Sequential induction of Hsp25 and proliferating cell nuclear antigen in the kidney after burn.
Burn injury elicits a wide range of intracellular signaling events leading to alterations in phenotypes of distant organs. Renal dysfunction is one of several serious postburn complications. To better understand the underlying mechanisms of renal dysfunction among burn patients, we investigated alterations in the expression of heat shock proteins (Hsps) and cell cycle-associated proteins in the kidney after burn. Following an approximately 18% total body surface area burn, blood and kidney samples were harvested from mice at several time points. Serum levels of blood urea nitrogen increased significantly at 3 h and returned to basal levels at Day 1 implying a transient dysfunction of glomerular filtration. The expression of Hsp25 was increased at Day 1, whereas no changes in Hsp70 expression were observed. An increase in proliferating cell nuclear antigen (PCNA), a marker of cell proliferation, peaked at Day 3, and its expression was predominantly limited to cells appearing to be tubular epithelial cells in the cortex. In contrast, no significant alterations in the p21 mitosis inhibitor were noted. Furthermore, increases in histones H1 and H2A at Day 3 paralleled the PCNA induction suggesting a burn-mediated alteration in cell cycle activities. The results from this study suggest that a sizeable burn may trigger sequential activation of signaling events involved in the early pathogenesis and subsequent recovery of the kidney after burn.


Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer.
Colorectal cancer is the third most common cancer worldwide. The prognosis of colorectal cancer patients still remains dismal and half of them will develop metastatic disease. Angiogenesis plays an essential role in colorectal tumorigenesis, and the VEGF pathway is one of the targets that has been validated up to now. The use of antiangiogenics along with chemotherapy has become an accepted standard for colorectal cancer. This review discusses the efficacy and safety profile of ramucirumab, a fully human immunoglobulin G1 monoclonal antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2), for the treatment of second-line metastatic colorectal cancer upon progression to first-line chemotherapy including anti-angiogenics. Ramucirumab in combination with chemotherapy represents a valid option in second-line treatment of advanced colorectal cancer patients, who progressed on previous bevacizumab-based combinations. This agent demonstrates a similar benefit in terms of overall survival to other angiogenesis inhibitors (bevacizumab and ziv-aflibercept) used in this setting.


Naturally occurring and braken-fern-induced bovine urinary bladder tumors. Clinical and morphological characteristics.
Clinical and morphological characteristics of 139 naturally occurring and 20 braken-fern-induced urinary bladder tumors of cows were studied. Hematuria was prominent and occurred as early as 60 days after braken fern feeding began. Anemia and changes in leukocytes were late manifestations. Papillomas appeared as early as 1 year, whereas invasive carcinomas did not develop until 2.6 years after initiation of feeding. Twenty of 30 cows fed braken fern developed bladder tumors within 5.3 years. None of eight untreated control cows that lived 4 years or six that lived 10 years developed neoplasms. Naturally occurring and fern-induced bladder tumors were epithelial (35%) or mixed epithelial and stromal (55%). Papillomas occurred in 24% and carcinomas in 61% of naturally occurring cases, whereas there were papillomas (40%) and carcinomas (50%) in fern-fed cows. Naturally occurring tumors were metastatic to regional lymph nodes and lung. No metastases were detected in fern-fed cows.


Lessons from Srebrenica: the contributions and limitations of physical anthropology in identifying victims of war crimes.
In July 1995, the town of Srebrenica fell to Bosnian-Serb forces, leaving more than 7000 Muslim men missing and presumed dead. Anthropologists participating in the identification process were faced with a unique problem: the victims appeared identical. All were adult males of a single ethnic group. Decomposition as well as the absence of antemortem (AM) medical and dental records confounded identification. As of December 1999, only 63 men had been positively identified using DNA, personal effects, and identification papers. Are current anthropological methods of sex, age, and stature estimation and AM trauma assessment sufficiently accurate to differentiate the remaining victims and aid in their identification? Comparisons of relative-reported AM information and postmortem examination records for 59 of the 63 identified individuals indicated that while all individuals were sexed correctly, only 42.4% were accurately aged and 29.4% had a stature estimate that included their reported height.


Effect of Saccharomyces cerevisiae fermentation product on ruminal fermentation and nutrient utilization in dairy cows.
The goal of this experiment was to investigate the effect of yeast culture (Saccharomyces cerevisiae) on rumen fermentation, nutrient utilization, and ammonia and methane emission from manure in dairy cows. Eight ruminally cannulated Holstein cows were allocated to 2 dietary treatments in a crossover design. Treatments were control (no yeast culture) and XP (yeast culture, fed at 56 g/head per day; XP, Diamond V Mills Inc., Cedar Rapids, IA). Dry matter intake, milk yield, milk composition, and body weight were similar between treatments. Milk urea nitrogen concentration was also not affected by treatment. Rumen pH was similar between the control and XP treatments, but rumen ammonia concentration tended to be lower with XP than with the control. Treatment had no effect on concentrations of total or individual volatile fatty acids, protozoal counts, polysaccharide-degrading activities (except amylase activity that tended to be increased by XP), or methane production in the rumen. Urinary N losses did not differ significantly between treatments, but allantoin and total purine derivative excretions and the estimated microbial N outflow from the rumen tended to be increased by XP compared with the control treatment. Total-tract apparent digestibility of dietary nutrients was not affected by XP. Milk fatty acid composition was also not altered by XP supplementation. Cumulative (253 h) ammonia and methane emissions from manure, measured in a steady-state gas emission system, were slightly decreased by XP. Overall, the yeast culture tested had little effect on ruminal fermentation, digestibility, or N losses, but tended to reduce rumen ammonia concentration and increase microbial protein synthesis in the rumen, and decreased ammonia and methane emissions from manure.


Occult primary breast cancer at a comprehensive cancer center.
Management of occult primary breast cancer (OPBC), that is, breast cancer that first presents through regional nodal or distant disease without clinical or mammographic evidence of disease in the breast, has been controversial and inconsistent. Here, we review OPBC patients treated at our institution. We conducted a retrospective review of women diagnosed with a first primary breast cancer between March 1999 and September 2010 to identify patients who presented with isolated axillary lymphadenopathy proven to be histologically consistent with primary breast malignancy but had no evidence of a breast mass on physical examination, mammography, or ultrasound. Descriptions of treatments received, recurrence, morbidity, and mortality as of October 2012 are reported. Of 5533 patients reviewed, seven (0.1%) patients were identified. The median age was 65 y old (range, 40-72), and the median length of follow-up was 86 mo (range, 42-124). Four patients underwent modified radical mastectomy, one patient had a lumpectomy and axillary lymph node dissection, and two patients had axillary lymph node dissection without breast surgery. Four patients received adjuvant radiation therapy. All seven patients received chemotherapy. Three patients received endocrine therapy, and two patients received anti-HER2 therapy. At the last follow-up, all seven patients were alive with no evidence of disease. Although there was some variation in the management of OPBC at our institution, our patients had excellent outcomes after multimodal treatment. Our results support a curative intent approach to the treatment of OPBC and illustrate the need for individualized treatment algorithms based on tumor biology and extent of the disease at diagnosis.


In Operando Stacking of Reduced Graphene Oxide for Active Hydrogen Evolution.
Despite the remarkable electronic and mechanical properties of graphene, improving the catalytic activity of the atomically flat, inert, and stable carbon network remains a challenging issue in both fundamental and application studies. In particular, the adsorption of most molecules and ions, including hydrogen (H2 or H+), on graphene is not favorable, underlining the challenge for an efficient electrochemical catalytic reaction on graphene. Various defects, edges, and functionalization have been suggested to resolve the catalytic issue in graphene, but cost-effectiveness and active catalysis with graphene have not been achieved yet. Here, we introduce dynamic stacking of reduced graphene oxide (rGO) with spontaneously generated hydrogen bubbles to form an efficient electrochemical catalyst with a graphene derivative; the in operando stacking of rGO, without using a high-temperature-based heteroatom doping process or plasma treatment, creates a large catalytic surface area with optimized edges and acidic groups in the rGO. Thus, the uniquely formed stable carbon network achieves active hydrogen evolution with a Tafel slope of 39 mV·dec-1 and a double layer capacitance of 12.41 mF·cm-2, which breaks the conventional limit of graphene-based catalysis, suggesting a promising strategy for metal-free catalyst engineering and hydrogen production.


Vascular injuries of the limbs.
Seven different kinds of arterial injury may occur to the limb. These may be accompanied by external bleeding and may result in ischemia sufficient to put the limb in jeopardy. There may be contusion of the arterial wall and thrombosis. There may be true or false aneurysms and arteriovenous fistulas. The extent and location of the injury must be ascertained early. The artery should be conservatively debrided and repaired by end-to-end anastomosis, interpositional grafting or bypass grafting. When possible, skeletal injuries should be stabilized by external fixation. Nerve injuries should be marked for later repair. Antibiotics should be used prophylactically. Mannitol may be used for diuresis. Amputation may be indicated. Fasciotomy is carried out in the presence of compartment compression.


Direct transformations of ketones to gamma-unsaturated thiols via
The reaction of a series of ketones with dimsylsodium in dimethyl sulfoxide resulting in the formation of gamma-unsaturated thiols was studied experimentally. [2,3]-Sigmatropic rearrangements of beta-unsaturated sulfinyl carbanions are involved at the key step of those transformations. DFT computations at the B3LYP/6-31+G level indicated that such rearrangements, as well as some typical [2, 3]-sigmatropic rearrangements, e.g., thermal rearrangements of allyl sulfoxides and Wittig rearrangements of sulfur ylides and lithiated allyloxy methyl anions, are concerted and moderately synchronous processes. Negative (diatropic) nucleus-independent chemical shifts (NICS) and high diamagnetic susceptibility exaltations indicate that the transition structures of these [2,3]-sigmatropic migrations are aromatic.


Recent advances in shell cross-linked micelles.
The field of shell cross-linked (SCL) micelles is briefly reviewed. Important advances over the last two years are emphasized, potential application areas are discussed and current technical problems with these fascinating nanoparticles are highlighted. Particular attention is paid to (i) the development of new cross-linking chemistries and (ii) the adsorption of SCL micelles at interfaces.


Distress and conception in infertile women: a complementary approach.
To examine the relationship of pretreatment psychological distress and demographics to conception in infertile women attending a group cognitive-behavioral treatment program. Pre- and postprogram psychological measures and live birth rates were collected for 132 infertile women attending a ten-session group cognitive-behavioral treatment program. Subjects completed the Beck Depression Inventory (BDI) and the Symptom Checklist-90 (Revised) (SCL-90R). Conceptions that resulted in live births within six months of completing the program were noted. Women who conceived viable pregnancies within six months of the program had higher levels of psychological distress at program entry. Using logistic regression analysis, the best predictors of viable birth were younger age and a higher score on the global severity index of the SCL-90R. Significant pre- to postprogram psychological improvement was demonstrated by the SCL-90R and the BDI. Forty-two percent of the sample conceived viable pregnancies within six months of completing the program. Preprogram psychological distress and younger age were associated with significantly higher viable pregnancy rates.


Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.
Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.


A Deep Learning Approach for Grading of Motor Impairment Severity in Parkinson's Disease.
Objective and quantitative monitoring of movement impairments is crucial for detecting progression in neurological conditions such as Parkinson's disease (PD). This study examined the ability of deep learning approaches to grade motor impairment severity in a modified version of the Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) using low-cost wearable sensors. A convolutional neural network architecture, XceptionTime, was used to classify lower and higher levels of motor impairment in persons with PD, across five distinct rhythmic tasks: finger tapping, hand movements, pronation-supination movements of the hands, toe tapping, and leg agility. In addition, an aggregate model was trained on data from all tasks together for evaluating bradykinesia symptom severity in PD. The model performance was highest in the hand movement tasks with an accuracy of 82.6% in the hold-out test dataset; the accuracy for the aggregate model was 79.7%, however, it demonstrated the lowest variability. Overall, these findings suggest the feasibility of integrating low-cost wearable technology and deep learning approaches to automatically and objectively quantify motor impairment in persons with PD. This approach may provide a viable solution for a widely deployable telemedicine solution.


Suitability of instant noodles for iron fortification to combat iron-deficiency anemia among primary schoolchildren in rural Vietnam.
Anemia is a significant public health problem among schoolchildren in Vietnam. Food fortification is considered one of the most sustainable long-term strategies to control iron-deficiency anemia in Vietnam. The success of a food-fortification program depends on the choice of the food vehicle. The aim of the present study was to identify an appropriate vehicle for iron fortification to be used in a school-feeding program aimed at improving the iron and anemia status of schoolchildren in rural Vietnam. Children 6 to 8 years of age in two primary schools in Tam Nong District, Phu Tho Province, and their parents were included in this study. The study consisted of three substudies: a food-consumption study with 24-hour recalls of two nonconsecutive days; a food-beliefs study, with focus group discussions, a pile-sorting test, and a food attributes and differences exercise; and a food-acceptance study using noodles and biscuits fortified with sodium iron ethylenediaminetetraacetic acid (NaFeEDTA). The average number of meals consumed daily was 3.2 +/- 0.4, and the average intakes of energy and iron were 1,218 +/- 406 kcal and 7.5 +/- 4.0 mg, respectively. Compared with biscuits and instant rice soup, instant noodles were consumed more frequently and in larger portion sizes and are more acceptable as children's food in the culture of the local people. The iron level of the fortified product did not affect the mean consumption of noodles, but a higher level of iron was associated with a lower mean consumption of biscuits (p < .05). The production process did not affect the NaFeEDTA level in noodles; however, during preparation at least 70% of the iron is leaked into the soup. Instant noodles are a suitable vehicle for iron fortification for use in school-based intervention to improve iron-deficiency anemia among primary schoolchildren in rural Vietnam.


CD45/isotypes expression in the immune cells of human periapical lesions.
Expression of some leukocyte antigens (including CD45) and its isoforms (CD2, CD4, CD5, CD6, CD7, and CD8) was examined in the human periapical granulation tissue samples in the present study. The majority of the infiltrating cells expressed heavy molecular-weight isoforms of the CD45 antigen. Expression of CD2, CD5, CD6, and CD7 antigens was also detected, implying significant roles for these antigens in the immune reaction taking place in periapical lesions. This suggests that the immune response taking place at the periapical region is predominantly cellular and the humoral responses to antigenic challenge are conducted mainly by regional lymph nodes.


Preschool classroom processes as predictors of children's cognitive self-regulation skills development.
This research focuses on the associations between interactive processes of early childhood classrooms and gains in children's cognitive self-regulation (CSR) across the preschool year. Data from 803 children (45.8% female; M = 54 months; 39.1% Caucasian, 26.3% African American, 24.6% Hispanic, 9.9% Other) were collected at fall and spring of the preschool year, and classroom observations were conducted three times throughout the year. Multilevel models tested associations between classroom behaviors of teachers and students using the Classroom Observation in Preschool and the Teacher Observation in Preschool and gains children made in a CSR composite score (Dimensional Change Card Sort, Peg Tapping, Head Toes Knees Shoulders, Copy Design, and Corsi Blocks) across the preschool year. After controlling for demographic covariates and children's pretest scores, both affective and cognitive classroom processes were associated with gains. More teacher behavior approving, less disapproving, and more positive emotional tone were associated with gains. The proportion of observed time teachers spent delivering instruction as well as the proportion of time children were involved with mathematics and literacy were also related to CSR gains, as was the quality of teacher instruction. Although exploratory, these results highlight the potential for modifications in classroom practices to aid in children's CSR development.


[Epidemiology of urinary lithiasis in our Unit. Clinical course in time and predictive factors].
To analyze the incidence of lithiasis and stone composition in our setting. The trend is compared with the results of the majority of studies on urinary calculi reported in the literature based on the number and composition of stones. The study comprised patients referred to the Urolithiasis Unit of our hospital over the last 21 years. Stone composition was analyzed by infra-red spectroscopy. The study period was divided into 4 time intervals: 1977-1979, 1977-1980, 1977-1987 and 1977-1998 in order to determine the trends of the incidence of lithiasis in our setting. A total of 5516 patients were reviewed; of these, 766 had recurrence. The distribution was 385, 995, 3378 and 5516, respectively. Calcium oxalate calculi showed an incidence of 61.3%, calcium phosphate 18.5%, uric acid 11.2%, infectious calculi (ammonium urate and ammonium magnesium phosphate) 6.6%, and finally the incidence of cysteine calculi was 0.77%. Concerning the distribution according to sex, 62% of the males had calcium oxalate stones, 68% uric acid, 42.5% phosphate and 45% infectious lithiasis. The trends for uric acid, infectious, oxalate and phosphate calculi changed over time. There is a clear trend of calculi prevalence in the male, particularly oxalate and uric acid calculi. There is a trend for cysteine calculi to remain the same, calcium phosphate and oxalate calculi to increase, and uric and infectious calculi to decrease. The changes observed may be due to dietary changes and improvement in the quality of life.


Biological synthesis of genistein in Escherichia coli.
Genistein is a type of isoflavonoid found predominantly in leguminous plants. Genistein has diverse biological activities, such as anthelmintic and antioxidant effects, as well as inhibitory effects on the growth of several cancers. In addition, genistein is well known as a phytoestrogen. In this study, we attempted to biologically synthesize genistein from either p-coumaric acid or naringenin using Escherichia coli as a biotransformation host. Four genes, Os4CL, PeCHS, RcIFS, and OsCPR, were used for genistein production. To functionally express RcIFS and OsCPR, two members of the cytochrome P450 family, in E. coli, the membrane-binding anchor domain of each gene was removed, and RcIFS and OsCPR were translationally fused to generate an RcIFS-OsCPR hybrid. Os4CL and PeCHS, or the RcIFS-OsCPR hybrid, were then transformed into E. coli BL21(DE3). Using these strains, we optimized our culture system at a laboratory scale in terms of the cell density, concentrations of substrate and isopropyl-β-D-thiogalactoside, temperature, and culture medium. Under the optimized culture conditions, genistein was produced at up to 35 mg/l and 18.6 mg/l using naringenin and p-coumaric acid, respectively.


Overview of physiological and pathophysiological effects of thromboxane A2.
Thromboxane (Tx) A2 is a biologically potent and chemically unstable metabolite of prostaglandin endoperoxides. Recent developments in measurement techniques and the availability of both selective inhibitors of Tx synthetase and TxA2 receptor antagonists have facilitated the implication of TxA2 as a physiological modulator and as a mediator in thrombotic, vasospastic, and bronchospastic conditions. TxA2 is synthesized by platelets and contributes to platelet activation and irreversible platelet aggregation in physiological hemostasis and in thrombosis (e.g., unstable angina, stroke). TxA2 is also synthesized in intestinal, pulmonary, and renal tissues by cells other than platelets. Particularly in these tissues, TxA2 appears to act as a physiological modulator of changes in blood flow distribution and airway caliber. Strong stimuli for TxA2 release from these tissues may initiate ulcer, pulmonary hypertension, bronchoconstriction, and renal vasoconstriction. Evidence supports participation of TxA2 and/or TxA2 receptors in modulation of natural cytotoxic cell cytotoxicity, in tumor growth and metastasis, in complications of pregnancy (e.g., preeclampsia), and in the progression of ischemic injury after coronary artery occlusion. This evidence supports pivotal involvement of TxA2 in pathophysiology and provides a strong rationale for pursuing TxA2-blocking strategies in drug development.


A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis.
Single nucleotide polymorphisms (SNPs) located at microRNA (miRNA) binding sites (miR-SNPs) can affect the expression of genes. This study aimed to identify the miR-SNPs associated with atherosclerosis and stroke. Patients with ischemic stroke (n = 657) and stroke- and myocardial infarction-free volunteers (n = 1571) were enrolled. The carotid intima-media thickness (IMT) was measured in the control participants. Seventy-nine stroke susceptibility genes were initially selected and 13 genes were predicted to have miR-SNPs at their 3' untranslated regions (3'UTR). The miRNA arrays were used to further identify potential miR-SNPs. The miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene was finally selected and its associations with stroke and carotid IMT were evaluated. The 3'UTR reporter and SNP functional assays were then performed to validate the results. Compared with CC genotype, patients with CT or TT genotype at rs3735590 had lower risk of ischemic stroke (OR = 0.72, p = 0.036; OR = 0.83, p = 0.077, respectively). Among the healthy participants, the CT or TT genotype was associated with thinner IMT in the internal carotid arteries in comparison with CC genotype (β = -0.76, p = 0.003; β = -0.022, p = 0.452, respectively). Our findings suggested that the minor allele T had a protective effect on atherosclerosis. Results from 3'UTR reporter assays showed that PON1 is a direct target gene of miR-616. In plasmid constructs carrying the risk allele C at rs3735590, miR-616 inhibited the genetic expression of PON1. However, substitution of C by T at rs3735590 reduced the miR-616 binding affinity, leading to overexpression of the PON1 gene. Our study is the first to show that the miR-SNP at PON1 could affect genetic expression and is associated with an elevated risk for ischemic stroke and subclinical atherosclerosis.


Potential Mechanisms of Ovarian Protection with Gonadotropin-Releasing Hormone Agonist in Breast Cancer Patients: A Review.
The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation.


[Sexual development of children and teenagers in the families deported from Abkhazia (dynamic observation)].
The aim of the study was the evaluation of physical and pubertal development of children from the families deported from Abkhazia who were exposed to significant psycho-somatic stress and prolonged socio-economical infringement. Dynamic observation started in 1998. Children, 9-15 years of age, have been studied. 200 children have been selected by the individualised methods (115 were girls and 85 were boys). In parallel children of appropriate age and gender groups from the local families have been studied. The investigations were conducted according to the generally accepted schemes and tables suggested by Tenner (17), for girls and by V.M. Vedenski (8) for boys, respectively. The analysis of obtained results showed that the total percent of delayed puberty in studying group was 21.4% versus 30.0% in the groups of 1998. Consequently, index of delay in control group was equal to 3.9% (2005) and 5.0% (1998). The group, exceeding the norms of puberty (accelerates) was 4.8% versus 11.2% in control group in comparison with the data of 1998--5.4% versus 15.0%, respectively. It should be concluded that due to the obtained results, comparing with the analogic groups of 1998, the number of delayed puberty has been reduced by approximately 9.0%. The number of cases exceeding the norms of puberty has been decreased slightly.


Adhesion of platelets to human artery subendothelium: effect of factor VIII-von Willebrand factor of various multimeric composition.
The relationship between the multimeric size of factor VIII-von Willebrand factor (FVIII-vWF) and the support of platelet adhesion to subendothelium was studied in an annular perfusion chamber, employing human renal and umbilical arteries. Commercial factor VIII concentrates containing multimers of low molecular weight that had been shown not to correct the bleeding time upon infusion into patients with von Willebrand's disease did not support platelet adhesion in the perfusion chamber. Cryoprecipitate and two experimental FVIII-vWF concentrates containing multimers of high molecular weight supported platelet adhesion. Factor VIII-vWF purified from cryoprecipitate was subdivided into three fractions of different molecular weights (6.0-14.0, 4.0-9.0, and 3.0-7.5 X 10(6) dalton). These fractions appeared to bind equally well and to be equally effective in supporting platelet adhesion. Factor VIII-vWF with multimers of low molecular weight (0.5-1.5 X 10(6) dalton) were prepared by partial reduction. Binding of FVIII-vWF to subendothelium was not impaired, and the support of platelet adhesion appeared to be more resistant to the effect of reduction than the ristocetin cofactor activity. At high shear rate (2,500 sec-1), increased platelet adhesion was observed with partially reduced FVIII-vWF. These data indicate that the ability of FVIII-vWF preparations to correct the bleeding time is reflected in enhanced platelet adhesion to subendothelium in a perfusion chamber. These data also emphasize that multimeric size is not the only factor determining whether FVIII-vWF will support platelet adhesion.


Collagen formation by the hepatocyte in primary monolayer culture and in vivo.
Immunohistochemical techniques were used to confirm biochemical evidence that parenchymal cells isolated from adult rat liver and maintained in nonreplicating monolayer culture for 2 days synthesized type IV basement membrane collagen. On continued incubation in serum-free medium, the hepatocytes also synthesized the interstitial collagens, types I and III. Consistent with these results in culture, type IV collagen was localized to the hepatocytes in slices of pathologic rat liver. Hence collagen formation is a previously unrecognized function of the hepatocyte that may be important in the pathogenesis of liver fibrosis or cirrhosis.


Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.
Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. NCT05338931; Date: 2022-04-01.


Magnetic Resonance Imaging (MRI) Results Following Discontinuation of Methotrexate in Rheumatoid Arthritis Treated with Subcutaneous Tocilizumab: The COMP-ACT MRI Substudy.
To assess differences in joint damage and inflammation using magnetic resonance imaging (MRI) between patients with rheumatoid arthritis (RA) who achieved low disease activity with tocilizumab (TCZ) + methotrexate (MTX) and subsequently continued or discontinued MTX. In the COMP-ACT trial, US patients with RA received subcutaneous TCZ 162 mg + MTX. Those who achieved 28-joint count Disease Activity Score calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to discontinue MTX (TCZ monotherapy; mono) or continue TCZ + MTX until Week 52. In a subset of patients, 1.5-Tesla MRI was used to obtain images of bilateral hands and wrists at weeks 24 and 40. Outcomes included changes in MRI-assessed synovitis, osteitis, erosion, and cartilage loss from Week 24 to Week 40, and in the proportion of patients with progression of each score. Of 296 patients who achieved DAS28-ESR ≤ 3.2 at Week 24, 79 were enrolled in the pilot MRI substudy and randomized to TCZ mono (n = 38) or TCZ + MTX (n = 41). Treatment with either TCZ mono or TCZ + MTX suppressed erosion progression, synovitis, osteitis, and cartilage loss. The proportion of patients with no progression in each outcome measure was similar between groups (range, TCZ mono: 84.8-97.0%; TCZ + MTX: 92.3-100%). In a subset of patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal in intraarticular inflammation and damage measures in patients who discontinued MTX versus those who continued TCZ + MTX.


Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings.
Combined methylmalonic aciduria and homocystinuria (MMA-HC) is caused by impaired hepatic conversion of dietary cobalamin to methylcobalamin and adenosylcobalamin, resulting in decreased activity of methylmalonyl-CoA mutase and methionine synthase. Patients with the early-onset variety present within 12 months of age with severe neurologic, hematologic, and gastrointestinal abnormalities. We describe the neuroradiologic features of early-onset MMA-HC and discuss related pathophysiological mechanisms. Twelve infants with hypotonia, failure to thrive, poor feeding, and hematologic abnormalities were diagnosed with MMA-HC on the basis of a typical plasmatic and urinary metabolic profile and enzyme activity in fibroblastic cultures. Complementation studies were performed in two cases, and yielded a CblC result. MR imaging was performed at presentation in four cases and later in the others. All patients showed prompt biochemical improvement with intramuscular hydroxocobalamin administration, and most had moderate neurologic improvement. Diffuse supratentorial white matter edema and dysmyelination was the typical MR picture at presentation, whereas white matter bulk loss characterized later stages of the disease. Nucleocapsular areas of gliosis were an additional finding in one case. One patient had tetraventricular hydrocephalus at presentation. White matter damage is probably caused by reduced methyl group availability and nonphysiological fatty acids toxicity, whereas focal gliosis results from homocysteine-induced toxicity to the endothelium. Hydrocephalus may result from diffuse intracranial extracerebral arterial stiffness, known as reduced arterial pulsation hydrocephalus. MR imaging features at presentation and at follow-up are nonspecific.


[Foreign bodies of gastrointestinal tract].
153 patients with swallowed foreign bodies in gastrointestinal tract (GIT) were treated for the last 10 years (1988-1997). In 85 (55.5%) cases foreign bodies (FB) were swallowed by psychopathic persons, in 45 (29.4%)--with the aim of mutilation, in 23 (15.0%)--due to carelessness. In 105 (68.63%) patients the foreign bodies were single, in 48 (31.37%) there were multiple foreign bodies of GIT. In 73 (47.71%) cases FB were found in the stomach. Clinical picture in patients with swallowed FB was variable. Dynamic roentgenological examination together with thorough anamnesis is the most important diagnostic tool in this pathology. The indications for urgent surgical treatment were sticking of the FB, peritonitis, gastro-duodenal bleeding, gastrointestinal obstruction. Elective surgery was used in patients with sticked F.B., with multiple FB, which formed conglomerates, as well as in single FB. with the length over 12-15 cm. Active expectant policy is valid FB of GIT with tendency for passage, due to conservative treatment.


Experimental determination of dynamic characteristics of the VentrAssist implantable rotary blood pump.
The VentrAssist implantable rotary blood pump, intended for long-term ventricular assist, is under development and is currently being tested for its rotor-dynamic stability. The pump consists of a shaftless impeller, which also acts as the rotor of the brushless DC motor. The impeller remains passively suspended in the pump cavity by hydrodynamic forces, which result from the small clearances between the outside surfaces of the impeller and the pump cavity. These small clearances range from approximately 50 microm to 230 microm in size in the version of pump reported here. This article presents experimental investigation into the dynamic characteristics of the impeller-bearing-pump housing system of the rotary blood pump for increasing pump speeds at different flow rates. The pump was mounted on a suspension system consisting of a platform and springs, where the natural frequency and damping ratio for the suspension system were determined. Real-time measurements of the impeller's displacement were performed using Hall effect sensors. A vertical disturbance force was exerted onto the pump housing, causing the impeller to be displaced in vertical direction from its dynamic equilibrium position within the pump cavity. The impeller displacement was represented by a decaying sine wave, which indicated the impeller restoring to its equilibrium position. From the decaying sine wave the natural frequency and stiffness coefficient of the system were determined. Furthermore, the logarithmic decrement method was used to determine the damping ratio and eventually the damping coefficient of the system. Results indicate that stiffness and damping coefficients increased as flow rate and pump speed increased, representing an increase in stability with these changing conditions. However, pump speed had a greater influence on the stiffness and damping coefficients than flow rate did, which was evident through dynamic analysis. Overall the experimental method presented in this article was successful in determining the dynamic characteristics of the system.


A retrospective study of traffic offenses associated with driving under the influence of drugs in China.
This study aimed to investigate the prevalence and pattern of traffic offenses associated with driving under the influence of drugs (DUID) in 31 provinces of mainland China. Traffic offenses were extracted from the nationally representative court file disclosure website. Drivers convicted of traffic offenses associated with DUID were included. The monthly percentage change (MPC) in rates was estimated by fitting negative binomial regression models to assess the time trends. Moran's I was used to determine the correlations of DUID-related rates among surrounding provinces. In total, 896 individuals convicted of DUID offenses were identified (April 2007 to March 2022). Of these, 769 individuals were involved in traffic crashes, and they killed 629 people. Regarding the types of drugs, 638 used amphetamine-type stimulants (ATS; methamphetamine, 3,4-methylenedioxymethamphetamine, amphetamine, and tenamfetamine), 104 used ketamine, 104 used opioids (heroin, morphine, methadone, codeine, and tramadol), 20 used caffeine, 4 used tetrahydrocannabinol, and 1 used gamma-hydroxybutyric acid. The offense trends among overall drug users (MPC, -1.1; p < .001) declined from 2014 to 2020. The trends also decreased for DUID-related traffic crashes (-1.5; p < .001) and deaths (-1.7; p < .001) during the same period. Except in three provinces, ATS-related offense rates were higher than opioid-related offense rates. Ketamine-related offense rates showed a significant positive correlation among the surrounding provinces (Moran's I, 0.22; p < .01), and South China had the highest ketamine-related offense rates. In the sample, the case fatality rate was 70.7%, which was a strong indicator of underreporting, and most minor DUID-related offenses could not be captured by Chinese court files. The frequency of drug screening tests for people should be increased. The traffic police in Qinghai, Tibet, and Xinjiang should always be equipped with fast screening test kits for drugs, which could increase the possibility of identifying DUID offenders.


New Mg-based 4,4'-biphenyldicarboxylate coordination polymer with layered crystal structure.
New magnesium 4,4'-biphenyldicarboxylate (BPDC) was solvothermally synthesized in the presence of N,N'-dimethylformamide (DMF). The crystal structure with formula Mg(3)(BPDC)(3)(DMF)(4) and denoted as NICS-7 was solved in monoclinic symmetry with space group Pn (no. 7) and unit cell parameters a = 12.6433(7) Å, b = 13.3950(5) Å, c = 19.9230(8) A, beta = 107.131(5) °. The structure consists of MgO(6) linear arranged trimers with common vertices connected through BPDC ligands forming extended 2-dimensional layered hybrid structure. Each terminal Mg atom within trimeric clusters is coordinated by two dimethylformamide molecules, respectively. Layers of Mg(3)(BPDC)(3)(DMF)(4) are stabilized by non-coordinated dimethylformamide molecules located within the voids in crystallographically disordered manner. Thermal properties of NICS-7 were determined by thermogravimetric and temperature-programmed X-ray diffraction. The structure remains stable only up to 50 °C. At higher temperatures, the removal of non-coordinated dimethylformamide molecules causes formation of amorphous Mg-BPDC phase.


Clinical Reasoning in Forensic Psychiatry: Concepts, Processes, and Pitfalls.
Forensic psychiatrists are often sought by the court of law to provide professional opinion on specific legal matters that have a major impact on the evaluee and possibly society at large. The quality of that opinion and recommendations rely on the quality of the analysis from the assessment results conducted by the psychiatrist. However, the definition and scope of a forensic psychiatric analysis is not clear. While existing literature on forensic psychiatric analysis generally includes organizing information, identifying relevant details, and formulating a set of forensic psychiatric opinions as components, there is no explicit and unified definition of these terms and process. This lack of clarity and guidelines may hinder forensic psychiatry from achieving its goal of providing objective information to the court or other relevant parties. Forensic psychiatric analysis exhibits numerous parallels to clinical reasoning in other fields of medicine. Therefore, this review aims to elaborate forensic psychiatric analysis through the lens of clinical reasoning, which has been developed by incorporating advances in cognitive sciences. We describe forensic psychiatric analysis through three prominent clinical reasoning theories: hypothetico-deductive model, illness script theory, and dual process theory. We expand those theories to elucidate how forensic psychiatrists use clinical reasoning not only to diagnose mental disorders, but also to determine mental capacities as requested by law. Cognitive biases are also described as potential threat to the accuracy of the assessment and analysis. Additionally, situated cognition theory helps elucidate how contextual factors influence risk of errors. Understanding the processes involved in forensic psychiatric analysis and their pitfalls can assist forensic psychiatrists to be aware of and try to mitigate their bias. Debiasing strategies that have been implemented in other fields of medicine to mitigate errors in clinical reasoning can be adapted for forensic psychiatry. This may also shape the training program of general psychiatrists and forensic psychiatrists alike.


Clinical Decision Support Systems and Medico-Legal Liability in Recall and Treatment: A Fresh Examination.
Clinical decision support systems (CDSSs) provide a valuable tool for clinicians to aid in the care of patients with chronic disease. Various questions have emerged about their implications for the doctor's legal duty of care to their patients, in terms of recognition of risk, recall, testing and treatment. In this article, through an analysis of Australian legislation and international case law, we address these questions, considering the potential impact of CDSSs on doctors' liability in negligence. We conclude that the appropriate use of a well-designed CDSS should minimise, rather than heighten, doctor's potential liability. It should support optimal patient care without diminishing the capacity of the doctor to make individualised decisions about recall, testing and treatment for each patient. We foreshadow that in the future doctors in Australia may have a duty to use available well-established software systems in patient care.


A new murine model of giant proximal axonopathy.
The aromatic gamma-diketone 1,2-diacetylbenzene (1,2-DAB), the putative active metabolite of the organic solvent 1,2-diethylbenzene, forms blue-colored polymeric protein adducts and induces the formation of amyotrophic lateral sclerosis (ALS)-like giant, intraspinal neurofilamentous axonal swellings in Sprague Dawley rats. The pathogenetic mechanism of this neuropathy has yet to be understood. We assessed whether these pathological changes are also seen in the C57BL/6 mouse, the animal of choice for toxicogenomic studies. Mice were treated intraperitoneally with 30, 35, 50, or 70 mg/kg 1,2-DAB or its inactive isomer 1,3-DAB per day (or on alternate days) for up to 43 days. Animals treated with 30 or 35 mg/kg per day 1,2-DAB, but not with 1,3-DAB, developed muscle spasms and progressive weakness, most prominently in hind limbs. Light microscopy revealed swollen axons in spinal anterior horns and proximal ventral roots, and to a lesser extent in dorsal root ganglia of 1,2-DAB-treated animals. Ultrastructural examination of swollen axons revealed clumps of maloriented 10-nm neurofilaments. Sciatic nerves showed clustering of axonal microtubules and other organelles. These findings are qualitatively comparable to those reported in rats treated with 1,2-DAB and represent a suitable phenotype with which to explore molecular mechanisms of proximal, giant neurofilamentous axonopathy using proteomic and genomic technologies.


[Does SWL for ureteral stone with less than 60 shock waves per minute improve treatment results?].
Extracorporeal shock wave lithotripsy (SWL) is a wide spread option for the treatment of the upper urinary tract urolithiasis. EAU guideline recommends the treatment with 60-90 shots per minute for the optimal frequency of SWL, but there is no report on the efficiency of SWL with the frequency less than 60 shots per minute. To determine the optimal shock wave frequency of SWL, we prospectively randomized total 247 patients with ureteral stone to the four different treatment groups: group A (76 pts.), group B (68 pts.), group C (55 pts.) and group D (48 pts.). These groups were treated with the frequencies of 80, 60, 45 and 30 shots per minute respectively using Dornier Lithotripter D. One treatment took forty minutes, resulting in the total shock waves per session of 3,200, 2,400, 1,800 and 1,200 for group A, B, C and D, respectively. The total numbers of the SWL sessions were statistically not different among the four groups. Importantly, there was statistically no difference among the four groups about the stone clearance rates and the stone reduction efficiencies on the next day, after one week and after one month of the treatment. In addition, only two additional ureteral stenting for pyelonephritis and one renal subcapsular hematoma were observed. This study suggests that the efficiency of SWL with the frequency of 30 or 45 shots per minute is similar to that of 60 or 80 shots for stone reduction and clearance.


Cognate T cell help is sufficient to trigger anti-nuclear autoantibodies in naive mice.
The mechanisms involved in the initiation of anti-nuclear autoantibodies are unknown. In this study, we show that one factor allowing anti-nuclear autoantibodies to develop is the incomplete nature of immune tolerance to many of these proteins. Immune responses in mice toward the ubiquitous nuclear autoantigen La/SS-B are much weaker than responses to the xenoantigen, human La (hLa; 74% identical). However, in transgenic (Tg) mice expressing hLa, the Ab response to this neo-autoantigen was reduced to a level resembling the weak autoimmune response to mouse LA: Partial tolerance to endogenous La autoantigen was restricted to the T compartment because transfer of CD4(+) T cells specific for one or more hLa determinants into mice bearing the hLa transgene was sufficient to elicit production of anti-hLa autoantibodies. Notably, only hLa- specific T cells from non-Tg mice, and not T cells from hLa Tg mice, induced autoantibody production in hLa Tg mice. These findings confirm partial Th tolerance to endogenous La and indicate the existence in normal animals of autoreactive B cells continuously presenting La nuclear AG: Therefore, the B cell compartment is constitutively set to respond to particular nuclear autoantigens, implicating limiting Th responses as a critical checkpoint in the development of anti-nuclear autoantibodies in normal individuals.


5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.
The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.


A sequence resembling a peroxisomal targeting sequence directs the interaction between the tetratricopeptide repeats of Ssn6 and the homeodomain of alpha 2.
The tetratricopeptide repeat (TPR) is a 34-aa sequence motif, typically found in tandem clusters, that occurs in proteins of bacteria, archea, and eukaryotes. TPRs interact with other proteins, although few details on TPR-protein interactions are known. In this paper we show that a portion of a loop in the homeodomain of the DNA-binding protein alpha2 is required for its recognition by the TPRs of the corepressor Ssn6. The amino acid sequence of this loop is similar to the sequences recognized by the TPRs of an entirely different protein, Pex5, which directs peroxisomal import. We further show that alpha2 can be made to bind specifically in vitro to the TPRs of Pex5 and that a point mutation that disrupts the alpha2-Ssn6 interaction also disrupts the alpha2-Pex5 interaction. These results demonstrate that two different TPR proteins recognize their target by a similar mechanism, raising the possibility that other TPR-target interactions could occur through the same means.


The effects of adult guidance and peer discussion on the development of children's representations: evidence from the training of pedestrian skills.
It was hypothesized that practical training is effective in improving children's pedestrian skills because adult scaffolding and peer discussion during training specifically promote E3 level representation (linguistically-encoded, experientially-grounded, generalizable knowledge), as defined by Karmiloff-Smith's (1992) representational redescription (RR) model. Two studies were conducted to examine in detail the impact of this social input in the context of simulation-based training in roadside search skills. A group of 5-8-year-olds were pre-tested on ability to detect relevant road-crossing features. They then participated in four training sessions designed to promote attunement to these, under peer discussion versus adult guidance conditions (Study 1), and adult-child versus adult-group conditions (Study 2). Performance at post-test was compared with that of controls who underwent no training. Study 1 found that children in the adult guidance condition improved significantly more than those in the peer discussion or control conditions, and this improvement was directly attributable to appropriation of E3 level representations from adult dialogue. Study 2 found that progress was greater still when adult scaffolding was supplemented by peer discussion, with E3 level representation attributable to the children's exploration of conflicting ideas. The implications of these findings for the RR model and for practical road safety education are discussed.


Magnetic resonance spectroscopic imaging detects abnormalities in normal-appearing frontal lobe of patients with Sturge-Weber syndrome.
In Sturge-Weber syndrome (SWS), structural MRI abnormalities are most common in the posterior brain regions. Frontal lobe involvement increases the risk of motor impairment. The goal of this study was to determine whether Magnetic Resonance Spectroscopic Imaging (MRSI) can improve detection of frontal lobe involvement in children with SWS. Sixteen children (age: .9-10.4 years) with unilateral SWS underwent MRI with MRSI prospectively. N-acetyl-aspartate (NAA) and choline asymmetries in the posterior and frontal regions were measured. Eight children presented normal-appearing frontal lobes on conventional MRI, but 7 of them showed abnormal NAA and/or choline content in the frontal lobe of the affected hemisphere. Lower frontal lobe gray matter NAA was associated with earlier onset of seizures (r= .76; P= .04) and impaired motor function (r=-.89, P < .001). Frontal NAA asymmetry was an independent predictor of motor function in a regression analysis (P= .01) MRSI is more sensitive than conventional structural MRI for detection of frontal lobe involvement in SWS. Decreased frontal lobe NAA is an excellent predictor of motor functions. Thus, MRSI can provide complementary information for the assessment of normal-appearing brain regions, and may assist prognosis evaluation in children with SWS.


Evaluation of the Accuracy of a Polymerase Chain Reaction-Based Assay for Polymerase Epsilon Mutation Detection in Endometrial Carcinoma.
Molecular stratification of endometrial carcinoma provides more accurate prognostic information than traditional clinicopathologic features. However, because next-generation sequencing is typically recommended for polymerase epsilon (POLE) mutation detection, the practical application of a test based on molecular stratification is limited in the clinical setting. To evaluate a polymerase chain reaction (PCR)-based assay for POLE mutation detection in endometrial carcinoma. We developed a PCR-based technology called Dalton Mutation Identifier Technology (Dalton-MIT) that targets 9 mutation sites within POLE exons. Endometrial carcinoma specimens from 613 patients were tested for POLE mutations. Correlations between POLE mutations with patient clinicopathologic characteristics and prognosis were analyzed. PCR detection data showed that the incidence rate of POLE mutation was 11.4% (70 of 613). Patients with POLE mutations presented better clinicopathologic characteristics and prognosis than those with non-POLE mutations. Comparison between Dalton-MIT and next-generation sequencing in 59.5% (365 of 613) of specimens showed that the sensitivity of Dalton-MIT for detecting POLE pathogenic mutations was 100%, the specificity was 99.3%, the Youden index was .993, and the κ value was .981 (P < .001). Our data demonstrate that POLE mutation detection by Dalton-MIT correlates with next-generation sequencing. This suggests that Dalton-MIT represents a promising alternative assay for detecting POLE mutations and will facilitate the wider application of molecular stratification tools for endometrial carcinoma in the clinic.


Diabetes-related changes in contractile responses of stomach fundus to endothelin-1 in streptozotocin-induced diabetic rats.
The contractile response of the stomach fundus to endothelin-1 (ET-1) was examined in streptozotocin (STZ)-induced diabetic rats. In STZ-diabetic rats (versus age-matched control rats) (a) ET-1 caused a longer-lasting contraction of stomach fundus strips, and (b) in the dose-response curve, the ET-1-induced contraction was significantly greater for a given concentration (3 x 10(-7) to 10(-7) M). Although repeated application of ET-1 led to desensitization, the desensitization was less pronounced in STZ-diabetic rats than in the controls. The density of the binding sites for [(125)I]-ET-1 was increased in the diabetic stomach fundus (versus the controls), but Kd values were similar between the two groups. The ET(B) receptor mRNA expression level was significantly increased in the diabetic stomach fundus. These results suggest that the diabetes-related enhancement of the ET-1-induced contraction of the stomach fundus may be due to an increase in the ET(B) receptor population.


Biotransformation of RDX and HMX by Anaerobic Granular Sludge with Enriched Sulfate and Nitrate.
RDX and HMX are widely used energetic materials and they are recognized as environmental contaminants at numerous locations. The present study investigated the biotransformation of RDX and HMX by anaerobic granular sludge under sulfate- and nitrate-enriched conditions. The results showed that RDX and HMX could be transformed by anaerobic granular sludge when nitrate was present. However, the biotransformation of RDX and HMX was negatively influenced, especially with high nitrate concentrations. Sulfate-enriched conditions were more favorable for the removal of ammunition compounds by anaerobic granular sludge than nitrate-enriched conditions. The removal of RDX and HMX under both nitrate- and sulfate-enriched conditions was facilitated by the use of glucose as additional substrate. This knowledge may help identify factors required for rapid removal of RDX and HMX in high-rate bioreactors. These results can also be applied to devise an appropriate and practical biological treatment strategy for explosive contaminated wastewater.


[The concept "a case in outpatient treatment" in military policlinic activity].
Substantiates the necessity of transition of military policlinics to the accounting system and evaluation of their activity on the finished cases of outpatient treatment. Only automating data-statistical processes can solve this problem. On the basis of analysis of the literature data, requirements of the guidance documents and observational results concludes that preliminarily should be done revisal (formalisation) of existing concepts of medical statistics from the position of information environment which in use - electronic databases. In this aspect specified the main features of outpatient treatment case as a unit of medical-statistical record, and formulated its definition.


Dynamic relocation of epigenetic chromatin markers reveals an active role of constitutive heterochromatin in the transition from proliferation to quiescence.
Quiescent lymphocytes have small nuclei, filled with masses of facultative heterochromatin. Upon receiving mitogenic signals, these cells undergo nuclear enlargement, chromatin decondensation, the reactivation of cell proliferation, and changes in the intranuclear positioning of key genes. We examined the levels and intranuclear localization of major histone modifications and non-histone heterochromatin proteins in quiescent and reactivated mouse spleen lymphocytes. Dramatic and selective changes in localization of two heterochromatin-associated proteins, the histone variant macroH2A and HP1alpha occurred during lymphocyte reactivation. Reciprocal changes in the locations of these two proteins were observed in activated lymphocytes and cultured mouse fibroblasts induced into quiescence. We also describe a new apocentric nuclear compartment with a unique set of histone modifications that occurs as a zone of chromatin surrounding centromeric heterochromatin in differentiated lymphocytes. It is within this zone that the most significant changes occur in the transition from proliferation to quiescence. Our results suggest that constitutive centromeric heterochromatin plays an active role in cell differentiation and reactivation.


Mechanism of insulin resistance in a rat model of kidney disease and the risk of developing type 2 diabetes.
Chronic kidney disease is associated with homeostatic imbalances such as insulin resistance. However, the underlying mechanisms leading to these imbalances and whether they promote the development of type 2 diabetes is unknown. The effect of chronic kidney disease on insulin resistance was studied on two different rat strains. First, in a 5/6th nephrectomised Sprague-Dawley rat model of chronic kidney disease, we observed a correlation between the severity of chronic kidney disease and hyperglycemia as evaluated by serum fructosamine levels (p<0.0001). Further, glucose tolerance tests indicated an increase of 25% in glycemia in chronic kidney disease rats (p<0.0001) as compared to controls whereas insulin levels remained unchanged. We also observed modulation of glucose transporters expression in several tissues such as the liver (decrease of ≈40%, p≤0.01) and muscles (decrease of ≈29%, p≤0.05). Despite a significant reduction of ≈37% in insulin-dependent glucose uptake in the muscles of chronic kidney disease rats (p<0.0001), the development of type 2 diabetes was never observed. Second, in a rat model of metabolic syndrome (Zucker Leprfa/fa), chronic kidney disease caused a 50% increased fasting hyperglycemia (p<0.0001) and an exacerbated glycemic response (p<0.0001) during glucose challenge. Similar modulations of glucose transporters expression and glucose uptake were observed in the two models. However, 30% (p<0.05) of chronic kidney disease Zucker rats developed characteristics of type 2 diabetes. Thus, our results suggest that downregulation of GLUT4 in skeletal muscle may be associated with insulin resistance in chronic kidney disease and could lead to type 2 diabetes in predisposed animals.


Effects of Cocoa Antioxidants in Type 2 Diabetes Mellitus.
Type 2 Diabetes mellitus (T2D) is the most common form of diabetes and one of the most common chronic diseases. Control of hyperglycaemia by hypoglycaemic drugs is insufficient in for patients and nutritional approaches are currently being explored. Natural dietary compounds such as flavonoids, abundant in fruits and vegetables, have received broad attention because of their potential capacity to act as anti-diabetic agents. Especially cocoa flavonoids have been proved to ameliorate important hallmarks of T2D. In this review, an update of the most relevant reports published during the last decade in cell culture, animal models and human studies is presented. Most results support an anti-diabetic effect of cocoa flavonoids by enhancing insulin secretion, improving insulin sensitivity in peripheral tissues, exerting a lipid-lowering effect and preventing the oxidative and inflammatory damages associated to the disease. While it could be suggested that daily consumption of flavanols from cocoa or dark chocolate would constitute a potential preventive tool useful for the nutritional management of T2D, this recommendation should be cautious since most of commercially available soluble cocoa products or chocolates contain low amount of flavanols and are rich in sugar and calories that may aggravate glycaemic control in T2D patients.


Burden of Persistent Vomiting With Cannabis Use Disorder: Report From 55,549 Hospitalizations in the United States.
With increase in incidence rate of persistent vomiting (PV) in the post-legalization period it is important to understand adverse effects of cannabis use and its relationship with PV. We investigated the relationship between cannabis use disorder (CUD) and PV-related hospitalization. A Nationwide Inpatient Sample was analyzed from 2010 to 2014 for patients (aged 15-54 y) with a primary diagnosis of PV (N = 55,549), and a comparison was made between patients with the International Classification of Diseases, Ninth Edition classification of CUD versus non-CUD cohorts. We used logistic regression to study the odds ratio between CUD and PV. The number of PV-related hospitalizations with CUD had a significantly increased trend (P < 0.001), with a 286% increase over 5 years. A higher proportion of these patients with CUD were younger (15-24 y), female, and African American/Hispanic. In regression analysis, cannabis was associated with a seven-fold higher odds (95% confidence interval: 6.931-7.260) of PV-related hospitalization. This study found that CUD was independently associated with a 609% increased likelihood of PV-related hospitalization, and this association persisted even after adjusting for known risk factors and other substances.


Nanosecond electric pulses are equally effective in electrochemotherapy with cisplatin as microsecond pulses.
Nanosecond electric pulses showed promising results in electrochemotherapy, but the underlying mechanisms of action are still unexplored. The aim of this work was to correlate cellular cisplatin amount with cell survival of cells electroporated with nanosecond or standardly used 8 × 100 μs pulses and to investigate the effects of electric pulses on cisplatin structure. Chinese hamster ovary CHO and mouse melanoma B16F1 cells were exposed to 1 × 200 ns pulse at 12.6 kV/cm or 25 × 400 ns pulses at 3.9 kV/cm, 10 Hz repetition rate or 8 × 100 μs pulses at 1.1 (CHO) or 0.9 (B16F1) kV/cm, 1 Hz repetition rate at three cisplatin concentrations. Cell survival was determined by the clonogenic assay, cellular platinum was measured by inductively coupled plasma mass spectrometry. Effects on the structure of cisplatin were investigated by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Nanosecond pulses equivalent to 8 × 100 μs pulses were established in vitro based on membrane permeabilization and cell survival. Equivalent nanosecond pulses were equally efficient in decreasing the cell survival and accumulating cisplatin intracellularly as 8 × 100 μs pulses after electrochemotherapy. The number of intracellular cisplatin molecules strongly correlates with cell survival for B16F1 cells, but less for CHO cells, implying the possible involvement of other mechanisms in electrochemotherapy. The high-voltage electric pulses did not alter the structure of cisplatin. Equivalent nanosecond pulses are equally effective in electrochemotherapy as standardly used 8 × 100 μs pulses.


Microfluidic platforms for advanced risk assessments of nanomaterials.
In the past few years, promising efforts to utilize microfabrication-based technologies have laid the foundation for developing advanced, and importantly more physiologically-realistic, microfluidic methods for risk assessment of engineered nanomaterials (ENMs). In the present review, we discuss the wave of recent developments using microfluidic-based in vitro models and platforms for nanotoxicological assays, such as determination of cell viability, cellular dose, oxidative stress and nuclear damage. Here, we specifically highlight the tangible advantages of microfluidic devices in providing promising tools to tackle many of the current and ongoing challenges faced with traditional toxicology assays. Most importantly, microfluidic technology not only allows to recreate physiologically-relevant in vitro models for nanotoxicity examinations, but also provides platforms that deliver an attractive strategy towards improved control over applied ENM doses. In a final step, we present examples of state-of-the-art microfluidic platforms for in vitro assessment of potential adverse ENM effects.


Image or Information? Examining the Nature and Impact of Visualization Perceptual Classification.
How do people internalize visualizations: as images or information? In this study, we investigate the nature of internalization for visualizations (i.e., how the mind encodes visualizations in memory) and how memory encoding affects its retrieval. This exploratory work examines the influence of various design elements on a user's perception of a chart. Specifically, which design elements lead to perceptions of visualization as an image (aims to provide visual references, evoke emotions, express creativity, and inspire philosophic thought) or as information (aims to present complex data, information, or ideas concisely and promote analytical thinking)? Understanding how design elements contribute to viewers perceiving a visualization more as an image or information will help designers decide which elements to include to achieve their communication goals. For this study, we annotated 500 visualizations and analyzed the responses of 250 online participants, who rated the visualizations on a bilinear scale as 'image' or 'information.' We then conducted an in-person study (n = 101) using a free recall task to examine how the image/information ratings and design elements impacted memory. The results revealed several interesting findings: Image-rated visualizations were perceived as more aesthetically 'appealing,' 'enjoyable,' and 'pleasing.' Information-rated visualizations were perceived as less 'difficult to understand' and more aesthetically 'likable' and 'nice,' though participants expressed higher 'positive' sentiment when viewing image-rated visualizations and felt less 'guided to a conclusion.' The presence of axes and text annotations heavily influenced the likelihood of participants rating the visualization as 'information.' We also found different patterns among participants that were older. Importantly, we show that visualizations internalized as 'images' are less effective in conveying trends and messages, though they elicit a more positive emotional judgment, while 'informative' visualizations exhibit annotation focused recall and elicit a more positive design judgment. We discuss the implications of this dissociation between aesthetic pleasure and perceived ease of use in visualization design.


[Ambulatory surgery and patients' experiences].
76 patients were interviewed by telephone 7-10 days after ambulant surgery for varicose veins, hernia inguinalis or sterilization (women). Of those who received spinal anaesthesia 24% developed headache and another 8% back-pain. Half of those who received general anaesthesia were too sleepy to recall the information they were given when they left the hospital. 22% of the patients reported that if they had to undergo the same operation again they would prefer to be admitted to hospital as inpatients. The interviews revealed many "minor" problems that could have been solved by a phone call on the first day after operation.


Mortality data analysis using a multiple-cause approach.
Death certificates are the primary source for information used to define general mortality patterns in the United States. Analyses of mortality data generally are restricted to one of the conditions listed on the certificate--the underlying cause of dealth. We review principles related to the use of mortality data and describe a study using mortality tapes ("multiple-cause tapes") that list all conditions recorded on dealth certificates. Using multiple-cause tapes, we found that the number of deaths associated with seven infectious diseases in 1968, 1969, and 1970 was from 24% (diphtheria) to 81% (rubella) greater than that officially reported. Multiple-cause tapes also permitted a review of the association of deaths attributed to measles and varicella and known complications of these diseases. these observations confirm the usefulness of multiple-cause tapes in analyzing mortality data and emphasize the importance of examining all conditions listed on the death certificate.


[Dyssymmetrical cytotomy and orientation of the spindles in early isolated blastomeres of gastropod molluscs].
While removing the vitelline membrane mechanically or by trypsinization, one or two blastomeres were isolated from two-, four- and eight-celled embryos Lymnaea stagnalis, Physa fontinalis and Ph. acuta. If a pair of blastomeres was isolated prior to the formation of the III and IV cleavage spindles, it became similar to a two-cell embryo; the spindles oriented in parallel to each other and the contact zone of blastomeres preserving the previous localization of the nuclei and the subsequent division was equal. If a pair of blastomeres was isolated in metaphase, the localization of spindles did not change and the relative size of sister blastomeres after the subsequent division resembled the normal size (in particular, the III division was unequal). In the course of division of isolated single blastomeres, as well as pairs of blastomeres with parallel spindles, mutual turns of sister cells along the plane of new furrow, always dexiotropic in Lymnaea and laetropic in Physa, were observed in all cycles. The ability of dissymmetrical invariant turns during cytotomy, shown earlier when studying the whole embryos, is, thus, inherent to each blastomere irrespective of the neighbour ones but is supressed during the normal development after the III division mechanically due to the dense cellular packing projected by the orientation of spindles.


[Rapid determination of alkaloids in tobacco using gas chromatography-mass spectrometry with full scan-selected ion monitoring mode].
Simultaneous full scan-selected ion monitoring mode (Scan-SIM) is a new improvement method of data acquisition of gas chromatography-mass spectrometry (GC-MS). A method of determing alkaloids in tobacco was established by GC-MS with Scan-SIM. Nicotine, nornicotine, anabasine and anatabine were determined with scan mode, and myosmine, nicotyrine, 2,3'-bipyridyl and cotinine were determined with SIM mode. The average recoveries of alkaloids ranged from 94.8% to 98.8%, and the relative standard deviations were less than 6.0% (n = 5). Therefore, it is a simple, rapid, accurate method. Tobacco samples picked in different years were determined using this method, and the results were satisfactory.


Electrofabrication of large volume di- and tripeptide hydrogels via hydroquinone oxidation.
The fabrication of protected peptide-based hydrogels on electrode surfaces can be achieved by employing the electrochemical oxidation of hydroquinone to benzoquinone, liberating protons at the electrode-solution interface. The localised reduction in pH below the dipeptide gelator molecules pKa initiates the neutralisation, self-assembly and formation of self-supporting hydrogels exclusively at the electrode surface. Previous examples have been on a nanometre to millimetre scale, using deposition times ranging from seconds to minutes. However, the maximum size to which these materials can grow and their subsequent mechanical properties have not yet been investigated. Here, we report the fabrication of the largest reported di- and tri-peptide based hydrogels using this electrochemical method, employing deposition times of two to five hours. To overcome the oxidation of hydroquinone in air, the fabrication process was performed under an inert nitrogen atmosphere. We show that this approach can be used to form multilayer gels, with the mechanical properties of each layer determined by gelator composition. We also describe examples where gel-to-crystal transitions and syneresis occur within the material.


HPLC-DAD-ESI-MS Analysis of Flavonoids from Leaves of Different Cultivars of Sweet Osmanthus.
Osmanthus fragrans Lour. has traditionally been a popular ornamental plant in China. In this study, ethanol extracts of the leaves of four cultivar groups of O. fragrans were analyzed by high-performance liquid chromatography coupled with diode array detection (HPLC-DAD) and high-performance liquid chromatography with electrospray ionization and mass spectrometry (HPLC-ESI-MS). The results suggest that variation in flavonoids among O. fragrans cultivars is quantitative, rather than qualitative. Fifteen components were detected and separated, among which, the structures of 11 flavonoids and two coumarins were identified or tentatively identified. According to principal component analysis (PCA) and hierarchical cluster analysis (HCA) based on the abundance of these components (expressed as rutin equivalents), 22 selected cultivars were classified into four clusters. The seven cultivars from Cluster III ('Xiaoye Sugui', 'Boye Jingui', 'Wuyi Dangui', 'Yingye Dangui', 'Danzhuang', 'Foding Zhu', and 'Tianxiang Taige'), which are enriched in rutin and total flavonoids, and 'Sijigui' from Cluster II which contained the highest amounts of kaempferol glycosides and apigenin 7-O-glucoside, could be selected as potential pharmaceutical resources. However, the chemotaxonomy in this paper does not correlate with the distribution of the existing cultivar groups, demonstrating that the distribution of flavonoids in O. fragrans leaves does not provide an effective means of classification for O. fragrans cultivars based on flower color.


[From "great Germans" and "proud peaks"--textbooks of German medical history and pathology (1858 to 1945)].
Textbooks on German medical history are a valuable source when analyzing the discipline's view on the foundation of scientific medicine. This paper deals with descriptions of the history of pathology found in textbooks between 1858 and 1945: In particular, pathological anatomy and Rudolf Virchow's "cellular pathology" were the cornerstones of the foundation of modern medicine in the 19th century. The way textbooks deal with the history of pathology mirrors the development of German history of medicine: Since the turn of the century the latter felt devoted to an ahistoric teleological approach which did not change in the "Third Reich". This situation hampered a critical histoography which would show relations of the history of pathology to cultural, social and political history.


Association between meeting daily step count goals with ambulatory function and quality of life in patients with claudication.
To determine (a) whether patients with peripheral artery disease (PAD) who walked at least 7000 and 10,000 steps/day had better ambulatory function and health-related quality of life (HRQoL) than patients who walked less than 7000 steps/day, and (b) whether differences in ambulatory function and HRQoL in patients grouped according to these daily step count criteria persisted after adjusting for covariates. Two hundred forty-eight patients were assessed on their daily ambulatory activity for 1 week with a step activity monitor, and were grouped according to daily step count targets. Patients who took fewer than 7000 steps/day were included in group 1 (n = 153), those who took 7000 to 9999 steps/day were included in group 2 (n = 57), and patients who took at least 10,000 steps/day were included in group 3 (n = 38). Primary outcomes were the 6-minute walk distance (6MWD) and Walking Impairment Questionnaire (WIQ) distance score, which is a disease-specific measurement of HRQoL. Patients were further characterized on demographic variables, comorbid conditions, and cardiovascular risk factors. The groups were significantly different on ankle-brachial index (P = .02), and on the prevalence of hypertension (P = .04), diabetes (P < .01), abdominal obesity (P < .01), arthritis (P = .04), and chronic obstructive pulmonary disease (P < .01). Thus, these variables served as covariates in adjusted analyses, along with age, weight, and sex. The 6MWD (mean ± standard deviation) was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 313 ± 90 m; group 2, 378 ± 84 m; and group 3, 414 ± 77 m), with groups 2 and 3 having a higher 6MWD than group 1 (P < .01). The WIQ distance score was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 30 ± 30%; group 2, 45 ± 35%; and group 3, 47 ± 34%), with groups 2 and 3 having higher WIQ distance scores than group 1 (P < .01). Patients with PAD who walked more than 7000 and 10,000 steps/day had greater ambulatory function and HRQoL than patients who walked fewer than 7000 steps/day. Second, the greater ambulatory function and HRQoL associated with walking 7000 and 10,000 steps/day persisted after adjusting for covariates. This study provides preliminary evidence that patients with PAD who walk more than 7000 steps/day have better ambulatory function and HRQoL than patients below this threshold.


Discovery of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent and selective heparanase-1 inhibitor utilizing an improved synthetic approach.
Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson's reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-β-d-glucuronidase (GUSβ) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson's reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSβ and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSβ and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.


Foreign bodies in the rectum: 2 Case reports.
Encountering a foreign object in the rectum is rare; however, the incidence has greatly increased in recent years. Treatment of these patients requires a multidisciplinary approach because this condition may have serious complications. Presently described is management of 2 cases of rectal foreign body treated in the clinic.


Two-phase stratified sampling and analysis for predicting binary outcomes.
The two-phase study design is a cost-efficient sampling strategy when certain data elements are expensive and, thus, can only be collected on a sub-sample of subjects. To date guidance on how best to allocate resources within the design has assumed that primary interest lies in estimating association parameters. When primary interest lies in the development and evaluation of a risk prediction tool, however, such guidance may, in fact, be detrimental. To resolve this, we propose a novel strategy for resource allocation based on oversampling cases and subjects who have more extreme risk estimates according to a preliminary model developed using fully observed predictors. Key to the proposed strategy is that it focuses on enhancing efficiency regarding estimation of measures of predictive accuracy, rather than on efficiency regarding association parameters which is the standard paradigm. Towards valid estimation and inference for accuracy measures using the resultant data, we extend an existing semiparametric maximum likelihood ethod for estimating odds ratio association parameters to accommodate the biased sampling scheme and data incompleteness. Motivated by our sampling design, we additionally propose a general post-stratification scheme for analyzing general two-phase data for estimating predictive accuracy measures. Through theoretical calculations and simulation studies, we show that the proposed sampling strategy and post-stratification scheme achieve the promised efficiency improvement. Finally, we apply the proposed methods to develop and evaluate a preliminary model for predicting the risk of hospital readmission after cardiac surgery using data from the Pennsylvania Health Care Cost Containment Council.


Insulin-stimulated adipocytes secrete lactate to promote endothelial fatty acid uptake and transport.
Insulin stimulates adipose tissue to extract fatty acids from circulation and sequester them inside adipose cells. How fatty acids are transported across the capillary endothelial barrier, and how this process is regulated, remains unclear. We modeled the relationship of adipocytes and endothelial cells in vitro to test the role of insulin in fatty acid transport. Treatment of endothelial cells with insulin did not affect endothelial fatty acid uptake, but endothelial cells took up more fatty acids when exposed to medium conditioned by adipocytes treated with insulin. Manipulations of this conditioned medium indicated that the secreted factor is a small, hydrophilic, non-proteinaceous metabolite. Factor activity was correlated with lactate concentration, and inhibition of lactate production in adipocytes abolished the activity. Finally, lactate alone was sufficient to increase endothelial uptake of both free fatty acids and lipids liberated from chylomicrons, and to promote transendothelial transport, at physiologically relevant concentrations. Taken together, these data suggest that insulin drives adipocytes to secrete lactate, which then acts in a paracrine fashion to promote fatty acid uptake and transport across the neighboring endothelial barrier.


[Extracorporeal circulation in no-cardiac surgery: experience at the Clinica Universidad de Navarra].
Analyse the use of the Extra-Corporeal Circulation (ECC) in no-cardiac operations at the Clinica Universidad de Navarra. Between 1985 and 2009, the ECC has been involved in 28 operations for retroperitoneal tumour with inferior vena cava thrombus, in 43 isolated hyperthermic perfusion of a limb for locally advanced cancer and in 8 cases of chest mass with invasion of the pulmonary veins or bronchial carina. The intraoperative mortality for renal cancer has been of 7% while the 28% of patients showed a major complication. None patient died for the isolated hyperthermic perfusion and the 81% showed no toxicity. 1 patient out of 8 for chest mass died during the surgery for impossibility of weaning from the ECC. The ECC has been utilised in our experience mostly in cases of advanced cancer. It is an aggressive technique with a certain rate of complications. Nevertheless mid- and long-term results are encouraging. The ECC is the only technique in some advanced cancer in order to safely perform the mass removal. The precise co-ordination of the team is necessary to reduce the complication rate.


International aid policy: public disease control and private curative care?
Integrating disease control with health care delivery increases the prospects for successful disease control. This paper examines whether current international aid policy tends to allocate disease control and curative care to different sectors, preventing such integration. Typically, disease control has been conceptualized in vertical programs. This changed with the Alma Ata vision of comprehensive care, but was soon encouraged again by the Selective Primary Health Care concept. Documents are analyzed from the most influential actors in the field, e.g. World Health Organization, World Bank, and European Union. These agencies do indeed have a doctrine on international aid policy: to allocate disease control to the public sector and curative health care to the private sector, wherever possible. We examine whether there is evidence to support such a doctrine. Arguments justifying integration are discussed, as well as those that critically analyze the consequences of non-integration. Answers are sought to the crucial question of why important stakeholders continue to insist on separating disease control from curative care. We finally make a recommendation for all international actors to address health care and disease control together, from a systems perspective.


AttPNet: Attention-Based Deep Neural Network for 3D Point Set Analysis.
Point set is a major type of 3D structure representation format characterized by its data availability and compactness. Most former deep learning-based point set models pay equal attention to different point set regions and channels, thus having limited ability in focusing on small regions and specific channels that are important for characterizing the object of interest. In this paper, we introduce a novel model named Attention-based Point Network (AttPNet). It uses attention mechanism for both global feature masking and channel weighting to focus on characteristic regions and channels. There are two branches in our model. The first branch calculates an attention mask for every point. The second branch uses convolution layers to abstract global features from point sets, where channel attention block is adapted to focus on important channels. Evaluations on the ModelNet40 benchmark dataset show that our model outperforms the existing best model in classification tasks by 0.7% without voting. In addition, experiments on augmented data demonstrate that our model is robust to rotational perturbations and missing points. We also design a Electron Cryo-Tomography (ECT) point cloud dataset and further demonstrate our model's ability in dealing with fine-grained structures on the ECT dataset.


BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline.
Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.


The pathology and immunology of atopic dermatitis.
Atopic dermatitis (AD) is a pruritic chronic inflammatory disease of the skin that is triggered by an underlying complicated interplay between the genetics of the individual and stimulation by allergens. Patients with AD demonstrate compromised barrier function that leads to activation of keratinocytes and immune cells which favor a strong Th2 bias. As a result of this immunological bias such patients also suffer from secondary pathogenic infections. A wide array of cytokines and chemokines interact to yield symptoms characteristic of AD. In addition, the involvement of different immunological cell types compounds our difficulty in understanding its immunopathogenesis. The use of various mouse models and transgenics has allowed us to intricately examine the functioning of the various molecules identified to play a role in AD. Such mouse models have also aided in the testing and development of various therapeutics for AD. This review is focused on examining the various factors contributing to the pathogenesis and exacerbation of AD as well as current treatments for AD. There is scope for improving the therapy of AD patients and thereby allowing them a better quality of life.