Optimal gross tumor volume definition in lung-sparing intensity modulated radiotherapy for pleural mesothelioma: an in silico study.
The gross tumor volume (GTV) definition for malignant pleural mesothelioma (MPM) is ill-defined. We therefore investigated which imaging modality is optimal: computed tomography (CT) with intravenous contrast (IVC), positron emission tomography-CT (PET/CT) or magnetic resonance imaging (MRI). Sixteen consecutive patients with untreated stage I-IV MPM were included. Patients with prior pleurodesis were excluded. CT with IVC, 18FDG-PET/CT and MRI (T2 and contrast-enhanced T1) were obtained. CT was rigidly co-registered with PET/CT and with MRI. Three sets of pleural GTVs were defined: GTVCT, GTVCT+PET/CT and GTVCT+MRI. Quantitative and qualitative evaluations of the contoured GTVs were performed. Compared to CT-based GTV definition, PET/CT identified additional tumor sites (defined as either separate nodules or greater extent of a known tumor) in 12/16 patients. Compared to either CT or PET/CT, MRI identified additional tumor sites in 15/16 patients (p = .7). The mean GTVCT, GTVCT+PET/CT and GTVCT+MRI [±standard deviation (SD)] were 630.1 cm3 (±302.81), 640.23 cm3 (±302.83) and 660.8 cm3 (±290.8), respectively. Differences in mean volumes were not significant. The mean Jaccard Index was significantly lower in MRI-based contours versus all the others. As MRI identified additional pleural disease sites in the majority of patients, it may play a role in optimal target volume definition.


Induction of competence and progression signals in human T lymphocytes by phorbol esters and calcium ionophores.
We have investigated the induction of competence (IL-2 responsiveness) and progression in human T lymphocyte proliferation triggered by phorbol ester and calcium ionophore. The degree of proliferation induced with the phorbol ester, phorbol 12,13-dibutyrate (PDB) and the calcium ionophore ionomycin was dependent on the duration of exposure to these agents, with more than 6 h required for obtaining maximum proliferation. Following brief exposure to both agents for 30 min, which did not cause significant proliferation, T cells became competent to proliferate in response to exogenous interleukin 2 (IL-2). These competent T cells also progressed to DNA synthesis following incubation with PDB in the absence of ionomycin. Induction of competence to proliferate in response to either PDB or IL-2 was blocked by EGTA, suggesting that transmembrane Ca2+ flux was obligatory at this stage. Since other phorbol esters and synthetic diacylglycerols also stimulated DNA synthesis in competent cells, it is likely that progression was triggered by activation of protein kinase C. Following a brief exposure to PDB and ionomycin, subsequent incubation with PDB induced gene expression and secretion of IL-2 and augmented the expression of IL-2 receptors in the competent cells. Thus, we have demonstrated that Ca2+ mobilization is required for rendering T cells competent to express functional IL-2 receptors, to produce IL-2 in response to subsequent incubation with PDB, and that sustained activation of protein kinase C seems necessary for IL-2 production and subsequent progression of competent T cells to DNA synthesis.


Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C.
Natural killer (NK) cells express killer inhibitory receptors that mediate negative regulation of NK cell cytotoxicity upon binding to MHC class I molecules on target cells. Unrelated inhibitory receptors on B cells have recently been shown to function through recruitment of phosphotyrosine phosphatase 1C (PTP-1C). Here, we show that a human killer inhibitory receptor specific for HLA-C also recruits PTP-1C after phosphorylation induced either by the pharmacological agent phenylarsine oxide or by conjugation with target cells. This recruitment is mediated by the binding of specific cytoplasmic phosphotyrosine-containing sequences to PTP-1C. These results implicate PTP-1C as a cytosolic component of the negative signaling pathway through NK cell inhibitory receptors.


Dynamics of HCV RNA levels during acute hepatitis C virus infection.
Understanding viral dynamics during acute hepatitis C virus (HCV) infection can provide important insights into immunopathogenesis and guide early treatment. The aim of this study was to investigate the dynamics of HCV RNA and alanine transaminase (ALT) levels during recent HCV infection in the Australian Trial in Acute Hepatitis C (ATAHC). ATAHC was a prospective study of the natural history of recently acquired HCV infection. Longitudinal HCV RNA and ALT levels were compared among individuals with persistent infection and spontaneous clearance. Among those with HCV persistence (n = 104) and HCV clearance (n = 30), median HCV RNA (5.2 vs. 4.1 log IU/ml, respectively) and ALT levels (779 vs. 1,765 IU/L, respectively) were high during month two following infection, and then declined during months three and four in both groups. Among those with HCV persistence, median HCV RNA was 2.9 log IU/ml during months four, increased to 5.5 log IU/ml during month five, and remained subsequently relatively stable. Among those with HCV clearance, median HCV RNA was undetectable by month five. Median HCV RNA levels were comparable between individuals with HCV persistence and HCV clearance during month three following infection (3.2 vs. 3.5 log IU/ml, respectively; P = 0.935), but markedly different during month five (5.5 vs. 1.0 log IU/ml, respectively; P < 0.001). In conclusion, dynamics of HCV RNA levels in those with HCV clearance and HCV persistence diverged between months three and five following infection, with the latter time-point being potentially useful for commencing early treatment.


Application of food waste disposers and alternate cycles process in small-decentralized towns: a case study.
The use of food waste disposers (FWDs) can be an interesting option to integrate the management of municipal wastewaters and household organic waste in small towns and decentralized areas. This strategy can be even more environmentally friendly if a suitable treatment process of the resulting sewage is performed in order to control nutrients emission. However, still nowadays, part of the scientific and technical community considers the application of this technology a possible source of problems. In this study, the FWDs were applied, with a market penetration factor of 67%, in a mountain village of 250 inhabitants. Further, the existing wastewater treatment plant (WWTP) was upgraded by applying an automatically controlled alternate cycles process for the management of nutrients removal. With specific reference to the observed results, the impact of the ground food waste on the sewerage system did not show particular solids sedimentation or significant hydraulic overflows. Further, the WWTP was able to face the overloads of 11, 55 and 2g per capita per day of TSS, COD and TN, respectively. Then, the increase of the readily biodegradable COD (rbCOD/COD from 0.20 to 0.25) and the favourable COD/TN ratio (from 9.9 to 12) led to a specific denitrification rate of some 0.06kgNO(3)-N/(kg MLVSS day). Therefore, not only COD removal, but also the total nitrogen removal increased: the denitrification efficiency reached 85%. That led to a better exploitation of the nitrogen-bound oxygen and a consequent reduction of energy requirements of 39%. The final economic evaluation showed the benefits of the application of this technology with a pay back time of 4-5 years.


Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer.
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density. STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase. Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.


The hemagglutinin genes hagB and hagC of Porphyromonas gingivalis are transcribed in vivo as shown by use of a new expression vector.
The hemagglutinin genes hagB and hagC of Porphyromonas gingivalis, a putative periodontopathic microorganism, have been cloned, sequenced, and characterized. However, the roles of these putative virulence genes have not yet been determined. In this study, an in vivo expression technology vector termed pPGIVET was constructed and used to determine if hagB and hagC were expressed during an infectious process. We constructed pPGIVET as a conjugative suicide plasmid containing a multiple-cloning site (MCS) upstream of two tandem promoterless reporter genes that encode tetracycline resistance [tetA(Q)2] and galactokinase (galK). The promoter and a portion of the open reading frame (ORF) of hagB were inserted into the MCS in both a positive and a negative orientation relative to the reporter genes. These constructs were conjugated into P. gingivalis 381. Southern blot analysis of different transconjugants indicated that Campbell insertions had occurred at the chromosomal hagB locus and also at the hagC locus, which has high (99%) homology to the ORF of hagB. pPGIVET-labeled clones in which the hag promoters were positively oriented relative to the reporter genes expressed tetracycline resistance and galactokinase activity in vitro and in vivo at significantly higher levels than did the wild-type strain or clones in which the hag promoters were negatively oriented. Expression of tetracycline resistance allowed substantial enrichment of heterodiploids over wild-type cells during a mixed infection in the mouse abscess model. These results indicate that hagB and hagC are transcriptionally active in vivo and suggested that pPGIVET may be used to isolate P. gingivalis genes expressed only during an infectious process.


Efficacy of NNRTI-based antiretroviral therapy initiated during acute HIV infection.
Characterize responses to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI). This was a prospective, single-arm evaluation of once-daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI. The primary endpoint is the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time to viral suppression and viral dynamics using linear mixed-effects models between acutely infected participants and chronically infected controls. Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to less than 200 copies/ml by week 24, and 35 of 41 (85.4%) to less than 50 copies/ml by week 48. The median time from ART initiation to suppression below 50 copies/ml was 93 days (range 14-337). Higher HIV RNA levels at ART initiation (P = 0.02), but not time from estimated date of infection to ART initiation (P = 0.86), were associated with longer time to viral suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T cells was 67% (range 40-95), and was not significantly associated with longer time to viral load suppression (P = 0.15). Viremia declined to less than 50 copies/ml more rapidly in AHI than chronically infected participants. Mixed-model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically infected participants, and more rapid viral decline in acutely infected participants in phase II. Once-daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.


Barriers to breast-feeding in obese women: A qualitative exploration.
to explore the factors that influence breast-feeding practices in obese women who had either stopped breast-feeding or were no longer exclusively breast-feeding 6-10 weeks following the birth of their babies, despite an original intention to do so for 16 weeks or longer. Specifically (i) to identify the barriers to successful breast-feeding and reasons for introducing formula and/or stopping breast-feeding, and (ii) to explore the women׳s views and experiences of current breast-feeding support services. descriptive, qualitative study comprising semi-structured face-to-face interviews. Interviews were audio recorded and transcribed. The data were analysed using thematic analysis. participants recruited from one large maternity unit in Scotland and interviewed in their homes. 28 obese women at 6-10 weeks following birth. three major themes emerged from the data analysis: the impact of birth complications, a lack of privacy, and a low uptake of specialist breast-feeding support. Impact of birth complications: 19 of 28 women had given birth by caesarean section and some felt this led to feeling 'out of it' post-operatively, a delay in establishing skin-to-skin contact, and in establishing breast-feeding. Lack of privacy; several women described reluctance to breast feed in front of others, difficulties in achieving privacy, in hospital, at home and in public. Low uptake of postnatal breast-feeding support; despite experiencing problems such as physical difficulties during breast-feeding or a perception of low milk supply, breast-feeding support services were underused by this sample of women. A small number of the women in this study used breast-feeding clinics and reported finding these useful. A further small number felt they benefitted from the support of a friend who was successfully breast-feeding. midwives should be mindful of the presence of additional factors alongside maternal obesity, such as caesarean delivery, physical difficulties when breast-feeding, poor body image, and lack of confidence about sufficient milk supply. Scope for innovation within hospital policies with regard to both the facilitation of early skin-to-skin contact and privacy in postnatal accommodation could be explored in future research. Women should be provided with information about the provision and specific purpose of breast-feeding support groups and services and encouraged to access these services when appropriate. Future research could assess the usefulness of sustained breast-feeding support by health professionals, as well as partner involvement and formal peer support for this group of women. The education and training needs of health professionals in terms of supporting this group of women to breast feed may also usefully be explored.


Efficiency strategies for facilitating computerized clinical documentation in ambulatory care.
Most providers have experienced increased documentation demands with the use of electronic health records (EHRs). We sought to identify efficiency strategies that providers use to complete clinical documentation tasks in ambulatory care. Two observers performed ethnographic observations and interviews with 22 ambulatory care providers in a U.S. Veterans Affairs Medical Center. Observation notes and interview transcripts were coded for recurrent strategies relating to completion of the EHR progress notes. Findings included: the use of paper artifacts for handwritten notations; electronic templates for automation of certain parts of the note; use of shorthand and phrases rather than narrative writing; copying and pasting from previous EHR notes; directly entering information into the EHR note during the patient encounter; reliance on memory; and pre-populating an EHR note prior to seeing the patient. We discuss the findings in the context of distributed cognition to understand how clinical information is propagated and represented toward completion of a progress note. The study findings have important implications for improving and streamlining clinical documentation related to human factors workload management strategies.


Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial.
Hypertension affects about 30% of adults worldwide. Garlic has blood pressure-lowering properties and the mechanism of action is biologically plausible. Our trial assessed the effect, dose-response, tolerability and acceptability of different doses of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with uncontrolled hypertension. A total of 79 general practice patients with uncontrolled systolic hypertension participated in a double-blind randomised placebo-controlled dose-response trial of 12 weeks. Participants were allocated to one of three garlic groups with either of one, two or four capsules daily of aged garlic extract (240/480/960 mg containing 0.6/1.2/2.4 mg of S-allylcysteine) or placebo. Blood pressure was assessed at 4, 8 and 12 weeks and compared with baseline using a mixed-model approach. Tolerability was monitored throughout the trial and acceptability was assessed at 12 weeks by questionnaire. Mean systolic blood pressure was significantly reduced by 11.8±5.4 mm Hg in the garlic-2-capsule group over 12 weeks compared with placebo (P=0.006), and reached borderline significant reduction in the garlic-4-capsule group at 8 weeks (-7.4±4.1 mm Hg, P=0.07). Changes in systolic blood pressure in the garlic-1-capsule group and diastolic blood pressure were not significantly different to placebo. Tolerability, compliance and acceptability were high in all garlic groups (93%) and highest in the groups taking one or two capsules daily. Our trial suggests aged garlic extract to be an effective and tolerable treatment in uncontrolled hypertension, and may be considered as a safe adjunct treatment to conventional antihypertensive therapy.


A polysaccharide (PNPA) from Pleurotus nebrodensis ameliorates hepatic ischemic/reperfusion (I/R) injury in rats.
The effects of a polysaccharide (PNPA) from the fruiting bodies of Pleurotus nebrodensis on hepatic ischemia/reperfusion (I/R) injury in rats were explored. Severe liver injury was shown in rats following I/R with high content of serum AST and ALT, as evidenced by histological examination, whereas less damage was noted after PNPA treatment compared to rats in the I/R group. Also, pre-treatment with PNPA (400mg/kg) could reduce the level of MDA in liver tissue and increase the activity of ROS scavengers (T-AOC, SOD, CAT, GSH-PX), Nitric oxide synthase (T-NOS and iNOS), and GSH. Moreover, PNPA could still reduce the production of I/R-induced inflammatory cytokines (IL-1β, IL-6, TNF-α and NF-κB) in liver, along with MPO. I/R-induced high level of pro-apoptotic indicators (cytochrome c, Bax, and caspase 3) and low level of anti-apoptotic indicators Bcl-2 were reversed after PNPA pretreatment. Therefore, PNPA might be a promising candidate for preventing hepatic I/R injury.


Molecularly imprinted composite cryogels for hemoglobin depletion from human blood.
A molecularly imprinted composite cryogel (MICC) was prepared for depletion of hemoglobin from human blood prior to use in proteome applications. Poly(hydroxyethyl methacrylate) based MICC was prepared with high gel fraction yields up to 90%, and characterized by Fourier transform infrared spectrophotometer, scanning electron microscopy, swelling studies, flow dynamics and surface area measurements. MICC exhibited a high binding capacity and selectivity for hemoglobin in the presence of immunoglobulin G, albumin and myoglobin. MICC column was successfully applied in fast protein liquid chromatography system for selective depletion of hemoglobin for human blood. The depletion ratio was highly increased by embedding microspheres into the cryogel (93.2%). Finally, MICC can be reused many times with no apparent decrease in hemoglobin adsorption capacity.


Superficial temporal artery as an external landmark for deeper-lying brain structures.
Additional localizing superficial landmarks for intracranial structures can be of use to the neurosurgeon. This study was performed to evaluate the usefulness of the superficial temporal artery (STA) as an external landmark for deeper brain structures. Thirteen adult cadavers (26 sides) underwent latex injection of their STA bilaterally. Dissections were next carried out to identify this vessel. Once the STA and its frontal and parietal branches were skeletonized, craniectomies were performed and the underlying dura mater excised. Measurements were made between the frontal and parietal branches of the STA and deeper brain structures. The STA was found to branch on average 3 cm superior to the tragus. The bifurcation of the STA was found to commonly bifurcate at the level of the floor of the middle cranial fossa or superior temporal gyrus. The Sylvian fissure was found at a mean of 2 cm superior to the STA bifurcation. The angle between the frontal branch of the STA and the zygomatic arch had a mean of 37 degrees. The angle between the frontal and parietal branches of the STA had a mean of 87 degrees. At the level of the glabella, the frontal branch of the STA was on average 3 cm posterior to the frontal pole. The temporal tip was located a mean of 3.2 cm anterior to the frontal branch of the STA. The plane of the foramen of Monro was found to lie at a mean distance of 2.3 cm posterior to the frontal branch of the STA. The parietal branch of the STA was noted to travel more or less parallel with the central sulcus in all specimens and to travel an average of 2 cm posterior to this sulcus. At the level of the lateral attachment of the tentorium cerebelli, the parietal branch of the STA was found to travel a mean of 4.8 cm anterior to the entrance of the vein of Labbé into the transverse sinus. The parietal branch of the STA was also found to travel a mean of 4.2 cm anterior to the angular gyrus and 3.9 cm anterior to the supramarginal gyrus. Palpation or Doppler identification of the STA and its branches with subsequent mapping on the lateral cranium may prove useful as an additional superficial landmark for the neurosurgeon.


Characterization of neonatal aortic cannula jet flow regimes for improved cardiopulmonary bypass.
During pediatric and neonatal cardiopulmonary bypass (CPB), tiny aortic outflow cannulae (2-3 mm inner diameter), with micro-scale blood-wetting features transport relatively large blood volumes (0.3 to 1.0 L/min) resulting in high blood flow velocities (2 to 5 m/s). These severe flow conditions are likely to complement platelet activation, release pro-inflammatory cytokines, and further result in vascular and blood damage. Hemodynamically efficient aortic outflow cannulae are required to provide high blood volume flow rates at low exit force. In addition, optimal aortic insertion strategies are necessary in order to alleviate hemolytic risk, post-surgical neurological complications and developmental defects, by improving cerebral perfusion in the young patient. The methodology and results presented in this study serve as a baseline for design of superior aortic outflow cannulae. In this study, direct numerical simulation (DNS) computational fluid dynamics (CFD) was employed to delineate baseline hemodynamic performance of jet wakes emanating from microCT scanned state-of-the-art pediatric cannula tips in a cuboidal test rig operating at physiologically relevant laminar and turbulent Reynolds numbers (Re: 650-2150 , steady inflow). Qualitative and quantitative validation of CFD simulated device-specific jet wakes was established using time-resolved flow visualization and particle image velocimetry (PIV). For the standard end-hole cannula tip design, blood damage indices were further numerically assessed in a subject-specific cross-clamped neonatal aorta model for different cannula insertion configurations. Based on these results, a novel diffuser type cannula tip is proposed for improved jet flow-control, decreased blood damage and exit force and increased permissible flow rates. This study also suggests that surgically relevant cannula orientation parameters such as outflow angle and insertion depth may be important for improved hemodynamic performance. The jet flow design paradigm demonstrated in this study represents a philosophical shift towards cannula flow control enabling favorable pressure-drop versus outflow rate characteristics.


The Effectiveness of Platelet-Rich Plasma Injections in Gluteal Tendinopathy: A Randomized, Double-Blind Controlled Trial Comparing a Single Platelet-Rich Plasma Injection With a Single Corticosteroid Injection.
Gluteus medius/minimus tendinopathy is a common cause of lateral hip pain or greater trochanteric pain syndrome. There would be no difference in the modified Harris Hip Score (mHHS) between a single platelet-rich plasma (PRP) injection compared with a corticosteroid injection in the treatment of gluteal tendinopathy. Randomized controlled trial; Level of evidence, 1. There were 228 consecutive patients referred with gluteal tendinopathy who were screened to enroll 80 participants; 148 were excluded (refusal: n = 42; previous surgery or sciatica: n = 50; osteoarthritis, n = 17; full-thickness tendon tear, n = 17; other: n = 22). Participants were randomized (1:1) to receive either a blinded glucocorticoid or PRP injection intratendinously under ultrasound guidance. A pain and functional assessment was performed using the mHHS questionnaire at 0, 2, 6, and 12 weeks and the patient acceptable symptom state (PASS) and minimal clinically important difference (MCID) at 12 weeks. Participants had a mean age of 60 years, a ratio of female to male of 9:1, and mean duration of symptoms of >14 months. Pain and function measured by the mean mHHS showed no difference at 2 weeks (corticosteroid: 66.95 ± 15.14 vs PRP: 65.23 ± 11.60) or 6 weeks (corticosteroid: 69.51 ± 14.78 vs PRP: 68.79 ± 13.33). The mean mHHS was significantly improved at 12 weeks in the PRP group (74.05 ± 13.92) compared with the corticosteroid group (67.13 ± 16.04) ( P = .048). The proportion of participants who achieved an outcome score of ≥74 at 12 weeks was 17 of 37 (45.9%) in the corticosteroid group and 25 of 39 (64.1%) in the PRP group. The proportion of participants who achieved the MCID of more than 8 points at 12 weeks was 21 of 37 (56.7%) in the corticosteroid group and 32 of 39 (82%) in the PRP group ( P = .016). Patients with chronic gluteal tendinopathy >4 months, diagnosed with both clinical and radiological examinations, achieved greater clinical improvement at 12 weeks when treated with a single PRP injection than those treated with a single corticosteroid injection. Registration: ACTRN12613000677707 (Australian New Zealand Clinical Trials Registry).


[The relationship between tuberculosis, vitamin D, potassium and AIDS. A message for South Africa?].
The converging epidemics of tuberculosis and acquired immunodeficiency syndrome (AIDS) in the RSA and their expected catastrophic interaction afford an ideal opportunity for well-planned and essential research by clinicians, molecular biologists, epidemiologists and other health workers. The enigmatic relationship between tuberculosis, vitamin D and calcium is a field of study which should be considered urgently. An optimal vitamin D status not only assures sound calcium-phosphorus homeostasis, but is also essential for maximal immune competency. Hypovitaminosis D probably predisposes towards vulnerability to tuberculosis due to deficient monocyte-macrophage function. In contrast, hypervitaminosis D can correct this deficiency, but would do so at the cost of both B- and T-lymphocyte efficiency. One example of such a state is the endogenous over-production of activated vitamin D by gamma-interferon-activated monocytes, tissue macrophages and granulomatous tissue in tuberculosis. This would not only cause the coincidental hypercalcaemia, but may also complicate the effective co-ordination of monocyte-lymphocyte interaction and consequently compromise an appropriate immune response. It can reasonably be expected that the raised plasma interferon levels in the AIDS patient may trigger similar vitamin D-related pathophysiological processes. It is proposed that the ideal situation for enhanced vulnerability to tuberculosis in the AIDS patient will have been created if the known destructive effects of the human immunodeficiency virus on CD4-positive lymphocytes act synergistically with the vitamin D-mediated complications listed above.


Unilateral acute lung injury induced by ethchlorvynol in anesthetized dogs.
Ethchlorvynol (ECV) was used to induce unilateral acute lung injury in anesthetized dogs. Measurements of extravascular thermal volume by double-indicator (thermal-dye) dilution with and without left main pulmonary arterial occlusion permitted sequential estimates of extravascular lung water (EVLW) for each lung. Determinations of EVLW by thermal-dye and gravimetric methods were highly correlated (r = 0.80). ECV (9-15 mg/kg) administered into the right pulmonary circulation produced progressive increases in right lung EVLW, which by 120 min post-ECV was increased 152 +/- 22% (SE) over control (P less than 0.001). Left lung EVLW remained unchanged. Similarly, right, but not left, peak airway pressure was increased. Thermal dilution, coupled with electromagnetic methods, permitted estimates of blood flow to each lung. Despite redistribution of flow to the uninjured lung, systemic PO2 decreased (P less than 0.001) and venous admixture increased (P less than 0.05), suggesting impaired matching of ventilation and perfusion. In summary, introduction of ECV into one lung produced unilateral acute lung injury. EVLW increased solely in the injured lung as did peak airway pressure. Although there was a partial redistribution of blood flow away from the injured lung to the uninjured one, it was apparently inadequate to prevent impaired oxygenation of the blood.


Is there a link between components of health-related functioning and incident impaired glucose metabolism and type 2 diabetes? The Australian Diabetes Obesity and Lifestyle (AusDiab) study.
To determine the longitudinal association of components of health-related functioning (HRF) with incident impaired glucose metabolism and type 2 diabetes. The Australian Diabetes Obesity and Lifestyle (AusDiab) study is a national, longitudinal study of adults aged > or =25 years from 42 randomly selected areas of Australia. Diabetes status was defined using the World Health Organization criteria, and HRF was assessed using the SF-36 questionnaire in 1999-2000 and 2004-2005. Incident impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes were associated with increased bodily pain at baseline compared with those with normal glucose tolerance (NGT) (IFG P = 0.005, IGT P < 0.004, and newly diagnosed type 2 diabetes P = 0.005), after adjustment. In addition, those with incident IGT and newly diagnosed type 2 diabetes had significantly reduced physical functioning, general health, mental health, and vitality at baseline compared with those with NGT. After we controlled for factors associated with incident diabetes, those in the lowest quartile of the physical component summary scale at baseline had at least a 50% higher risk of progression to impaired glucose metabolism and diabetes 5 years later. These findings show that incident IFG, IGT, and newly diagnosed type 2 diabetes are associated with reduced HRF independent of cardiovascular disease and that this is evident before the onset of these conditions. If future health promotion campaigns are to effectively target those at high risk of developing diabetes, an understanding of the process of declining health before onset of the disease is essential.


Recent advances and the potential for clinical use of xenotransplantation.
The success of allotransplantation has paradoxically led to a shortage in the supply of organs required to meet the increasing demand. Xenografts represent a potentially infinite supply of good quality organs. Recent advances in the understanding of the immunobiology of xenograft rejection has spurred experimental approaches aimed at abrogating or suppressing human xenospecific immune responses. The limited supply of colony-bred nonhuman primates (baboons) makes it highly unlikely that this species will be of widespread use as a donor source. Therefore, the pig has been proposed as a realistic alternative donor. Delineation of the major pig xenoantigens recognized by natural human xenoreactive antibodies has led to the development of strategies aimed at depletion of antibodies or the prevention of their binding to xenogeneic endothelium. Recognition that antibody binding leads to endothelial cell activation and complement-mediated injury has led to the development of genetically modified pigs whose organs are potentially resistant to damage by human complement by virtue of the fact that their endothelial cells express membranebound human complement regulatory proteins. Finally, dissection of the relative contributions of humoral and cellular immune responses directed against xenografts from closely or distantly related species has permitted rational recommendations for the administration of immunosuppressive regimens.


Early magnetic resonance imaging of radiographically occult osteoporotic fractures of the femoral neck.
Osteoporosis is associated with thinning of cortical and trabecular bone, which reduces bone strength and predisposes individuals to fracture development. Femoral neck fractures in patients with osteoporosis may not be apparent on radiographs. Magnetic resonance imaging is useful at detecting these radiographically occult fractures; yet, the practice has not been widely adopted in Hong Kong. In this article, we review our experience of early magnetic resonance imaging in this clinical context--that is, imaging performed within 48 hours of presentation to hospital. Twenty-eight patients (age range, 69-93 years) over a 3-year period were studied. Magnetic resonance imaging revealed radiographically occult neck fractures in 14 (50%) cases (equivalent to 4% of all femoral neck fractures). These fractures were treated surgically (64%) or conservatively (36%) with good bone healing and clinical outcome. When no femoral neck fracture was present, magnetic resonance imaging revealed an alternative cause for symptoms in all 14 cases. We strongly endorse the use of early magnetic resonance imaging for patients with osteoporosis who have a clinically suspected femoral neck fracture that is not visible radiographically.


Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors.
Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization of transcriptional lineage programs, with downregulation of megakaryocyte-erythroid genes from HSCs to LMPPs, sustained granulocyte-monocyte priming, and upregulation of common lymphoid (but not B and T cell-specific) genes. These biological and molecular relationships, implicating almost mutual exclusion of megakaryocyte-erythroid and lymphoid pathways, are established already in fetal hematopoiesis, as evidenced by existence of LMPPs in fetal liver. The identification of LMPPs and hierarchically ordered transcriptional activation and downregulation of distinct lineage programs is compatible with a model for HSC lineage commitment in which the probability for undergoing different lineage commitment fates changes gradually when progressing from HSCs to LMPPs.


In vitro penetration of Salmonella Enteritidis through yolk membranes of eggs from 6 genetically distinct commercial lines of laying hens.
Although deposition of Salmonella Enteritidis inside yolks is less common than deposition in albumen or on the vitelline (yolk) membrane in naturally contaminated eggs laid by infected hens, bacterial migration into the yolk to reach its nutrient-rich contents could lead to extensive multiplication. The present study used an in vitro egg contamination model to assess the ability of small initial numbers of Salmonella Enteritidis to penetrate the vitelline membrane and multiply inside yolks of eggs laid by 6 genetically distinct commercial lines of hens during 24 h of storage at 30 degrees C. Eggs from each line were tested at 4 different hen ages by inoculation of approximately 100 cfu of Salmonella Enteritidis onto the outside of the vitelline membranes of intact yolks in plastic centrifuge tubes and then adding back the albumen into each tube before incubation. Overall, the frequency of penetration of Salmonella Enteritidis into the yolk contents of eggs from individual lines of hens ranged from 30 to 58% and the mean concentration of Salmonella Enteritidis in yolk contents after incubation ranged from 0.8 to 2.0 log(10) cfu/mL. For both of these parameters, values for one hen line were significantly higher than for 2 other lines, but no other differences were observed. Hen age did not have a significant effect on egg yolk penetration by Salmonella Enteritidis. These results indicate that opportunities for the migration and growth of small initial numbers of Salmonella Enteritidis to attain more dangerous levels inside contaminated eggs during storage at warm temperatures can sometimes vary between different lines of laying hens.


Volumetric Bioprinting of Complex Living-Tissue Constructs within Seconds.
Biofabrication technologies, including stereolithography and extrusion-based printing, are revolutionizing the creation of complex engineered tissues. The current paradigm in bioprinting relies on the additive layer-by-layer deposition and assembly of repetitive building blocks, typically cell-laden hydrogel fibers or voxels, single cells, or cellular aggregates. The scalability of these additive manufacturing technologies is limited by their printing velocity, as lengthy biofabrication processes impair cell functionality. Overcoming such limitations, the volumetric bioprinting of clinically relevant sized, anatomically shaped constructs, in a time frame ranging from seconds to tens of seconds is described. An optical-tomography-inspired printing approach, based on visible light projection, is developed to generate cell-laden tissue constructs with high viability (>85%) from gelatin-based photoresponsive hydrogels. Free-form architectures, difficult to reproduce with conventional printing, are obtained, including anatomically correct trabecular bone models with embedded angiogenic sprouts and meniscal grafts. The latter undergoes maturation in vitro as the bioprinted chondroprogenitor cells synthesize neo-fibrocartilage matrix. Moreover, free-floating structures are generated, as demonstrated by printing functional hydrogel-based ball-and-cage fluidic valves. Volumetric bioprinting permits the creation of geometrically complex, centimeter-scale constructs at an unprecedented printing velocity, opening new avenues for upscaling the production of hydrogel-based constructs and for their application in tissue engineering, regenerative medicine, and soft robotics.


Synthesis of polyaspartic acid-aminobenzenesulfonic acid grafted copolymer and its scale inhibition performance and dispersion capacity.
Polysuccinimide (abridged as PSI) was synthesized by urea and maleic anhydride. Aminobenzenesulfonic acid (ABSA) was introduced at different mole ratio to PSI to generate polyaspartic acid (abridged as PASP)/ABSA graft copolymer. The scale inhibition behavior of resultant PASP/ABSA copolymer was evaluated by using static scale inhibition method. The transmittance of the supernatant of the copolymer solution was measured to evaluate its dispersion ability for ferric oxide. The corrosion inhibition performance of the copolymer for iron plates immersed in the refined testing water (including 0.555 g of CaCl2 2H2O, 0.493 g of MgSO4 7H2O, 50 mg PASP/ABSA graft copolymer and 0.168 g of NaCl) was tested. It was found that PASP/ABSA copolymer was able to efficiently inhibit CaCO3 and Ca3(PO4)2 scales and had good corrosion inhibition ability as well, and it also had good dispersion ability for Fe2O3. Besides, the inhibition efficiency of PASP/ABSA against CaCO3 and Ca3(PO4)2 scales and its dispersion capacity for Fe2O3 was highly dependent on dosage. The reason may lie in that PASP/ABSA copolymer simultaneously possesses carboxylic ion and sulfonic group which can chelate Ca2+ to form stabilized and dissoluble chelates, resulting in increase of solubility of calcium salts in water. Also it may lie in that the introduction of acidic hydrophilic sulfonic group with a strong electrolytic capacity into PASP molecule simultaneously enhances the dispersion of the inhibitor molecules and hinders the formation of Ca3(PO4)2 scale.


Structural and biochemical insights into the V/I505T mutation found in the EIAV gp45 vaccine strain.
The equine infectious anemia virus (EIAV) is a lentivirus of the Retrovirus family, which causes persistent infection in horses often characterized by recurrent episodes of high fever. It has a similar morphology and life cycle to the human immunodeficiency virus (HIV). Its transmembrane glycoprotein, gp45 (analogous to gp41 in HIV), mediates membrane fusion during the infection. However, the post-fusion conformation of EIAV gp45 has not yet been determined. EIAV is the first member of the lentiviruses for which an effective vaccine has been successfully developed. The attenuated vaccine strain, FDDV, has been produced from a pathogenic strain by a series of passages in donkey dermal cells. We have previously reported that a V/I505T mutation in gp45, in combination with other mutations in gp90, may potentially contribute to the success of the vaccine strain. To this end, we now report on our structural and biochemical studies of the gp45 protein from both wide type and vaccine strain, providing a valuable structural model for the advancement of the EIAV vaccine. We resolved crystal structures of the ecto-domain of gp45 from both the wild-type EIAV and the vaccine strain FDDV. We found that the V/I505T mutation in gp45 was located in a highly conserved d position within the heptad repeat, which protruded into a 3-fold symmetry axis within the six-helix bundle. Our crystal structure analyses revealed a shift of a hydrophobic to hydrophilic interaction due to this specific mutation, and further biochemical and virological studies confirmed that the mutation reduced the overall stability of the six-helix bundle in post-fusion conformation. Moreover, we found that altering the temperatures drastically affected the viral infectivity. Our high-resolution crystal structures of gp45 exhibited high conservation between the gp45/gp41 structures of lentiviruses. In addition, a hydrophobic to hydrophilic interaction change in the EIAV vaccine strain was found to modulate the stability and thermal-sensitivity of the overall gp45 structure. Our observations suggest that lowering the stability of the six-helix bundle (post-fusion), which may stabilizes the pre-fusion conformation, might be one of the reasons of acquired dominance for FDDV in viral attenuation.


Iron deficiency and impaired cognition in toddlers: an underestimated and undertreated problem.
Iron deficiency in toddlers is associated with impaired cognition and is an underestimated and undertreated problem. The prevalence of iron deficiency anemia (IDA) during the first year of life has been dramatically reduced in developed countries, mainly due to the increase in breastfeeding and the use of iron-fortified feeding formulae. However, in US and UK children aged 1-2 years, recent studies have shown prevalence rates of >10% and 30% for IDA and iron deficiency, respectively. The daily iron intake in children aged 1-2 years is lower than in any other age group during life. IDA during the first 2 years of life is associated with impaired mental and psychomotor development and these deficits are long lasting, and perhaps irreversible, despite the correction of the anemia. Another compelling reason to prevent iron deficiency in children, especially in children aged 1-2 years, is the proven association of iron deficiency with increased lead absorption. Lead-associated cognitive deficits occur at blood lead levels <10 microg/L, a level once thought to be harmless. The current prevalence rates of iron deficiency and IDA in toddlers, especially among those in the lower socioeconomic groups, are unacceptably high. These young children are doubly at risk for neurodevelopmental impairment, both from the iron deficiency itself as well as from CNS damage caused by the associated increased lead absorption. The current screening and treatment recommendations for IDA in the US and in other developed countries appear to have been unsuccessful in preventing iron deficiency and IDA in a large number of toddlers. Similarly, the associated problem of impaired mental and psychomotor development has not been adequately recognized or addressed in the existing medical literature. The author recommends that, after breastfeeding or an iron-fortified formula is stopped, iron deficiency and IDA be prevented by routine daily supplemental doses of 10mg of elemental iron via iron-fortified vitamins, iron drops, or iron-fortified drinks.


Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening.
Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus identify a common, multitarget site for antifungal development.


Intracellular oxygen diffusion: the roles of myoglobin and lipid at cold body temperature.
Cold temperature can constrain the rate of oxygen movement through muscle cells of ectothermic animals because the kinetic energy of the solvent-solute system decreases and the viscosity of the aqueous cytoplasm increases during cooling within the physiological range of body temperatures. These factors affect the movement of both dissolved oxygen and oxymyoglobin, the two predominant routes of intracellular oxygen diffusion in vertebrate oxidative muscles. In addition, reductions in temperature have been shown to increase the affinity of myoglobin for oxygen and to slow the rate of Mb O2-dissociation, compromising the ability of this oxygen-binding protein to facilitate intracellular oxygen diffusion. Experiments with both seasonally cold-bodied fishes and polar fish species suggest that several factors combine to overcome these limitations in delivery of oxygen from the blood to the mitochondria. First, reductions in body temperature induce increases in mitochondrial density of oxidative muscle cells, reducing the mean diffusional pathlength for oxygen between capillaries and mitochondria. Second, cold body temperature in both temperate-zone and polar fishes is frequently correlated with a high content of neutral lipid in oxidative muscles, providing an enhanced diffusional pathway for oxygen through the tissue. Third, recent data indicate that myoglobins from fish species bind and release oxygen more rapidly at cold temperature than do those from mammals. Data from both oxidative skeletal muscle and cardiac muscle of fishes suggest that these factors in various combinations contribute to enhance the aerobically supported mechanical performance of the tissues at cold cellular temperatures.


Prevalence of respiratory adenovirus species B and C in sewage sludge.
Human adenovirus diversity in sewage sludge was assessed by Ion Torrent sequencing and annotation of partial adenovirus hexon genes. The most abundant species identified were HAdV-C (average 78%) and -B (average 20%), which are associated with respiratory infections. These findings reinforce the necessity to consider aerosol exposure to sewage-derived pathogens.


Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability.
The FOXP1 gene, located on chromosome 3p13, encodes the Forkhead-box protein P1, one of the four forkhead transcription factors which repress transcription by forming active homo- and heterodimers and regulate distinct patterns of gene expression crucial for embryogenesis and normal development. FOXP1 mutations, mostly truncating, have been described in patients with mild to moderate intellectual disability (ID), autism spectrum disorder (ASD), and speech and language impairment (MIM #613670). Here, we report a small de novo heterozygous balanced inversion of 2.1 Mb located at 3p14.1p13 identified by Whole Genomic Sequencing (WGS) and disrupting the genes FAM19A4 and FOXP1. This inversion was found in a patient with severe ID, ASD, seizures and very unusual vascular anomalies which were never described in the clinical spectrum of FOXP1 mutations. We show that the neurodevelopmental phenotype observed in the patient most likely results from FOXP1 haploinsufficiency as this heterozygous inversion leads to a 60 to 85% decrease of FOXP1 mRNA levels and to the complete absence of FOXP1 full-length protein. These findings, in addition to expanding the molecular spectrum of FOXP1 mutations, emphasize the emerging role of WGS in identifying small balanced chromosomal rearrangements responsible for neurodevelopmental disorders and not detected by conventional cytogenetics.


Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13.
Myeloid-derived suppressor cells (MDSCs) are a well-defined population of cells that accumulate in the tissue of tumor-bearing animals and are known to inhibit immune responses. Within 4 days, bone marrow cells cultured in granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor resulted in the generation of CD11b(+)Ly6G(lo)Ly6C(+) MDSCs, the majority of which are interleukin-4Rα (IL-4Rα(+)) and F4/80(+). Such MDSCs potently inhibited in vitro allogeneic T-cell responses. Suppression was dependent on L-arginine depletion by arginase-1 activity. Exogenous IL-13 produced an MDSC subset (MDSC-IL-13) that was more potently suppressive and resulted in arginase-1 up-regulation. Suppression was reversed with an arginase inhibitor or on the addition of excess L-arginine to the culture. Although both MDSCs and MDSC-IL-13 inhibited graft-versus-host disease (GVHD) lethality, MDSC-IL-13 were more effective. MDSC-IL-13 migrated to sites of allopriming. GVHD inhibition was associated with limited donor T-cell proliferation, activation, and proinflammatory cytokine production. GVHD inhibition was reduced when arginase-1-deficient MDSC-IL-13 were used. MDSC-IL-13 did not reduce the graft-versus-leukemia effect of donor T cells. In vivo administration of a pegylated form of human arginase-1 (PEG-arg1) resulted in L-arginine depletion and significant GVHD reduction. MDSC-IL-13 and pegylated form of human arginase-1 represent novel strategies to prevent GVHD that can be clinically translated.


A double-stranded molecular probe for homogeneous nucleic acid analysis.
This paper reports the design and optimization of a double-stranded molecular probe for homogeneous detection of specific nucleotide sequences. The probes are labeled with either a fluorophore or a quencher such that the probe hybridization brings the two labels into close proximity, and this diminishes the fluorescence signal in the absence of a target. In the presence of a target, the fluorophore probe is thermodynamically driven to unzip from its hybridized form and bind with the target. An equilibrium analysis, which successfully describes all the major features of the assay without any fitting parameter, is performed to generalize the design of the probe. Several key parameters affecting the performance of the assay are examined. We show that the dynamic range and the signal-to-noise ratio of the assay can be optimized by the probe concentration, the quencher-to-fluorophore ratio, and the probe strand sequence. By proper design of the sequence, the probe discriminates single nucleotide mismatches in a single step without any separation step or measurement of melting profile.


Mobile App for Treatment of Stress Urinary Incontinence: A Cost-Effectiveness Analysis.
Mobile apps can increase access to care, facilitate self-management, and improve adherence to treatment. Stress urinary incontinence (SUI) affects 10-35% of women and, currently, an app with instructions for pelvic floor muscle training (PFMT) is available as first-line treatment. A previous randomized controlled study demonstrated that the app benefitted symptom severity and quality of life (QoL); in this study we investigate the cost-effectiveness of the app. The objective of this study was to evaluate the health economy of the app for treating SUI. This deterministic cost-utility analysis, with a 1-year societal perspective, compared the app treatment with no treatment. Health economic data were collected alongside a randomized controlled trial performed in Sweden from March 2013 to October 2014. This study included 123 community-dwelling women participants of 18 years and above, with stress urinary incontinence ≥1 time per week. Participants were self-assessed with validated questionnaires and 2-day leakage diaries, and then randomized to 3 months of treatment (app group, n=62) or no treatment (controls, n=61). The app focused on pelvic floor muscle training, prescribed 3 times daily. We continuously registered treatment delivery costs. Data were collected on each participant's training time, incontinence aids, and laundry at baseline and at a 3-month follow-up. We measured quality of life with the International Consultation on Incontinence Modular Questionnaire on Lower Urinary Tract Symptoms and Quality of Life, and calculated the quality-adjusted life years (QALYs) gained. Data from the 3-month follow-up were extrapolated to 1 year for the calculations. Our main outcome was the incremental cost-effectiveness ratios compared between app and control groups. One-way and multiway sensitivity analyses were performed. The mean age of participants was 44.7 years (SD 9.4). Annual costs were €547.0 for the app group and €482.4 for the control group. Annual gains in quality-adjusted life years for app and control groups were 0.0101 and 0.0016, respectively. Compared with controls, the extra cost per quality-adjusted life year for the app group ranged from -€2425.7 to €14,870.6, which indicated greater gains in quality-adjusted life years at similar or slightly higher cost. The app for treating stress urinary incontinence is a new, cost-effective, first-line treatment with potential for increasing access to care in a sustainable way for this patient group.


SAHG, a comprehensive database of predicted structures of all human proteins.
Most proteins from higher organisms are known to be multi-domain proteins and contain substantial numbers of intrinsically disordered (ID) regions. To analyse such protein sequences, those from human for instance, we developed a special protein-structure-prediction pipeline and accumulated the products in the Structure Atlas of Human Genome (SAHG) database at http://bird.cbrc.jp/sahg. With the pipeline, human proteins were examined by local alignment methods (BLAST, PSI-BLAST and Smith-Waterman profile-profile alignment), global-local alignment methods (FORTE) and prediction tools for ID regions (POODLE-S) and homology modeling (MODELLER). Conformational changes of protein models upon ligand-binding were predicted by simultaneous modeling using templates of apo and holo forms. When there were no suitable templates for holo forms and the apo models were accurate, we prepared holo models using prediction methods for ligand-binding (eF-seek) and conformational change (the elastic network model and the linear response theory). Models are displayed as animated images. As of July 2010, SAHG contains 42,581 protein-domain models in approximately 24,900 unique human protein sequences from the RefSeq database. Annotation of models with functional information and links to other databases such as EzCatDB, InterPro or HPRD are also provided to facilitate understanding the protein structure-function relationships.


Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode.
The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this "probe-before-destroy" approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. Kβ(1,3) XES spectra of Mn(II) and Mn(2)(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to >100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.


Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties.
Cyclooxygenase (COX)-3, a novel COX splice variant, was suggested as the key to unlocking the mystery of the mechanism of action of acetaminophen. Although COX-3 might have COX activity in canines, and this activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance. In rodents and humans, COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity; therefore, it is improbable that COX-3 in these species plays a role in prostaglandin-mediated fever and pain. The aim of this review is to evaluate the literature that seeks to point out critical theoretical and methodological limitations of the COX-3 studies that led several investigators to scientifically questionable conclusions.


BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews.
Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val(80) and [TTTA](n)) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val(80) G/G genotype was associated with significantly increased risk of breast cancer compared with the Val(80) A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val(80) polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val(80) G allele and three haplotype-tagging single nucleotide polymorphisms (rs727479, rs10046, and rs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA](n) found in linkage disequilibrium with Val(80). The present study suggests that the CYP19 Val(80) polymorphism and a haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations.


The accuracy of endoscopic features in eosinophilic esophagitis: the experience in children from rural West Virginia.
We assessed the accuracy of esophageal endoscopic features in children with eosinophilic esophagitis (EoE) living in rural communities in West Virginia. Specific esophageal endoscopic features for EoE disease have been identified in children and adults. In the published reports, the sensitivity of these features ranged between 19% and 56%. The accuracy of these features in children with EoE living in rural communities has not been published. A total of 271 patients' charts were reviewed of whom 53 children had EoE, 103 had gastroesophageal reflux disease, and 115 had normal esophagus. The calculated sensitivity, specificity, positive and negative predictive values, and accuracy rate for the presence of any mucosal feature for EoE disease were 88% (95% CI, 76-95), 98% (95% CI, 92-99), 96% (95% CI, 84-99), 94% (95% CI, 87-97), and 94.8%, respectively. The odds ratios for endoscopic furrows and erythema in EoE and gastroesophageal reflux disease patients were 155.4 (95% CI: 33.5, 719.8) and 13.4 (95% CI: 5.9, 30.5), respectively. When EoE patients were compared with normal patients, the odds ratio for erythema was 95.8 (95% CI: 31.4, 292.6). Dysphagia and choking were significantly more common in EoE children compared with control groups (P<0.001). Esophageal features of EoE in children living in rural communities have a high accuracy rate for the diagnosis of EoE compared with the data reported from children living in urban/semiurban communities. We suggest that in a proper clinical scenario, therapeutic measurement could be started before histology results are available. Future investigation of the phenotypic presentation of EoE disease in children from rural communities is warranted.


1H NMR metabolic profiling of cod (Gadus morhua) larvae: potential effects of temperature and diet composition during early developmental stages.
Marine aquaculture offers a great source of protein for the increasing human population, and farming of, for example, Atlantic salmon is a global industry. Atlantic cod farming however, is an example of a promising industry where the potential is not yet realized. Research has revealed that a major bottleneck to successful farming of cod is poor quality of the larvae and juveniles. A large research program was designed to increase our understanding of how environmental factors such as temperature and nutrition affects cod larvae development. Data on larvae growth and development were used together with nuclear magnetic resonance. The NMR data indicated that the temperature influenced the metabolome of the larvae; differences were related to osmolytes such as betaine/TMAO, the amino acid taurine, and creatine and lactate which reflect muscle activity. The larvae were fed Artemia from stage 2, and this was probably reflected in a high taurine content of older larvae. Larvae fed with copepods in the nutrition experiment also displayed a high taurine content, together with higher creatine and betaine/TMAO content. Data on the cod larvae metabolome should be coupled to data on gene expression, in order to identify events which are regulated on the genetic level versus regulation resulting from temperature or nutrition during development, to fully understand how the environment affects larval development.


Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes.
The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain. Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored. There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups. The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine. NCT01681875, Post-results.


Death and dementia.
To investigate the last phase of dementia and the causes of death; comparing autopsy and death certificate diagnoses. Prospective, 11-year, longitudinal study of behavioural and psychological changes in dementia, with autopsy follow-up. Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. Ninety-one people with dementia (Alzheimer's disease and/or vascular dementia) who died during the course of the study. At four-monthly intervals, carers were interviewed about the participants' behaviour using the Present Behavioural Examination. Participants were also assessed cognitively. Causes of death were established from death certificates and, where possible, from post-mortem examination. The main immediate cause of death recorded at autopsy was pneumonia (57%), followed by cardiovascular disease (16%) and pulmonary embolus (14%). This agreed with the immediate cause of death on 53% of death certificates. Pulmonary embolism and bronchopneumonia were under-reported on death certificates. Dementia was mentioned on 73% of death certificates. The dementing illness lasted for a mean of 8.5 years with 58% dying in a debilitated state associated with severe dementia. In the period before death, 35% were unable to walk, 58% were hypophagic, 73% were incontinent of urine, 21% incontinent of faeces and 76% entered an institution permanently for a mean period of 18 months. Family and professional carers of people with dementia can be given some information about prognosis to help them plan for the likely outcome of dementia.


Microbial colonization and competition on the marine alga Ulva australis.
Pseudalteromonas tunicata and Roseobacter gallaeciensis are biofilm-forming marine bacteria that are often found in association with the surface of the green alga Ulva australis. They are thought to benefit the plant host by producing inhibitory compounds that are active against common fouling organisms. We investigated factors that influence the ability of P. tunicata and R. gallaeciensis to attach to and colonize the plant surface and also the competitive interactions that occur between these organisms and other isolates from U. australis during biofilm formation on the plant surface. A surprisingly high number of P. tunicata cells, at least 10(8) cells ml(-1), were required for colonization and establishment of a population of cells that persists on axenic surfaces of U. australis. Factors that enhanced colonization of P. tunicata included inoculation in the dark and pregrowth of inocula in medium containing cellobiose as the sole carbon source (cellulose is a major surface polymer of U. australis). It was also found that P. tunicata requires the presence of a mixed microbial community to colonize effectively. In contrast, R. gallaeciensis effectively colonized the plant surface under all conditions tested. Studies of competitive interactions on the plant surface revealed that P. tunicata was numerically dominant compared with all other bacterial isolates tested (except R. gallaeciensis), and this dominance was linked to production of the antibacterial protein AlpP. Generally, P. tunicata was able to coexist with competing strains, and each strain existed as microcolonies in spatially segregated regions of the plant. R. gallaeciensis was numerically dominant compared with all strains tested and was able to invade and disperse preestablished biofilms. This study highlighted the fact that microbial colonization of U. australis surfaces is a dynamic process and demonstrated the differences in colonization strategies exhibited by the epiphytic bacteria P. tunicata and R. gallaeciensis.


Iris-based medical analysis by geometric deformation features.
Iris analysis studies the relationship between human health and changes in the anatomy of the iris. Apart from the fact that iris recognition focuses on modeling the overall structure of the iris, iris diagnosis emphasizes the detecting and analyzing of local variations in the characteristics of irises. This paper focuses on studying the geometrical structure changes in irises that are caused by gastrointestinal diseases, and on measuring the observable deformations in the geometrical structures of irises that are related to roundness, diameter and other geometric forms of the pupil and the collarette. Pupil and collarette based features are defined and extracted. A series of experiments are implemented on our experimental pathological iris database, including manual clustering of both normal and pathological iris images, manual classification by non-specialists, manual classification by individuals with a medical background, classification ability verification for the proposed features, and disease recognition by applying the proposed features. The results prove the effectiveness and clinical diagnostic significance of the proposed features and a reliable recognition performance for automatic disease diagnosis. Our research results offer a novel systematic perspective for iridology studies and promote the progress of both theoretical and practical work in iris diagnosis.


Hydroxyethyl starch or saline for fluid resuscitation in intensive care.
The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).


Effect of Roadside Vegetation Cutting on Moose Browsing.
Moose (Alces americanus ) vehicle collisions (MVCs) are an issue throughout the distribution of moose. Many mitigation strategies have been tested and implemented to reduce the number of MVCs, but there have been few empirical analyses of the effectiveness of roadside vegetation cutting. The goal of this study was to determine if roadside vegetation cutting attracted moose into roadside areas to browse on the vegetation regrowth. We hypothesized that moose would be attracted to roadside areas with cut vegetation. Consequently, we predicted that there would be higher levels of browsing in cut areas compared to uncut areas. To determine if moose were browsing more in cut or uncut areas, we measured the number of plants browsed by moose in paired treatment (cut on or after 2008) and control (not cut since at least 2008) sites, along with a suite of potential environmental covariates. Using a model selection approach, we fit generalized linear mixed-effects models to determine the most parsimonious set of environmental variables to explain variation in the proportion of moose browse among sites. In contrast to our hypothesis, our results show that the proportion of moose browse in the uncut control areas was significantly higher than in the cut treatment areas. The results of this study suggest that recently cut roadside areas (7 years or less based on our work) may create a less attractive foraging habitat for moose. The majority of the variance in the proportion of moose browse among sites was explained by treatment type and nested plot number within site identification (34.16%), with additional variance explained by traffic region (5.00%) and moose density (4.35%). Based on our study, we recommend that vegetation cutting be continued in roadside areas in Newfoundland as recently cut areas may be less attractive browsing sites for moose.


In-vitro accuracy and reproducibility evaluation of probing depth measurements of selected periodontal probes.
The purpose of the present in vitro study was to measure the accuracy and reproducibility of three periodontal probes. To eliminate environment- or examiner-related probing errors, two aluminum blocks with predrilled holes of varying depths were examined by participants who had been trained in probing before the study. This methodology improved the likelihood that any probing errors identified were generated by the probes themselves. Three probes, Williams 14 W (Hu-Friedy Mfg. Co., LLC, UK), Chapple UB-CF-15 (Implantium, Shrewsbury, UK), and Vivacare TPS (Ivoclar Vivadent, Enderby, UK), were randomly distributed to 23 participants (9 males and 14 females; mean age: 31.35 years). Participants measured 30 holes in two aluminum blocks, average 20 days, SD = 341.05. For each hole, the mean measured depth was calculated for each participant and compared to the true depth. Intra- and inter-examiner accuracy and reproducibility for each of the duplicate measurements were calculated. Data were analyzed by paired-samples t-test with the SPSS 18 software package (IBM Portsmouth, UK). A p-value <0.05 indicated statistical significance. Tables were constructed from the data. When used by participants, the Williams 14 W probe was reproducible but not necessarily accurate; Vivacare TPS was neither accurate nor reproducible; and Chapple UBCF-15 was both accurate and reproducible. Depth measurements with the Chapple UB-CF-15 probe were more accurate and reproducible compared to measurements with the Vivacare TPS and Williams 14 W probes. This in vitro model may be useful for intra-examiner calibration or clinician training prior to the clinical evaluation of patients or in longitudinal studies involving periodontal evaluation.


Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia.
Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function. Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements. The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle. Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.


A review of morphological characteristics relating to the production and reproduction of fat-tailed sheep breeds.
The purpose of this study is to survey the literature pertinent to some morphological traits which are related with the production and reproduction of fat-tailed sheep breeds. The fat-tailed breeds were identified according to Food and Agriculture Organization databases. Articles referring to all these sheep breeds were evaluated. The morphology of udders and their measurable variables were collected and described. The particularities of pelt and fleece features which are important from an economic point of view were summarized. Linear, planar, and spatial parameters of body, slaughter, and carcass factors were compared at various ages of breeding. Testicular dimensions and semen characteristics were recorded. Their relationships with productive and reproductive performance were discussed. The pattern of ovarian follicle development and the involution of the genital tract were assessed from the anatomical point of view in normal and untreated animals. The data presented here provide useful baseline information on the normal morphological aspects which are important in the animal production of these breeds.


Enhancing prototype reduction schemes with recursion: a method applicable for "large" data sets.
Most of the prototype reduction schemes (PRS), which have been reported in the literature, process the data in its entirety to yield a subset of prototypes that are useful in nearest-neighbor-like classification. Foremost among these are the prototypes for nearest neighbor classifiers, the vector quantization technique, and the support vector machines. These methods suffer from a major disadvantage, namely, that of the excessive computational burden encountered by processing all the data. In this paper, we suggest a recursive and computationally superior mechanism referred to as adaptive recursive partitioning (ARP)_PRS. Rather than process all the data using a PRS, we propose that the data be recursively subdivided into smaller subsets. This recursive subdivision can be arbitrary, and need not utilize any underlying clustering philosophy. The advantage of ARP_PRS is that the PRS processes subsets of data points that effectively sample the entire space to yield smaller subsets of prototypes. These prototypes are then, in turn, gathered and processed by the PRS to yield more refined prototypes. In this manner, prototypes which are in the interior of the Voronoi spaces, and thus ineffective in the classification, are eliminated at the subsequent invocations of the PRS. We are unaware of any PRS that employs such a recursive philosophy. Although we marginally forfeit accuracy in return for computational efficiency, our experimental results demonstrate that the proposed recursive mechanism yields classification comparable to the best reported prototype condensation schemes reported to-date. Indeed, this is true for both artificial data sets and for samples involving real-life data sets. The results especially demonstrate that a fair computational advantage can be obtained by using such a recursive strategy for "large" data sets, such as those involved in data mining and text categorization applications.


Periorbital dermatitis in 4779 patients - patch test results during a 10-year period.
The thinness of the periorbital skin may facilitate allergen penetration, making this area particularly susceptible to sensitization. For the cross-sectional study, data were collected by the 57 participating centres of the Information Network of Departments of Dermatology. A total of 101 403 patients patch tested between January 2001 and December 2010 were included. Of these, 4779 patients suffered from periorbital dermatitis. Two major subgroups with different general epidemiological data and sensitization to specific allergens have to be considered: (i) young females with increased rates of skin atopy and allergies, particularly from cosmetic and skin care products; and (ii) older subjects with allergy to topical medications. The prevalence of sensitization to ophthalmic allergens is generally less than that to environmental allergens. Allergic contact dermatitis is a leading cause of periorbital dermatitis. Patch testing should be considered in all patients with periorbital dermatitis when contact allergy is suspected, in order to identify and avoid offending allergens.


Commands, competence, and cariño: maternal socialization practices in Mexican American families.
Early research on the socialization of Latino children has posited that mothers exercise authoritarian practices, compared with lateral reasoning (authoritative) strategies emphasized by Anglo mothers. This work aimed to categorize fixed types of parenting practices tied to the mother's personality rather than to culturally bounded contexts; it often ignored the emotional warmth or harshness present in compliance attempts and relied on interview questions rather than naturalistic observation. We built from ecocultural theory to observe daily home activities in which Mexican American mothers attempted to correct their young child's behavior or encourage completion of a task (compliance attempt). We observed 24 first- or second-generation mothers and their 4-year-old children and analyzed the activity contexts and multiple forms of 1,477 compliance attempts. Mothers typically led with direct verbal commands in their attempt to achieve compliance. Many blended commands with other compliance strategies, rather than repeating simple behaviors. Drawing on Crockenberg and Litman's (1990) differentiation of variable compliance strategies, we find that most mothers relied on low power-assertive methods, including verbal commands, rather than inductive strategies that involved reasoning. Few compliance episodes prompted high power-assertive or harsh strategies. The degree of reliance on verbal commands and the complexity of mothers' repertoires appear to be related to their education and acculturation levels.


Dynamics and dissipation in enzyme catalysis.
We use quantized molecular dynamics simulations to characterize the role of enzyme vibrations in facilitating dihydrofolate reductase hydride transfer. By sampling the full ensemble of reactive trajectories, we are able to quantify and distinguish between statistical and dynamical correlations in the enzyme motion. We demonstrate the existence of nonequilibrium dynamical coupling between protein residues and the hydride tunneling reaction, and we characterize the spatial and temporal extent of these dynamical effects. Unlike statistical correlations, which give rise to nanometer-scale coupling between distal protein residues and the intrinsic reaction, dynamical correlations vanish at distances beyond 4-6 Å from the transferring hydride. This work finds a minimal role for nonlocal vibrational dynamics in enzyme catalysis, and it supports a model in which nanometer-scale protein fluctuations statistically modulate--or gate--the barrier for the intrinsic reaction.


Postmortem cesarean: report of our successful neonatal outcomes after severe trauma during pregnancy and review of the literature.
Postmortem cesarean is delivering of a child by cesarean section after the death of the mother. A prompt decision for cesarean delivery is very important in such cases. The survival of both the mother and the baby is dependent on a number of factors, including the time between maternal cardiac arrest and delivery, the underlying reasons for the arrest, the location of the arrest and the skills of the medical staffs. The earlier the fetus is delivered following maternal arrest the better is the fetal survival. Cesarean section should be performed no later than 4 minutes after initial maternal arrest. A fetus delivered within 5 minutes from initiation of CPR (cardiopulmonary resuscitation) has the best chance for survival. We reported 2 cases of successful postmortem cesarean section done 45 and 15 minutes after maternal death. The 1st case was a 29-year-old pregnant woman at 37 weeks gestation with cardiopulmonary arrest following gunshot head injuries. The baby survived with neurological sequels and ongoing treatment at our newborn intensive care unit. Second case admitted to the emergency service was a 28-year-old primigravida of 31 weeks gestation with cardiopulmonary arrest due to massive brain and thoracic hemorrhage after a road traffic accident. The baby recovered without neurological sequels.


The Dual Role of TNF in Pulmonary Edema.
-Pulmonary edema, a major manifestation of left ventricular heart failure, renal insufficiency, shock, diffuse alveolar damage and lung hypersensitivity states, is a significant medical problem worldwide and can be life-threatening. The proinflammatory cytokine tumor necrosis factor (TNF) has been shown to contribute to the pathogenesis and development of pulmonary edema. However, some recent studies have demonstrated surprisingly that TNF can also promote alveolar fluid reabsorption in vivo and in vitro. This protective effect of the cytokine is mediated by the lectin-like domain of the cytokine, which is spatially distinct from the TNF receptor binding sites. The TIP peptide, a synthetic mimic of the lectin-like domain of TNF, can significantly increase alveolar fluid clearance and improve lung compliance in pulmonary edema models. In this review, we will discuss the dual role of TNF in pulmonary edema. -tumor necrosis factor (TNF); acute lung injury (ALI); acute respiratory distress syndrome (ARDS); positive end-expiratory pressure (PEEP);epithelial sodium channel (ENaC);neural precursor cell-expressed developmentally downregulated (gene 4) protein (Nedd4-2);serum and glucocorticoid dependent kinase (Sgk-1);insulin-like growth factor 1 (IGF-1);Protein Kinase C (PKC);reactive oxygen species (ROS);myosin light chain (MLC);pneumolysin (PLY);listeriolysin (LLO);interleukin (IL);bronchoalveolar lavage fluids (BALF);Bacillus Calmette-Guerin (BCG);TNF receptor type 1 (TNFR1); TNF receptor type 2 (TNF-R2);


Determinants of feeling hindered by health problems in daily living at 60 years and above.
Although the ability to perform activities of daily living (ADL) is frequently used to identify the impact on daily living caused by health problems such as diseases, impaired eyesight or hearing, it is still not well known what makes people feel hindered in daily living with more or less inability to perform ADL. The aim of this study was to investigate feeling hindered by health problems in daily living among people (n = 958, 60-96 years) in relation to ADL capacity, health problems as well as social and financial resources, sense of coherence and life satisfaction. The data are taken from a baseline survey in one of the four included centres (Blekinge) of the longitudinal multicentre cohort study, The Swedish National Study on Aging and Care. The result showed that people felt hindered by their health problems despite no impairment in ADL capacity. Feeling greatly hindered by health problems was associated with factors linked to mobility but also to fatigue, no help when needed, and avoiding being outdoors due to fear of falling. Factors associated with feeling greatly hindered differed depending on whether people were impaired in ADL capacity or not. In people with excellent ADL capacity feeling hindered was associated with picking up things from the floor and rising from a chair and fatigue, whereas avoiding being outdoors, no help when needed and rising from a chair were found to be associated with feeling hindered by health problems among people with impaired ADL capacity. Combining people's ADL capacity with questions about feeling hindered may provide knowledge of determinant factors of feeling hindered in relation to ADL capacity, impaired or not, to identify people in need of rehabilitation or other interventions.


The natural history of nitrogen fixation.
In recent years, our understanding of biological nitrogen fixation has been bolstered by a diverse array of scientific techniques. Still, the origin and extant distribution of nitrogen fixation has been perplexing from a phylogenetic perspective, largely because of factors that confound molecular phylogeny such as sequence divergence, paralogy, and horizontal gene transfer. Here, we make use of 110 publicly available complete genome sequences to understand how the core components of nitrogenase, including NifH, NifD, NifK, NifE, and NifN proteins, have evolved. These genes are universal in nitrogen fixing organisms-typically found within highly conserved operons-and, overall, have remarkably congruent phylogenetic histories. Additional clues to the early origins of this system are available from two distinct clades of nitrogenase paralogs: a group composed of genes essential to photosynthetic pigment biosynthesis and a group of uncharacterized genes present in methanogens and in some photosynthetic bacteria. We explore the complex genetic history of the nitrogenase family, which is replete with gene duplication, recruitment, fusion, and horizontal gene transfer and discuss these events in light of the hypothesized presence of nitrogenase in the last common ancestor of modern organisms, as well as the additional possibility that nitrogen fixation might have evolved later, perhaps in methanogenic archaea, and was subsequently transferred into the bacterial domain.


5-Benzylidene-4-Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms.
The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5-benzylidene-4-oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen-matrix model of biofilm infection.


Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy.
Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers.