Cancer-Attributable Medical Costs for Colorectal Cancer Patients by Phases of Care: What Is the Effect of a Prior Cancer History?
Medical care costing studies have excluded patients with a prior cancer history. This study aims to update methods for estimating medical care costs attributable to cancer and to evaluate the effect of a prior history of cancer on costs for colorectal cancer (CRC) patients. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data and matched cancer patients to controls without cancer to estimate cancer-attributable costs by phases of care using Medicare 2007-2013 claims. CRC annualized average cancer-attributable costs were $56.0 K, $5.3 K, $92.5 K, and $24.3 K in the initial, continuing, and end-of-life cancer and noncancer death phases, respectively, in 2014 dollars. Costs were higher for patients diagnosed with more advanced stage, younger ages, and nonwhite races. Costs for patients with prior cancers were consistently higher than patients without prior cancers, especially in the continuing (4.9 K vs 7.2 K) and end-of-life noncancer death (22.7 K vs 30.0 K). Our CRC costs improve previous estimates by using more recent data and updated methods.


Development and Validation of Binary Classifiers to Predict Nocturnal Hypoglycemia in Adults With Type 1 Diabetes.
One of the biggest challenges for people with type 1 diabetes (T1D) using multiple daily injections (MDIs) is nocturnal hypoglycemia (NH). Recurrent NH can lead to serious complications; hence, prevention is of high importance. In this work, we develop and externally validate, device-agnostic Machine Learning (ML) models to provide bedtime decision support to people with T1D and minimize the risk of NH. We present the design and development of binary classifiers to predict NH (blood glucose levels occurring below 70 mg/dL). Using data collected from a 6-month study of 37 adult participants with T1D under free-living conditions, we extract daytime features from continuous glucose monitor (CGM) sensors, administered insulin, meal, and physical activity information. We use these features to train and test the performance of two ML algorithms: Random Forests (RF) and Support Vector Machines (SVMs). We further evaluate our model in an external population of 20 adults with T1D using MDI insulin therapy and wearing CGM and flash glucose monitoring sensors for two periods of eight weeks each. At population-level, SVM outperforms RF algorithm with a receiver operating characteristic-area under curve (ROC-AUC) of 79.36% (95% CI: 76.86%, 81.86%). The proposed SVM model generalizes well in an unseen population (ROC-AUC = 77.06%), as well as between the two different glucose sensors (ROC-AUC = 77.74%). Our model shows state-of-the-art performance, generalizability, and robustness in sensor devices from different manufacturers. We believe it is a potential viable approach to inform people with T1D about their risk of NH before it occurs.


[Evaluation the efficacy and safety of estradiol and drospirenone tablets in the treatment of menopausal symptoms among postmenopausal Chinese healthy women:a randomized, multi-center, double-blind, placebo-controlled clinical study].
To study the efficacy and safety of estradiol and drospirenone tablets (Angeliq) in treatment of menopausal symptoms among postmenopausal Chinese healthy women. Total 244 postmenopausal Chinese healthy women who had moderate to severe hot flushes were randomly assigned into estradiol and drospirenone (observation group, n = 183) or placebo group (n = 61) by the ratio of 3:1 for 16 weeks in this randomized multi-center double-blind placebo-controlled study. During the trial, the follow-up visits were conducted at week 4, 8, 12, 16 of treatment and 2 weeks after treatment respectively. Height, weight, vital signs, hot flushes, other relevant menopausal symptoms and vaginal bleeding were observed in each follow-up visit, while the clinical global impression scale was assessed at 16 weeks as well. It showed that hot flushes were reduced significantly more in observation group than that in placebo group (P < 0.01), although both treatments were effective. The absolute values of mean severity index of total hot flushes decreased by -0.6 ± 0.5 in observation group and -0.4 ± 0.4 in placebo group from baseline respectively, which reached significant difference (P < 0.05). However, the absolute values of mean severity index of moderate to severe hot flushes decreased by -0.6 ± 0.8 in observation group and -0.3 ± 0.6 in placebo group from baseline respectively, which had no significant difference (P > 0.05). After 16 weeks treatment, it also showed that estradiol and drospirenone had significant better efficacy than placebo on moderate to severe sweating, vaginal dryness and clinical global impression scale (P < 0.01). During the trial, blood pressure in observation group was stable. The rate of vaginal bleeding in observation group was higher than that in the placebo group, especially during the week 4 to week 8 when 48.9% (87/178) in observation group and 10.7% (6/56) in placebo group of patients bled. Although the cumulative amenorrhea rate of observation group was lower than that of placebo group in each cycle (28 days), it increased gradually along with duration of the treatment. The commonest adverse event in observation group was breast tenderness which accounted for 12.0% (22/183). The level of serum potassium was in the normal range in observation group mostly.Meanwhile, the other adverse events rate was low. Serious adverse events reported in this trial were assessed as not study drug related or as unlikely study drug related. Estradiol and drospirenone tablets which could effectively alleviate menopausal symptoms in postmenopausal Chinese healthy women is a novel hormone replacement therapy regimen with high safety and efficacy.


Evaluation of lipid profile and its relationship with blood pressure in patients with Cushing's disease.
The purpose of the study was to describe lipid profile and explore pathogenetic role of LDL-c on hypertension in patients with Cushing's disease (CD). Hypertension is a common feature in patients with CD. Previous study found low-density lipoprotein cholesterol (LDL-c) uptake in vascular cells might be involved in vascular remodeling in patients with CD. Therefore, we evaluated the relationship between lipid profile and the blood pressure in patients with CD. This retrospective study included 84 patients referred to Huashan Hospital for the evaluation and diagnosis of CD from January 2012 to December 2013. All subjects had detailed clinical evaluation by the same group of endocrinology specialists to avoid subjective influences. We found that high LDL-c patients had significant higher body mass index (BMI), systolic blood pressure (SBP), cholesterol (CHO), triglyceride (TG), and apolipoproteinB (apoB) (P < 0.05). An association was detected between SBP values and lipids profile including CHO, TG, LDL-c, apolipoproteinA (apoA), apoB and lipoprotein(a) (LP(a)). After adjustment for all covariates, the LDL-c remained positively associated with SBP. In patients with or without taking statins, patients with LDL-c ≥3.37 mmol/L had higher SBP than patients with LDL-c <3.37 mmol/L. Then, LDL-c was coded using restricted cubic splines (RCS) function with three knots located at the 5th, 50th and 95th percentiles of the distribution of LDL-c. Compared to individuals with 3.215 mmol/L of LDL-c, individuals with 4.0, 4.5 and 5.0 mmol/L of LDL-c had differences of 3.86, 8.53 and 14.11 mmHg in SBP, respectively. An independent association between LDL-c and SBP was found in patients with CD. We speculate that LDL-c may be a pathogenic factor for hypertension in those patients.


Manipulating systemic and mucosal immune responses with skin-deliverable adjuvants.
Most medically important bacterial and viral pathogens gain entry into the body either via the skin or a mucosal surface. Vaccination provides a viable and cost-effective strategy for the prevention of such diseases and it has always been a principal aim with vaccinologists, to be able to promote simultaneously, protective immune responses both systemically and at mucosal surfaces. The paradigm that mucosal immunity is best stimulated by exposure to antigen via a mucosal route simply because inductive sites such as Peyer's patches and bronchial associated lymphoid tissues are located in the mucosal epithelium, has promoted a plethora of immunizing strategies aimed at delivering both antigen and adjuvant to mucosal surfaces. We have developed a novel adjuvant system capable of intradermal delivery of antigens complexed in an ISCOSOME delivery vehicle. This adjuvant, referred to as a skin and mucosal adjuvant or SAMA4, was efficacious in eliciting both systemic and mucosal IgG and IgA antibodies in sheep, pigs and mice. SAMA4 does not induce granulomatous lesions at the site of vaccine delivery and can be used to deliver adjuvanted antigens by other routes including intranasal, oral and intravaginal. Using ovalbumin as a test antigen, intradermally delivered ovalbumin-SAMA4 complexes was found to be very effective in promoting a cytotoxic T cell response. Attempts to dissect the mode of action of SAMA4 by flow cytometric analysis of lymphocyte populations from the spleen, lung, liver and thymus revealed an effect of route of vaccine delivery upon the composition of specific lymphocyte subsets in these various organ compartments. From this, it can be inferred that SAMA4 induced a route-dependent re-mobilization and alteration in lymphocyte trafficking patterns. Other mucosal adjuvants such as cholera toxin B and microspheres, when injected intradermally, tended to promote primarily, an IgG and not an IgA response against hte carrier antigen.


Identification and characterization of the 285L and K145R proteins of African swine fever virus.
African swine fever (ASF) is a lethal disease of domestic pigs and wild boar, against which no vaccines are available to date. The large dsDNA genome of African swine fever virus (ASFV) contains up to 167 ORFs predicted to encode proteins. The functions and antigenic properties of many of these proteins are still unknown, which impedes vaccine development. Based on the results of mass spectrometry-based proteome analyses of ASFV-infected cells, two highly abundant but previously uncharacterized viral proteins, p285L and pK145R, were investigated in detail. To this end, monospecific rabbit antisera and corresponding gene deletion mutants of ASFV were prepared. RNA and immunoblot analyses revealed that p285L is an early gene product expressed prior to viral DNA replication, whereas pK145R is a true late protein. The predicted membrane protein p285L could be localized in purified ASFV particles. In contrast, pK145R was not detectable in virions, but accumulated diffusely in the cytoplasm of infected cells. Deletion of 285L or K145R from the genome of a virulent ASFV strain from Armenia did not significantly affect spread and productive growth in a permissive wild boar lung cell line, nor in primary macrophage cultures. Future studies must elucidate, whether p285L and pK145R, although non-essential for in vitro propagation of ASFV, are relevant for replication or virulence in swine. Furthermore, it remains to be investigated whether deletion of the abundant ASFV proteins p285L or pK145R might support serological differentiation from wild-type-infected animals.


In Silico and in Vitro Conductivity Models of the Left Heart Ventricle.
Ventricular Assist Devices (VADs) are used to treat patients with cardiogenic shock. As the heart is unable to supply the organs with sufficient oxygenated blood and nutrients, a VAD maintains the circulation to keep the patient alive. The observation of the patient's hemodynamics is crucial for an individual treatment; therefore, sensors to measure quantifiable hemodynmaic parameters are desirable. In addition to pressure measurement, the volume of the left ventricle and the progress of muscle recovery seem to be promising parameters. Ongoing research aims to estimate ventricular volume and changes in electrical properties of cardiac muscle tissue by applying bioimpedance measurement. In the case where ventricular insufficiency is treated by a catheter-based VAD, this very catheter could be used to conduct bioimpedance measurement inside the assisted heart. However, the simultaneous measurement of bioimpedance and VAD support has not yet been realized, although this would allow the determination of various loading conditions of the ventricle. For this purpose, it is necessary to develop models to validate and quantify bioimpedance measurement during VAD support. In this study, we present an in silico and an in vitro conductivity model of a left ventricle to study the application of bioimpedance measurement in the context of VAD therapy. The in vitro model is developed from casting two anatomical silicone phantoms: One phantom of pure silicone, and one phantom enriched with carbon, to obtain a conductive behavior close to the properties of heart muscle tissue. Additionally, a measurement device to record the impedance inside the ventricle is presented. Equivalent to the in vitro model, the in silico model was designed. This finite element model offers changes in material properties for myocardium and the blood cavity. The measurements in the in vitro models show a strong correlation with the results of the simulation of the in silico model. The measurements and the simulation demonstrate a decrease in impedance, when conductive muscle properties are applied and higher impedances correspond to smaller ventricle cross sections. The in silico and in vitro models are used to further investigate the application of bioimpedance measurement inside the left heart ventricle during VAD support. We are confident that the models presented will allow for future evaluation of hemodynamic monitoring during VAD therapy at an early stage of research and development.


Responses of hypoglossal motoneurons to mechanical stimulation of the teeth in rats.
Reflex discharges were evoked in the XIIth nerve single fibers and in the genioglossal muscle following mechanical stimulation of the homolateral incisor tooth in rats. The tooth mechanoreceptors affected the firing rate of 70% of the tested motoneurons mainly localized in the ventral region of the hypoglossal nucleus. Different types of response in relation to stimulus direction were recorded. Type A responded with excitation to labio-lingual and with inhibition to linguo-labial stimulus direction. Opposite effects were observed in type B motoneurons. However, these neurons did not respond to mechanical stimuli applied in medio-distal or disto-medial directions. Type C showed excitatory or inhibitory responses to mechanical stimulation in all directions. Type D only responded to one direction of stimulation. The stimulus was often able to excite motoneurons previously silent (type E). Some motoneurons showed complex responses to one stimulus direction. The results demonstrate that stimulation of the periodontal mechanoreceptors can evoke hypoglossal responses probably aimed at controlling tongue position in the mouth during mastication.


Binding and internalization of hyaluronate by human cutaneous fibroblasts.
Hyaluronate is a ubiquitous component of mammalian extracellular matrix. It influences numerous cellular processes and accumulates in fibrotic connective tissue disorders. Recently, hyaluronate catabolism has assumed additional importance because of the introduction into clinical practice of therapeutic procedures which deposit high concentrations of hyaluronate directly into tissues. Relatively little is known about the local metabolism, fate, or long-term effects of either endogenous or exogenous hyaluronate at deposition sites. A capacity for degrading hyaluronate within connective tissues, presumably by fibroblasts, has been inferred but remains controversial because direct proof that human fibroblasts endocytose and degrade hyaluronate has been lacking. In the present study, fibroblasts from normal and fibrotic skin were incubated with [3H]-hyaluronate. Binding and internalization of radiolabeled substrate were then measured: Binding assays revealed a saturable, dose-dependent increase in cell surface-associated [3H]-hyaluronate which was enhanced by pretreatment with hyaluronidase. Similar binding curves were obtained for all cells tested. All the cell lines internalized hyaluronate; however, fibroblasts in confluent cultures internalized 3.5- to 4.2-fold more radioactivity per cell than did fibroblasts from corresponding subconfluent cultures (p less than or equal to 0.002). Normal scar fibroblasts showed greater capacity for generating hyaluronate-derived partial degradation products. This work provides clear evidence that human cutaneous fibroblasts are capable of both binding and internalizing hyaluronate, possibly as a prerequisite for degradation.


Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC.
Members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at a much higher rate, and at a much younger age, than the general population. To quantify lifetime colorectal cancer risk in HNPCC family members, we calculated the cumulative incidence (CI) in different age categories, and compared this to the general population. Furthermore, we investigated whether successive generations of HNPCC families had earlier onset of disease. In 51 HNPCC families, selected according to the "Amsterdam criteria", the CI of colorectal cancer at age 75 was 40%, compared to only 4% in the general population. The CI ratio (CIR) of HNPCC family members relative to the general population was 148 at age 40, 79 at age 50 and 11 at age 75. Comparing successive generations of HNPCC families, the CI at age 75 increases from 19% in the ancestors to 32% in the first generation and 55% in the second generation. However, Cox proportional hazard analysis showed that this generation effect (RR per generation: 1.8, 95% CL = 1.4-2.2) largely disappears after adjustment for year of birth. In summary, at young ages, HNPCC family members experience an up-to-150 times higher risk for colorectal cancer than the general population. This risk difference declines from age 60 onwards. The earlier age of onset in successive HNPCC generations does not appear to be a biological feature of HNPCC, but reflects a secular time trend in cancer occurrence in these families, similar to that in the general population.


Summer dry-down modulates the isotopic composition of soil CO2 production in snow-dominated landscapes.
In mountainous landscapes, soil moisture is highly dynamic due to the effects of topography and the temporal variability imposed by seasonal precipitation, including rainfall and snow. Soil moisture is known to affect ecosystem carbon exchange both aboveground and belowground, as well as the stable isotopic composition of exchanged CO2. In this study we used an extensive suite of measurements to examine the effects of seasonal changes in soil moisture on the isotopic composition of soil CO2 production at the landscape level. We show that the seasonal decline in soil moisture (i.e., summer dry-down) appeared to impose a trend in the δ13C of soil CO2 production (δP) with more negative δP early in the growing season when soils were wet, and more positive δP as the growing season progressed and soils dried out. This seemingly generalizable pattern for a snow-dominated watershed is likely to represent the variability of recently assimilated C, tracked through the plant-soil system and imprinted in the respired CO2. Thus, our observations suggest that, at least for mountainous environments, seasonal changes in δP are largely mediated by soil moisture and their spatial variability is partially organized by topography.


Rectus fascial wrap: early results of a modification of the rectus fascial sling.
We describe an operation that increases bladder neck resistance in patients with urinary incontinence. It is a modification of the rectus fascial sling that was designed as an adjunct to augmentation cystoplasty and is used in association with clean intermittent catheterization. The operation is performed by circumferentially wrapping a rectus fascial defatted free graft around the bladder neck and suturing it to appose the bladder neck. The procedure was done in 17 patients, including 10 with myelodysplasia, 3 with sacral lipoma, 3 with bladder exstrophy and 1 with nonneurogenic neurogenic bladder. Leak point pressure improved in patients in whom it was measured preoperatively and postoperatively. Complications developed in 5 patients, including difficulty with catheterization in 2, ventral hernia at the graft harvest site in 1, bladder calculus in 1 and detrusor hyperreflexia in 1. Early results with the bladder fascial wrap indicate that it has the ability to improve continence in patients with a dysfunctional bladder neck who have undergone augmentation.


The role of Dpp and its inhibitors during eggshell patterning in Drosophila.
The Drosophila eggshell is patterned by the combined action of the epidermal growth factor [EGF; Gurken (Grk)] and transforming growth factor beta [TGF-beta; Decapentaplegic (Dpp)] signaling cascades. Although Grk signaling alone can induce asymmetric gene expression within the follicular epithelium, here we show that the ability of Grk to induce dorsoventral polarity within the eggshell strictly depends on Dpp. Dpp, however, specifies at least one anterior region of the eggshell in the absence of Grk. Dpp forms an anteriorposterior morphogen gradient within the follicular epithelium and synergizes with the dorsoventral gradient of Grk signaling. High levels of Grk and Dpp signaling induce the operculum, whereas lower levels of both pathways induce the dorsal appendages. We provide evidence that the crosstalk between both pathways occurs at least at two levels. First, Dpp appears to directly enhance the levels of EGF pathway activity within the follicular epithelium. Second, Dpp and EGF signaling collaborate in controlling the expression of Dpp inhibitors. One of these inhibitors is Drosophila sno (dSno), a homolog of the Ski/Sno family of vertebrate proto-oncogenes, which synergizes with daughters against dpp and brinker to set the posterior and lateral limits of the region, giving rise to dorsal follicle cells.


Veterans worry that unexplained medical problems a legacy of service during Gulf War.
Some Canadians who served in the military in the Persian Gulf 4 years ago complain of a range of symptoms commonly described as Gulf War syndrome. Although the syndrome is not recognized as a clinical entity, symptoms include fatigue, lack of sleep, depression, cognitive problems, rashes, bone aches, lassitude, lack of motivation, forgetfulness, mood changes irritability and diarrhea. The medical branch of the Department of National Defence has established programs to inform, guide diagnosis and reach out to symptomatic veterans of the Persian Gulf conflict. Civilian physicians who provide similar care to military personnel who participated in the conflict are invited to call the medical branch (613 996-3752) for further information.


The contents and readability of informed consent forms for oncology clinical trials.
To compare the quality of informed consent forms (ICF) for different trial phases, funding sources, oncology subspecialties, disease settings, and intervention modalities. ICF for prospectively conducted clinical trials were examined for their descriptions of benefits and risks, study alternatives, voluntary participation, and confidentiality. Readability was assessed with Flesch Reading Ease (FRE) score and Flesch-Kincaid Reading Grade Level. Among 262 evaluable trials, ICF contained an average of 3982 words, 379 sentences, and 10.5 pages. The mean FRE score and Reading Grade Level were 61.2 and 7.4, respectively. All ICF explicitly stated that the intervention was investigational. Only 2 (1%) promised direct personal benefits, 16 (6%) suggested the chance of cure or prolonged survival, and 89 (34%) indicated a potential for tumor response. Conversely, 239 (91%) mentioned the risk of serious harms, 217 (83%) admitted that some side effects could be unknown or unpredictable, and 126 (48%) reported hospitalization or death as a possibility. Alternatives to participation, right to withdraw from study, and data confidentiality were addressed in 242 (92%), 254 (97%), and 260 (99%) ICF, respectively. Hematology, industry-funded, metastatic, and systemic therapy trials were most likely to highlight major risks (P < 0.05). Readability was better in phase I trials and in studies, which were performed by medical oncologists, sponsored by governmental agencies, conducted in the metastatic setting, and involved systemic therapy (P < 0.05). ICF had acceptable readability and provided a realistic overview of the benefits and risks of clinical trials, but the potential for hospitalization or fatality was underreported.


Small-scale field evaluation of push-pull system against early- and outdoor-biting malaria mosquitoes in an area of high pyrethroid resistance in Tanzania.
Background: Despite high coverage of indoor interventions like insecticide-treated nets, mosquito-borne infections persist, partly because of outdoor-biting, early-biting and insecticide-resistant vectors. Push-pull systems, where mosquitoes are repelled from humans and attracted to nearby lethal targets, may constitute effective complementary interventions. Methods: A partially randomized cross-over design was used to test efficacy of push-pull in four experimental huts and four local houses, in an area with high pyrethroid resistance in Tanzania. The push-pull system consisted of 1.1% or 2.2% w/v transfluthrin repellent dispensers and an outdoor lure-and-kill device (odour-baited mosquito landing box). Matching controls were set up without push-pull. Adult male volunteers collected mosquitoes attempting to bite them outdoors, but collections were also done indoors using exit traps in experimental huts and by volunteers in the local houses. The collections were done hourly (1830hrs-0730hrs) and mosquito catches compared between push-pull and controls. An. gambiae s.l. and An. funestus s.l. were assessed by PCR to identify sibling species, and ELISA to detect Plasmodium falciparum and blood meal sources. Results: Push-pull in experimental huts reduced outdoor-biting for An. arabiensis and Mansonia species by 30% and 41.5% respectively. However, the reductions were marginal and insignificant for An. funestus (12.2%; p>0.05) and Culex (5%; p>0.05). Highest protection against all species occurred before 2200hrs. There was no significant difference in number of mosquitoes inside exit traps in huts with or without push-pull. In local households, push-pull significantly reduced indoor and outdoor-biting of An. arabiensis by 48% and 25% respectively, but had no effect on other species. Conclusion: This push-pull system offered modest protection against outdoor-biting An. arabiensis, without increasing indoor mosquito densities. Additional experimentation is required to assess how transfluthrin-based products affect mosquito blood-feeding and mortality in push-pull contexts. This approach, if optimised, could potentially complement existing malaria interventions even in areas with high pyrethroid resistance.


Impact of ZD1839 on non-small cell lung cancer-related symptoms as measured by the functional assessment of cancer therapy-lung scale.
The majority of patients with non-small cell lung cancer (NSCLC) present with advanced disease, which is associated with a poor prognosis and symptoms such as pain, coughing, and shortness of breath. In patients who present at an earlier stage, the progressive nature of NSCLC and its resistance to treatment often result in recurrence, with the associated symptoms of advanced disease. These symptoms negatively affect patient quality of life and performance status rating, both of which are predictive of treatment response and survival. There is increasing interest in using assessments of improvements in symptoms and quality of life as outcomes in clinical trials for patients with advanced NSCLC. Patients with NSCLC have limited therapeutic options. Even those patients who are able to tolerate chemotherapy can expect median survival increases of only 2 to 4 months. The new targeted therapies for lung cancer, in contrast, are relatively nontoxic and may provide benefits for symptoms and quality of life in addition to tumor responses. The Functional Assessment of Cancer Therapy-Lung (FACT-L) scale is a validated, sensitive, and reliable patient questionnaire that evaluates and quantifies quality of life across several dimensions, including lung cancer-related symptoms (Lung Cancer Subscale). The Lung Cancer Subscale ranges from 0 (severe debilitation) to 28 (asymptomatic). A change of two points reflects a clinically significant change in NSCLC-related symptoms and quality of life. In phase I studies and also in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II monotherapy trials, treatment of patients with advanced NSCLC with the epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) has shown tumor responses as well as rapid improvements in NSCLC-related symptoms and quality of life. In IDEAL-1 and IDEAL-2, improvements in NSCLC-related symptoms and quality of life, as measured by FACT-L, correlated with tumor response, and improvements in symptoms also correlated with progression-free and overall survival. Although symptom response is correlated with tumor response, it is also uniquely predictive of progression-free and overall survival. The FACT-L questionnaire has also been included in phase III trials of ZD1839 treatment in combination with chemotherapy regimens.


Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse.
Cyclooxygenase (COX)-2 is expressed in the heart in animal models of ischemic injury. Recent studies have suggested that COX-2 products are involved in inflammatory cell infiltration and fibroblast proliferation in the heart. Using a mouse model, we questioned whether 1). myocardial infarction (MI) in vivo induces COX-2 expression chronically, and 2). COX-2 inhibition reduces collagen content and improves cardiac function in mice with MI. MI was produced by ligation of the left anterior descending coronary artery in mice. Two days later, mice were treated with 3 mg/kg NS-398, a selective COX-2 inhibitor, or vehicle in drinking water for 2 wk. After the treatment period, mice were subjected to two-dimensional M-mode echocardiography to determine cardiac function. Hearts were then analyzed for determination of infarct size, interstitial collagen content, brain natriuretic peptide (BNP) mRNA, myocyte cross-sectional area, and immunohistochemical staining for transforming growth factor (TGF)-beta and COX-2. COX-2 protein, detected by immunohistochemistry, was increased in MI versus sham hearts. MI resulted in increased left ventricular systolic and diastolic dimension and decreased ejection fraction, fractional shortening, and cardiac output. NS-398 treatment partly reversed these detrimental changes. Myocyte cross-sectional area, a measure of hypertrophy, was decreased by 30% in the NS-398 versus vehicle group, but there was no effect on BNP mRNA. The interstitial collagen fraction increased from 5.4 +/- 0.4% in sham hearts to 10.4 +/- 0.9% in MI hearts and was decreased to 7.9 +/- 0.6% in NS-398-treated hearts. A second COX-2 inhibitor, rofecoxib (MK-0966), also decreased myocyte cross-sectional area and interstitial collagen fraction. TGF-beta, a key regulator of collagen synthesis, was increased in MI hearts. NS-398 treatment reduced TGF-beta immunostaining by 40%. NS-398 treatment had no effect on infarct size. These results suggest that COX-2 products contribute to cardiac remodeling and functional deficits after MI. Thus selected inhibition of COX-2 may be a therapeutic target for reducing myocyte damage after MI.


Interpersonal Victimization, Substance Use, and Mental Health Among Sexual and Gender Minority Youth: The Role of Self-concept Factors.
Reducing substance use and negative mental health outcomes of interpersonal victimization among sexual and gender minority youth (SGMY) represents a critical public health priority. Victimized individuals often develop cognitive schemas, or organized knowledge structures consisting of traits, values, and memories about the self, such as self-concept factors, in response to interpersonal victimization. Prior studies demonstrate the role of self-concept factors (e.g., mastery, control, and self-esteem) in explaining the relationship between victimization and substance use and mental health. However, mastery, control, and self-esteem have not been explored as mediators of interpersonal victimization and health among SGMY. This study is among the first to apply cognitive schema models of trauma-related health symptoms using a large sample of SGMY to examine (a) whether interpersonal victimization is associated with substance use (i.e., alcohol use, cannabis use, and cigarette use) and mental health problems (i.e., depressive symptoms, self-perceived stress, self-rated health issues) and (b) whether diminished sense of mastery and control and lower self-esteem can partially explain elevated rates of substance use and mental health problems in this population. We used the U.S.-based 2017 LGBTQ National Teen Survey (n = 17,112; Mage = 15.57, SD = 1.27); 6,401 (37.4%) identified as gay or lesbian, 7,396 (43.2%) as cisgender women, and 10,245 (59.9%) as White. Substance use and mental health variables were positively associated with interpersonal victimization variables and negatively associated with self-concept factors. Self-concept factors partially mediated the relationship between interpersonal victimization and mental health. This model explained 74.2% of the variance in mental health and 28.4% of the variance in substance use. Cognitive coping may represent an important modifiable factor that can be targeted by trauma-focused interventions in efforts to improve victimized SGMY's mental health. Findings call for the development of identity-affirmative, evidence-based, and trauma-focused interventions for SGMY to improve this populations' overall health.


A Workflow for Three-Dimensional Reconstruction and Quantification of the Monkey Optic Nerve Head Vascular Network.
A comprehensive characterization of the three-dimensional (3D) vascular network of the optic nerve head (ONH) is critical to understanding eye physiology and pathology. Current in vivo imaging technologies, however, do not have simultaneous high spatial resolution and imaging depth to resolve the small vessels deep within the ONH. We describe a workflow for the 3D reconstruction and quantitative morphological analysis of the ONH vasculature. The vessels of a normal monkey ONH were perfusion labeled. Serial cryosections of the ONH were imaged using fluorescence microscopy (FM) and instant polarized light microscopy (IPOL) to visualize the labeled vessels and label-free collagen, respectively. The IPOL images were registered and used to form a stack of FM images from which the vessels were segmented and skeletonized to reconstruct the 3D vascular network. The network consisted of 12,966 vessel segments, 7989 branching points, and 1100 terminal points at the boundaries. For each vessel segment, we measured its length, tortuosity, inclination (θ), and polar orientation (φ). The length followed a lognormal distribution, whereas the distribution of the tortuosity followed an exponential decay. The vessels were mainly oriented toward the coronal plane (θ = 90 deg). For orientation, there were nearly as many vessels aligned circumferentially (φ = 90 deg) and radially (φ = 0 deg). Our results demonstrate the workflow for 3D eye-specific reconstruction and quantification of the monkey ONH vascular network. This is a critical first step to analyze the blood flow and oxygenation within the ONH, which will help understand the role of vascular dysfunction in glaucoma.


A 0.5-V multi-channel low-noise readout front-end for portable EEG acquisition.
This article presents a low-noise readout front-end suitable for Electroencephalogram (EEG) acquisition. The chip includes 8-channel fully-differential instrumentation amplifiers, utilizing chopper stabilization technique for reducing the flicker noise, each amplifier with a small Gm-C low-pass filter, a programmable gain amplifier, and a 10-bit successive approximation register (SAR) ADC with a detect logic for DAC switching. The chip is fabricated with the TSMC 90nm CMOS process. The low-noise readout front-end has simulated frequency response from 0.57 Hz to 213 Hz, programmable gain from 54.4 dB to 87.6 dB, integrated input-referred noise of 0.358 μVrms within EEG bandwidth, a noise efficiency factor (NEF) of 2.43, and a power efficiency factor (PEF) of 2.95. The overall system consumes 32.08 μW under 0.5-V supply.


Different factors associated with loss to follow-up of infants born to HIV-infected or uninfected mothers: observations from the ANRS 12140-PEDIACAM study in Cameroon.
Loss to follow-up (LTFU) is a cause of potential bias in clinical studies. Differing LTFU between study groups may affect internal validity and generalizability of the results. Understanding reasons for LTFU could help improve follow-up in clinical studies and thereby contribute to goals for prevention, treatment, or research being achieved. We explored factors associated with LTFU of mother-child pairs after inclusion in the ANRS 12140-Pediacam study. From November 2007 to October 2010, 4104 infants including 2053 born to HIV-infected mothers and 2051 born to HIV-uninfected mothers matched individually on gender and study site were enrolled during the first week of life in three referral hospitals in Cameroon and scheduled for visits at 6, 10 and 14 weeks of age. Visits were designated 1, 2 and 3, in chronological order, irrespective of the child's age at the time of the visit. Mother-child pairs were considered lost to follow-up if they never returned for a clinical visit within the first six months after inclusion. Uni- and multivariable logistic regression were adjusted on matching variables to identify factors associated with LTFU according to maternal HIV status. LTFU among HIV-unexposed infants was four times higher than among HIV-exposed infants (36.7% vs 9.8%, p < 0.001). Emergency caesarean section (adjusted Odds Ratio (aOR) = 2.46 95% Confidence Interval (CI) [1.47-4.13]), young maternal age (aOR = 2.29, 95% CI [1.18-4.46]), and absence of antiretroviral treatment for prophylaxis (aOR = 3.45, 95% CI [2.30-5.19]) were independently associated with LTFU among HIV-exposed infants. Factors associated with LTFU among HIV-unexposed infants included young maternal age (aOR = 1.96, 95% CI [1.36-2.81]), low maternal education level (aOR = 2.77, 95% CI [1.95-3.95]) and housewife/unemployed mothers (aOR = 1.56, 95% CI [1.16-2.11]). Failure to return for at least one scheduled clinical visit is a problem especially among HIV-unexposed infants included in studies involving HIV-exposed infants. Factors associated with this type of LTFU included maternal characteristics, socio-economic status, quality of antenatal care and obstetrical context of delivery. Enhanced counselling in antenatal and intrapartum services is required for mothers at high risk of failure to return for follow-up visits.


Characteristics of users and implications for the use of complementary and alternative medicine in Ghanaian cancer patients undergoing radiotherapy and chemotherapy: a cross- sectional study.
There is widespread use of Complementary and Alternative Medicine (CAM) in Ghana, driven by cultural consideration and paradigm to disease causation. Whether there is concurrent use of conventional medicine and CAM in cancer patients is unknown. This study investigates the prevalence, pattern and predictors of CAM use in cancer patients. Overlapping toxicity, sources of information, and whether users inform their doctor about CAM use is examined. Cross-sectional study using a questionnaire administered to cancer patients, who were receiving radiotherapy and or chemotherapy or had recently completed treatment at a single institution was used. Ninety eight patients participated in the study with a mean age of 55.5 (18-89), made up of 51% females. Married individuals formed 56% of the respondents, whilst 49% had either secondary or tertiary education. Head and neck cancer patients were 15.3%, breast (21.4%), abdomen/pelvic cancers constituted (52%).Seventy seven (78.6%) patients received radiotherapy only, 16.3% received radiation and chemotherapy and 5.3% had chemotherapy only. Ninety five patients were diagnosed of cancer within the past 24 months,73.5% were CAM users as follows; massage(66.3%), herbal(59.2%), mega vitamins(55.1%), Chinese medicine(53.1%),and prayer(42.9%). Sixty eight percent were treated with curative intent. Overlapping toxicity was reported. Majority (83.3%) of users had not informed their doctor about CAM use. On univariate analysis, female (p=0.004) and palliative patients, p=0.032 were more likely to be CAM users. Multivariate analysis identified female (p<0.01), as significant for use, whilst head and neck site was significant for non use (p<0.028). Young, married and highly educated individuals are more likely to use CAM. Friends and Media are the main sources of information on CAM. There was increase in CAM use after the diagnosis of cancer mainly for Chinese Medicine and vitamins. There is high CAM usage among Cancer patients, comparable to use in the general population, there is concurrent use of CAM and conventional medicine with reported overlapping toxicity but without informing Oncologist about use. Women and palliative patients are more likely to use CAM. Doctor patient communication on herbal-radiotherapy and drug treatment interaction needs to be strengthened. Standardization and regulation of CAM use is paramount.


[Profile of spending on the treatment of rheumatoid arthritis for patients of the Unified Health System in the state of Minas Gerais - 2008-2013].
Rheumatoid arthritis (RA) is a chronic condition that affects about 1% of the adult population. In a historical cohort of Minas Gerais State, 11,573 RA patients registered in the Outpatient Information System (SIA) between 2008 and 2013 were identified. For this study we adopted the public funding body's perspective and the values were adjusted by the national inflation index (IPCA) of December 2015. Etanercept was the most expensive treatment. The mean cohort age was 52 years old and most of the patients were women. Multiple regression analysis indicated a negative association between higher expenditure and age, female sex, and diagnosis at entry in the cohort and positive association between high expenditure and the Human Development Index (HDI) of the municipality and use of tumor necrosis factor agents. This study identified the factors that have an impact on RA drug treatment expenditure. Also, we showed that methods that enable extracting demographic and expenditure data of administrative information systems may represent important tools in the construction of economic studies to subsidize economic health evaluations, especially from the standpoint of the managers.


Preoperative cardiac evaluation of the vascular surgery patient--an anesthesia perspective.
The morbidity and mortality associated with vascular surgery procedures are largely the results of cardiac events. National guidelines have been regularly proposed and updated by the American College of Cardiology (ACC)/American Heart Association (AHA) to ensure optimal perioperative management and risk stratification. Controversy remains between experts and other cardiology societies regarding several patient care issues including revascularization before surgery, timing of β-blocker therapy, and the administration of antiplatelet therapy. Several landmark articles recently published have helped to modify the guidelines in the hope of improving vascular patient outcomes. In this review, we searched all recent available literature pertaining to perioperative cardiac evaluation before major vascular surgery. We propose an algorithm for preoperative cardiac evaluation, which is a modification to the AHA recommendations. Incorporated in this algorithm are recent published pivotal articles that can help in guiding physicians caring for the vascular patient requiring major operative or endovascular interventions.


The Proteome of Pancreatic Cancer-Derived Exosomes Reveals Signatures Rich in Key Signaling Pathways.
Exosomes are membrane-bound vesicles that traffic small molecular cargos. These cargos participate in cell-cell communication and contribute to the pathogenesis of many disease including cancer. How these mechanisms contribute to communication within the pancreatic adenocarcinoma (PDAC) microenvironment and how they contribute to PDAC biology are poorly understood. Performed in this study are comprehensive, quantitative comparisons of the proteomes of three PDAC cell lines to those of the exosomes they produce. Approximately 35% of whole cell proteins sort into exosomes. Analysis of composition of microbiomes (ANCOM) determined a cluster of 98 enriched pancreatic cancer exosome core proteins (ePC-ECPs). Further, these proteins are predicted by ingenuity pathway analysis (IPA) as actively involved in signaling pathways regulating cell death and survival, cellular movement, and cell-to-cell signaling and interaction in particular (top three p-value significant pathways). Significant enrichment of canonical pathways of acute phase response signaling (inflammatory response signaling pathways) and FXR and RXR activation in biosynthetic pathways are also predicted; 97 ePC-ECPs are associated with cancer and among them, 34 are specifically associated with PDAC. In conclusion, exosomes from PDAC are enriched with cancer-associated signaling proteins. Further assessment of these proteins as PDAC biomarkers or therapeutic targets is warranted.


Reversibility of Neuroimaging Markers Influenced by Lifetime Occupational Manganese Exposure.
Manganese (Mn) is a neurotoxicant that many workers are exposed to daily. There is limited knowledge about how changes in exposure levels impact measures in magnetic resonance imaging (MRI). We hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABAThal). As part of a prospective cohort study, 17 welders were recruited and imaged on 2 separate occasions approximately 2 years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]Air) and cumulative exposure indexes of Mn (Mn-CEI) for the past 3 months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, whereas toenails were collected for analysis of internal Mn body burden. Finally, welders' motor function was examined using the Unified Parkinson's Disease Rating Scale (UPDRS). Median exposure decreased for all exposure measures between the first and second scan. ΔGABAThal was significantly correlated with ΔMn-CEI3M (ρ = 0.66, adjusted p = .02), ΔMn-CEI12M (ρ = 0.70, adjusted p = .006), and Δ[Mn]Air (ρ = 0.77, adjusted p = .002). ΔGABAThal significantly decreased linearly with ΔMn-CEI3M (quantile regression, β = 15.22, p = .02) as well as Δ[Mn]Air (β = 1.27, p = .04). Finally, Mn-CEILife interacted with Δ[Mn]Air in the substantia nigra where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = .005). Although R1 and GABA changed with Mn exposure, UPDRS was unaffected. In conclusion, our study shows that effects from changes in Mn exposure are reflected in thalamic GABA levels and brain Mn levels, as measured by R1, in most brain regions.


Evidence of Site-Specific and Male-Biased Germline Mutation Rate in a Wild Songbird.
Germline mutations are the ultimate source of genetic variation and the raw material for organismal evolution. Despite their significance, the frequency and genomic locations of mutations, as well as potential sex bias, are yet to be widely investigated in most species. To address these gaps, we conducted whole-genome sequencing of 12 great reed warblers (Acrocephalus arundinaceus) in a pedigree spanning 3 generations to identify single-nucleotide de novo mutations (DNMs) and estimate the germline mutation rate. We detected 82 DNMs within the pedigree, primarily enriched at CpG sites but otherwise randomly located along the chromosomes. Furthermore, we observed a pronounced sex bias in DNM occurrence, with male warblers exhibiting three times more mutations than females. After correction for false negatives and adjusting for callable sites, we obtained a mutation rate of 7.16 × 10-9 mutations per site per generation (m/s/g) for the autosomes and 5.10 × 10-9 m/s/g for the Z chromosome. To demonstrate the utility of species-specific mutation rates, we applied our autosomal mutation rate in models reconstructing the demographic history of the great reed warbler. We uncovered signs of drastic population size reductions predating the last glacial period (LGP) and reduced gene flow between western and eastern populations during the LGP. In conclusion, our results provide one of the few direct estimates of the mutation rate in wild songbirds and evidence for male-driven mutations in accordance with theoretical expectations.


Predictive validity of the Q16 questionnaire: a comparison between reported symptoms and neurobehavioral tests.
The correspondence between the answers to the Q16 questions regarding memory and attention-concentration and relevant neurobehavioral performance test scores has been evaluated. The sensitivity, specificity and diagnostic validity of Q16 have been assessed, taking the relevant neurobehavioral test score as a reference diagnostic criterion, the lower quartile of performance being considered as a poor response. The group under study consisted of 74 volunteers (24 females), aged 40 years on average (SD:7.5) and recruited among styrene-exposed workers and healthy controls. The test battery included the logical memory (short- and long-term) and the verbal learning (short- and long-term) tests of the Wechsler Adult Intelligence Scale (WAIS). The answers to the Q16 questions were poorly related to the performance: self-perceived forgetfulness showed a limited agreement with the long-term logical memory test (r=-0.23, p<0.05). The number of false negatives (no symptom but low test scores) was generally high, giving rise to a very low sensitivity of the questionnaire, despite a relatively high specificity. Accordingly, the positive diagnostic validity was low (<30%), whereas the negative diagnostic validity was high (>80%). Different methods used to investigate subtle neurological changes give rise to inconsistencies between self-perceived disturbances and objective measurements of relevant functions. Owing to its low sensitivity and positive diagnostic value, the Q16 cannot be recommended as a screening tool among workers occupationally exposed to neurotoxic chemicals.


Regulatory role of guanosine 3',5'-monophosphate in adrenocorticotropin hormone-induced steroidogenesis.
The relation between steroidogenesis induced by adrenocorticotropic hormone and the concentrations of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) was studied at different time intervals in isolated adrenal cells. Submaximal and supramaximal steroidogenic concentrations of the hormone did not cause detectable changes in cyclic AMP during the first 30 minutes, whereas there was an increase in the concentration of cyclic GMP that was accompanied by phosphorylation and steroidogenesis. It is therefore suggested that cyclic GMP, rather than cyclic AMP, is the physiological mediator of adrenocorticotropic hormone-induced adrenal steroidogenesis.


Acid-base changes and ventilator mode during maintenance ventilation.
Assist-control ventilation was compared to intermittent mandatory ventilation (IMV) for respiratory support of 35 patients without known respiratory disease, who had undergone coronary bypass surgery. Spontaneous respiratory rates and minute ventilation did not differ significantly between the two groups. Blood gas samples obtained during the assist-control mode had a significantly lower PaCO2 and higher pH than blood gases measured during high-rate IMV. There were six cases of severe alkalemia during assist-control ventilation, all respiratory in origin. These were attributable to the higher respiratory-rate settings and the extra respirator-delivered tidal volumes when spontaneous rates were higher than the set rates. IMV was associated with fewer ventilator-induced acid-base changes.


Immune localization of calmodulin in the ciliated cells of hamster tracheal epithelium.
Melachronous beating of cilia of epithelial surfaces of most respiratory airways moves the overlying mucous layer in a caudal direction. The molecular mechanisms controlling ciliary beat remain largely unknown. Calcium, an element in its cationic form, is ubiquitous in biological functions and its concentration is critical for ciliary beating. Calmodulin, a calcium-binding protein which regulates the activity of many enzymes and cellular processes, may regulate ciliary beating by controlling enzymes responsible for mechanochemical movement between adjacent peripheral microtubule doublets composing the ciliary axoneme. As a first step in describing a calmodulin-related controlling mechanism for ciliary beating, calmodulin was localized in the ciliated cells lining the respiratory tracts of hamsters by electron microscopy, using an indirect immunoperoxidase technique with anticalmodulin antibodies as the molecular probe. Thin-sections revealed calmodulin located on microtubules and dynein arms of the ciliary shaft, basal body, apical cytoskeletal microtubules, and plasma membranes in specimens fixed with 1 mM Ca+2. Specimens fixed with less Ca+2 (1 microM), Mn+2, Mg+2, and EGTA showed a diffuse pattern of calmodulin with loci of greatest densities on basal body microtubule triplets. Demembranated specimens showed a less specific localization on axonemal microtubules but only on cells fixed with Ca+2. Calmodulin, by binding calcium, may function in ciliary beating in the respiratory tract of mammals either directly or indirectly through its effects on the energy-producing enzymes and by control of Ca+2 flux through plasma membranes.


New antibiotic produced by bacteria, 5-beta-D-xylofuranosylneamine.
A new aminoglycoside antibiotic was isolated from the fermentation broths of two strains of Bacillus species. The antibiotic is active against gram-positive and some gram-negative bacteria, and its antimicrobial spectrum is similar to that of ribostamycin. The chemical structure was determined to be 5-beta-d-xylofuranosylneamine, which is identical to the deacylated product obtained from butirosin A.


Antidepressant treatment of the depressed patient with insomnia.
Sleep disturbances are an integral part of depressive disorder. As such, they are a part of all contemporary sets of diagnostic criteria for major depression and of all major symptom-based rating scales for depression. Insomnia is a particularly frequent complaint, and it is reported by more than 90% of depressed patients. Although the "kindling" or "illness transduction" model of depression remains hypothetical, there is evidence that people with recurrent depression have more pronounced abnormalities of sleep neurophysiology than those experiencing a single or initial episode. Therefore, early relief of insomnia in a depressed patient, in addition to alleviating other symptoms, may increase adherence to treatment and increase daytime performance and overall functioning, while complete relief of insomnia may improve prognosis. Stimulation of serotonin-2 (5-HT2) receptors is thought to underlie insomnia and changes in sleep architecture seen with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This is the reason why hypnotics or low-dose trazodone are commonly coprescribed at the initiation of the treatment with either the SSRIs or SNRIs. On the other hand, antidepressant drugs with 5-HT2 blocking properties, such as mirtazapine or nefazodone, alleviate insomnia and improve sleep architecture. In depressed patients, mirtazapine produces a significant shortening of sleep-onset latency, increases a total sleep time, and leads to a marked improvement in sleep efficiency. Antidepressants with preferential 5-HT2 blocking properties are therefore a good treatment option for depressed patients with marked insomnia.


Two-dimensional ARMA model order determination.
Determination of the order of a model is the key first step towards modeling any dynamic systems, particularly two-dimensional processes. In this paper, a new method for two-dimensional (2-D) Gaussian ARMA model order determination is proposed. In the proposed method, the AR and MA orders are first independently determined, then the procedure for model order determination of the 2-D ARMA model is outlined. The model is assumed to be causal, stable, linear, and spatial shift-invariant with p(1) x p(2) quarter-plane (QP) support. Numerical simulations are presented to show the effectiveness of the proposed new approach.


Is the NEI-VFQ-25 a useful tool in identifying visual impairment in an elderly population?
The use of self-report questionnaires to substitute for visual acuity measurement has been limited. We examined the association between visual impairment and self reported visual function in a population sample of older people in the UK. Cross sectional study of people aged more than 75 years who initially participated in a trial of health screening. The association between 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ) scores and visual impairment (defined as an acuity of less than 6/18 in the better eye) was examined using logistic regression. Visual acuity and NEI-VFQ scores were obtained from 1807 participants (aged 77 to 101 years, 36% male), from 20 general practices throughout the UK. After adjustment for age, gender, practice and NEI-VFQ sub-scale scores, those complaining of poor vision in general were 4.77 times (95% CI 3.03 to 7.53) more likely to be visually impaired compared to those who did not report difficulty. Self-reported limitations with social functioning and dependency on others due to poor vision were also associated with visual impairment (odds ratios, 2.52, 95% CI 1.55 to 4.11; 1.73, 95% CI 1.05 to 2.86 respectively). Those reporting difficulties with near vision and colour vision were more likely to be visually impaired (odds ratios, 2.32, 95% CI 1.30 to 4.15; 2.25, 95% CI 1.35 to 3.73 respectively). Other NEI-VFQ sub-scale scores were unrelated to measures of acuity. Similar but weaker odds ratios were found with reduced visual acuity (defined as less than 6/12 in the better eye). Although differences in NEI-VFQ scores were small, scores were strongly associated with visual acuity, binocular status, and difference in acuity between eyes. NEI-VFQ questions regarding the quality of general vision, social functioning, visual dependency, near vision and colour vision are strongly and independently associated with an objective measure of visual impairment in an elderly population.


Lymphokine-activated killer (LAK) cells modulate the effects of IL-2 on a T cell-mediated immune response.
The ability of LAK cells and/or IL-2 to affect the course of an established T cell response was examined in a delayed-type hypersensitivity (DTH) model. IL-2 greatly increased the magnitude of the response at 24 h, while LAK cells alone had no effect. The administration of LAK cells and IL-2 together also had no effect on the magnitude of the DTH response, demonstrating that LAK cells were able to remove the enhancement seen with IL-2 alone. The presence of LAK cells reduced the serum half-life of IL-2 significantly, but not to an extent able to account for the observed loss of IL-2 induced DTH enhancement. IL-2 administration influenced cell phenotypes in the spleen and draining lymph nodes (DLN), as well as increasing splenic weight; the additional presence of LAK cells markedly altered these effects of IL-2 in the spleen (but not the DLN). Taken together, these results suggest that LAK cells interact with activated T-cells within the immune system and modulate their function.


Fear on the move: predator hunting mode predicts variation in prey mortality and plasticity in prey spatial response.
Ecologists have long searched for a framework of a priori species traits to help predict predator-prey interactions in food webs. Empirical evidence has shown that predator hunting mode and predator and prey habitat domain are useful traits for explaining predator-prey interactions. Yet, individual experiments have yet to replicate predator hunting mode, calling into question whether predator impacts can be attributed to hunting mode or merely species identity. We tested the effects of spider predators with sit-and-wait, sit-and-pursue and active hunting modes on grasshopper habitat domain, activity and mortality in a grassland system. We replicated hunting mode by testing two spider predator species of each hunting mode on the same grasshopper prey species. We observed grasshoppers with and without each spider species in behavioural cages and measured their mortality rates, movements and habitat domains. We likewise measured the movements and habitat domains of spiders to characterize hunting modes. We found that predator hunting mode explained grasshopper mortality and spider and grasshopper movement activity and habitat domain size. Sit-and-wait spider predators covered small distances over a narrow domain space and killed fewer grasshoppers than sit-and-pursue and active predators, which ranged farther distances across broader domains and killed more grasshoppers, respectively. Prey adjusted their activity levels and horizontal habitat domains in response to predator presence and hunting mode: sedentary sit-and-wait predators with narrow domains caused grasshoppers to reduce activity in the same-sized domain space; more mobile sit-and-pursue predators with broader domains caused prey to reduce their activity within a contracted horizontal (but not vertical) domain space; and highly mobile active spiders led grasshoppers to increase their activity across the same domain area. All predators impacted prey activity, and sit-and-pursue predators generated strong effects on domain size. This study demonstrates the validity of utilizing hunting mode and habitat domain for predicting predator-prey interactions. Results also highlight the importance of accounting for flexibility in prey movement ranges as an anti-predator response rather than treating the domain as a static attribute.


Serum microRNA-based prediction of responsiveness to eribulin in metastatic breast cancer.
The identification of biomarkers for predicting the responsiveness to eribulin in patients with metastatic breast cancer pretreated with an anthracycline and a taxane remains an unmet need. Here, we established a serum microRNA (miRNA)-based prediction model for the emergence of new distant metastases after eribulin treatment. Serum samples were collected from metastatic breast cancer patients prior to eribulin treatment and comprehensively evaluated by miRNA microarray. The prediction model for estimating eribulin efficacy was established using the logistic LASSO regression model. Serum samples were collected from 147 patients, of which 52 developed at least one new distant metastasis after eribulin monotherapy and 95 did not develop new distant metastases. A combination of eight serum miRNAs (miR-4483, miR-8089, miR-4755-3p, miR-296-3p, miR-575, miR-4710, miR-5698 and miR-3160-5p) predicted the appearance of new distant metastases with an area under the curve of 0.79, sensitivity of 0.69 and specificity of 0.82. The serum levels of miR-8089 and miR-5698 were significantly associated with overall survival after the initiation of eribulin treatment. The present study provides evidence that serum miRNA profiling may serve as a biomarker for the responsiveness to eribulin and for predicting the development of new distant metastases in metastatic breast cancer.


Sensitivity to nicotine and brain nicotinic receptors are altered by chronic nicotine and mecamylamine infusion.
DBA/2 mice were chronically infused with saline (control), 4 mg/kg/hr of nicotine, 4 mg/kg/hr of mecamylamine or nicotine+mecamylamine for 7 days. The binding of L-[3H]nicotine was significantly increased in seven of eight brain regions dissected from mice 5 hr after cessation of drug treatment. Similarly, [3H]nicotine binding was increased in six of eight regions by chronic mecamylamine treatment. Treatment with both drugs led to increases in [3H]nicotine binding that were at least the sum of the those observed with either drug alone. These increases were partially reversed 48 hr after cessation of treatment. No significant effects of nicotine or mecamylamine treatment on alpha-[125I]bungarotoxin binding were observed 5 hr after treatment was stopped when assayed using a single ligand concentration. However, saturation analyses of the cerebral cortex detected small increases from control after treatment with nicotine or both drugs. No effects of chronic treatment on alpha-[125I]bungarotoxin binding were evident 48 hr after treatment was stopped. Mice treated with nicotine, mecamylamine or both drugs tested 5 hr after withdrawal were less sensitive to acute injection with nicotine than were saline-infused mice. However, the effects of mecamylamine may have been influenced by continued presence of this drug at the time of testing. Mice tested 48 hr after cessation of treatment were more sensitive to nicotine than those tested after 5 hr, but some tolerance to the effects of nicotine persisted in the nicotine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)


Acquired alteration in the expression of blood groups in a patient with sideroblastic anemia and chronic renal failure.
A patient with well-differentiated lymphocytic lymphoma in remission presented with renal failure, sideroblastic anemia, and an acquired diminution in the expression of A antigen on his red cells. Other red cell antigens (H, M, i, and I) also were expressed weakly. Lewis antigen was expressed only in secretions. The diminished expression of the A antigen could not be accounted for by diminution in the specific glycosyl transferases responsible for its expression, since the activity in the serum of both the H enzyme (alpha 1 leads to 2 fucosyltransferase) and the A enzyme (alpha 1 leads to 3 N-acetylgalactosaminyltransferase) was not diminished. When sialic acid was removed by enzymatic treatment, the expression of the A and i antigens was augmented markedly, suggesting that the sialic acid may have altered the expression or detection of the antigens. This abnormality was probably related to dysplasia of the bone marrow which was otherwise manifest by ringed sideroblasts, unsegmented megakaryocytes, and diminished growth in vitro.


Reaching young adult smokers through the internet: comparison of three recruitment mechanisms.
While young adults have the highest prevalence of cigarette smoking of any adult age group, studies of tobacco and other substance use have reported challenges in recruiting this age group. The Internet may be a useful tool for reaching young adult smokers. The present study compared three Internet-based recruitment methods for young adult smokers to complete a survey about tobacco and other substance use: Craigslist advertisements, other Internet advertisements, and E-mail invitations through a survey sampling service. Recruitment campaigns invited young adults aged 18-25 years who had smoked at least one cigarette in the past 30 days to complete an online survey. Recruitment methods were compared across recruitment numbers, costeffectiveness, and demographic and smoking characteristics of recruited participants. In 6 months, 920 people gave online consent to determine eligibility to complete the survey, of which 336 (36.5%) were eligible, and 201 (59.8%) completed the survey. While Internet advertisements yielded the largest proportion of recruited participants and completed surveys overall, Craigslist and sampling strategies were more successful at targeting young adult smokers who went on to complete the survey and were more costeffective. Participants differed in demographic and substance use characteristics across the three recruitment mechanisms. We identified success at reaching young adults who have smoked cigarettes recently through the Internet, though costs, participant eligibility, proportion of completed surveys, and respondent characteristics differed among the three methods. A multipronged approach to Internet recruitment is most likely to generate a broad diverse sample of young adult smokers.


Discovery of a highly efficient nitroaryl group for detection of nitroreductase and imaging of hypoxic tumor cells.
Hypoxia is a pathological hallmark of solid tumors. Detection of hypoxia is therefore of great interest for tumor diagnosis and treatment. As a well-established biomarker of hypoxia, nitroreductase (NTR) has been widely exploited in the development of hypoxia-responsive fluorescent probes on the basis of its enzymatic activity to reduce nitroaryl groups. However, studies on the relationship between the nitroaryl structure and the probe performance for optimal probe design are still rare. Here we report a comparative investigation of nitroaryl groups and identification of the optimal nitroaryl structure for developing new fluorescent probes with extremely high efficiency in the detection of NTR and the imaging of hypoxic tumor cells. Specifically, we synthesized a series of resorufin-based fluorescent probes containing different nitroaryl groups, compared their fluorescence responses to NTR, and identified 2-nitro-N-methyl-imidazolyl as the optimal nitroaryl group that is much more efficient than the most widely used 4-nitrophenyl for NTR detection. The structure-performance relationship was then studied by theoretical molecular docking, revealing the unique features of 2-nitro-N-methyl-imidazolyl in binding and reaction with NTR. We further incorporated the 2-nitro-N-methyl-imidazolyl group into a near-infrared (NIR) hemicyanine fluorophore and developed a NIR fluorescent probe NFP-7 for the detection of NTR and hypoxic tumor cells. NFP-7 exhibits a strong fluorescence increase toward NTR in vitro with an ultrafast (within 40 seconds to fluorescence maximum) and ultrasensitive (0.2 ng mL-1 detection limit) response. NFP-7 has also been demonstrated for imaging the degree of hypoxia in live tumor cells and, more importantly, in a murine tumor model. Our study provides important insights into hypoxia probe development and new tools for hypoxia imaging.


The Immunomodulatory Properties of Amniotic Cells: The Two Sides of the Coin.
Among the many cell types useful in developing therapeutic treatments, human amniotic cells from placenta have been proposed as valid candidates. Both human amniotic epithelial and mesenchymal stromal cells, and the conditioned medium generated from their culture, exert multiple immunosuppressive activities. Indeed, they inhibit T and B cell proliferation, suppress inflammatory properties of monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells, while promoting induction of cells with regulatory functions such as regulatory T cells and anti-inflammatory M2 macrophages. These properties have laid the foundation for their use for the treatment of inflammatory-based diseases, and encouraging results have been obtained in different preclinical disease models where exacerbated inflammation is present. Moreover, an immune-privileged status of amniotic cells has been often highlighted. However, even if long-term engraftment of amniotic cells has been reported into immunocompetent animals, only few cells survive after infusion. Furthermore, amniotic cells have been shown to be able to induce immune responses in vivo and, under specific culture conditions, they can stimulate T cell proliferation in vitro. Although immunosuppressive properties are a widely recognized characteristic of amniotic cells, immunogenic and stimulatory activities appear to be less reported, sporadic events. In order to improve therapeutic outcome, the mechanisms responsible for the suppressive versus stimulatory activity need to be carefully addressed. In this review, both the immunosuppressive and immunostimulatory activity of amniotic cells will be discussed.


Intestinal absorption of vitamin D: from the meal to the enterocyte.
Vitamin D plays key roles in bone, infectious, inflammatory and metabolic diseases. As most people get inadequate sun exposure for sufficient vitamin D status, they need adequate intake of dietary vitamin D. Many studies see optimizing vitamin D status as a public health priority. It is thus vital to gain deeper insight into vitamin D intestinal absorption. It was long assumed that vitamin D intestinal absorption is a passive process, but new data from our laboratory showed that it is actually far more complex than previously thought. This review describes the fate of vitamin D in the human upper gastrointestinal lumen during digestion and focuses on the proteins involved in the intestinal membrane and cellular transport of vitamin D across the enterocyte. Although recent data significantly improve our understanding of vitamin D intestinal absorption, further studies are still needed to increase our knowledge of the molecular mechanisms underlying this phenomenon.


The miR156b-GmSPL9d module modulates nodulation by targeting multiple core nodulation genes in soybean.
Symbiotic nodulation is initiated in the roots of legumes in response to low nitrogen and rhizobial signal molecules and is dynamically regulated by a complex regulatory network that coordinates rhizobial infection and nodule organogenesis. It has been shown that the miR156-SPL module mediates nodulation in legumes; however, conclusive evidence of how this module exerts its function during nodulation remains elusive. Here, we report that the miR156b-GmSPL9d module regulates symbiotic nodulation by targeting multiple key regulatory genes in the nodulation signalling pathway of soybean. miR156 family members are differentially expressed during nodulation, and miR156b negatively regulates nodulation by mainly targeting soybean SQUAMOSA promoter-binding protein-like 9d (GmSPL9d), a positive regulator of soybean nodulation. GmSPL9d directly binds to the miR172c promoter and activates its expression, suggesting a conserved role of GmSPL9d. Furthermore, GmSPL9d was coexpressed with the soybean nodulation marker genes nodule inception a (GmNINa) and GmENOD40-1 during nodule formation and development. Intriguingly, GmSPL9d can bind to the promoters of GmNINa and GmENOD40-1 and regulate their expression. Our data demonstrate that the miR156b-GmSPL9d module acts as an upstream master regulator of soybean nodulation, which coordinates multiple marker genes involved in soybean nodulation.


Self-regulated learning of basic arithmetic skills: a longitudinal study.
Several studies have examined young primary school children's use of strategies when solving simple addition and subtraction problems. Most of these studies have investigated students' strategy use as if they were isolated processes. To date, we have little knowledge about how math strategies in young students are related to other important aspects in self-regulated learning. The main purpose of this study was to examine relations between young primary school children's basic mathematical skills and their use of math strategies, their metacognitive competence and motivational beliefs, and to investigate how students with basic mathematics skills at various levels differ in respect to the different self-regulation components. The participants were comprised of 27 Year 2 students, all from the same class. The data were collected in three stages (autumn Year 2, spring Year 2, and autumn Year 3). The children's arithmetic skills were measured by age relevant tests, while strategy use, metacognitive competence, and motivational beliefs were assessed through individual interviews. The participants were divided into three performance groups; very good students, good students, and not-so-good students. Analyses revealed that young primary school children at different levels of basic mathematics skill may differ in several important aspects of self-regulated learning. Analyses revealed that a good performance in addition and subtraction was related not only to the children's use of advanced mathematics strategies, but also to domain-specific metacognitive competence, ability attribution for success, effort attribution for failure, and high perceived self-efficacy when using specific strategies. The results indicate that instructional efforts to facilitate self-regulated learning of basic arithmetic skills should address cognitive, metacognitive, and motivational aspects of self-regulation. This is particularly important for low-performing students.


Effect of growth hormone administration and treadmill exercise on serum and skeletal IGF-I in rats.
Growth factors may be mediators of local and systemic factors that enhance bone formation. This study examined the effect of treadmill exercise and ovine growth hormone administration on levels of insulin-like growth factor I (IGF-I) in serum (ng/ml), long bone, and vertebrae and on bone formation rate. Forty female rats were divided into four groups: control; exercise (17 m/min, 1 h/day); growth hormone (0.05 mg.100 g-1.day-1); growth hormone plus exercise. After 9 wk of study, the serum levels of IGF-I were higher in the intervention groups than in the control group; however, the IGF-I concentration and the periosteal bone formation rate in the long bone were significantly higher only in the exercised rats. The IGF-I concentration and the cancellous bone formation rate in the vertebrae did not differ among the experimental groups. The vertebral and long bone formation rate were correlated with bone concentrations of IGF-I. Serum levels of IGF-I were also correlated with serum osteocalcin and the long bone formation but not with the vertebral bone formation. The association of bone formation with serum and bone IGF-I supports the suggestion that IGF-I is one of the growth factors that regulate bone formation, in particular as a mediator of the response of bone to exercise.


An employer coalition to reduce costs and improve adherence.
A coalition of employers based in Ohio is addressing statin utilization on multiple fronts. By working through a new pharmacy benefits manager, it reduced its costs for statins by 9 percent over the course of one year, chiefly by replacing a relatively high-cost statin with a lower-cost statin believed to be of similar efficacy. The coalition also has worked on an individual basis with high prescribers of a high-cost statin, requesting them to consider a lower-cost statin. That effort also has met with success. Meanwhile, the coalition has launched a mail-based program intended to improve adherence among patients taking statins.


The selection rule of graphene in a composite magnetic field.
The generalized tight-binding model with exact diagonalization method is developed to calculate the optical properties of monolayer graphene in the presence of composite magnetic fields. The ratio of the uniform magnetic field and the modulated one accounts for a strong influence on the structure, number, intensity and frequency of absorption peaks, and thus the extra selection rules that are subsequently induced can be explained. When the modulated field increases, each symmetric peak, under a uniform magnetic field, splits into a pair of asymmetric peaks with lower intensities. The threshold absorption frequency exhibits an obvious evolution in terms of a redshift. These absorption peaks obey the same selection rule that is followed by Landau level transitions. Moreover, at a sufficiently strong modulation strength, the extra peaks in the absorption spectrum might arise from different selection rules.


Nematicidal potential of Taraxacum officinale.
This study was aimed to investigate the activity of the Asteraceae species Taraxacum officinale against the root-knot nematode Meloidogyne incognita. Leaf and root extracts of T. officinale were tested in vitro at a range of 62.5-1000 and 250-1000 μg mL-1 concentrations on nematode juveniles and eggs, respectively, whereas treatments with 10-40 g kg-1 soil rates of dry leaf and root T. officinale biomass were applied to soil infested by M. incognita in greenhouse experiments on potted tomato. Peak 36 and 50% juvenile mortality and 14.8 and 23.8% egg hatchability reduction were recorded at the maximum concentration of leaf and root extracts, respectively. Soil treatments with T. officinale leaf and root material strongly suppressed nematode multiplication and gall formation on tomato roots and significantly increased plant growth. Chicoric acid and 3-O- and 3,5-di-O-caffeoylquinic acid were found to be the main components of leaf and root extract, respectively, and proved, as the total hydroalcoholic extracts from T. officinale leaf and root material, for an antioxidant activity. Data from this study indicate the suitability of plant materials from T. officinale for a potential formulation of nematicidal products to include in sustainable nematode management strategies.


Risk Factors and Predictive Modeling for Post-Acute Sequelae of SARS-CoV-2 Infection: Findings from EHR Cohorts of the RECOVER Initiative.
Patients who were SARS-CoV-2 infected could suffer from newly incidental conditions in their post-acute infection period. These conditions, denoted as the post-acute sequelae of SARS-CoV-2 infection (PASC), are highly heterogeneous and involve a diverse set of organ systems. Limited studies have investigated the predictability of these conditions and their associated risk factors. In this retrospective cohort study, we investigated two large-scale PCORnet clinical research networks, INSIGHT and OneFlorida+, including 11 million patients in the New York City area and 16.8 million patients from Florida, to develop machine learning prediction models for those who are at risk for newly incident PASC and to identify factors associated with newly incident PASC conditions. Adult patients aged 20 with SARS-CoV-2 infection and without recorded infection between March 1st, 2020, and November 30th, 2021, were used for identifying associated factors with incident PASC after removing background associations. The predictive models were developed on infected adults. We find several incident PASC, e.g., malnutrition, COPD, dementia, and acute kidney failure, were associated with severe acute SARS-CoV-2 infection, defined by hospitalization and ICU stay. Older age and extremes of weight were also associated with these incident conditions. These conditions were better predicted (C-index >0.8). Moderately predictable conditions included diabetes and thromboembolic disease (C-index 0.7-0.8). These were associated with a wider variety of baseline conditions. Less predictable conditions included fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). This observational study suggests that a set of likely risk factors for different PASC conditions were identifiable from EHRs, predictability of different PASC conditions was heterogeneous, and using machine learning-based predictive models might help in identifying patients who were at risk of developing incident PASC.


Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial.
We assessed the efficacy of TJ-100 taken perioperatively to recovery among patients with periampullary tumor or tumor of the head of the pancreas who underwent pancreaticoduodenectomy (PD). In this multicenter, randomized, double-blinded, placebo-controlled, phase II trial (JAPAN-PD Study), patients were assigned randomly in a 1:1 ratio to receive TJ-100 or placebo. The coprimary endpoints were (1) incidence of postoperative paralytic ileus lasting >72 hours after surgery and (2) time to occurrence of postoperative paralytic ileus. This trial is registered at the UMIN Clinical Trials Registry (000007975) and at ClinicalTrials.gov (NCT01607307). From August 2012 through July 2013, we assessed 273 patients for eligibility, and 224 underwent randomization; 112 patients received TJ-100, and 112 patients received placebo. The population for analysis consisted of 104 patients who received TJ-100 and 103 who received placebo. Paralytic ileus occurred 35 (33.7%) in the TJ-100 group and 38 (36.9%) in the placebo group (P = .626). Time to first flatus was 2.25 (2.00-2.50) days in the TJ-100 group and 2.50 (1.50-2.50) days in the placebo group (P = .343). Among 23 patients who underwent a pylorus ring-preserving PD, time to first flatus was lower in the TJ-100 group than in the placebo group: 0.50 (0.50-1.00) days versus 1.50 (0.50-3.00) days (P = .034). Our findings suggest that use of TJ-100 did not improve recovery from paralytic ileus after PD, and may preclude the routine use of TJ-100 in clinical practice after PD operation.


Properties of matrix-bound dimer and monomer derivatives of immobilized creatine kinase from rabbit skeletal muscle.
Dimeric creatine kinase (EC 18.104.22.168) from rabbit skeletal muscle can be immobilized via a single subunit to CNBr-activated Sepharose 4B and subsequently treated with guanidine hydrochloride followed by renaturation to yield a catalytically active matrix-bound subunit derivative. The importance of the intact dimeric structure in the activation of the enzyme by acetate was demonstrated. Immobilization did not appear to alter the pH optimum of the enzyme, and the kinetic parameters fot the matrix-bound derivatives were generally similar to those for the soluble enzyme, but the matrix-bound derivatives showed higher thermal stability and greater resistance to denaturation than did the soluble enzyme. The rates of reaction of thiol groups of the matrix-bound derivatives with iodoacetamide in the absence and in the presence of combinations of substrates were similar to those of the soluble enzyme. Studies with 5,5'-dithiobis-(2-nitrobenzoic acid) and with iodoacetamide revealed the presence of an additional reactive thiol group in the matrix-bound subunit derivative, which is presumably masked in the dimeric derivatives.


The EFECT framework for interprofessional education in the patient centered medical home.
The very nature of the Patient-Centered Medical Home (PCMH) necessitates new instructional models that prepare learners for the roles they will have to assume in these transformed primary care practices. In this manuscript we describe a new instructional framework that seeks to blend the goals of patient-centered care and inter-professional education, and can be implemented in existing training environments while practice transformation continues to proceed. We propose a 5-step process, the EFECT framework, which is simultaneously a sequence of tasks for effective patient care and a guide for the learners and faculty in teaching and evaluating that care delivery. These steps include: (1) Eliciting a patient-centered narrative, (2) Facilitating an inter-professional team discussion, (3) Evaluating clinical evidence, (4) Creating a shared care plan, and (5) Tracking outcomes. We then report preliminary descriptive outcomes from the first EFECT pilot. Our proposed framework supports learners' abilities to construct a patient-centered narrative from multiple professional perspectives as the basis for developing an evidence-based, integrated care plan between the patient and the inter-professional care team and deliberately following up on outcomes. We present this framework to stimulate a process for creating new curricula and evaluative tools to measure and promote learner functioning in medical home environments.


A new protein quality evaluation index based on growth responses of rats.
The protein efficiency ratio (PER) is the official method for protein quality evaluation in the United States and Canada. Two other widely used indices of evaluation are the slope ratio and net protein ratio (NPR) methods. Each of these methods has problems associated with its calculation and interpretation. In this paper, a new index, actual protein utilization ( APU ) is discussed, and its relationship to the other indices is examined. Each of the indices is given a theoretical basis by relating it to the four parameter mathematical model for physiological responses. To compare the indices, growth bioassays were carried out using male rats (40, 60, 115 g) consuming three different proteins (casein, lactalbumin and soy) and an amino acid mixture (Rogers and Harper). Dose-response curves were generated for each diet, and the indices PER, NPR, Slope and APU were calculated. APU was shown to have certain characteristics that make it superior to the other methods of protein quality evaluation, i.e., it closely approximates the growth response curve and it incorporates a term for the protein intake required for maintenance.


The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury.
The topic of exercise-induced skeletal muscle injury has received considerable attention in recent years. Likewise, strategies to minimise the injury resulting from heavy resistance exercise have been studied. Over the past 15 years, several investigations have been performed focused on the role of nutritional supplements to attenuate signs and symptoms of muscle injury. Of these, some have reported favourable results, while many others have reported no benefit of the selected nutrient. Despite these mixed findings, recommendations for the use of nutritional supplements for the purposes of attenuating muscle injury are rampant within the popular fitness media and athletic world, largely without scientific support. Those nutrients include the antioxidant vitamin C (ascorbic acid) and vitamin E (tocopherol), N-acetyl-cysteine, flavonoids, L-carnitine, astaxanthin, beta-hydroxy-beta-methylbutyrate, creatine monohydrate, essential fatty acids, branched-chain amino acids, bromelain, proteins and carbohydrates. A discussion of all published peer-reviewed articles in reference to these nutrients and their impact on resistance exercise-induced skeletal muscle injury is presented, in addition to a brief view into the potential mechanism of action for each nutrient.Based on the current state of knowledge, the following conclusions can be made with regard to nutritional supplements and their role in attenuating signs and symptoms of skeletal muscle injury occurring as a consequence of heavy resistance exercise: (i) there appears to be a potential role for certain supplements (vitamin C, vitamin E, flavonoids, and L-carnitine); (ii) these supplements cannot effectively eliminate muscle injury, only attenuate certain signs and symptoms; (iii) it is presently unclear what the optimal dosage of these nutrients is (whether used alone or in combination); (iv) it is unclear what the optimal pretreatment period is; and (v) the effectiveness is largely specific to non-resistance trained individuals.Ultimately, because so few studies have been conducted in this area, it is difficult to recommend with confidence the use of selected nutrients for the sole purpose of minimising signs and symptoms of resistance exercise-induced muscle injury, in particular with regard to resistance-trained individuals.


Transdermal photopolymerized adhesive for seroma prevention.
The purpose of this study was to determine whether or not a synthetic photopolymerized tissue adhesive (polyethylene oxide hydrogel) is useful in seroma prevention using a well established rat mastectomy seroma model. Twenty-three Sprague-Dawley rats received mastectomies. The rats were randomly assigned to either the control group (n = 13) or the experimental group (n = 10). The control animals received 0.2 cc of saline into the wound before closure. The experimental group received either 0.2 cc (n = 5) or 0.4 cc (n = 5) of the polyethylene oxide polymer into their wounds before closure. The experimental animals were placed under an ultraviolet A lamp for 3 minutes to polymerize the adhesive. On postoperative day seven, the resultant seromas were quantified, and wound tissues were harvested for histologic evaluation. The rats in the control group had a mean seroma volume of 3.25 cc (SD = 2.41), whereas the rats treated with polymer had a mean seroma volume of 0.37 cc (SD = 0.51). A Student's t test was performed showing a statistically significant difference between the control and experimental groups (p < 0.005). The volume of polymer used (0.2 cc versus 0.4 cc) did not significantly impact the volume of the resultant seromas. This study demonstrates that photopolymerizable polyethylene oxide hydrogels can be used as a tissue adhesive and that such an adhesive significantly reduces seroma formation in the rat mastectomy model.


Repression in vitro, by human adenovirus E1A protein domains, of basal or Tat-activated transcription of the human immunodeficiency virus type 1 long terminal repeat.
Human adenovirus E1A proteins can repress the expression of several viral and cellular genes. By using a cell-free transcription system, we demonstrated that the gene product of the E1A 12S mRNA, the 243-residue protein E1A243R, inhibits basal transcription from the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). The HIV-1 transactivator protein Tat greatly stimulates transcription from the viral promoter in vitro. However, E1A243R can repress Tat-activated transcription in vitro. Strong repression of both basal and Tat-activated transcriptions requires only E1A N-terminal amino acid residues 1 to 80. Deletion analysis showed that E1A N-terminal amino acids 4 to 25 are essential for repression, whereas amino acid residues 30 to 49 and 70 to 80 are dispensable. Transcriptional repression by E1A in the cell-free transcription system is promoter specific, since under identical conditions, transcription of the adenovirus major late promoter and the Rous sarcoma virus LTR promoter was unaffected. The repression of transcription by small E1A peptides in vitro provides an assay for investigation of molecular mechanisms governing E1A-mediated repression of both basal and Tat-activated transcriptions of the HIV-1 LTR promoter.


Iatrogenic splenic injuries.
Inadvertent intraoperative injuries to the spleen by the surgical team represent an underestimated complication of many abdominal procedures. Surgical reports often lack the necessary details and frequently a clear justification as why a splenectomy was indicated is not provided. The wide variability of the incidence reported in literature makes it is difficult to evaluate the morbidity and mortality associated to these injuries and to assess the early and late consequences of this complication, although it is still possible to infer some of the reasons for these inconsistencies and to roughly estimate both clinical and socio-economical effects of this injury. Given the degree of uncertainty on the incidence of iatrogenic and traumatic splenic injuries and on the immediate and long-term sequelae suffered by asplenic patients, we thought that a multicentric prospective study was warranted. We are therefore announcing the start of a study involving several Institutions within the Regione Campania, aimed at obtaining an unbiased estimate of the incidence of these injuries, together with the extent and severity of their long-term complications. We also aim to help promoting a more effective prevention.


Comprehensive analysis of lung cancer pathology images to discover tumor shape and boundary features that predict survival outcome.
Pathology images capture tumor histomorphological details in high resolution. However, manual detection and characterization of tumor regions in pathology images is labor intensive and subjective. Using a deep convolutional neural network (CNN), we developed an automated tumor region recognition system for lung cancer pathology images. From the identified tumor regions, we extracted 22 well-defined shape and boundary features and found that 15 of them were significantly associated with patient survival outcome in lung adenocarcinoma patients from the National Lung Screening Trial. A tumor region shape-based prognostic model was developed and validated in an independent patient cohort (n = 389). The predicted high-risk group had significantly worse survival than the low-risk group (p value = 0.0029). Predicted risk group serves as an independent prognostic factor (high-risk vs. low-risk, hazard ratio = 2.25, 95% CI 1.34-3.77, p value = 0.0022) after adjusting for age, gender, smoking status, and stage. This study provides new insights into the relationship between tumor shape and patient prognosis.