Comparison of Color Flow Doppler Sonography (CFDS) and immunohistologic detection of microvessels for the assessment of the malignancy of thyroid nodules.
The assessment of tumor vascularization by color flow Doppler sonography (CFDS) has been suggested for the distinction between benign and malignant thyroid nodules. Our objective was to investigate if the CFDS results reflect the percentage of histologically determined microvessels in adenomas (As), adenomatous nodules (ANs), and papillary carcinomas (PCs). Tissue sections from 10 adenomas, 8 ANs and 13 PC and surrounding tissue of 10 PCs and 2 benign nodules were immunostained for CD34. A computerized image analysis was used to determine the microvessel density in four hot spots and ten systematically selected fields. Preoperatively CFDS was performed and classified according to Frates et al. We found a consistent percentage increase of CD34 stained microvessels in PCs (83 and 96%) as compared to adenomas and ANs (38 and 49%) determined by the hot spot analysis and systematic field analysis. A ROC analysis on the basis of the histologically determined number of microvessels demonstrated 70% microvessels as an optimal cut point for the diagnosis of PC with the highest sensitivity of 92% and highest specificity of 89%. The analysis of the CFDS-classification IV for the distinction between PCs and adenomas and ANs showed a sensitivity of 62% with a specificity of 100%. The lower sensitivity of the CFDS classification as compared with the immunohistologic determination of the microvessel density indicates that the CFDS classification detects the pathognomonic intranodular microvessels only incompletely. The higher CFDS specificity is most likely due to the detection of other vascular aspects of malignancy in addition to intranodular microvessels.


Neural correlates of delay discount alterations in addiction and psychiatric disorders: A systematic review of magnetic resonance imaging studies.
Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.


Two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 and affect Notch trafficking and signaling.
The Notch-signaling pathway is normally activated by Notch-ligand interactions. A recent structural analysis suggested that a novel O-linked hexose modification on serine 435 of the mammalian NOTCH1 core ligand-binding domain lies at the interface with its ligands. This serine occurs between conserved cysteines 3 and 4 of Epidermal Growth Factor-like (EGF) repeat 11 of NOTCH1, a site distinct from those modified by protein O-glucosyltransferase 1 (POGLUT1), suggesting that a different enzyme is responsible. Here, we identify two novel protein O-glucosyltransferases, POGLUT2 and POGLUT3 (formerly KDELC1 and KDELC2, respectively), which transfer O-glucose (O-Glc) from UDP-Glc to serine 435. Mass spectrometric analysis of NOTCH1 produced in HEK293T cells lacking POGLUT2, POGLUT3, or both genes showed that either POGLUT2 or POGLUT3 can add this novel O-Glc modification. EGF11 of NOTCH2 does not have a serine residue in the same location for this O-glucosylation, but EGF10 of NOTCH3 (homologous to EGF11 in NOTCH1 and -2) is also modified at the same position. Comparison of the sites suggests a consensus sequence for modification. In vitro assays with POGLUT2 and POGLUT3 showed that both enzymes modified only properly folded EGF repeats and displayed distinct acceptor specificities toward NOTCH1 EGF11 and NOTCH3 EGF10. Mutation of the O-Glc modification site on EGF11 (serine 435) in combination with sensitizing O-fucose mutations in EGF8 or EGF12 affected cell-surface presentation of NOTCH1 or reduced activation of NOTCH1 by Delta-like1, respectively. This study identifies a previously undescribed mechanism for fine-tuning the Notch-signaling pathway in mammals.


Conjugated linoleic acid increases in milk from cows fed condensed corn distillers solubles and fish oil.
Twelve lactating Holstein cows were randomly assigned to 1 of 4 experimental diets in a replicated 4 x 4 Latin square design with 4-wk periods to ascertain the lactational response to feeding fish oil (FO), condensed corn distillers solubles (CDS) as a source of extra linoleic acid, or both. Diets contained either no FO or 0.5% FO and either no CDS or 10% CDS in a 2 x 2 factorial arrangement of treatments. Diets were fed as total mixed rations for ad libitum consumption. The forage to concentrate ratio was 55:45 on a dry matter basis for all diets and the diets contained 16.2% crude protein. The ether extract concentrations were 2.86, 3.22, 4.77, and 5.02% for control, FO, CDS, and FOCDS diets, respectively. Inclusion of FO or CDS or both had no effect on dry matter intake, feed efficiency, body weight, and body condition scores compared with diets without FO and CDS, respectively. Yields of milk (33.3 kg/d), energy-corrected milk, protein, lactose, and milk urea N were similar for all diets. Feeding FO and CDS decreased milk fat percentages (3.85, 3.39, 3.33, and 3.12%) and yields compared with diets without FO and CDS. Proportions of trans-11 C18:1 (vaccenic acid), cis-9 trans-11 conjugated linoleic acid (CLA; 0.52, 0.90, 1.11, and 1.52 g/100 g of fatty acids), and trans-10 cis-12 CLA (0.07, 0.14, 0.13, and 0.16 g/100 g of fatty acids) in milk fat were increased by FO and CDS. No interactions were observed between FO and CDS on cis-9 trans-11 CLA although vaccenic acid tended to be higher with the interaction. The addition of CDS to diets increased trans-10 C18:1. Greater ratios of vaccenic acid to cis-9 trans-11 CLA in plasma than in milk fat indicate tissue synthesis of cis-9 trans-11 CLA in the mammary gland from vaccenic acid in cows fed FO or CDS. Feeding fish oil at 0.5% of diet dry matter with a C18:2 n-6 rich source such as CDS increased the milk CLA content but decreased milk fat percentages.


Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types.
Most human pre-mRNAs are spliced into linear molecules that retain the exon order defined by the genomic sequence. By deep sequencing of RNA from a variety of normal and malignant human cells, we found RNA transcripts from many human genes in which the exons were arranged in a non-canonical order. Statistical estimates and biochemical assays provided strong evidence that a substantial fraction of the spliced transcripts from hundreds of genes are circular RNAs. Our results suggest that a non-canonical mode of RNA splicing, resulting in a circular RNA isoform, is a general feature of the gene expression program in human cells.


Knowledge-making distinctions in synthetic biology.
Synthetic biology is an increasingly high-profile area of research that can be understood as encompassing three broad approaches towards the synthesis of living systems: DNA-based device construction, genome-driven cell engineering and protocell creation. Each approach is characterized by different aims, methods and constructs, in addition to a range of positions on intellectual property and regulatory regimes. We identify subtle but important differences between the schools in relation to their treatments of genetic determinism, cellular context and complexity. These distinctions tie into two broader issues that define synthetic biology: the relationships between biology and engineering, and between synthesis and analysis. These themes also illuminate synthetic biology's connections to genetic and other forms of biological engineering, as well as to systems biology. We suggest that all these knowledge-making distinctions in synthetic biology raise fundamental questions about the nature of biological investigation and its relationship to the construction of biological components and systems.


Quantified aneurysm shape and rupture risk.
The authors investigated whether quantified shape or size indices could better discriminate between ruptured and unruptured aneurysms. Several custom algorithms were created to quantifiy the size and shape indices of intracranial aneurysms by using three-dimensional computerized tomography angiography models of the brain vasculature. Data from 27 patients with ruptured or unruptured aneurysms were evaluated in a blinded fashion to determine whether aneurysm size or shape better discriminated between the ruptured and unruptured groups. Five size and eight shape indices were calculated for each aneurysm. Two-tailed independent Student t-tests (significance p < 0.05) were used to determine statistically significant differences between ruptured and unruptured aneurysm groups for all 13 indices. Receiver-operating characteristic-area under curve analyses were performed for all indices to quantify the predictability of each index and to identify optimal threshold values. None of the five size indices were significantly different between the ruptured and unruptured aneurysms. Five of the eight shape indices were significantly different between the two lesion groups, and two other shape indices showed a trend toward discriminating between ruptured and unruptured aneurysms, although these differences did not reach statistical significance. Quantified shape is more effective than size in discriminating between ruptured and unruptured aneurysms. Further investigation will determine whether quantified aneurysm shape will prove to be a reliable predictor of aneurysm rupture.


Combination Therapy in Pulmonary Arterial Hypertension: Single Centre Long-term Experience.
Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vascular bed and causes right heart failure and death. Combination therapy which targets three different pathways is necessary due to the progressive nature of the disease. In patients with PAH, there are two approaches in combination therapy: "first-line up-front" and "sequential add-on" treatment. In "firstline up-front" treatment, patients receive double or triple drug therapy from the start. In the "sequential add-on" approach, a single drug is initially started and then according to the patient's requirements, a second or third drug is added. There is insufficient evidence about the efficiency and safety of treatment approaches. In this study, we aimed to evaluate the treatment approach in patients with PAH at a tertiary centre. Pulmonary arterial hypertension was diagnosed according to clinical, echocardiographic and right heart catheterization findings. The patients received bosentan, sildenafil and iloprost treatment in accordance with guidelines recommendations. Clinical worsening in patients was defined as death, requirement of hospitalization for PAH, a 15% decline in the six-minute walk test (6MWT) distance, deterioration in functional capacity, and symptoms and findings of right heart failure. At the end of the follow-up period, clinical and echocardiographic findings, brain natriuretic peptide (BNP) levels and oxygen saturation were similar between patients who completed the study with monotherapy and with combination therapy. The follow-up period was significantly longer in patients who required combination treatment. Two patients (6.9%) died and four patients (13.8%) were hospitalized due to recurrent symptoms and findings of right heart failure. At the end of follow-up, 10 patients (34.5%) completed the study with a single drug, 15 patients (51.7%) with two drugs and four patients (13.8%) with three drugs. In this study, combination therapy was given to patients as "sequential add-on therapy". At the end of the follow-up period, monotherapy was sufficient in 34.5% of patients of the study group and in eight patients, sildenafil or prostaglandin analogues were added; a total of 15 patients (48.4%) completed the study under dual therapy. Four patients (12.9%) received combination therapy with three drugs.


[Genetic control of rhombencephalon development by Hox genes studied in bird embryo by the quail-chick chimera method].
The rhombencephalic neural tube is transiently segmented along the anteroposterior axis into 8 rhombomeres. Each rhombomere, as well as its derived neural crest cells, is characterized by the expression of a specific set of Hox genes which constitute its Hox code. This code is supposed to define the morphogenetic program of these cells according to their position. We took advantage of the quail/chick chimera system to study the regulation of Hox gene expression in neural tube and neural crest cells. We have therefore ectopically transplanted the presumptive territories of the future rhombomeres and studied the evolution of their Hox code. We evidence in the posterior rhombencephalon and the spinal cord a posteriorising signal able to induce Hox gene expression, to repress anterior molecular markers and to control the subsequent development of the neural tube. This signal is conveyed horizontally in the plane of the neuroepithelium and vertically from the mesoderm to the ectoderm. The anteroposterior identity of the neural crest cells seem independent from this inducer after formation of the neural fold.


[Witches' ointments and love-potions: a contribution to the cultural history of nightshades].
The nightshades (solanaceae) were used as intoxicants since the ancient civilizations and are still in use today. Their alkaloids, atropine and scopolamine, were the major active substances of the ointments of witches, of medieval "anaesthetics", and of modern poisons for murder. In a medium dose-range the predominant symptoms are hallucinations and illusions. This explains the use of nightshades in fortune-telling and religious rituals. In higher doses the alkaloids produce coma and apnea. Scopolamine enjoyed a particular popularity as a poison for murder. In the 19th century the nightshade alkaloids were also in clinical use. This article focusses on the medical history of the psychosis due to intoxication with solanaceae.


The genetic landscape of Equatorial Guinea and the origin and migration routes of the Y chromosome haplogroup R-V88.
Human Y chromosomes belonging to the haplogroup R1b1-P25, although very common in Europe, are usually rare in Africa. However, recently published studies have reported high frequencies of this haplogroup in the central-western region of the African continent and proposed that this represents a 'back-to-Africa' migration during prehistoric times. To obtain a deeper insight into the history of these lineages, we characterised the paternal genetic background of a population in Equatorial Guinea, a Central-West African country located near the region in which the highest frequencies of the R1b1 haplogroup in Africa have been found to date. In our sample, the large majority (78.6%) of the sequences belong to subclades in haplogroup E, which are the most frequent in Bantu groups. However, the frequency of the R1b1 haplogroup in our sample (17.0%) was higher than that previously observed for the majority of the African continent. Of these R1b1 samples, nine are defined by the V88 marker, which was recently discovered in Africa. As high microsatellite variance was found inside this haplogroup in Central-West Africa and a decrease in this variance was observed towards Northeast Africa, our findings do not support the previously hypothesised movement of Chadic-speaking people from the North across the Sahara as the explanation for these R1b1 lineages in Central-West Africa. The present findings are also compatible with an origin of the V88-derived allele in the Central-West Africa, and its presence in North Africa may be better explained as the result of a migration from the south during the mid-Holocene.


Phenotype of atopic dermatitis subjects with a history of eczema herpeticum.
A subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum. This National Institute of Allergy and Infectious Diseases-funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH(+) and ADEH(-) subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals. We analyzed the data from 901 subjects (ADEH(+) subjects, n = 134; ADEH(-) subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers. ADEH(+) subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell-attracting chemokine) than ADEH(-) subjects (P < .001). ADEH(+) subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens (P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH(+) subjects (78% and 8%, respectively) than in ADEH(-) subjects (29% and 2%, respectively; P < .001). Subjects with AD in whom eczema herpeticum develops have more severe T(H)2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S. aureus or molluscum contagiosum.


Increased prevalence of small airways dysfunction in patients with systemic sclerosis as determined by impulse oscillometry.
The prevalence and clinical implications of small airways involvement in SSc are still to be fully elucidated. The goal of the present work is to assess the prevalence of small airways dysfunction by impulse oscillometry and to determine whether it correlates with selected disease-related features and respiratory-related quality of life. Ninety-four SSc patients and 93 healthy controls were studied by impulse oscillometry measurements. Small airways dysfunction was defined as the difference between resistance at low frequency, i.e. 5 Hz, and resistance at high frequency, i.e. 20 Hz, termed 'R5-R20', ⩾0.07 kPa/l/s. The St George's Respiratory Questionnaire was used to measure health impairment in SSc patients. Radiological features of small airways disease and parenchymal abnormalities on high resolution CT chest scans were jointly assessed by two thoracic radiologists. Small airways dysfunction was present in 21.5% of the SSc patient cohort, with a prevalence almost 5-fold higher compared with controls, and it was significantly associated with worse respiratory-related quality of life. Radiological features consistent with small airways abnormalities were detected in 25% of SSc patients, mostly in the absence of interstitial lung changes. Combining functional and radiological evaluations, one-third of the SSc cohort showed at least one feature of small airways involvement, which was associated with the lcSSc phenotype and with longer disease duration. The current study strengthens the hypothesis that small airway dysfunction might be a feature of SSc-related lung involvement, providing the first data on its significant impact on respiratory-related quality of life. A full assessment of lung function in SSc patients should include impulse oscillometry as a complementary technique, due to potential clinical and therapeutic implications.


Perceptions of psychological content in the GP consultation--the role of practice, personal and prescribing attributes.
The aim of the present study was to determine the relationship between the characteristics of general practices and the perceptions of the psychological content of consultations by GPs in those practices. A cross-sectional survey was conducted of all GPs (22 GPs based in nine practices) serving a discrete inner city community of 41 000 residents. GPs were asked to complete a log-diary over a period of five working days, rating their perception of the psychological content of each consultation on a 4-point Likert scale, ranging from 0 (no psychological content) to 3 (entirely psychological in content). The influence of GP and practice characteristics on psychological content scores was examined. Data were available for every surgery-based consultation (n = 2206) conducted by all 22 participating GPs over the study period. The mean psychological content score was 0.58 (SD 0.33). Sixty-four percent of consultations were recorded as being without any psychological content; 6% were entirely psychological in content. Higher psychological content scores were significantly associated with younger GPs, training practices (n = 3), group practices (n = 4), the presence of on-site mental health workers (n = 5), higher antidepressant prescribing volumes and the achievement of vaccine and smear targets. Training status had the greatest predictive power, explaining 51% of the variation in psychological content. Neither practice consultation rates, GP list size, annual psychiatric referral rates nor volumes of benzodiazepine prescribing were related to psychological content scores. Increased awareness by GPs of the psychological dimension within a consultation may be a feature of the educational environment of training practices.


Distinct right frontal lobe activation in language processing following left hemisphere injury.
Right hemisphere activation during functional imaging studies of language has frequently been reported following left hemisphere injury. Few studies have anatomically characterized the specific right hemisphere structures engaged. We used functional MRI (fMRI) with verbal fluency tasks in 12 right-handed patients with left temporal lobe epilepsy (LTLE) and 12 right-handed healthy controls to localize language-related activity in the right inferior frontal gyrus (RIFG). During the phonemic task, LTLE patients activated a significantly more posterior region of the right anterior insula/frontal operculum than healthy controls (P = 0.02). Activation of the left inferior frontal gyrus (LIFG) did not differ significantly between the two groups. This suggests that, following left hemisphere injury, language-related processing in the right hemisphere differs from that with a functionally normal left hemisphere. The localization of activation in the left and right inferior frontal gyri was determined with respect to the anatomical sub-regions pars opercularis (Pop), pars triangularis (Ptr) and pars orbitalis (Por). In the LIFG, both healthy controls (8 out of 12) and LTLE patients (9 out of 12) engaged primarily Pop during phonemic fluency. Activations in the RIFG, however, were located mostly in the anterior insula/frontal operculum in both healthy controls (8 out of 12) and LTLE patients (8 out of 12), albeit in distinct regions. Mapping the locations of peak voxels in relation to previously obtained cytoarchitectonic maps of Broca's area confirmed lack of homology between activation regions in the left and right IFG. Verbal fluency-related activation in the RIFG was not anatomically homologous to LIFG activation in either patients or controls. To test more directly whether RIFG activation shifts in a potentially adaptive manner after left hemisphere injury, fMRI studies were performed in a patient prior to and following anatomical left hemispherectomy for the treatment of Rasmussen's encephalitis. An increase in activation magnitude and posterior shift in location were found in the RIFG after hemispherectomy for both phonemic and semantic tasks. Together, these results suggest that left temporal lobe injury is associated with potentially adaptive changes in right inferior frontal lobe functions in processing related to expressive language.


Low-dose growth hormone therapy reduces inflammation in HIV-infected patients: a randomized placebo-controlled study.
Combination antiretroviral therapy (cART) has drastically increased the life expectancy of HIV-infected patients. However, HIV-infected patients exhibit increased inflammation and 33-58% exhibit a characteristic fat re-distribution termed HIV-associated lipodystrophy syndrome (HALS). Recombinant human growth hormone (rhGH) has been tested as treatment of HALS. Low-dose rhGH therapy improves thymopoiesis and fat distribution in HIV-infected patients and appears to be well tolerated. However, since high-dose rhGH is associated with adverse events related to inflammation, we wanted to investigate the impact of low-dose rhGH therapy on inflammation in HIV-infected patients. Forty-six cART-treated HIV-infected men were included in the HIV-GH low-dose (HIGH/Low) study: a randomized, placebo-controlled, double-blinded trial. Subjects were randomized 3:2 to 0.7 mg/day rhGH, or placebo for 40 weeks. rhGH was self-administered between 1 pm and 3 pm. The primary outcome of this substudy was changes in inflammation measured by plasma C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR). Both CRP (-66%, p = 0.002) and suPAR (-9.7%, p = 0.06) decreased in the rhGH group compared to placebo; however, only CRP decreased significantly. The effect of rhGH on inflammation was not mediated through rhGH-induced changes in insulin-like growth factor 1, body composition, or immune parameters. Daily 0.7 mg rhGH treatment for 40 weeks, administered at nadir endogenous GH secretion, significantly reduced CRP. The effect does not appear to be mediated by other factors. Our findings suggest that low-dose rhGH treatment may minimize long-term risks associated with high-dose rhGH therapy.


The urine circulating cathodic antigen (CCA) dipstick: a valid substitute for microscopy for mapping and point-of-care diagnosis of intestinal schistosomiasis.
The World Health Organization now recommends the provision of praziquantel treatment to preschool-aged children infected with schistosomiasis. For intestinal schistosomiasis the current operational field diagnostic standard is examination of a thick Kato-Katz smear by microscopy prepared from a single stool specimen, and although pragmatic, this methodology has well-known shortcomings. Here, as a potential alternative, the performance of the urine circulating cathodic antigen (CCA) dipstick test was assessed in terms of disease-mapping and point-of-care diagnosis for intestinal schistosomiasis in preschool-aged children. Our manuscript reports on findings at baseline and at the end of a one-year longitudinal treatment study. A total of 925 children (mean age 2.8 years) were initially recruited from six lakeshore villages representative of high, moderate and low levels of disease transmission. At baseline, all children were tested for intestinal schistosomiasis by microscopic examination of duplicate Kato-Katz smears prepared from a single stool faecal, by antigen detection with the urine CCA dipstick test and by serology with a commercially available ELISA test (as 'gold-standard') that measures host antibody titres to soluble egg antigens. As a point-of-care diagnosis, the urine CCA dipstick test achieved sensitivity and specificity values ranging from 52.5-63.2% and 57.7-75.6%, respectively, with faecal microscopy achieving very high specificities (>87%) but sensitivities as low as 16.7% in the low transmission setting. The urine CCA test was shown to be more effective than faecal microscopy especially in lower transmission settings. The diagnostic performance of this test was not significantly impacted by treatment history or co-infections with other intestinal helminths.


Hydroboration of alkynes and nitriles using an α-diimine cobalt hydride catalyst.
Addition of NaEt3BH to (Ph2PPrDI)CoCl2 affords the corresponding monohydride, (Ph2PPrDI)CoH. X-ray diffraction and DFT calculations indicate that this compound possesses a radical monoanion α-DI chelate and a Co(ii) centre. Notably, (Ph2PPrDI)CoH catalyzes the hydroboration of alkynes and dihydroboration of nitriles under mild conditions.


A proposal to solve the comparability problem in cost-utility analysis.
In cost-utility analysis it is assumed that health state valuations are directly comparable across individuals. Instead, health state valuations may be relative and related to people's expectations and abilities. Then health state valuations are not fully comparable across people and, consequently, cost utility analysis cannot be applied in full. The present paper analyzes this comparability problem and proposes a method to solve it.


Radial Spokes-A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella.
Propulsive forces generated by cilia and flagella are used in events that are critical for the thriving of diverse eukaryotic organisms in their environments. Despite distinctive strokes and regulations, the majority of them adopt the 9+2 axoneme that is believed to exist in the last eukaryotic common ancestor. Only a few outliers have opted for a simpler format that forsakes the signature radial spokes and the central pair apparatus, although both are unnecessary for force generation or rhythmicity. Extensive evidence has shown that they operate as an integral system for motility control. Recent studies have made remarkable progress on the radial spoke. This review will trace how the new structural, compositional, and evolutional insights pose significant implications on flagella biology and, conversely, ciliopathy.


Association of the Asthma Control Test with peak flow measures in a population in Puerto Rico.
The Asthma Control Test (ACT) questionnaire has been widely used and validated in various ethnic groups, showing an adequate correlation with physician assessment of asthma control. We sought to evaluate the relationship between ACT-defined asthma control and peak flow measures in subjects living in Puerto Rico. A retrospective evaluation of data collected by a mobile asthma clinic in 2 cities in Puerto Rico was conducted. The participants completed an asthma and rhinitis survey. Self-reported asthmatics answered the age-appropriate Spanish version of the ACT. Peak flows (PEF) were measured. Subjects were skin-tested against the common local aeroallergens. The study was approved by the University of Puerto Rico's IRB. We evaluated data from 70 subjects aged 4 to 68. Of them, 82.85% were 12 years old or older, 64.3% reported having a history of asthma, 57.14% reported that they still suffered from asthma, 81.4% reported that they suffered from rhinitis, and 78.57% were sensitized to at least 1 antigen. The mean ACT score of current asthmatics was 18.97, while that of past asthmatics was 23.83 (p = 6.6e-6). The variability of PEF increased as the ACT score increased. Age had no impact on asthma control (p > 0.25), while the effect of PEF on the control of asthma was tied to gender. Rhinitis was also associated with poor asthma control as defined by the ACT score. No other covariate was found to be statistically significant (p < 0.05). Our study supports the use of the ACT to evaluate asthma control in asthmatics living in Puerto Rico. Research into factors associated with poor asthma control, and the importance of rhinitis with regard to such control, is needed.


Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma.
Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS. A core group of pediatric rheumatologists, dermatologists, and a lay advisor was engaged by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to develop standardized treatment plans and assessment parameters for juvenile LS using consensus methods/nominal group techniques. Recommendations were validated in 2 face-to-face conferences with a larger group of practitioners with expertise in juvenile LS and with the full membership of CARRA, which encompasses the majority of pediatric rheumatologists in the US and Canada. Consensus was achieved on standardized treatment plans that reflect the prevailing treatment practices of CARRA members. Standardized clinical assessment methods and provisional treatment response criteria were also developed. Greater than 90% of pediatric rheumatologists responding to a survey (66% of CARRA membership) affirmed the final recommendations and agreed to utilize these consensus plans to treat patients with juvenile LS. Using consensus methodology, we have developed standardized treatment plans and assessment methods for juvenile LS. The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile LS.


Hemodynamic characteristics of the intestinal microcirculation in renal hypertension.
This study investigated the microvascular changes that affect vascular resistance in the rat small intestine during two-kidney, one clip renal hypertension 4 weeks after renal artery stenosis. To study the intestinal microcirculation, a loop of the small intestine was exteriorized with intact circulation and innervation and a section of the bowel wall was prepared for observation with an intravital video microscopy system. Microvascular diameter, pressure, and flow velocity were measured for first, second, and third branch order arterioles and venules, using an image shearing monitor, servo-null micropipette system, and an optical Doppler velocimeter, respectively. The diameters of the first order arterioles and venules were significantly (p less than 0.05) reduced in hypertensive rats; however, diameters were unaltered in smaller second and third order arterioles and venules as compared with normotensive vessels. In hypertensive rats, mean arterial pressure was significantly (p less than 0.05) elevated (47%) and pressures also were elevated significantly (p less than 0.05) throughout the microcirculation, although by a proportionally smaller amount. Total network flow (i.e., first order arteriole flow) was significantly (p less than 0.05) reduced (40%) in hypertensive rats, but volume flows in individual second and third order arterioles were similar to flows measured in normotensive rats. Calculated total network resistance was increased (124%) in hypertensive rats. Thus, the intestinal microcirculation in rats with two-kidney, one clip renal hypertension is disturbed by elevated pressure and decreased total flow. The presence of normal flows in individual second and third order arterioles without any demonstrable difference in their diameters suggests that the predominant cause of elevated resistance across this segment of the intestinal microcirculation is a reduction in the number of perfused small arterioles.


FITNESSGRAM® Friday: A Middle School Physical Activity and Fitness Intervention.
Texas Senate Bill 530 (2007) mandated fitness assessment as part of the annual K-8 Physical Education (PE) curricula, yet no studies have reported interventions designed to improve and quantify individual student passing rates or individual school performance. Students (Total 2008-2010 N=1484; 729 females, 755 males; mean age = 11.85 y; mean BMI = 22.69 or > 90%-tile, overweight) were evaluated on individual FITNESSGRAM® performances in a cross-sectional analysis of 6th graders comparing baseline scores (year 1) with outcomes of a physical activity intervention in years 2 and 3. Students participated in regular PE classes (including campus wellness center activities) with a once a week focus (FITNESSGRAM® Friday) on improving mile run scores and other assessment scores. Students significantly improved FITNESSGRAM® scores following the PE intervention to levels similar to state reported averages. On average, boys improved their pushups by 32.7%, trunk lift by 17.4% and mile run times by 29.5%. Averages for girls improved by 15.4% for pushups, 6.7% for truck lift, and by 38.6% for the mile run. The percentage of boys in our study achieving all six FITNESSGRAM® tests in the HFZ was 3% at baseline and 22% following intervention. The percentage of girls meeting the criteria for the HFZ on all six FITNESSGRAM® tests was 4.5% at baseline and 20% following intervention. This study provides a potential model for fitness success in other middle school PE interventions, in Texas and the nation.


A new species group of the genus Epicauta Dejean of southern South America, the bella group (Coleoptera: Meloidae).
Epicauta includes two subgenera, and within the nominotypical subgenus several species groups. Analyzing species of southern South America, a set of species of Epicauta has the particularity to present two distinctive characters which separates this group from the other species groups of American Epicauta: color pattern of pubescence in elytra is not coincident with color pattern of tegument and endophalic hook robust. Based on these characters I propose a new group of species herein named bella group. This group includes the Neotropical species Epicauta bella Mäklin, E. brunneipennis (Haag-Rutemberg), E. diagramma (Burmeister), E. griseonigra (Fairmaire), E. luctifera (Fairmaire), E. riojana (Fairmaire) (new status), and E. zebra (Dohrn). This group is endemic of southern South America, inhabiting the Chaco biogeographical subregion, mainly in the arid northern areas of Argentina. Here we redefine the species of the bella group, consider new characters, illustrate the species in the group, provide maps of their distribution, and a key to identify them.


Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D.
Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. Here, we demonstrate that cell cycle regulators Cyclin D1-3 control cell fate decisions in human pluripotent stem cells by recruiting transcriptional corepressors and coactivator complexes onto neuroectoderm, mesoderm, and endoderm genes. This activity results in blocking the core transcriptional network necessary for endoderm specification while promoting neuroectoderm factors. The genomic location of Cyclin Ds is determined by their interactions with the transcription factors SP1 and E2Fs, which result in the assembly of cell cycle-controlled transcriptional complexes. These results reveal how the cell cycle orchestrates transcriptional networks and epigenetic modifiers to instruct cell fate decisions.


Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs.
A sustained inflation (SI) rapidly restores cardiac function in asphyxic, bradycardic newborns but its effects on cerebral haemodynamics and brain injury are unknown. We determined the effect of different SI strategies on carotid blood flow (CaBF) and cerebral vascular integrity in asphyxiated near-term lambs. Lambs were instrumented and delivered at 139 ± 2 d gestation and asphyxia was induced by delaying ventilation onset. Lambs were randomised to receive 5 consecutive 3 s SI (multiple SI; n = 6), a single 30 s SI (single SI; n = 6) or conventional ventilation (no SI; n = 6). Ventilation continued for 30 min in all lambs while CaBF and respiratory function parameters were recorded. Brains were assessed for gross histopathology and vascular leakage. CaBF increased more rapidly and to a greater extent during a single SI (p = 0.01), which then decreased below both other groups by 10 min, due to a higher cerebral oxygen delivery (p = 0.01). Blood brain barrier disruption was increased in single SI lambs as indicated by increased numbers of blood vessel profiles with plasma protein extravasation (p = 0.001) in the cerebral cortex. There were no differences in CaBF or cerebral oxygen delivery between the multiple SI and no SI lambs. Ventilation with an initial single 30 s SI improves circulatory recovery, but is associated with greater disruption of blood brain barrier function, which may exacerbate brain injury suffered by asphyxiated newborns. This injury may occur as a direct result of the initial SI or to the higher tidal volumes delivered during subsequent ventilation.


Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response.
Endoplasmic reticulum (ER) stress-induced activation of ATF6, an ER membrane-bound transcription factor, requires a dissociation step from its inhibitory regulator, BiP. It has been generally postulated that dissociation of the BiP-ATF6 complex is a result of the competitive binding of misfolded proteins generated during ER stress. Here we present evidence against this model and for an active regulatory mechanism for dissociation of the complex. Contradictory to the competition model that is based on dynamic binding of BiP to ATF6, our data reveal relatively stable binding. First, the complex was easily isolated, in contrast to many chaperone complexes that require chemical cross-linking. Second, ATF6 bound at similar levels to wild-type BiP and a BiP mutant form that binds substrates stably because of a defect in its ATPase activity. Third, ER stress specifically induced the dissociation of BiP from ER stress transducers while the competition model would predict dissociation from any specific substrate. Fourth, the ATF6-BiP complex was resistant to ATP-induced dissociation in vitro when isolated without detergents, suggesting that cofactors stabilize the complex. In favor of an active dissociation model, one specific region within the ATF6 lumenal domain was identified as a specific ER stress-responsive sequence required for ER stress-triggered BiP release. Together, our results do not support a model in which competitive binding of misfolded proteins causes dissociation of the BiP-ATF6 complex in stressed cells. We propose that stable BiP binding is essential for ATF6 regulation and that ER stress dissociates BiP from ATF6 by actively restarting the BiP ATPase cycle.


Primary endovascular therapy with clot retrieval and balloon angioplasty for acute basilar artery occlusion.
This case report demonstrates that mechanical clot disruption and retrieval may be performed safely and successfully in a child with basilar artery (BA) thrombosis. A 16-year-old boy presented to our institution with locked-in syndrome 20 h after symptom onset. Brain MRI and cerebral angiography findings were consistent with BA occlusion. The child underwent endovascular therapy with clot retrieval followed by balloon angioplasty achieving immediate recanalization and clinical recovery on 3-month follow-up. This case highlights the use of primary neurointerventional devices in children with BA occlusion presenting beyond the conventional therapeutic window for other interventions.


Modeling the effects of environmental conditions on HT2 and T2 toxin accumulation in field oat grains.
Fusarium head blight (FHB) of wheat and barley has been extensively researched worldwide; in contrast, there is limited information on the effects of environmental conditions on Fusarium toxin accumulation in oat grains. More than 300 samples of oat grain from various regions of the United Kingdom from 2006 to 2008 were analyzed for mycotoxin contamination due to infection by Fusarium spp. HT2 and T2 toxins were the two most commonly detected, and their concentrations in individual samples were highly correlated. Hourly weather data were obtained from meteorological recording stations near most of the sampling sites. Statistical modeling was applied to both the original toxin (HT2 plus T2) data and the toxin data adjusted for oat cultivars and number of cereal crops in the previous four seasons. Accumulation of HT2 and T2 toxin was positively correlated with warm and wet conditions during early May and dry conditions thereafter. Using a collection of 51 environmental variables summarized over three lengths (10, 15, and 20 days) of time periods encompassing early May, late May, and early July, all-subsets regression showed that many models, consisting of three to six predictor variables, could be identified with similar explanatory strength for the effect of environmental conditions on toxin accumulation. Most important predictor variables were related to wet conditions during the early-May period, which was before anthesis. These results suggest that the predominant period for Fusarium langsethiae infection of oat is likely to be before rather than during anthesis, as for other head blight pathogens. These empirical models may be further improved by using quantified pathogen biomass within the grains and weather predictor variables summarized in relation to plant growth stages (instead of calendar times).


Renoprotective effects of gamma-aminobutyric acid on cisplatin-induced acute renal injury in rats.
To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline- and GABA-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP-induced ARI.


Prognostic Factors for Physical Functioning After Multidisciplinary Rehabilitation in Patients With Chronic Musculoskeletal Pain: A Systematic Review and Meta-Analysis.
This systematic review aimed to identify and evaluate prognostic factors for long-term (≥6 mo) physical functioning in patients with chronic musculoskeletal pain following multidisciplinary rehabilitation (MDR). Electronic searches conducted in MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, and Cochrane CENTRAL revealed 25 original research reports, published 1983-2016, (n=9436). Potential prognostic factors relating to initial pain and physical and psychological functioning were synthesized qualitatively and quantitatively in random effects meta-analyses. The level of evidence (LoE) was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE). Pain-related factors (intensity and chronicity) were not associated with function/disability at long-term follow-up, odds ratio (OR)=0.84; 95% confidence interval (CI), 0.65-1.07 and OR=0.97; 95% CI, 0.93-1.00, respectively (moderate LoE). A better function at follow-up was predicted by Physical factors; higher levels of initial self-reported functioning, OR=1.07; 95% CI, 1.02-1.13 (low LoE), and Psychological factors; low initial levels of emotional distress, OR=0.77; 95% CI, 0.65-0.92, low levels of cognitive and behavioral risk factors, OR=0.85; 95% CI, 0.77-0.93 and high levels of protective cognitive and behavioral factors, OR=1.49; 95% CI, 1.17-1.90 (moderate LoE). While pain intensity and long-term chronicity did not predict physical functioning in chronic pain patients after MDR, poor pretreatment physical and psychological functioning influenced the prognosis negatively. Thus, treatment should further target and optimize these modifiable factors and an increased focus on positive, psychological protective factors may perhaps provide an opening for yet untapped clinical gains.


SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis.
In the present study, we screened for subtilisin-like proprotein convertases (SPCs) that potentially regulate the activation of known growth factors during embryonic development. We isolated a novel protease, SPC7, as well as several known SPCs. SPC7, like SPC1, is expressed ubiquitously throughout development. In contrast, SPC4 and SPC6 exhibit dynamic expression patterns. SPC4 transcripts were initially detected in the granulosa cells of secondary follicles. Shortly after implantation, SPC4 transcripts are localized to extraembryonic cell populations, and at later stages are detected in discrete tissues including the primitive gut, heart, neural tube, and limb buds. Within the limb buds, SPC4 mRNA is most abundant in the apical ectodermal ridge (AER). At later stages of limb development, SPC4 mRNA is strongly expressed in cartilage and in the interdigital mesenchyme. In contrast, high SPC6 mRNA levels are detected in somites, the dorsal surface ectoderm, and in vertebral cartilage primordia. In limb buds, SPC6 is strongly expressed in the AER, and at later stages in dorsal mesenchyme. A comparison of these expression patterns with those of several bone morphogenetic proteins (BMPs) indicates that processing of these growth factors may be limited by the local availability of SPCs.


Simulation data for the estimation of numerical constants for approximating pairwise evolutionary distances between amino acid sequences.
Estimating the number of substitution events per site that have occurred during the evolution of a pair of amino acid sequences is a common task in phylogenetics and comparative genomics that often requires quite slow maximum-likelihood procedures when taking into account explicit evolutionary models. Data presented in this article are large sets of numbers of substitution events and associated numbers of observed differences between pairs of aligned amino acid sequences that have been generated through a simulation procedure of sequence evolution under a broad range of evolutionary models. These data are available at https://zenodo.org/record/2653704 (doi:10.5281/zenodo.2653704). They are accompanied in this paper by figures showing the strong relationship between the corresponding evolutionary and uncorrected distances, as well as estimated numerical constants that determine non-linear functions that fit the simulated data. These numerical constants can be useful to quickly estimate pairwise evolutionary distances directly from uncorrected distances between aligned amino acid sequences.


Imaging for the selection and monitoring of men on active surveillance for prostate cancer.
Traditional prostate imaging is fairly limited, and only a few imaging modalities have been used for this purpose. Until today, grey scale ultrasound was the most widely used method for the characterization of the prostatic gland, however its limitations for prostate cancer (PCa) detection are well known and hence ultrasound is primarily used to localize the prostate and facilitate template prostate biopsies. In the past decade, multiparametric magnetic resonance imaging (mpMRI) of the prostate has emerged as a promising tool for the detection of PCa. Evidence has shown the value of mpMRI in the active surveillance (AS) population, given its ability to detect more aggressive disease, with data building up and supporting its use for the selection of patients suitable for surveillance. Additionally, mpMRI targeted biopsies have shown an improved detection rate of aggressive PCa when compared to regular transrectal ultrasound (TRUS) guided biopsies. Current data supports the use of mpMRI in patients considered for AS for reclassification purposes; with a negative mpMRI indicating a decreased risk of reclassification. However, a percentage of patients with negative imaging or low suspicion lesions can experience reclassification, highlighting the importance of repeat confirmatory biopsy regardless of mpMRI findings. At present, no robust data is available to recommend the substitution of regular biopsies with mpMRI in the follow-up of patients on AS and efforts are being made to determine the role of integrating genomic markers with imaging with the objective of minimizing the need of biopsies during the follow up period.


Zebrafish Models of Kidney Damage and Repair.
The vertebrate kidney possesses the capacity to repair damaged nephrons, and this potential is conserved regardless of the complexity of species-specific kidneys. However, many aquatic vertebrates possess the ability to not only repair existing nephrons, but also generate new nephrons after injury. Adult zebrafish have the ability to recover from acute renal injury not only by replacing lost injured epithelial cells of endogenous nephrons, but by also generating de novo nephrons. This strong regeneration potential, along with other unique characteristics such as the high degree of genetic conservation with humans, the ease of harvesting externally fertilized, transparent embryos, the accessibility to larval and adult kidneys, and the ability to perform whole organism phenotypic small molecule screens, has positioned zebrafish as a unique vertebrate model to study kidney injury. In this review, we provide an overview of the contribution of zebrafish larvae/adult studies to the understanding of renal regeneration, diseases, and therapeutic discovery.


Blood metals concentration in type 1 and type 2 diabetics.
Mechanisms for the onset of diabetes and the development of diabetic complications remain under extensive investigations. One of these mechanisms is abnormal homeostasis of metals, as either deficiency or excess of metals, can contribute to certain diabetic outcomes. Therefore, this paper will report the blood levels of chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), mercury (Hg), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in subjects with type 1 diabetes (n = 192, mean age 48.8 years, mean disease duration 20.6 years), type 2 diabetes (n = 68, mean age 68.4 years, mean disease duration 10.2 years), and in control subjects (n = 59, mean age 57.2 years), and discuss the results indicating their possible role in diabetes. The metal concentrations were measured by sector field inductively coupled plasma mass spectrometry after microwave-induced acid digestion of blood samples. The accuracy was checked using a blood-based certified reference material, and recoveries of all elements were in the range of 92-101 % of certified values. Type 1 diabetes was found to be associated with Cr (p = 0.02), Mn (p < 0.001), Ni (p < 0.001), Pb (p = 0.02), and Zn (p < 0.001) deficiency, and type 2 diabetes with Cr (p = 0.014), Mn (p < 0.001), and Ni (p < 0.001) deficiency. These deficiencies were appreciated also subdividing the understudied patients for gender and age groups. Furthermore, in type 1 diabetes, there was a positive correlation between Pb and age (p < 0.001, ρ = 0.400) and Pb and BMI (p < 0.001, ρ = 0.309), while a negative correlation between Fe and age (p = 0.002, ρ = -0.218). In type 2 diabetes, there was a negative correlation between Fe and age (p = 0.017, ρ = -0.294) and Fe and BMI (p = 0.026, ρ = -0.301). Thus, these elements may play a role in both forms of diabetes and combined mineral supplementations could have beneficial effects.


Pneumococcal conjugate vaccine use during humanitarian crises.
Streptococcus pneumoniae is a common human commensal that causes a sizeable part of the overall childhood mortality in low income settings. Populations affected by humanitarian crises are at especially high risk, because a multitude of risk factors that are enhanced during crises increase pneumococcal transmission and disease severity. Pneumococcal conjugate vaccines (PCVs) provide effective protection and have been introduced into the majority of routine childhood immunisation programmes globally, though several barriers have hitherto limited their uptake during humanitarian crises. When PCV coverage cannot be sustained during crises or when PCV has not been part of routine programmes, mass vaccination campaigns offer a quick acting and programmatically feasible bridging solution until services can be restored. However, we currently face a paucity of evidence on which to base the structure of such campaigns. We believe that, now that PCV can be procured at a substantially reduced price through the Humanitarian Mechanism, this lack of information is a remaining hurdle to PCV use in humanitarian crises. Considering the difficulties in conducting research in crises, we propose an evidence generation pathway consisting of primary data collection in combination with mathematical modelling followed by quasi-experimental evaluation of a PCV intervention, which can inform on optimal vaccination strategies that consider age targeting, dosing regimens and impact duration.


The effect of hand dimensions, hand shape and some anthropometric characteristics on handgrip strength in male grip athletes and non-athletes.
It has been suggested that athletes with longer fingers and larger hand surfaces enjoy stronger grip power. Therefore, some researchers have examined a number of factors and anthropometric variables that explain this issue. To our knowledge, the data is scarce. Thus, the aim of this study was to investigate the effect of hand dimensions, hand shape and some anthropometric characteristics on handgrip strength in male grip athletes and non-athletes. 80 subjects aged between 19 and 29 participated in this study in two groups including: national and collegian grip athletes (n=40), and non-athletes (n=40). Body height and mass were measured to calculate body mass index. The shape of the dominant hand was drawn on a piece of paper with a thin marker so that finger spans, finger lengths, and perimeters of the hand could be measured. The hand shape was estimated as the ratio of the hand width to hand length. Handgrip strength was measured in the dominant and non-dominant hand using a standard dynamometer. Descriptive statistics were used for each variable and independent t test was used to analyze the differences between the two groups. The Pearson correlation coefficient test was used to evaluate the correlation between studied variables. Also, to predict important variables in handgrip strength, the linear trend was assessed using a linear regression analysis. There was a significant difference between the two groups in absolute handgrip strength (p<0.001) and handgrip/height ratio (p<0.001). The indices of body height, body mass, lean body mass and body fat content (p<0.001) were significantly greater in grip athletes. All hand variables except FS1-4 (p>0.05) were significantly different between the groups (p<0.001). After controlling body mass all hand anthropometric characteristics except thumb length (r=0.240, p= 0.135), hand shape (r=-0.029, p=0.858), middle finger length (r=0.305, p=0.056) and forearm circumference (r=0.162, p=0.319) significantly correlated with handgrip strength in grip athletes, but not in non-athletes, except for forearm circumference (r=0.406, p=0.010). The results showed that handgrip strength and some of the hand dimensions may be different in athletes who have handgrip movements with an object or opponent in comparison to non-athletes. Also, there was a significant positive correlation between handgrip strength and most of the hand dimensions in grip athletes. Therefore, these can be used in talent identification in handgrip-related sports and in clinical settings as well.


Oncostatin M and TLR-4 ligand synergize to induce MCP-1, IL-6, and VEGF in human aortic adventitial fibroblasts and smooth muscle cells.
Accumulating evidence suggests that adventitial fibroblasts play a significant role in contributing to inflammation of the arterial wall and pathogenesis of atherosclerosis. The effects of gp130 cytokines on these cells (including oncostatin M-[OSM] and IL-6), some of which have been implicated in atherosclerosis, are currently unknown. Experiments were performed to determine whether gp130 cytokines regulate human aortic adventitial fibroblasts (HAoAFs) or smooth muscle cells (HAoSMCs) alone or in context of TLR-4 ligands (also implicated in atherosclerosis). HAoAFs and HAoSMCs were stimulated with LPS and/or one of OSM, IL-6, IL-11, IL-31, or LIF. ELISAs performed on cell supernatants showed that stimulation with OSM alone caused increased MCP-1, IL-6, and VEGF levels. When combined, LPS and OSM synergized to increase MCP-1, IL-6, VEGF protein, and mRNA expression as assessed by qRT-PCR, in both HAoAFs and HAoSMCs, while LPS-induced IL-8 levels were reduced. Such effects were not observed with other gp130 cytokines. Signalling pathways including STATs, MAPKinases, and NF κ B were activated, and LPS induced steady state mRNA levels of the OSM receptor chains OSMR β and gp130. The results suggest that OSM is able to synergize with TLR-4 ligands to induce proinflammatory responses by HAoAFs and HAoSMCs, supporting the notion that OSM regulation of these cells contributes to the pathogenesis of atherosclerosis.


Prediction of benefit from carotid endarterectomy in individual patients: a risk-modelling study. European Carotid Surgery Trialists' Collaborative Group.
Carotid endarterectomy lowers the risk of carotid territory ipsilateral ischaemic stroke, and is the treatment of choice, in patients with recently symptomatic 70-99% carotid stenosis. However, the 3-year risk of stroke on medical treatment alone is only about 20%. We investigated whether the efficacy of endarterectomy would be improved if patients with a high risk of stroke on medical treatment and a low risk of operative stroke or death could be identified. We developed two prognostic models from data on patients with 0-69% carotid stenosis in the European Carotid Surgery Trial (ECST). The medical model predicted risk of ipsilateral carotid territory major ischaemic stroke (fatal or lasting longer than 7 days) on medical treatment and the surgical model predicted risk of major stroke and death within 30 days of endarterectomy. From these models we developed a prognostic score to identify patients with a high risk of stroke on medical treatment but a low operative risk. We validated the models and tested the scoring system on 990 ECST patients with 70-99% carotid stenosis assigned surgery (594) or medical treatment only (396). When patients with 70-99% stenosis were stratified by the scoring system, which was based on seven independent prognostic factors, endarterectomy was beneficial in only 162 (16%) patients. The 5-year absolute risk of carotid territory ipsilateral major ischaemic stroke, operative major stroke, or death was lowered by 33% in the 16% of patients with a score of 4 or more (odds ratio 0.12 [95% CI 0.05-0.29], p<0.0001), but not in the other 828 (84%) patients (1.00 [0.65-1.54], p=0.7). Many patients with recently symptomatic 70-99% carotid stenosis may not benefit from carotid endarterectomy. Validation of the predictive score is needed on external datasets, but risk-factor modelling could be useful to identify those patients in whom endarterectomy will be beneficial.


Neural correlates of implicit object identification.
The present study sought to assess neural correlates of implicit identification of objects by means of fMRI, using tasks that require matching of the physical properties of objects. Behavioural data suggests that there is automatic access to object identity when observers attend to a physical property of the form of an object (e.g. the object's orientation) and no evidence for semantic processing when subjects attend to colour. We evaluated whether, in addition to neural areas associated with decisions to specific perceptual properties, areas associated with access to semantic information were activated when tasks demanded processing of the global configuration of pictures. We used two perceptual matching tasks based on the global orientation or on the colour of line drawings. Our results confirmed behavioural data. Activations in the inferior occipital cortex, fusiform and inferior temporal gyri in both tasks (orientation and colour) account for perceptual and structural processing involved in each task. In contrast, activations in the posterior and medial parts of the fusiform gyrus, shown to be involved in explicit semantic judgements, were more pronounced in the orientation-matching task, suggesting that semantic information from the pictures is processed in an implicit way even when not required by the task. Thus, this study suggests that cortical regions usually involved in explicit semantic processing are also activated when implicit processing of objects occurs.


Catecholamine metabolism and disposition in healthy and depressed subjects.
Depressed patients as a group have been found to excrete greater amounts of catecholamines (CAs) and metabolites than healthy control subjects, but these differences were not uniform for all metabolites. Patients may differ from controls in the metabolism and/or disposition of CAs. We analyzed the suggested metabolic-dispositional differences by determining 24-hour urine values for norepinephrine (NE), epinephrine (E), normetanephrine (NM), metanephrine (M), vanillylmandelic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). For each subject, we calculated ratios of CAs or metabolites to an estimate of CA synthesis and determined ratios of CAs and metabolites to each other based on a precursor-product paradigm. The results indicate that as a group, patients have modestly but significantly greater CA synthesis rates than controls; patients excrete disproportionately more NE and E and disproportionately less MHPG relative to estimated CA synthesis, as well as other metabolites, than do controls; in contrast to NE, E, and MHPG, the increased NM, M, and VMA excretion rates by patients are proportional to each other as well as to the increase in CA synthesis; and the differences in NE, E, and metabolite excretion in the patients as a group are due principally to unipolar rather than bipolar depressives. The differences would be expected if patients, relative to controls, released more NE and E into the circulation. These data indicate the need to measure several CAs and metabolites when evaluating differences between groups since the significance of any given metabolite value needs to be examined in the context of total CA and metabolite production and excretion.


Thalamic and subthalamic deep brain stimulation for essential tremor: where is the optimal target?
The ventrolateral thalamus (ventral intermediate nucleus [Vim]) is the traditional target for neurosurgical treatment of essential tremor. The target, however, has varied substantially among different neurosurgeons. To evaluate the effect of deep brain stimulation in the thalamus and posterior subthalamic area (PSA) in relation to electrode location. Thirty-six (17 Vim/19 PSA) patients with 44 deep brain stimulation electrodes were included in this retrospective study. The effect of stimulation was evaluated with standardized settings for each contact using items from the Essential Tremor Rating Scale. When each contact was evaluated in terms of the treated hand with standardized stimulation, the electrode contact providing the best effect in the individual patient was located in the zona incerta or radiation prelemniscalis in 54% and the Vim in 12%. Forty contacts provided a tremor reduction of > 90%. Of these, 43% were located in the PSA and 18% in the Vim according to the Schaltenbrand atlas. Of these 40 contacts, 37 were found in the PSA group. More contacts yielding an optimal effect were found in the PSA group than in the Vim. Many patients operated on in the Vim got the best effect from a contact located in the PSA. This might suggest that the PSA is a more efficient target than the Vim.


Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth.
A common feature of temporal lobe epilepsy and of animal models of epilepsy is the growth of hippocampal mossy fibers into the dentate molecular layer, where at least some of them innervate granule cells. Because the mossy fibers are axons of granule cells, the recurrent mossy fiber pathway provides monosynaptic excitatory feedback to these neurons that could facilitate seizure discharge. We used the pilocarpine model of temporal lobe epilepsy to study the synaptic responses evoked by activating this pathway. Whole cell patch-clamp recording demonstrated that antidromic stimulation of the mossy fibers evoked an excitatory postsynaptic current (EPSC) in approximately 74% of granule cells from rats that had survived >10 wk after pilocarpine-induced status epilepticus. Recurrent mossy fiber growth was demonstrated with the Timm stain in all instances. In contrast, antidromic stimulation of the mossy fibers evoked an EPSC in only 5% of granule cells studied 4-6 days after status epilepticus, before recurrent mossy fiber growth became detectable. Notably, antidromic mossy fiber stimulation also evoked an EPSC in many granule cells from control rats. Clusters of mossy fiber-like Timm staining normally were present in the inner third of the dentate molecular layer at the level of the hippocampal formation from which slices were prepared, and several considerations suggested that the recorded EPSCs depended mainly on activation of recurrent mossy fibers rather than associational fibers. In both status epilepticus and control groups, the antidromically evoked EPSC was glutamatergic and involved the activation of both AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors. EPSCs recorded in granule cells from rats with recurrent mossy fiber growth differed in three respects from those recorded in control granule cells: they were much more frequently evoked, a number of them were unusually large, and the NMDA component of the response was generally much more prominent. In contrast to the antidromically evoked EPSC, the EPSC evoked by stimulation of the perforant path appeared to be unaffected by a prior episode of status epilepticus. These results support the hypothesis that recurrent mossy fiber growth and synapse formation increases the excitatory drive to dentate granule cells and thus facilitates repetitive synchronous discharge. Activation of NMDA receptors in the recurrent pathway may contribute to seizure propagation under depolarizing conditions. Mossy fiber-granule cell synapses also are present in normal rats, where they may contribute to repetitive granule cell discharge in regions of the dentate gyrus where their numbers are significant.


Principal component analysis of the excluded area of two-dimensional hard particles.
The excluded area between a pair of two-dimensional hard particles with given relative orientation is the region in which one particle cannot be located due to the presence of the other particle. The magnitude of the excluded area as a function of the relative particle orientation plays a major role in the determination of the bulk phase behavior of hard particles. We use principal component analysis (PCA) to identify the different types of excluded areas corresponding to randomly generated two-dimensional hard particles modeled as non-self-intersecting polygons and star lines (line segments radiating from a common origin). Only three principal components are required to have an excellent representation of the value of the excluded area as a function of the relative particle orientation for sufficiently anisotropic particles. Independent of the particle shape, the minimum value of the excluded area is always achieved when the particles are antiparallel to each other. The property that affects the value of the excluded area most strongly is the elongation of the particle shape. PCA identifies four limiting cases of excluded areas with one to four global minima at equispaced relative orientations. We study selected particle shapes using Monte Carlo simulations.


Efficient light amplification in low gain materials due to a photonic band edge effect.
One of the possibilities of increasing optical gain of a light emitting source is by embedding it into a photonic crystal (PhC). If the properties of the PhC are tuned so that the emission wavelength of the light source with gain falls close to the photonic band edge of the PhC, then due to low group velocity of the light modes near the band edge caused by many multiple reflections of light on the photonic structure, the stimulated emission can be significantly enhanced. Here, we perform simulation of the photonic band edge effect on the light intensity of spectrally broad source interacting with a diamond PhC with low optical gain. We show that even for the case of low gain, up to 10-fold increase of light intensity output can be obtained for the two-dimensional PhC consisting of only 19 periodic layers of infinitely high diamond rods ordered into a square lattice. Moreover, considering the experimentally feasible structure composed of diamond rods of finite height - PhC slab - we show that the gain enhancement, even if reduced compared to the ideal case of infinite rods, still remains relatively high. For this particular structure, we show that up to 3.5-fold enhancement of light intensity can be achieved.


A soft decision algorithm for obstructive sleep apnea patient classification based on fast estimation of wavelet entropy of RRI data.
A soft decision algorithm for Obstructive Sleep Apnea (OSA) patient classification using R-R interval (RRI) data is investigated. This algorithm is based on fast and approximate estimation of the entropy of the wavelet-decomposed bands of the RRI data. The classification is done on the whole record as OSA patient or non-patient (normal). The ratio of the estimated entropy of the low-frequency (LF) band to that of the very-low frequency (VLF) band is used as a classification factor. RRI data used in this work are drawn from MIT database. The MIT trial records are used to set the threshold value of the classification factor using the Receiver Operating Characteristics (ROC). This threshold value is used then to classify the MIT challenge (test) records to obtain the efficiency of classification. The new algorithm classifies correctly 30/30 of MIT-test data using different wavelet filters. Comparison of the results of different wavelet filters is done in terms of complexity and distance parameters. The method is also compared with other two techniques using wavelets in their analysis. The consistency of the results is examined using the leave-one-out technique.


Leptin and maternal growth during adolescent pregnancy.
Maternal growth on the basis of knee height occurs in nearly 50% of pregnant teenagers and is associated with greater gestational weight gain and accrual of subcutaneous fat in the mother but lower fetal growth compared with nongrowing teenagers and mature pregnant women. The objective of this study was to determine whether leptin is a biomarker for continued maternal growth. Leptin concentrations were measured in 162 growing and nongrowing teenage gravidas (aged </=18 y) and in mature gravidas (aged 19-29 y) from the Camden Study at 2 time points during pregnancy and 1 time point postpartum. Growing teenagers had leptin concentrations that increased with gestation and were higher at 28 wk gestation and postpartum than in nongrowing teenagers and mature gravidas. The differences were related to a leptin surge between entry into the study (16.9 wk) and week 28, primarily in still-growing gravidas. Leptin-surge quartiles were associated with higher knee-height velocity and weight gain, increased skinfold thicknesses in late pregnancy (28 wk) and early postpartum (4-6 wk), and changes in postpartum weight and body mass index. For the highest quartile, low birth weight increased >5-fold, fetal growth restriction increased >6-fold, and infant birth weight decreased by approximately 200 g. Gravidas who developed pregnancy-induced hypertension showed a different pattern-higher leptin concentrations at entry and week 28, no difference in the leptin surge, and no postpartum difference in leptin concentration. A leptin surge by week 28 appears to mark reduced mobilization of maternal fat stores that is associated with maternal growth on the basis of knee height during adolescent pregnancy.


Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.
Although methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes. Retrospective cohort study (2001-2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression. Sixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9-71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as "difficult-to-treat" in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9-36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7-103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166-24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013-1.271). The important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.


Ovarian mitochondrial and oxidative stress proteins are altered by glyphosate exposure in mice.
Glyphosate (GLY) usage for weed control is extensive. To investigate ovarian impacts of chronic GLY exposure, female C57BL6 mice were orally administered saline as vehicle control (CT) or GLY at 0.25 (G0.25), 0.5 (G0.5), 1.0 (G1.0), 1.5 (G1.5), or 2 (G2.0) mg/kg for five days per wk. for 20 wks. Feed intake increased (P < .05) in G1.5 and G2.0 mice and body weight increased (P < .05) in G1.0 mice. There was no impact of GLY on estrous cyclicity, nor did GLY affect circulating levels of 17β-estradiol or progesterone. Exposure to GLY did not impact heart, liver, spleen, kidney or uterus weight. Both ovarian weight and follicle number were increased (P < .05) by G2.0 but not affected at lower GLY concentrations. There were no detectable effects of GLY on ovarian protein abundance of pAKT, AKT, pAKT:AKT, γH2AX, STAR, CYP11A1, HSD3B, CYP19A, ERA or ERB. Increased (P < .05) abundance of ATM protein was observed at G0.25 but not higher GLY doses. A dose-dependent effect (P < .10) of GLY exposure on ovarian protein abundance as quantified by LC-MS/MS was observed (G0.25-4 increased, 19 decreased; G0.5-5 increased, 25 decreased; G1.0-65 increased, 7 decreased; G1.5-145 increased, 2 decreased; G2.0-159 increased, 4 decreased). Pathway analysis was performed using DAVID and identified glutathione metabolism, metabolic and proteasome pathways as GLY exposure targets. These data indicate that chronic low-level exposure to GLY alters the ovarian proteome and may ultimately impact ovarian function.


Contributions of genetic drift and negative selection on the evolution of three strains of wheat streak mosaic tritimovirus.
Genome sequences of three Wheat streak mosaic virus (WSMV) strains were compared. The Type and Sidney 81 strains of WSMV from the American Great Plains were closely related, with sequence identities of 97.6% (nucleotide) and 98.7% (amino acid). In contrast, the El Batán 3 strain from central Mexico was divergent, and shared only 79.2-79.3% (nucleotide) and 90.3-90.5% (amino acid) sequence identity with Type and Sidney 81. All three WSMV strains were serologically related, however the El Batán 3 capsid protein (CP) had 15 fewer amino acid residues. Phylogenetic analysis of the CP cistron indicated that Type, Sidney 81, and nine other American isolates of WSMV were closely related and distinct from the El Batán 3 sequence. Nucleotide substitutions among the WSMV strains were not randomly distributed across the genome with more variation within P1, HC-Pro, and CP, and less within P3. One 400-nucleotide region of the genome, corresponding to the 3'-end of P3, was strikingly deficient in silent substitutions. Nonetheless, the ratio of synonymous to non-synonymous substitutions throughout the genome was essentially the same for all three WSMV strains. Collectively, our data indicate that both genetic drift and negative selection have contributed to the evolution of WSMV strains.


Nutritional supplements use, cost, source of information, and practices by Johannesburg North gym goers.
Nutritional supplements are defined as any dietary supplement manufactured product that is generally intended to supplement the diet when taken by mouth as a pill, capsule, tablet, or liquid. Currently, the use of nutritional supplements is on the increase worldwide, predominantly in Western countries but also more recently expanding to other parts of the world for what has become a multibillion-dollar global industry. As a result, consumer demand has caused the increase in the advertising and marketing of these products. This contributes to early exposure to nutritional supplements by potential consumers and is an influencing factor for the use of performance-enhancing and/or appearance substances by adolescents. For the nutritional supplement industry the container is thus the manifestation of innovative ideas for the enterprising business-minded mogul. For the consumer, body image and ideal body discrepancy, and social influences manifest in the belief that the perfection of body development cannot be achieved without the use of nutritional supplements. This makes the consumer a captive audience for the industry and a challenge for the health care provider when suggesting alternatives to nutritional supplements, based on cost-benefit, and risk assessment. To determine the association between commercial gym goers and nutritional supplements, in particular the commencement of use, reasons and purpose for use, and the financial and risk implications of use. A self-administered questionnaire based on a cross-sectional quantitative design and systematic convenience sampling was given to the 364 recruited males and female gym goers. This study's finding shows that the main reasons why females attend gyms are for muscle gain (57%), weight loss (48%), staying healthy (47%), and a 'spiritual motive' (39%) In males, it is predominantly for muscle gain (54%). Protein supplements were the most popular products that were consumed (84%) followed by carbohydrates (72%) and vitamins (71%). It was found that the consumption of nutritional supplements often starts at high school age and continues into adulthood. The analysis shows that natural source protein products are better priced than nutritional supplement products. The study shows the importance of educating gym goers, the general public, and the guardians of minors to make a behaviour change towards nutritional supplement consumption. The change should also incorporate a cost-benefit risk assessment which is practical for the consumer when comparing supplement use as alternative sources of protein.


Interfacial properties of hydrocarbon/water systems predicted by molecular dynamic simulations.
The presence of small hydrocarbons is known to reduce the interfacial tension of the gas-water interface, and this phenomenon can affect the formation of the clathrate hydrates of these gases. In this work, the interfacial behavior of the pure methane-, ethane-, and propane-water, and the ternary 90:7:3 mol. % gas mixture of (methane + ethane + propane)-water were studied with molecular dynamics simulations. The interfacial tension, γ, and z-density profiles for the gases and water from simulations of the gas-water systems were determined at the temperatures of 275.15 and 298.15 K, and pressures up to 10 MPa for methane and up to near the experimental saturation pressures of ethane and propane. The goal is to accurately calculate the interfacial tension for the hydrocarbon/water systems and to analyze the molecular behaviors at the interfaces which lead to the observed trends. At the same hydrostatic gas phase pressure, propane, ethane, and methane reduce the gas-water interfacial tension in that order. The local density of the gas molecules at the interface is enhanced relative to the bulk gas, and it was determined that about 13%-20%, 33%-40%, and 54%-59% of the gas molecules in the simulation congregated at the interfaces for the CH4-, C2H6-, and C3H8-water systems, respectively, at the different simulated hydrostatic pressure ranges. For all gases in the pressure range studied, a complete monolayer of gas had not formed at the water interface. Furthermore, a dynamic equilibrium with fast exchange between molecules at the interface and in the gas phase was observed. For the gas mixture, deviations were observed between total calculated interfacial tension, γmix, and the "ideal mixture" value, ∑xiγi,pure, calculated from the interfacial tensions of the pure gases, where xi is the mole fraction of each substance in the simulation. Some possible implications of the results on the mechanism of clathrate hydrate formation are discussed.


Innocent heart murmurs and enuresis: Examining a possible link.
The aim of this study was to evaluate the prevalence of innocent heart murmurs in children affected by nocturnal enuresis (NE). The prevalence of innocent heart murmurs in G2 was 6.34%. This condition was significantly more frequent in children who suffered from NE. Indeed, in G1, the prevalence of innocent heart murmurs was 21.45%, although there were few differences between the children with monosymptomatic NE and non-monosymptomatic NE; moreover, this prevalence was higher in males. We enrolled a total of 401 children (G1), 300 males and 101 females, aged 5-15 years, affected by NE and referred to the Service of Pediatrics, "Campus Bio-Medico" University Hospital of Rome, from September 2013 to September 2018, into the study. The control group was composed of 394 children without NE (G2). The study was carried out in compliance with the Helsinki Declaration. These findings made us aware of the presence of possible underlying mechanisms, which explain the association between a higher prevalence of innocent heart murmurs and enuresis, and further studies are required to explore this issue.


Imposed Work of Breathing for Flow Meters with In-Line versus Flow-Through Technique during Simulated Neonatal Breathing.
The ability to determine airflow during nasal CPAP (NCPAP) treatment without adding dead space or resistance would be useful when investigating the physiologic effects of different NCPAP systems on breathing. The aim of this study was to investigate the effect on pressure stability of different flow measuring devices at the in-line and flow-through position, using simulated neonatal breathing. Six different flow measure devices were evaluated by recording pressure changes and imposed work of breathing for breaths with 16 and 32 ml tidal volumes. The tests were performed initially with the devices in an in line position and with 5 and 10 L/min using flow through technique, without CPAP. The flow meters were then subsequently tested with an Infant Flow CPAP system at 3, 5 and 8 cm H2O pressure using flow through technique. The quality of the recorded signals was compared graphically. The resistance of the measuring devices generated pressure swings and imposed work of breathing. With bias flow, the resistance also generated CPAP pressure. Three of the devices had low resistance and generated no changes in pressure stability or CPAP pressure. The two devices intended for neonatal use had the highest measured resistance. The importance of pressure stability and increased work of breathing during non-invasive respiratory support are insufficiently studied. Clinical trials using flow-through technique have not focused on pressure stability. Our results indicate that a flow-through technique might be a way forward in obtaining a sufficiently high signal quality without the added effects of rebreathing and increased work of breathing. The results should stimulate further research and the development of equipment for dynamic flow measurements in neonates.


Expression of inducible nitric oxide synthase in human heart failure.
There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiological importance in heart failure. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS), but there is very little information on the role of the inducible isoform. We analyzed inducible NOS (iNOS) expression in ventricular myocardium taken from 11 control subjects (who had died suddenly from noncardiac causes), from 10 donor hearts before implantation, and from 51 patients with heart failure (24 with dilated cardiomyopathy [DCM], 17 with ischemic heart disease [IHD], and 10 with valvular heart disease [VHD]). Reverse transcription-polymerase chain reaction was used to confirm the presence of intact mRNA and to detect expression of iNOS and atrial natriuretic peptide (ANP). ANP was used as a molecular phenotypic marker of ventricular failure. iNOS was expressed in 36 of 51 biopsies (71%) from patients with heart failure and in none of the control patients (P<.0001). iNOS expression could also be detected in 50% of the donor hearts. All samples that expressed iNOS also expressed ANP. iNOS gene expression occurred in 67% of patients with DCM, 59% of patients with IHD, and 100% of patients with VHD. To determine whether iNOS protein was expressed in failing ventricles, immunohistochemistry was performed on three donor hearts and nine failing hearts with iNOS mRNA expression. Staining for iNOS was almost undetectable in the donor myocardium and in control sections, but all failing hearts showed diffuse cytoplasmic staining in cardiac myocytes. Expression of iNOS could be observed in all four chambers. Western blot analysis with the same primary antibody showed a specific positive band for iNOS protein in the heart failure specimens; minimal iNOS protein expression was seen in donor heart samples. iNOS expression occurs in failing human cardiac myocytes and may be involved in the pathophysiology of DCM, IHD, and VHD.


Generic and diabetes-specific parent-child behaviors and quality of life among youth with type 1 diabetes.
To evaluate associations among parent-child behaviors and generic and diabetes-specific health-related quality of life (HRQOL) in a multi-site sample of youth with type 1 diabetes. One hundred and twenty-one youth and their primary caregivers completed measures of parent-child behaviors, child HRQOL, and participated in an observed family interaction task. Diabetes-specific parent-child variables were associated significantly with both generic and diabetes-specific HRQOL above and beyond the contributions of demographic and generic parent-child variables, accounting for between 13% and 31% of the variance in HRQOL. Diabetes-specific family conflict and negative diabetes-specific family communication were associated with lower HRQOL. Collaborative parent involvement in diabetes care was associated with higher levels of HRQOL. Interventions that target diabetes-specific family interactions will be beneficial to the quality of life of children with type 1 diabetes.


The role of obesity in the biomechanics and radiological changes of the spine: an in vitro study.
The effects of obesity on lumbar biomechanics are not fully understood. The aims of this study were to analyze the biomechanical differences between cadaveric L4-5 lumbar spine segments from a large group of nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) donors and to determine if there were any radiological differences between spines from nonobese and obese donors using MR imaging. A total of 168 intact L4-5 spinal segments (87 males and 81 females) were tested using pure-moment loading, simulating flexion-extension, lateral bending, and axial rotation. Axial compression tests were performed on 38 of the specimens. Sex, age, and BMI were analyzed with biomechanical parameters using 1-way ANOVA, Pearson correlation, and multiple regression analyses. MR images were obtained in 12 specimens (8 from obese and 4 from nonobese donors) using a 3-T MR scanner. The segments from the obese male group allowed significantly greater range of motion (ROM) than those from the nonobese male group during axial rotation (p = 0.018), while there was no difference between segments from obese and nonobese females (p = 0.687). There were no differences in ROM between spines from obese and nonobese donors during flexion-extension or lateral bending for either sex. In the nonobese population, the ROM during axial rotation was significantly greater for females than for males (p = 0.009). There was no significant difference between sexes in the obese population (p = 0.892). Axial compressive stiffness was significantly greater for the obese than the nonobese population for both the female-only group and the entire study group (p < 0.01); however, the difference was nonsignificant in the male population (p = 0.304). Correlation analysis confirmed a significant negative correlation between BMI and resistance to deformation during axial compression in the female group (R = -0.65, p = 0.004), with no relationship in the male group (R = 0.03, p = 0.9). There was also a significant negative correlation between ROM during flexion-extension and BMI for the female group (R = -0.38, p = 0.001), with no relationship for the male group (R = 0.06, p = 0.58). Qualitative analysis using MR imaging indicated greater facet degeneration and a greater incidence of disc herniations in the obese group than in the control group. Based on flexibility and compression tests, lumbar spinal segments from obese versus nonobese donors seem to behave differently, biomechanically, during axial rotation and compression. The differences are more pronounced in women. MR imaging suggests that these differences may be due to greater facet degeneration and an increased amount of disc herniation in the spines from obese individuals.


Effects of a local auxiliary protein on the two-dimensional affinity of a TCR-peptide MHC interaction.
The affinity of T-cell receptors (TCRs) for major histocompatibility complex molecules (MHCs) presenting cognate antigens likely determines whether T cells initiate immune responses, or not. There exist few measurements of two-dimensional (2D) TCR-MHC interactions, and the effect of auxiliary proteins on binding is unexplored. Here, Jurkat T-cells expressing the MHC molecule HLA-DQ8-glia-α1 and the ligand of an adhesion protein (rat CD2) were allowed to bind supported lipid bilayers (SLBs) presenting fluorescently labelled L3-12 TCR and rat CD2, allowing measurements of binding unconfounded by cell signaling effects or co-receptor binding. The 2D Kd for L3-12 TCR binding to HLA-DQ8-glia-α1, of 14±5 molecules/μm2 (mean±s.d.), was only marginally influenced by including CD2 up to ∼200 bound molecules/μm2 but higher CD2 densities reduced the affinity up to 1.9-fold. Cell-SLB contact size increased steadily with ligand density without affecting binding for contacts at up to ∼20% of total cell area, but beyond this lamellipodia appeared, giving an apparent increase in bound receptors of up to 50%. Our findings show how parameters other than the specific protein-protein interaction can influence binding behavior at cell-cell contacts.