[Duration of inhalation and exhalation in increasing hypercapnia and the effect of additional resistive inspiratory resistance].
In healthy subjects, patterns of inhalation and exhalation durations during growing hypercapnia were studied in free breathing and under the effect of resistive inspiratory resistance 20 and 35 cm H2O/1/sec. Pattern of the inhalation duration was divided into two ranges: the inhalation elongated in the first range and shortened in the second one. The border between these ranges corresponded in free breathing to CO2 tension of exhalation terminal portion (PETCO2)--47.2 +/- 1.0 mm Hg (M +/- m). The 1st range was found in 2/3 of cases in the exhalation duration pattern. Under the effect of additional inspiratory resistance, the border between the two ranges of inhalation pattern shifted towards greater PETCO2 values and was 51.0 +/- 1.0 mm Hg for the greater resistance. The 1st range was found in 1/3 of cases in the exhalation duration dynamics. The shift of the border between the ranges of the inhalation duration pattern occurring in breathing with a resistive load in the course of growing hypercapnia seems to result from an augmentation of cortical effects upon breathing and/or weakening of afferent influences from the lung stretch receptors under these conditions.


Comparison of different nonlinear functions to describe Nelore cattle growth.
This work aims to compare different nonlinear functions for describing the growth curves of Nelore females. The growth curve parameters, their (co)variance components, and environmental and genetic effects were estimated jointly through a Bayesian hierarchical model. In the first stage of the hierarchy, 4 nonlinear functions were compared: Brody, Von Bertalanffy, Gompertz, and logistic. The analyses were carried out using 3 different data sets to check goodness of fit while having animals with few records. Three different assumptions about SD of fitting errors were considered: constancy throughout the trajectory, linear increasing until 3 yr of age and constancy thereafter, and variation following the nonlinear function applied in the first stage of the hierarchy. Comparisons of the overall goodness of fit were based on Akaike information criterion, the Bayesian information criterion, and the deviance information criterion. Goodness of fit at different points of the growth curve was compared applying the Gelfand's check function. The posterior means of adult BW ranged from 531.78 to 586.89 kg. Greater estimates of adult BW were observed when the fitting error variance was considered constant along the trajectory. The models were not suitable to describe the SD of fitting errors at the beginning of the growth curve. All functions provided less accurate predictions at the beginning of growth, and predictions were more accurate after 48 mo of age. The prediction of adult BW using nonlinear functions can be accurate when growth curve parameters and their (co)variance components are estimated jointly. The hierarchical model used in the present study can be applied to the prediction of mature BW in herds in which a portion of the animals are culled before adult age. Gompertz, Von Bertalanffy, and Brody functions were adequate to establish mean growth patterns and to predict the adult BW of Nelore females. The Brody model was more accurate in predicting the birth weight of these animals and presented the best overall goodness of fit.


Intraocular Lens Calculation after Refractive Surgery: A Long-Term Retrospective Comparison of Eight Formulas.
The aim of this study was to compare the accuracy of 8 IOL power calculation formulas for eyes post-refractive surgery. In this Retrospective study, a chart review and data analysis of post-corneal refractive surgery patients who subsequently underwent cataract surgery with IOL implantation in Tertiary surgical center, Draper, UT, USA. The surgery was done in a single surgical center in Draper, UT by one surgeon. The study was approved by the organization's ethics board. The IOL power formulas used were Barrett True K (BTK), Average Pupil Power (APP), Shammas, Haigis, Galilei, Potvin-Hill Pentacam (PVP), OCT and Barrett True K No History (BTKNH). The percent of time each formula was within ±0.5 D and ±0.75 D of refractive prediction error was calculated. Statistical analysis was performed comparing these 8 methodologies at four post-operative follow-up time points and on the summative time points. Mean follow-up time periods were: 4 weeks, 3 months, 6 months, and 12 months. A total of 64 eyes were included in the study. All IOL formulas showed a myopic trend except APP and Shammas, which showed a hyperopic trend. All tests showed a statistically significant mean absolute value difference from zero. OCT, BTKNH, and BTK had consistently high percentages within ±0.5D and ±0.75 D of refractive error. Linear mixed model analysis showed a statistically significant change in predictive value over time for all formulas. Linear mixed model analysis suggests that it is inadequate to evaluate the performance of IOL power formulae in the short term. Longer-term follow-up is needed to determine accuracy as several factors can result in refractive changes greater than 3 months postoperatively. Our analysis did not demonstrate any formula that was clearly superior to the other methods for predicting IOL power at any time point.


Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat.
The role of xanthine dehydrogenase and oxidase as a source of free radicals contributing to focal cerebral ischemic injury was evaluated in Long-Evans rats after the middle cerebral artery was permanently occluded and both carotid arteries were clamped for 90 min. The fraction of xanthine dehydrogenase present as the free radical producing oxidase increased slightly from 22% in control cortex to 30% in the ischemic right cortex during the first 3 h of reperfusion and then remained relatively unchanged over the next 24 h. This increase may in part be due to entrapped plasma, which contained 4.5 +/- 0.8 nmol.min-1.ml-1 xanthine oxidase entirely in the free radical-producing form. Infarct volume was unaffected by pretreatment with 50 mg allopurinol/kg per day over 3 days before surgery but was decreased by 8% with 100 mg/kg and 24% with 150 mg/kg of allopurinol (P less than 0.05). However, inhibition of xanthine oxidase by dietary depletion of the essential molybdenum cofactor increased infarct volume by 19%, suggesting that protection by allopurinol at higher dosages was independent of xanthine oxidase inhibition. Neither xanthine oxidase present in rat brain nor circulating in plasma appears to be the primary source of oxygen radicals that contributes to infarction in focal cerebral ischemia.


Alix, a protein regulating endosomal trafficking, is involved in neuronal death.
Alix/AIP1 is a cytoplasmic protein, which was first characterized as an interactor of ALG-2, a calcium-binding protein necessary for cell death. Alix has also recently been defined as a regulator of the endo-lysosomal system. Here we have used post-mitotic cerebellar neurons to test Alix function in caspase-dependent and -independent cell death. Indeed, these neurons survived when cultured in 25 mm potassium-containing medium but underwent apoptosis soon after the extracellular potassium was lowered to 5 mm. In agreement with other studies, we show that caspases are activated after K+ deprivation, but that inhibition of these proteases, using the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone, has no effect on cell survival. Transfection experiments demonstrated that Alix overexpression is sufficient to induce caspase activation, whereas overexpression of its C-terminal half, Alix-CT, blocks caspase activation and cell death after K+ deprivation. We also define a 12-amino acid PXY repeat of the C-terminal proline-rich domain necessary for binding ALG-2. Deletion of this domain in Alix or in Alix-CT abolished the effects of the overexpressed proteins on neuronal survival, demonstrating that the ALG-2-binding region is crucial for the death-modulating function of Alix. Overall, these findings define the Alix/ALG-2 complex as a regulator of cell death controlling both caspase-dependent and -independent pathways. They also suggest a molecular link between the endo-lysosomal system and the effectors of the cell death machinery.


Crepidotus thermophilus comb. nov., a reassessment of Melanomphalia thermophila, a rarely collected tropical agaric.
Melanomphalia thermophila (Sing.) Sing. is a rarely collected agaric previously known only from Florida and Brazil. This taxon was originally described as a species of Tubaria and much of Singer's rationale for placing Tubaria within the Crepidotaceae (Imai) Sing. was based on anatomical similarities between T. thermophila and Crepidotus (Fr.) Staude. In later works, T. thermophila was transferred to Melanomphalia M.P. Christ., again forming the basis upon which Singer placed Melanomphalia within the Crepidotaceae. Based on examination of newly collected specimens from Puerto Rico and Panama, type studies, and nuclear large subunit rDNA analysis, we conclude that this taxon is, in fact, a centrally stipitate Crepidotus. Melanomphalia thermophila is transferred to Crepidotus, fully described and illustrated.


The Attachments of the Breast to the Chest Wall: A Dissection Study.
The anatomical descriptions of the attachments of the female breast to the chest wall vary in their structure, location, and terminology within the published literature. A dissection study of the attachments of the breast to the chest wall was conducted on 18 female embalmed breasts in the coronal (n = 15) and sagittal planes (n = 3). Perimeter, posterior wall, and horizontal septum attachments were observed. The perimeter along its entire length was attached to the chest wall. Regional and anatomical variation was observed in this structure and location. Sharp dissection was required to remove it from the chest wall, in contrast to the blunt dissection required to remove the posterior wall and horizontal septum attachments. The breast attaches to the chest wall along its entire perimeter, posterior wall, and horizontal septum, with the perimeter functioning as the primary anchor of the breast to the chest wall. The structure of the perimeter attachment is both periosteal and fascial and requires sharp dissection to remove it from the chest wall. The fascial structures of the posterior wall and horizontal septum require blunt dissection only. The structure of the perimeter has regional variation, and its location on the chest wall has anatomical variation. Detailed anatomical descriptions and illustrations are supported by photographic evidence of cadaver dissections in two planes. Clinical and anatomical terminology are linked, with clinical implications for medical anatomy education, breast modeling, and breast surgery.


Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C.
To assess the prevalence of clinical and biologic extrahepatic manifestations of hepatitis C virus (HCV) infection and to identify associations between clinical and biologic manifestations. To analyze the natural history of extrahepatic manifestations of HCV infection, we reviewed only the data recorded prospectively during the first visit of 1,614 patients with chronic HCV infection, coming from a single monocenter cohort. Exclusion criteria were positivity for hepatitis B surface antigen or human immunodeficiency virus. The prevalence of dermatologic, rheumatologic, neurologic, and nephrologic manifestations; diabetes; arterial hypertension; autoantibodies; and cryoglobulins were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunologic, virologic, and liver histologic factors associated with the presence of extrahepatic manifestations. At least 1 clinical extrahepatic manifestation was observed in each of 1,202 patients (74%). Five manifestations had a prevalence >10%: arthralgia (23%), paresthesia (17%), myalgia (15%), pruritus (15%), and sicca syndrome (11%). Four biologic abnormalities had a prevalence >5%: cryoglobulins (40%), antinuclear antibodies (10%), low thyroxine level (10%), and anti-smooth muscle antibodies (7%). Only vasculitis, arterial hypertension, purpura, lichen planus, arthralgia, and low thyroxine level were associated with cryoglobulin positivity. By univariate and multivariate analyses, the most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations were age, female sex, and extensive liver fibrosis. Extrahepatic clinical manifestations are frequently observed in HCV patients and involve primarily the joints, muscles, and skin. The most frequent immunologic abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti-smooth muscle antibodies. The most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations are advanced age, female sex, and extensive liver fibrosis.


Factorizing the motion sensitivity function into equivalent input noise and calculation efficiency.
The photopic motion sensitivity function of the energy-based motion system is band-pass peaking around 8 Hz. Using an external noise paradigm to factorize the sensitivity into equivalent input noise and calculation efficiency, the present study investigated if the variation in photopic motion sensitivity as a function of the temporal frequency is due to a variation of equivalent input noise (e.g., early temporal filtering) or calculation efficiency (ability to select and integrate motion). For various temporal frequencies, contrast thresholds for a direction discrimination task were measured in presence and absence of noise. Up to 15 Hz, the sensitivity variation was mainly due to a variation of equivalent input noise and little variation in calculation efficiency was observed. The sensitivity fall-off at very high temporal frequencies (from 15 to 30 Hz) was due to a combination of a drop of calculation efficiency and a rise of equivalent input noise. A control experiment in which an artificial temporal integration was applied to the stimulus showed that an early temporal filter (generally assumed to affect equivalent input noise, not calculation efficiency) could impair both the calculation efficiency and equivalent input noise at very high temporal frequencies. We conclude that at the photopic luminance intensity tested, the variation of motion sensitivity as a function of the temporal frequency was mainly due to early temporal filtering, not to the ability to select and integrate motion. More specifically, we conclude that photopic motion sensitivity at high temporal frequencies is limited by internal noise occurring after the transduction process (i.e., neural noise), not by quantal noise resulting from the probabilistic absorption of photons by the photoreceptors as previously suggested.


Subjective Visual Vertical in PD Patients with Lateral Trunk Flexion.
Lateral trunk flexion (LTF) is a common phenomenon in patients with Parkinson's disease (PD) and has recently been associated with peripheral vestibular dysfunction. Since deviation of the subjective visual vertical (SVV) is a well-recognized feature of disorders involving vestibular processing, we analyzed SVV angles in 30 PD patients with and without LTF to assess the possible role of vestibular dysfunction in the pathogenesis of LTF in PD. Quantification of SVV was obtained using a simple bedside test. PD patients with LTF had significantly greater SVV angles as compared to PD patients without LTF (median: 4.3° [range: 0.1-17.7], n = 21, versus 0.8° [0.1-1.9], n = 9; p < 0.001). 14 of 21 patients with LTF showed pathological SVV, while all 9 patients without LTF had normal SVV. Abnormal SVV was more frequent when LTF was reversible in the supine position compared to fixed LTF. In a subgroup of PD patients with LTF, pathological SVV suggests vestibular dysbalance, which might be involved in the pathophysiological mechanisms underlying LTF.


Seroprevalence of Neospora caninum and abortion in dairy cows in northern Spain.
The seroprevalence of Neospora caninum infection was estimated from a sample of 889 cattle from 43 dairy herds in three counties in the Asturias region of Spain. The true prevalence of infection was estimated to be 30.6 per cent (95 per cent confidence interval (CI) 27.6 to 33.6). Seropositivity was associated with abortion during the previous year (odds ratio (OR)=3.31, P<0.001) and was slightly higher among purchased cattle (37.6 per cent), than among cattle raised on the farm (29.1 per cent) (P=0.078). Seropositive cows were more likely than seronegative cows to have had a seropositive dam (OR=2.3, P=0.011), suggesting that congenital transmission contributed to about 56 per cent of the infections. Herds with a true seroprevalence above 10 per cent had more dogs on the farm, than herds with a lower prevalence (P=0.032). The ORS relating abortion to seropositivity in individual herds ranged from 0.7 to 19, indicating that some herds experienced few abortions caused by N. caninum, while others experienced more abortions due to the organism. Overall, 38.7 per cent of the abortions were estimated to have been attributable to N. caninum.


[Mechanism of ca(2+) pump as revealed by mutations, development of stable analogs of phosphorylated intermediates, and their structural analyses].
Sarco(endo)plasmic reticulum Ca(2+)-ATPase is a representative member of P-type cation transporting ATPases and catalyzes Ca(2+) transport coupled with ATP hydrolysis. The ATPase possesses three cytoplasmic domains (N, P, and A) and ten transmembrane helices (M1-M10). Ca(2+) binding at the transport sites in the transmembrane domain activates the ATPase and then the catalytic aspartate is auto-phosphorylated to form the phosphorylated intermediate (EP). Structural and functional studies have shown that, during the isomerization of EP in the Ca(2+) transport cycle, large motions of the three cytoplasmic domains take place, which then rearranges the transmembrane helices thereby destroying the Ca(2+) binding sites, opening the lumenal gate, and thus releasing the Ca(2+) into lumen. Stable structural analogues for the Ca(2+)-occluded and -released states of phosphorylated intermediates and for the transition and product states of the phosphorylation and dephosphorylation reactions were developed for biochemical and atomic-level structural studies to reveal the coupled changes in the catalytic and transport sites. Mutation studies identified the residues and structural regions essential for the structural changes and Ca(2+) transport function. Genetic dysfunction of Ca(2+)-ATPase causes various isoform-specific diseases. In this manuscript, recent understanding of the Ca-ATPase will be reviewed.


[Barriers and motivations perceived by adolescents related to physical activity. Qualitative study through discussion groups].
Acquiring the habit of doing regular physical activity in adolescents has shown positive effects in the prevention of diseases and the maintenance of physical and psychological health. The objective was to explore the topics related to physical activity of a group of adolescents, to identify the barriers and motivators of regular physical activity practice. Qualitative research of phenomenological explanatory design. The information was obtained through four Discussion Groups conducted with: a) expert professionals (6 participants); b) adolescents of both sexes (10 participants); c) female adolescents (6 participants); d) male adolescents (9 participants). Perceived barriers and motivations were detected in all groups of adolescents, contributing a total of 104 units of analysis. The group of experts emphasized the need to involve the family, the school, and the agents that surround the teenagers. The adolescents showed barriers related to incompatibilities due to lack of time, participation in leisure activities and demotivation due to routine and imposed activities (37; 35.5%). Motivation was related to participation in team sports and the positive influence of friends (28; 28%). The girls also showed concern about their body image and diet (39; 37.5%). Barriers were identified in relation to the close environment of the adolescents in three main areas: family, friends and school. Motivators were linked to social and multicultural components. Priority actions in this group are to promote activities that include team sports as a mean to enhance social support.


[Superproton transport as a mechanism of microwave absorption].
Microwave absorption mechanism based on the concept of ionic transport in biological membranes as superionic movement is proposed. Meanwhile the same order of magnitude of jump and residence time let us consider ions as quasifree particles, the value of jump time brings the dispersion in the microwave frequency range because of the same order of magnitude of jump time and electrical field period. Synchronism between carriers and the wave is responsible for additional microwave active conductivity.


Novel phosphorescent triptycene-based Ir(iii) complexes for organic light-emitting diodes.
A series of charge-neutral cyclometalated iridium(iii) complexes (1-3 and 5-7) containing triptycene-substituted ligands (tbt and tpbi) and two parent complexes (4 and 8) were synthesized and characterized. The crystal structures indicated that π-π stacking interactions existed in ligand tbtH, but not in complex 6. However, a large intramolecular repulsion was found in complex 6. These triptycene-based complexes exhibited good thermal stability, which was higher compared with that of the parent complexes. These complexes showed green to yellow emission with peaks that ranged from 503 to 563 nm. The introduction of the rigid non-conjugate triptycene skeleton caused a slight emission red shift (<25 nm), but a significant increase in the PLQYs (>47%) was observed. The electroluminescent devices employing 2 and 6 as phosphors displayed impressive performance improvements and low efficiency roll-off because of the higher PLQYs and HOMO levels of these triptycene-based complexes. The maximum current and external quantum efficiencies of the devices based on complexes 2 and 6 were 41.7 cd A-1, 11.9% and 41.2 cd A-1, 12.6%, respectively, which were about 31% higher than that of the devices based on the parent complexes 4 and 8. This work provides a novel approach to develop highly efficient phosphors with a triptycene skeleton.


Clinical usefulness of ELISA technique in the assessment of thyroid function.
The clinical usefulness of Enzyme-linked Immunosorbent analysis (ELISA) for the assay of triiodothyronine (T3), thyroxine (T4) and T4 Uptake was studied in groups of clinically defined subjects. The following ranges of values were obtained in the normal control subjects: T3: 1.1-2.9 nmol/1; T4: 61.8-144 nmol/l; T4-Uptake: 0.7-1.34 and Free Thyroxine Index (FTI): 52.8-136. The diagnostic sensitivity of the technique was found to be reasonably good: showing good discrimination between hypothyroid, hyperthyroid and euthyroid subjects. Free thyroxine Index provided the best consistent correlation with the clinical states of the subjects particularly in subjects with altered binding protein levels. Several advantages offered by ELISA technique over radiochemical methods such as freedom from radiation hazards, non-requirement of specialized laboratories with expensive equipment and cheaper reagents with relatively longer shelf lives, make this procedure particularly suitable for use in small laboratories.


Lack of soluble fiber drives diet-induced adiposity in mice.
Diet-induced obesity is often modeled by comparing mice fed high-fat diet (HFD), which is made from purified ingredients, vs. normal chow diet (NCD), which is a low-fat assemblage of relatively unrefined plant and animal products. The mechanism by which HFD promotes adiposity is complex but thought to involve low-grade inflammation and altered gut microbiota. The goal of this study was to investigate the extent to which HFD-induced adiposity is driven by fat content vs. other factors that differentiate HFD vs. NCD. Mice were fed NCD, HFD, or other compositionally defined diets (CDD), designed to mimic NCD and/or explore the role of HFD components. A range of metabolic parameters reflecting low-grade inflammation and adiposity were assayed. Relative to NCD, HFD, and to a lesser, but, nonetheless, significant extent, CDD induced increased adiposity, indicating both lipid content and other aspects of HFD are obesogenic. Moreover, HFD and CDD induced a rapid and marked loss of cecal and colonic mass. Such CDD-induced effects were not affected by adjusting dietary protein levels/types but could be largely eliminated by exchanging insoluble fiber (cellulose) for soluble fiber (inulin). Replacing cellulose with inulin in HFD also protected mice against decreased intestinal mass, hyperphagia, and increased adiposity. Such beneficial effects of inulin were microbiota dependent, correlated with elevated fecal short-chain fatty acid levels analyzed via (1)H-NMR-based metabolomics and were partially recapitulated by administration of short-chain fatty acid. HFD-induced obesity is strongly promoted by its lack of soluble fiber, which supports microbiota-mediated intestinal tissue homeostasis that prevents inflammation driving obesity and metabolic syndrome.


Has the profile of heart transplantation recipients changed within the last three decades?
Heart transplantation remains the most durable treatment for patients with end-stage heart failure refractory to medical treatment. Central elements of the listing criteria for heart transplantation have remained largely unchanged in the last three decades whereas treatment of heart failure has significantly increased survival and reduced disease-related symptoms. It remains unknown whether the improvement of heart failure therapy changed the profile of heart transplantation candidates or affected post-transplant survival. The study investigated a total of 323 heart transplant recipients of the Lausanne University Hospital with 328 transplant operations between 1987 and 2018. Patients were separated into three groups on the basis of availability of heart failure therapy: period 1 (1987-1998; n = 115) when renin-angiotensin system blockade and diuretic treatment were available; period 2 (1999-2010; n = 106) marked by the addition of beta-blocker and mineralocorticoid receptor antagonist treatment in severe heart failure, and the establishment of cardiac defibrillator and resynchronisation therapy; period 3 (2011-2018; n = 107) characterised by the increasing use of ventricular assist devices for bridge to transplantation. The patient characteristics age (all: 53.4 years), male sex (all: 79%) and body mass index (all: 24.5 kg/m2) did not differ between periods. History of arterial hypertension was less prevalent in period 2 (period 1 vs 2 vs 3: 44 vs 28 vs 43%, p = 0.04) whereas other cardiovascular risk factors were equally distributed. Left ventricular ejection fraction, VO2max, and pulmonary vascular resistance were not different between the three periods. The prevalence of ischaemic cardiomyopathy was higher in periods 1 and 3; dilated non-ischaemic cardiomyopathy was more frequent in period 2. Post-transplant 1-year survival was highest in period 3 (1 vs 2 vs 3: 87.2 ± 3.2% vs 70.8 ± 4.4% vs 93.0 ± 2.6%, p always ≤0.02), and the Kaplan-Meier estimates of survivors of the first year post-transplant were not different between the three periods. In descriptive analysis, early mortality was not associated with acknowledged pretransplant predictors of post-transplant mortality. Availability of different medical heart failure treatments did not result in greatly different pretransplant characteristics of heart transplantation recipients across the three periods. This suggests that the maintained central criteria of listing for heart transplantation still identify end-stage heart failure patients with a similar profile. This finding can explain the unchanged overall mortality on condition of 1-year survival across the three periods, since pretransplant characteristics are relevant for long-term survival after heart transplantation.


Expression of neurotrophic factors and their receptors in keratoconic cornea.
To measure the expression level and pattern of neurotrophic factors and their receptors in keratoconus (KC) cornea using quantitative RT-PCR (qPCR) and immunostaining. Twenty-one recipient corneal buttons after keratoplasty from KC cornea and four age-matched normal corneas were obtained. The 25 corneal tissues were divided into two pieces; one fragment of each sample was used for immunostaining whereas the other fragment was used for qPCR. Using primary antibodies and specific qPCR primer, immunostaining and qPCR were performed to analyze the expression level of the neurotrophic factors and receptors. Nerve growth factor and its receptors (TrkA and p75NTR) were not expressed in the center of normal cornea. However, TrkA and the p75NTR were clearly expressed in a membrane bound staining pattern and the mRNA levels were significantly higher in KC (p < 0.001). The mRNA expression of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and neurotrophin (NT)-4 mRNA was also elevated in KC (p < 0.001). BDNF was expressed in epithelium of normal cornea. However, in KC, its expression was found to be extending into the anterior stromal layer. CNTF was hardly expressed in normal cornea. In KC, the entire epithelium expressed CNTF, especially in perinuclear area. NT-4 was expressed throughout the epithelium and stroma in KC. The change in expression of neurotrophic factors in KC may suggest that these factors play an important role in the pathogenesis of KC and serve as new markers for the progression of KC.


Impetigo herpetiformis in a primigravida: successful treatment with etretinate.
Impetigo herpetiformis (IH) is a rare dermatosis which usually occurs during the third trimester of pregnancy. It is characterized by acute erythematosquamous plaques covered with tiny superficial pustules in a herpetiform distribution with less likely mucus membranes involvement. It can be associated with constitutional symptom s such as fever, chills, nausea, vomiting and diarrhea. Impetigo herpetiformis can cause serious complications to the mother and fetus which include: maternal hypocalcemia leading to delirium, convulsions, and tetany in the mother, and placental insufficiency leading to still birth, neonatal death or fetal abnormalities. Lesions are expected to disappear after birth but may recur during subsequent pregnancies at an earlier gestational age. Presented here is a case of IH occurring during the 37th week of gestation in a primigravida who failed to respond to oral steroid but successfully cleared with oral etretinate.


Cytoplasmic streaming in Chara corallina studied by laser light scattering.
An apparatus is described by means of which the power versus frequency spectrum of the photomultiplier current can be obtained for laser light scattered by streaming cytoplasm in the algal cell Chara corallina. A Doppler peak is noted in the spectrum which is abolished when cytoplasmic streaming is arrested by electrical stimulation. For 5 cells of Chara, this simple laser-Doppler velocimeter gave streaming velocities (46-7 mum s-1, S.D. +/- 4-8 at 20 degrees C) similar to those obtained for the same cells using the light microscope (44-3 mum s-1, S.D. +/- 5-3 at 20 degrees C). A narrow distribution of streaming velocities is indicated. The technique described provides a rapid, quantitative assay of the in vivo rheological properties of cytoplasm.


Effect of adding non-volatile oil as a core material for the floating microspheres prepared by emulsion solvent diffusion method.
Eudragit microspheres, to float in the gastrointestinal tract, were prepared to prolong a gastrointestinal transit time. To enhance their buoyancy, non-volatile oil was added to the dispersed phase. When an oil component was not miscible with water, over 90% was entrapped within the microspheres and prolonged the floating time of the microspheres. Depending on the solvent ratio, the morphologies of the microspheres were different and the best result was obtained when the ratio of dichloromethane:ethanol:isopropanol was 5:6:4. As the isopropanol portion increased, the time to form microspheres was delayed and the amount of fibre-like substance produced was decreased, due to the slow diffusion rate of the solvent. Compared with microspheres prepared without non-volatile oil, the release rate of the drug from microspheres was faster in all cases tested, except the microspheres containing mineral oil. The solubility of the drug in the non-volatile oil affected the release profiles of the drugs. The non-volatile oil tends to decrease the glass transition temperature of prepared microspheres and change the release profile. The internal morphology of the microspheres was slightly different depending on the entrapped oil phase used. Tiny spherical objects were present at the inner surface of microspheres and the inside of the shell.


The KCaSrTa5O15 photocatalyst with tungsten bronze structure for water splitting and CO2 reduction.
KCaSrTa5O15 with tungsten bronze structure and a band gap of 4.1 eV showed activity for water splitting without cocatalysts. The activity was improved by loading the NiO cocatalyst. The apparent quantum yield of optimized NiO-loaded KCaSrTa5O15 was 2.3% at 254 nm for water splitting. When CO2 gas was bubbled into the reactant aqueous solution, Ag cocatalyst-loaded KCaSrTa5O15 produced CO and H2 as reduction products of CO2 and H2O, respectively, and O2 as an oxidation product of H2O. The carbon source of CO was confirmed to be CO2 molecules by using (13)CO2. The ratio of the number of electrons to that of holes calculated from the amounts of products (CO, H2 and O2) was almost unity. Additionally, the ratio of the turnover number of electrons consumed for CO production to the total number of an Ag atom of the cocatalyst that was the active site for CO2 reduction was 8.6 at 20 h. These results indicate that water was consumed as an electron donor for this photocatalytic CO2 reduction in an aqueous medium. Thus, KCaSrTa5O15 with tungsten bronze structure has arisen as a new photocatalyst that is active for water splitting and CO2 reduction utilizing water as an electron donor.


Refinement of gene expression patterns in the early Xenopus embryo.
During blastula and gastrula stages of Xenopus development, cells become progressively and asynchronously committed to a particular germ layer. We have analysed the expression of genes normally expressed in ectoderm, mesoderm or endoderm in individual cells from early and late gastrula embryos, by both in situ hybridization and single-cell RT-PCR. We show that at early gastrula stages, individual cells in the same region may express markers of two or more germ layers, and 'rogue' cells that express a marker outside its canonical domain are also observed at these stages. However, by the late gastrula stage, individual cells express markers that are more characteristic of their position in the embryo, and 'rogue' cells are seen less frequently. These observations exemplify at the gene expression level the observation that cells of the early gastrula are less committed to one germ layer than are cells of the late gastrula embryo. Ectodermal cells induced to form mesendoderm by the addition of Activin respond by activating expression of different mesodermal and endodermal markers in the same cell, recapitulating the response of marginal zone cells in the embryo.


Rearrangement and junctional-site sequence analyses of T-cell receptor gamma genes in intestinal intraepithelial lymphocytes from murine athymic chimeras.
The molecular organization of rearranged T-cell receptor (TCR) gamma genes intraepithelial lymphocytes (IEL) was studied in athymic radiation chimeras and was compared with the organization of gamma gene rearrangements in IEL from thymus-bearing animals by polymerase chain reaction and by sequence analyses of DNA spanning the junction of the variable (V) and joining (J) genes. In both thymus-bearing mice and athymic chimeras, IEL V-J gamma-gene rearrangements occurred for V gamma 1.2, V gamma 2, and V gamma 5 but not for V gamma 3 or V gamma 4. Sequence analyses of cloned V-J polymerase chain reaction-amplified products indicated that in both thymus-bearing mice and athymic chimeras, rearrangement of V gamma 1.2 and V gamma 5 resulted in in-frame as well as out-of-frame genes, whereas nearly all V gamma 2 rearrangements were out of frame from either type of animal. V-segment nucleotide removal occurred in most V gamma 1.2, V gamma 2, and V gamma 5 rearrangements; J-segment nucleotide removal was common in V gamma 1.2 but not in V gamma 2 or V gamma 5 rearrangements. N-segment nucleotide insertions were present in V gamma 1.2, V gamma 2, and V gamma 5 IEL rearrangements in both thymus-bearing mice and athymic chimeras, resulting in a predominant in-frame sequence for V gamma 5 and a predominant out-of-frame sequence for V gamma 2 genes. These findings demonstrate that (i) TCR gamma-gene rearrangement occurs extrathymically in IEL, (ii) rearrangements of TCR gamma genes involve the same V gene regardless of thymus influence; and (iii) the thymus does not determine the degree to which functional or nonfunctional rearrangements occur in IEL.


Desmoplastic small round cell tumor: impact of F-FDG PET induced treatment strategy in a patient with long-term outcome.
The desmoplastic small round cell tumor (DSRCT) is an uncommon and highly aggressive cancer. The role of (18)F-FDG PET in management of DSRCT is little reported. We report a case of metastasized abdominal DSRCT detected in a 43-year old patient whose diagnostic and therapeutic approaches were influenced by (18)F-FDG PET-CT. The patient is still alive ten years after diagnosis. (18)F-FDG PET-CT seems to be a useful method for assessing therapeutic efficiency and detecting early recurrences even in rare malignancies such as DSRCT.


scGRN: a comprehensive single-cell gene regulatory network platform of human and mouse.
Gene regulatory networks (GRNs) are interpretable graph models encompassing the regulatory interactions between transcription factors (TFs) and their downstream target genes. Making sense of the topology and dynamics of GRNs is fundamental to interpreting the mechanisms of disease etiology and translating corresponding findings into novel therapies. Recent advances in single-cell multi-omics techniques have prompted the computational inference of GRNs from single-cell transcriptomic and epigenomic data at an unprecedented resolution. Here, we present scGRN (https://bio.liclab.net/scGRN/), a comprehensive single-cell multi-omics gene regulatory network platform of human and mouse. The current version of scGRN catalogs 237 051 cell type-specific GRNs (62 999 692 TF-target gene pairs), covering 160 tissues/cell lines and 1324 single-cell samples. scGRN is the first resource documenting large-scale cell type-specific GRN information of diverse human and mouse conditions inferred from single-cell multi-omics data. We have implemented multiple online tools for effective GRN analysis, including differential TF-target network analysis, TF enrichment analysis, and pathway downstream analysis. We also provided details about TF binding to promoters, super-enhancers and typical enhancers of target genes in GRNs. Taken together, scGRN is an integrative and useful platform for searching, browsing, analyzing, visualizing and downloading GRNs of interest, enabling insight into the differences in regulatory mechanisms across diverse conditions.


Pathology and laboratory medicine as a service.
Quality is multidimensional. The relative importance of these dimensions to those using the service of the laboratory and a pathologist has not been previously defined as a conceptual model for measuring and investigating service quality. Ten major determinants of service quality are described: access, communication, competence, courtesy, credibility, reliability, responsiveness, security, technology, and understanding. These components must be integrated into any formula for a successful health-care outcome.


Coronal ring involvement in patients treated for unilateral coronal craniosynostosis.
The etiopathology of the clinical entity normally referred to as unilateral coronal synostosis is commonly used to connote unilateral fusion of the frontoparietal suture. However, other sutures in the coronal ring may exhibit synostosis concomitant with or independent from frontoparietal synostosis and give rise to similar clinical phenotypes. This study retrospectively analyzes high-resolution computed tomographic data sets to determine patency of sutures within the coronal ring. Computed tomographic scan digital data from 33 infants who subsequently underwent surgical correction of unilateral coronal synostosis were assessed for sutural patency using Analyze imaging software. The frontosphenoidal suture was subdivided into intraorbital frontosphenoidal and extraorbital frontosphenoidal portions, and the patency of the frontoethmoidal suture was also assessed. Patients were sorted into two groups on the basis of the status of their frontosphenoidal sutures: group 1 had patent frontosphenoidal but synostotic frontoparietal sutures (n = 21) and group 2 had both frontosphenoidal and frontoparietal synostoses. Observer reproducibility was tested. The vertical and horizontal dimensions of the bony orbit and the endocranial base deflection angle were measured with the observer blinded with regard to sutural status group. Frontoethmoidal synostosis was not noted in any patients in either group. Two patients had no frontoparietal suture synostosis with isolated intraorbital frontosphenoidal and extraorbital frontosphenoidal suture closures. Suture diagnosis reproducibility was 99 percent. In group 1, the ipsilateral-to-contralateral vertical orbit dimension ratio averaged 1.11, whereas in group 2 it averaged 1.04 (p < 0.05). The ratio of horizontal orbit measurements was not significantly different between groups. In both groups, the endocranial base was deflected ipsilateral to the synostotic frontoparietal suture, with an average angle of 12 degrees in group 1 and 17 degrees in group 2 (p < 0.005). The extent of synostosis along the coronal sutural ring contributes to the dysmorphology of the orbit and the endocranial base deflection in patients whose clinical phenotypic diagnosis is unilateral coronal synostosis.


Ethanol decreases Glial-Derived Neurotrophic Factor (GDNF) protein release but not mRNA expression and increases GDNF-stimulated Shc phosphorylation in the developing cerebellum.
Ethanol exposure during development leads to substantial neuronal loss in multiple regions of the brain. Although differentiating Purkinje cells of the cerebellum are particularly vulnerable to ethanol exposure, the mechanisms underlying ethanol-induced Purkinje cell loss have not been well defined. Our previous research indicated that exogenous Glial-Derived Neurotrophic Factor (GDNF) attenuated ethanol-induced Purkinje cell loss in cerebellar explant cultures, which suggests that ethanol, in turn, may decrease endogenous trophic factor-mediated survival mechanisms. The present experiments used an explant culture model of the developing rat cerebellum to test the hypothesis that ethanol decreases endogenous trophic support by limiting the availability of trophic factors, such as GDNF, or by altering the activation of key adapter proteins such as Shc (Src homology domain carboxy-terminal) that couple GDNF binding to multiple intracellular signaling pathways. GDNF mRNA and protein levels were measured by reverse northern blot analysis and sandwich enzyme-linked immunosorbent assay respectively, whereas Shc phosphorylation was measured by immunoprecipitation/western immunoblot analysis. The developing cerebellum expresses both GDNF mRNA and protein in vitro. Ethanol exposure (68, 103, or 137 mM) had no effect on cerebellar levels of GDNF mRNA. However, ethanol (68 and 137 mM) decreased levels of GDNF protein released into culture medium. In addition, ethanol itself had no effect on She phosphorylation. However, in the presence of the highest dose of ethanol (137 mM) GDNF did stimulate Shc phosphorylation. Together, these results suggest that ethanol decreases GDNF-mediated trophic support of Purkinje cells in the developing cerebellum. However, GDNF in turn activates intracellular signaling pathways throughout the developing cerebellum as part of its Purkinje cell-selective neuroprotective response to ethanol exposure.


Beyond the single-outcome approach: A comparison of outcome-wide analysis methods for exposome research.
Outcome-wide analysis can offer several benefits, including increased power to detect weak signals and the ability to identify exposures with multiple effects on health, which may be good targets for preventive measures. Recently, advanced statistical multivariate techniques for outcome-wide analysis have been developed, but they have been rarely applied to exposome analysis. In this work, we provide an overview of a selection of methods that are well-suited for outcome-wide exposome analysis and are implemented in the R statistical software. Our work brings together six different methods presenting innovative solutions for typical problems arising from outcome-wide approaches in the context of the exposome, including dependencies among outcomes, high dimensionality, mixed-type outcomes, missing data records, and confounding effects. The identified methods can be grouped into four main categories: regularized multivariate regression techniques, multi-task learning approaches, dimensionality reduction approaches, and bayesian extensions of the multivariate regression framework. Here, we compare each technique presenting its main rationale, strengths, and limitations, and provide codes and guidelines for their application to exposome data. Additionally, we apply all selected methods to a real exposome dataset from the Human Early-Life Exposome (HELIX) project, demonstrating their suitability for exposome research. Although the choice of the best method will always depend on the challenges to be faced in each application, for an exposome-like analysis we find dimensionality reduction and bayesian methods such as reduced rank regression (RRR) or multivariate bayesian shrinkage priors (MBSP) particularly useful, given their ability to deal with critical issues such as collinearity, high-dimensionality, missing data or quantification of uncertainty.


Prevalence of diagnosed and undiagnosed type 2 diabetes mellitus among US adolescents: results from the continuous NHANES, 1999-2010.
Although prevalence and incidence of type 2 diabetes mellitus (T2DM) are reportedly increasing among adolescents, national data are lacking, particularly in regard to undiagnosed T2DM. To estimate the prevalence of diagnosed and undiagnosed T2DM among US adolescents, we analyzed a nationally representative cross-section of 11,888 adolescents aged 12-19 years who received a diabetes interview in the Continuous National Health and Nutrition Examination Survey during 1999-2010. Among them, a random subsample of 4,661 adolescents also had fasting blood samples collected. Persons who reported a previous diabetes diagnosis and were either taking no medication or taking an oral hypoglycemic agent (with or without insulin) were classified as having T2DM; persons who reported using insulin alone were classified as having type 1 diabetes. Undiagnosed diabetes was defined as a fasting plasma glucose concentration of ≥126 mg/dL and was assumed to be type 2. In the fasting subsample, 31 diabetes cases (types 1 and 2) were identified, representing a prevalence of 0.84% (weighted 95% confidence interval (CI): 0.51, 1.40) (276,638 cases; 95% CI: 134,255, 419,020). Estimates of the prevalences of type 1 and type 2 diabetes were 0.48% (95% CI: 0.23, 1.02) and 0.36% (95% CI: 0.20, 0.67), respectively, indicating that T2DM accounted for 43% of all cases. Further, undiagnosed T2DM prevalence was 0.12% (95% CI: 0.05, 0.31), representing 34% of T2DM cases (40,611 cases; 95% CI: 2,850, 78,373). T2DM accounts for approximately half of adolescent diabetes in the United States, and one-third of these cases are undiagnosed.


Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy.
Although there is tremendous interest in stem cell (SC)-based therapies for cardiomyopathy caused by chronic myocardial infarction, many unanswered questions regarding the best approach remain. The TAC-HFT study is a phase I/II randomized, double-blind, placebo-controlled trial designed to address several of these questions, including the optimal cell type, delivery technique, and population. This trial compares autologous mesenchymal SCs (MSCs) and whole bone marrow mononuclear cells (BMCs). In addition, the study will use a novel helical catheter to deliver cells transendocardially. Although most trials have used intracoronary delivery, the optimal method is unknown and data suggest that the transendocardial approach may have important advantages. Several trials support the benefit of SCs in patients with chronic ischemic cardiomyopathy (ICMP), although the sample sizes have been small and the number of trials sparse. After a pilot phase of 8 patients, 60 patients with ICMP (left ventricular ejection fraction 15%-50%) will be randomized to group A (30 patients further randomized to receive MSC injection or placebo in a 2:1 fashion) or group B (30 patients further randomized to BMCs or placebo in a 2:1 fashion). All patients will undergo bone marrow aspiration and transendocardial injection of SCs or placebo. The primary and secondary objectives are, respectively, to demonstrate the safety and efficacy (determined primarily by cardiac magnetic resonance imaging) of BMCs and MSCs administered transendocardially in patients with ICMP.


Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells.
There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells. We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes. Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells. These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.


[Results of a study of the effectiveness of simultaneous immunization against influenza with live and inactivated vaccines (1980-1983)].
A comparative evaluation of immunological and epidemiological effectiveness of commercial live and killed vaccine preparations used simultaneously or separately was first carried out in simultaneous field trials of various methods of influenza vaccine prevention in a human population of 10,449 subjects. The advantage of simultaneous immunization was confirmed by immunological parameters and protective effect in the period of influenza A epidemic of 1983. The correlation of immunological and epidemiological effectiveness of influenza vaccines in joint or separate administration is discussed.


[Indicators to measure the performance of emergency trauma care].
The objective of this paper was to identify the main indicators used to measure the performance in emergency trauma care. A literature review was carried out in the electronic databases: PubMEd, LILACS and Epistemónikos, including publications between January 2011 and December 31, 2021, in Spanish, English and Portuguese. A total of 962 publications were identified. When reviewing the full text, 48 articles were included. The indicators were classified in the dimensions of process and results. 100 different indicators were identified to analyze the performance of emergency trauma care. 71% were process indicators, including service time and triage. In the results dimension 29 indicators were identified; mortality was the indicator most analyzed as well as length of stay. Six indicators on the disability of injured people and 14 indicators related to satisfaction were identified, the most frequent being complaints. Various indicators have been used to assess the performance of emergency trauma care. In the results dimension, the indicators related to satisfaction and disability after injuries have been little explored. Decision-makers and those responsible for emergency care must promote performance evaluation exercises to learn about their current situation using appropriate and sensitive indicators with the available data.


Continuously manufactured magnetic polymersomes--a versatile tool (not only) for targeted cancer therapy.
Micromixer technology was used to prepare polymeric vesicles (Pluronic® L-121) dual loaded with the anti-cancer drug camptothecin and magnetic nanoparticles. Successful incorporation of the magnetic nanoparticles was confirmed by transmission electron microscopy. Dynamic light scattering measurements showed a relatively narrow size distribution of the hybrid polymersomes. Camptothecin polymersomes reduced the cell viability of prostate cancer cells (PC-3) measured after 72 h significantly, while drug-free polymersomes showed no cytotoxic effects. Covalent attachment of a cancer targeting peptide (bombesin) as well as a fluorescent label (Alexa Fluor® 647) to the hybrid polymersomes was performed and specific cell binding and internalization were shown by flow cytometry and confocal microscopy. Relaxometry measurements clearly demonstrated the capacity of magnetic polymersomes to generate significant T2-weighted MRI contrast and potentially allow for direct monitoring of the biodistribution of the polymersomes. Micromixer technology as an easy, fast and efficient way to manufacture hybrid polymersomes as theranostic drug delivery devices is a further step from basic research to personalized medicine.


Ultranarrow-linewidth, efficient amplification of low-power seed sources by a fiber amplifier.
We report efficient amplification of an external cavity diode laser in the 1.06-microm range. The diode laser radiation is coupled into a Nd-doped silica fiber. The fiber is pumped by a diode array with up to 6.15 W of power. After a single pass of the seed radiation through the fiber amplifier, we observe up to 1.74 W of single-mode, narrow-linewidth laser radiation that is tunable over a relatively wide range of 1.060-1.067 microm. The output from our amplifier has the same spectral characteristics as the seed beam.


Relaxation of the stability condition of the complex-valued neural networks.
Jankuwski et al. (1996) have proposed a complex-valued neural network (CVNN) that is capable of storing and recalling gray-scale images. However, the weight matrix of the CVNN must be Hermitian with nonnegative diagonal entries in order to preserve the stability of the network. The Hermitian assumption poses difficulties in both physical realizations and practical applications of the networks. In this paper, a new stability condition is derived. The obtained result not only permits a little relaxation on the Hermitian assumption of the connection matrix, but also generalizes some existing results.


Dominant optic atrophy: updates on the pathophysiology and clinical manifestations of the optic atrophy 1 mutation.
Review recent advances in clinical and experimental studies of dominant optic atrophy (DOA) to better understand the complexities of pathophysiology caused by the optic atrophy 1 (OPA1) mutation. DOA is the most commonly diagnosed inherited optic atrophy, causing progressive bilateral visual loss that begins early in life. During the past 25 years, there has been substantial progress in the understanding of the clinical, genetic, and pathophysiological basis of this disease. The histopathological hallmark of DOA is the primary degeneration of retinal ganglion cells, preferentially in the papillomacular bundle, which results temporal optic disc pallor and cecocentral scotomata in patients with DOA. Loss of OPA1 protein function by OPA1 gene mutations causes mitochondrial dysfunction because of the loss of mitochondrial fusion, impaired mitochondrial oxidative phosphorylation, increases in reactive oxygen species, and altered calcium homeostasis. These factors lead to apoptosis of retinal ganglion cells by a haploinsufficiency mechanism. Improved understanding of the pathophysiology of DOA provides insights that can be used to develop therapeutic approaches to the DOA.


End-to-end physics-informed deep neural network optimization of sub-Nyquist lenses.
In this paper, an approach for optimizing sub-Nyquist lenses using an end-to-end physics-informed deep neural network is presented. The simulation and optimization of these sub-Nyquist lenses is investigated for image quality, classification performance, or both. This approach integrates a diffractive optical model with a deep learning classifier, forming a unified optimization framework that facilitates simultaneous simulation and optimization. Lenses in this work span numerical apertures from approximately 0.1 to 1.0, and a total of 707 models are trained using the PyTorch-Lightning deep learning framework. Results demonstrate that the optimized lenses produce better image quality in terms of mean squared error (MSE) compared to analytical lenses by reducing the impact of diffraction order aliasing. When combined with the classifier, the optimized lenses show improved classification performance and reduced variability across the focal range. Additionally, the absence of correlation between the MSE measurement of image quality and classification performance suggests that images that appear good according to the MSE metric may not necessarily be beneficial for the classifier.


Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.
Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.


Extracapsular Mandibular Condyle Fractures Are Associated with Severe Blunt Internal Carotid Artery Injury: Analysis of 605 Patients.
Mandibular condyle fractures are common following facial trauma and carry an increased risk for concomitant blunt carotid artery injuries. Further elucidation of this relationship may improve vascular injury screening and management. A retrospective cohort study was performed for all patients sustaining condylar fractures presenting to a large trauma center over twelve years. Fracture locations were classified according to the Strasbourg Osteosynthesis Research Group (1, condylar head; 2, condylar neck; and 3, extracapsular condylar base). Carotid artery injury severity was based on the Biffl scale. Severe vascular injury was defined as a Biffl score greater than I. 605 patients were identified with mandibular condyle fractures consisting of 21.0 percent (n = 127) condylar head; 26.8 percent (n = 162) condylar neck; and 52.2 percent (n = 316) extracapsular condylar base. The incidence of vascular injuries in this population was 5.5 percent (n = 33), of which 75.8 percent (n = 25) were severe. Severe vascular injuries occurred in 1.6 percent (n = 2) of condylar head, 2.5 percent (n = 4) of condylar neck, and 6.0 percent (n = 19) of extracapsular condylar base fractures (p < 0.05). Extracapsular condylar base fractures were independently associated with a 2.94-fold increased risk of a severe blunt carotid artery injury compared with other condyle fractures on multivariable analysis (p < 0.05). Extracapsular subcondylar fractures should heighten suspicion for concomitant blunt carotid artery injury. The data support a force transmission mechanism of injury in addition to direct injury from bony fragments. Risk, II.


Impact of transcatheter aortic valve implantation in symptomatic patients with very severe aortic stenosis.
Aortic stenosis (AS) is a progressive disease, and valve replacement-the only treatment option-should be performed after it becomes symptomatic and before irreversible myocardial damages develop. Surgical valve replacement is recommended in patients with very severe AS (VSAS), even if they are asymptomatic. However, there is no detailed study on the effect of transcatheter aortic valve implantation (TAVI) in patients with VSAS. Our aim in this study is to show the feasibility and safety of TAVI in symptomatic patients with VSAS. A total of 505 consecutive patients with symptomatic AD who underwent TAVI in our center were retrospectively studied. The mean age of the patients was 77.8±7.6 years, and 56.4% of them were women. The patients were divided into 2 groups: a group with VSAS (n=134 patients) and a group with high-gradient AS (HGAS) (n=371 patients). Female sex, left ventricular ejection fraction, small left ventricle, hypertrophic left ventricle were more common in the group with VSAS; on the other hand, histories of coronary artery disease bypass surgery, myocardial infarction, and atrial fibrillation were less frequent. Predilatation and Edwards SAPIEN 3 were less used in the group with VSAS. There was no statistical difference in major complications and in-hospital mortality (group with VSAS: 5 patients, group with HGAS: 16 patients; p=0.769) according to the Valve Academic Research Consortium-2 criteria. There was a significant difference between the 2 groups in favor of the group with VSAS on the Cox regression model survival curve (p<0.001). In this study, it has been shown that TAVI can be feasible and safe in symptomatic VSAS, with acceptable complications and higher survival rates. Currently, further randomized studies are required to perform TAVI in patients with asymptomatic VSAS currently indicated for surgical aortic valve replacement.


Inflammatory pseudotumor of the choroid plexus. Case report.
The authors report a case of inflammatory pseudotumor that developed in the choroid plexus of the lateral ventricle. The patient was a 73-year-old man who had undergone surgery for rectal cancer at another hospital 5 years earlier. He was referred to the authors' department, with his chief symptoms consisting of disorientation, right hemiparesis, and gait disorder that had gradually developed during the preceding month. On computed tomography and magnetic resonance imaging, a well-demarcated and homogeneously contrasted tumorous lesion was noted in the region from the trigone to the medial wall of the inferior horn of the left lateral ventricle. Expansion of the inferior horn was also evident. Intraoperative findings showed that the tumor originated from the choroid plexus of the lateral ventricle, and the histopathological diagnosis was inflammatory pseudotumor. There are only 4 previously reported cases of inflammatory pseudotumor that developed in the choroid plexus; the authors review the literature and discuss the clinicopathological characteristics of the condition.


Availability of emergency contraception: a survey of hospital emergency department gynaecologists and emergency physicians in Piedmont, Italy.
To compare the knowledge and the willingness of emergency physicians and gynaecologists caring for women in Italian emergency departments (EDs) to prescribe levonorgestrel-only emergency contraceptive pills (LNG-EC pills). A cross-sectional survey was conducted in 2009; anonymous postal questionnaires were mailed to the medical staff working at the 30 EDs located in Piedmont (Italy). Emergency physicians and gynaecologists have similar knowledge of the pharmacokinetics and pharmacodynamics of LNG-EC pills, but do not feel at ease in prescribing these and consider the prescription of LNG-EC pills an inappropriate activity for ED staff. In Italy, unlike in most other European countries, LNG-EC pills are still prescription drugs. Thus it may be useful to further investigate the reasons why Italian ED medical staff do not feel the prescription of LNG-EC pills should be within their remit and whether women can successfully obtain the prescription from physicians working in other services that can be accessed around the clock.


Overview of Current Drug Delivery Methods Across the Blood-Brain Barrier for the Treatment of Primary Brain Tumors.
Existing drug delivery methods have not led to a significant increase in survival for patients with malignant primary brain tumors. While the combination of conventional therapies consisting of surgery, radiotherapy, and chemotherapy has improved survival for some types of brain tumors (e.g., WNT medulloblastoma), other types of brain tumors (e.g., glioblastoma and diffuse midline glioma) still have a poor prognosis. The reason for the differences in response can be largely attributed to the blood-brain barrier (BBB), a specialized structure at the microvasculature level that regulates the transport of molecules across the blood vessels into the brain parenchyma. This structure hampers the delivery of most chemotherapeutic agents for the treatment of primary brain tumors. Several drug delivery methods such as nanoparticles, convection enhanced delivery, focused ultrasound, intranasal delivery, and intra-arterial delivery have been developed to overcome the BBB in primary brain tumors. However, prognosis of most primary brain tumors still remains poor. The heterogeneity of the BBB in primary brain tumors and the distinct vasculature of tumors make it difficult to design a drug delivery method that targets the entire tumor. Drug delivery methods that combine strategies such as focused ultrasound and nanoparticles might be a more successful approach. However, more research is needed to optimize and develop new drug delivery techniques to improve survival of patients with primary brain tumors.


Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT.
Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. NCT01206062.


Bullying and Peer Victimization of Minority Youth: Intersections of Sexual Identity and Race/Ethnicity.
Youth with multiple minority identities, such as those who are both sexual minority (eg, lesbian, gay, bisexual) and racial/ethnic minority (eg, Black, Latino) may be at increased risk for bullying and peer victimization. Youth Risk Behavior Surveillance data (2011-2017) were analyzed (N = 114,881; 50.8% girls; mean age = 15.7 years, SD = 0.03). We used chi-square tests and sex-stratified multiple linear regression models to examine sexual identity and racial/ethnic differences and the intersection between sexual identity and race/ethnicity across 3 forms of bullying and peer victimization, co-occurrence of traditional and electronic bullying, and any type of bullying or peer victimization. Sexual minority youth reported higher odds of bullying and peer victimization than heterosexual youth. White youth reported higher odds of bullying than racial/ethnic minority youth. In intersectional analyses, all sexual minority and racial/ethnic minority boys, and bisexual racial/ethnic minority girls were at higher risk for bullying and peer victimization compared to heterosexual peers of the same race/ethnicity. This study of a large diverse sample of youth advances our understanding of vulnerability to bullying and peer victimization among youth with multiple minority identities. This research can inform policy initiatives and interventions to prevent peer victimization of vulnerable youth.


Increasing secure base script knowledge among parents with Attachment and Biobehavioral Catch-up.
This study evaluated whether Attachment and Biobehavioral Catch-up (ABC), a parenting intervention, altered the attachment representations of parents (average age of 34.2 years) who had been referred to Child Protective Services (CPS) due to risk for child maltreatment when their children were infants. Approximately 7 years after completing the intervention, parents who had been randomized to receive ABC (n = 43) exhibited greater secure base script knowledge than parents who had been randomized to receive a control intervention (n = 51). Low-risk parents (n = 79) exhibited greater secure base script knowledge than CPS-referred parents who had received a control intervention. However, levels of secure base script knowledge did not differ between low-risk parents and CPS-referred parents who had received the ABC intervention. In addition, secure base script knowledge was positively associated with parental sensitivity during interactions with their 8-year-old children among low-risk and CPS-referred parents. Mediational analyses supported the idea that the ABC intervention enhanced parents' sensitivity 7 years later indirectly via increases in parents' secure base script knowledge.


Effectiveness of bisphosphonate use and risk of contralateral breast cancer and recurrence in women with early-stage breast cancer treated with tamoxifen.
The effectiveness of bisphosphonates (BP) in reducing risk of second breast cancer and recurrence in observational studies has been minimally studied. We examined the association of oral BP use on risk of contralateral breast cancer (CBC) and recurrence in 16,781 women diagnosed with early-stage breast cancer from 1996 to 2007, treated with tamoxifen, and followed through December 31, 2009 at Kaiser Permanente Northern California (KPNC, n = 8857) and Southern California (KPSC, n = 7924). Sociodemographic, clinical, and pharmacy information were extracted from electronic medical records and cancer registries. CBC was identified from cancer registries, and recurrences from electronic health records and chart reviews. Multivariate Cox regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) treating BP use and hormonal therapy as time-varying variables. After mean 6.4 years of follow-up, 494 (3.0 %) women developed CBC. BP use post-breast cancer diagnosis (>93 % alendronate) ranged from 14.5 to 24.9 % at both study sites. Overall, there was no association of BP use with reduced risk of CBC (ever use, HR = 0.96; 95 % CI 0.67-1.38 and continuous use, HR = 1.03; 95 % CI 0.88, 1.20). Similar null associations were observed for recurrence (ever use, HR = 0.98; 95 % CI 0.82, 1.17 and continuous use, HR = 1.00; 95 % CI 0.92, 1.09). Associations varied somewhat by site yet confidence intervals overlapped. BP use was not associated with reduced risk of recurrence or new primary disease among women diagnosed with early breast cancer and treated with tamoxifen.


Enzymic differentiation in cultured foetal hepatocytes of the rat. Induction of serine dehydratase activity by dexamethasone and dibutyryl cyclic AMP.
Serine dehydratase activity is absent from the rat foetal liver and normally appears in the immediate postnatal period. In foetal hepatocytes cultured from livers of various gestational ages, enzyme activity can be induced only in the simultaneous presence of dexamethasone and dibutyryl cyclic AMP in the culture medium. Adrenalin and glucagon can replace dibutyryl cyclic AMP. Actinomycin D and cordycepin both repress the response, a result that suggests the induction of enzyme synthesis involves the initial transcription of the enzyme gene(s). Inducibility is assessed in cultures prepared from foetuses aged between 15 and 19 days of gestation after 48 h of culture. No induction is obtained in cells from 15 day foetuses, only a marginal induction from 16 day foetuses, and a substantial induction from older foetuses. In cultures from older foetuses, 6-18 fold inductions are already demonstrable after 24 h of culture. While hepatocytes from more mature foetuses are able to acquire inductibility during culture, cells taken from 15 day foetuses do not develop in the same manner in spite of being maintained under identical conditions. These results suggest that a differentiation event occurs in vivo at about day 16 of foetal development which renders the hepatocyte inducible when cultured. Cells taken prior to this stage do not appear to acquire inducibility. This system represents a case of enzymic differentiation and requires the simultaneous presence of two inducer molecules. The mechanism of induction may represent a unique system in cellular differentiation.


CD4 count is predictive of outcome in HIV-positive patients undergoing abdominal operations.
The impact of immune status and surgical outcome in patients with HIV and acquired immunodeficiency syndrome (AIDS) remains unknown. Clinical variables of HIV/AIDS patients undergoing abdominal surgery were examined for their impact on outcome. Major abdominal procedures were performed in 77 patients with a diagnosis of HIV/AIDS (55 males, mean age 41.1 years, mean CD4 count 210 mg/dL). A majority of operations (53%) were performed on an urgent basis. Patients undergoing urgent procedures had lower CD4 counts (129 ± 121 vs 303 ± 324, P = .002). The mean CD4 count was lower for patients with complications (146 ± 156 vs 288 ± 319, P = .013) and for those who died (112 ± 113 vs 251 ± 283, P = .026). On multivariate analysis, CD4 count was independently associated with an increased risk for complication, and urgent operation was associated with an increased risk for mortality. Patients with HIV/AIDS who had lower CD4 counts were more likely to require an urgent operation and experience a complication with increased mortality.


Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity.
Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases.


Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK.
MIRO (mitochondrial Rho GTPase) consists of two GTPase domains flanking two Ca2+-binding EF-hand domains. A C-terminal transmembrane helix anchors MIRO to the outer mitochondrial membrane, where it functions as a general adaptor for the recruitment of cytoskeletal proteins that control mitochondrial dynamics. One protein recruited by MIRO is TRAK (trafficking kinesin-binding protein), which in turn recruits the microtubule-based motors kinesin-1 and dynein-dynactin. The mechanism by which MIRO interacts with TRAK is not well understood. Here, we map and quantitatively characterize the interaction of human MIRO1 and TRAK1 and test its potential regulation by Ca2+ and/or GTP binding. TRAK1 binds MIRO1 with low micromolar affinity. The interaction was mapped to a fragment comprising MIRO1's EF-hands and C-terminal GTPase domain and to a conserved sequence motif within TRAK1 residues 394 to 431, immediately C-terminal to the Spindly motif. This sequence is sufficient for MIRO1 binding in vitro and is necessary for MIRO1-dependent localization of TRAK1 to mitochondria in cells. MIRO1's EF-hands bind Ca2+ with dissociation constants (KD) of 3.9 μM and 300 nM. This suggests that under cellular conditions one EF-hand may be constitutively bound to Ca2+ whereas the other EF-hand binds Ca2+ in a regulated manner, depending on its local concentration. Yet, the MIRO1-TRAK1 interaction is independent of Ca2+ binding to the EF-hands and of the nucleotide state (GDP or GTP) of the C-terminal GTPase. The interaction is also independent of TRAK1 dimerization, such that a TRAK1 dimer can be expected to bind two MIRO1 molecules on the mitochondrial surface.


Elevated IgA concentration in milk produced by mothers delivered of preterm infants.
Concentrations of immunoglobulins G, M, and A were measured by double-antibody radioimmunoassay in morning milk samples collected during the first month postpartum from 35 mothers delivered of preterm infants and 14 mothers delivered of term infants. Mean concentrations of IgG (1.8, to 2.8 mg/gm protein) and IgM (2.8 to 11.7 mg/gm protein) were similar in milk from both groups of mothers. In contrast, IgA was present in significantly higher concentrations throughout the first month postpartum in milk from mothers delivered of preterm infants than in milk from those giving birth at term (P less than 0.01). To determine the effect of milk flow on IgA concentration, IgA was also measured in complete 24-hour milk collections; milk from mothers with preterm deliveries again contained significantly higher concentrations of IgA than milk from mothers with term deliveries (P less than 0.01). This higher IgA concentration was not secondary to method of milk expression. The concentration of IgA was found, however, to vary inversely with milk volume (P less than 0.01). Although mean values of milk volumes for the groups were not statistically different, the overall lower volumes of milk produced by mothers giving birth preterm resulted in comparable total IgA production per 24 hours. There were no differences in serum IgA concentrations of preterm infants fed their own mother's milk and comparable infants fed a cow milk formula, suggesting that IgA in milk is not absorbed from the intestine in significant amounts.


Courageous leaders. The integral force behind organizational excellence.
For more than a decade, Total Quality Management (TQM) has been used as a powerful instrument in shaping the competitive strategies of businesses, and producing quality products and services has become the credo of firms trying to defend or expand their markets. During this time, we have come to realize that without effective leadership no quality program can succeed. That is why the quality guru, W. Edwards Deming, refused to work in any organization unless he could begin with the CEO. That is why the first criterion examined for the Malcolm Baldridge National Quality Award is leadership. Focusing on quality will not guarantee success in today's rapidly changing markets. Increasingly discriminating consumers have come to expect quality in the products and services they buy, and businesses that fail to deliver it will not survive. In a very real sense, quality performance is the price you must pay simply to play the game. But consumers want more, and satisfying their expectations will determine tomorrow's winners and losers. Building organizations capable of producing superior results that consistently meet the needs of customers is the responsibility of leaders. For this reason, leaders are more important today than they have ever been before. Leaders in successful businesses must show the way for their employees by nurturing "cultures" that encourage and reward superior performance and by exhibiting personal characteristics that inspire excellence. Great leaders possess three crucial characteristics--vision, strong values and beliefs, and the courage to do the job despite seemingly insurmountable obstacles. These characteristics make the difference between excellence and "business as usual."


A quantitative trait locus influencing fasting plasma glucose in chromosome region 18q22-23.
Fasting plasma glucose is a multigenic trait related to both diabetes and obesity. We performed a genome scan for quantitative fasting plasma glucose levels in 320 families (1,514 subjects), segregating extreme obesity and normal weight using 382 autosomal microsatellite markers. We found significant linkages on 18q22-23 using family regression (logarithm of odds [LOD] 3.67, P = 0.00002, D18S1371 at 116 cM) and variance components (LOD 4.48, P < 0.00001) methods. Evidence for linkage remained strong when restricted to European Americans (260 families, 1,258 individuals). After an additional 60 families were added, the linkage signal strengthened (LOD 6.59). The result on 18q22-23 remained significant, even after controlling for both BMI and diabetes status. We also found suggestive linkages on chromosomes 2 (LOD 1.58, 216 cM) and 7 (LOD 1.78, 163 cM). Our results suggest that there is a quantitative trait locus in chromosome region 18q22-23 that influences fasting glucose levels and may play a role in the pathogenesis of type 2 diabetes. The strength of the serum glucose results after controlling for BMI suggests that this putative gene does not influence glucose levels merely through an effect on obesity.


Lifestyle and Pain following Cancer: State-of-the-Art and Future Directions.
This review discusses chronic pain, multiple modifiable lifestyle factors, such as stress, insomnia, diet, obesity, smoking, alcohol consumption and physical activity, and the relationship between these lifestyle factors and pain after cancer. Chronic pain is known to be a common consequence of cancer treatments, which considerably impacts cancer survivors' quality of life when it remains untreated. Improvements in lifestyle behaviour are known to reduce mortality, comorbid conditions (i.e., cardiovascular diseases, other cancer, and recurrence) and cancer-related side-effects (i.e., fatigue and psychological issues). An inadequate stress response plays an important role in dysregulating the body's autonomic, endocrine, and immune responses, creating a problematic back loop with pain. Next, given the high vulnerability of cancer survivors to insomnia, addressing and treating those sleep problems should be another target in pain management due to its capacity to increase hyperalgesia. Furthermore, adherence to a healthy diet holds great anti-inflammatory potential for relieving pain after cancer. Additionally, a healthy diet might go hand in hand with weight reduction in the case of obesity. Consuming alcohol and smoking have an acute analgesic effect in the short-term, with evidence lacking in the long-term. However, this acute effect is outweighed by other harms on cancer survivors' general health. Last, informing patients about the benefits of an active lifestyle and reducing a sedentary lifestyle after cancer treatment must be emphasised when considering the proven benefits of physical activity in this population. A multimodal approach addressing all relevant lifestyle factors together seems appropriate for managing comorbid conditions, side-effects, and chronic pain after cancer. Further research is needed to evaluate whether modifiable lifestyle factors have a beneficial influence on chronic pain among cancer survivors.


Quercetin is a Useful Medicinal Compound Showing Various Actions Including Control of Blood Pressure, Neurite Elongation and Epithelial Ion Transport.
Quercetin has multiple potential to control various cell function keeping our body condition healthy. In this review article, we describe the molecular mechanism on how quercetin exerts its action on blood pressure, neurite elongation and epithelial ion transport based from a viewpoint of cytosolic Cl- environments, which is recently recognized as an important signaling factor in various types of cells. Recent studies show various roles of cytosolic Cl- in regulation of blood pressure and neurite elongation, and prevention from bacterial and viral infection. We have found the stimulatory action of quercetin on Cl- transporter, Na+-K+-2Cl- cotransporter 1 (NKCC1; an isoform of NKCC), which has been recognized as one of the most interesting, fundamental actions of quercetin. In this review article, based on this stimulatory action of quercetin on NKCC1, we introduce the molecular mechanism of quercetin on: 1) blood pressure, 2) neurite elongation, and 3) epithelial Cl- secretion including tight junction forming in epithelial tissues. 1) Quercetin induces elevation of the cytosolic Cl- concentration via activation of NKCC1, leading to anti-hypertensive action by diminishing expression of epithelial Na+ channel (ENaC), a key ion channel involved in renal Na+ reabsorption, while quercetin has no effects on the blood pressure with normal salt intake. 2) Quercetin also has stimulatory effects on neurite elongation by elevating the cytosolic Cl- concentration via activation of NKCC1 due to tubulin polymerization facilitated through Cl--induced inhibition of GTPase. 3) Further, in lung airway epithelia quercetin stimulates Cl- secretion by increasing the driving force for Cl- secretion via elevation of the cytosolic Cl- concentration: this leads to water secretion, participating in prevention of our body from bacterial and viral infection. In addition to transcellular ion transport, quercetin regulates tight junction function via enhancement of tight junction integrity by modulating expression and assembling tight junction-forming proteins. Based on these observations, it is concluded that quercetin is a useful medicinal compound keeping our body to be in healthy condition.


Inhibition of nuclear factor kappaB activation and cyclooxygenase-2 expression by aqueous extracts of Hispanic medicinal herbs.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a primary choice of therapy for diseases with a chronic inflammatory component. Unfortunately, long-term NSAID therapy is often accompanied by severe side effects, including cardiovascular and gastrointestinal complications. Because of this, there is critical need for identification of new and safer treatments for chronic inflammation to circumvent these side effects. Inflammatory diseases have been successfully remedied with natural herbs by many cultures. To better understand the potential of natural herbs in treating chronic inflammation and to identify their mechanism of action, we have evaluated the anti-inflammatory activities of 20 medicinal herbs commonly used in the Hispanic culture. We have established a standardized method for preparing aqueous extracts (teas) from the selected medicinal herbs and screened for inhibition of tumor necrosis factor-alpha-induced activation of nuclear factor kappaB (NF-kappaB), which is the central signaling pathway of the inflammatory response. A number of herbal teas were identified that exhibited significant anti-inflammatory activity. In particular, tea from the herb commonly called laurel was found to be an especially potent inhibitor of NF-kappaB-dependent cyclooxygenase-2 gene expression and prostaglandin E(2) production in cultured murine macrophages. These findings indicate that laurel tea extract contains potent anti-inflammatory compounds that function by inhibiting the major signal transduction pathway responsible for inducing an inflammatory event. Based on these results, laurel may represent a new, safe therapeutic agent for managing chronic inflammation.


Halloween genes and nuclear receptors in ecdysteroid biosynthesis and signalling in the pea aphid.
The pea aphid (Acyrthosiphon pisum) is the first whole genome sequenced insect with a hemimetabolic development and an emerging model organism for studies in ecology, evolution and development. The insect steroid moulting hormone 20-hydroxyecdysone (20E) controls and coordinates development in insects, especially the moulting/metamorphosis process. We, therefore present here a comprehensive characterization of the Halloween genes phantom, disembodied, shadow, shade, spook and spookiest, coding for the P450 enzymes that control the biosynthesis of 20E. Regarding the presence of nuclear receptors in the pea aphid genome, we found 19 genes, representing all of the seven known subfamilies. The annotation and phylogenetic analysis revealed a strong conservation in the class of Insecta. But compared with other sequenced insect genomes, three orthologues are missing in the Acyrthosiphon genome, namely HR96, PNR-like and Knirps. We also cloned the EcR, Usp, E75 and HR3. Finally, 3D-modelling of the ligand-binding domain of Ap-EcR exhibited the typical canonical structural scaffold with 12 alpha-helices associated with a short hairpin of two antiparallel beta-strands. Upon docking, 20E was located in the hormone-binding groove, supporting the hypothesis that EcR has a role in 20E signalling.


Could Activity Modifications Indicate Physical Decline Among Adults With Symptomatic Knee Osteoarthritis?
Mobility activity modifications indicate early functional losses that act as precursors to future declines among community-dwelling older adults. However, there is scarce evidence on whether activity modifications indicate poorer physical health among adults with symptomatic osteoarthritis, a major cause of disability. Our purpose was to investigate whether patient-reported mobility activity modifications indicated poorer physical health among adults with symptomatic knee osteoarthritis. Secondary cross-sectional analysis of randomized trial data was performed. Preclinical Disability Questionnaire was used to group participants into the following three categories: difficulty, modified, and no difficulty walking/stair climbing. Kruskal Wallis and χ tests were used to compare clinical factors across groups. Among 121 participants (median age = 60 yrs; 73% female; 60% white), less than 10% had modified walking/stair climbing. Compared with those with no walking difficulty, participants with modified walking had significantly less balance (P = 0.01) and global health (P = 0.01) as well as greater knee pain (P = 0.05) and physical disability (P = 0.04). Those with modified stair climbing had significantly smaller walking distances (P = 0.03) compared with those with no difficulty stair climbing. Activity modifications may signal early impairments in physical health among people with symptomatic knee osteoarthritis. If confirmed, patient-reported activity modifications may enhance symptom evaluation in osteoarthritis and enable a better understanding of the disablement process.


Natural and anthropogenic inputs of hydrocarbons to the Strait of Georgia.
Sediment cores from the Fraser estuary, Vancouver Harbour and Strait of Georgia, suspended sediment samples from the Fraser River and sediment grabs from Vancouver Harbour have been analyzed for alkanes and parent and alkyl PAHs (polycyclic aromatic hydrocarbons). Principal components analysis (PCA) clearly distinguishes mixed sources by separating parent PAHs according to molecular size, and separating alkyl substituted PAHs from higher plant PAHs. We find the Fraser River to be the predominant source for natural and anthropogenic hydrocarbons to the Strait of Georgia. The natural hydrocarbon burden from the Fraser River is augmented principally by petroleum hydrocarbons and combustion PAHs from Vancouver. Contaminated sediments from Vancouver Harbour very likely have also been transported to a major ocean disposal site off the Fraser estuary. Petroleum alkanes, which dominate Fraser River suspended sediment samples, are lost by processes such as dissolution or microbial degradation during transport and sedimentation, while PAHs from the river are delivered essentially unchanged to sediments in the strait. Hydrocarbon composition undergoes little change with depth at a reference location in the Strait of Georgia, indicating that PAH inputs have changed very little since the early part of this century. In Vancouver Harbour the low rate of sediment accumulation coupled with surface mixing has led to the retention of contaminant PAHs within the surface mixed layer, while the rapid delivery of sediments from the Fraser River has buried contaminant PAHs from historical ocean disposal in the Strait of Georgia.