Fat in the lumbar multifidus muscles - predictive value and change following disc prosthesis surgery and multidisciplinary rehabilitation in patients with chronic low back pain and degenerative disc: 2-year follow-up of a randomized trial.
Evidence is lacking on whether fat infiltration in the multifidus muscles affects outcomes after total disc replacement (TDR) surgery and if it develops after surgery. The aims of this study were 1) to investigate whether pre-treatment multifidus muscle fat infiltration predicts outcome 2 years after treatment with TDR surgery or multidisciplinary rehabilitation, and 2) to compare changes in multifidus muscle fat infiltration from pre-treatment to 2-year follow-up between the two treatment groups. The study is secondary analysis of data from a trial with 2-year follow-up of patients with chronic low back pain (LBP) and degenerative disc randomized to TDR surgery or multidisciplinary rehabilitation. We analyzed (aim 1) patients with both magnetic resonance imaging (MRI) at pre-treatment and valid data on outcome measures at 2-year follow-up (predictor analysis), and (aim 2) patients with MRI at both pre-treatment and 2-year follow-up. Outcome measures were visual analogue scale (VAS) for LBP, Oswestry Disability Index (ODI), work status and muscle fat infiltration on MRI. Patients with pre-treatment MRI and 2-year outcome data on VAS for LBP (n = 144), ODI (n = 147), and work status (n = 137) were analyzed for prediction purposes. At 2-year follow-up, 126 patients had another MRI scan, and change in muscle fat infiltration was compared between the two treatment groups. Three radiologists visually quantified multifidus muscle fat in the three lower lumbar levels on MRI as <20% (grade 0), 20-50% (grade 1), or >50% (grade 2) of the muscle cross-section containing fat. Regression analysis and a mid-P exact test were carried out. Grade 0 pre-treatment multifidus muscle fat predicted better clinical results at 2-year follow-up after TDR surgery (all outcomes) but not after rehabilitation. At 2-year follow-up, increased fat infiltration was more common in the surgery group (intention-to-treat p = 0.03, per protocol p = 0.08) where it was related to worse pain and ODI. Patients with less fat infiltration of multifidus muscles before TDR surgery had better outcomes at 2-year follow-up, but findings also indicated a negative influence of TDR surgery on back muscle morphology in some patients. The rehabilitation group maintained their muscular morphology and were unaffected by pre-treatment multifidus muscle fat. NCT 00394732 (retrospectively registered October 31, 2006).


Associations between perceived cancer risk and established risk factors in a national community sample.
Perceptions of personal cancer risk may not accurately reflect individual's exposure to established risk factors. The purpose of this study was to assess associations between perceived cancer risk and selected established risk factors, using a large nationally representative sample. We used data from the 2000 National Health Interview Survey (NHIS) to perform a cross-sectional analysis of 30,223 adults without a cancer diagnosis. Multinominal logistic regression analyses were used to assess factors associated with medium and high perceived cancer risk. The effects of age, family history, and smoking status on perceived risk were linear and more pronounced on those with high perceived risk. High perceived risk was associated with every day smoking (relative risk ratio [RRR] = 4.27, 95% confidence intervals [CI] = 3.65-5.01), alcohol consumption (e.g. RRR = 1.26, 95% CI = 1.01-1.56 for current drinker), number of relatives with cancer (e.g. RRR = 20.64, 95% CI = 16.37-26 for those with both parents positive), low income (RRR = 1.25, 95% CI = 1.08-1.45), and female (RRR = 1.39, 95% CI = 1.23-1.57). Obesity (RRR = 1.32, 95% CI 1.1-1.6), but not overweight, was identified as an independent determinant. High perceived risk was inversely related to age (e.g. RRR = 0.19, 95% CI = 0.16-0.24 for adults 60 and older). Ethnic minorities were less likely to perceive cancer risk. Physical inactivity was not associated with high perceived risk. Among established risk factors, family history appears to be most reflected in the single measure of perceived cancer risk. The relationship between perceived cancer risk and exposure to established risk factors differs in important ways from what public campaigns have communicated with the public. Prevention messages should highlight that cancer risk increases with age and certain modifiable risk factors, including overweight and physical inactivity. The relationship between cancer risk perceptions and ethnicity merits further exploration.


Light-emitting diode therapy increases collagen deposition during the repair process of skeletal muscle.
This study analyzed the effects of light-emitting diode (LED) therapy on the morphology of muscle tissue as well as collagen remodeling and matrix metalloproteinase 2 (MMP-2) activity in the skeletal muscle of rats following acute injury. Wistar rats were divided into four groups: (1) control, (2) sham, (3) untreated cryoinjury, and (4) cryoinjury treated with LED. Cryoinjury was induced by two applications of a metal probe cooled in liquid nitrogen directly onto the belly of the tibialis anterior muscle. For treatment, the LED equipment (wavelength 850 nm, output power 30 mW, and total energy 3.2 J) was used daily. The study periods were 1, 3, and 7 days after cryoinjury. Morphological aspects were evaluated through hematoxylin-eosin staining. The amount of collagen fibers was evaluated using Picro Sirius Red staining under polarized light. The gelatinase activity of MMP-2 was evaluated using zymography. The results showed significant reductions in inflammatory infiltrate after 3 days and an increased number of immature muscle fibers after 7 days. Furthermore, treatment induced a reduction in the gelatinolytic activity of MMP-2 after 1, 3, and 7 days in comparison to the untreated injury groups and increased the collagen deposition after 3 and 7 days in the treated groups. LED therapy at 850 nm induced a significant reduction in inflammation, decreased MMP-2 activity, and increased the amount of immature muscle and collagen fibers during the muscle repair process following acute injury.


Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties.
Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was ∼17 μM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 μM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.


Cigarette Smoke Exposure Increases Glucose-6-phosphate Dehydrogenase, Autophagy, Fibrosis, and Senescence in Kidney Cells In Vitro and In Vivo.
Cigarette smoke (CS) is a risk factor for chronic obstructive pulmonary disease. We attempted to investigate fully the possible effects of CS on kidney cells. We found that the viability of a human kidney proximal tubular epithelial cell line (HK-2 cells) was decreased after treatment with CS extract (CSE). In particular, the effects of CSE at low concentrations did not change the expression of apoptosis and necrosis. Furthermore, CSE increased autophagy- and fibrosis-related proteins in HK-2 cells. Senescence-related proteins and the senescence-associated secretory phenotype (SASP) increased after HK-2 cells were treated with CSE. In addition, both RNA sequencing and gene set enrichment analysis data revealed that glucose-6-phosphate dehydrogenase (G6PD) in the reactive oxygen species (ROS) pathway is responsible for the changes in CSE-treated HK-2 cells. CSE increased G6PD expression and its activity. Moreover, the inhibition of G6PD activity increased senescence in HK-2 cells. The inhibition of autophagy reinforced senescence in the CSE-treated cells. In a mouse model of CS exposure, CS caused kidney damage, including tubular injury and glomerulosclerosis. CS increased fibrosis, autophagy, and G6PD expression in kidney tissue sections. In conclusion, CS induced G6PD expression, autophagy, fibrosis, and senescence in kidney cells. G6PD has a protective role in CS-induced nephrotoxicity.


Investigation of the Reliability of Saddle Fitters to Determine the Position of the Last Thoracic Vertebra of Horses Using Palpation Techniques: A Pilot Study.
Published guidelines indicate an English saddle tree should not extend beyond the 18th thoracic vertebra (T18). The study aimed to assess reliability of saddle fitters (SFs) to identify the T18 spinous process (SP). Part 1 investigated agreement between T18 (T18SF) as identified by three SFs using palpation and a veterinary surgeon (VS) using radiography (T18VS) in seven horses. Saddle fitter 1 and SF2 palpated the lumbosacral joint and counted cranially six SPs, whereas SF3 followed the rib curvature toward the dorsal midline. In part 2, SF1 and SF2 identified T18 by counting cranially five SPs in seven horses on two occasions. Agreement between SFs and VS was assessed using t tests and Bland-Altman plots. Interrater and intrarater reliability were estimated using intraclass correlation coefficients. In part 1, SF1 and SF2 found T18SF 4.3 cm (±4.1 and 4.0 cm, respectively) cranial to T18VS. Mean difference between T18SF3 and T18VS was 0.1 ± 4.9 cm (95% CI: -9.5 cm, 9.6 cm, P = .976). When counting cranially five SPs, mean difference between T18SF1 and T18VS was -1.5 ± 3.4 cm (95% CI: -8.3 cm; 5.1 cm; P = .265) and T18SF2 and T18VS was -0.3 cm ± 4.5 cm (95% CI: -8.8 cm; 8.5 cm; P = .847). Interrater reliability was "good" (ICC = 0.798). Intrarater reliability was "excellent" for SF1 (ICC = 0.905) and "good" for SF2 (ICC = 0.847). Counting cranially five SPs from the lumbosacral joint, when coupled with observation of the rib position and curvature should ensure a saddle is not placed beyond T18.


Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.
Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes.


Anatomy-driven design of a prototype video laryngoscope for extremely low birth weight infants.
Extremely low birth weight (ELBW) infants frequently require endotracheal intubation for assisted ventilation or as a route for administration of drugs or exogenous surfactant. In adults and less premature infants, the risks of this intubation can be greatly reduced using video laryngoscopy, but current products are too large and incorrectly shaped to visualize an ELBW infant's airway anatomy. We design and prototype a video laryngoscope using a miniature camera set in a curved acrylic blade with a 3×6-mm cross section at the tip. The blade provides a mechanical structure for stabilizing the tongue and acts as a light guide for an LED light source, located remotely to avoid excessive local heating at the tip. The prototype is tested on an infant manikin and found to provide sufficient image quality and mechanical properties to facilitate intubation. Finally, we show a design for a neonate laryngoscope incorporating a wafer-level microcamera that further reduces the tip cross section and offers the potential for low cost manufacture.


Incidence and Treatment of Arterial Access Dissections Occurring during Cardiac Catheterization.
Arterial access dissections may complicate cardiac catheterization and can often be treated percutaneously. The goal of this study was to examine the incidence, consequences, and the treatment of arterial access dissections at a tertiary referral hospital with an active training program. Patients experiencing arterial access dissection during coronary angiography or intervention at our institution between October 1, 2004, and January 31, 2007, were identified and their records were retrospectively reviewed. Thirteen of the 3,062 consecutive patients (0.42%) had arterial access dissection during the study period. The location of the dissection was in the common femoral artery (CFA) (n = 6), the external iliac artery (EIA) (n = 6), or in an aortobifemoral graft (n = 1). Three of the six patients with CFA dissection were diagnosed during coronary angiography, and because of significant comorbidities were treated with self-expanding stents. After a mean follow-up of 7 months, they experienced no stent fracture or other complication. Six patients had EIA dissections. In one such patient, the dissection was not flow limiting and was treated conservatively. The remaining five patients underwent successful implantation of self-expanding stents, and during a mean follow-up of 9.6 months, no patient had any symptoms or events related to lower extremity ischemia. Finally, one patient had an aortobifemoral graft dissection. Due to the patient's critical condition, secondary to sepsis, his family elected to withdraw care, and he subsequently expired. Arterial access dissections occur infrequently during cardiac catheterization. Routine femoral artery angiography may help identify vascular access complications, often allowing simultaneous endovascular treatment, with excellent short-term outcomes.


Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis.
Migration of neural progenitors in the complex tissue environment of the central nervous system is not well understood. Progress in this area has the potential to drive breakthroughs in neuroregenerative therapies, brain cancer treatments, and neurodevelopmental studies. To a large extent, advances have been limited due to a lack of controlled environments recapitulating characteristics of the central nervous system milieu. Reductionist cell culture models are frequently too simplistic, and physiologically more relevant approaches such as ex vivo brain slices or in situ experiments provide little control and make information extraction difficult. Here, we present a brain-on-chip model that bridges the gap between cell culture and ex vivo/in vivo conditions through recapitulation of self-organized neural differentiation. We use a new multi-layer silicone elastomer device, over the course of four weeks to differentiate pluripotent human (NTERA2) cells into neuronal clusters interconnected with thick axonal bundles and interspersed with astrocytes, resembling the brain parenchyma. Neurons within the device express the neurofilament heavy (NF200) mature axonal marker and the microtubule-associated protein (MAP2ab) mature dendritic marker, demonstrating that the devices are sufficiently biocompatible to allow neuronal maturation. This neuronal-glial environment is interfaced with a layer of human brain microvascular endothelial cells showing characteristics of the blood-brain barrier including the expression of zonula occludens (ZO1) tight junctions and increased trans-endothelial electrical resistance. We used this device to model migration of human neural progenitors in response to chemotactic cues within a brain-tissue setting. We show that in the presence of an environment mimicking brain conditions, neural progenitor cells show a significantly enhanced chemotactic response towards shallow gradients of CXCL12, a key chemokine expressed during embryonic brain development and in pathological tissue regions of the central nervous system. Our brain-on-chip model thus provides a convenient and scalable model of neural differentiation and maturation extensible to analysis of complex cell and tissue behaviors.


Far infrared ray (FIR) therapy: An effective and oncological safe treatment modality for breast cancer related lymphedema.
The incidence of breast cancer related lymphedema is approximately 5%. Far infrared ray (FIR) treatment can potentially reduce fluid volume and extremity circumference as well as the frequency of dermato-lymphangitis (DLA). However, there is no published data on the oncological safety of FIR and the potential for activation of any residual breast cancer cells. The aim of this study is to investigate the safety of far infrared ray (FIR) treatment of postmastectomy lymphedema, clinically and in vitro. Patients who underwent mastectomy more than 5years ago complicated by upper extremity lymphedema for more than 1year were included. The enrolled patients were divided into an FIR treatment group and a control group (conservative treatment using bandage compression). Outcome measures included tumor markers (CA153, CA125), ultrasonography of relevant structures and monitoring for adverse reactions 1year after treatment. For the in vitro part of the study, the effects of FIR on human breast adenocarcinoma cell lines (MCF7, MDA-MB231) compared to the effects of FIR on human dermal fibroblasts as a control were considered. The viability, proliferation, cell cycle and apoptotic statistics of the adenocarcinoma and human dermal fibroblast cell lines were analyzed and compared. Results demonstrated that after treatment with FIR, tumor marker (CA153, CA125) concentrations in both the FIR and control groups were not elevated. There was no statistically significant difference between FIR and control group marker expression (p>0.05). Furthermore, no patients were diagnosed with lymphadenectasis or newly enlarged lymph nodes in these two groups. Importantly, there were no adverse events in either group. The in vitro experiment indicated that FIR radiation does not affect viability, proliferation, cell cycle and apoptosis of fibroblasts, MCF-7 and MDA-MB-231 cells. FIR should be considered as feasible and safe for the treatment of breast cancer related lymphedema patients 5years after mastectomy. FIR does not promote recurrence or metastasis of breast cancer and is a well-tolerated therapy with no adverse reactions.


Functional and diffusion MRI reveal the neurophysiological basis of neonates' noxious-stimulus evoked brain activity.
Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n = 18). Applying this prediction model to independent Developing Human Connectome Project data (n = 215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology.


Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta.
The emergence of the first adult hematopoietic stem cells (HSCs) during mammalian ontogeny has been under intense investigation. It is as yet unresolved whether these first HSCs are derived from intraembryonic hemangioblasts, hemogenic endothelial cells, or other progenitors. Thus, to examine the spatial generation of functional HSCs within the mouse embryo, we used the well-known HSC marker, Sca-1, and a transgenic approach with an Ly-6A (Sca-1) GFP marker gene. Our results show that this transgene marker is expressed in all functional HSCs in the midgestation aorta. Immunohistology of aorta-gonads-mesonephros (AGM) regions show that GFP(+) cells are specifically localized to the endothelial layer lining the wall of the dorsal aorta but not to the mesenchyme, strongly suggesting that HSC activity arises within a few cells within the endothelium of the major vasculature.


Renal responses to sodium restriction in patients with early diabetes mellitus.
Increased GFR and decreased renal vascular resistance are common renal hemodynamic changes in persons with early, uncomplicated, insulin-dependent diabetes mellitus. It has been hypothesized that excess total-body sodium in patients with diabetes contributes to the renal vasodilation, possibly by suppressing vasoconstricting neurohormonal systems. This study was undertaken to examine whether sodium restriction could normalize these renal abnormalities. Subjects were 12 male patients with uncomplicated insulin-dependent diabetes mellitus (duration, < 5 yr). Results were compared with those of an age- and gender-matched control group. All subjects received either a high-sodium diet (200 mmol/day) or a sodium-restricted diet (20 mmol/day) for 7 days, according to a randomized crossover protocol. GFR and RPF were measured using inulin and para-aminohippurate clearance techniques, respectively. Subjects with diabetes were maintained euglycemic during the clearance measurements. GFR was significantly higher in the diabetic group than in the control group with sodium repletion (124 +/- 4 versus 107 +/- 8 mL/min/1.73 m2; P = 0.03), and renal vascular resistance was significantly reduced (94 +/- 6 versus 107 +/- 17 mm Hg/L/min; P = 0.05). In response to sodium restriction, the hematocrit increased significantly in both groups, as did PRA and aldosterone, although responses in the diabetic group were somewhat blunted, indicating persisting volume expansion. Despite this humoral activation, sodium restriction had little effect on renal hemodynamic function in control subjects. In the diabetic subjects, this maneuver appeared to exacerbate the underlying renal abnormalities, with the GFR increasing to 131 +/- 4 mL/min/1.73 m2 (P = 0.05) and the renal vascular resistance declining to 73 +/- 5 mm Hg/L/min (P = 0.001). These data indicate that, rather than correcting renal hyperperfusion, sodium restriction exacerbates these characteristic abnormalities, suggesting that mechanisms other than suppression of vasoconstrictor activity are operative in the underlying renal hemodynamic abnormalities of early, uncomplicated, insulin-dependent diabetes mellitus.


Patients' attitudes toward screening for medical conditions in a dental setting.
Previous studies demonstrated the efficacy of chairside medical screening by dentists to identify patients who are at increased risk for developing cardiovascular-associated events and the favorable attitude of dentists toward chairside medical screening. This study assessed patient attitudes toward chairside medical screening in a dental setting. A self-administered questionnaire of eight five-point response scale questions was given to a convenience sample of adult patients attending an inner-city dental school clinic and two private practice settings. Wilcoxon-Mann-Whitney tests and t-tests were used to compare responses between study groups. Friedman nonparametric analysis of variance was used to compare response items within each question. Regardless of setting, the majority of respondents was willing to have a dentist conduct screening for heart disease, high blood pressure, diabetes, human immunodeficiency virus infection, and hepatitis infection (55-90 percent); discuss results immediately (79 percent and 89 percent); provide oral fluids, finger-stick blood, blood pressure measurements, and height and weight (60-94 percent); and pay up to $20 (50-67 percent). Respondents reported that their opinion of the dentist would improve regarding the dentist's professionalism, knowledge, competence, and compassion (48-77 percent). The fact that the test was not done by a physician was ranked as the least important potential barrier. While all respondents expressed a favorable attitude toward chairside screening, the mean score was significantly lower among clinic patients across most questions/items. The priority rankings within an item were similar for both groups. Acceptance by patients of chairside medical screening in a dental setting is a critical element for successful implementation of this strategy.


[Prevalence and factors associated with vitamin A deficiency in preschool children from Teresina, Piauí, Brazil].
Vitamin A deficiency is a public health problem in the Northeast of Brazil. This study aimed to determine the prevalence of vitamin A deficiency and associated factors among preschool children in Teresina, Piauí, Brazil. We studied the serum retinol levels and socioeconomic and demographic characteristics of 631 children from 36 to 83 months of age. The statistical association between each of the above characteristics and serum retinol levels was investigated by univariate and multivariate linear regression analysis. Mean serum retinol was 1.21 mmol/L (95%CI: 1.17-1.25 micromol/L) and was independent of gender (p = 0.259). Prevalence of vitamin A deficiency (retinol < 0.69 micromol/L) was 15.4% (95%CI: 12.7-18.4), with a tendency to decrease with age. Acceptable but not adequate retinol levels (0.70 to 1.04 micromol/L) were observed in 29% of children (95%CI: 25.2-32.4). There were positive associations between retinol levels and age, income, vitamin A supplementation, and maternal schooling. Vitamin A deficiency appeared as a moderately serious public health problem, emphasizing the importance of strategies to combat this problem in the region.


High levels of lung resident CD4+CD28null cells in COPD: implications of autoimmunity.
Chronic obstructive pulmonary disease (COPD) is a worldwide burden and a major cause of death. Pathogenetic mechanisms underlying the disease are still largely unknown. However, a continuous toxic injury due to tobacco smoking leading to a self-maintaining inflammatory process is considered a key factor in the pathophysiology of the disease. Evidence that autoimmunity might be involved in the maintenance of COPD has been recently noticed with great interest.During the chronic phase of an autoimmune response, lymphocytes lose their costimulatory signals. Previously, CD4+CD28null cells were reported to be systemically heightened in COPD patients. However, a direct role of CD4+CD28null cells in the pathogenesis of COPD is still under discussion, since there is no evidence that CD4+CD28null cells originate from the lungs of diseased patients. Therefore, we evaluated lungs from end-stage COPD patients and compared the levels of tissue infiltrating CD4+CD28null cells to systemic levels. We could show that CD4+CD28null cells are present in high amounts in lung tissue obtained from COPD GOLD IV patients suggesting a direct involvement of those cells in the pathophysiology of COPD. Furthermore, purified lung-resident CD4+ cells showed a stable proliferative response to lung specific elastin and collagen.These results further corroborate the role of autoreactive CD4+ cells in the maintenance of the inflammatory destruction in COPD. Modulating CD4+ cell function might be a new promising tool for future therapeutic approaches.


Through their own eyes: a media-based group approach to adolescent trauma.
This paper describes the process of two groups of students from high schools located in the immediate vicinity of the World Trade Center grappling to make sense of the events of September 11 through the creation of a documentary chronicling their experiences. The process of creating these videos mirrored the process and curative factors of a psychotherapy group in a non-stigmatizing, innovative, and accessible format, one generated by the students themselves with the assistance of professionals in the visual and performing arts. After reviewing the literature on the potential impact of violence on adolescents and the use of group treatment, especially in school settings, as an optimal choice for this population, we describe the distinctive process of the two separate groups of students, each culminating in different expressions of their very personal experience of September 11. We understand and contextualize their process through the lens of the therapeutic dynamics and elements of group work.


The beta-subunit of human chorionic gonadotrophin exists as a homodimer.
The free beta-subunit of human chorionic gonadotrophin (hCGbeta) is well recognised as a product of many epithelial tumours. Recently, it has been shown that this ectopic production may have a functional relationship to tumour growth. The growth-promoting activity of hCGbeta may be explained by its structural similarity to a family of growth factors which all contain the same distinct topological fold known as the cystine-knot motif. Since the other members of this family all exhibit their activities as homo- and heterodimers, it is possible that the same may be true for hCGbeta. Using size-exclusion chromatography, low stringency SDS-PAGE and matrix assisted laser desorption/ionisation (MALDI) time-of-flight (TOF) mass spectrometry (MS) we have shown that pure preparations of hCGbeta contain hCGbetabeta homodimers. Size-exclusion chromatography revealed asymmetric elution profiles with a forward peak corresponding to the size-exclusion characteristic of a globular protein with an approximate mass of 44-54 kDa and a late shoulder centered around an elution position expected for a globular protein of approximately 29 kDa. Two immunoreactive hCGbeta species, of approximately 32 and 64 kDa, were clearly resolved by SDS-PAGE and Western blotting. When analysed by MALDI-TOF MS a |mf23 kDa monomer and a |mf46 kDa dimer were identified. Formation of hCGbetabeta homodimers is consistent with the behaviour of other cystine-knot growth factors and strengthens the inclusion of the glycoprotein hormones within this superfamily. It has yet to be determined whether it is this dimeric molecular species that is responsible for growth-promoting activity of hCGbeta preparations in tumours.


Adaptation and evolutionary rescue in metapopulations experiencing environmental deterioration.
It is not known whether evolution will usually be rapid enough to allow a species to adapt and persist in a deteriorating environment. We tracked the eco-evolutionary dynamics of metapopulations with a laboratory model system of yeast exposed to salt stress. Metapopulations experienced environmental deterioration at three different rates and their component populations were either unconnected or connected by local dispersal or by global dispersal. We found that adaptation was favored by gradual deterioration and local dispersal. After further abrupt deterioration, the frequency of evolutionary rescue depended on both the prior rate of deterioration and the rate of dispersal. Adaptation was surprisingly frequent and rapid in small peripheral populations. Thus, evolutionary dynamics affect both the persistence and the range of a species after environmental deterioration.


Prehospital notification by emergency medical services reduces delays in stroke evaluation: findings from the North Carolina stroke care collaborative.
Individuals with stroke-like symptoms are recommended to receive rapid diagnostic evaluation. Emergency medical services (EMS) transport, compared with private modes, and hospital notification before arrival may reduce delays in evaluation. This study estimated associations between hospital arrival modes (EMS or private and with or without EMS prenotification) and times for completion and interpretation of initial brain imaging in patients with presumed stroke. Among patients with suspected stroke identified and enrolled by the North Carolina Stroke Care Collaborative registry in 2008 to 2009, we analyzed data on arrival modes, meeting recommended targets for brain imaging completion and interpretation times (<25 minutes and <45 minutes since hospital arrival, respectively) and patient- and hospital-level characteristics. We used modified Poisson regression to estimate adjusted risk ratios and 95% CIs. Of 13 894 eligible patients, 21% had their brain imaging completed and 23% had their brain imaging interpreted by a physician within target times. Arrival by EMS (versus private transport) was associated with both brain imaging completed within 25 minutes of arrival (EMS with prenotification: risk ratio, 3.0; 95% CI, 2.1 to 4.1; EMS without prenotification: risk ratio, 1.9; 95% CI, 1.6 to 2.3) and brain imaging interpreted within 45 minutes (EMS with prenotification: risk ratio, 2.7; 95% CI, 2.3 to 3.3; EMS without prenotification: risk ratio, 1.7; 95% CI, 1.4 to 2.1). Patients with presumed stroke arriving to the hospital by EMS were more likely to receive brain imaging and have it interpreted by a physician in a timely manner than those arriving by private transport. Moreover, EMS arrivals with hospital prenotification experienced the most rapid evaluation.


Inability of mice with a defect in B-lymphocyte maturation to respond to phosphorycholine on immunogenic carriers.
Mice with the CBA/N defect are unresponsive to the hapten phosphorylcholine (PC) even when presented on a variety of immunogenic carriers. Since these mice have the variable region gene for PC, their inability to respond may reflect deletion or suppression of the line of B lymphocytes which is responsible for the anti-PC response.


Who is being referred to cancer genetic counseling? Characteristics of counselees and their referral.
Both physician and patient play a role in the referral process for cancer genetic counseling. Access to such counseling is not optimal because some eligible patients are not being reached by current referral practice. We aimed to identify factors associated with the initiator of referral. During a 7-month period, we recorded demographic characteristics like gender, personal and family history of cancer, ethnicity and eligibility for genetic testing for 406 consecutive counselees using a specially designed questionnaire. Counselees were seen in a university hospital or a community hospital (n = 7) in the Netherlands. We also recorded educational level of each counselee, clinical setting and who initiated referral. Descriptive statistics were used to describe the counselees' general characteristics. We analysed the association between counselee characteristics and the initiator of referral by logistic regression. The majority of counselees seemed to have initiated referral themselves but were indeed eligible for genetic testing. In comparison to the general population in the Netherlands, the counselees had a higher level of education, and there were fewer immigrants, although a higher level of education was not found to be a facilitating factor for referral. The clinical setting where a counselee was seen was associated with initiator of referral, although this relationship was not straightforward. There is a complex interaction between clinical setting and initiator of referral, which warrants further research to elucidate the factors involved in this relationship. Patients seen in cancer genetic counseling do not reflect the general population in terms of educational level or ethnicity.


Minimally invasive transforaminal lumbar interbody fusion (TLIF): technical feasibility and initial results.
Forty-nine patients underwent minimally invasive transforaminal lumbar interbody fusion (TLIF) from October 2001 to August 2002 (minimum 18-month follow-up). The diagnosis was degenerative disc disease with herniated nucleus pulposus (HNP) in 26, spondylolisthesis in 22, and a Chance-type seatbelt fracture in 1. The majority of cases (n = 45) were at L4-L5 or L5-S1. A paramedian, muscle-sparing approach was performed through a tubular retractor docked unilaterally on the facet joint. A total facetectomy was then conducted, exposing the disc space. Discectomy and endplate preparation were completed through the tube using customized surgical instruments. Structural support was achieved with allograft bone or interbody cages. Bone grafting was done with local autologous or allograft bone, augmented with recombinant human bone morphogenetic protein-2 in some cases. Bilateral percutaneous pedicle screw-rod placement was accomplished with the Sextant system. There were no conversions to open surgery. Operative time averaged 240 minutes. Estimated blood loss averaged 140 mL. Mean length of hospital stay was 1.9 days. All patients presenting with preoperative radiculopathy (n = 45) had resolution of symptoms postoperatively. Complications included two instances of screw malposition requiring screw repositioning and two cases of new radiculopathy postoperatively (one from graft dislodgement, the other from contralateral neuroforaminal stenosis). Narcotic use was discontinued 2-4 weeks postoperatively. Improvements in average Visual Analogue Pain Scale and Oswestry Disability Index (preoperative to last follow-up) scores were 7.2-2.1 and 46-14, respectively. At last follow-up, all patients had solid fusions by radiographic criteria. Results of this study indicate that minimally invasive TLIF is feasible and offers several potential advantages over traditional open techniques.


The Influence of Sex, Parasitism, and Ontogeny on the Physiological Response of European Eels (Anguilla anguilla) to an Abiotic Stressor.
Migration of adult European eels (Anguilla anguilla) from freshwater feeding grounds to oceanic spawning grounds is an energetically demanding process and is accompanied by dramatic physiological and behavioral changes. Humans have altered the aquatic environment (e.g., dams) and made an inherently challenging migration even more difficult; human activity is regarded as the primary driver of the collapse in eel populations. The neuroendocrine stress response is central in coping with these challenging conditions, yet little is known about how various biotic factors such as sex, parasites, and ontogeny influence (singly and via interactions) the stress response of eels. In this study, mixed-effects and linear models were used to quantify the influence of sex, parasitism (Anguillicola crassus), life stage (yellow and silver eels), and silvering stage on the stress response of eels when exposed to a standardized handling stressor. The physiological response of eels to a standardized abiotic stressor (netting confinement in air) was quantified through measurements of blood glucose and plasma cortisol. The relationships between biotic factors and the activity of gill Na+/K+-ATPase was also examined. Analyses revealed that in some instances a biotic factor acted alone while in other cases several factors interacted to influence the stress response. Blood glucose concentrations increased after exposure to the standardized stressor and remained elevated after 4 h. Variation in plasma cortisol concentrations after exposure to the stressor were found to be time dependent, which was exacerbated by life stage and parasitism condition. Males and nonparasitized silver eels had the highest Na+/K+-ATPase activity. Silvering stage was strongly positively correlated with Na+/K+-ATPase activity in female eels. Collectively, these findings confirm that the factors mediating stress responsiveness in fish are complicated and that aspects of inherent biotic variation cannot be ignored.


Anticholinergic medications in patients admitted with cognitive impairment or falls (AMiCI). The impact of hospital admission on anticholinergic cognitive medication burden. Results of a multicentre observational study.
Drugs with anticholinergic properties increase the risk of falls, delirium, chronic cognitive impairment, and mortality and counteract procholinergic medications used in the treatment of dementia. Medication review and optimisation to reduce anticholinergic burden in patients at risk is recommended by specialist bodies. Little is known how effective this review is in patients who present acutely and how often drugs with anticholinergic properties are used temporarily during an admission. The aim of the study was to describe the changes in the anticholinergic cognitive burden (ACB) in patients admitted to hospital with a diagnosis of delirium, chronic cognitive impairment or falls and to look at the temporary use of anticholinergic medications during hospital stay. This is a multi-centre observational study that was conducted in seven different hospitals in the UK, Finland, The Netherlands and Italy. 21.1% of patients had their ACB score reduced by a mean of 1.7%, 19.7% had their ACB increased by a mean of 1.6%, 22.8% of DAP naïve patients were discharged on anticholinergic medications. There was no change in the ACB scores in 59.2% of patients. 54.1% of patients on procholinergics were taking anticholinergics. Out of the 98 medications on the ACB scale, only 56 were seen. Medications with a low individual burden were accounting for 64.9% of the total burden. Anticholinergic drugs were used temporarily during the admission in 21.9% of all patients. A higher number of DAPs used temporarily during admission was associated with a higher risk of ACB score increase on discharge (OR = 1.82, 95% CI for OR: 1.36-2.45, P < .001). There was no reduction in anticholinergic cognitive burden during the acute admissions. This was the same for all diagnostic subgroups. The anticholinergic load was predominantly caused by medications with a low individual burden. More than 1 in 5 patients not taking anticholinergics on admission were discharged on them and similar numbers saw temporary use of these medications during their admission. More than half of patients on cholinesterase-inhibitors were taking anticholinergics at the same time on admission, potentially directly counteracting their effects.


Proliferative and antiapoptotic signaling stimulated by nuclear-localized PDK1 results in oncogenesis.
Enhanced activation of phosphoinositide 3-kinase (PI3K) is a hallmark of many human tumors because it promotes cell proliferation and survival through several mechanisms. One of these mechanisms is the phosphorylation of the serine and threonine kinase Akt at the cytosolic side of the plasma membrane by phosphoinositide-dependent protein kinase 1 (PDK1), which is recruited and activated by binding to the phosphoinositides produced by PI3K. We previously demonstrated increased nuclear accumulation of PDK1 in cells with enhanced PI3K activity. We report that nuclear PDK1 promoted cell proliferation by suppressing FOXO3A-dependent transcription of the gene encoding p27Kip1 (an inhibitor of cell cycle progression), whereas it enhanced cell survival by inhibiting the activation of c-Jun amino-terminal kinase. Cells with nuclear-localized PDK1 showed anchorage-independent growth, and when injected into mice, these cells induced the formation of solid tumors. In human prostate tumors, cytoplasmic localization of PDK1 correlated only with early-stage, low-risk tumors, whereas nuclear PDK1 localization correlated with high-risk tumors. Together, our findings suggest a role for nuclear-translocated PDK1 in oncogenic cellular transformation and tumor progression in mice and humans.


Survivin, a novel anti-apoptosis inhibitor, expression in uterine cervical cancer and relationship with prognostic factors.
A novel inhibitor of apoptosis, Survivin, seems to be involved in the critical steps of cancer onset and progression and may be associated with unfavorable clinical outcome. We investigated the expression of Survivin in patients with cervical intraepithelial neoplasia grade 3 (CIN3) and uterine cervical cancer, to determine whether Survivin expression is related to poor prognosis. Fourteen cases of CIN3, 53 cases of invasive uterine cervical squamous cell carcinoma (SCC), and 11 cases of normal control group were analyzed retrospectively. Immunohistochemical staining and Western blot was performed with antihuman Survivin antibody and analyzed with respect to patient outcome. Survivin was significantly expressed in cervical cancer groups compared to the normal control group (P < 0.05). Significant Survivin expression was also noted in cancer patients with lesion size > or =4 cm, lymphovascular invasion, elevated SCC antigen levels, and no response to initial therapy. In more advanced stages, Survivin expression tended to increase but without statistical significance (P = 0.081). No association was noted between Survivin expression and survival rate (P = 0.1011). We conclude that Survivin expression provides some prognostic information regarding uterine cervical cancer, even though it was not correlated with survival. It could represent a possible new prognostic marker of uterine cervical SCC patients.


On sample sizes to estimate the protective efficacy of a vaccine.
To estimate vaccine protective efficacy, defined as VE = 1 - ARV/ARU where ARV is the disease attack rate in the vaccinated group and ARU is the disease attack rate in the controls, investigators have used both cohort and case-control designs. For each design, we present a method for calculation of the sample size required to provide an approximate confidence interval for VE of predetermined width and probability of coverage. The required sample size is a function of the desired width of the confidence interval, the probability of coverage, the assumed VE, and, for cohort designs, the assumed disease attack rate in the controls, and for case-control designs, the assumed vaccine exposure prevalence for the controls.


A leucine-rich repeat containing receptor-like kinase marks somatic plant cells competent to form embryos.
The first somatic single cells of carrot hypocotyl explants having the competence to form embryos in the presence of 2,4-dichlorophenoxyacetic acid (2,4-D) were identified using semi-automatic cell tracking. These competent cells are present as a small subpopulation of enlarged and vacuolated cells derived from cytoplasm-rich and rapidly proliferating non-embryogenic cells that originate from the provascular elements of the hypocotyl. A search for marker genes to monitor the transition of somatic into competent and embryogenic cells in established suspension cell cultures resulted in the identification of a gene transiently expressed in a small subpopulation of the same enlarged single cells that are formed during the initiation of the embryogenic cultures from hypocotyl explants. The predicted amino acid sequence and in vitro kinase assays show that this gene encodes a leucine-rich repeat containing receptor-like kinase protein, designated Somatic Embryogenesis Receptor-like Kinase (SERK). Somatic embryos formed from cells expressing a SERK promoter-luciferase reporter gene. During somatic embryogenesis, SERK expression ceased after the globular stage. In plants, SERK mRNA could only be detected transiently in the zygotic embryo up to the early globular stage but not in unpollinated flowers nor in any other plant tissue. These results suggest that somatic cells competent to form embryos and early globular somatic embryos share a highly specific signal transduction chain with the zygotic embryo from shortly after fertilization to the early globular embryo.


Modeling the fate of benzo[a]pyrene in the wastewater-irrigated areas of Tianjin with a fugacity model.
A Level III fugacity model was applied to characterize the transfer processes and environmental fate of benzo[a]pyrene in wastewater-irrigated areas of Tianjin, China. The physical-chemical properties and transfer parameters of benzo[a]pyrene were used in the model and the concentration distribution of benzo[a]pyrene in sediment, soil, water, air, fish, and crop compartments, as well as transfer fluxes across the compartments, were then derived under steady-state assumptions. The calculated results were compared with monitoring data for air, soil, water, and sediment collected from the literature. The results indicate that there was generally good agreement and the differences were within an order of magnitude for air, soil, and sediment. The concentration of benzo[a]pyrene in the ambient air in the area was very low with a majority present sorbed to aerosol. In the water compartment, approximately 70% of benzo[a]pyrene dissolved in water phase. Relatively high concentrations of the compound were found in the soil and sediment, with the soil serving as the dominant sink in the area. Benzo[a]pyrene, with a slow metabolic rate, was found to accumulate in fish in the area.


Using ion-selective electrodes to study the drug release from porous cellulose matrices.
Polyvinyl chloride (PVC)-based solid-contact ion-selective electrodes (SC-ISEs), responding to propranolol hydrochloride (Pr+) and lidocaine hydrochloride (Ld+) cations as the model drugs with potassium tetrakis(4-chlorophenyl) borate (KTpClPB) as the ion exchanger, were studied. Different drug-polymer solutions were prepared with the model drugs, using different blend ratios of ethylcellulose (EC) and hydroxypropyl cellulose (HPC). Two different solid dosage forms were used. Polymer films were produced by solvent casting method and drug containing porous cellulose samples were prepared by depositing the drug-polymer solutions onto filter paper substrates. The quality of the electrodes and the release profile of Pr+ and Ld+ were investigated with the potentiometric method. The results were compared to UV spectrophotometry. The electrodes were found to be sensitive, precise and functional with a Nernstian behavior over the range of 1.0 × 10-3-3.1 × 10-6 M (9.2 × 10-4-3.0 × 10-1 mg/mL) and 1 × 10-3-2 × 10-6 M (5.4 × 10-4-2.7 × 10-1 mg/mL) at 25 °C for Pr+ and Ld+ sensitive electrodes, respectively. The dynamic response time for the electrodes was less than 10 s. The Pr+ release from porous filter paper was always higher than its equivalent film formulation. Also, lidocaine had higher and faster release from the samples with higher drug concentration. The comparison of the two analytical methods showed near identical results. The ISEs provided a powerful and flexible alternative to UV method in determination of drug release from porous cellulose substrates in a small scale dissolution testing.


(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice.
We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg(-1)·day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.


A comprehensive evaluation of the precision (repeatability and reproducibility) of the Oculus Pentacam HR.
To evaluate the precision (repeatability and reproducibility) of the Pentacam HR (high-resolution) tomographer (Oculus, Wetzlar, Germany) across a large range of measurement parameters. A randomly selected healthy eye of 100 subjects was scanned twice with the Pentacam HR by one observer for each of the three measurement modes: 25-picture (1 second) scan, 50-picture (2 second) scan, and cornea fine scan (50 pictures in 1 second). The repeatability of each scan mode was assessed. One additional 25-picture scan was acquired by a second observer to test reproducibility. Overall, the Pentacam HR had good precision, with the cornea fine scan returning the most precise results: The 25- and 50-picture scans showed similar precision. The repeatability limits, expressed as the within-subject SD × 1.96√2 of the anterior keratometry (K)1 and K2 readings with the standard 25-picture scan, were 0.25 and 0.36 D, respectively. Pachymetry maps, corneal maps, anterior chamber depth maps, corneal volume, topometric Q values and indices were also found to be precise. Poor precision was found for estimates of axis (astigmatic and progression index), pupil center pachymetry, single points on corneal maps, refractive power maps, and equivalent K readings. Measurements taken with the Pentacam HR are repeatable and reproducible, especially those obtained with the cornea fine scan. Although the Pentacam HR is clearly a very useful clinical and research tool, the measurement of corneal axes, pupil center pachymetry, front meridional and axial maps, refractive power maps, and equivalent K readings should be interpreted with caution.


High efficiency photonic crystal based wavelength demultiplexer.
A highly efficient design of a two-channel wavelength demultiplexer in the visible region is presented with finite-difference time-domain simulations. The design process is described in detail with particular attention to the challenges inherent in fabrication of an actual device. A 2D triangular lattice photonic crystal with 75nm air pores in a silicon nitride planar waveguide provides the confinement for visible light. The device losses due to fabrication errors such as stitching misalignment of write fields during e-beam lithography and variation in air pore diameters from etching are modeled using realistic parameters from initial fabrication runs. These simulation results will be used to guide our next generation design of high efficiency photonic crystal based demultiplexing devices.


Recombinant adenovirus vaccine encoding a chimeric T-cell antigen receptor induces protective immunity against a T-cell lymphoma.
Vaccination using recombinant tumor-derived T-cell antigen receptor (TCR) protein induces a protective, idiotype-specific immune response against a murine T-cell tumor. However, the technically demanding task of producing patient-specific, recombinant TCR protein restricts the translation of TCR vaccines for clinical use. We report here the development of an effective recombinant TCR adenovirus vaccine. Individual adenoviruses were constructed to encode a chimeric TCR derived from either tumor Valpha or Vbeta regions fused to xenogeneic human constant regions. Coinjection of the chimeric alpha- and the beta-TCR adenoviruses protected mice against tumors. The level of protection was comparable to that achieved by an optimized regimen of recombinant TCR protein vaccines. Tumor immunity induced by TCR adenoviruses required the xenogeneic constant regions and was mediated by CD8+ T cells. Independent vaccines consisting of adenovirus expressing either chimeric alpha- or beta-TCR chain also stimulated a protective immune response. Immunization with TCR adenovirus may offer a new efficacious, protein-free vaccination approach for the treatment of T-cell malignancies.


Active head motion reduction in magnetic resonance imaging using tactile feedback.
Head motion is a common problem in clinical as well as empirical (functional) magnetic resonance imaging applications, as it can lead to severe artefacts that reduce image quality. The scanned individuals themselves, however, are often not aware of their head motion. The current study explored whether providing subjects with this information using tactile feedback would reduce their head motion and consequently improve image quality. In a single session that included six runs, 24 participants performed three different cognitive tasks: (a) passive viewing, (b) mental imagery, and (c) speeded responses. These tasks occurred in two different conditions: (a) with a strip of medical tape applied from one side of the magnetic resonance head coil, via the participant's forehead, to the other side, and (b) without the medical tape being applied. Results revealed that application of medical tape to the forehead of subjects to provide tactile feedback significantly reduced both translational as well as rotational head motion. While this effect did not differ between the three cognitive tasks, there was a negative quadratic relationship between head motion with and without feedback. That is, the more head motion a subject produced without feedback, the stronger the motion reduction given the feedback. In conclusion, the here tested method provides a simple and cost-efficient way to reduce subjects' head motion, and might be especially beneficial when extensive head motion is expected a priori.


Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC).
Focal non-epidermolytic palmoplantar keratoderma (PPK or palmoplantar ectodermal dysplasia type III) is associated with oesophageal cancer in three families: two large pedigrees located in Liverpool, UK and in the midwestern American states and one smaller family from Germany. In these families, the PPK is inherited as autosomal dominant and has a late onset, usually manifesting between 7 and 8 years of age. The disease is characterised by thickening of the pressure areas of the soles, but is not restricted to the feet and also presents with oral leukokeratosis and follicular hyperkeratosis. The disease locus [previously termed the "tylosis oesophageal cancer gene' (TOC) locus] has been mapped to 17q23-qter by linkage analysis. This region is located telomeric to the keratin 16 gene, in which mutations have been identified in focal PPK families who show no increased cancer risk. We describe the close mapping of this locus to the interval between AFMb054zf9 and D17S1603 using haplotype analysis of additional Généthon markers in the region and show that although the American family is unlikely to be related to either of the other two, the UK and German pedigrees may share a common descent. This work provides a basis for positional cloning and candidate gene analysis in order to identify a gene that may be involved in familial oesophageal cancer.


Prognostic factors and primary treatment for Waldenström macroglobulinemia - a Swedish Lymphoma Registry study.
We present a nationwide prospective Swedish registry-based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.


Rarity of monodominance in hyperdiverse Amazonian forests.
Tropical forests are known for their high diversity. Yet, forest patches do occur in the tropics where a single tree species is dominant. Such "monodominant" forests are known from all of the main tropical regions. For Amazonia, we sampled the occurrence of monodominance in a massive, basin-wide database of forest-inventory plots from the Amazon Tree Diversity Network (ATDN). Utilizing a simple defining metric of at least half of the trees ≥ 10 cm diameter belonging to one species, we found only a few occurrences of monodominance in Amazonia, and the phenomenon was not significantly linked to previously hypothesized life history traits such wood density, seed mass, ectomycorrhizal associations, or Rhizobium nodulation. In our analysis, coppicing (the formation of sprouts at the base of the tree or on roots) was the only trait significantly linked to monodominance. While at specific locales coppicing or ectomycorrhizal associations may confer a considerable advantage to a tree species and lead to its monodominance, very few species have these traits. Mining of the ATDN dataset suggests that monodominance is quite rare in Amazonia, and may be linked primarily to edaphic factors.


WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization.
In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology, and the response to therapeutic drugs. Visualization of the metabolic pathways that comprise the metabolic network is extremely useful for interpreting a wide variety of experiments. Detailed annotated metabolic pathway maps for C. elegans are mostly limited to pan-organismal maps, many with incomplete or inaccurate pathway and enzyme annotations. Here, we present WormPaths, which is composed of two parts: (1) the careful manual annotation of metabolic genes into pathways, categories, and levels, and (2) 62 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on the WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the future, we envision further developing these maps to be more interactive, analogous to road maps that are available on mobile devices.


Alpha-Lipoic Acid Plays a Role in Endometriosis: New Evidence on Inflammasome-Mediated Interleukin Production, Cellular Adhesion and Invasion.
Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-β levels and enhanced ER-β activity were detected in endometriotic tissues. It is well known that ER-β interacts with components of the cytoplasmic inflammasome-3 (NALP-3), the NALP-3 activation increases interleukin (IL)-1β and IL-18, enhancing cellular adhesion and proliferation. Otherwise, the inhibition of ER-β activity suppresses the ectopic lesions growth. The present study aims to investigate the potential effect of α-lipoic acid (ALA) on NALP-3 and ER-β expression using a western blot analysis, NALP-3-induced cytokines production by ELISA, migration and invasion of immortalized epithelial (12Z) and stromal endometriotic cells (22B) using a 3D culture invasion assay, and matrix-metalloprotease (MMPs) activity using gelatin zymography. ALA significantly reduces ER-β, NALP-3 protein expression/activity and the secretion of IL-1β and IL-18 in both 12Z and 22B cells. ALA treatment reduces cellular adhesion and invasion via a lower expression of adhesion molecules and MMPs activities. These results provide convincing evidence that ALA might inhibit endometriosis progression.


A 10-year review of indications for penetrating keratoplasty in a tertiary care setting in Karachi Pakistan.
The retrospective study was conducted to determine the indications and outomes of penetrating keratoplasty(PKP) in a tertiary care setting in Pakistan. All eyes that had undergone PKP between January 2005 and December 2014 at the Aga Khan University Hospital, Karachi, were included.Data were collected on the indications of PKP, graft survival (graft clarity at final follow-up), andbest corrected visual acuity (BCVA).Kaplan-Meier\'s method was usedto analyse graft survival.Out of 437 eyes, 383(87%) were for visual purpose. Trauma-related corneal scarring 113(26.2%) was the leading cause of PKP, followed by keratoconus 74(17.1%), redo graft 56(13%), infection-related corneal opacity 46(10.6%), corneal dystrophy 44(10.2%) and bullous keratopathy 36(8.3%). The probability of graft survival at 30 months was 90% for keratoconusversus 75% for the non-keratoconus grafts. Most of the PKPs in this case series were due to preventable causes. Our long-term PKP results were favourable, with a graft survival ratecomparable to those of other centres.


Fascioliasis: 3 cases with three different clinical presentations.
Fascioliasis, which is a zoonotic infestation caused by the trematode Fasciola hepatica (liver fluke), is primarily a disease of herbivorous animals such as sheep and cattle. Humans become accidental hosts through ingesting uncooked aquatic plants such as watercress. It presents a wide spectrum of clinical pictures ranging from fever, eosinophilia and vague gastrointestinal symptoms in the acute phase to cholangitis, cholecystitis, biliary obstruction, extrahepatic infestation, or asymptomatic eosinophilia in the chronic phase. However, it may often be overlooked, especially in the acute phase, because of vague symptoms. As a result of newly introduced serological assays facilitating the diagnosis, there has been an increase in the number of reported cases. Here, we report the clinical and laboratory assessment and therapeutic approach of a series of three cases diagnosed (in order of) one week, three months and one and a half years after presentation of the first symptoms of the disease.


Association between mouse nude gene expression and the initiation of epithelial terminal differentiation.
Loss-of-function mutations in Whn (Hfh 11), a winged-helix/forkhead transcription factor, result in the nude mouse phenotype. To determine the whn expression pattern during development, we utilized mice in which a beta-galactosidase reporter gene was placed under the control of the wild-type whn promoter by homologous recombination (M. Nehls et al., 1996, Science 272, 886-889). Sites of reporter expression were confirmed by immunohistochemical staining for Whn protein or by in situ hybridization for whn mRNA. At all developmental stages, whn expression is restricted to epithelial cells. In addition to the skin and thymus, whn is expressed in the developing nails, nasal passages, tongue, palate, and teeth. In embryonic epidermis, suprabasal cells induce whn expression at the same time that terminal differentiation markers first appear. As the epidermis matures, whn promoter activity is found primarily in the first suprabasal layer, which contains keratinocytes in the early stages of terminal differentiation. In developing and mature anagen hair follicles, whn is expressed at high levels in the postmitotic precursor cells of the hair shaft and inner root sheath. Though principally associated with terminal differentiation, whn expression is also detected in progenitor cell compartments; in the hair bulb matrix and basal epidermal layer, a small subclass of cells expresses whn, while in the outer root sheath, whn promoter activity is induced as the follicle completes its elongation. Within these compartments, rare cells exhibit both whn expression and the nuclear proliferation marker Ki-67. The results suggest that whn expression encompasses the transition from a proliferative to a postmitotic state and that whn regulates the initiation of terminal differentiation.


Niemann-Pick C1-Like 1 deletion in mice prevents high-fat diet-induced fatty liver by reducing lipogenesis.
Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal absorption of dietary and biliary cholesterol. Ezetimibe, by inhibiting NPC1L1 function, is widely used to treat hypercholesterolemia in humans. Interestingly, ezetimibe treatment appears to attenuate hepatic steatosis in rodents and humans without a defined mechanism. Over-consumption of a high-fat diet (HFD) represents a major cause of metabolic disorders including fatty liver. To determine whether and how NPC1L1 deficiency prevents HFD-induced hepatic steatosis, in this study, we fed NPC1L1 knockout (L1-KO) mice and their wild-type (WT) controls an HFD, and found that 24 weeks of HFD feeding causes no fatty liver in L1-KO mice. Hepatic fatty acid synthesis and levels of mRNAs for lipogenic genes are substantially reduced but hepatic lipoprotein-triglyceride production, fatty acid oxidation, and triglyceride hydrolysis remain unaltered in L1-KO versus WT mice. Strikingly, L1-KO mice are completely protected against HFD-induced hyperinsulinemia under both fed and fasted states and during glucose challenge. Despite similar glucose tolerance, L1-KO relative WT mice are more insulin sensitive and in the overnight-fasted state display significantly lower plasma glucose concentrations. In conclusion, NPC1L1 deficiency in mice prevents HFD-induced fatty liver by reducing hepatic lipogenesis, at least in part, through attenuating HFD-induced insulin resistance, a state known to drive hepatic lipogenesis through elevated circulating insulin levels.


The IgE-reactive autoantigen Hom s 2 induces damage of respiratory epithelial cells and keratinocytes via induction of IFN-gamma.
Hom s 2, the alpha-chain of the nascent polypeptide-associated complex, is an intracellular autoantigen that has been identified with IgE autoantibodies from atopic dermatitis patients. We investigated the humoral and cellular immune response to purified recombinant Hom s 2 (rHom s 2). rHom s 2 exhibited IgE reactivity comparable to exogenous allergens, but did not induce relevant basophil cell degranulation. The latter may be attributed to the fact that patients recognized single epitopes on Hom s 2 as revealed by IgE epitope mapping with rHom s 2 fragments. In contrast to exogenous allergens, rHom s 2 had the intrinsic ability to induce the release of IFN-gamma in cultured peripheral blood mononuclear cells from atopic as well as non-atopic individuals. IFN-gamma-containing culture supernatants from Hom s 2-stimulated peripheral blood mononuclear cells caused disintegration of respiratory epithelial cell layers and apoptosis of skin keratinocytes, which could be inhibited with a neutralizing anti-IFN-gamma antibody. Our data demonstrate that the Hom s 2 autoantigen can cause IFN-gamma-mediated cell damage.


Tracking Cholera through Surveillance of Oral Rehydration Solution Sales at Pharmacies: Insights from Urban Bangladesh.
In Bangladesh, pharmacy-purchased oral rehydration solution (ORS) is often used to treat diarrhea, including cholera. Over-the-counter sales have been used for epidemiologic surveillance in the past, but rarely, if ever, in low-income countries. With few early indicators for cholera outbreaks in endemic areas, diarrhea-related product sales may serve as a useful surveillance tool. We tracked daily ORS sales at 50 pharmacies and drug-sellers in an urban Bangladesh community of 129,000 for 6-months while simultaneously conducting surveillance for diarrhea hospitalizations among residents. We developed a mobile phone based system to track the sales of ORS and deployed it in parallel with a paper-based system. Our objectives were to determine if the mobile phone system was practical and acceptable to pharmacists and drug sellers, whether data were reported accurately compared to a paper-based system, and whether ORS sales were associated with future incidence of cholera hospitalizations within the community. We recorded 47,215 customers purchasing ORS, and 315 hospitalized diarrhea cases, 22% of which had culture-confirmed cholera. ORS sales and diarrhea incidence were independently associated with the mean daily temperature; therefore both unadjusted and adjusted models were explored. Through unadjusted cross-correlation statistics and generalized linear models, we found increases in ORS sales were significantly associated with increases in hospitalized diarrhea cases up to 9-days later and hospitalized cholera cases up to one day later. After adjusting for mean daily temperature, ORS was significantly associated with hospitalized diarrhea two days later and hospitalized cholera one day later. Pharmacy sales data may serve as a feasible and useful surveillance tool. Given the relatively short lagged correlation between ORS sales and diarrhea, rapid and accurate sales data are key. More work is needed in creating actionable algorithms that make use of this data and in understanding the generalizability of our findings to other settings.


Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC).
Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease. From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies; the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007-2010 to 10.9% in 2015-2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association >II, systemic ejection fraction <40%, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017. Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH.


Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules.
The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the α2-1-helix of MHC-I, 'loosening' the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop11-20 of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.


Analysis of experimental time-resolved crystallographic data by singular value decomposition.
Singular value decomposition (SVD) separates time-dependent crystallographic data into time-independent and time-dependent components. Procedures for the effective application of SVD to time-resolved macromolecular crystallographic data have yet to be explored systematically. Here, the applicability of SVD to experimental crystallographic data is tested by analyzing 30 time-resolved Laue data sets spanning a time range of nanoseconds to milliseconds through the photocycle of the E46Q mutant of photoactive yellow protein. The data contain random and substantial systematic errors, the latter largely arising from crystal-to-crystal variation. The signal-to-noise ratio of weighted difference electron-density maps is significantly improved by the SVD flattening procedure. Application of SVD to these flattened maps spreads the signal across many of the 30 singular vectors, but a rotation of the vectors partitions the large majority of the signal into only five singular vectors. Fitting the time-dependent vectors to a sum of simple exponentials suggests that a chemical kinetic mechanism can describe the time-dependent structural data. Procedures for the effective SVD analysis of experimental time-resolved crystallographic data have been established and emphasize the necessity for minimizing systematic errors by modification of the data-collection protocol.


Determining Factors that Influence Adoption of New Post-Stroke Sensorimotor Rehabilitation Devices in the USA.
Rehabilitation device efficacy alone does not lead to clinical practice adoption. Previous literature identifies drivers for device adoption by therapists but does not identify the best settings to introduce devices, the roles of different stakeholders including rehabilitation directors, or specific criteria to be met during device development. The objective of this work was to provide insights into these areas to increase clinical adoption of post-stroke restorative rehabilitation devices. We interviewed 107 persons including physical/occupational therapists, rehabilitation directors, and stroke survivors and performed content analysis. Unique to this work, care settings in which therapy goals are best aligned for restorative devices were found to be outpatient rehabilitation, followed by inpatient rehabilitation. Therapists are the major influencers for adoption because they typically introduce new rehabilitation devices to patients for both clinic and home use. We also learned therapists' utilization rate of a rehabilitation device influences a rehabilitation director's decision to acquire the device for facility use. Main drivers for each stakeholder are identified, along with specific criteria to add details to findings from previous literature. In addition, drivers for home adoption of rehabilitation devices by patients are identified. Rehabilitation device development should consider the best settings to first introduce the device, roles of each stakeholder, and drivers that influence each stakeholder, to accelerate successful adoption of the developed device.


Safety and efficacy of antioxidants-loaded nanoparticles for an anti-aging application.
The aim of this work was to perform a pilot study on the safety and efficacy of nanoparticle formulation for cosmetic application. The encapsulated actives in the nanoparticles were a blend of coenzyme Q10, retinyl palmitate, tocopheryl acetate, grape seed oil and linseed oil. The nanoparticle suspension was characterized in terms of pH and particle size. For the safety assessment, alternative methods as cytotoxicity and HET CAM were used. The clinical skin compatibility tests were also performed. The efficacy was evaluated in healthy volunteers presenting different degrees of periorbital wrinkles. Skin hydration was performed by corneometry. The nanoparticles presented narrow size around 140 nm and pH close to neutral and were suitable to cutaneous application. The alternative tests demonstrated that the nanoparticles did not present potential to induce skin irritant effects, cytotoxicity or generate oxidative stress. The clinical assays confirmed the in vitro results, demonstrating the safety of the nanoparticles, which were not irritant, sensitizing and comedogenic. Furthermore, the exposure to UVA light did not cause photoxicity. Regarding the efficacy, nanoparticles presented significant reduction in wrinkle degree after 21 days of application compared to the control. The volunteers could differentiate the nanoparticles and the control product by means of subjective analyses. In conclusion, the nanoparticles containing antioxidant actives were safe for topical use and presented anti-aging activity in vivo and are suitable to be used as cosmetic ingredient.


Ecological forecasts: an emerging imperative.
Planning and decision-making can be improved by access to reliable forecasts of ecosystem state, ecosystem services, and natural capital. Availability of new data sets, together with progress in computation and statistics, will increase our ability to forecast ecosystem change. An agenda that would lead toward a capacity to produce, evaluate, and communicate forecasts of critical ecosystem services requires a process that engages scientists and decision-makers. Interdisciplinary linkages are necessary because of the climate and societal controls on ecosystems, the feedbacks involving social change, and the decision-making relevance of forecasts.


Triggering social interactions: chimpanzees respond to imitation by a humanoid robot and request responses from it.
Even the most rudimentary social cues may evoke affiliative responses in humans and promote social communication and cohesion. The present work tested whether such cues of an agent may also promote communicative interactions in a nonhuman primate species, by examining interaction-promoting behaviours in chimpanzees. Here, chimpanzees were tested during interactions with an interactive humanoid robot, which showed simple bodily movements and sent out calls. The results revealed that chimpanzees exhibited two types of interaction-promoting behaviours during relaxed or playful contexts. First, the chimpanzees showed prolonged active interest when they were imitated by the robot. Second, the subjects requested 'social' responses from the robot, i.e. by showing play invitations and offering toys or other objects. This study thus provides evidence that even rudimentary cues of a robotic agent may promote social interactions in chimpanzees, like in humans. Such simple and frequent social interactions most likely provided a foundation for sophisticated forms of affiliative communication to emerge.


In consumer-directed health plans, a majority of patients were unaware of free or low-cost preventive care.
Consumer-directed health plans are plans with high deductibles that typically require patients to bear no out-of-pocket costs for preventive care, such as annual physicals or screening tests, in order to ease financial barriers and encourage patients to seek such care. We surveyed people in California who had a consumer-directed health plan and found that fewer than one in five understood that their plan exempted preventive office visits, medical tests, and screenings from their deductible, meaning that this care was free or had a modest copayment. Roughly one in five said that they had delayed or avoided a preventive office visit, test, or screening because of cost. Those who were confused about the exemption were significantly more likely to report avoiding preventive visits because of cost concerns. Special efforts to educate consumers about preventive care cost-sharing exemptions may be necessary as more health plans, including Medicare, adopt this model.


Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers.
Oncogene amplification and overexpression occur in tumor cells. Amplification status may provide diagnostic and prognostic information and may lead to new treatment strategies. Chromosomal regions 8p12, 8q24, 11q13, 17q12 and 20q13 are recurrently amplified in breast cancers. To assess the frequencies and clinical impact of amplifications, we analyzed 547 invasive breast tumors organized in a tissue microarray (TMA) by fluorescence in situ hybridization (FISH) and calculated correlations with histoclinical features and prognosis. BAC probes were designed for: (i) two 8p12 subregions centered on RAB11FIP1 and FGFR1 loci, respectively; (ii) 11q13 region centered on CCND1; (iii) 12p13 region spanning NOL1; and (iv) three 20q13 subregions centered on MYBL2, ZNF217 and AURKA, respectively. Regions 8q24 and 17q12 were analyzed with MYC and ERBB2 commercial probes, respectively. We observed amplification of 8p12 (amplified at RAB11FIP1 and/or FGFR1) in 22.8%, 8q24 in 6.1%, 11q13 in 19.6%, 12p13 in 4.1%, 17q12 in 9.9%, 20q13Z (amplified at ZNF217 only) in 9.9%, and 20q13Co (co-amplification of two or three 20q13 loci) in 8.5% of cases. The 8q24, 12p13, and 17q12 amplifications were correlated with high grade. The most frequent single amplifications were 8p12 (9.8%), 8q24 (3.3%) and 12p13 (3.3%), 20q13Z and 20q13Co (1.6%) regions. The 17q12 and 11q13 regions were never found amplified alone. The most frequent co-amplification was 8p12/11q13. Amplifications of 8p12 and 17q12 were associated with poor outcome. Amplification of 12p13 was associated with basal molecular subtype. Our results establish the frequencies, prognostic impacts and subtype associations of various amplifications and co-amplifications in breast cancers.


Information processing speed and 8-year mortality among community-dwelling elderly Japanese.
Cognitive function is an important contributor to health among elderly adults. One reliable measure of cognitive functioning is information processing speed, which can predict incident dementia and is longitudinally related to the incidence of functional dependence. Few studies have examined the association between information processing speed and mortality. This 8-year prospective cohort study design with mortality surveillance examined the longitudinal relationship between information processing speed and all-cause mortality among community-dwelling elderly Japanese. A total of 440 men and 371 women aged 70 years or older participated in this study. The Digit Symbol Substitution Test (DSST) was used to assess information processing speed. DSST score was used as an independent variable, and age, sex, education level, depressive symptoms, chronic disease, sensory deficit, instrumental activities of daily living, walking speed, and cognitive impairment were used as covariates. During the follow-up period, 182 participants (133 men and 49 women) died. A multivariate Cox proportional hazards model showed that lower DSST score was associated with increased risk of mortality (hazard ratio [HR] = 1.62, 95% CI = 0.97-2.72; HR = 1.73, 95% CI = 1.05-2.87; and HR = 2.55, 95% CI = 1.51-4.29, for the third, second, and first quartiles of DSST score, respectively). Slower information processing speed was associated with shorter survival among elderly Japanese.


The spectrum of gastric cancer as seen in a large quaternary hospital in KwaZulu-Natal, South Africa.
Gastric cancer (GC) is the fifth most commonly diagnosed cancer in the world, with the third-highest associated mortality. It has a varying geographical, ethnic and socioeconomic distribution. To assess the presentation and management of GC in the Durban metropolitan area, South Africa. A retrospective review of 131 patients treated at the quaternary Inkosi Albert Luthuli Central Hospital in Durban from 2009 to 2014 was performed. The 131 patients were predominantly black African (n=59, 45.0%) and Indian (n=63, 48.1%). Gender was evenly distributed, with 72 males (55.0%) and 59 females (45.0%). The average age of the patients was 60 years (standard deviation 13.3). More than 70% were in advanced stages of cancer and were treated conservatively. There was no significant relationship between body mass index (BMI) and the position of the tumour (p=0.175). Creatinine and albumin levels differed significantly between the genders (p<0.001 and p=0.01, respectively). GC appears to have a disproportionately high prevalence among Indians in Durban, and the prevalence of GC appears to be slightly higher among males. Both these observations may simply reflect referral patterns and warrant further investigation. More than 70% of patients presented with advanced-stage disease, and anaemia was common. No relationship was found between BMI and the location of the tumour, although most of the cancers were in the body and distal part of the stomach.


Non-barrier contraceptive use and relation to condom use behaviour by partner type among female sex workers in Andhra Pradesh, India.
The study assessed non-barrier contraceptive use among female sex workers (FSW) in Andhra Pradesh, India and relation to inconsistent condom use among commercial and non-commercial male sexual partners. FSW at least 18 years of age (n=2338) were recruited through respondent-driven sampling for an HIV risk survey. Analysis was restricted to women of childbearing age (n=2197). Crude and adjusted logistic regression models were used to assess non-barrier contraceptive use and relation to inconsistent condom use with husbands or regular male partners (i.e. non-clients), regular clients and occasional clients. Non-barrier methods of contraception included contraceptive pills (3.8%) and sterilisation (68.4%). In logistic regression models adjusted for relevant demographics, FSW using contraceptive pills were more likely to report inconsistent condom use with a regular client (past week) [adjusted odds ratio (AOR) 2.2, 95% confidence interval (CI) 1.2-4.0] and with an occasional client (past week) (AOR 2.6, 95% CI 1.6-5.3), as well as accepting more money for sex without a condom (past 30 days) (AOR 2.5, 95% CI 1.5-4.3). No significant associations were found between pill use and inconsistent condom use among women's non-client partners, potentially related to small sample sizes within these subgroups. Reporting sterilisation, which was more common among FSW who were older in age, was not associated with inconsistent condom use with client or non-client sexual partners. Findings document potential unmet need for modern, spacing contraceptives (i.e. pill, intrauterine device), but also indicate the importance for family planning services, particularly those promoting modern contraceptive methods to be provided alongside HIV prevention among FSW in Andhra Pradesh, India.


De novo transcriptome assembly in chili pepper (Capsicum frutescens) to identify genes involved in the biosynthesis of capsaicinoids.
The capsaicinoids are a group of compounds produced by chili pepper fruits and are used widely in many fields, especially in medical purposes. The capsaicinoid biosynthetic pathway has not yet been established clearly. To understand more knowledge in biosynthesis of capsaicinoids, we applied RNA-seq for the mixture of placenta and pericarp of pungent pepper (Capsicum frutescens L.). We have assessed the effect of various assembly parameters using different assembly software, and obtained one of the best strategies for de novo assembly of transcriptome data. We obtained a total 54,045 high-quality unigenes (transcripts) using Trinity software. About 92.65% of unigenes showed similarity to the public protein sequences, genome of potato and tomato and pepper (C. annuum) ESTs databases. Our results predicted 3 new structural genes (DHAD, TD, PAT), which filled gaps of the capsaicinoid biosynthetic pathway predicted by Mazourek, and revealed new candidate genes involved in capsaicinoid biosynthesis based on KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. A significant number of SSR (Simple Sequence Repeat) and SNP (Single Nucleotide Polymorphism) markers were predicted in C. frutescens and C. annuum sequences, which will be helpful in the identification of polymorphisms within chili pepper populations. These data will provide new insights to the pathway of capsaicinoid biosynthesis and subsequent research of chili peppers. In addition, our strategy of de novo transcriptome assembly is applicable to a wide range of similar studies.


A numerical approach to evaluate the fatigue life of monolimb.
Monolimb refers to a transtibial prosthesis with the prosthetic socket and the shank being molded into one piece of thermoplastic material. Shank flexibility of a monolimb can improve gait and comfort. However, fatigue failure of monolimbs under cyclic walking load is an important concern. This study is to evaluate the fatigue life of a monolimb designed for a transtibial amputee, based on finite element analysis, the statistical Miner's rule and reliability analysis. Stress uncertainty due to modeling error and the scatter in fatigue test data were considered. Results indicated that the accuracy of fatigue life evaluation of monolimb depends significantly on the precision of stress estimation. In addition, relationship between fatigue failure probability and the number of walking steps was suggested providing a reference for clinicians to determine the interval of the inspection for the monolimb.


Phosphorodithioate DNA as a potential therapeutic drug.
This article summarizes methods for the synthesis of phosphorodithioate-linked deoxyoligonucleotides and details an analysis of one of the distinctive properties of phosphorodithioate DNA oligomers, their ability to strongly inhibit human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT). Mechanistic studies indicate that oligomers of this type interfere with enzyme function by binding tightly to the active site for primer-template, which results in low or subnanomolar inhibitory constants. Although many of these studies have used deoxyoligocytidine analogs, a rationally designed approach has led to the discovery of a very active phosphorodithioate deoxyoligonucleotide inhibitor. This type of inhibitor, which binds strongly to the primer-template active site of HIV-1 RT, provides another type of potential therapeutic agent against HIV-1.


Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2.
Apolipoprotein E receptor 2 (Apoer2), a member of the LDL receptor gene family, and its ligand Reelin control neuronal migration during brain development. Apoer2 is also essential for induction of long-term potentiation (LTP) in the adult brain. Here we show that Apoer2 is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors. Reelin signaling through Apoer2 markedly enhances LTP through a mechanism that requires the presence of amino acids encoded by an exon in the intracellular domain of Apoer2. This exon is alternatively spliced in an activity-dependent manner and is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits. Mice constitutively lacking the exon perform poorly in learning and memory tasks. Thus, alternative splicing of Apoer2, a novel component of the NMDA receptor complex, controls the modulation of NMDA receptor activity, synaptic neurotransmission, and memory by Reelin.