Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener's): long-term followup of a multicenter longitudinal cohort.
An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup. The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.


The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses.
Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the alpha1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 (no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f. Not surprisingly, the b-waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cells in vivo, under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with Cacna1f mutations causing CSNB2, and the subsequent effects on visual information processing. Further, the nob2 mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.


Stress-induced cardiomyopathy in Sweden: evidence for different ethnic predisposition and altered cardio-circulatory status.
In this paper, we report about new insights regarding clinical course, long-term outcome, ethnic/genetic predisposition and cardio-circulatory status in the large stress-induced cardiomyopathy (SIC) cohort from Sweden. We have included 115 consecutive SIC patients between January 2005 and January 2010 at Sahlgrenska University Hospital in Gothenburg. Hemodynamic status and sympathetic nerve activity were evaluated and compared with those of healthy controls. Mean age was 64, and 14% were males. Thirty-day and 3-year mortality was 6 and 10%, respectively. Eleven percent had ischemic heart disease, 3% developed thromboembolic complications, 6% had cardiac arrest and 14% developed cardiogenic shock. The great majority of SIC patients (93%) were ethnic Swedes. In three families, several close relatives developed SIC. Fourteen percent developed two or more episodes of SIC. Hemodynamic evaluation has shown subnormal systemic vascular resistance, 22% lower sympathetic activity and preserved cardiac output in SIC patients. SIC affects both men and women of different ages and is associated with significant short- and long-term mortality. There is a strong signal for the presence of ethnic/genetic predisposition to develop SIC. Sympathetic activity and systemic vascular resistance are lower in SIC patients, suggesting that SIC is a cardio-circulatory phenomenon.


Stillbirths: recall to action in high-income countries.
Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.


The effects of gender and a co-occurring depressive disorder on neurocognitive functioning in patients with alcohol dependence.
The present study aims to examine neuropsychological impairments by comorbidity and gender among patients with alcohol dependence. The study sample is comprised of 123 subjects who fulfilled a Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) diagnosis of alcohol dependence from January 2006 to December 2007. Subjects were asked to complete the following psychological tests: the Barratt Impulsivity Scale (BIS), Wechsler Adult Intelligence Scale, Wechsler Memory Scale and Color Trails Test. We compared the results of neuropsychological assessments based on two types of classifications: people with comorbid depression and people without comorbidity; females and males. The immediate visual memory and the BIS scores in patients with comorbid depression were significantly different from the scores in patients without comorbidity. In addition, females performed significantly poorer on the Working Memory Index than males and had a later age of regular drinking. Further investigation of the mechanism associated with the gender difference on cognition and exploration of the temporal relationship between alcohol dependence and depressive disorder on the cognitive aspect is needed.


Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases.
Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials, but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is nontoxic until activated specifically in the tumor by membrane-type 1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were nonresponsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma, and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor ilomastat. In HT1080 tumor-bearing mice, ICT2588 administration resulted in the formation of the active metabolite, diminution of tumor vasculature, and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect, and greater efficacy. Coadministration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 d growth delay), which was superior to the administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588, which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment.


The conserved B3 domain of VIVIPAROUS1 has a cooperative DNA binding activity.
The biochemical activities that underlie the genetically defined activator and repressor functions of the VIVIPAROUS1 (VP1) protein have resisted in vitro analysis. Here, we show that a glutathione S-transferase (GST) fusion protein, including only the highly conserved B3 domain of VP1, has a highly cooperative, sequence-specific DNA binding activity. GST fusion proteins that include larger regions of the VP1 protein have very low activity, indicating that removal of the flanking protein sequences is necessary to elicit DNA binding in vitro. DNA competition and DNase I footprinting analyses show that B3 binds specifically to the Sph element involved in VP1 activation of the C1 gene, whereas binding to the G-box-type VP1-responsive element is of low affinity and is nonspecific. Footprint analysis of the C1 promoter revealed that sequences flanking the core TCCATGCAT motif of Sph also contribute to the recognition of the Sph element in its native context. The salient features of the in vitro GST-B3 DNA interaction are in good agreement with the protein and DNA sequence requirements defined by the functional analyses of VP1 and VP1-responsive elements in maize cells.


FLT3 overexpression in acute leukaemias: New insights into the search for molecular mechanisms.
FLT3 overexpression is a recurrent event in various acute leukaemia subtypes. This transcriptional deregulation is important to define the prognostic risk for many patients. Of note, the molecular mechanisms leading to this gene upregulation are unknown for a substantial number of cases. In this Mini-Review, we highlight the role of FLT3 overexpression in acute leukaemia and discuss emerging mechanisms accounting for this upregulation. The benefits of using targeted therapy are also addressed in the overexpression context, posing other therapeutic possibilities based on state-of-the-art knowledge that could be considered for future research.


Ten questions concerning occupant health in buildings during normal operations and extreme events including the COVID-19 pandemic.
Even before the COVID-19 pandemic, people spent on average around 90% of their time indoors. Now more than ever, with work-from-home orders in place, it is crucial that we radically rethink the design and operation of buildings. Indoor Environmental Quality (IEQ) directly affects the comfort and well-being of occupants. When IEQ is compromised, occupants are at increased risk for many diseases that are exacerbated by both social and economic forces. In the U.S. alone, the annual cost attributed to sick building syndrome in commercial workplaces is estimated to be between $10 billion to $70 billion. It is imperative to understand how parameters that drive IEQ can be designed properly and how buildings can be operated to provide ideal IEQ to safeguard health. While IEQ is a fertile area of scholarship, there is a pressing need for a systematic understanding of how IEQ factors impact occupant health. During extreme events, such as a global pandemic, designers, facility managers, and occupants need pragmatic guidance on reducing health risks in buildings. This paper answers ten questions that explore the effects of buildings on the health of occupants. The study establishes a foundation for future work and provides insights for new research directions and discoveries.


Understanding maternal food choice for preschool children across urban-rural settings in Vietnam.
Improving diet quality of preschool children is challenging in countries undergoing food environment and nutrition transition. However, few studies have sought to understand how mothers in these countries decide what and how to feed their children. This study aims to explore maternal experiences, perspectives and beliefs when making food choice decisions for preschool children in urban, peri-urban and rural areas in northern Vietnam. Two focus group discussions and 24 in-depth interviews were carried out and analysed using thematic analysis. The results showed that mothers across the urban-rural spectrum shared the intention to feed children safe, nutritious food for better health and weight gain while satisfying child food preferences to improve appetite and eating enjoyment. These food choice intentions were embedded within family food traditions, whereby mothers emphasised nutritious food and adopted strict feeding styles during lunch and dinner but were flexible and accommodating of child preferences during breakfast and side meals. These intentions were also embedded within the physical food environment, which provided a mix of healthy and unhealthy food through informal food retailers. Despite these intentions, mothers faced financial constraints and difficulties in managing children's refusal to chew, changes in eating mood and strong eating temperament. These findings support policies to limit the presence of unhealthy food in informal food retail and encourage meal-specific feeding strategies to help children enjoy nutritious food, transition from soft to textured food and become more cooperative during mealtime.


Phosphorylated p68 RNA helicase activates Snail1 transcription by promoting HDAC1 dissociation from the Snail1 promoter.
The nuclear p68 RNA helicase is a prototypical member of the DEAD-box family of RNA helicases. p68 RNA helicase has been implicated in cell proliferation and early organ development and maturation. However, the functional role of p68 RNA helicase in these biological processes at the molecular level is not well understood. We previously reported that tyrosine phosphorylation of p68 RNA helicase mediates the effects of platelet-derived growth factor (PDGF) in induction of epithelial mesenchymal transition by promoting β-catenin nuclear translocation. Here, we report that phosphorylation of p68 RNA helicase at Y593 upregulates transcription of the Snail1 gene. The phosphorylated p68 activates transcription of the Snail1 gene by promoting histone deacetylase (HDAC)1 dissociation from the Snail1 promoter. Our results showed that p68 interacted with the nuclear remodeling and deacetylation complex MBD3:Mi-2/NuRD. Thus, our data suggested that a DEAD-box RNA unwindase could potentially regulate gene expression by functioning as a protein 'displacer' to modulate protein-protein interactions at the chromatin-remodeling complex.


A New Generalized Partition Crossover for the Traveling Salesman Problem: Tunneling between Local Optima.
Generalized Partition Crossover (GPX) is a deterministic recombination operator developed for the Traveling Salesman Problem. Partition crossover operators return the best of 2k reachable offspring, where k is the number of recombining components. This article introduces a new GPX2 operator, which finds more recombining components than GPX or Iterative Partial Transcription (IPT). We also show that GPX2 has O(n) runtime complexity, while also introducing new enhancements to reduce the execution time of GPX2. Finally, we experimentally demonstrate the efficiency of GPX2 when it is used to improve solutions found by the multitrial Lin-Kernighan-Helsgaum (LKH) algorithm. Significant improvements in performance are documented on large (n>5000) and very large (n=100,000) instances of the Traveling Salesman Problem.


Low-temperature growth of near-infrared luminescent Bi-doped SiO(x)N(y) thin films.
Bi-doped siliconoxynitride (SiON:Bi) thin films were prepared by a sputtering method and the photoluminescence (PL) properties were studied. Without any thermal treatments, broad Bi-related luminescence was observed in the near-infrared (NIR) range. The luminescence efficiency depended strongly on the film composition. It was found that N atoms play a crucial role for the formation of Bi NIR luminescence centers. The effect of annealing on the luminescence efficiency was also studied. The optimum annealing temperature to have the largest number of Bi NIR luminescence centers depended strongly on the film composition and it was lower for films with lower N concentration. The PL excitation spectra revealed that two different Bi NIR luminescence centers exist in the films.


The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3'-azido-3'-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus type 1.
N-[4-Chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furanca rbothioamide (UC781) is an exceptionally potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We found that a 1:1 molar combination of UC781 and 3'-azido-3'-deoxythymidine (AZT) showed high-level synergy in inhibiting the replication of AZT-resistant virus, implying that UC781 can restore antiviral activity to AZT against AZT-resistant HIV-1. Neither the nevirapine plus AZT nor the 2',5'-bis-O-(t-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxathi ole- 2",2"-dioxide plus AZT combinations had this effect. Studies with purified HIV-1 reverse transcriptase (from a wild type and an AZT-resistant mutant) showed that UC781 was a potent inhibitor of the pyrophosphorolytic cleavage of nucleotides from the 3' end of the DNA polymerization primer, a process that we have proposed to be critical for the phenotypic expression of AZT resistance. Combinations of UC781 plus AZT did not act in synergy to inhibit the replication of either wild-type virus or UC781-resistant HIV-1. Importantly, the time to the development of viral resistance to combinations of UC781 plus AZT is significantly delayed compared to the time to the development of resistance to either drug alone.


A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.
Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 μg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.


Endovascular management of bleeding events following robotic pancreaticobiliary surgery.
To describe the utility, safety, and efficacy of endovascular intervention for treating bleeding events after robotic pancreaticobiliary surgery. In this retrospective study, six patients (male/female, 3/3; mean age, 64 years) with histories of robotic pancreaticobiliary resection were referred for endovascular management of delayed postoperative intra-abdominal hemorrhage. Visceral angiography was performed, and the sites of suspected arterial hemorrhage were interrogated with selective microcatheter arteriography. The visualized bleeding sources were treated using catheter-directed embolotherapy with metallic coils, bare metal or covered stent insertion, or a combination of the two. The measured outcomes included the technical success of the angiographic occlusion, procedure safety, and procedure efficacy. Pseudoaneurysms resulted in bleeding in six cases (100%). The endovascular interventions included coil embolization in three cases (50%), covered stent exclusion in two cases (33%), and bare metal stent-assisted coil embolization in one case (17%). The technical success was 100%, with complete cessation of bleeding in all cases. No immediate or delayed procedure-related complications were encountered in any of the patients. The efficacy of the endovascular therapy was 100% in this series, with no recurrent hemorrhage during the mean clinical follow-up period of 262 days (range, 67-446 days). Endovascular therapy provides a minimally invasive, safe, and effective method for managing hemorrhagic events after complicated pancreaticobiliary surgery.


Microporous annealed particle hydrogel stiffness, void space size, and adhesion properties impact cell proliferation, cell spreading, and gene transfer.
Designing scaffolds for polyplex-mediated therapeutic gene delivery has a number of applications in regenerative medicine, such as for tissue repair after wounding or disease. Microporous annealed particle (MAP) hydrogels are an emerging class of porous biomaterials, formed by annealing microgel particles to one another in situ to form a porous bulk scaffold. MAP gels have previously been shown to support and enhance proliferative and regenerative behaviors both in vitro and in vivo. Therefore, coupling gene delivery with MAP hydrogels presents a promising approach for therapy development. To optimize MAP hydrogels for gene delivery, we studied the effects of particle size and stiffness as well as adhesion potential on cell surface area and proliferation and then correlated this information with the ability of cells to become transfected while seeded in these scaffolds. We find that the void space size as well as the presentation of integrin ligands influence transfection efficiency. This work demonstrates the importance of considering MAP material properties for guiding cell spreading, proliferation, and gene transfer. STATEMENT OF SIGNIFICANCE: Microporous annealed particle (MAP) hydrogels are an emerging class of porous biomaterials, formed by annealing spherical microgels together in situ, creating a porous scaffold from voids between the packed beads. Here we investigated the effects of MAP physical and adhesion properties on cell spreading, proliferation, and gene transfer in fibroblasts. Particle size and void space influenced spreading and proliferation, with larger particles improving transfection. MAP stiffness was also important, with stiffer scaffolds increasing proliferation, spreading, and transfection, contrasting studies in nonporous hydrogels that showed an inverse response. Last, RGD ligand concentration and presentation modulated spreading similar to non-MAP hydrogels. These findings reveal relationships between MAP properties and cell processes, suggesting how MAP can be tuned to improve future design approaches.


Low depressive symptoms in acute spinal cord injury compared to other neurological disorders.
The aim of the study was to reveal the incidence and time course of depressive symptoms following acute spinal cord injury (SCI) in relation to clinical outcomes for comparison to other neurological disorders with severe impairment. In patients with acute traumatic SCI (n = 130), combined follow up assessments of neurological and functional outcomes, pain and patient-rated affective factors (e.g. mood, anxiety) were prospectively (1, 3, 6, 12 months after injury) collected during rehabilitation and follow up in out-patient clinics. We related these to the severity of depressive symptoms (no, mild, moderate and severe) based on the Beck Depression Inventory (BDI) scores. The mean 65% of patients showed no depressive symptoms and 30% mild depressive symptoms, while less than 5% presented moderate to severe depressive symptoms. The group findings and symptoms in individual patients remained stable over 1 year though patients revealed significant clinical recovery. Although two-thirds of the patients experienced pain, BDI scores were not related to pain intensity. BDI mean scores were only slightly higher than in control populations, but rather low compared to patients with other neurological disorders (e.g. stroke and multiple sclerosis) that are also associated with severe functional impairment. The prevalence of depressive symptoms following acute SCI is rather low and remains stable within the first year after injury despite the severe neurological impairment and loss of independency. In comparison to other neurological disorders that also involve brain function SCI patients seem to be less challenged by depressive symptoms that constitute additional burdens to respond to the severe functional impairments.


The bronchitis index. A semiquantitative visual scale for the assessment of airways inflammation.
Flexible fiberoptic bronchoscopy has been proven to be an effective tool for the assessment and characterization of airway inflammation. Visual inspection of airways affected by chronic bronchitis discloses an abnormal appearance characterized by erythema, edema, secretions, and friability. It was hypothesized that the visual appearance of airway inflammation could be assessed in a semiquantitative manner. A bronchitis index (BI) was developed that scores the visual appearance of airways according to the presence or absence of abnormal edema, erythema, secretions, and friability (0 = normal, 3 = remarkably abnormal). The BI was determined in three study groups: 86 subjects with chronic bronchitis, 15 subjects who smoked cigarettes, but did not have chronic bronchitis, and 25 normal, nonsmoking control subjects. The reproducibility of the BI was determined by comparing the results from pairs of two independent observers assessing 249 subjects undergoing fiberoptic bronchoscopy under various investigative protocols. In total, nine investigators scored the airways. For the three observer pairs with more than six observations, there were no differences noted in the BI (p = 0.43, 0.67, 0.82). To control for the effect of cough upon the BI, lidocaine usage was recorded. No correlation was found between lidocaine usage and BI. As previously noted for a smaller group of subjects, the BI was found to be elevated in those with chronic bronchitis (13.2 +/- 0.53) compared with both asymptomatic smokers (8.5 +/- 0.89, p < 0.0005) and normal volunteers (2.3 +/- 0.55, p < 0.0001); the latter two groups also differed significantly (p < 0.0001). The BI was also found to correlate significantly with bronchial sample lavage fluid neutrophil content in lavage fluid obtained after determination of the BI and with cigarette smoking as quantitated by pack years. Conversely, the BI correlated negatively with the spirometric measures of airway obstruction, FEV1, FEV1/FVC, FEV25-75, and FEFmax. Thus, the BI appears to be a reproducible, semiquantitative assessment of the visual appearance of airway inflammation. It may be a useful bronchoscopic adjunct for the assessment of airway inflammation in clinical investigations.


Bed nets used to protect against malaria do not last long in a semi-arid area of Ethiopia: a cohort study.
Long-lasting insecticidal nets (LLINs) are a key tool for malaria prevention and control. Currently, the recommended serviceable life of an LLIN is 3 years under field conditions. However, field studies show considerable variation in LLIN lifespan, from less than 2 years to more than 4 years. This study aimed to determine the attrition, physical integrity, functional survival, and bio-efficacy of LLINs under field conditions in south-central Ethiopia. In October 2014, 7740 LLINs (PermaNet® 2.0) were distributed to 3006 households. Among the distributed LLINs, a cohort study involving 1532 LLINs in 659 households was carried out from October 2014 to November 2016. Data were collected every 6 months by observation, and through interviews with the heads of households. The proportional hole index was used to categorize LLINs as either serviceable or torn. In addition, 120 randomly selected LLINs were tested for bio-efficacy. The overall attrition of LLINs was 96% (n = 993) during the study period. The nets' attrition was mainly due to disposal (64.2%; n = 638). The proportion of LLINs with a hole size 0.5 cm or larger was 79.5% after 24 months. The use of the net on the previous night and having a clean net were associated with a good physical integrity. However, living in a household more than 1 km away from the mosquitoes' breeding site was associated with poor physical integrity. By the 24th month, only 4% of the nets met the criteria for functional survival. The median functional survival time of the nets was 12 months. A longer functional survival was associated with having a clean net, and shorter survival was associated with living in a household more than 1 km away from the mosquitoes' breeding site. The PermaNet® 2.0 met the criteria of effective bio-efficacy up to month 24 after distribution. The study showed that the median serviceable life of LLINs is only 12 months. However, the bio-efficacy of the LLINs is acceptable for at least 24 months. Therefore, stronger and more efficient LLINs need to be developed for conditions similar to those studied here.


Identification and structure of four yeast genes (SLY) that are able to suppress the functional loss of YPT1, a member of the RAS superfamily.
In Saccharomyces cerevisiae, the GTP-binding Ypt1 protein (Ypt1p) is essential for endoplasmic reticulum-to-Golgi protein transport. By exploiting a GAL10-YPT1 fusion to regulate YPT1 expression, three multicopy suppressors, SLY2, SLY12, and SLY41, and a single-copy suppressor, SLY1-20, that allowed YPT1-independent growth were isolated. Wild-type Sly1p is hydrophilic, is essential for cell viability, and differs from Sly1-20p by a single amino acid. SLY2 and SLY12 encode proteins with hydrophobic tails similar to synaptobrevins, integral membrane proteins of synaptic vesicles in higher eucaryotes. Sly41p is hydrophobic and exhibits sequence similarities with the chloroplast phosphate translocator. SLY12 but not SLY41 is an essential gene. The SLY2 null mutant is cold and heat sensitive. The SLY gene products may comprise elements of the protein transport machinery.


Macular telangiectasia type 2.
Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.


Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups.
The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m(2) daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 x 10(9)/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P =.002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs.


Usefulness of C-Reactive Protein in Differentiating Acute Leptospirosis and Dengue Fever in French Guiana.
Leptospirosis and dengue fever (DF) are hard-to-differentiate diseases in cocirculating areas, especially during DF epidemics. Misdiagnosis and ensuing lack of antibiotic therapy can be detrimental in leptospirosis. The objective of this study was to identify factors that help differentiate acute leptospirosis from dengue fever on admission. Patients with leptospirosis (positive serology or polymerase chain reaction) were compared with patients with DF (positive nonstructural 1 [NS1] antigen) in a case-control study with age matching. Data on admission were compared using bivariate analysis and multivariate analysis. Seventy-two patients with leptospirosis were compared to 216 patients with DF. In bivariate analysis, the factors associated with leptospirosis were male gender, cough, anemia, and elevated blood levels of C-reactive protein (CRP), leukocytes, creatinine, bilirubin, and creatine phosphokinase. Exanthema, purpura, myalgia, headache, and neutropenia were associated with DF. In multivariate analysis, elevated blood levels of leukocytes, bilirubin, and CRP were associated with leptospirosis. The CRP threshold of 50 mg/L taken alone had elevated sensitivity and specificity. The CRP level, an easy-to-obtain biomarker, was a powerful tool to differentiate on admission leptospirosis and DF. Facing a dengue-like syndrome in cocirculating areas and awaiting new specific rapid diagnostic tests, CRP dosing could help the clinician to promptly consider the diagnosis of leptospirosis and initiate antibiotic therapy early.


A survey of child care centers about breastfeeding support in Adelaide, South Australia.
Australia has high rates of breastfeeding initiation, with a consistent decline over the first year. Furthermore, there is a growing trend of maternal employment and rising numbers of children enrolled in different types of child care services, both of which can have a negative impact on breastfeeding. To provide evidence to better inform implementation of breastfeeding-friendly strategies in child care settings, this study examined breastfeeding policy and practice in child care centers in metropolitan Adelaide. The paper reports on a survey sent to 292 child care centers in metropolitan Adelaide in 2010. The survey collected information on center location and type, number of enrolled children under age 2, and number of breastfed babies. The survey also included questions about breastfeeding facilities and support, breastfeeding policies, staff training, and barriers to and recommendations to enhance breastfeeding support in child care centers. Of the 62 completed returned surveys (21% response rate), 43 centers (69.4%) reported that they currently have children who receive breast milk at the center; however, in most centers, the total number of breastfed children was reported to be between 1 and 4; 76% reported that the center was supportive of exclusive breastfeeding for 6 months; and 80.6% had statements on breastfeeding as part of their food and nutrition policies or guidelines. Furthermore, 64.5% reported there was no formal or informal training for staff on breastfeeding support, but 50% reported that staff members do provide breastfeeding advice to mothers of children in their center. Despite some strategies in place to support breastfeeding, there are no standards on breastfeeding policies, practices, and training in child care settings. Therefore, the extent and scope of such support depend on parental request and the perceptions and attitudes of child care center staff toward breastfeeding.


Breakdown of electroneutrality in nanopores.
Ion transport in extremely narrow nanochannels has gained increasing interest in recent years due to unique physical properties at the nanoscale and the technological advances that allow us to study them. It is tempting to approach this confined regime with the theoretical tools and knowledge developed for membranes and microfluidic devices, and naively apply continuum models, such as the Poisson-Nernst-Planck and Navier-Stokes equations. However, it turns out that some of the most basic principles we take for granted in larger systems, such as the complete screening of surface charge by counter-ions, can break down under extreme confinement. We show that in a truly one-dimensional system of ions interacting with three-dimensional electrostatic interactions, the screening length is exponentially large, and can easily exceed the macroscopic length of a nanotube. Without screening, electroneutrality breaks down within the nanotube, with fundamental consequences for ion transport and electrokinetic phenomena. In this work, we build a general theoretical framework for electroneutrality breakdown in nanopores, focusing on the most interesting case of a one-dimensional nanotube, and show how it provides an elegant interpretation for the peculiar scaling observed in experimental measurements of ionic conductance in carbon nanotubes.


Global emergency medicine journal club: a social media discussion about the Age-Adjusted D-Dimer Cutoff Levels To Rule Out Pulmonary Embolism trial.
Annals of Emergency Medicine collaborated with an educational Web site, Academic Life in Emergency Medicine (ALiEM), to host an online discussion session featuring the 2014 Journal of the American Medical Association publication on the Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism (ADJUST-PE) trial by Righini et al. The objective is to describe a 14-day (August 25 to September 7, 2014) worldwide academic dialogue among clinicians in regard to 4 preselected questions about the age-adjusted D-dimer cutoff to detect pulmonary embolism. Five online facilitators hosted the multimodal discussion on the ALiEM Web site, Twitter, and Google Hangout. Comments across the social media platforms were curated for this report, as framed by the 4 preselected questions, and engagement was tracked through various Web analytic tools. Blog and Twitter comments, as well as video expert commentary involving the ADJUST-PE trial, are summarized. The dialogue resulted in 1,169 page views from 391 cities in 52 countries on the ALiEM Web site, 502,485 Twitter impressions, and 159 views of the video interview with experts. A postdiscussion summary on the Journal Jam podcast resulted in 3,962 downloads in its first week of publication during September 16 to 23, 2014. Common themes that arose in the multimodal discussions included the heterogeneity of practices, D-dimer assays, provider knowledge about these assays, and prevalence rates in different areas of the world. This educational approach using social media technologies demonstrates a free, asynchronous means to engage a worldwide audience in scholarly discourse.


The Treatment Intensity of Anticoagulant Therapy for Patients With Sepsis-Induced Disseminated Intravascular Coagulation and Outcomes: A Multicenter Cohort Study.
We examined the institutional variations in anticoagulation therapy for sepsis-induced disseminated intravascular coagulation (DIC) and their effects on patient outcomes. This post hoc analysis of a cohort study included 3195 patients with severe sepsis across 42 intensive care units. To evaluate differences in the intensity of anticoagulation therapy, the proportion of patients receiving anticoagulation therapy and the total number of patients with sepsis-induced DIC were compared. Predicted in-hospital mortality for each patient was calculated using logistic regression analysis. To evaluate survival outcomes, the actual/mean predicted in-hospital mortality ratio in each institution was calculated. Thirty-eight institutions with 2897 patients were included. Twenty-five institutions treated 60% to 100% (high-intensity institutions), while the rest treated 0% to 50% (low-intensity institutions) of patients with sepsis-induced DIC having anticoagulant therapy. Every 10-unit increase in the intensity of anticoagulant therapy was associated with lower in-hospital mortality (odds ratio: 0.904). A higher number of high-intensity institutions (compared to low-intensity institutions) had lower in-hospital mortality and fewer bleeding events than predicted. In conclusion, institutional variations existed in the use of anticoagulation therapy in patients with sepsis-induced DIC. High-intensity anticoagulation therapy was associated with better outcomes.


Limb movement, coordination and muscle activity during a cross-coordination movement on a stable and unstable surface.
At a clinical level, the intensity of dynamic balance tasks incorporating cross-coordination movements (CCM) is typically progressed by changing the stability of the support surface on which the movement is undertaken. However, biomechanical changes in CCMs performed on stable and unstable surfaces have not yet been quantified. Do movement patterns, muscle activity, coordination strategies, knee joint loading and center of mass (CoM) movement differ during a CCM performed on stable and unstable surfaces? Motion analysis was used to monitor limb kinematics and surface electromyography to analyze supporting leg muscle activity in sixteen healthy athletes during a single-limb support task involving a cyclic CCM on a stable and unstable surface. Angle-angle plots were used to explore coordination strategies in sagittal movement of the hip and shoulder, while differences in kinematics and muscle activity between stable and unstable conditions were evaluated using dependent t-tests (α-level = 0.05). CCMs on an unstable surface were performed at a slower speed (p < .05), with a more flexed posture of the support knee (p < .05) and ankle (p < .05) and resulted in reduced hip and shoulder movement of the swing limbs (p < .05). Instability increased activation of selected muscles of the ankle and knee (p < .05), resulted in a two-fold increase in the peak knee adduction moment (p < .05), and was accompanied by greater CoM movement (p < .05). Three coordination patterns of the swing limbs observed when performing CCM on a stable surface, which were mostly preserved on the unstable surface. Despite adopting several stabilization strategies, CCM undertaken on an unstable surface still evoked greater excursion of the center of mass and, as such, presented a greater challenge to sensorimotor control. Adding instability in form of a swinging platform provides progression of dynamic balance CCM difficulty in an athletic population.


Soil origin and plant genotype structure distinct microbiome compartments in the model legume Medicago truncatula.
Understanding the genetic and environmental factors that structure plant microbiomes is necessary for leveraging these interactions to address critical needs in agriculture, conservation, and sustainability. Legumes, which form root nodule symbioses with nitrogen-fixing rhizobia, have served as model plants for understanding the genetics and evolution of beneficial plant-microbe interactions for decades, and thus have added value as models of plant-microbiome interactions. Here we use a common garden experiment with 16S rRNA gene amplicon and shotgun metagenomic sequencing to study the drivers of microbiome diversity and composition in three genotypes of the model legume Medicago truncatula grown in two native soil communities. Bacterial diversity decreased between external (rhizosphere) and internal plant compartments (root endosphere, nodule endosphere, and leaf endosphere). Community composition was shaped by strong compartment × soil origin and compartment × plant genotype interactions, driven by significant soil origin effects in the rhizosphere and significant plant genotype effects in the root endosphere. Nevertheless, all compartments were dominated by Ensifer, the genus of rhizobia that forms root nodule symbiosis with M. truncatula, and additional shotgun metagenomic sequencing suggests that the nodulating Ensifer were not genetically distinguishable from those elsewhere in the plant. We also identify a handful of OTUs that are common in nodule tissues, which are likely colonized from the root endosphere. Our results demonstrate strong host filtering effects, with rhizospheres driven by soil origin and internal plant compartments driven by host genetics, and identify several key nodule-inhabiting taxa that coexist with rhizobia in the native range. Our results set the stage for future functional genetic experiments aimed at expanding our pairwise understanding of legume-rhizobium symbiosis toward a more mechanistic understanding of plant microbiomes. Video Abstract.


Characterization of a novel dual-core elliptical hollow optical fiber with wavelength decreasing differential group delay.
The modal distribution of a novel elliptical hollow optical fiber is experimentally and numerically characterized. The fiber has a central elliptical air hole surrounded by a germanosilicate lanceolate ring core. Experiments reveal that the fiber behaves like a dual core waveguide and it is found that the differential group delay of each core decreases with wavelength with a PMD coefficient slope of ~10(-2) ps/m/THz. Experimental results are also compared with numerical modeling based on scanning electron microscopy images.


Iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from Streptosporangium sp. induces apoptosis selectively in myeloid leukemia cell lines and patient cells.
Despite recent improvement in therapy, acute myeloid leukemia (AML) is still associated with high lethality. In the presented study, we analyzed the bioactive compound iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from a marine actinomycetes bacterium for the ability to induce cell death in a range of cell types. Iodinin showed selective toxicity to AML and acute promyelocytic (APL) leukemia cells, with EC50 values for cell death up to 40 times lower for leukemia cells when compared with normal cells. Iodinin also successfully induced cell death in patient-derived leukemia cells or cell lines with features associated with poor prognostic such as FLT3 internal tandem duplications or mutated/deficient p53. The cell death had typical apoptotic morphology, and activation of apoptotic signaling proteins like caspase-3. Molecular modeling suggested that iodinin could intercalate between bases in the DNA in a way similar to the anti-cancer drug daunorubicin (DNR), causing DNA-strand breaks. Iodinin induced apoptosis in several therapy-resistant AML-patient blasts, but to a low degree in peripheral blood leukocytes, and in contrast to DNR, not in rat cardiomyoblasts. The low activity towards normal cell types that are usually affected by anti-leukemia therapy suggests that iodinin and related compounds represent promising structures in the development of anti-cancer therapy.


Association between Mediterranean diet and head and neck cancer: results of a large case-control study in Italy.
The Mediterranean diet (MD) is a known protective factor for head and neck cancer (HNC); however, there is still a lack of studies investigating this association by HNC subsite. The aim of the present study was therefore to evaluate the association between adherence to MD and HNC overall and by cancer subsite, as well as the effect of the individual food components on HNC risk. A case-control study was carried out at the Gemelli Hospital of Rome (Italy). A total of 500 HNC cases and 433 controls were interviewed. Dietary intake was assessed through a validated food frequency questionnaire that collected information on over 25 food items. Odds ratios (ORs) and 95% confidence intervals (CI) of HNC were calculated using a multiple logistic regression model. We found a reduced risk of both oral cavity and pharynx cancer (OR=0.61; CI: 0.54-0.70) and larynx cancer (OR=0.64; CI: 0.56-0.73) with increasing adherence to MD. We also found a high consumption of fruit, vegetables, and legumes to be significantly associated with a lower risk of larynx as well as oral cavity and pharynx cancers. Our study showed that adherence to MD acts protectively against HNC overall and by cancer subsite.


An efficient strategy to estimate thermodynamics and kinetics of G protein-coupled receptor activation using metadynamics and maximum caliber.
Computational strategies aimed at unveiling the thermodynamic and kinetic properties of G Protein-Coupled Receptor (GPCR) activation require extensive molecular dynamics simulations of the receptor embedded in an explicit lipid-water environment. A possible method for efficiently sampling the conformational space of such a complex system is metadynamics (MetaD) with path collective variables (CVs). Here, we applied well-tempered MetaD with path CVs to one of the few GPCRs for which both inactive and fully active experimental structures are available, the μ-opioid receptor (MOR), and assessed the ability of this enhanced sampling method to estimate the thermodynamic properties of receptor activation in line with those obtained by more computationally expensive adaptive sampling protocols. While n-body information theory analysis of these simulations confirmed that MetaD can efficiently characterize ligand-induced allosteric communication across the receptor, standard MetaD cannot be used directly to derive kinetic rates because transitions are accelerated by a bias potential. Applying the principle of Maximum Caliber (MaxCal) to the free-energy landscape of morphine-bound MOR reconstructed from MetaD, we obtained Markov state models that yield kinetic rates of MOR activation in agreement with those obtained by adaptive sampling. Taken together, these results suggest that the MetaD-MaxCal combination creates an efficient strategy for estimating the thermodynamic and kinetic properties of GPCR activation at an affordable computational cost.


Efficacy and safety of Chlorella supplementation in adults with chronic hepatitis C virus infection.
To evaluate the safety and efficacy of Chlorella in 18 patients chronically infected with hepatitis C virus (HCV) genotype 1. Eighteen adults with chronic infection by HCV genotype 1 received daily oral supplementation of Chlorella for 12 wk. Changes in the RNA levels of HCV, as well as those of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated following this treatment period. Paired t tests were conducted to compare the means of the different variables at the beginning and end of the study. Side effects and quality of life aspects were also compared between weeks 0 and 12 of the study period. A majority 84.61% of the patients had a significant decrease in their ALT levels from week 0 to week 12. Evaluation of side effects showed that Chlorella was well tolerated. Quality of life assessment showed that 76.9 of the participants reported an improvement in their energy levels and 46.1% reported an improvement in their perception of general health. Although 69.23% also showed a decrease in their AST levels, this was not statistically significant. Most patients that exhibited an improvement in their ALT and AST levels also showed a tendency toward a decreased HCV viral load. The HCV RNA levels showed a decrease in 69.23% of the patients, which along with changes in AST/ALT ratios from week 0 to week 12, these results were not statistically significant. Chlorella supplementation was well tolerated in patients with chronic HCV and associated with a significant decrease in ALT liver enzyme levels.


Mental health of returnees: refugees in Germany prior to their state-sponsored repatriation.
Many refugees live for years in exile. The combination of stress in the host country, together with long-term effects resulting from traumatic stress usually experienced in the home country may affect mental health. Little is known, to what extent these and other factors promote or stall the willingness to return to the country of origin. Here, we investigate, as an example, refugees who will return to their country of origin after having lived in exile in Germany for some 11 years. What is the mental health status of returnees before the actual return who have been living in exile for an extended period? We also asked, what are the current living conditions in Germany and what are the motives for and reasons against a voluntary return to the country of origin? Forty-seven participants of programs for assisted voluntarreturn were interviewed about their present living situation, their view regarding their home country and voluntary return. These findings were compared to a group of 53 refugees who had decided to remain in Germany (stayers). Participants were recruited by means of advertisements posted in refugee centres, language schools, at doctors' offices and in organisations involved in the management of voluntary return in Germany. The prevalence of psychiatric disorders among respondents was tested using the structured interview M.I.N.I. The Posttraumatic Stress Diagnostic Scale (PDS) was used to assess PTSD in more detail and EUROHIS was applied to measure the subjective quality of life of participants. We found a prevalence rate of 44% psychiatric disorders in the group of returnees and a rate of 78% in the group of stayers. We also recorded substantial correlations between the living situation in Germany, disposition to return and mental health. In almost two thirds of the participants the decision to return was not voluntary but strongly influenced by immigration authorities. The most important reason for participants to opt for a stay in Germany were their children, who have been born and raised in Germany. Psychological strains among the study participants were very high. Traumatic stress, experienced during war and refuge, has left the victims vulnerable and not well equipped to cope with post-migration stressors in exile. It is noteworthy that the majority returned under pressure of the immigration authorities. The fear of an uncertain future after the return was substantial. These factors should be taken into account in programs designed to assist returnees, including those that offer support after return to the country of origin.


Acute hepatitis C infection after sexual exposure.
A case is described of a woman with acute hepatitis C infection whose partner had chronic hepatitis C infection and where heterosexual contact was the only major risk factor. Infection of both partners was confirmed serologically and by the finding of virus RNA by reverse transcription and polymerase chain reaction amplification. Nucleotide sequence analysis of the NS5 region (RNA polymerase) was used to show that both partners were infected with virus of the same genotype (1a). The nucleotide sequence of virus RNA found in the female patient is closest to variants cocirculating in the male contact, consistent with transmission having occurred between the two.


Simultaneous excitatory and inhibitory dynamics in an excitable laser.
Neocortical systems encode information in electrochemical spike timings, not just mean firing rates. Learning and memory in networks of spiking neurons is achieved by the precise timing of action potentials that induces synaptic strengthening (with excitation) or weakening (with inhibition). Inhibition should be incorporated into brain-inspired spike processing in the optical domain to enhance its information-processing capability. We demonstrate the simultaneous excitatory and inhibitory dynamics in an excitable (i.e., a pulsed) laser neuron, both numerically and experimentally. We investigate the bias strength effect, inhibitory strength effect, and excitatory and inhibitory input timing effect, based on the simulation platform of an integrated graphene excitable laser. We further corroborate these analyses with proof-of-principle experiments utilizing a fiber-based graphene excitable laser, where we introduce inhibition by directly modulating the gain of the laser. This technology may potentially open novel spike-processing functionality for future neuromorphic photonic systems.


Sterilization and polyethylene wear: clinical studies to support laboratory data.
Recently, in vitro studies have linked gamma radiation sterilization in air and subsequent oxidation to decreasing mechanical properties and rapid polyethylene wear. As a result of these studies, orthopaedic device manufacturers have developed alternate sterilization strategies designed to limit or to prevent oxidative degradation. We compared how the in vivo wear performance of conventional and highly-crystalline polyethylene acetabular liners was affected by two sterilization strategies (gas plasma sterilization and gamma radiation sterilization in vacuum-barrier packaging) as compared with gamma radiation sterilization in air. Using multivariate linear regression analysis, we analyzed radiographic wear data on 385 total hip implants after a mean duration of follow-up of 6.2 years (range, four to eleven years). Two hundred and twenty-seven components had been sterilized with gamma radiation in air, seventy-seven had been sterilized with gas plasma, and eighty-one had been sterilized with gamma radiation in vacuum-barrier packaging. The liners had a mean shelf life of 0.65 +/- 0.85 year. Two hundred and fifty-two components were made from conventional ultra-high molecular weight polyethylene (Enduron), and 133 were made from highly crystalline ultra-high molecular weight polyethylene (Hylamer). In the conventional polyethylene group, the clinical wear performance of the components that had been sterilized with gamma radiation, either in air or in vacuum-barrier packaging, was superior to that of the nonirradiated components that had been sterilized with gas plasma. However, in the highly-crystalline polyethylene group, only the components that had been sterilized with radiation in vacuum-barrier packaging had a reduced rate of in vivo wear; the components that had been sterilized with gamma radiation in air had essentially the same high wear rate as did the liners that had been sterilized with gas plasma. The radiographic wear data on conventional polyethylene are consistent with the findings of laboratory studies that have demonstrated that radiation-induced cross-linking has a beneficial effect on polyethylene wear resistance. The conventional and highly-crystalline polyethylene liners in the present study, however, responded differently to gamma radiation sterilization in air despite the fact that the implants in both groups had very short shelf lives. This finding probably was due to the difference in the morphological structures of the two polyethylenes and the resulting greater susceptibility of highly-crystalline polyethylene to oxidative degradation. These findings provide clinical information that will help surgeons to make informed decisions concerning which components to implant. The data on Hylamer polyethylene liners provide insight into the expected performance of liners of this type that have already been implanted as well as potential insight into the performance of new polyethylenes. In particular, this information demonstrates that differences in the structure of polyethylene, as seen with the different highly cross-linked polyethylenes currently on the market, can affect clinical wear behavior. Therapeutic study, Level III-2 (retrospective cohort study). See Instructions to Authors for a complete description of levels of evidence.


Recreational cyclists: The relationship between low back pain and training characteristics.
This study investigated the relationship between low back pain (LBP) and training characteristics in recreational cyclists. Purposive sampling was used to recruit sixty-six recreational cyclists from nine cycling clubs. Participants completed a survey reporting training characteristics and LBP behaviour during a usual week of cycling. This included percent of time spent cycling in three common riding positions, cycling terrain, average cycling pace, number of gears, days per week cycled and number of cycling events per year. Fifty percent reported LBP during or after cycling or smoking and LBP. Cyclists who reported LBP cycled significantly further in a usual week of cycling than cyclists who did not report LBP (p=0.022). An odds ratio indicated that people who cycle 160 km or more per week are 3.6 times as likely to experience LBP compared with people who cycle less than 160 km per week (OR=3.6, CI=1.29-10.15). Preference for riding with the hands on the brakes approached significance with respect to LBP reports (P=0.06). No other significant relationship between LBP and training characteristics was identified. In order to reduce the risk of LBP recreational cyclists who report LBP should consider decreasing cycling distance to less than 160 km per week.


High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption.
C57BL/6J (B6) inbred mice are well known to drink large amounts of alcohol (ethanol) voluntarily and to have only modest ethanol-induced withdrawal under fixed dose conditions. In contrast, DBA/2J (D2) mice are "teetotallers" and exhibit severe ethanol withdrawal. Speculation that an inverse genetic relationship existed between these two traits was substantiated by meta-analysis of existing data collected in multiple genetic models, including large panels of standard and recombinant inbred strains, their crosses, and selectively bred mouse lines. Despite methodological differences among laboratories in measurement of both preference drinking and withdrawal, a nearly universal finding was that genotypes consuming large amounts of 10% ethanol (calculated as g/kg/day) during two-bottle choice preference drinking were genetically predisposed to low withdrawal scores in independent studies after either acute or chronic ethanol treatment. Conversely, low-drinking genotypes had higher withdrawal severity scores. The genetic relationship appears to be strongest in populations derived from B6 and D2, where data from more genotypes (BXD RIs, B6D2F2s, BXD RI F1s, and B6D2F2-derived selectively bred lines) were available for analysis. Gene mapping studies in these populations identified four chromosome regions [on Chromosomes (Chrs) 1, 2, 4, and 15] where genes might potentially influence both traits. Among genotypes with greater genetic diversity (for example, a panel of standard inbred strains or selectively bred lines), the relationship was less pronounced. Thus, reduced susceptibility to the development of high alcohol use may be supported by increased genetic susceptibility to ethanol withdrawal symptoms.


Predictors of health-related quality of life after burn injuries: a systematic review.
Identifying predictors of health-related quality of life (HRQL) following burns is essential for optimization of rehabilitation for burn survivors. This study aimed to systematically review predictors of HRQL in burn patients. Medline, Embase, Web of Science, Cochrane, CINAHL, and Google Scholar were reviewed from inception to October 2016 for studies that investigated at least one predictor of HRQL after burns. The Quality in Prognostic Studies tool was used to assess risk of bias of included studies. Thirty-two studies were included. Severity of burns, postburn depression, post-traumatic stress symptoms, avoidance coping, less emotional or social support, higher levels of neuroticism, and unemployment postburn were found to predict a poorer HRQL after burns in multivariable analyses. In addition, weaker predictors included female gender, pain, and a postburn substance use disorder. Risk of bias was generally low in outcome measurement and high in study attrition and study confounding. HRQL after burns is affected by the severity of burns and the psychological response to the trauma. Both constructs provide unique information and knowledge that are necessary for optimized rehabilitation. Therefore, both physical and psychological problems require attention months to years after the burn trauma.


A new MEMS-based system for ultra-high-resolution imaging at elevated temperatures.
In recent years, an increasing number of laboratories have been applying in situ heating (and ultimately, gas reaction) techniques in electron microscopy studies of catalysts and other nanophase materials. With the advent of aberration-corrected electron microscopes that provide sub-Angström image resolution, it is of great interest to study the behavior of materials at elevated temperatures while maintaining the resolution capabilities of the microscope. In collaboration with Protochips Inc., our laboratory is developing an advanced capability for in situ heating experiments that overcomes a number of performance problems with standard heating stage technologies. The new heater device allows, for example, temperature cycling from room temperature to greater than 1000 degrees C in 1 ms (a heating rate of 1 million Centigrade degrees per second) and cooling at nearly the same rate. It also exhibits a return to stable operation (drift controlled by the microscope stage, not the heater) in a few seconds after large temperature excursions. With Protochips technology, we were able to demonstrate single atom imaging and the behavior of nanocrystals at high temperatures, using high-angle annular dark-field imaging in an aberration-corrected (S)TEM. The new capability has direct applicability for remote operation and (ultimately) for gas reaction experiments using a specially designed environmental cell.


Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease.
Respiratory pathogens are frequently isolated from the airways of patients with chronic obstructive pulmonary disease (COPD) in the absence of an exacerbation. This bacterial "colonization" by potential pathogens is associated with host inflammatory and immune responses, which could increase respiratory symptoms. To study whether bacterial colonization impacts daily respiratory symptoms in COPD. In a longitudinal prospective observational study of COPD, patients recorded daily symptoms electronically on the Breathlessness, Cough, and Sputum Scale (BCSS). Sputum cultures and quantitative polymerase chain reaction (PCR) were performed every 2 weeks. The relationship of BCSS and bacterial colonization was analyzed with generalized linear mixed effects models, after controlling for exacerbations, weather conditions, lung function, and demographic variables. A total of 41 patients recorded daily symptoms for 12,527 days. The average BCSS score was higher during the periods of colonization, determined by sputum culture with one or more of the following pathogens: nontypeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa, compared to periods without colonization (5.28 vs. 4.46; P = 0.008) after controlling for confounding variables. The finding did not change when colonization was defined by quantitative PCR (average BCSS, 4.77 vs. 4.25; P = 0.006). Sputum IL-8 levels were elevated with bacterial colonization. Even in the absence of clinical exacerbation, colonization by bacterial pathogens in COPD was associated with a clinically significant moderate increase in daily symptoms, likely mediated by increased airway inflammation. Novel therapies that decrease bacterial colonization in COPD could improve daily symptoms and quality of life.


Ultrasound evaluation of foot muscles and plantar fascia in pes planus.
Multiple intrinsic and extrinsic soft tissue structures that apply forces and support the medial longitudinal arch have been implicated in pes planus. These structures have common functions but their interaction in pes planus is not fully understood. The aim of this study was to compare the cross-sectional area (CSA) and thickness of the intrinsic and extrinsic foot muscles and plantar fascia thickness between normal and pes planus feet. Forty-nine adults with a normal foot posture and 49 individuals with pes planus feet were recruited from a university population. Images of the flexor digitorum longus (FDL), flexor hallucis longus (FHL), peroneus longus and brevis (PER), flexor hallucis brevis (FHB), flexor digitorum brevis (FDB) and abductor hallucis (AbH) muscles and the plantar fascia were obtained using a Venue 40 ultrasound system with a 5-13 MHz transducer. The CSA and thickness of AbH, FHB and PER muscles were significantly smaller (AbH -12.8% and -6.8%, FHB -8.9% and -7.6%, PER -14.7% and -10%), whilst FDL (28.3% and 15.2%) and FHL (24% and 9.8%) were significantly larger in the pes planus group. The middle (-10.6%) and anterior (-21.7%) portions of the plantar fascia were thinner in pes planus group. Greater CSA and thickness of the extrinsic muscles might reflect compensatory activity to support the MLA if the intrinsic foot muscle function has been compromised by altered foot structure. A thinner plantar fascia suggests reduced load bearing, and regional variations in structure and function in feet with pes planus.


Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging.
High grade and metastatic brain tumours exhibit considerable spatial variations in proliferation, angiogenesis, invasion, necrosis and oedema. Vascular heterogeneity arising from vascular co-option in regions of invasive growth (in which the blood-brain barrier remains intact) and neoangiogenesis is a major challenge faced in the assessment of brain tumours by conventional MRI. A multiparametric MRI approach, incorporating native measurements and both Gd-DTPA (Magnevist) and ultrasmall superparamagnetic iron oxide (P904)-enhanced imaging, was used in combination with histogram and unsupervised cluster analysis using a k-means algorithm to examine the spatial distribution of vascular parameters, water diffusion characteristics and invasion in intracranially propagated rat RG2 gliomas and human MDA-MB-231 LM2-4 breast adenocarcinomas in mice. Both tumour models presented with higher ΔR1 (the change in transverse relaxation rate R1 induced by Gd-DTPA), fractional blood volume (fBV) and apparent diffusion coefficient than uninvolved regions of the brain. MDA-MB-231 LM2-4 tumours were less densely cellular than RG2 tumours and exhibited substantial local invasion, associated with oedema, whereas invasion in RG2 tumours was minimal. These additional features were reflected in the more heterogeneous appearance of MDA-MB-231 LM2-4 tumours on T2 -weighted images and maps of functional MRI parameters. Unsupervised cluster analysis separated subregions with distinct functional properties; areas with a low fBV and relatively impermeable blood vessels (low ΔR1 ) were predominantly located at the tumour margins, regions of MDA-MB-231 LM2-4 tumours with relatively high levels of water diffusion and low vascular permeability and/or fBV corresponded to histologically identified regions of invasion and oedema, and areas of mismatch between vascular permeability and blood volume were identified. We demonstrate that dual contrast MRI and evaluation of tissue diffusion properties, coupled with cluster analysis, allows for the assessment of heterogeneity within invasive brain tumours and the designation of functionally diverse subregions that may provide more informative predictive biomarkers.


An epigenetic signature of adhesion molecules predicts poor prognosis of ovarian cancer patients.
DNA methylation is a promising biomarker for cancer. The epigenetic effects of cell adhesion molecules may affect the therapeutic outcome and the present study examined their effects on survival in ovarian cancer. We integrated methylomics and genomics datasets in The Cancer Genome Atlas (n = 391) and identified 106 highly methylated adhesion-related genes in ovarian cancer tissues. Univariate analysis revealed the methylation status of eight genes related to progression-free survival. In multivariate Cox regression analysis, four highly methylated genes (CD97, CTNNA1, DLC1, HAPLN2) and three genes (LAMA4, LPP, MFAP4) with low methylation were significantly associated with poor progression-free survival. Low methylation of VTN was an independent poor prognostic factor for overall survival after adjustment for age and stage. Patients who carried any two of CTNNA1, DLC1 or MFAP4 were significantly associated with poor progression-free survival (hazard ratio: 1.59; 95% confidence interval: 1.23, 2.05). This prognostic methylation signature was validated in a methylomics dataset generated in our lab (n = 37, hazard ratio: 16.64; 95% confidence interval: 2.68, 103.14) and in another from the Australian Ovarian Cancer Study (n = 91, hazard ratio: 2.43; 95% confidence interval: 1.11, 5.36). Epigenetics of cell adhesion molecules is related to ovarian cancer prognosis. A more comprehensive methylomics of cell adhesion molecules is needed and may advance personalized treatment with adhesion molecule-related drugs.


Association between alcohol use and periodontal pockets in Finnish adult population.
To investigate whether alcohol use is associated with deepened periodontal pockets and whether this association is dependent on age, gender or socioeconomic position (SEP). This cross-sectional study, based on the Health 2000 Survey, consisted of dentate, non-smoking Finnish adults aged 30-65 years (n = 3059). The outcome was the number of teeth with deepened (≥4 mm) periodontal pockets. The exposure was self-reported alcohol use assessed as amount, frequency, and use over the risk limit. Zero-inflated negative binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CI). In this study, alcohol use did not consistently associate with the number of teeth with deepened periodontal pockets. An association with the number of teeth with deepened periodontal pockets was found among men, older participants, and those participants belonging to basic or intermediate educational groups. An association with poor periodontal health was observed among men or older participants who belonged to the basic or intermediate educational group, whereas such associations were not observed among those participants belonging to the higher educational group. The association between alcohol use and periodontal health appears to be confounded by individual characteristics such as age, gender, and especially one's SEP.


Antioxidant vitamin C prevents decline in endothelial function during sitting.
This study was designed to test the hypothesis that antioxidant Vitamin C prevents the impairment of endothelial function during prolonged sitting. Eleven men (24.2 ± 4.4 yrs) participated in 2 randomized 3-h sitting trials. In the sitting without vitamin C (SIT) and the sitting with vitamin C (VIT) trial, participants were seated for 3 h without moving their legs. Additionally, in the VIT trial, participants ingested 2 vitamin C tablets (1 g and 500 mg) at 30 min and 1 h 30 min, respectively. Superficial femoral artery (SFA) flow-mediated dilation (FMD) was measured hourly for 3 h. By a 1-way ANOVA, there was a significant decline in FMD during 3 h of SIT (p<0.001). Simultaneously, there was a significant decline in antegrade (p=0.04) and mean (0.037) shear rates. For the SIT and VIT trials by a 2-way (trial x time) repeated measures ANOVA, there was a significant interaction (p=0.001). Pairwise testing revealed significant between-SFA FMD in the SIT and VIT trial at each hour after baseline, showing that VIT prevented the decline in FMD 1 h (p=0.009), 2 h (p=0.016), and 3 h (p=0.004). There was no difference in the shear rates between SIT and VIT trials (p>0.05). Three hours of sitting resulted in impaired SFA FMD. Antioxidant Vitamin C prevented the decline in SFA FMD, suggesting that oxidative stress may contribute to the impairment in endothelial function during sitting.


Amputation and prosthesis implantation shape body and peripersonal space representations.
Little is known about whether and how multimodal representations of the body (BRs) and of the space around the body (Peripersonal Space, PPS) adapt to amputation and prosthesis implantation. In order to investigate this issue, we tested BR in a group of upper limb amputees by means of a tactile distance perception task and PPS by means of an audio-tactile interaction task. Subjects performed the tasks with stimulation either on the healthy limb or the stump of the amputated limb, while wearing or not wearing their prosthesis. When patients performed the tasks on the amputated limb, without the prosthesis, the perception of arm length shrank, with a concurrent shift of PPS boundaries towards the stump. Conversely, wearing the prosthesis increased the perceived length of the stump and extended the PPS boundaries so as to include the prosthetic hand, such that the prosthesis partially replaced the missing limb.


Development and destruction of the first state funded anti-smoking campaign in the USA.
Minnesota was the first state in the USA to implement a large state funded tobacco control programme (in 1985). Despite evidence of effectiveness, it was dismantled in 1993. To describe and analyse how and why these events transpired and identify lessons for tobacco control advocates facing similar challenges in the 21st century. Case study based on previously secret tobacco industry documents, news reports, research reports, official documents, and interviews with health advocates and state government officials. Unable to defeat funding for this campaign in 1985, the tobacco industry organised groups which eliminated it later. Despite the programme's documented effectiveness, it was dismantled based on claims of fiscal crisis. These claims were not true; the real debate was what to do with the state's surplus. Health advocates failed to challenge the claim of fiscal crisis or mobilise public support for the programme. Simply quoting evidence that a tobacco control programme is effective does not ensure its continuing survival. Claims of fiscal crisis are an effective cover for tobacco industry efforts to dismantle successful programmes, particularly if health advocates accept these claims and fail to mobilise political pressure to defend the programme.


Push-pull farming systems.
Farming systems for pest control, based on the stimulo-deterrent diversionary strategy or push-pull system, have become an important target for sustainable intensification of food production. A prominent example is push-pull developed in sub-Saharan Africa using a combination of companion plants delivering semiochemicals, as plant secondary metabolites, for smallholder farming cereal production, initially against lepidopterous stem borers. Opportunities are being developed for other regions and farming ecosystems. New semiochemical tools and delivery systems, including GM, are being incorporated to exploit further opportunities for mainstream arable farming systems. By delivering the push and pull effects as secondary metabolites, for example, (E)-4,8-dimethyl-1,3,7-nonatriene repelling pests and attracting beneficial insects, problems of high volatility and instability are overcome and compounds are produced when and where required.


Oxidation of 1,1,1,2-tetrafluoroethane in rat liver microsomes is catalyzed primarily by cytochrome P-450IIE1.
1,1,1,2-Tetrafluoroethane (R-134a), a nonozone-depleting alternative air-conditioning refrigerant and propellant for pharmaceutical preparations, is oxidatively defluorinated by rat hepatic microsomes. In this report we show that induction of cytochrome P-450IIE1 in rats, by pyridine administration, resulted in an 8-fold increase in the rate of R-134a metabolism by hepatic microsomes (Vmax 47 vs. 6 nmol F-/mg microsomal protein/15 min). Furthermore, when data were normalized for P-450 content, a 4-fold increase in R-134a metabolism was noted for IIE1-enriched microsome preparations. In contrast, phenobarbital and Aroclor 1254 decreased the specific activity of hepatic microsomes for this function. The microsomal content of P-450IIE1, as evaluated by Western blot, was elevated significantly only in microsomes from pyridine-treated rats. p-Nitrophenol and aniline, which are metabolized at high rates by rat P-450IIE1, decreased the rate of R-134a defluorination by hepatic microsomes; Dixon plot analysis indicated competitive inhibition with a Ki of 36 microM p-nitrophenol or 115 microM aniline. Pyridine also potently induced defluorination of R-134a catalyzed by rabbit liver microsomes. Studies with individual P-450 isozymes purified from rabbit liver showed that the phenobarbital- and polycyclic hydrocarbon-induced isozymes (IIB1 and IA2) defluorinated R-134a at negligible rates (1.9 and 0.4 nmol F-/nmol P-450/60 min, respectively). In contrast, P-450IIE1 catalyzed defluorination of R-134a at a relatively high rate (16.2 nmol F-/nmol P-450/60 min); isozyme IA1, which also is induced by nitrogen-containing heterocycles such as pyridine, was somewhat active (5.3 nmol F-/nmol P-450/60 min).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of deworming on milk production in dairy cattle and buffaloes infected with gastrointestinal parasites in the Kavrepalanchowk district of central Nepal.
In Nepal, knowledge of proper handling, management and causes of cattle diseases is still limited. The main objective of this study was to explore the impact of deworming on milk production and its effect on milk qualities. A total of 200 faecal samples (100 buffaloes and 100 cows) were collected and analysed for parasitic burden. Half of the infected cattle (buffaloes, Bos bubalis; cow native, B indicus; European, B taurus) were then dewormed with Levamisole Hydrochloride-Oxyclozanide bolus, and the remaining 50 per cent were left untreated. The milk yield from both infected and dewormed cattle was recorded for 30 days and the qualities of milk were analysed. The prevalence of parasitic infection was found to be 22.0 per cent. Fasciola hepatica was the predominant parasite (81.8 per cent), followed by Toxocara vitulorum (34.1 per cent), Strongyloides papillosus (6.8 per cent) and Bunostomum phlebotomum (4.5 per cent). The average milk yield (litre/day/cow) significantly increased, which was 1.22 litres per day for treated cows and 1.06 litres for treated buffaloes. The intervention effect of deworming among cows was 0.79 (14.06 per cent increment) and for buffaloes was 0.42 (8.32 per cent increment). After deworming the infected cattle, the protein percentage was significantly improved in cows (P=0.035), whereas the lactose percentage and solid percentage had increased significantly in buffaloes (P=0.002 and P=0.028). Antiparasitic treatment in cattle had positive effects on milk qualities such as solid non-fat, lactose, solid percentage and total protein percentage.


Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II.
Helicobacter pylori infection persists for the life of the host due to the failure of the immune response to eradicate the bacterium. Determining how H. pylori escapes the immune response in its gastric niche is clinically important. We have demonstrated in vitro that macrophage NO production can kill H. pylori, but induction of macrophage arginase II (Arg2) inhibits inducible NO synthase (iNOS) translation, causes apoptosis, and restricts bacterial killing. Using a chronic H. pylori infection model, we determined whether Arg2 impairs host defense in vivo. In C57BL/6 mice, expression of Arg2, but not arginase I, was abundant and localized to gastric macrophages. Arg2(-/-) mice had increased histologic gastritis and decreased bacterial colonization compared with wild-type (WT) mice. Increased gastritis scores correlated with decreased colonization in individual Arg2(-/-) mice but not in WT mice. When mice infected with H. pylori were compared, Arg2(-/-) mice had more gastric macrophages, more of these cells were iNOS(+), and these cells expressed higher levels of iNOS protein, as determined by flow cytometry and immunofluorescence microscopy. There was enhanced nitrotyrosine staining in infected Arg2(-/-) versus WT mice, indicating increased NO generation. Infected Arg2(-/-) mice exhibited decreased macrophage apoptosis, as well as enhanced IFN-γ, IL-17a, and IL-12p40 expression, and reduced IL-10 levels consistent with a more vigorous Th1/Th17 response. These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining proinflammatory cytokine responses.


Treatment adherence and health outcomes in patients with bronchiectasis.
We aimed to determine adherence to inhaled antibiotics, other respiratory medicines and airway clearance and to determine the association between adherence to these treatments and health outcomes (pulmonary exacerbations, lung function and Quality of Life Questionnaire-Bronchiectasis [QOL-B]) in bronchiectasis after 12 months. Patients with bronchiectasis prescribed inhaled antibiotics for Pseudomonas aeruginosa infection were recruited into a one-year study. Participants were categorised as "adherent" to medication (medication possession ratio ≥80% using prescription data) or airway clearance (score ≥80% in the Modified Self-Reported Medication-Taking Scale). Pulmonary exacerbations were defined as treatment with a new course of oral or intravenous antibiotics over the one-year study. Spirometry and QOL-B were completed at baseline and 12 months. Associations between adherence to treatment and pulmonary exacerbations, lung function and QOL-B were determined by regression analyses. Seventy-five participants were recruited. Thirty-five (53%), 39 (53%) and 31 (41%) participants were adherent to inhaled antibiotics, other respiratory medicines, and airway clearance, respectively. Twelve (16%) participants were adherent to all treatments. Participants who were adherent to inhaled antibiotics had significantly fewer exacerbations compared to non-adherent participants (2.6 vs 4, p = 0.00) and adherence to inhaled antibiotics was independently associated with having fewer pulmonary exacerbations (regression co-efficient = -0.51, 95% CI [-0.81,-0.21], p < 0.001). Adherence to airway clearance was associated with lower QOL-B Treatment Burden (regression co-efficient = -15.46, 95% CI [-26.54, -4.37], p < 0.01) and Respiratory Symptoms domain scores (regression co-efficient = -10.77, 95% CI [-21.45; -0.09], p < 0.05). There were no associations between adherence to other respiratory medicines and any of the outcomes tested. Adherence to treatment was not associated with FEV1 % predicted. Treatment adherence is low in bronchiectasis and affects important health outcomes including pulmonary exacerbations. Adherence should be measured as part of bronchiectasis management and future research should evaluate bronchiectasis-specific adherence strategies.


Pancreas transplantation: lessons learned from a decade of experience at Wake Forest Baptist Medical Center.
This article reviews the outcome of pancreas transplantations in diabetic recipients according to risk factors, surgical techniques, and immunosuppression management that evolved over the course of a decade at Wake Forest Baptist Medical Center. A randomized trial of alemtuzumab versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous kidney-pancreas transplantation (SKPT) at our institution demonstrated lower rates of acute rejection and infection in the alemtuzumab group. Consequently, alemtuzumab induction has been used exclusively in all pancreas transplantations since February 2009. Early steroid elimination has been feasible in the majority of patients. Extensive experience with surveillance pancreas biopsies in solitary pancreas transplantation (SPT) is described. Surveillance pancreas biopsy-directed immunosuppression has contributed to equivalent long-term pancreas graft survival rates in SKPT and SPT recipients at our center, in contrast to recent registry reports of persistently higher rates of immunologic pancreas graft loss in SPT. Furthermore, the impact of donor and recipient selection on outcomes is explored. Excellent results have been achieved with older (extended) donors and recipients, in recipients of organs from donation after cardiac death donors managed with extracorporeal support, and in African-American patients. Type 2 diabetics with detectable C-peptide levels have been transplanted successfully with outcomes comparable to those of insulinopenic diabetics. Our experiences are discussed in the light of findings reported in the literature.


Dynamic remodeling of the guinea pig intrinsic cardiac plexus induced by chronic myocardial infarction.
Myocardial infarction (MI) is associated with remodeling of the heart and neurohumoral control systems. The objective of this study was to define time-dependent changes in intrinsic cardiac (IC) neuronal excitability, synaptic efficacy, and neurochemical modulation following MI. MI was produced in guinea pigs by ligation of the coronary artery and associated vein on the dorsal surface of the heart. Animals were recovered for 4, 7, 14, or 50 days. Intracellular voltage recordings were obtained in whole mounts of the cardiac neuronal plexus to determine passive and active neuronal properties of IC neurons. Immunohistochemical analysis demonstrated an immediate and persistent increase in the percentage of IC neurons immunoreactive for neuronal nitric oxide synthase. Examination of individual neuronal properties demonstrated that after hyperpolarizing potentials were significantly decreased in both amplitude and time course of recovery at 7 days post-MI. These parameters returned to control values by 50 days post-MI. Synaptic efficacy, as determined by the stimulation of axonal inputs, was enhanced at 7 days post-MI only. Neuronal excitability in absence of agonist challenge was unchanged following MI. Norepinephrine increased IC excitability to intracellular current injections, a response that was augmented post-MI. Angiotensin II potentiation of norepinephrine and bethanechol-induced excitability, evident in controls, was abolished post-MI. This study demonstrates that MI induces both persistent and transient changes in IC neuronal functions immediately following injury. Alterations in the IC neuronal network, which persist for weeks after the initial insult, may lead to alterations in autonomic signaling and cardiac control.


Measles immunization strategy: measles antibody response following MMR II vaccination of children at one year of age.
Measles antibody levels were determined by the plaque reduction neutralization (PRN) test in 580 one-year-old children before vaccination and four to six weeks after MMR II vaccination. Fifty-one (8.8%) had maternally derived measles antibody at prevaccination, and this was more common among children of women born before 1967 (10.6%) vs. 4.3%; p < 0.01). Among those with maternal antibody, only 22 (43.1%) responded with a protective PRN titre of over 120, in contrast to 463 (87.5%) of the 529 without maternal antibody at prevaccination (p < 0.0001). Also, the geometric mean titre was significantly lower for the former (114.1 vs. 378.5; p < 0.0001). Overall, 15 (2.6%) of the 580 children had no antibody response after vaccination, and a further 80 (13.8%) had a subprotective response (PRN titre < 120). This lack of response could not be attributed entirely to the presence of maternal measles antibody at the time of vaccination. The MMR II vaccine may not be sufficiently immunogenic in inducing adequate measles antibody response after a single dose given at one year of age.


Computer-aided tumor diagnosis using shear wave breast elastography.
The shear wave elastography (SWE) uses the acoustic radiation force to measure the stiffness of tissues and is less operator dependent in data acquisition compared to strain elastography. However, the reproducibility of the result is still interpreter dependent. The purpose of this study is to develop a computer-aided diagnosis (CAD) method to differentiate benign from malignant breast tumors using SWE images. After applying the level set method to automatically segment the tumor contour and hue-saturation-value color transformation, SWE features including average tissue elasticity, sectional stiffness ratio, and normalized minimum distance for grouped stiffer pixels are calculated. Finally, the performance of CAD based on SWE features are compared with those based on B-mode ultrasound (morphologic and textural) features, and a combination of both feature sets to differentiate benign from malignant tumors. In this study, we use 109 biopsy-proved breast tumors composed of 57 benign and 52 malignant cases. The experimental results show that the sensitivity, specificity, accuracy and the area under the receiver operating characteristic ROC curve (Az value) of CAD are 86.5%, 93.0%, 89.9%, and 0.905 for SWE features whereas they are 86.5%, 80.7%, 83.5% and 0.893 for B-mode features and 90.4%, 94.7%, 92.3% and 0.961 for the combined features. The Az value of combined feature set is significantly higher compared to the B-mode and SWE feature sets (p=0.0296 and p=0.0204, respectively). Our results suggest that the CAD based on SWE features has the potential to improve the performance of classifying breast tumors with US.


In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction.
Mutations affecting the expression of the Janus family kinase JAK3 were recently shown to be responsible for autosomal recessive severe combined immunodeficiency (SCID). JAK3-deficient patients present with a clinical phenotype virtually indistinguishable from boys affected by X-linked SCID, a disease caused by genetic defects of the common gamma chain (gamma c) that is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The specific interaction of JAK3 and gamma c represents the biochemical basis for the similarities between these two immunodeficiencies. Both forms of SCID are characterized by recurrent, severe infections leading to death in infancy unless successfully treated by allogeneic bone marrow transplantation. Because of the potentially lethal complications associated with allogeneic bone marrow transplantation and the frequent lack of suitable marrow donors, the development of alternative forms of therapy is highly desirable. To this end, we investigated a retroviral-mediated gene correction approach for JAK3-deficiency. A vector carrying a copy of JAK3 cDNA was constructed and used to transduce B cell lines derived from patients with JAK3-deficient SCID. We demonstrate restoration of JAK3 expression and phosphorylation upon IL-2 and IL-4 stimulation. Furthermore, patients' cells transduced with JAK3 acquired the ability to proliferate normally in response to IL-2. These data indicate that the biological defects of JAK3-deficient cells can be efficiently corrected in vitro by retroviral-mediated gene transfer, thus providing the basis for future investigation of gene therapy as treatment for JAK3-deficient SCID.