Natural history of non-lethal Raine syndrome during childhood.
Raine syndrome (RS) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations of FAM20C. The most common clinical features are microcephaly, exophthalmos, hypoplastic nose and severe midface hypoplasia, leading to choanal atresia. The radiological findings include generalized osteosclerosis and brain calcifications. RS is usually lethal during the neonatal period due to severe respiratory distress. However, there exists a non-lethal RS form, the phenotype of which is extremely heterogeneous. There is paucity of data about clinical course and life expectancy of these patients. This is the first description of follow-up features of non-lethal RS patients. Moreover, we present three unpublished cases. There are five Asian and two Arab patients. All were born to consanguineous parents. The most common neonatal comorbidity was respiratory distress secondary to choanal atresia. A variable degree of neurodevelopmental delay was seen in the majority of our cases and seizures and hearing or vision involvement were also frequent. Neurological and orthopedic issues were the most frequent complications seen at follow-up in our group. Persistent hypophosphatemic rickets was the most striking endocrinological manifestation, which was scarcely responsive to therapy with phosphate salts and alfacalcidol. Life expectancy of our patients goes beyond childhood, with the oldest of those described being 18 years old at present. Manifestations of RS in those surviving the neonatal period are being increasingly recognized. Our study supports previous findings and provides clinical and biochemical observations and data from longer follow up. Finally, we propose multidisciplinary follow up for patients with non-lethal RS.


Living bacterial sacrificial porogens to engineer decellularized porous scaffolds.
Decellularization and cellularization of organs have emerged as disruptive methods in tissue engineering and regenerative medicine. Porous hydrogel scaffolds have widespread applications in tissue engineering, regenerative medicine and drug discovery as viable tissue mimics. However, the existing hydrogel fabrication techniques suffer from limited control over pore interconnectivity, density and size, which leads to inefficient nutrient and oxygen transport to cells embedded in the scaffolds. Here, we demonstrated an innovative approach to develop a new platform for tissue engineered constructs using live bacteria as sacrificial porogens. E.coli were patterned and cultured in an interconnected three-dimensional (3D) hydrogel network. The growing bacteria created interconnected micropores and microchannels. Then, the scafold was decellularized, and bacteria were eliminated from the scaffold through lysing and washing steps. This 3D porous network method combined with bioprinting has the potential to be broadly applicable and compatible with tissue specific applications allowing seeding of stem cells and other cell types.


mRNA levels of alpha1(VI) collagen, alpha1(XII) collagen, and beta ig in rabbit cornea during normal development and healing.
Type VI and XII collagens and beta ig, major components of the interfibrillar matrix, may maintain proper spacing among collagen fibrils, necessary for corneal transparency. During normal corneal stroma development and healing, changes in mRNA levels of these proteins were measured to determine whether differences in steady state levels are indicative of the unique structure produced by each corneal tissue. A full-thickness excision wound was made in each cornea of six adult rabbits and allowed to heal for 1, 2, or 4 weeks. Scar tissue from two rabbits (four scars) were used from each time period and processed for RNA extraction. Total RNA from 23-day-old fetal rabbit corneas (equivalent to approximately 1 week of stromal development) and 8-day-old neonate corneas (equivalent to approximately 3.5 weeks of stromal development) was also extracted. Relative quantities of alpha1(VI) collagen, alpha1(XII) collagen, beta ig, and beta-actin mRNAs were determined by competitive reverse transcriptase-polymerase chain reaction. Glyceraldehyde-3-phosphate dehydrogenase was used as a housekeeping gene. Increased mRNA levels for alpha1(VI) and alpha1(XII) collagens, beta ig, and beta-actin were seen during the first 2 weeks of healing and were followed by a decrease in 4-week-old scars. Similar increases were seen in fetal corneas with a further increase in the neonate. Differences in the beta ig mRNA levels relative to that of alpha1(XII) collagen in fetal stroma and in comparison with 1-week-old wounds suggest a higher production of beta ig in early healing tissue. Alterations of mRNA levels during healing and development are consistent with the cellular events and deposition of extracellular matrices in these corneal tissues. Assuming that extracellular matrix protein production is regulated at the transcriptional level, relative changes in beta ig and collagen mRNA levels reflect differences in protein deposition in early fetal and healing tissues. This is consistent with differences in the organization of the interfibrillar matrices of these tissues and their transparency.


Are subjective memory complaints indicative of objective cognitive decline or depressive symptoms? Findings from the English Longitudinal Study of Ageing.
Older adults often complain about their memory ability, but it is not clear to what extent subjective memory complaints accurately reflect objective cognitive dysfunctions. The concordance between objective and subjective cognitive performance may be affected by depressive symptoms and by declining insight into cognitive deficits. This study aims to examine longitudinal associations between subjective memory complaints, objective cognitive performance and depressive symptoms. 11,092 participants aged 50 years and above from the English Longitudinal Study of Ageing were followed-up every 2 years over a 6-year period. Two processes latent growth curve models (LGCM) examined associations between levels and changes in several cognitive abilities and subjective memory complaints, unadjusted for depression symptoms. Then three processes LGCM examined associations between levels and changes in depressive symptoms, subjective memory complaints and objective cognitive abilities in the overall sample, and separately among persons with mild cognitive impairment at baseline. More subjective memory complaints were associated with poorer performance in all cognitive domains at baseline. Steeper decline in immediate recall, verbal fluency and processing speed performance was associated increasing subjective memory complaints both in the overall sample and among persons with mild cognitive impairment. Increasing depressive symptoms were associated with both objective and subjective cognitive decline in the overall sample, and only with subjective memory decline among cognitively impaired persons. Self-reported memory complaints may have the potential to identify decline in objective cognitive performance that cannot be explained by depressive symptoms. Among cognitively impaired persons depressive symptoms may amplify subjective but not objective cognitive decline.


Mesoporous silica coated CeO2 nanozymes with combined lipid-lowering and antioxidant activity induce long-term improvement of the metabolic profile in obese Zucker rats.
Obesity is one of the most important public health problems that is associated with an array of metabolic disorders linked to cardiovascular disease, stroke, type 2 diabetes, and cancer. A sustained therapeutic approach to stop the escalating prevalence of obesity and its associated metabolic comorbidities remains elusive. Herein, we developed a novel nanocomposite based on mesoporous silica coated cerium oxide (CeO2) nanozymes that reduce the circulating levels of fatty acids and remarkably improve the metabolic phenotype in a model of obese Zucker rats five weeks after its administration. Lipidomic and gene expression analyses showed an amelioration of the hyperlipidemia and of the hepatic and adipose metabolic dysregulations, which was associated with a down-regulation of the hepatic PI3K/mTOR/AKT pathway and a reduction of the M1 proinflammatory cytokine TNF-α. In addition, the coating of the CeO2 maximized its cell antioxidant protective effects and minimized non-hepatic biodistribution. The one-pot synthesis method for the nanocomposite fabrication is implemented entirely in aqueous solution, room temperature and open atmosphere conditions, favoring scalability and offering a safe and translatable lipid-lowering and antioxidant nanomedicine to treat metabolic comorbidities associated with obesity. This approach may be further applied to address other metabolic disorders related to hyperlipidemia, low-grade inflammation and oxidative stress.


Mathematics for demosaicking.
Digital color cameras sample the continuous color spectrum using three or more filters; however, each pixel represents a sample of only one of the color bands. This arrangement is called a mosaic. To produce a full-resolution color image, the recorded image must be processed to estimate the values of the pixels for all the other color bands. This restoration process is often called demosaicking. This paper uses stacked notation to represent the mosaicked image capture and derives the minimum mean square error (MMSE) estimator for the demosaicked image. By making common assumptions, the restoration can be computed in a cost-effective manner. Extensions to the linear method are proposed to allow adaptive behavior.


Mammalian COPII coat component SEC24C is required for embryonic development in mice.
COPII-coated vesicles mediate the transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi. SEC24 is the COPII component primarily responsible for recruitment of protein cargoes into nascent vesicles. There are four Sec24 paralogs in mammals, with mice deficient in SEC24A, -B, and -D exhibiting a wide range of phenotypes. We now report the characterization of mice with deficiency in the fourth Sec24 paralog, SEC24C. Although mice haploinsufficient for Sec24c exhibit no apparent abnormalities, homozygous deficiency results in embryonic lethality at approximately embryonic day 7. Tissue-specific deletion of Sec24c in hepatocytes, pancreatic cells, smooth muscle cells, and intestinal epithelial cells results in phenotypically normal mice. Thus, SEC24C is required in early mammalian development but is dispensable in a number of tissues, likely as a result of compensation by other Sec24 paralogs. The embryonic lethality resulting from loss of SEC24C occurs considerably later than the lethality previously observed in SEC24D deficiency; it is clearly distinct from the restricted neural tube phenotype of Sec24b null embryos and the mild hypocholesterolemic phenotype of adult Sec24a null mice. Taken together, these results demonstrate that the four Sec24 paralogs have developed unique functions over the course of vertebrate evolution.


Effects of Acute Caffeine Ingestion on Cognitive Performance before and after Repeated Small-Sided Games in Professional Soccer Players: A Placebo-Controlled, Randomized Crossover Trial.
Soccer is a team sport that requires players to process a significant amount of information quickly and respond with both speed and accuracy to the ever-changing demands of the game. As such, success in soccer depends not only on physical attributes but also on cognitive abilities such as perception and decision-making. The aim of the current study was to investigate the acute effects of caffeine ingestion on Stroop test performance before and after repeated small-sided games (SSG) in professional soccer players. Twelve professional male soccer players (29 ± 4.1 years; 78.1 ± 7.7 kg body mass) participated in this study. A randomized crossover double-blind placebo-controlled trial was used. Caffeine (5 mg.kg-1) or a placebo was ingested 45 min before a protocol consisting of five 5 min SSG with 1 min rest intervals. A computerized version of the colour Stroop test was completed immediately before and after the exercise protocol. During the Stroop test, words appeared on the computer screen in three different ways: (i) neutral words (neutral condition); (ii) correspondent colour (i.e., "red" painted in red; congruent condition), or; (iii) different colour (i.e., "red" painted in green; incongruent condition). The incongruent condition aimed to cause the interference effect, as the colour and the word did not match. Ratings of perceived exertion (RPE) were assessed after each SSG. RPE increased during the five sets of the SSG protocol (p < 0.001), without differences between the caffeine and placebo trials. The soccer-specific exercise protocol promoted a faster response during the Stroop test (two-way ANOVA main effect for SSG protocol: p < 0.05), with no differences in accuracy (p > 0.05). Caffeine ingestion resulted in slower reaction time during the Stroop test during the congruent and neutral trials but not during the incongruent trial (two-way ANOVA main effect for supplementation: p = 0.009, p = 0.045, and p = 0.071, respectively). Accuracy was lower in the caffeine trial in congruent and incongruent trials (p < 0.05 caffeine vs. placebo both on the pre- and post-SSG protocol). In conclusion, a soccer-specific exercise protocol improved the Stroop test performance in professional soccer players, but acute caffeine ingestion (5 mg.kg-1) was detrimental.


Evaluation of a Web-based intervention providing tailored advice for self-management of minor respiratory symptoms: exploratory randomized controlled trial.
There has been relatively little research on the role of web-based support for self-care in the management of minor, acute symptoms, in contrast to the wealth of recent research into Internet interventions to support self-management of long-term conditions. This study was designed as an evaluation of the usage and effects of the "Internet Doctor" website providing tailored advice on self-management of minor respiratory symptoms (eg, cough, sore throat, fever, runny nose), in preparation for a definitive trial of clinical effectiveness. The first aim was to evaluate the effects of using the Internet Doctor webpages on patient enablement and use of health services, to test whether the tailored, theory-based advice provided by the Internet Doctor was superior to providing a static webpage providing the best existing patient information (the control condition). The second aim was to gain an understanding of the processes that might mediate any change in intentions to consult the doctor, by comparing changes in relevant beliefs and illness perceptions in the intervention and control groups, and by analyzing usage of the Internet Doctor webpages and predictors of intention change. Participants (N = 714) completed baseline measures of beliefs about their symptoms and self-care online, and were then automatically randomized to the Internet Doctor or control group. These measures were completed again by 332 participants after 48 hours. Four weeks later, 214 participants completed measures of enablement and health service use. The Internet Doctor resulted in higher levels of satisfaction than the control information (mean 6.58 and 5.86, respectively; P = .002) and resulted in higher levels of enablement a month later (median 3 and 2, respectively; P = .03). Understanding of illness improved in the 48 hours following use of the Internet Doctor webpages, whereas it did not improve in the control group (mean change from baseline 0.21 and -0.06, respectively, P = .05). Decline in intentions to consult the doctor between baseline and follow-up was predicted by age (beta = .10, P= .003), believing before accessing the website that consultation was necessary for recovery (beta = .19, P < .001), poor understanding of illness (beta = .11, P = .004), emotional reactions to illness (beta = .15, P <.001), and use of the Diagnostic section of the Internet Doctor website (beta = .09, P = .007). Our findings provide initial evidence that tailored web-based advice could help patients self-manage minor symptoms to a greater extent. These findings constitute a sound foundation and rationale for future research. In particular, our study provides the evidence required to justify carrying out much larger trials in representative population samples comparing tailored web-based advice with routine care, to obtain a definitive evaluation of the impact on self-management and health service use.


Sickle cell disease: from membrane pathophysiology to novel therapies for prevention of erythrocyte dehydration.
Sickle cell anemia is characterized by the presence of dense dehydrated erythrocytes that have lost most of their K content. Due to the unique dependence of Hb S polymerization on intracellular Hb S concentration, preventing this dehydration should markedly reduce polymerization. The erythrocyte intermediate conductance Ca-activated K channel (hSK4 or KCNN4), first described by Gardos, has been shown to be a major pathway for sickle cell dehydration. Studies with the imidazole antimycotic clotrimazole have shown reduction of sickle cell dehydration in vivo in a small number of patients with sickle cell disease; dose-limiting gastrointestinal and liver toxicities were observed. Based on the chemical structure of clotrimazole metabolites, a novel Gardos channel inhibitor, ICA-17043, has been developed. It has shown substantial activity both in vitro and in vivo in transgenic sickle mice. ICA-17043 is currently in phase 2 human trials. Another potential therapeutic target is the K-Cl cotransport. When sickle erythrocytes are exposed to relatively acidic conditions, they undergo cell shrinkage via activation of this pathway. K-Cl cotransport can be blocked by increasing the abnormally low erythrocyte Mg content of sickle erythrocytes. Oral Mg supplementation has been shown to reduce sickle cell dehydration in vivo in transgenic sickle mice and in patients in two separate clinical trials. Oral Mg pidolate is being tested in clinical trials in homozygous sickle cell disease and in Hb S/HbC (SC) disease, either as a single agent or in combination with hydroxyurea. The ongoing trials will determine the clinical effectiveness of therapies aimed at preventing sickle erythrocyte dehydration.


GABAA receptor biogenesis is impaired by the γ2 subunit febrile seizure-associated mutation, GABRG2(R177G).
A missense mutation in the GABAA receptor γ2L subunit, R177G, was reported in a family with complex febrile seizures (FS). To gain insight into the mechanistic basis for these genetic seizures, we explored how the R177G mutation altered the properties of recombinant α1β2γ2L GABAA receptors expressed in HEK293T cells. Using a combination of electrophysiology, flow cytometry, and immunoblotting, we found that the R177G mutation decreased GABA-evoked whole-cell current amplitudes by decreasing cell surface expression of α1β2γ2L receptors. This loss of receptor surface expression resulted from endoplasmic reticulum (ER) retention of mutant γ2L(R177G) subunits, which unlike wild-type γ2L subunits, were degraded by ER-associated degradation (ERAD). Interestingly, when compared to the condition of homozygous γ2L(R177G) subunit expression, disproportionately low levels of γ2L(R177G) subunits reached the cell surface with heterozygous expression, indicating that wild-type γ2L subunits possessed a competitive advantage over mutant γ2L(R177G) subunits for receptor assembly and/or forward trafficking. Inhibiting protein synthesis with cycloheximide demonstrated that the R177G mutation primarily decreased the stability of an intracellular pool of unassembled γ2L subunits, suggesting that the mutant γ2L(R177G) subunits competed poorly with wild-type γ2L subunits due to impaired subunit folding and/or oligomerization. Molecular modeling confirmed that the R177G mutation could disrupt intrasubunit salt bridges, thereby destabilizing secondary and tertiary structure of γ2L(R177G) subunits. These findings support an emerging body of literature implicating defects in GABAA receptor biogenesis in the pathogenesis of genetic epilepsies (GEs) and FS.


Endophytic Fungus Aspergillus japonicus Mediates Host Plant Growth under Normal and Heat Stress Conditions.
We have isolated an endophytic fungus with heat stress alleviation potential from wild plant Euphorbia indica L. The phylogenetic analysis and 18S rDNA sequence homology revealed that the designated isolate was Aspergillus japonicus EuR-26. Analysis of A. japonicus culture filtrate displayed higher concentrations of salicylic acid (SA), indoleacetic acid (IAA), flavonoids, and phenolics. Furthermore, A. japonicus association with soybean and sunflower had improved plant biomass and other growth features under high temperature stress (40°C) in comparison to endophyte-free plants. In fact, endophytic association mitigated heat stress by negotiating the activities of abscisic acid, catalase, and ascorbic acid oxidase in both soybean and sunflower. The nutritional quality (phenolic, flavonoids, soluble sugars, proteins, and lipids) of the A. japonicus-associated seedlings has also improved under heat stress in comparison to endophyte-free plants. From the results, it is concluded that A. japonicus can modulate host plants growth under heat stress and can be used as thermal stress alleviator in arid and semiarid regions of the globe (where mean summer temperature exceeds 40°C) to sustain agriculture.


Exploring Online Peer Support Groups for Adults Experiencing Long COVID in the United Kingdom: Qualitative Interview Study.
Long COVID is an emerging public health concern. A growing number of individuals are experiencing prolonged, multifaceted health challenges and accompanying social impacts after COVID-19 infections. Support services in the United Kingdom remain insufficient and fraught with complexity. Responding to persistent gaps in care, patients joined forces in online peer support groups. However, little is known about how these groups impact patients with long COVID and their lived experiences of the condition. The aim of this study is to explore the roles that online peer support groups take on and the impact they have on patients experiencing and recovering from long COVID in the United Kingdom. In doing so, this study aims to identify ways to inform future long COVID care, including online peer support and broader long COVID care structures. I conducted 11 semistructured interviews virtually on Zoom in July 2021. Participants had long COVID, were UK-based, and used long COVID online peer support groups. Topics discussed in interviews included what led participants to these groups, experiences within them, and feelings about the roles that the groups took on. I analyzed the results by manually conducting thematic analysis. Long COVID online peer support groups had numerous roles, significantly impacting users. I identified 5 themes and 13 subthemes through thematic analysis. The identified themes were as follows: (1) filling professional care gaps, (2) societal awareness, (3) engagement behavior, (4) diversity, and (5) social connections. Given the void of professional support, those experiencing long COVID gained some benefit from these groups. However, participants emphasized notable concerns about the all-encompassing roles these groups embody and speculated over potential improvements. If used appropriately, online peer support groups could be immensely beneficial for patient well-being, beyond simply filling gaps in long COVID care. However, it appears many groups take on more than they can manage and become potentially harmful. Through prioritizing patient voices, long COVID care could be restructured to maximize peer support's benefits within broader care structures.


The effect of gender, ethnicity, and income on college students' use of communication technologies.
Because campus officials are relying on personal communication technologies to communicate with students, a question arises about access and usage. Although communication technologies are popular among college students, some evidence suggests that differences exist in ownership and use. We examined patterns of student ownership and use of cell phones and use of instant messaging, focusing on three predictors of digital inequality: gender, ethnicity, and income. Logistic and hierarchical linear regression analyses were used to analyze results from 4,491 students. The odds that female and white students owned cell phones were more than twice as high as for men and African-American students. Students in the $100,000-$149,000 per year income bracket were more than three times as likely to own a cell phone than those from the median bracket. However, being female, African-American, and/or from the highest income brackets was positively predictive of the number of text messages sent and the amount of time spent talking on a cell phone per week. We found no differences between students on the use of instant messaging. Implications of these results, as well as areas for further research, are provided.


Areas of controversy in neuroprogression in bipolar disorder.
We aimed to review clinical features and biological underpinnings related to neuroprogression in bipolar disorder (BD). Also, we discussed areas of controversy and future research in the field. We systematically reviewed the extant literature pertaining to neuroprogression and BD by searching PubMed and EMBASE for articles published up to March 2016. A total of 114 studies were included. Neuroimaging and clinical evidence from cross-sectional and longitudinal studies show that a subset of patients with BD presents a neuroprogressive course with brain changes and unfavorable outcomes. Risk factors associated with these unfavorable outcomes are number of mood episodes, early trauma, and psychiatric and clinical comorbidity. Illness trajectories are largely variable, and illness progression is not a general rule in BD. The number of manic episodes seems to be the clinical marker more robustly associated with neuroprogression in BD. However, the majority of the evidence came from cross-sectional studies that are prone to bias. Longitudinal studies may help to identify signatures of neuroprogression and integrate findings from the field of neuroimaging, neurocognition, and biomarkers.


Deep learning potential of mean force between polymer grafted nanoparticles.
Grafting polymer chains on the surfaces of nanoparticles is a well-known route to control their self-assembly and distribution in a polymer matrix. A wide variety of self-assembled structures are achieved by changing the grafting patterns on the surface of an individual nanoparticle. However, an accurate estimation of the effective potential of mean force between a pair of grafted nanoparticles that determines their assembly and distribution in a polymer matrix is an outstanding challenge in nanoscience. We address this problem via deep learning. As a proof of concept, here we report a deep learning framework that learns the interaction between a pair of single-chain grafted spherical nanoparticles from their molecular dynamics trajectory. Subsequently, we carry out the deep learning potential of mean force-based molecular simulation that predicts the self-assembly of a large number of single-chain grafted nanoparticles into various anisotropic superstructures, including percolating networks and bilayers depending on the nanoparticle concentration in three-dimensions. The deep learning potential of mean force-predicted self-assembled superstructures are consistent with the actual superstructures of single-chain polymer grafted spherical nanoparticles. This deep learning framework is very generic and extensible to more complex systems including multiple-chain grafted nanoparticles. We expect that this deep learning approach will accelerate the characterization and prediction of the self-assembly and phase behaviour of polymer-grafted and unfunctionalized nanoparticles in free space or a polymer matrix.


Synthesis and Mechanism of Action of Novel Thiocarbamate Inhibitors of Human Leukocyte Elastase.
Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P(3) and ornithine at the P(4) positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8) M. Compounds immobilized on poly,alpha,beta-[N-(2-hydroxyethyl)-d,l-aspartamide] (PHEA) polymers with an average molecular weight of 36,000 showed higher inhibitory capacity than their free forms.


Prevalence of fibromyalgia in hemodialysis patients.
This study sought to determine the prevalence of fibromyalgia syndrome and to identify whether fibromyalgia was associated with various clinical symptoms and laboratory parameters in hemodialysis patients. One hundred and forty-eight hemodialysis patients were examined for fibromyalgia symptoms according to the American College of Rheumatology criteria. Demographic characteristics, as well as causes of kidney failure, dialysis duration, and symptoms related to fibromyalgia were investigated. Of 148 patients, 18 (12.2%) were diagnosed with fibromyalgia. Patients with fibromyalgia had significantly poorer sleeping satisfaction than the control group (P = .02).The Beck Depression Inventory score was higher in 77.8% of the fibromyalgia patients than that in the control group (P = .006), but there was no significant difference in the anxiety score between the two groups (P = .86).In conclusion, there was a higher prevalence of fibromyalgia in hemodialysis patients than previously reported. Sleep disturbances and depression levels correlated with fibromyalgia.


Functional study of lipids of PNH red cell membranes: susceptibility of liposomes to reactive lysis.
Lipids extracted with chloroform-methanol from red blood cell membranes of 7 PNH and 13 control subjects were used for the preparation of liposomes, which were then examined with the reactive lysis test. PNH liposomes lysed to a higher extent than control liposomes as indicated by the higher dilution of the limiting complement reagent that was necessary to lyse 50% of the PNH liposomes. A similar finding was also observed with liposomes made of lipids from AET-treated red cells. The enhanced reactive lysis can be attributed to the polar lipid fraction, as indicated by the increased lysis of hybrid liposomes prepared from this polar lipids extracted from PNH erythrocyte membrane and lipids extracted from normal erythrocyte membrane. The increased susceptibility to reactive lysis does not seem to be specific of PNH liposomes, since it was also observed with liposomes prepared from lipids of red cells from beta-thalassemia major and autoimmune hemolytic disease.


Impaired metabolism of guanidinoacetic acid in uremia.
In order to investigate the guanidinoacetic acid (GAA) metabolism in uremia, we have measured serum guanidino compounds in patients with chronic renal failure (CRF) in comparison with normal subjects, and the renal content of GAA and glycine amidinotransferase (GAT) activity in the kidney of experimental CRF rabbits. Serum concentrations of guanidinosuccinic acid (GSA) and methylguanidine (MG) in the patients with CRF were higher than those in the normal subjects, as well as serum urea nitrogen (BUN) and creatinine (Cr) levels. The serum GAA levels were however, significantly lower and showed a tendency to decrease inversely with the elevation of BUN in the patients with CRF under conservative therapy. On the contrary, in the patients under maintenance hemodialysis (MHD) therapy, the serum GAA level did not decrease in spite of the elevation of BUN. Four anephric patients under MHD therapy showed a level of serum GAA similar to the other MHD patients. In the CRF rabbits, the renal GAA content was significantly lower than in the sham-operated rabbits and showed an inverse correlation with BUN. Renal GAT activity was also significantly lower in the CRF rabbits, showing a positive correlation with serum GAA concentration and an inverse correlation with BUN. These results indicate that renal GAT activity decreases as the BUN level rises in the course of renal damage, resulting in lower concentration of serum GAA in the uremic state; in a more advanced stage of renal failure, the inability of the kidney to synthesize GAA may be compensated by other organ(s). Some dialyzable substances which might inhibit renal GAT activity may also be present.


Bone marrow transplantation from a cadaveric donor.
A 2.5-year-old girl with neurogenic Gaucher's disease was transplanted with donor bone marrow from her HLA-compatible 12-year-old brother whose marrow was harvested 30 min post-mortem, after he suffered a severe head and neck injury. The marrow was stored in liquid nitrogen for 30 days prior to infusion. The post-transplantation period was uneventful with good engraftment and no signs of graft-versus-host disease. Currently, 6 months post-allogeneic bone marrow transplantation (alloBMT), analysis of both bone marrow and blood samples by PCR documented only cells of donor origin. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells. To our knowledge, this patient is the only survivor of alloBMT from a cadaveric donor.


Prospects for future studies in head and neck cancer.
Present therapy of head and neck cancer patients includes surgical procedures, radiotherapy and sometimes chemotherapy. Over recent decades no dramatic improvements have been obtained with these treatment modalities with respect to efficacy and associated morbidity. Of patients with early stage disease (stage I and II), about 25% cannot be cured, while for patients with advanced disease (stage III and IV) this percentage may be as high as 70%. However, owing to advances in our knowledge of molecular biology, immunology, (bio)chemistry and biology of head and neck squamous cell carcinoma (HNSCC), new perspectives on therapy are arising. After several years of optimization several new therapeutic approaches are leaving their infancy and are being evaluated in clinical trials with HNSCC patients. Among other approaches, photodynamic therapy, gene therapy and antibody-based therapy are attracting most attention. The basic concepts and the potential applications of these treatment modalities in the management of head and neck cancer are discussed in this paper.


Vitamin D insufficiency in myeloproliferative neoplasms and myelodysplastic syndromes: clinical correlates and prognostic studies.
Vitamin D insufficiency is commonly observed in the general population; observational studies have suggested an association with increased risk of cancer development. We examined the clinical and prognostic relevance of low plasma levels of 25-hydroxyvitamin D (25[OH]D) in myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). A total of 409 patients were studied: 247 (60%) with primary myelofibrosis (PMF), 74 (18%) with de novo MDS, 63 (15%) with polycythemia vera (PV), and 25 (6%) with essential thrombocythemia (ET). Plasma 25(OH)D levels were measured by liquid chromatography-tandem mass spectrometry; a level lower than 25 ng/mL indicated vitamin D insufficiency and a level lower than 10 ng/mL indicated severe deficiency. The proportion of patients with 25(OH)D insufficiency was significantly greater in PMF (48%) and PV (43%) when compared with ET (28%) and MDS (28%) (P = 0.01). Severe 25(OH)D deficiency was significantly more frequent in ET (12%) and PMF (9%), compared with PV (3%) and MDS (1%) (P = 0.05). There were no significant correlations between 25(OH)D insufficiency, or severe deficiency, and a variety of clinical or laboratory variables in PMF, MDS, or PV. Furthermore, Vitamin D insufficiency did not influence either overall or leukemia-free survival in PMF, MDS, or PV (P > 0.05). We conclude that while hypovitaminosis D is relatively common in MPN and MDS, its clinical relevance for prognosis is limited.


Development of a standardized and validated flow cytometry approach for monitoring of innate myeloid immune cells in human blood.
Innate myeloid cell (IMC) populations form an essential part of innate immunity. Flow cytometric (FCM) monitoring of IMCs in peripheral blood (PB) has great clinical potential for disease monitoring due to their role in maintenance of tissue homeostasis and ability to sense micro-environmental changes, such as inflammatory processes and tissue damage. However, the lack of standardized and validated approaches has hampered broad clinical implementation. For accurate identification and separation of IMC populations, 62 antibodies against 44 different proteins were evaluated. In multiple rounds of EuroFlow-based design-testing-evaluation-redesign, finally 16 antibodies were selected for their non-redundancy and separation power. Accordingly, two antibody combinations were designed for fast, sensitive, and reproducible FCM monitoring of IMC populations in PB in clinical settings (11-color; 13 antibodies) and translational research (14-color; 16 antibodies). Performance of pre-analytical and analytical variables among different instruments, together with optimized post-analytical data analysis and reference values were assessed. Overall, 265 blood samples were used for design and validation of the antibody combinations and in vitro functional assays, as well as for assessing the impact of sample preparation procedures and conditions. The two (11- and 14-color) antibody combinations allowed for robust and sensitive detection of 19 and 23 IMC populations, respectively. Highly reproducible identification and enumeration of IMC populations was achieved, independently of anticoagulant, type of FCM instrument and center, particularly when database/software-guided automated (vs. manual "expert-based") gating was used. Whereas no significant changes were observed in identification of IMC populations for up to 24h delayed sample processing, a significant impact was observed in their absolute counts after >12h delay. Therefore, accurate identification and quantitation of IMC populations requires sample processing on the same day. Significantly different counts were observed in PB for multiple IMC populations according to age and sex. Consequently, PB samples from 116 healthy donors (8-69 years) were used for collecting age and sex related reference values for all IMC populations. In summary, the two antibody combinations and FCM approach allow for rapid, standardized, automated and reproducible identification of 19 and 23 IMC populations in PB, suited for monitoring of innate immune responses in clinical and translational research settings.


Inhibition of Lymphatic Drainage With a Self-Designed Surgical Approach Prolongs the Vascularized Skin Allograft Survival in Rats.
Vascularized composite allotransplantation (VCA) is an emerging treatment for significant tissue defects. However, VCAs usually consist of multiple highly antigenic skin tissues. Previous studies have shown that the lymphatic system in skin plays important roles in the initiation of immune responses during acute rejection, by transporting T cells and antigen-presenting dendritic cells to regional lymph nodes. Therefore, we designed a new surgical treatment to inhibit lymphatic drainage of skin allografts and investigated whether this approach could promote the survival of allografts and suppress immunological events after transplantation. This procedure was achieved by connecting the vascularized allografts to recipient tissues with only an annular plastic holder, allowing the minimum of allograft contact with recipients. Our results showed that the self-designed treatment for inhibiting lymphatic drainage promoted the survival of allografts, reduced the serum concentration of IL-2, and decreased the percentage of CD4CD25 and CD8CD25 from the lymphatic nodes draining the transplantation region. In conclusion, these data suggest that self-designed surgical approach is effective in inhibiting lymphatic drainage of skin allografts, and the lymphatic system may be new therapeutic targets for developing techniques or drugs against acute rejection after VCAs.


Proposed methodology and classification of Infarct in New Territory (INT) after endovascular stroke treatment.
While the overall complication rates for endovascular treatment for acute stroke has been extremely low in recent trials, it is important to separate out and accurately document complications. One of these complications that is usually related to the endovascular intervention is Infarct in New Territory (INT). We propose a standardized methodology for documenting INT after the procedure. This new classification takes into account variations in vascular anatomy and location of the occlusion. In addition, given that after the recent trials, vascular imaging (eg, CT angiography (CTA)) is now the standard of care in the work up of acute ischemic stroke, this classification utilizes the information on the pre-procedure non-invasive vascular imaging, the angiography images from end of procedure and the location of lesions on the follow-up scan.


In vivo staging of regional amyloid deposition.
To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology. Multiregional analysis of florbetapir (18F-AV45)-PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort. According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia. The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.


Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury.
Epiregulin (EPI) and amphiregulin (AR) are epidermal growth factor receptor (EGFR) ligands implicated in mucosal repair and tumorigenesis. We have shown that Toll-like receptor 4 (TLR4) induces intestinal epithelial cell (IEC) proliferation by activating EGFR through AR expression. We examined whether TLR4 differentially regulates expression of EGFR ligands in response to mucosal injury. The human IEC line SW480 was examined expression of EGFR ligands, EGFR phosphorylation, and proliferation in response to lipopolysaccharide (LPS). Small-interfering RNA (siRNA) was used to block TLR4. Neutralizing antibodies to EGFR ligands were used to examine inhibition of LPS-dependent EGFR activation. Acute colitis and recovery were examined in the mice given 2.5% dextran sodium sulfate (DSS). Colonic secretion of EPI and AR was analyzed by enzyme-linked immunosorbent assay. LPS selectively induces EPI and AR but not other EGFR ligands. LPS induced early EPI mRNA expression between 30 min and 24 h. The neutralizing antibodies to EPI and AR prevented activation of EGFR by LPS. LPS induces IEC proliferation (200%, P=0.01) in 24 h but blocking EPI and AR significantly decreased proliferation. In vivo, mucosal EPI and AR expression are significantly decreased in TLR4(-/-) mice (P=0.02) compared to wild-type mice during acute colitis. EPI and AR exhibit different kinetics in response to mucosal damage: EPI expression is upregulated acutely at day 7 of DSS, but falls during recovery at day 14. By contrast, a sustained upregulation of AR expression is seen during mucosal injury and repair. We show that TLR4 regulates EPI and AR expression and that both these EGFR ligands are necessary for optimal proliferation of IEC. The diverse kinetics of EPI and AR expression suggest that they function in distinct roles with respect to acute injury vs repair. Our results highlight the role of bacterial sensing for IEC homeostasis and may lead to targeted therapy for mucosal healing and prevention of tumorigenesis.


[Study on reference extracts for quality assessment on traditional Chinese medicines based on akebiae saponin].
On the basis of analysis and summary of current application of reference extracts of traditional Chinese medicine, reference extracts for quality assessment of traditional Chinese medicines are divided into three classes by purpose: 1. herbal or volatile oil reference extracts for TLC identification of original herbal medicines or patent traditional Chinese medicines containing original herbal medicines. 2. component reference extracts for identification of certain components or positioning of chromatographic peaks. 3. reference extracts marked with component content to be determined for quantitative analysis on samples. For the third kind of reference extracts, akebiae saponin was taken as an example for preparation thought and methods in such aspects as preparation process, component identification and content analysis.


Screening of fungi for the presence of the trichodiene synthase encoding sequence by hybridization to the Tri5 gene cloned from Fusarium poae.
A trichodiene synthase gene (Tri5) was amplified from F. poae by polymerase chain reaction using synthetic primers constructed on the basis of the coding portion of the same gene from F. sporotrichioides. Sequence analysis showed a high degree of similarity with other trichodiene synthase genes. A 378 bp HindIII fragment of the gene that contains the genetic information for the putative active site of the trichodiene synthase enzyme was radiolabelled and used for dot blot analysis. This probe could detect Tri5 hybridization in 1-10 ng DNA of fusaria that have the genetic potentiality to synthesize toxic trichothecene compounds, but gave no reaction with trichothecene nonproducing members of the genus. When other fungi reported to produce trichothecenes (Myrothecium, Stachybotrys, Trichoderma, Trichothecium spp.) were tested, only strains of Myrothecium and Stachybotrys gave strong positive reaction. Faint but consistent hybridization signals were obtained in four species (F. semitectum, F. tricinctum, Trichoderma viride and Trichothecium roseum) indicating the presence of nonhomologous evolutionary variants or inactive remnants of the Tri5 gene in these fungi.


Frequency-constrained robust principal component analysis: a sparse representation approach to segmentation of dynamic features in optical coherence tomography imaging.
Sparse representation theory is an exciting area of research with recent applications in medical imaging and detection, segmentation, and quantitative analysis of biological processes. We present a variant on the robust-principal component analysis (RPCA) algorithm, called frequency constrained RPCA (FC-RPCA), for selectively segmenting dynamic phenomena that exhibit spectra within a user-defined range of frequencies. The algorithm lacks subjective parameter tuning and demonstrates robust segmentation in datasets containing multiple motion sources and high amplitude noise. When tested on 17 ex-vivo, time lapse optical coherence tomography (OCT) B-scans of human ciliated epithelium, segmentation accuracies ranged between 91-99% and consistently out-performed traditional RPCA.


Transseptal puncture versus patent foramen ovale or atrial septal defect access for left atrial appendage closure.
The aim of this study was to compare the periprocedural and late clinical outcomes of left atrial appendage closure (LAAC) with AMPLATZER devices by access through transseptal puncture (TSP) versus a patent foramen ovale (PFO) or an atrial septal defect (ASD). Between 2009 and 2018, 578 consecutive patients underwent LAAC via TSP or PFO/ASD access in three centres. After a 3:1 propensity score matching, 246 (TSP) versus 91 (PFO/ASD) patients were compared using the primary efficacy endpoint of all-cause stroke, systemic embolism and cardiovascular/unexplained death and the primary safety endpoint of major periprocedural complications and major bleedings at follow-up. Mean age was 75.2±8.7 (TSP) vs 74.4±10.9 (PFO/ASD) years, CHA2DS2-VASc score 4.5±1.6 vs 4.3±1.4 and HAS-BLED score 3.3±1.0 vs 3.3±0.9. Device success (97.6% vs 97.8%, p=0.90) was similar. After 2.5±1.4 vs 2.6±1.6 years, clinical efficacy (46/603, 7.6% [TSP] vs 21/233, 9.0% [PFO/ASD], hazard ratio [HR] 1.2; 95% confidence interval [CI]: 0.69-0.85, p=0.54) and safety (24/603, 4.0% vs 11/233, 4.7%; HR 1.4; 95% CI: 0.52-3.6, p=0.49) did not differ. Use of a PFO/ASD access for LAAC with AMPLATZER devices offers similar periprocedural and late clinical outcomes to TSP. Simultaneous PFO/ASD closure for an additional protective benefit does not increase risk.


The Role of Preoperative Urinalysis in Predicting Postoperative Infection After Retrograde Intrarenal Surgery in Patients with Sterile Urine Culture.
Postoperative urinary tract infection is the most common complication of retrograde intrarenal surgery, and no consensus has been obtained that would reveal exact reasons yet. It was aimed to determine the possible factors, especially preoperative urinalysis, of postoperative urinary tract infection after retrograde intrarenal surgery. Patients who underwent retrograde intrarenal surgery in our clinic between 2013 and 2019 were retrospectively screened. Stone size 2 cm and pediatric patients were excluded from the study. The patients were divided into 2 groups as those with and without urinary infections in the early postoperative period. Urine analysis parameters and sterile urine cultures that were taken before the procedure were also analyzed separately. A total of 289 patients meeting the defined criteria were included in the study. There was no statistical difference between the 2 groups in terms of demographics. The number of patients with previous urinary tract infection history (55% vs. 20.5%) and operation time (62.5 ± 16.6 minutes vs. 60 ± 19.4 minutes) were significantly higher in those who had postoperative early urinary tract infection. Among urinalysis, the presence of pyuria, leukocyte count, leukocyte esterase positivity, and nitrite positivity were significantly higher in those who had postoperative early urinary tract infection. In multivariate analysis, urinary tract infection history, operation time, and nitrite positivity were found as independent factors in predicting postoperative early urinary tract infection. Previous urinary tract infection history, prolonged operation time, and nitrite positivity in urinalysis were determined as independent risk factors for postoperative urinary tract infection in kidney stones between 1 and 2 cm.


Leveraging multimodal microscopy to optimize deep learning models for cell segmentation.
Deep learning provides an opportunity to automatically segment and extract cellular features from high-throughput microscopy images. Many labeling strategies have been developed for this purpose, ranging from the use of fluorescent markers to label-free approaches. However, differences in the channels available to each respective training dataset make it difficult to directly compare the effectiveness of these strategies across studies. Here, we explore training models using subimage stacks composed of channels sampled from larger, "hyper-labeled," image stacks. This allows us to directly compare a variety of labeling strategies and training approaches on identical cells. This approach revealed that fluorescence-based strategies generally provide higher segmentation accuracies but were less accurate than label-free models when labeling was inconsistent. The relative strengths of label and label-free techniques could be combined through the use of merging fluorescence channels and using out-of-focus brightfield images. Beyond comparing labeling strategies, using subimage stacks for training was also found to provide a method of simulating a wide range of labeling conditions, increasing the ability of the final model to accommodate a greater range of candidate cell labeling strategies.


An Evaluation of Drug-Drug Interaction Alerts Produced by Clinical Decision Support Systems in a Tertiary Hospital.
Introduction Drug-drug interactions (DDIs) have the potential to harm patients. Hence, DDI alerts are meant to prevent harm; as a result, their usefulness is reduced when most alerts displayed to providers are ignored. This study aims to explore the rates and reasons for overriding alerts of DDI. Methods This is a retrospective study of DDI alert overrides that occurred between January 2020 and December 2020 within the inpatient medical records at a tertiary hospital, Medina City, Kingdom of Saudi Arabia. Results A total of 7,098 DDI alerts were generated from inpatient settings, of which 6,551(92.2%) were overridden by the physicians at the point of prescribing. "Will Monitor as Recommended" (33%) was the most common reason for the override, followed by 'Will Adjust the Dose as Recommended (27.1%)," "The Patient Has Already Tolerated the Combination" (25.7%), and "No Overridden Reason Selected" (13.0%). Discussion The DDI alert overriding is still high and is comparable to other studies. However, this study reveals that physicians are ready to deal with the consequences of around 58% of DDI alerts. Additionally, 13% of physicians were not willing to report the reason for overriding. This indicates an urgent need to review and restructure the DDI alert system. Conclusion The DDI alert override rates are high, and this is undesirable. It is recommended to revise the DDI alert system. Future studies should dig deep for real reasons for overriding and seek inputs from all stakeholders, including developing actionable metrics to track and monitor DDI alerting system.


Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma.
Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates. In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug's PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer. This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications. ClinicalTrials.gov: NCT05055323.


Diabetic glomerulopathy following unilateral nephrectomy in the rat.
One month following induction of diabetes with streptozotocin, one half of diabetic and control rats underwent unilateral nephrectomy. Subsequently, all animals were studied with respect to renal function and glomerular alterations of diabetes. Blood pressure levels were similar in all animals. Diabetic and control animals with unilateral nephrectomy had similar but elevated serum creatinine levels and lower creatinine clearance values as compared with the intact rats. However, on a per kidney basis the creatinine clearance levels were higher in the animals with unilateral nephrectomy. At both three and six months following nephrectomy, markedly increased mesangial matrix thickening and mesangial deposition of IgG and C3 were observed in diabetic rats with unilateral nephrectomy as compared with intact diabetic animals. Nephrectomy had no detectable effects on glomerular morphology or immunohistochemistry of nondiabetic rats. Thus, unilateral nephrectomy in the rat increases, at as early as three months, the severity of diabetic glomerular lesions.


Water temperature induces jaw deformity and bone morphogenetic proteins (BMPs) gene expression in golden pompano Trachinotus ovatus larvae.
Golden pompano Trachinotus ovatus larvae were kept at 26, 29 and 33 °C for 15 days from 3-day post hatching (DPH) to 18 DPH to test temperature-dependent growth and jaw malformation. The growth, survival, jaw deformity and the gene expressions of bone morphogenetic proteins (BMPs) were used as criteria to examine the fish response to temperature manipulation. The growth rate of fish at 29 or 33 °C was significantly faster than fish at 26 °C, while fish survival at 29 °C was significantly higher than fish at 33 °C. Jaw deformity was significantly affected by water temperature. The highest jaw deformity occurred on fish at 33 °C, and the lowest jaw deformity was at 26 °C. The expressions of all BMP genes except BMP10 were significantly affected by water temperature. The highest gene expression of BMP2 was on fish at 29 °C, and the lowest expression was at 33 °C. For the BMP4 gene, the highest and lowest expressions were found on fish at 33 and 26 °C, respectively. The present study indicates that jaw deformity of golden pompano larvae increases with increasing temperature, and the gene expression of BMP4 proteins coincides with high jaw deformity and water temperature elevation.


Evaluation of full-facepiece respirator fit on fire fighters in the municipality of Jeddah, Saudi Arabia.
The purpose of this study was to assess the effect of personal variables on the fit of the respirators used by firefighters and workers in highly polluted environments. However, resistance from many plants managers was met to conduct the study on their workers. Therefore, we were forced to limit the study on firefighters who were found very cooperative. Forty volunteer firefighters from different departments participated in the study. They were subjected to a daily leak rate measurement using a Control Negative Pressure (CNP) fit tester for five consecutive days. Two types of respirators were used for each volunteer: the Drager type and the MSA. At the end of the study, the association between face shape and presence of beard with the respirator leak rates was investigated. A significant difference in the leak rate was detected between the two types of respirators used, with the Drager respirator having higher leak rates. The presence of a beard increased dramatically the leak rate whatever the face shape was. The oval shape was the best fitting to the respirators, followed by the rounded and finally the rectangular face. The study recommends that personal variables like face shape must be taken into consideration and fit testing must be carried out periodically, to specify the respirator that best fits each firefighter. Having beard must be absolutely prohibited, since it can be life threatening in environmental dangerous conditions such those encountered during extinguishing fires and overhaul situations.


The use of self-efficacy in cardiac rehabilitation.
Cardiac rehabilitation patients' perceptions of their ability to perform an exercise prescription can mediate how much effort they will expand toward exercise compliance. A review is made of self-efficacy theory and its application in research investigating the relationship between the self-efficacy and physical activity. This article explores how the nurse in cardiac rehabilitation can utilize the sources of efficacy information to assist the patient to modify the cardiovascular disease risk factor of sedentary lifestyle.


Electronic Properties and Dissociative Photoionization of Thiocyanates, Part III. The Effect of the Group's Electronegativity in the Valence and Shallow-Core (Sulfur and Chlorine 2p) Regions of CCl3SCN and CCl2FSCN.
Both photoelectron spectroscopy (PES) data and PhotoElectron-PhotoIon-Coincidence (PEPICO) spectra obtained from a synchrotron facility have been used to examine the electronic structure and the dissociative ionization of halomethyl thiocyantes in the valence and shallow-core S 2p and Cl 2p regions. Two simple and closely related molecules, namely, CCl3SCN and CCl2FSCN, have been analyzed to assess the role of halogen substitution in the electronic properties of thiocyanates. The assignment of the He(I) photoelectron spectra has been achieved with the help of quantum chemical calculations at the outer-valence Green's function (OVGF) level of approximation. The first ionization energies observed at 10.55 and 10.78 eV for CCl3SCN and CCl2FSCN, respectively, are assigned to ionization processes from the sulfur lone pair orbital [n(S)]. When these molecules are compared with CX3SCN (X = H, Cl, F) species, a linear relationship between the vertical first ionization energy and electronegativity of CX3 group is observed. Irradiation of CCl3SCN and CCl2FSCN with photons in the valence energy regions leads to the formation of CCl2X+ and CClXSCN+ ions (X = Cl or F). Additionally, the achievement of the fragmentation patterns and the total ion yield spectra obtained from the PEPICO data in the S 2p and Cl 2p regions and several dissociation channels can be inferred for the core-excited species by using the triple coincidence PEPIPICO (PhotoElectron-PhotoIon-PhotoIon-Coincidence) spectra.


Extracting temporal constraints from clinical research eligibility criteria using conditional random fields.
Temporal constraints are present in 38% of clinical research eligibility criteria and are crucial for screening patients. However, eligibility criteria are often written as free text, which is not amenable for computer processing. In this paper, we present an ontology-based approach to extracting temporal information from clinical research eligibility criteria. We generated temporal labels using a frame-based temporal ontology. We manually annotated 150 free-text eligibility criteria using the temporal labels and trained a parser using Conditional Random Fields (CRFs) to automatically extract temporal expressions from eligibility criteria. An evaluation of an additional 60 randomly selected eligibility criteria using manual review achieved an overall precision of 83%, a recall of 79%, and an F-score of 80%. We illustrate the application of temporal extraction with the use cases of question answering and free-text criteria querying.


p38 MAPK activation and function following osmotic shock of erythrocytes.
p38 protein kinase is activated by hyperosmotic shock, participates in the regulation of cell volume sensitive transport and metabolism and is involved in the regulation of various physiological functions including cell proliferation and apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which is paralleled by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include hyperosmotic shock, which increases cytosolic Ca(2+) activity and ceramide formation. The present study explored whether p38 kinase is expressed in human erythrocytes, is activated by hyperosmotic shock and participates in the regulation of eryptosis. Western blotting was utilized to determine phosphorylation of p38 kinase, forward scatter to estimate cell volume, annexin V binding to depict phosphatidylserine exposure and Fluo3 fluorescence to estimate cytosolic Ca(2+) activity. As a result, erythrocytes express p38 kinase, which is phosphorylated upon osmotic shock (+550 mM sucrose). Osmotic shock decreased forward scatter, increased annexin V binding and increased Fluo3 fluorescence, all effects significantly blunted by the p38 kinase inhibitors SB203580 (2 μM) and p38 Inh III (1 μM). In conclusion, p38 kinase is expressed in erythrocytes and participates in the machinery triggering eryptosis following hyperosmotic shock.


Hamstring muscle forces prior to and immediately following an acute sprinting-related muscle strain injury.
A thorough understanding of the biomechanics of the hamstrings during sprinting is required to optimise injury rehabilitation and prevention strategies. The main aims of this study were to compare hamstrings load across different modes of locomotion as well as before and after an acute sprinting-related muscle strain injury. Bilateral kinematic and ground reaction force data were captured from a single subject whilst walking, jogging and sprinting prior to and immediately following a significant injury involving the right semitendinosis and biceps femoris long head muscles. Experimental data were input into a three-dimensional musculoskeletal model of the body and used, together with optimisation theory, to determine lower-limb muscle forces for each locomotor task. Hamstrings load was found to be greatest during terminal swing for sprinting. The hamstrings contributed the majority of the terminal swing hip extension and knee flexion torques, whilst gluteus maximus contributed most of the stance phase hip extension torque. Gastrocnemius contributed little to the terminal swing knee flexion torque. Peak hamstrings force was also substantially greater during terminal swing compared to stance for sprinting, but not for walking and jogging. Immediately following the muscle strain injury, the hamstrings demonstrated an intolerance to perform an eccentric-type contraction. Whilst peak hamstrings force during terminal swing did not decrease post-injury, both peak hamstrings length and negative work during terminal swing were considerably reduced. These results lend support to the paradigm that the hamstrings are most susceptible to muscle strain injury during the terminal swing phase of sprinting when they are contracting eccentrically.


Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation.
Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Activated NF-κB induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces Ca2+ oscillation via activated phospholipase Cγ2 (PLCγ2) together with c-Fos/AP-1, wherein Ca2+ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteoclast-specific target genes that are responsible for cell fusion and function.


Increased incidence of cage migration and nonunion in instrumented transforaminal lumbar interbody fusion with bioabsorbable cages.
Recent advances in the field of spinal implants have led to the development of the bioabsorbable interbody cage. Although much has been written about their advantageous characteristics, little has been reported regarding complications associated with these cages. The authors conducted this prospective cohort study to compare fusion and complication rates in patients undergoing transforaminal lumbar interbody fusion (TLIF) with carbon fiber cages versus biodegradable cages made from 70/30 poly(l-lactide-co-d,l-lactide) (PLDLA). Between January 2005 and May 2006, 81 patients with various degenerative and/or structural pathologies affecting the lumbar spine underwent single- or multilevel TLIF with posterior segmental pedicle screw fixation using implants made of carbon fiber (37 patients) or 70/30 PLDLA (44 patients). Clinical and radiological follow-up was performed at 6 weeks, 3 months, 6 months, and 1 year, and is ongoing. The incidence of nonunion, screw breakage, and cage migration were compared between the 2 groups. There was no significant difference in demographic data between the 2 groups, the mean number of lumbar levels operated, or distribution of the levels operated. There was a significantly increased incidence of nonunion (8 patients, 18.2%) and cage migrations (8 patients, 18.2%) in patients receiving the PLDLA implants compared with carbon fiber implants (no patients) (p = 0.006 and 0.007, respectively). There was no significant difference in demographic data between patients with cage migration and the rest of the patient population. Five of the 8 cases of migration occurred at the L5-S1 level while the remaining 3 occurred at the L4-5 level. The mean time to implant failure was 9.3 months. This study showed an increased incidence of nonunion (18.2%) and postsurgical cage migration (18.2%) in patients undergoing TLIF with biodegradable cages versus carbon fiber implants (0%) (p = 0.006 and 0.007, respectively).


Towards a classification approach using meta-biclustering: impact of discretization in the analysis of expression time series.
Biclustering has been recognized as a remarkably effective method for discovering local temporal expression patterns and unraveling potential regulatory mechanisms, essential to understanding complex biomedical processes, such as disease progression and drug response. In this work, we propose a classification approach based on meta-biclusters (a set of similar biclusters) applied to prognostic prediction. We use real clinical expression time series to predict the response of patients with multiple sclerosis to treatment with Interferon-β. As compared to previous approaches, the main advantages of this strategy are the interpretability of the results and the reduction of data dimensionality, due to biclustering. This would allow the identification of the genes and time points which are most promising for explaining different types of response profiles, according to clinical knowledge. We assess the impact of different unsupervised and supervised discretization techniques on the classification accuracy. The experimental results show that, in many cases, the use of these discretization methods improves the classification accuracy, as compared to the use of the original features.


Drivers of prohibited natural resource collection in Chitwan National Park, Nepal.
Protected areas (PAs) are critical for achieving conservation, economic and development goals, but the factors that lead households to engage in prohibited resource collection in PAs are not well understood. We examine collection behaviours in community forests and the protected Chitwan National Park in Chitwan, Nepal. Our approach incorporates household and ecological data, including structured interviews, spatially explicit data on collection behaviours measured with computer tablets and a systematic field survey of invasive species. We pair our data with a framework that considers factors related to a household's demand for resources, barriers to prohibited resource collection, barriers to legal resource collection and alternatives to resource collection. The analysis identifies key drivers of prohibited collection, including sociodemographic variables and perceptions of an invasive plant (Mikania micrantha). The social-ecological systems approach reveals that household perceptions of the presence of M. micrantha were more strongly associated with resource collection decisions than the actual ecologically measured presence of the plant. We explore the policy implications of our findings for PAs and propose that employing a social-ecological systems approach leads to conservation policy and scientific insights that are not possible to achieve with social or ecological approaches alone.


Understanding the cultural meanings of stroke in the Ghanaian setting: A qualitative study exploring the perspectives of local community residents.
Background: Stroke has undergone different medical constructions over the years. While the medical profession posits that disease is a biological condition, universal and unchanging, social constructionists perceive illness as the social meaning of the biological condition. Even though the medical notion of stroke is monolithic and sometimes contradicts the representations by local community residents, little attention has been paid to understanding the cultural meanings of stroke. This study explores the cultural meanings of stroke in five different cultural settings in Ghana. Methods: 30 focus group discussions (FGDs) were conducted with local community members in five communities (Ga Mashie, Tafo, Gyegyeano, Chanshegu and Agorve) located in five regions in Ghana. The FGDs were conducted in Ga, Twi, Fante, Ewe and Dagbani, and were transcribed verbatim into English. The transcripts were analysed thematically. Results: The local words used for stroke in all the five cultural settings focused on physical disability associated with stroke after its onset, and this formed the dominant source of fear about the condition. Participants mentioned that spiritual and left-side stroke have the most debilitating impact on the sufferer. Although there was a general consensus that anyone can be at risk of stroke, there was a gender dynamics in the explanation of risk relativity. Participants believed that stroke can be cured through early detection and treatment, use of herbal medicines, and availability of financial resources. Compared to other disabling conditions, the community residents perceived stroke to be more severe due to its multifaceted disabilities. Conclusions: This study showed that the social meanings of stroke in the five communities are multifaceted, and reflected co-existence of biomedical and cultural frameworks. The findings showed the need to pay good attention to the sociocultural context when developing interventions strategies on stroke prevention and control.


Conservative treatment of borderline ovarian tumors.
Of 61 patients with stage IA borderline ovarian tumors, 41 were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, and 20 were treated by a variety of more limited operations, including cystectomy with (one patient) and without (three patients) a contralateral ovarian wedge biopsy, and unilateral salpingo-oophorectomy with (six patients) and without (ten patients) a contralateral wedge biopsy. In the group treated conservatively, there were 11 serous, seven mucinous, and two mixed seromucinous borderline tumors, whereas in the total abdominal hysterectomy and bilateral salpingo-oophorectomy treatment group there were 26 serious, 12 mucinous, and three mixed seromucinous borderline tumors. After a mean follow-up of 89 months (range 36 to 244 months), subsequent borderline neoplasms had developed in three patients (15%) with serious borderline tumors initially treated conservatively and in two patients (5%) with serous or mixed seromucinous borderline tumors initially treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patient with a mucinous borderline tumor treated either conservatively or with total abdominal hysterectomy and bilateral salpingo-oophorectomy developed a subsequent neoplasm. All 61 patients in the study group are alive and free of disease, including those who developed recurrent neoplasm.


Model-Based Estimation of Ankle Joint Stiffness.
We address the estimation of biomechanical parameters with wearable measurement technologies. In particular, we focus on the estimation of sagittal plane ankle joint stiffness in dorsiflexion/plantar flexion. For this estimation, a novel nonlinear biomechanical model of the lower leg was formulated that is driven by electromyographic signals. The model incorporates a two-dimensional kinematic description in the sagittal plane for the calculation of muscle lever arms and torques. To reduce estimation errors due to model uncertainties, a filtering algorithm is necessary that employs segmental orientation sensor measurements. Because of the model's inherent nonlinearities and nonsmooth dynamics, a square-root cubature Kalman filter was developed. The performance of the novel estimation approach was evaluated in silico and in an experimental procedure. The experimental study was conducted with body-worn sensors and a test-bench that was specifically designed to obtain reference angle and torque measurements for a single joint. Results show that the filter is able to reconstruct joint angle positions, velocities and torque, as well as, joint stiffness during experimental test bench movements.


Properties of the Cigarette Dependence Scale and the Fagerström Test of Nicotine Dependence in a representative sample of smokers in Norway.
To compare the properties of four measures of dependence to nicotine/tobacco, the 12-item Cigarette Dependence Scale (CDS-12), the six-item Fagerström Test of Nicotine Dependence (FTND) and two shorter versions of the same measures. In a cross-sectional telephone survey of smokers in a representative general population sample in Norway, we compared the measures. We assessed (i) internal consistency reliability with Cronbach's alpha; (ii) compared item scores; and (iii) tested the validity of the questionnaires. Test-retest reliability was assessed in a smaller convenience sample. Among 1265 respondents (64%), 290 (23%) were daily smokers and included in further analysis. Their mean age was 42 years [standard deviation (SD) 15] and 46% were female. They smoked on average 13 cigarettes per day (SD 6). Internal consistency reliability was 0.61 for the FTND (n = 267) and 0.81 for the CDS-12 (n = 266). Score distributions suggested a floor effect for the FTND. Test-retest reliability was 0.90 for the FTND and 0.97 for the CDS-12 (n = 31). The correlation between the scale scores and a question about the maximum willingness to pay for a cigarette after not smoking all day was 0.36 (P < 0.001) for the FTND (n = 262) and 0.45 (P < 0.001) for the CDS-12 (n = 263). There was little difference in the associations of the two scales or their abbreviated versions with external variables. Telephone administration was acceptable for both questionnaires, and we have established population reference values for the four scales. The questionnaires were associated with each other and showed similar properties. The findings support the construct validity of the scales.


Late outcomes after carotid artery stenting versus carotid endarterectomy: insights from a propensity-matched analysis of the Reduction of Atherothrombosis for Continued Health (REACH) Registry.
In patients with carotid artery disease, carotid endarterectomy (CEA) and carotid stenting (CAS) are treatment options. Controversy exists as to the relative efficacy of the 2 techniques in preventing late events. The Reduction of Atherothrombosis for Continued Health (REACH) Registry recruited > 68,000 outpatients ≥ 45 years of age with established atherothrombotic disease or ≥ 3 risk factors for atherothrombosis. Patients with CAS or CEA were chosen and followed up prospectively for the occurrence of cardiovascular events. Propensity score matching was performed to assemble a cohort of patients in whom all baseline covariates would be well balanced. Primary outcome was defined as death or stroke at the 2-year follow-up. Secondary outcome was stroke or transient ischemic attack. Tertiary outcome was a composite of death, myocardial infarction, or stroke and the individual outcomes. Of the 68 236 patients with atherothrombosis, 3412 patients (5%) had a history of carotid artery revascularization (70% asymptomatic carotid stenosis), 1025 (30%) with CAS and 2387 (70%) with CEA. Propensity score analyses matched 836 CAS patients with 836 CEA patients. At the end of 2 years of follow-up, in the propensity score-matched cohort, CAS was associated with a risk similar to CEA for the primary (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.57 to 1.26), secondary (HR, 1.20; 95% CI, 0.73 to 1.96), and tertiary (HR, 0.72; 95% CI, 0.51 to 1.01) composite outcome, death (HR, 0.63; 95% CI, 0.40 to 1.00), and stroke (HR, 1.48; 95% CI, 0.79 to 2.80). In a real-world cohort of patients with a history of carotid artery revascularization, CAS was comparable to CEA for late outcomes.


Insulin causes insulin-receptor internalization in human erythrocyte ghosts.
The effect of incubation with insulin on insulin-receptor internalization by erythrocyte ghosts was investigated. The number of surface insulin receptors decreased by 30-40% after incubation of ghosts with insulin. Total insulin-receptor binding to solubilized ghosts was the same in insulin-incubated and control ghosts, whereas insulin binding to an internal vesicular fraction was substantially increased in insulin-incubated ghosts. Our findings suggest that erythrocyte-ghost insulin receptors are internalized to a vesicular compartment in response to incubation with insulin.


The Canadian National Calibration Reference Centre for In-Vivo Monitoring: thyroid monitoring. Part I: The national inter-comparison programme.
This article is the first part of a five-part series covering various aspects of occupational thyroid monitoring. The Canadian National Calibration Reference Centre for In-Vivo Monitoring conducts a thyroid inter-comparison programme that now includes more than 100 facilities. The scope of the programme, begun in 1988, has greatly expanded in the last two years following a considerable effort to locate and inform facilities. This article presents the details of the programme, its results, and the lessons learned. Subsequent articles will discuss sources of errors, methodology, instrumental configuration, and counting geometry optimization.


Hepatitis B vaccination status and needle stick injuries among medical students in a Nigerian university.
Hepatits B virus (HBV) is the most common blood borne pathogen that poses an occupational risk to Health-care workers. The incidence of infection following needle stick injury has been reported to be high among medical students. Effective vaccines against HBV are available. The aim of this study was to determine the vaccination status and prevalence of needlestick injury among medical students in a tertiary institution in a developing country (Nigeria). Information regarding hepatitis B status, history of needlestick injury and awareness of risk factors for HBV were obtained from clinical medical students using a self administered questionnaire. Three hundred and forty six students responded. Three hundred and five (88.7%) agreed that medical education exposes one to HBV infection and 315 (91.6%) were aware of the availability of vaccine against HBV. Only 42 (47.7%) were vaccinated against HBV. Majority (57.4%) gave lack of opportunity as reason for non immunization while 34.7% had never given it a thought. One hundred and sixty-six (48%) of the respondents admitted to a previous needlestick injury and only 17 (10.2%) of those who reported history of needlestick injury had post-exposure prophylaxis against HBV infection. HBV vaccination status is very low among medical students in Nigeria and the prevalence of needle stick injuries is high. Universities must not only provide HBV vaccination free of charge but also enforce its use by these students.


Beat the Fear of Public Speaking: Mobile 360° Video Virtual Reality Exposure Training in Home Environment Reduces Public Speaking Anxiety.
With this article, we aim to increase our understanding of how mobile virtual reality exposure therapy (VRET) can help reduce speaking anxiety. Using the results of a longitudinal study, we examined the effect of a new VRET strategy (Public Speech Trainer, PST), that incorporates 360° live recorded VR environments, on the reduction of public speaking anxiety. The PST was developed as a 360° smartphone application for a VR head-mounted device that participants could use at home. Realistic anxiety experiences were created by means of live 360° video recordings of a lecture hall containing three training sessions based on graded exposure framework; empty classroom (a) and with a small (b) and large audience (c). Thirty-five students participated in all sessions using PST. Anxiety levels were measured before and after each session over a period of 4 weeks. As expected, speaking anxiety significantly decreased after the completion of all PST sessions, and the decrement was the strongest in participants with initially high speaking anxiety baseline levels. Results also revealed that participants with moderate and high speaking anxiety baseline level differ in the anxiety state pattern over time. Conclusively and in line with habituation theory, the results supported the notion that VRET is more effective when aimed at reducing high-state anxiety levels. Further implications for future research and improvement of current VRET strategies are discussed.


The use of a simulated environment (easy street) to retrain independent living skills in elderly persons: a randomized controlled trial.
Older adults who receive training for functional skills in contextually appropriate environments may show greater functional improvement than persons trained in a traditional environment. Functionally limited older adults receiving training in contextually appropriate environments (simulated home and community settings) may show greater improvement in activities of daily living (ADL) than persons trained in a traditional manner. Eighty-eight patients from a day hospital, aged 65 years or older, were randomized to either receive rehabilitation in a simulated environment (Easy Street) or in a gymnasium setting. Rehabilitation focused on retraining functional skills in a contextually appropriate environment (Easy Street) or in a traditional setting (gymnasium) using motor learning principles for a period of 16 weeks. Outcome measures included the Structured Assessment of Instrumental Living Skills (SAILS), a performance measure with criterion and timed components; a self-report health status questionnaire, the Short Form-36 (SF-36); and the patient-orientated goal-directed Canadian Occupational Performance Measure (COPM). There were no group differences on any of the outcome measures: SAILS (p = .3); the SF-36 physical (p = .83) and mental (p = .51); and the COPM performance scale (p = .94) and satisfaction scale (p = .40). Although we have not excluded benefits of contextually appropriate rehabilitation environments with different intervention approaches, at different stages of rehabilitation or with patients at higher functional levels, our results suggest the appropriateness of a moratorium on these expensive interventions pending demonstration of clear positive effects determined from further study.


The effect of #enhancement-free Instagram images and hashtags on women's body image.
Instagram is a popular social networking site where users can post and share photos. One increasing trend on the site is the posting of natural and unaltered images. The present study aimed to experimentally investigate the effect of enhancement-free (i.e., no makeup, no digital alteration) Instagram images and their accompanying hashtags on women's body image. Participants were 204 female undergraduate students who were randomly assigned to view one of three sets of Instagram images: standard (i.e., idealised) images, enhancement-free images, or the same set of enhancement-free images with hashtags indicating their enhancement-free nature. As predicted, exposure to enhancement-free images resulted in significantly lower facial dissatisfaction than exposure to the standard images. However, the addition of hashtags resulted in significantly greater facial dissatisfaction than the same enhancement-free images with no hashtags. There were no significant effects for body dissatisfaction. Effects on facial dissatisfaction were moderated by self-photo manipulation, whereby the difference between standard and enhancement-free images was greater for women who digitally manipulate their own photos. Overall, the findings suggest that, under some conditions, enhancement-free images have the potential to protect Instagram users against appearance concerns.


Determinants of Quit Attempts and Short-Term Abstinence among Smokers in India: Global Adult Tobacco Survey, 2016-17.
The objective was to study the determinants of quit attempts and abstinence among smokers in India using nationally representative data from the Global Adult Tobacco Survey (GATS-2). Data from GATS-India, (2016-17) was analysed. Key outcome variables included quitting attempts in the previous 12 months among smokers and duration of abstinence among those who attempted quitting. The receipt of messages through mass media, warning labels and quit advice by doctors or healthcare providers were key exposure variables for both outcomes. The use of cessation methods was an exposure variable for abstinence. Logistic regression analyses were employed to identify determinants of quit attempt and survival analysis for the duration of abstinence. The adjusted analyses showed that those who received quit advice from doctors or healthcare providers had higher odds (2.11; CI 1.88-2.37) of quit attempts. Exposure to anti-smoking messages through media and warning labels was associated with higher quit attempt odds of 1.53 (1.33-1.77) and 1.63 (1.38-1.92), respectively, when the anti-smoking messages made the smokers think about quitting. The use of counselling as a cessation method had a lower risk (Hazard Ratio 0.80; 0.69-0.93) of relapse compared to the non-use of cessation aids. The use of counselling and modern pharmacotherapy also had a lower risk of relapse (Hazard Ratio 0.77; 0.59-0.99). However, only 6.0% had used counselling, and another 2.0% had used a combination of modern pharmacotherapy and counselling as cessation aids. Addiction to tobacco and higher consumption of smoked sticks were negatively associated with both outcomes. Quit advice by healthcare providers is associated with a higher likelihood of quit attempts. Counselling can help increase the period of abstinence in pragmatic settings, and there is a need to improve the access of smokers to counselling services.


Canine hip dysplasia: phenotypic scoring and the role of estimated breeding value analysis.
Canine hip dysplasia (CHD) is a developmental orthopaedic disease of the coxofemoral joints with a multifactorial mode of inheritance. Multiple gene effects are influenced by environmental factors; therefore, it is unlikely that a simple genetic screening test with which to identify susceptible individuals will be developed in the near future. In the absence of feasible methods for objectively quantifying clinical CHD, radiographic techniques have been developed and widely used to identify dogs for breeding which are less affected by the disease. A hip-extended ventrodorsal view of the pelvis has been traditionally used to identify dogs with subluxation and/or osteoarthritis of the coxofemoral joints. More recently, there has been emphasis on the role of coxofemoral joint laxity as a determinant of CHD and methods have been developed to measure passive hip laxity. Though well-established worldwide, the effectiveness of traditional phenotypic scoring schemes in reducing the prevalence of CHD has been variable. The most successful implementation of traditional CHD scoring has occurred in countries or breeding colonies with mandatory scoring and open registries with access to pedigree records. Several commentators have recommended that for quantitative traits like CHD, selection of breeding stock should be based on estimated breeding values (EBV) rather than individual hip score/grade. The EBV is a reflection of the genetic superiority of an animal compared to its counterparts and is calculated from the phenotype of an individual and its relatives and their pedigree relationship. Selecting breeding stock on the basis of a dog's genetic merit, ideally based on a highly predictive phenotype, will confer the breeder with greater selection power, accelerate genetic improvement towards better hip conformation and thus more likely decrease the prevalence of CHD.


Is children's acquisition of the passive a staged process? Evidence from six- and nine-year-olds' production of passives.
We report a syntactic priming experiment that examined whether children's acquisition of the passive is a staged process, with acquisition of constituent structure preceding acquisition of thematic role mappings. Six-year-olds and nine-year-olds described transitive actions after hearing active and passive prime descriptions involving the same or different thematic roles. Both groups showed a strong tendency to reuse in their own description the syntactic structure they had just heard, including well-formed passives after passive primes, irrespective of whether thematic roles were repeated between prime and target. However, following passive primes, six-year-olds but not nine-year-olds also produced reversed passives, with well-formed constituent structure but incorrect thematic role mappings. These results suggest that by six, children have mastered the constituent structure of the passive; however, they have not yet mastered the non-canonical thematic role mapping. By nine, children have mastered both the syntactic and thematic dimensions of this structure.


Application of physiological computational fluid dynamics models to predict interspecies nasal dosimetry of inhaled acrolein.
Acrolein is a highly soluble and reactive aldehyde and is a potent upper-respiratory-tract irritant. Acrolein-induced nasal lesions in rodents include olfactory epithelial atrophy and inflammation, epithelial hyperplasia, and squamous metaplasia of the respiratory epithelium. Nasal uptake of inhaled acrolein in rats is moderate to high, and depends on inspiratory flow rate, exposure duration, and concentration. In this study, anatomically accurate three-dimensional computational fluid dynamics (CFD) models were used to simulate steady-state inspiratory airflow and to quantitatively predict acrolein tissue dose in rat and human nasal passages. A multilayered epithelial structure was included in the CFD models to incorporate clearance of inhaled acrolein by diffusion, blood flow, and first-order and saturable metabolic pathways. Kinetic parameters for these pathways were initially estimated by fitting a pharmacokinetic model with a similar epithelial structure to time-averaged acrolein nasal extraction data and were then further adjusted using the CFD model. Predicted air:tissue flux from the rat nasal CFD model compared well with the distribution of acrolein-induced nasal lesions from a subchronic acrolein inhalation study. These correlations were used to estimate a tissue dose-based no-observed-adverse-effect level (NOAEL) for inhaled acrolein. A human nasal CFD model was used to extrapolate effects in laboratory animals to human exposure conditions on the basis of localized tissue dose and tissue responses. Assuming that equivalent tissue dose will induce similar effects across species, a NOAEL human equivalent concentration for inhaled acrolein was estimated to be 8 ppb.


Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors.
Dopamine D2 receptors (D2Rs) are of crucial importance in the striatal processing of motor information received from the cortex. Disruption of the D2R gene function in mice results in a severe locomotor impairment. This phenotype has analogies with Parkinson's disease symptoms. D2R-null mice were used to investigate the role of this receptor in the generation of striatal synaptic plasticity. Tetanic stimulation of corticostriatal fibers produced long-term depression (LTD) of EPSPs in slices from wild-type (WT) mice. Strikingly, recordings from D2R-null mice showed the converse: long-term potentiation (LTP). This LTP, unlike LTD, was blocked by an NMDA receptor antagonist. In magnesium-free medium, LTP was also revealed in WT mice and found to be enhanced by L-sulpiride, a D2R antagonist, whereas it was reversed into LTD by LY 17555, a D2R agonist. In D2R-null mice this modulation was lost. Thus, our study indicates that D2Rs play a key role in mechanisms underlying the direction of long-term changes in synaptic efficacy in the striatum. It also shows that an imbalance between D2R and NMDA receptor activity induces altered synaptic plasticity at corticostriatal synapses. This abnormal synaptic plasticity might cause the movement disorders observed in Parkinson's disease.