep on human osteoblasts were tested. Results showed that SmartBonePep enhanced proliferation and osteogenic effects. In order to verify the bioactivity of P2 and P6, these peptides were tested indirectly by being added to cell culture media too. Here, P2 or P6 exhibited promoting effects on osteogenic-related gene expressions. In this study, we showed highly effective osteoinductive synthetic peptides P2 or P6, which possess proline-rich and intrinsically disordered structural characters. This use of IDPs may provide promising bone enhancement biomolecules for clinical usage.


Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells.
The calcium-sensing receptor (CaSR)-specific allosteric modulator cinacalcet has revolutionized the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. However, its application is limited to patients with end-stage renal disease because of hypocalcemic side effects presumably caused by CaSR-mediated calcitonin secretion from thyroid parafollicular C-cells. These hypocalcemic side effects might be dampened by compounds that bias the signaling of CaSR, causing similar therapeutic effects as cinacalcet without stimulating calcitonin secretion. Because biased signaling of CaSR is poorly understood, the objective of the present study was to investigate biased signaling of CaSR by using rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. By doing concentration-response experiments we focused on the ability of two well known CaSR agonists, calcium and strontium, to activate six different signaling entities: G(q/11) signaling, G(i/o) signaling, G(s) signaling, extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, intracellular calcium ([Ca(2+)](i)) mobilization, and calcitonin secretion. The experiments showed that strontium biases CaSR signaling toward ERK1/2 signaling and possibly another pathway independent of G(q/11) signaling and [Ca(2+)](i) mobilization. It is noteworthy that the potency of strontium-stimulated calcitonin secretion was elevated compared with calcium. Combining these results with experiments investigating signaling pathway components involved in calcitonin secretion, we found that the enhanced potency of strontium-mediated calcitonin secretion was caused by a different signaling pattern than that produced by calcium. Together, our results suggest that calcitonin secretion can be affected by CaSR-stimulated signaling bias, which may be used to develop novel drugs for the treatment of secondary hyperparathyroidism.


The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool.
Notch signaling is critical for osteoblastic differentiation; however, the specific contribution of individual Notch ligands is unknown. Parathyroid hormone (PTH) regulates the Notch ligand Jagged1 in osteoblastic cells. To determine if osteolineage Jagged1 contributes to bone homeostasis, selective deletion of Jagged1 in osteolineage cells was achieved through the presence of Prx1 promoter-driven Cre recombinase expression, targeting mesenchymal stem cells (MSCs) and their progeny (PJag1 mice). PJag1 mice were viable and fertile and did not exhibit any skeletal abnormalities at 2 weeks of age. At 2 months of age, however, PJag1 mice had increased trabecular bone mass compared to wild-type (WT) littermates. Dynamic histomorphometric analysis showed increased osteoblastic activity and increased mineral apposition rate. Immunohistochemical analysis showed increased numbers of osteocalcin-positive mature osteoblasts in PJag1 mice. Also increased phenotypically defined Lin- /CD45- /CD31- /Sca1- /CD51+ osteoblastic cells were measured by flow cytometric analysis. Surprisingly, phenotypically defined Lin- /CD45- /CD31- /Sca1+ /CD51+ MSCs were unchanged in PJag1 mice as measured by flow cytometric analysis. However, functional osteoprogenitor (OP) cell frequency, measured by Von Kossa+ colony formation, was decreased, suggesting that osteolineage Jagged1 contributes to maintenance of the OP pool. The trabecular bone increases were not due to osteoclastic defects, because PJag1 mice had increased bone resorption. Because PTH increases osteoblastic Jagged1, we sought to understand if osteolineage Jagged1 modulates PTH-mediated bone anabolism. Intermittent PTH treatment resulted in a significantly greater increase in BV/TV in PJag1 hind limbs compared to WT. These findings demonstrate a critical role of osteolineage Jagged1 in bone homeostasis, where Jagged1 maintains the transition of OP to maturing osteoblasts. This novel role of Jagged1 not only identifies a regulatory loop maintaining appropriate populations of osteolineage cells, but also provides a novel approach to increase trabecular bone mass, particularly in combination with PTH, through modulation of Jagged1. © 2017 American Society for Bone and Mineral Research.


Late acute rejection after liver transplantation impacts patient survival.
Hepatic allograft rejection still remains an important problem following liver transplantation. Early acute rejection, occurring within three months of transplant, is a common event and usually of lesser significance with respect to prognosis than other non-immune-related post-transplant morbidities. However, little is known about late acute rejection (LAR) including factors affecting its occurrence and long-term outcome. In this study, we analyzed LAR including the incidence, clinical risk factors, patient survival, and graft survival. LAR was defined as acute cellular rejection later than six months after liver transplant. Adult patients who had a minimum of 24 months of graft survival were included in this study. A total of 1604 case records of consecutive adult patients (over age 18 yr) who underwent liver transplant between 1985 and 2003 were reviewed. Of the 1604 patients, 305 (19.0%) developed LAR. Patients with primary diagnoses of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis had higher incidences of LAR, while patients with metabolic disease and retransplant had lower incidence of LAR (p = 0.0024). The LAR group had more female and younger recipients than the no LAR group (p = 0.0026, p = 0.0131, respectively). Patient survival as well as graft survival were significantly lower in the LAR group (p = 0.0083, p = 0.0075, respectively). PTLD was the only significant independent predictor of late rejection. The careful management and treatment of PTLD, especially immunosuppressive management, is important to prevent LAR, which is related to poorer patient survival.


Ultralow fouling zwitterionic polymers grafted from surfaces covered with an initiator via an adhesive mussel mimetic linkage.
In this work, nonfouling zwitterionic polymers were grafted via surface-initiated atom transfer radical polymerization (ATRP) from surfaces covered with an adhesive catechol initiator. The catechol initiator was attached to both bare gold and amino-functionalized surfaces, and the nonfouling performances of the resulting polymer brushes were compared. Under optimal conditions, ultralow protein adsorption from both single-protein solutions of fibrinogen and lysozyme and complex media of 10% blood serum and 100% blood plasma/serum was achieved. Furthermore, the 3-day accumulation of Pseudomonas aeruginosa on the treated glass surfaces was studied in situ using a laminar flow chamber. The results showed that these zwitterionic coatings dramatically reduced the biofilm formation of P. aeruginosa as compared to the reference bare glass.


Elevation of efficacy of cancer vaccine combined with interferon and inducer of endogeneous interferon synthesis amixin.
To study in vivo efficacy of combined administration of cancer vaccine (CV), interferon (IFN) and inducer of endogenous IFN - amixin. Sarcoma-37 cells were transplanted to female Balb/c mice. For the treatment, CV prepared from sarcoma-37 cells with the use of cytotoxic lectines from B. subtilis B-7025, murine IFN and amixin or their combinations were used. IFN production, content of circulating immune complexes and level of specific IgG antibodies in blood serum were determined by standard immunologic methods. Using solid form of sarcoma-37 it has been shown that introduction of IFN and amixin significantly elevated efficacy of vaccine therapy, in particular index of tumor growth inhibition reach 89.2% and 81.7%. Upon combined use of CV and IFN or CV and amixin (25 mg/kg) respectively. Significant prolongation of average life span of the animals treated with CV and IFN or CV and amixin (25 mg/kg) has been registered (up to 92.7 -/+ 10.4 and 95.0 -/+ 6.2 days respectively, vs 46.8 -/+ 1.5 days for control animals). Obtained results have shown expediency of the development of schemes for combined introduction of CV with exogenous IFN, and with inducer of endogenous IFN (amixin) for elevation of efficacy of vaccine therapy.


Aging Impairs Whole-Body Heat Loss in Women under Both Dry and Humid Heat Stress.
This study was designed to determine whether age-related impairments in whole-body heat loss, which are known to exist in dry heat, also occur in humid heat in women. To evaluate this possibility, 10 young (25 ± 4 yr) and 10 older (51 ± 7 yr) women matched for body surface area (young, 1.69 ± 0.11; older, 1.76 ± 0.14 m, P = 0.21) and peak oxygen consumption (V˙O2peak) (young, 38.6 ± 4.6; older, 34.8 ± 6.6 mL·kg·min, P = 0.15) performed four 15-min bouts of cycling at a fixed metabolic heat production rate (300 W; equivalent to ~45% V˙O2peak), each separated by a 15-min recovery, in dry (35°C, 20% relative humidity) and humid heat (35°C, 60% relative humidity). Total heat loss (evaporative ± dry heat exchange) and metabolic heat production were measured using direct and indirect calorimetry, respectively. Body heat storage was measured as the temporal summation of heat production and loss. Total heat loss was lower in humid conditions compared with dry conditions during all exercise bouts in both groups (all P < 0.05), resulting in 49% and 39% greater body heat storage in young and older women, respectively (both P < 0.01). Total heat loss was also lower in older women compared with young women during exercise bouts 1, 2 and 3 in dry heat (all P < 0.05) and bouts 1 and 2 in humid heat (both P < 0.05). Consequently, body heat storage was 29% and 16% greater in older women compared with young women in dry and humid conditions, respectively (both P < 0.05). Increasing ambient humidity reduces heat loss capacity in young and older women. However, older women display impaired heat loss relative to young women in both dry and humid heat, and may therefore be at greater risk of heat-related injury during light-to-moderate activity.


Raspberry seed flour attenuates high-sucrose diet-mediated hepatic stress and adipose tissue inflammation.
Chronic intake of high sucrose (HS) diet exacerbates high-fat (HF) diet-induced obesity and its associated metabolic complications. Previously, we have demonstrated that ellagic acid (EA), an abundant polyphenol found in some fruits and nuts, exerts distinct lipid-lowering characteristics in hepatocytes and adipocytes. In this study, we hypothesized that EA supplementation inhibits HS diet-mediated hepatic toxicity and its accompanied metabolic dysregulation. To test this hypothesis, C57BL/6 male mice were randomly assigned to three isocaloric HF diets (41% calories from fat) containing either no-sucrose (HF), high-sucrose (HFHS), or high-sucrose plus EA (HFHS-R) from raspberry seed flour (RSF, equivalent to 0.03% of EA), and fed for 12weeks. The inclusion of EA from RSF significantly improved HFHS diet-mediated dyslipidemia and restored glucose homeostasis levels similar to the HF diet-fed mice. Despite marginal difference in hepatic triglyceride content, the addition of EA substantially reversed the activation of endoplasmic reticulum (ER) stress and oxidative damage triggered by HFHS diet in the liver. These effects of EA were further confirmed in human hepatoma cells by reducing ER stress and reactive oxygen species (ROS) production. Moreover, HFHS-R diet significantly decreased visceral adipocyte hypertrophy and adipose tissue inflammation evidenced by reduced proinflammatory gene expression and macrophage infiltration. In summary, EA supplementation from RSF was effective in reducing HFHS diet-mediated metabolic complication by attenuating hepatic ER and oxidative stresses as well as adipocyte inflammation. Our results suggest that the inclusion of EA in diets may normalize metabolic insults triggered by HS consumption.


A public health timeline to prepare for COVID-19 vaccines in Canada.
For control of COVID-19, community immunity is required, necessitating widespread immunization. COVID-19 vaccines are coming to Canada, with the government announcing in August 2020 agreements with four different companies for their COVID-19 vaccine if their trials are successful. Never before has public health had to rapidly develop a vaccine introduction program for multiple new but differing vaccines with the added pressure that the program is needed across all ages and in all Canadian communities and there is high probability of not enough vaccine to go around at the start. Traditional public health vaccine introduction planning will need to be both accelerated and more comprehensive to ensure optimal uptake across the country. This overview highlights a number of points for consideration by public health in their planning for COVID-19 vaccines before these COVID-19 vaccines are available, once they are available, once supplies are plentiful, and throughout the vaccine program. Targeted and tailored communications are key elements needed to reach and positively influence diverse communities, regions, ages, languages, education levels and lived experiences.


Histone deacetylase activity is required for Botrylloides leachii whole-body regeneration.
The colonial tunicate Botrylloides leachii is exceptional at regenerating from a piece of vascular tunic after loss of all adults from the colony. Previous transcriptome analyses indicate a brief period of healing before regeneration of a new adult (zooid) in as little as 8-10 days. However, there is little understanding of how the resulting changes to gene expression, required to drive regeneration, are initiated and how the overall process is regulated. Rapid changes to transcription often occur in response to chromatin changes, mediated by histone modifications such as histone acetylation. Here, we investigated a group of key epigenetic modifiers, histone deacetylases (HDAC), which are known to play an important role in many biological processes such as development, healing and regeneration. Through our transcriptome data, we identified and quantified the expression levels of HDAC and histone acetyltransferase enzymes during whole-body regeneration (WBR). To determine whether HDAC activity is required for WBR, we inhibited its action using valproic acid and trichostatin A. HDAC inhibition prevented the final morphological changes normally associated with WBR and resulted in aberrant gene expression. Botrylloides leachii genes including Slit2, TGF-β, Piwi and Fzd4 all showed altered mRNA levels upon HDAC inhibition in comparison with the control samples. Additionally, atypical expression of Bl_Piwi was found in immunocytes upon HDAC inhibition. Together, these results show that HDAC function, specifically HDAC I/IIa class enzymes, are vital for B. leachii to undergo WBR successfully.


Amyloidogenic potential of foie gras.
The human cerebral and systemic amyloidoses and prion-associated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck- or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses.


Emergency department nurse's attitudes towards patients who self-harm: A meta-analysis.
Self-harm is a major challenge to public health. Emergency department (ED) nurses treat significant proportions of patients with self-harm injuries, and positive therapeutic patient-nurse interactions are imperative to the physical and psychological outcome of this vulnerable patient group. Research, both nationally and internationally, suggests that treating those with self-harm injuries is emotionally challenging, and ambivalence, powerlessness, and ineffectiveness are commonly manifested in negative attitudes towards these patients. Following the PRISMA guidelines, this systematic review with meta-analyses examined the attitudes of ED nurses towards patients who self-harm, based on currently available evidence. The following databases were searched: CINAHL complete; Medline complete; PsycARTICLES; PsycINFO; The Allied and Complementary Medicine Database; Health Source: Nursing/Academic Edition; PsycEXTRA; and Psychology and Behavioural Sciences Collection. Clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant reports to identify additional studies, were also searched. Five studies were included in the meta-analysis. The Self-Harm Antipathy Scale (SHAS) was used as an outcome in two studies appropriate for meta-analysis. The Attitudes Towards Deliberate Self-Harm Questionnaire (ADSHQ) scale was used as an outcome in three studies appropriate for meta-analysis. Results demonstrated limited empathy and negativity towards patients who self-harm, indicating a requirement for education and supervision of ED staff, where the SHAS or the ADSHQ can be used to monitor attitude change. Self-harm educational content for ED staff should include areas of knowledge building including explanations and causes of self-harm; range, forms, and functions of self-harm; staff responses to self-harm; assessment, management, and interventions; professional practice issues.


Production of type II collagen specific monoclonal antibodies.
Immunoassays are used for the specific measurement of type II collagen, a major cartilage protein, which is lost in osteoarthritic joints. Poor immunogenicity and species dependent immune response to type II collagen make it difficult to obtain specific antibodies required for immunoassay development. In addition, type II collagen antibodies exhibit reactivity to structurally dissimilar antigens such as actin, myoglobin, thyroglobulin and ssDNA, complicating the isolation of specific antibodies. It is therefore necessary to characterize the antibody reactivity against both noncollagenous antigens and different collagen types. In this study, immune response to type II collagen was improved by conjugation to carrier proteins, KLH and BSA. Hybridomas were generated by fusions of lymphocytes derived from lymph nodes or spleens with X63-653-Ag8 myeloma cells. Compared to spleens, the utilization of lymph nodes as a source of lymphocytes resulted in a 23% higher number of hybridomas secreting type II collagen antibodies. Hybridomas secreting polyreactive antibodies were identified based on their reactivity to thyroglobulin and eliminated. Extensive testing of the remaining monoclonal antibodies with other structurally dissimilar antigens and various types of collagen for reactivity, allowed us to isolate specific monoclonal antibodies to type II collagen. We emphasize the importance of characterization of the reactivity of type II collagen monoclonal antibodies before employing them for immunoassays.


Early Medical Complications and Delayed Discharge after Spinopelvic Fusion: A Comparative Analysis of 887 NSQIP Cases from 2006 to 2016.
The effect of pelvic fixation on postoperative medical complications, blood transfusion, length of hospital stay, and discharge disposition is poorly understood. Determining factors that predispose patients to increased complications after spinopelvic fusion will help surgeons to plan these complex procedures and optimize patients preoperatively. We conducted a retrospective cohort study using data from the ACS-NSQIP database between 2006 and 2016 of patients who underwent lumbar fusion with and without spinopelvic fixation. Data regarding demographics, complications, hospital stay, and discharge disposition were collected. A total of 57,417 (98.5%) cases of lumbar fusion without spinopelvic fixation (LF) and 887 (1.5%) cases of lumbar fusion with spinopelvic fixation (SPF) were analyzed. The transfusion rate in the SPF group was 59.3% vs 13% in the LF group (p < 0.001). The mean length of stay (LOS) and discharge to skilled nursing facility (SNF) were significantly different (LOS: SPF 6.5 days vs LF 3.5 days p < 0.001; SNF: SPF 21.3% vs LF 10.4% p < 0.001). After controlling for demographic differences, the overall complication rates were not significantly different between the groups (p = 0.531). The odds ratio for transfusion in the SPF group was 2.9 (p < 0.001). The odds ratio for increased LOS and increased care discharge disposition were elevated in the SPF group (LOS OR: 1.3, p < 0.012, Discharge disposition OR: 1.8, p < 0.001). Patients who underwent SPF had increased complications, transfusion rate, LOS, and discharge to SNF or subacute rehab facilities as compared with patients who underwent LF. SPF remains an effective technique for achieving lumbosacral arthrodesis. Surgeons should consider the implications of the associated complication profile for SPF and the value of preoperative optimization in a select cohort of patients.


NK cells propagate T cell immunity following in situ tumor vaccination.
We report an in situ vaccination, adaptable to nearly any type of cancer, that combines radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and interleukin-2 (IL-2; 3xTx). In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8+ T cell effector polyfunctionality. This suggests the potential for 3xTx to promote antitumor immunity against metastatic tumors. In poorly immunogenic syngeneic murine melanoma or head and neck carcinoma models, 3xTx stimulates CD8+ T cell-mediated antitumor responses at targeted and non-targeted tumors. During 3xTx treatment, natural killer (NK) cells promote CTLA4+ regulatory T cell (Treg) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases Treg infiltration, diminishing CD8+ T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8+ T cell immunity following 3xTx.


Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness.
Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration-response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.


Ultrastructural analysis of IpaD at the tip of the nascent MxiH type III secretion apparatus of Shigella flexneri.
Shigella flexneri is a Gram-negative enteric pathogen that is the predominant cause of bacillary dysentery. Shigella uses a type III secretion system to deliver effector proteins that alter normal target cell functions to promote pathogen invasion. The type III secretion apparatus (T3SA) consists of a basal body, an extracellular needle, and a tip complex that is responsible for delivering effectors into the host cell cytoplasm. IpaD [Ipa (invasion plasmid antigen)] is the first protein to localize to the T3SA needle tip, where it prevents premature effector secretion and serves as an environmental sensor for triggering recruitment of the translocator protein IpaB to the needle tip. Thus, IpaD would be expected to form a stable structure whose overall architecture supports its functions. It is not immediately obvious from the published IpaD crystal structure (Protein Data Bank ID 2j0o) how a multimer of IpaD would be incorporated at the tip of the first static T3SA intermediate, nor what its functional role would be in building a mature T3SA. Here, we produce three-dimensional reconstructions from transmission electron microscopy images of IpaD localized at the Shigella T3SA needle tip for comparison to needle tips from a Shigella ipaD-null mutant. The results demonstrate that IpaD resides as a homopentamer at the needle tip of the T3SA. Furthermore, comparison to tips assembled from the distal domain IpaD(Δ192-267) mutation shows that IpaD adopts an elongated conformation that facilitates its ability to control type III secretion and stepwise assembly of the T3SA needle tip complex.


Shedding LIGHT (TNFSF14) on the tumor microenvironment of colorectal cancer liver metastases.
T-cell infiltration in primary colon tumors is associated with improved patient survival. Preliminary data supports a similar association in colorectal liver metastases (CRLM), and we previously identified increased CRLM expression of the immunostimulatory cytokine LIGHT (TNFSF14) to be related to improved patient prognosis. Therefore, mechanisms to augment the T-cell response in CRLM may be a promising treatment modality, however, the tumor immune microenvironment and LIGHT expression in CRLM remains to be characterized. Utilizing a syngeneic and immunocompetent model of CRLM, the immune microenvironment was characterized for lymphocyte phenotype, function, and location utilizing flow cytometry, immunoassays, and immunofluorescence microscopy. CD3+ and CD4+ lymphocytes were decreased, and CD8+ cells were increased in CRLM compared to control liver. When present, greater populations of tumor infiltrating lymphocytes (TIL) were found peritumoral than intratumoral. The TIL expressed significantly higher levels of CD69 and CD107a, but lower levels of LIGHT. Cytokine expression profiles revealed increased levels of the T-helper 1 (Th1) cytokines IFN gamma, IL-12, IL-1b, and IL-8 in CRLM compared to control liver tissue. There was no difference in T-helper 2 (Th2) cytokines between the groups. Characterization of the tumor microenvironment of CRLM revealed that although a limited number of activated T-cells infiltrate the tumor and initiate an immune response, the number of LIGHT + T cells infiltrating the tumor were very low. Techniques to decrease suppressive influences or augment the cytotoxic T-cell response are needed and may be possible through mechanisms that can increase intratumoral TIL LIGHT expression.


Partial mastectomy with axillary lymph node dissection and radiotherapy as a new treatment modality of breast cancer (I).
This is the first preliminary report among two consecutive papers. Partial mastectomy(PM), axillary lymph node dissection(AD) and radiotherapy (RT) were performed on seventeen operable breast cancer patients who had been admitted from April 1991 to March 1992 to the department of surgery, Yongdong Severance Hospital for improved cosmetic appearance and better survival rate. Of seventeen patients, 47% were T1 lesion and 76% were stage I and II. Extensive intraductal component(EIC) within or around the tumor was also analyzed. Twenty nine per cent of the patients were EIC positive. The mean number of axillary lymph nodes was 21.5 after PM with AD and 20.5 after mastectomy. For radiotherapy, 4,500 rad was delivered to the breast parenchyma and 1,600 rad of boost to the primary tumor site using the electron beam method after surgery. All patients have since been living well without any local recurrence and were satisfied with breast preservation for the one-year follow-up period. We concluded that the PM, AD and RT can be another surgical treatment modality of breast cancer. A longer follow-up data will be followed on the second paper.


Diode-pumped Kerr-lens mode-locked Yb:KY(WO(4))(2) laser.
A self-starting Kerr-lens mode-locked Yb:KY(WO(4))(2) laser directly end pumped by two 1.6-W diodes is demonstrated for what is to our knowledge the first time. Pulses as short as 71 fs with 120-mW average output power, at a center wavelength of 1057 nm, were obtained at a repetition rate of 110 MHz. A 10-nm tuning range was achieved with longer pulses and higher average output power.


Amerindian mitochondrial DNA haplogroups predominate in the population of Argentina: towards a first nationwide forensic mitochondrial DNA sequence database.
The study presents South American mitochondrial DNA (mtDNA) data from selected north (N = 98), central (N = 193) and south (N = 47) Argentinean populations. Sequence analysis of the complete mtDNA control region (CR, 16024-576) resulted in 288 unique haplotypes ignoring C-insertions around positions 16193, 309, and 573; the additional analysis of coding region single nucleotide polymorphisms enabled a fine classification of the described lineages. The Amerindian haplogroups were most frequent in the north and south representing more than 60% of the sequences. A slightly different situation was observed in central Argentina where the Amerindian haplogroups represented less than 50%, and the European contribution was more relevant. Particular clades of the Amerindian subhaplogroups turned out to be nearly region-specific. A minor contribution of African lineages was observed throughout the country. This comprehensive admixture of worldwide mtDNA lineages and the regional specificity of certain clades in the Argentinean population underscore the necessity of carefully selecting regional samples in order to develop a nationwide mtDNA database for forensic and anthropological purposes. The mtDNA sequencing and analysis were performed under EMPOP guidelines in order to attain high quality for the mtDNA database.


Quantifying urbanization as a risk factor for noncommunicable disease.
The aim of this study was to investigate the poorly understood relationship between the process of urbanization and noncommunicable diseases (NCDs) in Sri Lanka using a multicomponent, quantitative measure of urbanicity. NCD prevalence data were taken from the Sri Lankan Diabetes and Cardiovascular Study, comprising a representative sample of people from seven of the nine provinces in Sri Lanka (n = 4,485/5,000; response rate = 89.7%). We constructed a measure of the urban environment for seven areas using a 7-item scale based on data from study clusters to develop an "urbanicity" scale. The items were population size, population density, and access to markets, transportation, communications/media, economic factors, environment/sanitation, health, education, and housing quality. Linear and logistic regression models were constructed to examine the relationship between urbanicity and chronic disease risk factors. Among men, urbanicity was positively associated with physical inactivity (odds ratio [OR] = 3.22; 2.27-4.57), high body mass index (OR = 2.45; 95% CI, 1.88-3.20) and diabetes mellitus (OR = 2.44; 95% CI, 1.66-3.57). Among women, too, urbanicity was positively associated with physical inactivity (OR = 2.29; 95% CI, 1.64-3.21), high body mass index (OR = 2.92; 95% CI, 2.41-3.55), and diabetes mellitus (OR = 2.10; 95% CI, 1.58 - 2.80). There is a clear relationship between urbanicity and common modifiable risk factors for chronic disease in a representative sample of Sri Lankan adults.


Presence of contagious yawning in children with autism spectrum disorder.
Most previous studies suggest diminished susceptibility to contagious yawning in children with autism spectrum disorder (ASD). However, it could be driven by their atypical attention to the face. To test this hypothesis, children with ASD and typically developing (TD) children were shown yawning and control movies. To ensure participants' attention to the face, an eye tracker controlled the onset of the yawning and control stimuli. Results demonstrated that both TD children and children with ASD yawned more frequently when they watched the yawning stimuli than the control stimuli. It is suggested therefore that the absence of contagious yawning in children with ASD, as reported in previous studies, might relate to their weaker tendency to spontaneously attend to others' faces.


Differential trends in cigarette smoking in the USA: is menthol slowing progress?
Mentholated cigarettes are at least as dangerous to an individual's health as non-mentholated varieties. The addition of menthol to cigarettes reduces perceived harshness of smoke, which can facilitate initiation. Here, we examine correlates of menthol use, national trends in smoking menthol and non-menthol cigarettes, and brand preferences over time. We estimated menthol cigarette use during 2004-2010 using annual data on persons ≥12 years old from the National Surveys on Drug Use and Health. We adjusted self-reported menthol status for selected brands that were either exclusively menthol or non-menthol, based on sales data. Data were weighted to provide national estimates. Among cigarette smokers, menthol cigarette use was more common among 12-17 year olds (56.7%) and 18-25 year olds (45.0%) than among older persons (range 30.5% to 34.7%). In a multivariable analysis, menthol use was associated with being younger, female and of non-Caucasian race/ethnicity. Among all adolescents, the percentage who smoked non-menthol cigarettes decreased from 2004-2010, while menthol smoking rates remained constant; among all young adults, the percentage who smoked non-menthol cigarettes also declined, while menthol smoking rates increased. The use of Camel menthol and Marlboro menthol increased among adolescent and young adult smokers, particularly non-Hispanic Caucasians, during the study period. Young people are heavy consumers of mentholated cigarettes. Progress in reducing youth smoking has likely been attenuated by the sale and marketing of mentholated cigarettes, including emerging varieties of established youth brands. This study should inform the Food and Drug Administration regarding the potential public health impact of a menthol ban.


The success rate and safety of internal jugular vein cannulation using anatomical landmark technique in patients undergoing cardiothoracic surgery.
Landmark-guided internal jugular vein (IJV) cannulation is a basic procedure, which every anesthetist is expected to acquire. A successful first attempt is desirable as each attempt increases the risk of complications. The present study is an analysis of 976 IJV cannulations performed in adults undergoing cardiothoracic surgery. The IJV was cannulated with a triple lumen catheter using the anatomical landmarks. The following data were recorded: Patient demographics, age, sex, body mass index, diagnosis, operative procedure, operator (resident/consultant), site of cannulation (central approach, right IJV, left IJV, external jugular vein), number of attempts and duration of cannulation, length of insertion of the catheter, number of correct placements on X-ray and any complications. The success rate of IJV cannulation was 100%. In 809 (82.9%) patients, cannulation was performed in the first attempt. Residents performed 792 cannulations and the consultants performed 184 cannulations. In 767 patients, the residents were successful in inserting the catheter and in 25 they failed after 5 attempts, hence, they were cannulated by the consultant. The time taken for insertion of the catheter was 6.89 ± 3.2 minutes. Carotid artery puncture was the most common complication, it occurred in 22 (2.3%) patients. IJV cannulation with landmark technique is highly successful with minimal complications in the adult patients undergoing cardiothoracic surgery. Basic training of cannulating the IJV by landmark technique should be imparted to all the traines as ultrasound may not be available in all locations.


Emergency use of the Airtraq laryngoscope in traumatic asphyxia: case report.
This case report describes the emergency use of a novel, single-use, anatomically shaped laryngoscope that has recently become commercially available in the UK (Airtraq, Prodol Meditec, Spain). It was used to successfully intubate a severely injured 41-year-old patient who had sustained traumatic asphyxia after attempting suicide by hanging. He was bleeding into his upper airway, necessitating regular suctioning. The patient underwent an emergency rapid sequence intubation at the scene of injury, with in-line immobilisation and cricoid pressure while lying on the ground in bright sunlight. A Cormack and Lehane grade 1 view of the oedematous vocal cords was readily obtained, and successful endotracheal intubation was rapidly achieved at the first attempt. The endotracheal tube was clearly seen to pass through the vocal cords and enter the trachea. The Airtraq required minimal manipulation to obtain a close-up, panoramic, high-grade view of the larynx. Further evaluation of this device is warranted to define its role in the emergency department and in prehospital care.


DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood.
There is increasing evidence that metabolic diseases originate in early life, and epigenetic changes have been implicated as key drivers of this early life programming. This led to the hypothesis that epigenetic marks present at birth may predict an individual's future risk of obesity and type 2 diabetes. In this study, we assessed whether epigenetic marks in blood of newborn children were associated with body mass index (BMI) and insulin sensitivity later in childhood. DNA methylation was measured in neonatal blood spot samples of 438 children using the Illumina Infinium 450 k BeadChip. Associations were assessed between DNA methylation at birth and BMI z-scores, body fat mass, fasting plasma glucose, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) at age 5 years, as well as birth weight, maternal BMI and smoking status. No individual methylation sites at birth were associated with obesity or insulin sensitivity measures at 5 years. DNA methylation in 69 genomic regions at birth was associated with BMI z-scores at age 5 years, and in 63 regions with HOMA-IR. The methylation changes were generally small (<5%), except for a region near the non-coding RNA nc886 (VTRNA2-1) where a clear link between methylation status at birth and BMI in childhood was observed (P=0.001). Associations were also found between DNA methylation, maternal smoking and birth weight. We identified a number of DNA methylation regions at birth that were associated with obesity or insulin sensitivity measurements in childhood. These findings support the mounting evidence on the role of epigenetics in programming of metabolic health. Whether many of these small changes in DNA methylation are causally related to the health outcomes, and of clinical relevance, remains to be determined, but the nc886 region represents a promising obesity risk marker that warrants further investigation.


Structure and interactions of the human programmed cell death 1 receptor.
PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C" strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1 · ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.


Prevalence of non-communicable disease risk factors among poor shantytown residents in Dhaka, Bangladesh: a community-based cross-sectional survey.
This study aims to describe the prevalence of non-communicable disease (NCD) risk factors among the urban poor in Bangladesh. We conducted a community-based cross-sectional epidemiological study. The study was conducted in a shantytown in the city of Dhaka. There were 8604 households with 34 170 residents in the community. Those households were categorised into two wealth strata based on the housing structure. The study targeted residents aged 18-64 years. A total of 2986 eligible households with one eligible individual were selected by simple random sampling stratified by household wealth status. A total of 2551 residents completed the questionnaire survey, and 2009 participated in the subsequent physical and biochemical measurements. A modified WHO survey instrument was used for assessing behavioural risk factors and physical and biochemical measurements, including glycated haemoglobin (HbA1c). The prevalence of NCD risk factors, such as tobacco use, fruit and vegetable intake, overweight/obesity, hypertension, diabetes (HbA1c ≥6.5%) and dyslipidaemia, was described according to household wealth status and gender differences. The prevalence of current tobacco use was 60.4% in men and 23.5% in women. Most of them (90.8%) consumed more than 1 serving of fruits and vegetables per day; however, only 2.1% consumed more than 5 servings. Overweight/obesity was more common in women (39.2%) than in men (18.9%), while underweight was more common in men (21.0%) than in women (7.1%). The prevalence of hypertension was 18.6% in men and 20.7% in women. The prevalence of diabetes was 15.6% in men and 22.5% in women, which was much higher than the estimated national prevalence (7%). The prevalence of raised total cholesterol (≥190 mg/dL) was 25.7% in men and 34.0% in women. The study identified that tobacco use, both overweight and underweight, diabetes, hypertension and dyslipidaemia were prevalent among the urban poor in Bangladesh.


Waterbirth: a national retrospective cohort study of factors associated with its use among women in England.
Waterbirth is widely available in English maternity settings for women who are not at increased risk of complications during labour. Immersion in water during labour is associated with a number of maternal benefits. However for birth in water the situation is less clear, with conclusive evidence on safety lacking and little known about the characteristics of women who give birth in water. This retrospective cohort study uses electronic data routinely collected in the course of maternity care in England in 2015-16 to describe the proportion of births recorded as having occurred in water, the characteristics of women who experienced waterbirth and the odds of key maternal and neonatal complications associated with giving birth in water. Data were obtained from three population level electronic datasets linked together for the purposes of a national audit of maternity care. The study cohort included women who had no risk factors requiring them to give birth in an obstetric unit according to national guidelines. Multivariate logistic regression models were used to examine maternal (postpartum haemorrhage of 1500mls or more, obstetric anal sphincter injury (OASI)) and neonatal (Apgar score less than 7, neonatal unit admission) outcomes associated with waterbirth. 46,088 low and intermediate risk singleton term spontaneous vaginal births in 35 NHS Trusts in England were included in the analysis cohort. Of these 6264 (13.6%) were recorded as having occurred in water. Waterbirth was more likely in older women up to the age of 40 (adjusted odds ratio (adjOR) for age group 35-39 1.27, 95% confidence interval (1.15,1.41)) and less common in women under 25 (adjOR 18-24 0.76 (0.70, 0.82)), those of higher parity (parity ≥3 adjOR 0.56 (0.47,0.66)) or who were obese (BMI 30-34.9 adjOR 0.77 (0.70,0.85)). Waterbirth was also less likely in black (adjOR 0.42 (0.36, 0.51)) and Asian (adjOR 0.26 (0.23,0.30)) women and in those from areas of increased socioeconomic deprivation (most affluent versus least affluent areas adjOR 0.47 (0.43, 0.52)). There was no association between delivery in water and low Apgar score (adjOR 0.95 (0.66,1.36)) or incidence of OASI (adjOR 1.00 (0.86,1.16)). There was an association between waterbirth and reduced incidence of postpartum haemorrhage (adjOR 0.68 (0.51,0.90)) and neonatal unit admission (adjOR 0.65 (0.53,0.78)). In this large observational cohort study, there was no association between waterbirth and specific adverse outcomes for either the mother or the baby. There was evidence that white women from higher socioeconomic backgrounds were more likely to be recorded as giving birth in water. Maternity services should focus on ensuring equitable access to waterbirth.


Comparison of shear bond strength of orthodontic brackets bonded with a universal adhesive using different etching methods.
The aim of this study was to compare the effects of three enamel etching modes - laser-etch, self-etch and acid-etch (5, 10 and 15 s) - on bracket bonding, using a universal adhesive. Eighty-four maxillary premolars were randomly divided into seven groups (n=12) based on the etching method and the adhesive used for bracket bonding. After water storage and thermocycling, shear bond strength was measured, and adhesive remnant index scores on debonded enamel were determined. There were significant differences between the seven groups regarding bond strength values (p< 0.001). The highest values were observed in universal adhesive with laser etching group, while Transbond XT with acid or laser etching, and universal adhesive used in self-etch mode demonstrated the lowest bond strength. The universal adhesive with the three different etching times presented with statistically similar results, all showing an improvement in bond strength, compared with Scotchbond universal (SBU)/SE. The universal adhesive evaluated in the present study demonstrated statistically similar bond strengths to conventional orthodontic adhesive in self-etch mode. The bond strength can be improved by adding an initial acid etching or laser conditioning step, although enamel damage was observed in some cases.


Self-assembly and chemical modifications of bisphenol a on Cu(111): interplay between ordering and thermally activated stepwise deprotonation.
Bisphenol A (BPA) is a chemical widely used in the synthesis pathway of polycarbonates for the production of many daily used products. Besides other adverse health effects, medical studies have shown that BPA can cause DNA hypomethylation and therefore alters the epigenetic code. In the present work, the reactivity and self-assembly of the molecule was investigated under ultra-high-vacuum conditions on a Cu(111) surface. We show that the surface-confined molecule goes through a series of thermally activated chemical transitions. Scanning tunneling microscopy investigations showed multiple distinct molecular arrangements dependent on the temperature treatment and the formation of polymer-like molecular strings for temperatures above 470 K. X-ray photoelectron spectroscopy measurements revealed the stepwise deprotonation of the hydroxy groups, which allows the molecules to interact strongly with the underlying substrate as well as their neighboring molecules and therefore drive the organization into distinct structural arrangements. On the basis of the combined experimental evidence in conjunction with density functional theory calculations, structural models for the self-assemblies after the thermal treatment were elaborated.


Risk-averse personalities have a systemically potentiated neuroendocrine stress axis: A multilevel experiment in Parus major.
Hormonal pleiotropy-the simultaneous influence of a single hormone on multiple traits-has been hypothesized as an important mechanism underlying personality, and circulating glucocorticoids are central to this idea. A major gap in our understanding is the neural basis for this link. Here we examine the stability and structure of behavioral, endocrine and neuroendocrine traits in a population of songbirds (Parus major). Upon identifying stable and covarying behavioral and endocrine traits, we test the hypothesis that risk-averse personalities exhibit a neuroendocrine stress axis that is systemically potentiated-characterized by stronger glucocorticoid reactivity and weaker negative feedback. We show high among-individual variation and covariation (i.e. personality) in risk-taking behaviors and demonstrate that four aspects of glucocorticoid physiology (baseline, stress response, negative feedback strength and adrenal sensitivity) are also repeatable and covary. Further, we establish that high expression of mineralocorticoid and low expression of glucocorticoid receptor in the brain are linked with systemically elevated plasma glucocorticoid levels and more risk-averse personalities. Our findings support the hypothesis that steroid hormones can exert pleiotropic effects that organize behavioral phenotypes and provide novel evidence that neuroendocrine factors robustly explain a large fraction of endocrine and personality variation.


Effect of L-arginine and an arginine-containing pentapeptide on canine femoral arterial blood flow.
The amino acid L-arginine is a precursor of endothelium derived relaxing factor (EDRF). The pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) released by plasmin degradation of fibrinogen also contains arginine and relaxes vascular smooth muscle by releasing EDRF (nitric oxide). To determine and compare the effects of L-arginine, peptide 6A and a combination of L-arginine and peptide 6A on femoral artery blood flow and vascular resistance, anesthetized mongrel dog were administered saline, L-arginine, D-arginine, peptide 6A and L-arginine + peptide 6A in a random order. L-arginine and peptide 6A both induced an immediate dose-dependent short-lasting increase in femoral blood flow and a decrease in vascular resistance. Peptide 6A exerted a much greater (P less than 0.01) vasodilatory effect than did L-arginine at the same molar concentration suggesting that properties besides the arginine content are important in the effect of the pentapeptide. D-arginine had much less effect than L-arginine, indicating that the effect of L-arginine may be related to its utilization for synthesis of EDRF. When the peptide 6A was given soon after L-arginine, its effect on blood flow was not greater than that of L-arginine alone suggesting that L-arginine in a large amount makes guanylate cyclase less available for the more active peptide.


An approach to understanding sleep and depressed mood in adolescents: person-centred sleep classification.
Depressive mood in youth has been associated with distinct sleep dimensions, such as timing, duration and quality. To identify discrete sleep phenotypes, we applied person-centred analysis (latent class mixture models) based on self-reported sleep patterns and quality, and examined associations between phenotypes and mood in high-school seniors. Students (n = 1451; mean age = 18.4 ± 0.3 years; 648 M) completed a survey near the end of high-school. Indicators used for classification included school night bed- and rise-times, differences between non-school night and school night bed- and rise-times, sleep-onset latency, number of awakenings, naps, and sleep quality and disturbance. Mood was measured using the total score on the Center for Epidemiologic Studies-Depression Scale. One-way anova tested differences between phenotype for mood. Fit indexes were split between 3-, 4- and 5-phenotype solutions. For all solutions, between phenotype differences were shown for all indicators: bedtime showed the largest difference; thus, classes were labelled from earliest to latest bedtime as 'A' (n = 751), 'B' (n = 428) and 'C' (n = 272) in the 3-class solution. Class B showed the lowest sleep disturbances and remained stable, whereas classes C and A each split in the 4- and 5-class solutions, respectively. Associations with mood were consistent, albeit small, with class B showing the lowest scores. Person-centred analysis identified sleep phenotypes that differed in mood, such that those with the fewest depressive symptoms had moderate sleep timing, shorter sleep-onset latencies and fewer arousals. Sleep characteristics in these groups may add to our understanding of how sleep and depressed mood associate in teens.


Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain.
Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α(4)β(2) NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α(4)β(2) NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α(4)β(2) NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α(4)β(2) NNRs may not be a viable approach to treating neuropathic pain.


Thrill of victory or agony of defeat? Perceivers fail to utilize information in facial movements.
Although the distinction between positive and negative facial expressions is assumed to be clear and robust, recent research with intense real-life faces has shown that viewers are unable to reliably differentiate the valence of such expressions (Aviezer, Trope, & Todorov, 2012). Yet, the fact that viewers fail to distinguish these expressions does not in itself testify that the faces are physically identical. In Experiment 1, the muscular activity of victorious and defeated faces was analyzed. Higher numbers of individually coded facial actions--particularly smiling and mouth opening--were more common among winners than losers, indicating an objective difference in facial activity. In Experiment 2, we asked whether supplying participants with valid or invalid information about objective facial activity and valence would alter their ratings. Notwithstanding these manipulations, valence ratings were virtually identical in all groups, and participants failed to differentiate between positive and negative faces. While objective differences between intense positive and negative faces are detectable, human viewers do not utilize these differences in determining valence. These results suggest a surprising dissociation between information present in expressions and information used by perceivers.


Monoclonal antibody to single-stranded DNA: a potential tool for DNA repair studies.
Growing evidence suggests that DNA repair capacity is an important factor in cancer risk and is therefore essential to assess. Immunochemical assays are amenable to the detection of repair products in complex matrices, such as urine, facilitating noninvasive measurements, although diet and extra-DNA sources of lesion can confound interpretation. The production of single-stranded, lesion-containing DNA oligomers characterises nucleotide excision repair (NER) and hence defines the repair pathway from which a lesion may be derived. Herein we describe the characterisation of a monoclonal antibody which recognises guanine moieties in single-stranded DNA. Application of this antibody in ELISA, demonstrated such oligomers in supernatants from repair-proficient cells post-insult. Testing of urine samples from volunteers demonstrated a relationship between oligomer levels and two urinary DNA damage products, thymine dimers and 8-oxo-2'-deoxyguanosine, supporting our hypothesis that NER gives rise to lesion-containing oligomers which are specific targets for the investigation of DNA repair.


Issues in mapping LOINC laboratory tests to SNOMED CT.
Comprehensive clinical terminologies such as SNOMED CT tend to overlap with specialized terminologies such as LOINC (e.g., for the domain of laboratory procedures). Terminological systems such as the UMLS are often used to bridge between terminologies. However, the integration of LOINC in the UMLS and with other terminologies remains suboptimal. We mapped concepts for laboratory tests from LOINC to pre-coordinated SNOMED CT concepts, based on shared relations to other concepts. As LOINC is finer-grained than SNOMED CT, several LOINC codes tend to map to the same SNOMED CT concept. However, a large proportion of LOINC codes could not be mapped to SNOMED CT through this approach, because of underspecified definitions in SNOMED CT and a lack of fine-grained, pre-coordinated concepts in SNOMED CT.


Post-treatment stage of change predicts 12-month outcome of treatment for alcohol problems.
To evaluate relationships between clients' self-reported 'stage of change' and outcomes after treatment for alcohol problems. Using data from the 'United Kingdom Alcohol Treatment Trial', clients who had received at least one session of treatment and who had complete data (n = 392) entered the analysis. Two continuous measures of drinking behaviour (% days abstinent (PDA) and drinks per drinking day (DDD)) and categorical outcomes at the 12-month follow-up were compared between clients in Pre-action and Action stages of change at either pre- or post-treatment assessment. Multiple and logistic regression analyses examined the relationships between stage of change and treatment outcomes, evaluating the strength of these relationships by controlling for likely confounders. Pre-treatment stage of change did not predict outcome but post-treatment stage of change predicted PDA and DDD at the 12-month follow-up. In unadjusted and adjusted analyses, clients in Action at post-treatment were two to three times more likely to show a favourable categorical outcome, variously defined, than those in Pre-action. There were no differences between clients who had received Motivational Enhancement Therapy and those who had received Social Behaviour and Network Therapy in proportions maintaining or moving towards Action from before to after treatment. These findings confirm previous reports that motivational variables predict outcome of treatment but add that such a relationship is seen for post-treatment stage of change. For therapists, it would seem important to monitor the client's stage of change-which in good clinical practice often occurs in informal ways-and have strategies to deal with low motivation to change whenever it occurs throughout treatment. The findings are also consistent with a 'common factors' perspective on effective treatment for alcohol problems.


Links between law enforcement and veterinary animal health: a case study of the United Kingdom and the United States of America.
The anthrax attacks carried out in the United States of America in the latter part of 2001 served as a clarion call to most law enforcement agencies among developed countries as, until this time, they had not recognised the threat posed by the criminal use of pathogens and/or toxins. Law enforcement agencies include the local and federal police, Customs, Immigration and any other agencies that perform a law-enforcing role. That a criminal or terrorist group could commit such an act was considered nearly inconceivable, even though biological weapons had been used against humans and animals in warfare many times over the last several hundred years. Similarly, it is without doubt that the terrorist threat to all societies changed after the events of 11 September 2001 during which the clear intention had been to cause as many fatalities and casualties as possible. As a result, the biological threat to human health became a focus for many governments.


International variability in 20 m shuttle run performance in children and youth: who are the fittest from a 50-country comparison? A systematic literature review with pooling of aggregate results.
To describe and compare 20 m shuttle run test (20mSRT) performance among children and youth across 50 countries; to explore broad socioeconomic indicators that correlate with 20mSRT performance in children and youth across countries and to evaluate the utility of the 20mSRT as an international population health indicator for children and youth. A systematic review was undertaken to identify papers that explicitly reported descriptive 20mSRT (with 1-min stages) data on apparently healthy 9-17 year-olds. Descriptive data were standardised to running speed (km/h) at the last completed stage. Country-specific 20mSRT performance indices were calculated as population-weighted mean z-scores relative to all children of the same age and sex from all countries. Countries were categorised into developed and developing groups based on the Human Development Index, and a correlational analysis was performed to describe the association between country-specific performance indices and broad socioeconomic indicators using Spearman's rank correlation coefficient. Performance indices were calculated for 50 countries using collated data on 1 142 026 children and youth aged 9-17 years. The best performing countries were from Africa and Central-Northern Europe. Countries from South America were consistently among the worst performing countries. Country-specific income inequality (Gini index) was a strong negative correlate of the performance index across all 50 countries. The pattern of variability in the performance index broadly supports the theory of a physical activity transition and income inequality as the strongest structural determinant of health in children and youth. This simple and cost-effective assessment would be a powerful tool for international population health surveillance.


New estimates of the number of children living with substance misusing parents: results from UK national household surveys.
The existing estimates of there being 250,000 - 350,000 children of problem drug users in the UK (ACMD, 2003) and 780,000 - 1.3 million children of adults with an alcohol problem (AHRSE, 2004) are extrapolations of treatment data alone or estimates from other countries, hence updated, local and broader estimates are needed. The current work identifies profiles where the risk of harm to children could be increased by patterns of parental substance use and generates new estimates following secondary analysis of five UK national household surveys. The Health Survey for England (HSfE) and General Household Survey (GHS) (both 2004) generated consistent estimates - around 30% of children under-16 years (3.3 - 3.5 million) in the UK lived with at least one binge drinking parent, 8% with at least two binge drinkers and 4% with a lone (binge drinking) parent. The National Psychiatric Morbidity Survey (NPMS) indicated that in 2000, 22% (2.6 million) lived with a hazardous drinker and 6% (705,000) with a dependent drinker. The British Crime Survey (2004) and NPMS (2000) indicated that 8% (up to 978,000) of children lived with an adult who had used illicit drugs within that year, 2% (up to 256,000) with a class A drug user and 7% (up to 873,000) with a class C drug user. Around 335,000 children lived with a drug dependent user, 72,000 with an injecting drug user, 72,000 with a drug user in treatment and 108,000 with an adult who had overdosed. Elevated or cumulative risk of harm may have existed for the 3.6% (around 430,000) children in the UK who lived with a problem drinker who also used drugs and 4% (half a million) where problem drinking co-existed with mental health problems. Stronger indicators of harm emerged from the Scottish Crime Survey (2000), according to which 1% of children (around 12,000 children) had witnessed force being used against an adult in the household by their partner whilst drinking alcohol and 0.6% (almost 6000 children) whilst using drugs. Whilst harm from parental substance use is not inevitable, the number of children living with substance misusing parents exceeds earlier estimates. Widespread patterns of binge drinking and recreational drug use may expose children to sub-optimal care and substance-using role models. Implications for policy, practice and research are discussed.


Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer.
Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study. Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds). BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress. Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.


Contrast media extravasations in patients undergoing computerized tomography scanning: a systematic review and meta-analysis of risk factors and interventions.
To identify risk factors and interventions preventing or reducing contrast medium extravasation. Computed tomography (CT) is a radiological examination essential for the diagnosis and monitoring of many diseases. It is often performed with the intravenous (IV) injection of contrast agents. Use of these products can result in a significant complication, extravasation, which is the accidental leakage of IV material into the surrounding tissue. Patients may feel a sharp pain and skin ulceration or necrosis may develop. This review considered studies that included patients (adults and children) undergoing a CT with IV administration of contrast media. The risk factors considered were patient demographics, comorbidities and medication history. This review also investigated any strategies related to: contrast agent, injection per se, material used for injection, apparatus used, healthcare professionals involved, and patient risk assessment performed by the radiology personnel. The comparators were other interventions or usual care. This review investigated randomized controlled trials and non-randomized controlled trials. When neither of these were available, other study designs, such as prospective and retrospective cohort studies, case-control studies and case series, were considered for inclusion. Primary outcomes considered were: extravasation frequency, volume, severity and complications. The databases PubMed, CINAHL, Embase, the Cochrane Register of Controlled Trials, Web of Science PsycINFO, ProQuest Dissertations and Theses A&I, TRIP Database and ClinicalTrials.gov were searched to find both published and unpublished studies from 1980 to September 2016. Papers were assessed by two independent reviewers for methodological validity using the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). Data were extracted using the standardized data extraction tool from JBI SUMARI. In one case, quantitative data from two cohort studies were pooled in a statistical meta-analysis. However, generally, statistical pooling was not possible due to heterogeneity of the interventions, populations of interest or outcomes. Accordingly, the findings have been presented in narrative form. Fifteen articles were selected from a total of 2151 unique studies identified. Two were randomized controlled trials and 13 were quasi-experimental and observational studies. The quality of these studies was judged to be low to moderate. Some patient characteristics, such as female sex and inpatient status, appeared to be risk factors for extravasation. Additionally, injection rate, venous access site and catheter dwelling time could affect the volume extravasated. Preliminary studies seemed to indicate the potential of extravasation detection accessories to identify extravasation and reduce the volume extravasated. The other interventions either did not result in significant reduction in the frequency/volume of extravasation, or the results were mixed across the studies. The majority of the studies included in this review evaluated the outcomes of extravasation frequency and volume. Given the quality of the primary studies, this systematic review identified only potential risk factors and interventions. It further highlighted the research gap in this area and the importance of conducting trials with solid methodological designs.


Passive standoff detection of Bacillus subtilis aerosol by Fourier-transform infrared radiometry.
An analysis is presented on the passive standoff detection and identification of Bacillus subtilis (BG) clouds with the Compact ATmospheric Sounding Interferometer (CATSI) sensor. This research is based on recent spectral measurements obtained during the Technology Readiness Evaluation trial held July 2002 at Dugway Proving Ground, Utah. Results obtained from three trial BG cloud episodes are used to explain and demonstrate the detection capability of the CATSI sensor. The BG clouds were measured at a distance of 3 km from the sensor in a near-horizontal path scenario. It was found that the low thermal contrast of approximately 0.2 K between the BG cloud and the background yielded weak but observable spectral signatures. The processing of the spectral signatures with the GASeous Emission Monitoring (GASEM) algorithm has provided a rough estimate of BG cloud column densities. The results of a series of simulations with the FASCOD3 transmission model have shown that the detection sensitivity for BG can be greatly improved for both slant path uplooking and downlooking scenarios.


The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.


[Mesothelioma: advances in chemotherapy].
Chemotherapy is often the only treatment possible for locally advanced or metastatic mesothelioma. This paper recalls which drugs might have therapeutic benefits in this condition and reviews recent studies of chemotherapy or targeted therapy. If the patient cannot be enrolled in a therapeutic trial the first line therapy in the absence of contraindications is a combination of cisplatin and pemetrexed, the latter having received a licence for this indication in September 2004. Among the alternatives reviewed are taxanes, liposomal anthracyclines, topoisomerase inhibitors, cisplatin derivatives, vinca alkaloids, and antimetabolites. Although the first three have show little or no benefit the vinca alkaloids (vinorelbine, vinflunine) and particularly the antimetabolites (gemcitabine, raltitrexed, pemetrexed) are very promising. Recent studies have looked most frequently at combinations of an anti-metabolite and a platinum salt, with data available from nearly 200 patients treated with gemcitabine. These studies have had fairly homogeneous results showing a one year survival of about 50%. Some preliminary data from studies of second line chemotherapy is also available. Finally studies of targeted therapies such as anti-EGFR, anti VEGF and anti PDGF are underway but have not as yet demonstrated major therapeutic benefit.


S-MART, a software toolbox to aid RNA-Seq data analysis.
High-throughput sequencing is now routinely performed in many experiments. But the analysis of the millions of sequences generated, is often beyond the expertise of the wet labs who have no personnel specializing in bioinformatics. Whereas several tools are now available to map high-throughput sequencing data on a genome, few of these can extract biological knowledge from the mapped reads. We have developed a toolbox called S-MART, which handles mapped RNA-Seq data. S-MART is an intuitive and lightweight tool which performs many of the tasks usually required for the analysis of mapped RNA-Seq reads. S-MART does not require any computer science background and thus can be used by all of the biologist community through a graphical interface. S-MART can run on any personal computer, yielding results within an hour even for Gb of data for most queries. S-MART may perform the entire analysis of the mapped reads, without any need for other ad hoc scripts. With this tool, biologists can easily perform most of the analyses on their computer for their RNA-Seq data, from the mapped data to the discovery of important loci.


Changes in maternal age distribution and their possible impact on demand for prenatal diagnostic services.
Between 1977 and 1985 there was a 65% increase in births to women aged 35 or more in England and Wales, but only a 15% increase in all births. Two factors of roughly equal importance were responsible for this differential increase. Firstly, the proportion of older women (35-44) among all women of reproductive age (15-44) increased from 28% in 1977 to 31% in 1985; and, secondly, in the same period the fertility rate for women aged 35-39 increased from 18.2 to 24.1 per 1000 and for women aged 40-44 from 4.1 to 4.6 per 1000. The increased fertility rate among older women is not due to an extension of the reproductive period but to a delay in childbearing. This delay was seen in women married only once and also in those who had remarried. As prenatal diagnosis for the exclusion of chromosome abnormalities is customarily offered to older mothers the increased numbers of women aged 35 or more and their increased fertility rate have important implications for the provision of obstetric and laboratory services. There were 51,859 live births to women aged 35 and over in 1985; the projected figure for 2001 is 85,000. If the use of prenatal diagnosis continues to increase facilities for about 70,000 prenatal cytogenetic analyses will be needed in 2001.


Neural induction by the secreted polypeptide noggin.
The Spermann organizer induces neural tissue from dorsal ectoderm and dorsalizes lateral and ventral mesoderm in Xenopus. The secreted factor noggin, which is expressed in the organizer, can mimic the dorsalizing signal of the organizer. Data are presented showing that noggin directly induces neural tissue, that it induces neural tissue in the absence of dorsal mesoderm, and that it acts at the appropriate stage to be an endogenous neural inducing signal. Noggin induces cement glands and anterior brain markers, but not hindbrain or spinal cord markers. Thus, noggin has the expression pattern and activity expected of an endogenous neural inducer.


Homelessness and HIV risk behaviors among injection drug users.
This article uses data from an 8-year study of injection drug users to examine whether homelessness independently influenced the likelihood of engaging in human immunodeficiency virus (HIV) risk behaviors. Fixed effects regression analyses are used to estimate the associations between four different housing contexts and four different behaviors related to transmitting HIV infections. Results showed that 16% of the study group experienced homelessness at some point during the study, and that homelessness was significantly associated with a higher likelihood of frequenting shooting galleries (odds ratio = 2.05), but did not have a significant effect on sharing syringes, sharing other injection drug paraphernalia, or participating in paid sex. These results provide limited support for positing homelessness as independently associated with increased levels of HIV-related risk behavior among injection drug users and highlights the need for more research that examines the housing dynamics among this population.


Drug-target network in myocardial infarction reveals multiple side effects of unrelated drugs.
The systems-level characterization of drug-target associations in myocardial infarction (MI) has not been reported to date. We report a computational approach that combines different sources of drug and protein interaction information to assemble the myocardial infarction drug-target interactome network (My-DTome). My-DTome comprises approved and other drugs interlinked in a single, highly-connected network with modular organization. We show that approved and other drugs may both be highly connected and represent network bottlenecks. This highlights influential roles for such drugs on seemingly unrelated targets and pathways via direct and indirect interactions. My-DTome modules are associated with relevant molecular processes and pathways. We find evidence that these modules may be regulated by microRNAs with potential therapeutic roles in MI. Different drugs can jointly impact a module. We provide systemic insights into cardiovascular effects of non-cardiovascular drugs. My-DTome provides the basis for an alternative approach to investigate new targets and multidrug treatment in MI.


Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan.
Enteric fever remains a major public health problem in Asia. Planning appropriate preventive measures such as immunization requires a clear understanding of disease burden. We conducted a community-based surveillance for Salmonella Typhi infection in children in Karachi, Pakistan. A de jure household census was conducted at baseline in the study setting to enumerate all individuals. A health-care facility-based passive surveillance system was used to capture episodes of fever lasting three or more 3 days in children 2 to 16 years old. A total of 7,401 blood samples were collected for microbiological confirmation, out of which 189 S. Typhi and 32 S. Paratyphi A isolates were identified with estimated annual incidences of 451/100,000 (95% CI: 446 - 457) and 76/100,000 (95% CI: 74 - 78) respectively. At the time of presentation, after adjusting for age, there was an association between the duration of fever and temperature at presentation, and being infected with multidrug-resistant S. Typhi. Of 189 isolates 83 were found to be resistant to first-line antimicrobial therapy. There was no statistically significant difference in clinical presentation of blood culture sensitive and resistant S. Typhi isolates. Incidence of S. Typhi in children is high in urban squatter settlements of Karachi, Pakistan. Findings from this study identified duration of fever and temperature at the time of presentation as important symptoms associated with blood culture-confirmed typhoid fever. Preventive strategies such as immunization and improvements in water and sanitation conditions should be the focus of typhoid control in urban settlements of Pakistan.


A comparison of specimen adequacy in fine needle aspiration biopsies performed by pathologists, trained nursing staff and clinicians.
Fine needle aspiration biopsies (FNAB) performed by trained professional nurses and pathology registrars in an FNAB clinic were compared with aspirates by clinicians from regional clinics and hospitals. Of the 7709 reports retrieved from the archives, the highest number of unsatisfactory aspirates came from clinicians (42%), followed by registrars (20.09%) while the nurses had the lowest overall unsatisfactory rate (14.32%). We conclude that, in countries experiencing a shortage of adequately qualified and experienced medical personnel, it is essential to train nurses to perform and manage FNAB clinics.


High-spin ferric ions in Saccharomyces cerevisiae vacuoles are reduced to the ferrous state during adenine-precursor detoxification.
The majority of Fe in Fe-replete yeast cells is located in vacuoles. These acidic organelles store Fe for use under Fe-deficient conditions and they sequester it from other parts of the cell to avoid Fe-associated toxicity. Vacuolar Fe is predominantly in the form of one or more magnetically isolated nonheme high-spin (NHHS) Fe(III) complexes with polyphosphate-related ligands. Some Fe(III) oxyhydroxide nanoparticles may also be present in these organelles, perhaps in equilibrium with the NHHS Fe(III). Little is known regarding the chemical properties of vacuolar Fe. When grown on adenine-deficient medium (A↓), ADE2Δ strains of yeast such as W303 produce a toxic intermediate in the adenine biosynthetic pathway. This intermediate is conjugated with glutathione and shuttled into the vacuole for detoxification. The iron content of A↓ W303 cells was determined by Mössbauer and EPR spectroscopies. As they transitioned from exponential growth to stationary state, A↓ cells (supplemented with 40 μM Fe(III) citrate) accumulated two major NHHS Fe(II) species as the vacuolar NHHS Fe(III) species declined. This is evidence that vacuoles in A↓ cells are more reducing than those in adenine-sufficient cells. A↓ cells suffered less oxidative stress despite the abundance of NHHS Fe(II) complexes; such species typically promote Fenton chemistry. Most Fe in cells grown for 5 days with extra yeast-nitrogen-base, amino acids and bases in minimal medium was HS Fe(III) with insignificant amounts of nanoparticles. The vacuoles of these cells might be more acidic than normal and can accommodate high concentrations of HS Fe(III) species. Glucose levels and rapamycin (affecting the TOR system) affected cellular Fe content. This study illustrates the sensitivity of cellular Fe to changes in metabolism, redox state and pH. Such effects broaden our understanding of how Fe and overall cellular metabolism are integrated.


Viral dynamics and anti-viral pharmacodynamics: rethinking in vitro measures of drug potency.
Most current assays used to quantitate the pharmacodynamic effect of anti-viral agents measure the net inhibitory effect of a drug on virus replication over several days in an in vitro cell culture. Such endpoint experiments give cumulative measures of inhibition that vary with the assay used and therefore provide suboptimal information on likely in vivo drug performance. We argue that instantaneous inhibition (proportion of cell infection prevented at a point in time) is a more robust pharmacodynamic measure, and propose techniques to estimate this quantity from endpoint data. Implications for the quantification of drug interactions are discussed.


Carbon burial over the last four millennia is regulated by both climatic and land use change.
Carbon sequestration by sediments and vegetated marine systems contributes to atmospheric carbon drawdown, but little empirical evidence is available to help separate the effects of climate change and other anthropogenic activities on carbon burial over centennial timescales. We used marine sediment organic carbon to determine the role of historic climate variability and human habitation in carbon burial over the past 5,071 years. There was centennial-scale sensitivity of carbon supply and burial to climatic variability, with Little Ice Age cooling causing an abrupt ecosystem shift and an increase in marine carbon contributions compared to terrestrial carbon. Although land use changes during the late 1800s did not cause marked alteration in average carbon burial, they did lead to marked increases in the spatial variability of carbon burial. Thus, while carbon burial by vegetated systems is expected to increase with projected climate warming over the coming century, ecosystem restructuring caused by abrupt climate change may produce unexpected change in carbon burial whose variability is also modulated by land use change.


Ethnic inequalities in obesity among children and adults in the UK: a systematic review of the literature.
Ethnic minority groups are growing as a proportion of the British population. Although disparate, literature suggests inequalities in obesity risk within and among ethnic minority groups relative to Caucasians in the UK. We summarize and appraise the existing peer-reviewed literature about the prevalence and determinants of obesity among ethnic minority groups relative to Caucasians among children and adults in the UK. There was no consensus about obesity prevalence relative to Caucasians among South Asian or Black children or among South Asian adults relative to Caucasians. Black adults generally had higher risk for obesity than Caucasians. Both Chinese children and adults had lower risk for obesity than Caucasians. Few studies have considered differences in the aetiology of obesity by ethnicity. The lack of consensus regarding obesity risk among large ethnic minority groups relative to Caucasians in the UK, and the paucity of studies concerned with differences in obesity aetiology by ethnicity warrant further research in this area. Certain obesity metrics may bias obesity prevalence among particular ethnic groups relative to Caucasians. We summarize key methodological limitations to the current literature and suggest avenues for future research.


Repulsion-attraction switching of nematic colloids formed by liquid crystal dispersions of polygonal prisms.
Self-assembly of colloidal particles due to elastic interactions in nematic liquid crystals promises tunable composite materials and can be guided by exploiting surface functionalization, geometric shape and topology, though these means of controlling self-assembly remain limited. Here, we realize low-symmetry achiral and chiral elastic colloids in the nematic liquid crystals using colloidal polygonal concave and convex prisms. We show that the controlled pinning of disclinations at the prism edges alters the symmetry of director distortions around the prisms and their orientation with respect to the far-field director. The controlled localization of the disclinations at the prism's edges significantly influences the anisotropy of the diffusion properties of prisms dispersed in liquid crystals and allows one to modify their self-assembly. We show that elastic interactions between polygonal prisms can be switched between repulsive and attractive just by controlled re-pinning the disclinations at different edges using laser tweezers. Our findings demonstrate that elastic interactions between colloidal particles dispersed in nematic liquid crystals are sensitive to the topologically equivalent but geometrically rich controlled configurations of the particle-induced defects.