Development of a bead-based assay for detection and differentiation of field strains and four vaccine strains of type 2 porcine reproductive and respiratory syndrome virus (PRRSV-2) in the USA.
Porcine reproductive and respiratory syndrome (PRRS) remains one of the most economically devastating diseases in swine population in the United States of America. Due to high mutation rate of the PRRS virus (PRRSV) genome, it is difficult to develop an accurate diagnostic assay with high strain coverage. Differentiation of field strains from the four vaccines that have been used in the USA, namely Ingelvac PRRS MLV, Ingelvac ATP, Fostera PRRS and Prime Pac PRRS, adds an additional challenge. It is difficult to use current real-time PCR systems to detect and differentiate the field strains from the vaccine strains. Luminex xTAG technology allows us to detect more molecular targets in a single reaction with a cost similar to a single real-time PCR reaction. By analysing all available 678 type 2 PRRSV (PRRSV-2) complete genome sequences, including the 4 vaccine strains, two pairs of detection primers were designed targeting the conserved regions of ORF4-ORF7, with strain coverage of 98.8% (670/678) based on in silico analysis. The virus strains sharing ≥98% identity of the complete genomes with the vaccine strains were considered vaccine or vaccine-like strains. One pair of primers for each vaccine strain were designed targeting the nsp2 region. In silico analysis showed the assay matched 94.7% (54/57) of Ingelvac PRRS® MLV (MLV) strain and the MLV-like strains, and 100% of the other three vaccine strains. Analytical sensitivity of the Luminex assay was one to two logs lower than that of the reverse transcription real-time PCR assay. Evaluated with 417 PRRSV-2 positive clinical samples, 95% were detected by the Luminex assay. Compared to ORF5 sequencing results, the Luminex assay detected 92.4% (73/79) of MLV strains, 78.3% (18/23) of Fostera strains and 50% (2/4) of ATP strains. None of the 472 samples were the Prime Pac strain tested by either ORF5 sequencing or the Luminex assay.


Anomalous Dynamics of Concentrated Silica-PNIPAm Nanogels.
We present the structure and dynamics of highly concentrated core-shell nanoparticles composed of a silica core and a poly(N-isoproylacrylamide) (PNIPAm) shell suspended in water. With X-ray photon correlation spectroscopy, we are able to follow dynamical changes over the volume phase transition of PNIPAm at LCST = 32 °C. On raising the temperature beyond LCST, the structural relaxation times continue to decrease. The effect is accompanied by a transition from stretched to compressed exponential shape of the intensity autocorrelation function. Upon further heating, we find a sudden slowing down for the particles in their collapsed state. The q dependence of the relaxation time shows an anomalous change from τc ∝ q-3 to τc ∝ q-1. Small angle X-ray scattering data evidence a temperature-induced transition from repulsive to attractive forces. Our results indicate a temperature-induced phase transition from a colloidal liquid with polymer-driven dynamics toward a colloidal gel.


Naturally occurring food toxins.
Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States.


A biophysical analysis of the tetratricopeptide repeat-rich mitochondrial import receptor, Tom70, reveals an elongated monomer that is inherently flexible, unstable, and unfolds via a multistate pathway.
Proteins destined for all submitochondrial compartments are translocated across the outer mitochondrial membrane by the TOM (translocase of the outer membrane) complex, which consists of a number of specialized receptor subunits that bind mitochondrial precursor proteins for delivery into the translocation channel. One receptor, Tom70, binds large, hydrophobic mitochondrial precursors. The current model of Tom70-mediated import involves multiple dimers of the receptor recognizing a single molecule of substrate. Here we show via a battery of biophysical and spectroscopic techniques that the cytosolic domain of Tom70 is an elongated monomer. Thermal and urea-induced denaturation revealed that the receptor, which unfolds via a multistate pathway, is a relatively unstable molecule undergoing major conformational change at physiological temperatures. The data suggest that the malleability of the monomeric Tom70 receptor is an important factor in mitochondrial import.


B cell activation and the establishment of Epstein-Barr virus latency.
Linear EBV genomes undergo a transition to the circular form characteristic of latency by 16-20 h post-infection. This transition requires that the infected cells be activated to the G1 stage of the cell cycle. Cellular proliferation and expression of the activation marker CD23 were not required. Nevertheless, 36 h post-infection, only cells expressing CD23 contained covalently closed, circular episomes (CCC), at an average of one copy per cell. Since the presence of CD23 at this time is predictive that a cell will immortalize, we suggest that the presence of CCC is required for CD23 expression and subsequent immortalization. The one CCC present in each CD23+ cell did not undergo amplification until well after the cells had acquired all of the characteristic phenotypic markers of immortalization. Therefore, while amplification is not necessary for proliferation and immortalization, circularization of a single genome is crucial to the establishment and maintenance of latency by EBV.


Assessment of Myocardial Perfusion at Rest and During Stress Using Dynamic First-Pass Contrast-Enhanced Magnetic Resonance Imaging in Healthy Dogs.
Objective: To assess the feasibility of myocardial perfusion analysis in healthy dogs using dynamic contrast-enhanced cardiac magnetic resonance (DCE-MR) imaging at rest and during simulated stress with two doses of adenosine. Animals: Ten healthy beagle dogs. Procedures: Dogs were anesthetized and positioned in dorsal recumbency in a 3.0 Tesla MR scanner. Electrocardiogram-triggered dynamic T1-weighted ultrafast gradient echo images of three slices in short-axis orientation of the heart were acquired during breath holds and the first pass of gadolinium contrast. Image acquisition was performed after 4 min infusion of 140 μg/kg/min and 280 μg/kg/min adenosine and, after a washout period, without adenosine, respectively. Images were processed by dividing each slice into 6 radial segments and perfusion analysis was performed from signal intensity-time data. Results: No differences in perfusion parameters were found between segments within any of the slices, but significant differences were found between slices for peak enhancement, accumulated enhancement, and the maximum upslope. In addition, significant differences were found within each slice between data at rest and during adenosine-induced stress for the relative and absolute maximum upslope, relative peak enhancement, time to peak, and accumulated enhancement although inter-individual variation was large and no difference was found between the two stress tests for some parameters. Conclusion and Clinical Relevance: Results of this study showed that rest and stress myocardial perfusion can be assessed using DCE-CMR in dogs using the methods described. Both, adenosine dose and slice appear to affect perfusion parameters in healthy dogs and individual response to adenosine was variable.


[Chagas disease: impact of Triatoma infestans control program in Alto del Carmen, Huasco Province, III Region Atacama, Chile].
A control program of Triatoma infestans has been carried out in Alto del Carmen, an endemic chagasic rural county in the III Region, Chile. The program started in 1988 with an attack phase consisting in a masshouse spraying with residual insecticide, followed by an entomological surveillance phase with health education for community participation and vector detection in eventually reinfested houses. A yearly evaluation in 1992, 1993, 1994 and 1995 was carried out in order to determine the effectiveness of vector control activities. In 1992, 24.1% of dwellings was infested, whereas in 1993, 1994 and 1995 the infestation rates were 3.9%, 2.8% and 4.0% respectively. The similar infestation rates found in 1993, 1994 and 1995 suggest passive dispersion of triatomas from areas without surveillance. Additionally, in 1994, 110 (16.0%) out of 688 examined people resulted serologically positive. It is noteworthy that all of the children in the 0-4 year age group--born after the attack phase--resulted serologically negative. This fact may indicate the interruption of vectorial transmission of Chagas' disease in Alto del Carmen county. It is concluded that the control activities performed in the county constitute good strategies to the Nacional Program of Control of T. infestans, but for the success of such a program it is necessary to integrate the efforts of all endemic areas with an active community participation.


Molecular cloning of a human rotavirus genome.
The genes of a field isolate of human rotavirus were cloned into pBR322. The strategy used involved polyadenylation of denatured double-stranded (ds) genomic RNA, followed by cDNA synthesis using reverse transcriptase. Oligo(dC) tails were added to the 3' end of the single-stranded cDNA and then separated by alkaline agarose electrophoresis. Sized cDNA of both polarities were allowed to hybridize and inserted into the PstI site of pBR322. Transformations done with sized cDNA always resulted in the selection of hybrid plasmids carrying inserts with a size representative of the original cDNA. Four individual clones were selected for preliminary characterization. One clone has an insert of 1360 base pairs (bp) and corresponds to gene 6. The second clone has an insert of 1140 bp and corresponds to one of the genes in the triplet 7-8-9. The other two genes, with inserts of 780 and 660 bp, were identified as corresponding to dsRNA segments 10 and 11.


Positive Mental Health from the perspective of Iranian society: A qualitative study.
Background: According to the World Health Organization, mental health relates, not only to the absence of mental disorder, but also to Positive Mental Health. Studies have shown that promoting positive mental health, not only reduces the prevalence and incidence of mental disorders, but also affects the process of treatment and reduces related burden. However, this concept has different interpretations in different cultures, and in many societies, mental health is still considered the absence of mental illness. Thus, the present study was conducted to provide an in-depth understanding of Iranian adults` perspective towards the concept of positive mental health. Materials and Methods: In the present qualitative study, eight focus group discussions (6 to 8 adults in each session) were held consisting of 30 to 60 year-old men and women from Tehran. Data were analyzed in "DeDoose" qualitative software using content analysis. Results: According to the data obtained, participants found no difference between positive mental health and mental health, mostly equating it to the absence of mental disorders and having positive energy, peace in and satisfaction with life. According to the results, positive mental health has four domains of emotional/psychological, spiritual, social, and life skills. Conclusion: Understanding an individual's positive mental health concepts culturally and providing appropriate community based programs can significantly promote the mental health of the community.


"The beginning of health is to know the disease".
There is public impatience over the pace of medical progress. Some say prevention and health have not been well served by the research community. Rather than devising extended investigations, scientists should apply now what we know now. Activists argue that, although research on a better understanding of disease must continue, a companion effort to develop strategies for health promotion and disease prevention should exist. The national effort should emphasize "health" and not "disease," as the names of the various NIH Institutes would imply. I disagree with that proposed direction of prevention research. It is not possible to divorce research on health from research on disease. Are the secrets of nature open to us through mere observation? Does not research require the perturbation of a system in order to make valid observations on the nature of that system? This, after all, is the nature of the scientific method. Disease is, itself, a perturbation of the state of health and it is through our research on disease that we learn how to prevent it. I believe that the National Institutes of Health does devote equal time to the study of health. For it is my thesis that by studying disease we have, in fact, given our total time to the study of health. "The beginning of health is to know the disease."


Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency.
The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.


The C-terminal domain of the adenomatous polyposis coli (Apc) protein is involved in thyroid morphogenesis and function.
Adenomatous polyposis coli (APC) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of Apc, we have investigated Apc ( 1638T/1638T ) mice, which express a truncated Apc that lacks the C-terminal domain. Apc ( 1638T/1638T ) mice are tumor free and exhibit growth retardation. In the present study, we analyzed the morphology and functions of the thyroid gland in Apc ( 1638T/1638T ) mice. There was no significant difference in the basal concentration of serum thyroid hormones between Apc ( 1638T/1638T ) and Apc (+/+) mice. Thyroid follicle size was significantly larger in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. The extent of serum T4 elevation following exogenous thyroid-stimulating hormone (TSH) injection was lower in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. TSH also induced a greater reduction in thyroid follicle size in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. Analyses using immunohistochemistry and electron microscopy indicated that follicular epithelial cells in Apc ( 1638T/1638T ) mice had an enlarged rough endoplasmic reticulum of irregular shape. These results suggest that the C-terminal domain of Apc is involved in thyroid morphology and function.


Role of the cellular matrix in haemopoiesis. I. Synthesis of glycosaminoglycans by mouse bone marrow cell cultures.
Haemopoietically active mouse bone marrow cultures, incubated for 48 h with [3H]glucosamine and Na2(35)SO4, synthesized radiolabelled hyaluronic acid, heparan sulphate and chondroitin sulphate. Heparan sulphate was enriched in a trypsin extract of the adherent cells whereas hyaluronic acid and chondroitin sulphate were distributed mainly to the culture medium. Analysis of nitrous acid scission products of heparan sulphate by gel chromatography demonstrated the close association of N- and O-sulphate groups along the polysaccharide chain. Chondroitinase AC degradation established the copolymeric nature of chondroitin sulphate in which about 38% of the hexuronic acid residues were in the form of GlcUA. Studies on non-haemopoietic cultures, derived from W/Wv mice or from normal marrow cells maintained in foetal calf serum instead of horse serum, indicated that adherent stromal cells were the major source of glycosaminoglycans.


Darier's disease and vitamin A. Concentrations of retinoids in serum and epidermis of untreated patients.
Blood samples and skin biopsy specimens from 13 male patients with Darier s disease (DD) and 11 healthy male controls were analyzed for carotene, retinol (vitamin A), dehydroretinol (vitamin A2), and retinol-binding protein (RBP). The serum carotene level was lower in the patients than in the controls, but the vitamin A and RBP levels did not differ from those of the controls regardless of the severity of the disease. The RBP could be visualized by immunofluorescence microscopy in the epidermis of both unaffected and lesional skin of patients with DD. In the epidermis of patients with DD (uninvolved and lesional), the carotene content was similar to that of the controls. The retinol content was probably higher than in the controls. By contrast, the dehydroretinol concentration was normal in the uninvolved skin but markedly higher than normal in the lesions, especially in the severe cases. The abnormal distribution of retinoids in DD may reflect localized disturbances of epidermal vitamin A metabolism rather than a defect in serum vitamin A transport.


Leukotriene biosynthetic enzymes as therapeutic targets.
Leukotrienes are powerful immune-regulating lipid mediators with established pathogenic roles in inflammatory allergic diseases of the respiratory tract - in particular, asthma and hay fever. More recent work indicates that these lipids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, and metabolic diseases as well as cancer. Biosynthesis of leukotrienes involves oxidative metabolism of arachidonic acid and proceeds via a set of soluble and membrane enzymes that are primarily expressed by cells of myeloid origin. In activated immune cells, these enzymes assemble at the endoplasmic and perinuclear membrane, constituting a biosynthetic complex. This Review describes recent advances in our understanding of the components of the leukotriene-synthesizing enzyme machinery, emerging opportunities for pharmacological intervention, and the development of new medicines exploiting both antiinflammatory and pro-resolving mechanisms.


Major neurovascular complications of clavicle fracture surgery.
Clavicle fracture fixation is becoming an increasingly common operation, with good clinical outcomes and a low rate of significant complications. However, there are several reports of rare but potentially life or limb threatening, neurovascular complications. Arterial injuries are usually pseudoaneurysms associated with prominent screws. These may be clinically silent for several years before presenting as subcritical upper limb ischaemia. Venous injuries are a result of tearing of the vessel wall by fracture manipulation, drills or implants. This produces intra-operative haemorrhage and potentially air embolism, which can be fatal if not rapidly recognized and managed. Brachial plexopathy is the result of traction on adherent plexus or impingement by fracture fragments or callus. It presents as severe arm pain and paralysis immediately postoperatively. Neurovascular injuries can be avoided by a combination of pre-operative planning, communication with anaesthetic staff and strategic surgical technique. The plane of the surgical exposure, release of the soft tissues, drill direction and depth and screw length are all important factors.


Influence of pre-treatment bacillary load on treatment outcome of pulmonary tuberculosis patients receiving DOTS under revised national tuberculosis control programme.
To study the influence of initial bacillary load on sputum conversion rates and treatment outcome of new smear positive pulmonary tuberculosis patients. A retrospective study was done among 2938 new smear positive pulmonary tuberculosis patients, registered at the peripheral centres, covering a population of 1.6 million in Delhi, India. The patients pre-treatment sputum smears were graded as 1+, 2+ or 3+ based on three samples. Patients were given intermittent short-course chemotherapy under supervision and the treatment outcome was analysed. Sputum conversion rates among patients graded as sputum 3+ and rest of the patients (combined graded sputum 1+ and 2+) at the end of two months were 62.2% and 76.8% respectively (p<0.001), and at the end of three months were 81.3% and 89.5% respectively (p<0.001). Cure rates among same group of patients were 76.6% and 85.1% respectively (p<0.001), and failure rates were 7.7% and 4.5% respectively (p<0.001). Under field conditions even with directly observed treatment (DOT) new smear positive patients with heavy bacillary load showed statistically significant poor sputum conversion rates at two and three months and higher failure rates as compared to patients with lesser bacillary load. To investigate possible reasons for this poor response and possible solutions further studies are needed.


Aspiration of parenteral nutrition -- a previously unreported complication of central venous access in an infant: a case report.
The insertion of percutaneous central venous catheters is a common procedure in neonatal intensive care nurseries. Placement of the catheter tip in a large central vein is most desirable. Occasionally, due to difficult venous access, catheter tips are left in places that are less than ideal. A female infant with a complicated gastroschisis developed signs of short bowel syndrome post surgery. She was treated with a combination of parenteral nutrition and enteral feeds. A central venous line was inserted through a scalp vein. The tip was noted to be in a vessel at the level of the mandible. She subsequently became unwell with large milky pharyngeal aspirates and episodes of bradycardia. Chest radiography revealed aspiration. The central venous line was removed because of presumed extravasation. This is the first reported case of parenteral nutrition extravasation into the pharynx causing aspiration in an infant. This complication may have been prevented by recognising that the tip of the catheter was not correctly placed. When catheters are in unusual positions it may be useful to obtain a second radiograph from a different angle or an ultrasound scan to confirm the positioning of the catheter tip.


Nonsteroidal anti-inflammatory drugs and the gut.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory, and antithrombotic indications. Such use carries the risk of significant side effects on nontarget organs, especially the gut. Some of these effects may be serious, especially among the elderly, whose NSAID use is proportionately greatest. Upper gastrointestinal mucosal lesions range from trivial (petechiae and superficial erosions) to significant and potentially serious (chronic peptic ulcers, esophagitis, and small and large gut ulcers). The most serious side effects are perforation of peptic or gut ulcers and gastrointestinal bleeding, which NSAIDs may promote from both ulcerous and nonulcerous lesions of both the upper and lower gastrointestinal tract, ie, both acid-dependent and non-acid-dependent. Symptoms may be independent of observable lesions, and serious lesions may occur without previous symptoms. NSAIDs may also delay healing of peptic ulcers, even to the extent of intractability, and may cause recurrence after gastric surgery. Until we can separate the mechanisms whereby NSAIDs both cause injury and provide therapeutic benefits, the problem of side effects and their prevention or treatment remains unresolvable.


The role of the cilium in hereditary tumor predisposition syndromes.
The primary cilium is a highly conserved cell organelle that is closely connected to processes involved in cell patterning and replication. Amongst their many functions, cilia act as "signal towers" through which cell-cell signaling cascades pass. Dysfunction of cilia or the myriad processes that are connected with cilium function can lead to disease. Due to the sheer number of cellular processes that at some point involve the primary cilium, the effects of misregulation are highly heterogeneous between different cell populations. However, because of the importance of primary cilia in the development, growth, patterning and orientation of cells and tissues, a common thread has emerged in which defective cilia can lead to disorganization, which can contribute to the growth of neoplasms, including cancer and pre-cancerous phenotypes. Because cilia are so vital for signaling during cell replication and the cell fate decisions that are important in childhood growth, symptoms often arise early in life. Here we review recent work connecting misregulation of the primary cilium with tumor formation in a variety of tissues in the developing body, with a particular focus on the syndromes in which classic tumor genes are mutated, including von Hippel-Lindau disease (OMIM 193300), adenomatous polyposis coli (OMIM 175100), tuberous sclerosis (OMIM 191100) and Birt-Hogg-Dubé syndrome (OMIM 135150). Timely diagnosis of these syndromes is essential for entry into appropriate screening protocols, which have been shown to effectively prolong life expectancy in these cohorts of patients.


Glutathione transferase P1-1: self-preservation of an anti-cancer enzyme.
Self-preservation is a typical property of living organisms, observed in the simplest prokaryotic cell as well as in the more complex pluricellular organisms. Surprisingly we found a self-preservation mechanism operating at the level of a single enzyme. Human glutathione transferase P1-1 operates in such a way towards either killer compounds (competitive and irreversible inhibitors) or physical factors (temperature and UV-rays), which could suppress its detoxicating and anti-cancer activity in the cell. This property, here termed 'co-operative self-preservation', is based on a structural intersubunit communication, by which one subunit, as a consequence of an inactivating modification, triggers a defence arrangement in the other subunit. Paradoxically this ability, developed during evolution for the survival of the cell, may not always be advantageous for us. In fact, glutathione transferase P1-1 is overexpressed in most tumour cells and pharmacological attempts to inhibit this enzyme in vivo, to prevent the drug resistance phenomenon during chemotherapy, may be thwarted by such self-preservation.


Blueprints in Sweden. Symptom load in Swedish adolescents in studies of Functional Family Therapy (FFT), Multisystemic Therapy (MST) and Multidimensional Treatment Foster Care (MTFC).
The purpose of the present study was to compare symptom load in youth groups treated with three Swedish Blueprint programmes - Functional Family Therapy (FFT), Multisystemic Therapy (MST) and Multidimensional Treatment Foster Care (MTFC) - to see if symptom load matches the intensity of the treatment model as expected. These youth groups were also compared with in- and outpatients from child and adolescent psychiatry, and a normal comparison group. In addition, we compared the symptom load of their mothers. Symptom load was measured by the Achenbach System of Empirically Based Assessment (ASEBA) in the adolescents, and by the Symptom Checklist 90 in their mothers. The results showed that youth in the MST and MTFC studies had a higher symptom load than in the FFT study, and the same pattern of results was found in their mothers. It is concluded that there seems to be a reasonable correspondence between the offered resources and the symptom load among youth and parents; treatment methods with higher intensity have been offered to youth with higher symptom load. The correlation between internalized and externalized symptoms was high in all study groups. The MST and MTFC groups had an equally high total symptom load as the psychiatric inpatient sample.


Changes in liver function parameters after percutaneous radiofrequency ablation therapy in patients with hepatocellular carcinoma.
To evaluate changes in liver function parameters and risk factors 1 year after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC). Subjects in this retrospective study comprised 45 patients with HCC who underwent RFA therapy (RFA alone, n = 25; transcatheter arterial embolization therapy before RFA, n = 20) and showed no recurrence of HCC 1 year after RFA. Serial changes in serum total bilirubin, albumin, prothrombin time and Child-Pugh score (CPs) were evaluated before and after RFA. In addition, Cox proportional hazards regression analysis was used to clarify risk factors for aggravation of liver function after RFA therapy. Serum albumin levels showed a significant decrease from before (3.6 +/- 0.4 g/dL) to 12 months after RFA therapy (3.2 +/- 0.4 g/dL; P </= 0.05). CPs was significantly increased from before (6.4 +/- 1.4) to both 6 months (6.8 +/- 1.9; P </= 0.05) and 12 months after RFA (6.9 +/- 2.0; P </= 0.05). Based on stepwise multivariate analysis, CPs of 9 or more before RFA was selected as a significant risk factor for long-term aggravation of liver function after RFA. Liver function parameters, particularly serum albumin level, gradually and dominantly decreased in HCC patients with grade B and C according to the CPs classification over the course of 1 year after RFA therapy. A CPs of 9 or more represents a major risk factor for the aggravation of liver function after RFA therapy.


Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.
Midazolam kinetics and psychomotor function were studied after an intravenous dose of 0.075 mg/kg body weight in seven patients with alcoholic cirrhosis and eight control patients. Four of the seven cirrhotics died of complications of their liver disease within six months of the study. The metabolism of midazolam was significantly impaired in the cirrhotic patients (p less than 0.025). These patients also had evidence of greater sedation than the control group for up to six hours after the dose was administered (p less than 0.05). The clearance of midazolam did not correlate significantly with the serum albumin, or bilirubin, or with the kinetics of antipyrine, or indocyanine green. This study shows significant delay in the elimination of midazolam and decreased psychomotor function in patients with severe alcoholic liver disease. Caution is needed in using this drug for premedication in such patients before endoscopy.


Fibrinolytic activity of carcinoma of the colorectum.
Twenty patients with carcinoma, mostly of the colorectum, and five without malignant tumors who were used as controls, have been investigated to elucidate the relationship between tumor fibrinolytic activity and the release of circulating malignant cells. The nature of the tumor fibrinolytic activity has been considered. The most significant fibrinolytic activity was seen in blood draining from the tumors and was evident in 80 per cent. Circulating malignant cells were recovered from half the patients, and in those with significant blood fibrinolysis, recovery from the draining vein reached 89 per cent. The most undifferentiated tumors appeared to be more active and released more cells. Fibrinolytic activity of tumor tissue derives from inflammatory cells, dead tumor cells, avascular areas of the tumor and vascular endothelium and is probably proteolytic as well as purely fibrinolytic.


QALYs and rare diseases: exploring the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing for childhood and adult-onset rare genetic conditions in Australia.
Genomic testing transforms the diagnosis and management of rare conditions. However, uncertainty exists on how to best measure genomic outcomes for informing healthcare priorities. Using the HTA-preferred method should be the starting point to improve the evidence-base. This study explores the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing across childhood and adult-onset genetic conditions. Self-reported patient-reported outcomes (PRO) were obtained from: primary caregivers of children with suspected neurodevelopmental disorders (NDs) or genetic kidney diseases (GKDs) (carers' own PRO), adults with suspected GKDs using SF-12v2; adults with suspected complex neurological disorders (CNDs) using EQ-5D-5L; and adults with dilated cardiomyopathy (DCM) using AQol-8D. Responsiveness was assessed using the standardised response mean effect-size based on diagnostic (having a confirmed genomic diagnosis), personal (usefulness of genomic information to individuals or families), and clinical (clinical usefulness of genomic information) utility anchors. In total, 254 people completed PRO measures before genomic testing and after receiving results. For diagnostic utility, a nearly moderate positive effect size was identified by the AQoL-8D in adult DCM patients. Declines in physical health domains masked any improvements in mental or psychosocial domains in parents of children affected by NDs and adult CNDs and DCM patients with confirmed diagnosis. However, the magnitude of the changes was small and we did not find statistically significant evidence of these changes. No other responsiveness evidence related to diagnostic, clinical, and personal utility of genomic testing was identified. Generic PRO measures may lack responsiveness to the diagnostic, clinical and personal outcomes of genomics, but further research is needed to establish their measurement properties and relevant evaluative space in the context of rare conditions. Expected declines in the physical health of people experiencing rare conditions may further challenge the conventional application of quality of life assessments.


Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice.
Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse haemodynamic effects. We hypothesised that inhaled PDE5 inhibitors are able to restore ion transport in F508del CF airway epithelium. We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulised for 15 min at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 h after a single inhalation of sildenafil, vardenafil or tadalafil in F508del CF and normal homozygous mice. After nebulisation with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalised; the forskolin response was increased, with the largest values being observed with tadalafil and intermediate values with vardenafil. No detectable effect was observed on sodium conductance. Our results confirm the role of PDE5 inhibitors in restoring chloride transport function of F508del CF transmembrane conductance regulator protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.


[Programs for optimizing the use of antibiotics (PROA) in Spanish hospitals: GEIH-SEIMC, SEFH and SEMPSPH consensus document].
The antimicrobial agents are unique drugs for several reasons. First, their efficacy is higher than other drugs in terms of reduction of morbidity and mortality. Also, antibiotics are the only group of drugs associated with ecological effects, because their administration may contribute to the emergence and spread of microbial resistance. Finally, they are used by almost all medical specialties. Appropriate use of antimicrobials is very complex because of the important advances in the management of infectious diseases and the spread of antibiotic resistance. Thus, the implementation of programs for optimizing the use of antibiotics in hospitals (called PROA in this document) is necessary. This consensus document defines the objectives of the PROA (namely, to improve the clinical results of patients with infections, to minimise the adverse events associated to the use of antimicrobials including the emergence and spread of antibiotic resistance, and to ensure the use of the most cost-efficacious treatments), and provides recommendations for the implementation of these programs in Spanish hospitals. The key aspects of the recommendations are as follows. Multidisciplinary antibiotic teams should be formed, under the auspices of the Infection Committees. The PROA need to be considered as part of institutional programs and the strategic objectives of the hospital. The PROA should include specific objectives based on measurable indicators, and activities aimed at improving the use of antimicrobials, mainly through educational activities and interventions based more on training activities directed to prescribers than just on restrictive measures.


Effects of a progressive aquatic resistance exercise program on the biochemical composition and morphology of cartilage in women with mild knee osteoarthritis: protocol for a randomised controlled trial.
Symptoms associated with osteoarthritis of the knee result in decreased function, loss of working capacity and extensive social and medical costs. There is a need to investigate and develop effective interventions to minimise the impact of and even prevent the progression of osteoarthritis. Aquatic exercise has been shown to be effective at reducing the impact of osteoarthritis. The purpose of this article is to describe the rationale, design and intervention of a study investigating the effect of an aquatic resistance exercise intervention on cartilage in postmenopausal women with mild knee osteoarthritis. A minimum of 80 volunteers who meet the inclusion criteria will be recruited from the local population through newspaper advertisements. Following initial assessment volunteers will be randomised into two groups. The intervention group will participate in a progressive aquatic resistance exercise program of 1-hour duration 3 times a week for four months. The control group will be asked to maintain normal care during this period. Primary outcome measure for this study is the biochemical composition of knee cartilage measured using quantitative magnetic resonance imaging; T2 relaxation time and delayed gadolinium-enhanced magnetic resonance imaging techniques. In addition, knee cartilage morphology as regional cartilage thickness will be studied. Secondary outcomes include measures of body composition and bone traits using dual energy x-ray absorptiometry and peripheral quantitative computed tomography, pain, function using questionnaires and physical performance tests and quality of life. Measurements will be performed at baseline, after the 4-month intervention period and at one year follow up. This randomised controlled trial will investigate the effect a progressive aquatic resistance exercise program has on the biochemical composition of cartilage in post-menopausal women with mild knee osteoarthritis. This is the first study to investigate what impact aquatic exercise has on human articular cartilage. In addition it will investigate the effect aquatic exercise has on physical function, pain, bone and body composition and quality of life. The results of this study will help optimise the prescription of aquatic exercise to persons with mild knee osteoarthritis. ISRCTN65346593.


Monolithically integrated multi-wavelength VCSEL arrays using high-contrast gratings.
We propose a novel design for multi-wavelength arrays of vertical cavity surface-emitting lasers (VCSELs) using high-contrast gratings (HCGs) as top mirrors. A range of VCSEL cavity wavelengths in excess of 100 nm is predicted by modifying only the period and duty-cycle of the high-contrast gratings, while leaving the epitaxial layer thickness unchanged. VCSEL arrays fabricated with this novel design can easily accommodate the entire Er-doped fiber amplifier bandwidth with emission wavelengths defined solely by lithography with no restrictions in physical layout. Further, the entire process is identical to that of solitary VCSELs, facilitating cost-effective manufacturing.


[Puncture vertebroplasty in aggressive hemangiomas of the vertebrae bodies].
The paper presents the results of treatment in 15 patients with aggressive hemangiomas of the vertebral bodies, operated on by puncture vertebroplasty. The authors analyze current approaches to treating patients with this pathology, present criteria for aggressiveness of hemangiomas. The results of the treatment indicate that puncture vertebroplasty is highly effective and safe in treating patients with hemangiomas of the vertebral bodies.


Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery.
The contributions of acetylcholine and/or nitric oxide (NO) to the rapid changes in human forearm blood flow (FBF) at the onset and recovery from mild exercise were studied in eight subjects. Rhythmic handgrip contractions were performed during brachial artery infusions of saline (2 ml/min; control), atropine (0.2 mg over 3 min), to block acetylcholine binding to muscarinic receptors, or atropine + NG-monomethyl-L-arginine (L-NMMA; 4 mg/min for 4 min), to additionally inhibit NO synthase. Brachial artery mean blood velocity (MBV; pulsed Doppler ultrasound) and diameter (echo Doppler) were measured continuously, and FBF was calculated. Atropine reduced acetylcholine-induced increases in FBF by approximately 71% (P < 0.05). FBF at rest was reduced by atropine and further reduced with atropine + L-NMMA. Both drug conditions reduced FBF during exercise by approximately 10% compared with control, with no difference between drug treatments. Brachial artery diameter was unchanged from rest by exercise, recovery, and drug treatments. Neither drug treatment altered the rate or magnitude of the increase in FBF above rest. Peak FBF after exercise was reduced by atropine and atropine + L-NMMA. Total FBF during 5 min of recovery was reduced with atropine + L-NMMA compared with control and atropine. The results suggest that 1) acetylcholine and NO mechanisms additively contribute to FBF levels at rest, 2) a cholinergic mechanism adjusts the absolute FBF levels during exercise, 3) neither acetylcholine nor NO is essential to observe the normal time course or magnitude of the exercise response, and 4) NO contributes to the FBF response during recovery from exercise.


The effect of producer groups on the productivity and technical efficiency of smallholder cocoa farmers in Ghana.
Producer groups are influential in Ghana's cocoa value chain. They facilitate training, extension, education and inputs to their members. Still, there is no study on the impact of these producer groups on the technical efficiency and productivity of smallholder cocoa farmers. Using data from 217 and 199 members and non-members of cocoa producer groups, this study aimed to analyse producer groups' impact on smallholder farmers' technical efficiency and yield. The truncated normal distribution stochastic frontier model was adopted to estimate the farmers' technical efficiency. Since the model showed an issue of inefficiency among the farmers, we added socio-demographic and institutional variables to account for determinants of inefficiency. Finally, we adopted an endogenous treatment regression model to analyse producer groups' impact on the farmers' technical efficiency by accounting for observed and unobserved biases. The study results show that farm size, labour, and capital significantly positively impact the partial elasticity of production. Age, education, use of hybrid cocoa, involvement in off-farm jobs, extension access, and producer group membership significantly affect inefficiency. The results further show that producer group membership significantly impacts technical efficiency and yield from the endogenous treatment regression model. To deal with the issues of non-participating in the producer groups, the study recommends that producer groups should be made accessible to farmers. Policymakers can promote the formation and strengthening of producer groups, leading to improved productivity and technical efficiency among cocoa farmers. This approach empowers farmers, enhances their access to resources and knowledge, and enables them to collectively address common challenges, ultimately contributing to sustainable cocoa production and better livelihoods for cocoa farming communities.


Activation of tyrosine kinases in cancer.
Receptor and nonreceptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating certain types of cancer. Epidermal growth factor receptor (EGFR)-TK is a transmembrane receptor TK that is overexpressed or aberrantly activated in the most common solid tumors, including non-small cell lung cancer and cancers of the breast, prostate, and colon. Activation of the EGFR-TK enzyme results in autophosphorylation, which drives signal transduction pathways leading to tumor growth and malignant progression. Randomized clinical trials of the EGFR-TK inhibitor gefitinib have demonstrated clinical benefits in patients with advanced non-small cell lung cancer whose disease had previously progressed on platinum- and docetaxel-based chemotherapy regimens. Bcr-Abl is a constitutively activated nonreceptor TK enzyme found in the cytoplasm of Philadelphia chromosome-positive leukemia cells. STI571 (imatinib mesylate) inhibits the Bcr-Abl TK, blocks the growth of these leukemia cells, and induces apoptosis. STI571 also inhibits other TKs, including the receptor TK c-kit, which is expressed in gastrointestinal stromal tumors. As TK inhibitors become available for clinical use, new challenges include predicting which patients are most likely to respond to these targeted TK inhibitors. Additional clinical trials are needed to develop the full potential of receptor and nonreceptor TK inhibitors for cancer treatment.


Relationship of lymphocytotoxic antibodies to lymphopenia and parameters of disease activity in systemic lupus erythematosus.
Peripheral blood lymphocyte subpopulations determined in 40 patients with systemic lupus erythematosus, revealed significant lymphopenia in comparison to normal controls. The lymphopenia was caused by decreases in the absolute numbers of both T cells and surface immunoglobulin bearing (SIg) cells. There were significant percentage decreases in T cells and normal percentages of SIg cells, resulting in an increased percentage of "null" cells. The lymphopenia was significantly greater in patients considered to have active disease on the basis of clinical parameters, and was strongly correlated with lymphocytotoxic antibodies, DNA antibodies, and hypocomplementemia. The lymphocytotoxic antibodies were reactive with both T and B lymphocytes from normal and ill donors, human organs, and various lymphoblastoid cell lines. In 30 patients who were followed for up to 22 months, the lymphopenia was clearly seen to develop during, but not before, periods of clinical disease activity, independent of changes in therapy.


Dynamic cytoskeleton rearrangements in giant cells and syncytia of nematode-infected roots.
Giant cells induced by root knot nematodes and syncytia caused by cyst nematodes are large multinucleated feeding cells containing a dense cytoplasm generated during a complex host-parasite association in plant roots. To find out whether cytoskeleton changes occurred during feeding cell development, transcriptional activity of actin (ACT) and tubulin genes and organization of the ACT filaments and of the microtubules (MTs) were analyzed in situ. The importance of changes in the cytoskeleton architecture for the proper initiation and development of galls and syncytia was demonstrated by perturbing the cytoskeleton with chemical inhibitors. The expression levels of cytoskeletal components, such as tubulins and ACTs, are proposed to be upregulated to allow the assembly of a new cytoskeleton in expanding feeding cells. However, MTs and ACT filaments failed to properly organize and appeared partially depolymerized throughout feeding site development. Both the actin and tubulin cytoskeletons were strongly disrupted in syncytia and mitotic figures were never observed. In contrast, in giant cells, an ACT and cortical MT cytokeleton, although disturbed, was still visible. In addition, a functional mitotic apparatus was present that contained multiple large spindles and arrested phragmoplasts, but no pre-prophase bands. Chemical stabilization of the microtubular cytoskeleton with taxol blocked feeding site development. On the other hand, when the ACT or MT cytoskeleton of feeding cells was depolymerized by cytochalasin D or oryzalin, nematodes could complete their life cycle. Our data suggest that the cytoskeleton rearrangements and depolymerization induced by parasitic nematodes may be essential for a successful feeding process.


Differences in quality of life between infertile women and men in Turkey.
To examine potential differences in quality of life between infertile women and men. A descriptive, cross-sectional design. A questionnaire was used to collect individuals' sociodemographic data; the World Health Organization Quality of Life-BREF (WHOQOL-BREF) tool was used to collect information about quality of life. The research sample comprised 248 infertile individuals (141 women and 107 men) admitted to the clinic for the first time for diagnosis and treatment between January 1 and June 30, 2007, and who voluntarily agreed to participate. The research was conducted at the Ege University Family Planning and Infertility Research and Training Center Infertility Clinic in Izmir, Turkey. Physical health, psychological health, and social relations domain score means did not show significant differences between infertile women and infertile men (p>.05). However, score means for the environment domain were significantly higher (p<.05) for infertile women than for infertile men. Unemployed infertile men had significantly lower score means in the physical health and social relation domains (p<.01). No such significant differences were found for the other quality of life domain scores for infertile women or infertile men (p>.05). In the environmental domain, the quality of life of infertile women was greater than that of infertile men. Variables affecting quality of life of infertile individuals were seen to affect women and men in similar ways. Nurses and health care professionals caring for infertile individuals should be aware of the factors that affect quality of life and should plan to meet their care needs accordingly.


Rapid Effect of Nitrogen Supply for Soybean at the Beginning Flowering Stage on Biomass and Sucrose Metabolism.
Nitrogen application at the beginning flowering stage (R1 stage) increased the soybean grain yield, however, the rapid effect of enriched nitrogen at R1 growth stage on soybean dry matter accumulation and sugar metabolism is still unclear. Continuous high nitrogen (CHN), Continuous low nitrogen (CLN), Enriched nitrogen supply at R1 stage (ENS) treatments were applied on two soybean cultivars (Liaodou11, Liaodou14), to investigate the effect of enriched nitrogen on plant biomass accumulation and sucrose metabolism. After 12 h of ENS treatment, the root/shoot rate of both cultivars were lower than that of CLN, but at 24 h it was no significant difference between ENS and CLN. Enriched N at R1 stage, soybean kept a balance of sucrose synthesis and decomposition in leaf by affecting sucrose synthetase (SS) and sucrose phosphate synthase (SPS) activities. Under N limitation condition the plant dry matter accumulation supported root growth priority. Enriched N at R1 stage resulted in the rapid shoot biomass accumulation. In high yield cultivar, the shoot growth was priority to root growth, the common yield cultivar was on the contrary. Our result suggest that enrich N at R1 stage resulted in the accumulation of biomass in shoot rapidly.


Analysis of seasonal influenza vaccine uptake among children and adolescents with an intellectual disability.
The aim of the present study was to describe the seasonal influenza vaccination rate and to examine its determinants for children and adolescents with intellectual disabilities (ID) living in the community. A cross-sectional survey was conducted to analyze the data on seasonal influenza vaccination rate among 1055 ID individuals between the ages of 12-18 years. The results found that 22.9% of the study participants used the vaccine during the past three years, and the vaccination rate among different age groups varied from 18.1 to 26.5%. There was no gender difference of seasonal influenza vaccination rate among age groups. Multilevel logistic regression analysis revealed that ID individuals with moderate (OR = 1.59, 95% CI = 1.08-2.34) or severe (OR = 2.31, 95% CI = 1.20-4.45) disability, with an illness (OR = 1.64, 95% CI = 1.02-2.63), who have general health exams (ever used, OR = 1.57, 95% CI = 1.03-2.40; regularly used, OR = 1.89, 95% CI = 1.05-3.41) were more likely to have seasonal influenza vaccination than their counterparts. The present study highlights that the substantial disparity in receipt of seasonal influenza vaccine in children and adolescents with ID reflects the effects of disability level, disease condition, and general health exam experience and suggests the need for greater attention to factors affecting ID individuals to improve their preventive health care.


Excretory role of the midgut in larvae of the tobacco hornworm, Manduca sexta (L.).
Caterpillars of Manduca sexta use two distinct transport mechanisms for the excretion of dyes. One pump (Type A) has a high affinity for acid (anionic) dyes and occurs in the midgut and medial Malpighian tubules. Acid dyes accumulate rapidly in the lumen of the midgut while the Malpighian tubules appear to play only a minor role in the excretion of these dyes. The other pump (Type B) excretes basic (cationic) dyes and is located primarily in the proximal Malpighian tubules. Evidence is presented that hippuric acid competes with acid dyes for excretion by both midgut and Malpighian tubules. After the final-instar larva purges its gut the ability of the midgut and Malpighian tubules to excrete dyes gradually decreases. Sixty hours after the purge only the Malpighian tubules retain some dye excreting activity.


Estimating the hemodynamic impact of interventional treatments of aneurysms: numerical simulation with experimental validation: technical case report.
The goal of this study was to use phase-contrast magnetic resonance imaging and computational fluid dynamics to estimate the hemodynamic outcome that might result from different interventional options for treating a patient with a giant fusiform aneurysm. We followed a group of patients with giant intracranial aneurysms who have no clear surgical options. One patient demonstrated dramatic aneurysm growth and was selected for further analysis. The aneurysm geometry and input and output flow conditions were measured with contrast-enhanced magnetic resonance angiography and phase-contrast magnetic resonance imaging. The data was imported into a computational fluid dynamics program and the velocity fields and wall shear stress distributions were calculated for the presenting physiological condition and for cases in which the opposing vertebral arteries were either occluded or opened. These models were validated with in vitro flow experiments using a geometrically exact silicone flow phantom. Simulation indicated that altering the flow ratio in the two vertebrals would deflect the main blood jet into the aneurysm belly, and that this would likely reduce the extent of the region of low wall shear stress in the growth zone. Computational fluid dynamics flow simulations in a complex patient-specific aneurysm geometry were validated by in vivo and in vitro phase-contrast magnetic resonance imaging, and were shown to be useful in modeling the likely hemodynamic impact of interventional treatment of the aneurysm.


Cell-matrix Interactions of Factor IX (FIX)-engineered human mesenchymal stromal cells encapsulated in RGD-alginate vs. fibrinogen-alginate microcapsules.
The success of cell microencapsulation technology in tissue engineering and protein delivery applications depends on the viability and functionality of the encapsulated cells, which in turn are dependent upon cell/matrix interactions. In this work, we compared the viability of cord blood-derived mesenchymal stromal cells (CB MSCs), engineered to secrete factor IX (FIX) for hemophilia treatment, and encapsulated in arginine-glycine-aspartate (RGD)-alginate versus fibrinogen-alginate microcapsules. We evaluated the effect of the biomimetic matrix on cell attachment, proliferation, and secretion of FIX. Compared with nonsupplemented alginate matrix, RGD-alginate significantly enhanced the viability of the encapsulated MSCs. Further, cells in RGD-alginate displayed distinct attachment morphology, thus suggesting that RGD-alginate can potentially be used for the encapsulation of MSCs in tissue engineering applications that require enhanced cell attachment and viability. However, our data also showed that RGD-alginate microcapsules, in contrast to fibrinogen-alginate microcapsules, did not significantly improve cell proliferation of or FIX secretion by encapsulated MSCs. Our findings suggest that evidence of cell attachment alone may not accurately predict the functionality of cells in biomimetic microcapsules.


The natural course of bulimia nervosa and eating disorder not otherwise specified is not influenced by personality disorders.
To examine prospectively the natural course of bulimia nervosa (BN) and eating disorder not otherwise specified (EDNOS) and to test the effects of personality disorder (PD) comorbidity on the outcomes. Ninety-two female patients with current BN (N=23) or EDNOS (N=69) were evaluated at baseline enrollment in the Collaborative Longitudinal Personality Disorders Study (CLPS). Eating disorders (EDs) were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Personality disorders (PDs) were assessed with the Diagnostic Interview for DSM-IV PD (DIPD-IV). The course of BN and EDNOS was assessed with the Longitudinal Interval Follow-up Evaluation and the course of PDs was evaluated with the Follow-Along version of the DIPD-IV at 6, 12, and 24 months. Probability of remission at 24 months was 40% for BN and 59% for EDNOS. To test the effects of PD comorbidity on course, ED patients were divided into groups with no, one, and two or more PDs. Cox proportional regression analyses revealed that BN had a longer time to remission than EDNOS (p<.05). The number of PDs was not a significant predictor of time to remission, nor was the presence of Axis I psychiatric comorbidity or Global Assessment of Functioning scores. Analyses using proportional hazards regression with time-varying covariates revealed that PD instability was unrelated to changes in ED. BN has a worse 24-month course (longer time to remission) than EDNOS. The natural course of BN and EDNOS is not influenced significantly by the presence, severity, or time-varying changes of co-occurring PDs, co-occurring Axis I disorders, or by global functioning.


Two types of two-component gels formed from pseudoenantiomeric ethynylhelicene oligomers.
Two-component gels formed from pseudoenantiomeric ethynylhelicene oligomers in toluene exhibited two different properties depending on difference in numbers of helicenes in the two components. The combinations (M)-5/(P)-4, (M)-6/(P)-4, and (M)-7/(P)-4, which contained oligomers with comparable numbers of helicenes, formed transparent gels (Type I gels). The combinations (M)-6/(P)-3, (M)-7/(P)-3, and (M)-8/(P)-3, which contained oligomers with considerably different numbers of helicenes, formed turbid gels (Type II gels). Negative Cotton effects were observed for the Type I gels in the region between 350 and 450 nm, and were positive for the Type II gels, despite the use of (M)-oligomers for the longer components. UV/vis exhibited absorption maxima at 350 nm for the Type I gels and at 338 nm for the Type II gels. Different behaviors in gel formation processes were observed by fluorescence studies. Atomic force microscopy analysis showed fiber structures of 25-50 nm diameter for Type I gels and bundles of 100-150 nm diameter for Type II gels. The stoichiometry in gel formation also differed: The Type I gels showed 1:1 stoichiometry of the two components; the Type II gels showed no 1:1 stoichiometry, likely 1:2 stoichiometry. Using the Type I and II gels, two-layer gel systems were constructed.


Concordance between whole exome sequencing of circulating tumor DNA and tumor tissue.
Next generation sequencing of circulating tumor DNA (ctDNA) has been used as a noninvasive alternative for cancer diagnosis and characterization of tumor mutational landscape. However, low ctDNA fraction and other factors can limit the ability of ctDNA analysis to capture tumor-specific and actionable variants. In this study, whole-exome sequencings (WES) were performed on paired ctDNA and tumor biopsy in 15 cancer patients to assess the extent of concordance between mutational profiles derived from the two source materials. We found that up to 16.4% ctDNA fraction can still be insufficient for detecting tumor-specific variants and that good concordance with tumor biopsy is consistently achieved at higher ctDNA fractions. Most importantly, ctDNA analysis can consistently capture tumor heterogeneity and detect key cancer-related genes even in a patient with both primary and metastatic tumors.


Patterns of self-medication with medicinal plants and related adverse events--a South American survey.
Medicinal plants are useful as a natural therapy to treat minor illnesses, as gastrointestinal disorders or as topic antiinflammatories. Also, they have been increasingly used as a coadjuvant in cronic diseases as hypertension, diabetes or hyperlipidemias. Nevertheless, many of the plants have active principles which are contraindicated or need precaution in certain illnesses as coagulation disorders or in certain states as pregnancy or breastfeeding. In this review we had compiled the side-effects, precautions and interactions with other medicines of many plants which are used in self-medication in our region. A previous population study gave us information on the consumption of medicinal plants in 73 pharmacies of the Buenos Aires province, in Argentina. During a period of one year, there were 37102 self-medicated plants, while only 1532 were prescribed by the physician. Among the most frequently self-medicated plants are Malva sylvestris L., Matricaria chamomile L, and Quassia amara. Among the most frequently prescribed are also "malva" and "chamomile", Tilia cordata Mill. and Valeriana officinalis. Based in the most consumed medicinal plants in our region, we reviewed the risks of such plants and the precautions that should be taken for a rational use. Also, we detected 15 adverse-reactions reported by the pharmacists through a pharmaceutical vigilance program, which are described and analyzed here. The results of the study and other reports suggest that adverse reactions of herbal medicines could be avoided if preventing self-medication, and taking into consideration possible contraindications and interactions.


Hospital-based Surveillance: Accuracy, Adequacy, and Timeliness of Dengue Case Report in Bandung, West Java, Indonesia of 2015.
Dengue fever (DF) altogether with its severe forms, dengue hemorrhagic fever (DHF) and dengue shock syndrome, has become public health concerns. Indonesia belongs to category A of endemicity for DF/DHF. One of the several efforts to control dengue virus infection in Indonesia is a passive surveillance called "Dengue Case Surveillance." Timeliness report defined as a report sent within 24 h after the clinical diagnosis is needed to have a proper surveillance. The study on the evaluation of dengue case report in terms of accuracy, adequacy, and timeliness in Indonesia is still limited. The aim of this study was to identify the accuracy, adequacy, and timeliness from the reports of dengue viral infection (DVI) cases admitted from January 1 to December 31, 2015 to 7 major hospitals in Bandung, West Java, Indonesia. This was a retrospective analysis study. To evaluate the accuracy, all medical records of DVI patients were reviewed epidemiologically, clinically, and laboratory using a standardized questionnaire. To evaluate the adequacy, hospital data were compared with reported data in Bandung Municipality Health Authority. To evaluate the timeliness of report, interview to the person in charge for dengue reporting cases in each hospital and in Bandung Municipality Health Authority were performed. Univariate analysis was used for statistical analysis. A total of 4096 (72%) of 5712 hospitalized DVI cases lived in Bandung Municipality. The accuracy of the clinical diagnosis was 3397 out of 4096 cases (82.9%). The adequacy of the accurate cases was 1553 out of 3397 cases (45.7%). The timeliness of report was varied, ranging from days to month. The accuracy of dengue cases was good, but the adequacy and timely reporting should be strengthened.


Immigrant and refugee social networks: determinants and consequences of social support among women newcomers to Canada.
Recent immigrants and refugees (newcomers) vary on many dimensions but do share similar challenges. Newcomers must rebuild social networks to obtain needed social support but often face social exclusion because of their race, language, religion, or immigrant status. In addition, most have limited access to personal, social, and community resources. Effects of situational and personal variables on the benefits and limitations associated with the social networks of female newcomers were explored through interviews and focus groups with 87 women from 7 communities. Using thematic analysis, the authors identify 5 sources of informal support across all 7 communities, which were almost exclusively limited to co-ethnic relationships, and the types of support, limitations, and reciprocity within each. Perceived support was strongest from family and close friends and, when support from close relationships was unavailable, from primary care providers. The results suggest that co-ethnic peer support networks may be overwhelmed in newcomer communities because of their limited size and resources.


Evaluation of a "Just-in-Time" Nurse Consultation on Bone Health: A Pilot Randomized Controlled Trial.
Evidence is inconclusive whether a nurse consultation can improve osteoporosis-related patient outcomes. To evaluate whether a nurse consultation immediately after dual-energy x-ray absorptiometry (DXA) produced better osteoporosis-related outcomes than a simple intervention to activate adults in good bone health practices or usual care. Pilot randomized controlled trial, conducted within the larger Patient Activation After DXA Result Notification (PAADRN) trial (NCT01507662). After DXA, consenting adults age 50 years or older were randomly assigned to 3 groups: nurse consultation, PAADRN intervention (mailed letter with individualized fracture risk and an educational brochure), or usual care (control). Nurse consultation included reviewing DXA results, counseling on bone health, and ordering needed follow-up tests or physician referrals. Change from baseline to 52 weeks in participant-reported osteoporosis-related pharmacotherapy, lifestyle, activation and self-efficacy, and osteoporosis care satisfaction. Nurse consultation participants (n = 104) reported 52-week improvements in strengthening and weight-bearing exercise (p = 0.09), calcium intake (p < 0.01), osteoporosis knowledge (p = 0.04), activation (p < 0.01), dietary self-efficacy (p = 0.06), and osteoporosis care satisfaction (p < 0.01). Compared with PAADRN intervention participants (n = 39), nurse consultation participants had improved dietary self-efficacy (p = 0.07) and osteoporosis care satisfaction (p = 0.05). No significant improvements in osteoporosis-related outcomes were achieved vs PAADRN controls (n = 70). "Just-in-time" nurse consultation yielded a few improvements over 52 weeks in osteoporosis-related outcomes; however, most changes were not different from those obtained through the lower-cost PAADRN intervention or usual care.


Thalidomide as elective treatment in persistent erythema multiforme; report of two cases.
Recurrent erythema multiforme is a rare disorder, clinically characterized by symmetrically distributed, erythematous, and bullous skin and mucous lesions, mainly precipitated by a preceding herpes simplex infection. In rare cases, EM presents continuous or persistent relapses, and has been related to an Epstein-Barr virus infection. We report 2 cases of severe, persistent erythema multiforme, treated with thalidomide, with complete disease suppression in both cases. Thalidomide induces immunomodulator, anti-inflammatory, and anti-angiogenic effects, and may be considered as the elective treatment of this rare variety of erythema multiforme. However, in order to avoid neuropathic side effects, patients under thalidomide therapy should be monitored every 6 months with nerve conduction studies while taking the drug.


Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-Sponsored Expert Panel.
Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy.


Cardiac disturbances during the administration of taxol.
The clinical development of taxol, a new antimicrotubule agent with a unique mechanism of cytotoxic action, has proceeded slowly due to serious hypersensitivity reactions (HSRs) and shortages in its supply. Nevertheless, large-scale phase II trials have been initiated as taxol has recently demonstrated impressive activity in advanced and cisplatin-refractory ovarian carcinoma. Furthermore, the incidence of HSRs has been reduced substantially with premedications and modifications in the administration schedule. However, various manifestations of potential cardiotoxicity have been observed in several patients who participated in four phase I and II studies of taxol. Asymptomatic bradycardia has occurred in a high proportion of patients, including 29% of ovarian cancer patients who were treated with maximally tolerated doses of taxol in a phase II study. More profound cardiac disturbances, including a range of atrioventricular conduction blocks, left bundle branch block, ventricular tachycardia (VT), and manifestations of cardiac ischemia, have been observed in seven of 140 patients (5%) who received taxol. Descriptions of these events are presented in this report to alert investigators to the potential for these adverse effects. Although these disturbances did not result in serious sequelae in most patients, investigators should continue to maintain a high degree of caution until precise risk factors, frequency, and clinical significance of these adverse cardiac effects are determined.


Evidence from computer simulations for alterations in the membrane biophysical properties and dendritic processing of synaptic inputs in mutant superoxide dismutase-1 motoneurons.
A critical step in improving our understanding of the development of amyotrophic lateral sclerosis (ALS) is to identify the factors contributing to the alterations in the excitability of motoneurons and assess their individual contributions. Here we investigated the early alterations in the passive electrical and morphological properties of neonatal spinal motoneurons that occur by 10 d after birth, long before disease onset. We identified some of the factors contributing to these alterations, and estimated their individual contributions. To achieve this goal, we undertook a computer simulation analysis using realistic morphologies of reconstructed wild-type (WT) and mutant superoxide dismutase-1 (mSOD1) motoneurons. Ion channel parameters of these models were then tuned to match the experimental data on electrical properties obtained from these same motoneurons. We found that the reduced excitability of mSOD1 models was accompanied with decreased specific membrane resistance by approximately 25% and efficacy of synaptic inputs (slow and fast) by 12-22%. Linearity of summation of synaptic currents was similar to WT. We also assessed the contribution of the alteration in dendritic morphology alone to this decreased excitability and found that it reduced the input resistance by 10% and the efficacy of synaptic inputs by 7-15%. Our results were also confirmed in models with dendritic active conductances. Our simulations indicated that the alteration in passive electrical properties of mSOD1 models resulted from concurrent alterations in their morphology and membrane biophysical properties, and consequently altered the motoneuronal dendritic processing of synaptic inputs. These results clarify new aspects of spinal motoneurons malfunction in ALS.


ST-segment elevation myocardial infarction in women with type 2 diabetes.
To evaluate the effect of type 2 diabetes on the clinical course and prognosis of women with ST-segment elevation myocardial infarction (STEMI) and diabetes. A total of 26,035 consecutive patients with STEMI who were hospitalized in 456 hospitals in Poland during 1 year were analyzed. The data were obtained from the Polish Registry of Acute Coronary Syndromes (PL-ACS). Type 2 diabetes occurred more frequently in women than in men (28 vs. 16.6%; P < 0.0001). The proportion of women was larger among patients with diabetes (47.1 vs. 31.3%; P < 0.0001), and compared with women without diabetes, diabetic women had worse clinical profiles. Women with diabetes were most frequently treated conservatively. Both women and men with diabetes had significantly more advanced atherosclerotic lesions than women without diabetes. Women with diabetes had the highest in-hospital, 6-month, and 1-year mortality rates. Multivariate analysis indicated that type 2 diabetes was a significant independent risk factor for in-hospital and 1-year mortality in women with STEMI. Primary percutaneous coronary intervention (pPCI) was a significant factor associated with the decreased 1-year mortality in women without diabetes. Type 2 diabetes was a significant independent risk factor for in-hospital and 1-year mortality in women with STEMI. Women with diabetes had the poorest early and 1-year prognoses after STEMI when compared with women without diabetes and men with diabetes. Although pPCI improves the long-term prognosis of women with diabetes, it is used less frequently than in women without diabetes or men with diabetes.


Development of a Screencast-Based Flipped Classroom to Enrich Learning and Reduce Faculty Time Requirements in an Animal Welfare Master's Degree.
A new distance learning Master of Science (MSc) degree in Animal Welfare Science, Ethics and Law was established in 2016 within the Centre for Animal Welfare at the University of Winchester, UK. Our program recruited students worldwide, with enrollments increasing dramatically since its inception in 2016. However, despite rapid growth, our MSc has had only one full-time equivalent faculty member. With further projected sharp increases in student numbers, significant programmatic change was required for the MSc to remain viable. After consultation with our students and program team, we decided to transition to a flipped classroom teaching model. Piloting a screencast-based flipped classroom in one course, our objectives were to provide a more enriched, engaging, and effective student learning experience and to increase student satisfaction while concurrently saving staff time in future years. We aimed to provide a series of enriched screencast videos of short (∼20-minute) durations, with contents clearly signposted. The new teaching model was well received. Within our 2021 program survey, 100% of respondents expressed a wish to see our screencast-based flipped classroom approach continued, and 71%-86% wished to see it implemented in various additional courses. This model has greatly enriched students' learning experiences, increasing student engagement and satisfaction while also freeing staff time to engage in discussion fora and additional live sessions. Learning and achievement outcomes also appear positive. We plan to steadily integrate this model across additional courses, although initial time investment will be significant. Hence, this new model will be implemented over several semesters.


Impact of letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF: a multicentre, randomized, double-blinded placebo-controlled trial.
Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [-25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference -100 IU, 95% CI [-192; -21], P = 0.03). Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. NCT02939898 and NCT02946684. 15 August 2016. 22 August 2016.


Correction of odds ratios in case-control studies for exposure misclassification with partial knowledge of the degree of agreement among experts who assessed exposures.
Estimates of association between exposures and diseases are often distorted by error in exposure classification. When the validity of exposure assessment is known, this can be used to adjust these estimates. When exposure is assessed by experts, even if validity is not known, we sometimes have information about interrater reliability. We present a Bayesian method for translating the knowledge of interrater reliability, which is often available, into knowledge about validity, which is often needed but not directly available, and applying this to correct odds ratios (OR). The method allows for inclusion of observed potential confounders in the analysis, as is common in regression-based control for confounding. Our method uses a novel type of prior on sensitivity and specificity. The approach is illustrated with data from a case-control study of lung cancer risk and occupational exposure to diesel engine emissions, in which exposure assessment was made by detailed job history interviews with study subjects followed by expert judgement. Using interrater agreement measured by kappas (κ), we estimate sensitivity and specificity of exposure assessment and derive misclassification-corrected confounder-adjusted OR. Misclassification-corrected and confounder-adjusted OR obtained with the most defensible prior had a posterior distribution centre of 1.6 with 95% credible interval (Crl) 1.1 to 2.6. This was on average greater in magnitude than frequentist point estimate of 1.3 (95% Crl 1.0 to 1.7). The method yields insights into the degree of exposure misclassification and appears to reduce attenuation bias due to misclassification of exposure while the estimated uncertainty increased.


Multiplex digital colour-coded barcode technology on RNA extracted from routine cytological samples of patients with non-small cell lung cancer: pilot study.
In the advanced stages of non-small cell lung cancer (NSCLC), molecular testing is often performed on archival cytological smears. The nCounter system (NanoString Technologies) is a new promising multiplex digital colour-coded barcode technology. However, its feasibility to evaluate the RNA expression of clinical relevant biomarkers on routine cytological smears is still uncertain. To this end, RNA was extracted from 12 NSCLC routine stained cytological smears, and nCounter analysis performed by using a 48-gene panel. Overall, 11/12 (92%) of the smears were adequate for the secondary analysis, fulfilling the quality check parameter analysis of nSolver software. This pilot study shows that RNA nCounter analysis is feasible on routine cytological smears preparing the field for the implementation of this technology in the routine setting.


Invasion and multiplication of Helicobacter pylori in gastric epithelial cells and implications for antibiotic resistance.
Helicobacter pylori is a Gram-negative, spiral-shaped bacterium that infects more than 50% of the human population and can cause gastritis, peptic ulcer, or gastric malignancies. It is generally viewed as an extracellular microorganism. In a gentamicin protection assay on AGS or MKN45 cells, H. pylori could invade the epithelial cells and multiply within double-layer vesicles either on the plasma membrane or in the cytoplasm. A 5-fold increase in the number of bacteria was recultured from the infected cells at 12 h, compared with the number of invading cells at 2.5 h postinfection. The autophagic vesicles induced by H. pylori are the sites of replication and also of the degradation of the replicating bacteria after fusion with lysosomes. Many H. pylori bacteria in coccoid form associated with the plasma membrane can be released into culture. Only cell-penetrating antibiotics can enhance the intracellular killing of the replicating bacteria. The multiplication of H. pylori within cells provides a niche for its resistance to antibacterial therapy and has a significant impact on its biological life cycle.


Discussion of Extinction-Based Behavioral Sleep Interventions for Young Children and Reasons Why Parents May Find Them Difficult.
The majority of behavioral sleep interventions for young children involve extinction procedures where parents must ignore their child's cries for a period. Many parents have difficulties with this, contributing to attrition, non-compliance, and treatment avoidance. Yet why these methods are difficult to implement has rarely been addressed in the literature. This paper discusses seven potential reasons why parents may find extinction sleep interventions difficult: enduring crying, practical considerations, fear of repercussions, misinformation, incongruence with personal beliefs, different cultural practices, and parent wellness. These reasons are discussed in relation to the current literature. Practicing health professionals and sleep researchers could benefit from an awareness of these issues when suggesting extinction interventions and offering alternatives which may be more appropriate for family circumstances and facilitate parental informed choice.


Mutations and deletions of PRC2 in prostate cancer.
The Polycomb group of proteins (PcGs) are transcriptional repressor complexes that regulate important biological processes and play critical roles in cancer. Mutating or deleting EZH2 can have both oncogenic and tumor suppressive functions by increasing or decreasing H3K27me3. In contrast, mutations of SUZ12 and EED are reported to have tumor suppressive functions. EZH2 is overexpressed in many cancers, including prostate cancer, which can lead to silencing of tumor suppressors, genes regulating epithelial to mesenchymal transition (EMT), and interferon signaling. In some cases, EZH2 overexpression also leads to its use of non-histone substrates. Lastly, PRC2 associated factors can influence the progression of cancer through progressive mutations or by specific binding to certain target genes. Here, we discuss which mutations and deletions of the PRC2 complex have been detected in different cancers, with a specific focus on the overexpression of EZH2 in prostate cancer.


Data mining and spatio-temporal characteristics of urban road traffic emissions: A case study in Shijiazhuang, China.
Accurate estimation of traffic emissions and analysis of spatio-temporal distribution on urban roads play a crucial role in the development of low-carbon transportation system. Traditionally, a region's emission characteristics have been studied using numerous emission models with GPS-based spatio-temporal data. Due to the heavy data processing needs of GPS-based data, emission characteristics for a large region have been studied by dividing the region into a limited number of smaller areas or units. Additionally, GPS data are based on a few vehicles in the traffic which does not fully reflect road conditions. This paper proposed an approach that can be used to study and calculate the spatio-temporal emission pattern of a region at a roadway section level by using Baidu's online traffic data and COPERT model. The proposed method can be used to estimate road-level emission patterns while avoiding the impact of redundant data in large datasets, making the dataset more reliable, applicable, and scalable. The proposed approach has been demonstrated through a study of spatio-temporal emission patterns in the Qiaoxi district within city of Shijiazhuang, China. Online data crawling technology was used to obtain data on urban road traffic speed and driving distance. The linear reference technology was used to construct a two-layer road network model to conduct the coupling and matching of traffic data with the road network data. The COPERT model was implemented to calculate the average traffic emissions on each road in the road network, and a traffic emission intensity index was proposed to quantify the CO, VOC, NOx and CO2 emissions on urban roads in the study area. The analysis results show that the traffic emission intensity of the expressway, trunk road, secondary road, and branch road is high during the morning peak (7 AM-9 AM) and evening peak (5 PM-7 PM). The sections with higher traffic emission intensity are mainly concentrated on the main roads and secondary roads such as Jiefang South Street, Shitong Road and Xinhua Road. Nearly one-third of 2nd Ring and 3rd Ring roads also have relatively high emission intensity. The research results provide new ideas for estimating traffic emissions in urban road networks and analyzing the spatio-temporal distribution of traffic emissions. The research results can also provide a decision-making basis for traffic management departments to formulate energy-saving and emission-reduction measures and promote the development of urban green and low-carbon transportation.


Adaptive phenotype of microglial cells during the normal postnatal development of the somatosensory "Barrel" cortex.
Accumulative evidence indicates that microglial cells influence the normal development of central nervous system (CNS) synapses. Yet, the functional properties of microglia in relation with synapse development remain unclear. We recently showed that in layer 4 of the whisker-related barrel field of the mouse somatosensory cortex, microglial cells are recruited only after postnatal day (P)5 in the center of the barrels where thalamo-cortical synapses are concentrated and begin their maturation. In the present study, we analyzed the phenotype of microglia during this developmental process. We show that between P5 and P7 microglial cells acquire a more ramified morphology with a smaller soma, they express classical markers of microglia (Iba1, CD11b, and CD68) but never markers of activation (Mac-2 and MHCII) and rarely the proliferation marker Ki67. Electrophysiological recordings in acute cortical slices showed that at P5 a proportion of layer 4 microglia transiently express voltage-dependant potassium currents of the delayed rectifier family, mostly mediated by Kv1.3 subunits, which are usually expressed by activated microglia under pathological conditions. This proportion of cells with rectifying properties doubles between P5 and P6, in concomitance with the beginning of microglia invasion of the barrel centers. Finally, analysis of the responses mediated by purinergic receptors indicated that a higher percentage of rectifying microglia expressed functional P2Y6 and P2Y12 receptors, as compared with nonrectifying cells, whereas all cells expressed functional P2X7 receptors. Our results indicate that during normal cortical development distinct microglia properties mature differentially, some of them being exquisitely influenced by the local environment of the maturating neuronal network.


Influence of axial length on thickness measurements using spectral-domain optical coherence tomography.
The purpose of this study was to assess the influence of axial length on spectral-domain optical coherence tomography (SD-OCT) thickness measurements in patients with subretinal visual implants. Data from eight emmetropic pseudophakic eyes of eight patients with subretinal visual implants were analyzed retrospectively. These patients participated in the monocentric part of a multicenter trial. The axial length was measured in three short (<22.5 mm), three medium (22.51-25.50 mm), and two long (>25.52 mm) eyes. Using Heidelberg Spectralis, the known thickness of a subretinal implant microchip (70 μm) was measured on 15 images per eye with SD-OCT, using the software calipers. The mean axial length was 20.8 ± 0.8 mm in short eyes, 23.3 ± 0.4 mm in medium eyes, and 26.3 ± 0.5 mm in long eyes. We found in short eyes, in medium eyes, and in long eyes a mean value of microchip thickness measurements from SD-OCT of 82.9 ± 1.4 μm, 70.5 ± 1.3 μm, and 64.2 ± 1.3 μm, respectively. The thickness measurements decreased in SD-OCT measurements with longer axial lengths significantly (P < 0.0001). Axial length influences SD-OCT thickness measurements. Our findings demonstrate accuracy of the scaling in SD-OCT thickness measurements in emmetropic medium eyes. Caution is recommended when comparing the measured values of short and long eyes with the normative database of the instrument. There is a need for larger sample-size studies to confirm our results. (ClinicalTrials.gov number, NCT01024803.).


Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process.
The Hedgehog (Hh) signaling pathway controls growth, cell fate decisions, and morphogenesis during development. Damage to Hh transduction machinery can lead to birth defects and cancer. The transmembrane protein Smoothened (Smo) relays the Hh signal and is an important drug target in cancer. Smo enrichment in primary cilia is thought to drive activation of target genes. Using small-molecule agonists and antagonists to dissect Smo function, we find that Smo enrichment in cilia is not sufficient for signaling and a distinct second step is required for full activation. This 2-step mechanism--localization followed by activation--has direct implications for the design and use of anticancer therapeutics targeted against Smo.