Interaction of chlordecone with biological membranes.
Chlordecone (Kepone) is a close structural analog of mirex, but it differs considerably from mirex in toxic action. Chlordecone primarily produces neurotoxic symptoms such as tremors in humans and animals. As with other organochlorine pesticides, the mechanism of the toxic action of chlordecone is not completely understood. An attempt is made in this paper to review the effects of chlordecone on the membrane-bound adenosinetriphosphatases (ATPases) and related phenomena. Chlordecone is shown to be a potent inhibitor of ATPases in different tissue preparations of several species. The order of sensitivity of the ATPases tested to chlordecone was: oligomycin-sensitive (mitochondrial) Mg2+-ATPase greater than Na+,K+-ATPase greater than Ca2+-ATPase greater than oligomycin-insensitive Mg2+-ATPase. Compared to other tissues tested, brain Na+K+-ATPase and heart mitochondrial Mg2+-ATPase were more sensitive to chlordecone. Oligomycin-insensitive Mg2+-ATPase was the least affected enzyme. Membrane-bound Na+, K+-ATPase has been associated with catecholamine uptake processes, and inhibitors of this enzyme, such as ouabain, have been found to decrease catecholamine uptake. Chlordecone decreased the uptake of catecholamines by rat heart membranes in a dose-dependent manner. Various cellular processes such as catecholamine uptake are dependent for energy on ATP, and most of this ATP is produced in the mitochondria through oxidative phosphorylation. Oligomycin-sensitive Mg2+-ATPase is involved in this coupling process. Chlordecone inhibition of this enzyme may result in depletion of mitochondrial ATP. This chain of events suggest that chlordecone interacts with membrane ATPases and thus may impair various energy-dependent cellular processes.


The making of contemporary American psychiatry, Part 2: therapeutics and gender before and after World War II.
In this article, the 2nd in a 2-part series, the authors use patient records from California's Stockton State Hospital to explore the changing role of gender norms and other cultural values in the care of psychiatric patients. The authors show that cultural values are always imbedded in psychiatric practice and that their role in that practice depends on the patients, treatments, and therapeutic rationales present in a given therapeutic encounter. Because the decade following World War II witnessed dramatic changes in psychiatry's patients, therapeutics, and rationales, Stockton State Hospital's patient records from this time period allow the authors to show not only the extent to which gender norms shape psychiatric practice but also how psychiatry's expansion into the problems of everyday life has led to psychiatry taking a more subtle and yet more active role in enforcing societal norms.


Mapping the central effects of (±)-ketamine and traxoprodil using pharmacological magnetic resonance imaging in awake rats.
Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [3H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).


[Epidemiological investigation of 605 patients with chemical burns in northeastern China].
To investigate the pathogenic and clinical characteristics of chemical burns in recent years, so as to provide reference for its prevention and treatment. Medical records of patients with chemical burns out of 6299 burn patients admitted to our unit from January 1992 to December 2011 were screened and retrospectively analyzed, including gender, age, onset time of the injury, pre-hospital management, injury cause, injury-causing chemicals, body site of wound, burn area and depth, complications, treatment and follow-up results. The data of age distribution and incidence of complications were processed with chi-square test. Investigation showed that 605 out of 6299 burn patients (accounting for 9.60%) were chemically injured. (1) Among the patients with chemical burns, the ratio of male to female was 5.11:1.00, with the mean age of 37.6 years, and the highest incidence occurred in patients aged from 20 to 29 years (29.42%, 178/605). The difference in the numbers of patients among different age groups was statistically significant (χ(2) = 207.298, P < 0.01). (2) Chemical burns mainly occurred in summer (28.43%, 172/605) and autumn (38.35%, 232/605). About 72.07% (436/605) of patients received irrigation before admission. (3) In 453 (74.88%) patients, injury occurred during industrial production. The main injury-causing chemicals were acid (46.61%, 282/605) and alkali (20.66%, 125/605), and among them the sulfuric acid accounted for the highest ratio (18.18%, 110/605). (4) The main wound positions of chemical burns were the limbs (289 patients) and the head, face, and neck region (263 patients). The mean burn area was 5.98% TBSA. The depth ranged from superficial partial-thickness to full-thickness. (5) Three hundred and forty-eight patients with chemical burns suffered common complications, including inhalation injury (154, 44.25%), ocular burns (113, 32.47%), and poisoning (81, 23.28%). There was statistically significant difference in the incidence of the three complications (χ(2) = 23.086, P < 0.01). (6) Five hundred and twenty-one patients were cured, with the cure rate of 86.12%, and 76.20% out of them healed with scars (397/521). Three patients died of poisoning, with a mortality of 0.50%. The patients with chemical burns accounted for a high proportion of the burn patients admitted to our unit in the same period. The chemical burns mainly involved young males with the relatively close time of onset, and acid and alkali were the main causative factors in the process of industrial production. Most patients had the clinical features of deep wound, high incidence of complications, and liability of scar formation after wound healing.


Local Glioma Cells Are Associated with Vascular Dysregulation.
Malignant glioma is a highly infiltrative malignancy that causes variable disruptions to the structure and function of the cerebrovasculature. While many of these structural disruptions have known correlative histopathologic alterations, the mechanisms underlying vascular dysfunction identified by resting-state blood oxygen level-dependent imaging are not yet known. The purpose of this study was to characterize the alterations that correlate with a blood oxygen level-dependent biomarker of vascular dysregulation. Thirty-two stereotactically localized biopsies were obtained from contrast-enhancing (n = 16) and nonenhancing (n = 16) regions during open surgical resection of malignant glioma in 17 patients. Preoperative resting-state blood oxygen level-dependent fMRI was used to evaluate the relationships between radiographic and histopathologic characteristics. Signal intensity for a blood oxygen level-dependent biomarker was compared with scores of tumor infiltration and microvascular proliferation as well as total cell and neuronal density. Biopsies corresponded to a range of blood oxygen level-dependent signals, ranging from relatively normal (z = -4.79) to markedly abnormal (z = 8.84). Total cell density was directly related to blood oxygen level-dependent signal abnormality (P = .013, R2 = 0.19), while the neuronal labeling index was inversely related to blood oxygen level-dependent signal abnormality (P = .016, R2 = 0.21). The blood oxygen level-dependent signal abnormality was also related to tumor infiltration (P = .014) and microvascular proliferation (P = .045). The relationship between local, neoplastic characteristics and a blood oxygen level-dependent biomarker of vascular function suggests that local effects of glioma cell infiltration contribute to vascular dysregulation.


Platelet Transfusion in Cardiac Surgery: A Systematic Review and Meta-Analysis.
Blood transfusion is a well-established independent risk factor for mortality in patients undergoing cardiac surgery but the impact of platelet transfusion is less clear. We performed a systematic review and meta-analysis of observational studies comparing outcomes of patients who received platelet transfusion after cardiac surgery. We searched MEDLINE and EMBASE databases to January 2019 for studies comparing perioperative outcomes in patients undergoing cardiac surgery with and without platelet transfusion. There were nine observational studies reporting 101,511 patients: 12% with and 88% without platelet transfusion. In unmatched/unadjusted studies, patients who received platelet transfusion were older, with greater incidence of renal, peripheral, and cerebrovascular disease, myocardial infarction, left ventricular dysfunction, and anemia. They were more likely to have nonelective, combined surgery; preoperative hemodynamic instability and endocarditis; and more likely to be receiving clopidogrel preoperatively. Perioperative complications were significantly increased without adjusting for these baseline differences. After pooling only matched/adjusted data, differences were not found between patients who did receive platelets and patients who did not in operative mortality (risk ratio [RR] 1.26; 95% confidence interval [CI], 0.69 to 2.32, P = .46, five studies), stroke (RR 0.94; 95% CI, 0.62 to 1.45; P = .79; five studies), myocardial infarction (RR 1.29; 95% CI, 0.95 to 1.77; P = .11; three studies), reoperation for bleeding (RR 1.20; 95% CI, 0.46 to 3.18; P = .71; three studies), infection (RR 1.02; 95% CI, 0.86 to 1.20; P = .85; six studies); and perioperative dialysis (RR 0.91; 95% CI, 0.63 to 1.32; P = .62; three studies). After accounting for baseline differences, platelet transfusion was not linked with perioperative complications in cardiac surgery patients. Given the small number of observational studies, these findings should be considered hypothesis generating.


A comparative study of obsessive-compulsive disorder in Costa Rica and the United States.
This study compares the presentation and expression of obsessive-compulsive symptoms between a Latin-American and North American sample. In Costa Rica (CR) and the United States (US), respectively, 26 and 52 affected individuals with early-onset obsessive-compulsive disorder (OCD) were recruited. The Yale Brown Obsessive Compulsive Scale (YBOCS), a semi-structured psychiatric interview, and self-report questionnaires were administered. Age of onset and the distribution of OCD across men and women were similar across groups. Both CR and US participants reported obsessions and compulsions, with similar frequencies of symptoms, and contamination, symmetry, and hoarding as the most common symptom subtypes. The US sample had higher YBOCS total severity scores than the Costa Rican group. Similarly, there were significant ethnicity effects for YBOCS compulsion [F(1, 70)=17.88, P<.001] and obsession severity [F(1, 70)=8.78, P<.001], with Caucasians having higher scores than Costa Ricans on both subscales. Comorbidity rates were higher for US Caucasians than Costa Ricans for all disorders; differences were significant for mood disorders [64.7% versus 34.6%], alcohol use [21.3% versus 3.8%], cannabis use disorders [19.1% versus 0%], and other substance use disorders [39.4% versus 0%]. Regression analyses revealed that ethnicity, trait anxiety, and proband status were the only significant predictors of total YBOCS severity. Findings suggest that the core phenotype of OCD is the same in both CR and the US, and perhaps biologically driven. However some features of OCD, such as impairment, may be culturally influenced, leading to differences in prevalence rates and treatment utilization.


ERP correlates of conscious error recognition: aware and unaware errors in an antisaccade task.
Event-related potential (ERP) studies identified the error-related negativity (Ne/ERN) and the error positivity (Pe) to be associated with performance errors. However, the functional significance of these components is not yet resolved. With the present study we intended to further investigate to what extent these components are related to error awareness. ERPs were recorded during an antisaccade task, and error awareness was obtained from accuracy ratings on each trial. In accordance with earlier findings, aware and unaware errors did not differ in Ne/ERN amplitude. Whereas the late Pe (400-600 ms) shows an increased parietal positivity for aware compared with unaware errors, the early Pe (200-300 ms) shows no dissociation between aware and unaware errors. These data lend further support to the view that the Ne/ERN and the (late) Pe reflect different processes in performance monitoring. In fact the present results provide a clear replication of [S. Nieuwenhuis et al. (2001) Psychophysiology, 38, 752-760], showing that the Pe is associated with error awareness and remedial action. Furthermore, it has been shown that this is only true for the late Pe, whereas the early Pe like the Ne/ERN is not modulated by error awareness.


[Formation of self concept in the transition from adolescence to adulthood. An empirical comparative study of psychiatric patients and healthy control probands].
The psychosocial development of psychiatrically ill and mentally healthy young adults is being explored in a series of comparative studies based on developmental tasks typical of this age. In a first study a patient group was compared with a control group with the Offer Self-Image Questionnaire as an indicator of patterns of psychosocial adaptation thus far. The patients showed significantly poorer adaptation on 10 dimensions of psychosocial life. In relation to a representative sample of young adults they especially reported disturbances in their own personality development and in family relations, but judged their adaptation to norms for behavior in public as less impaired. The nonpsychotic patients had a significantly less favorable pattern of self-concepts than the psychotic patients. The patients with affective disorders had a relatively healthy profile of psychosocial development compared with the schizophrenic patients. There was no significant difference between patients with schizophrenia of the disorganized type and other schizophrenic patients. There was a close relationship between subjective measures of self-concept and objective measures of psychosocial development, e.g. premorbid adaptation and current psychosocial development, e.g. premorbid adaptation and current psychosocial competence, in the different subgroups. The findings on self-concept seemed to be largely independent of the present severity of psychopathology.


Epichloë hybrida, sp. nov., an emerging model system for investigating fungal allopolyploidy.
Endophytes of the genus Epichloë (Clavicipitaceae, Ascomycota) frequently occur within cool-season grasses and form interactions with their hosts that range from mutualistic to antagonistic. Many Epichloë species have arisen via interspecific hybridization, resulting in species with two or three subgenomes that retain all or nearly all of their original parental genomes, a process termed allopolyploidization. Here, we characterize Epichloë hybrida, sp. nov., a mutualistic species that has increasingly become a model system for investigating allopolyploidy in fungi. The Epichloë species so far identified as the closest known relatives of the two progenitors of E. hybrida are E. festucae var. lolii and E. typhina. We confirm that the nuclear genome of E. hybrida contains two homeologs of most protein-coding genes from E. festucae and E. typhina, with genome-wide gene expression analysis indicating a slight bias in overall gene expression from the E. typhina subgenome. Mitochondrial DNA is detectable only from E. festucae, whereas ribosomal DNA is detectable only from E. typhina. Inheriting ribosomal DNA from just one parent might be expected to preferentially favor interactions with ribosomal proteins from the same parent, but we find that ribosomal protein genes from both parental subgenomes are nearly all expressed equally in E. hybrida. Finally, we provide a comprehensive set of resources for this model system that are intended to facilitate further study of fungal hybridization by other researchers.


Body Mass Index as a Measure of Obesity: Racial Differences in Predictive Value for Health Parameters During Pregnancy.
As a measure of obesity, body mass index (BMI; kg/m2) is an imperfect predictor of health outcomes, particularly among African Americans. However, BMI is used to guide prenatal care. We examined racial differences in the predictive value of maternal BMI for physiologic correlates of obesity, serum interleukin (IL)-6 and C-reactive protein (CRP), as well as cesarean section and infant birth weight. One hundred five pregnant women (40 European American, 65 African American) were assessed during the second trimester. BMI was defined as per prepregnancy weight. Electrochemiluminescence and enzyme-linked immunosorbent assays were used to quantify IL-6 and CRP, respectively. Birth outcomes were determined by medical record review. Women of both races classified as obese had higher serum IL-6 and CRP than their normal-weight counterparts (ps ≤ 0.01). However, among women with overweight, elevations in IL-6 (p < 0.01) and CRP (p = 0.06) were observed among European Americans, but not African Americans (ps ≥ 0.61). Maternal obesity was a significantly better predictor of cesarean section among European Americans versus African Americans (p = 0.03) and BMI was associated with infant birth weight among European Americans (p < 0.01), but not African Americans (p = 0.94). Effects remained after controlling for gestational age at delivery, gestational diabetes, and gestational weight gain as appropriate. BMI may be a less valid predictor of correlates of overweight/obesity among African Americans versus European Americans during pregnancy. This should be considered in epidemiological studies of maternal-child health. In addition, studies examining the comparative validity of alternative/complementary measures to define obesity in pregnancy are warranted to inform clinical care.


Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children.
Recombinant AAV serotype vectors and their variants have been or are currently being used for gene therapy for hemophilia in several phase I/II/III clinical trials in humans. However, none of these trials have included children with hemophilia since the traditional liver-directed AAV gene therapy will not work in these patients because of the following reasons: (i) Up until age 10-12, the liver is still growing and dividing, and with every cell division, the AAV vector genomes will be diluted out due to their episomal nature; and (ii) Repeated gene delivery will be needed, but repeat dosing, even with an ideal AAV vector is not an option because of pre-existing antibodies to AAV vectors following the first administration. Here we describe the development of an optimized human Factor IX (hF.IX) gene expression cassette under the control of a human liver-specific transthyretin promoter covalently flanked by AAV inverted terminal repeats (ITRs) with no open ends (optNE-TTR-hF.IX), which mediated ~sixfold higher hF.IX levels than that from a linear TTR-hF.IX DNA construct in human hepatoma cells up to four-weeks post-transfection. In future studies, encapsidation of the optNE-TTR-hF.IX DNA in liver-targeted synthetic liposomes, may provide a viable approach for the potential gene therapy for hemophilia in children.


NADH- and oxygen-dependent multiple turnovers of cytochrome P-450-CAM without putidaredoxin and putidaredoxin reductase.
Phenazine methosulfate (PMS) has been successfully used to mediate electron transfer from NADH to cytochrome P-450-CAM in the absence of putidaredoxin and putidaredoxin reductase under aerobic conditions. Identification and quantitation of exo-5- hydroxycamphor , the only product, has been accomplished by gas chromatography. In the absence of cytochrome P-450-CAM, or when other heme proteins (hemoglobin, myoglobin, horseradish peroxidase) are substituted for P-450-CAM, no exo-5- hydroxycamphor is detected. Product formation is not inhibited by the addition of catalase, superoxide dismutase, or hydroxyl radical scavengers; however, significant inhibition is observed with carbon monoxide and metyrapone, known inhibitors of the fully reconstituted P-450 system. Addition of 2,3-dimercaptopropanol to the NADH/PMS/P-450 system leads to a 4-fold increase in product formation; when putidaredoxin is added (without dimercaptopropanol), a 20-fold increase in product formation is observed. Constant bubbling with oxygen results in a further increase in the amount of product (150-fold increase overall). Our results show that PMS can substitute for the electron-transfer proteins putidaredoxin and putidaredoxin reductase in the transfer of electrons from NADH to P-450-CAM, resulting in multiple turnovers. Molecular oxygen dependent multiple turnovers of cytochrome P-450 have not been previously observed without the fully reconstituted, three-protein system.


Treatment of femoral shaft fractures in children using the "Tobruk" method.
The "Tobruk" technique of plaster augmentation of a Thomas' splint can be used for the treatment of femoral shaft fractures in children. The radiological and clinical data of 118 patients treated using this method were reviewed over a consecutive 3-year period. The mean age of the patients was 4.25 years. Mean hospital stay was 14.11 days. Mean time spent in the "Tobruk" splint was 44.77 days. Loss of reduction during splintage occurred in 9.32% of patients. Skin complications occurred in 5 patients (4.2%), and cast repairs were necessary in 3 patients. "Tobruk" splinting is a relatively safe and effective way of treating femoral shaft fractures in children. Although its use is not widespread, especially in the United States, until better results are achieved with spica casting and elastic stable intramedullary nails, it does provide a valid option in the treatment of these fractures. A controlled randomized prospective trial with long-term follow-up is needed to fully elucidate its value.


Peripheral osteoma of the maxillary alveolar process.
Osteoma is a benign, slow-growing tumor characterized by proliferation of compact or cancellous bone. Solitary osteomas are classified as peripheral, central, or extraskeletal. Peripheral osteomas of the oral cavity are unusual and the maxilla is rarely affected. They manifest as asymptomatic, fixed tumors of bony-hard consistency that may be sessile or pedunculated. Radiographically, a well-circumscribed round or oval radiopaque mass is seen that is microscopically composed of cancellous or trabecular bone. A case of a compact, peripheral osteoma arising from the buccal plate of the alveolar ridge of the maxilla in a 64-year-old patient is presented. According to our literature review, this is the seventh case reported in the maxillary ridge.


Building and breaking mechanical bridges between the nucleus and cytoskeleton: Regulation of LINC complex assembly and disassembly.
The nucleus is physically coupled to the cytoskeleton through LINC complexes, macromolecular bridges composed of SUN and KASH proteins that span the nuclear envelope. LINC complexes are involved in a wide variety of critical cellular processes. For these processes to occur, cells regulate the composition, assembly, and disassembly of LINC complexes. Here we discuss recent studies on the regulation of the SUN-KASH interaction that forms the core of the LINC complex. These new findings encompass the stages of LINC complex assembly, from the formation of SUN-KASH heterooligomers to higher-order assemblies of LINC complexes. There is also new work on how components of the LINC complex are selectively dismantled, particularly by proteasomal degradation. It is becoming increasingly clear that LINC complexes are subject to multiple layers of regulation.


Nurses as first responders in a mass casualty: are you prepared?
A mass casualty event is a situation in which the need for medical care and resources, including personnel, exceeds that which is available. As the largest component of the health care workforce, nurses represent a significant resource that can be called on to act as first responders during a mass casualty. However, current education and national guidelines fail to provide specific instruction on pre-hospital nursing considerations and interventions. This article provides evidence-based guidelines designed for nurses to use when acting as first responders during a disaster and presents recommendations for future nursing practice related to mass casualty events.


Analysis of Engineered Tobacco Mosaic Virus and Potato Virus X Nanoparticles as Carriers for Biocatalysts.
Plant virus nanoparticles are promising candidates for the development of novel materials, including nanocomposites and scaffolds/carriers for functional molecules such as enzymes. Their advantages for enzyme immobilization include a modular organization, a robust and programmable structure, and a simple, cost-effective production. However, the activity of many enzymes relies on posttranslational modification and most plant viruses replicate in the cytoplasm, so functional enzymes cannot be displayed on the virus surface by direct coat protein fusions. An alternative display system to present the Trichoderma reesei endoglucanase Cel12A on potato virus X (PVX) using SpyTag/SpyCatcher (ST/SC) technology was recently developed by the authors, which allows the carrier and enzyme to be produced separately before isopeptide conjugation. Although kinetic analysis clearly indicated efficient biocatalyst activity, the PVX carrier interfered with substrate binding. To overcome this, the suitability of tobacco mosaic virus (TMV) was tested, which can also accommodate a larger number of ST peptides. We produced TMV particles displaying ST as a new platform for the immobilization of enzymes such as Cel12A, and compared its performance to the established PVX-ST platform in terms of catalytic efficiency. Although more enzyme molecules were immobilized on the TMV-ST particles, we found that the rigid scaffold and helical spacing significantly affected enzyme activity.


Homologous Recombination Repair Polymorphisms and the Risk for Osteosarcoma.
DNA repair mechanisms are essential for maintaining genome stability, and genetic variability in DNA repair genes may contribute to cancer susceptibility. Our aim was to evaluate the influence of polymorphisms in the homologous recombination repair genes XRCC3, RAD51, and NBN on the risk for osteosarcoma. In total, 79 osteosarcoma cases and 373 controls were genotyped for eight single nucleotide polymorphisms (SNPs) in XRCC3, RAD51, and NBN. Logistic regression was used to determine the association of these SNPs with risk for osteosarcoma. None of the investigated SNPs was associated with risk for osteosarcoma in the whole cohort of patients, however, in patients diagnosed before the age of thirty years XRCC3 rs861539 C>T and NBN rs1805794 G>C were associated with significantly decreased risk for osteosarcoma (P=0.047, OR=0.54, 95% CI=0.30-0.99 and P=0.036, OR=0.42, 95% CI=0.19-0.94, respectively). Moreover, in the carriers of a combination of polymorphic alleles in both SNPs risk for osteosarcoma was decreased even more significantly (Ptrend=0.007). The risk for developing osteosarcoma was the lowest in patients with no wild-type alleles for both SNPs (P=0.039, OR=0.31, 95% CI=0.10-0.94). Our results suggest that polymorphisms in homologous recombination repair genes might contribute to risk for osteosarcoma in patients diagnosed below the age of thirty years.


Disturbances of automatic gait control mechanisms in higher level gait disorder.
The underlying mechanisms responsible for the gait changes in frontal gait disorder (FGD), a form of higher level gait disorders, are poorly understood. We investigated the relationship between stride length and cadence (SLCrel) in people with FGD (n=15) in comparison to healthy older adults (n=21) to improve our understanding of the changes to gait in FGD. Gait data was captured using an electronic walkway system as participants walked at five self-selected speed conditions: preferred, very slow, slow, fast and very fast. Linear regression was used to determine the strength of the relationship (R(2)), slope and intercept. In the FGD group 9 participants had a strong SLCrel (linear group) (R(2)>0.8) and 6 a weak relationship (R(2)<0.8) (nonlinear group). The linear FGD group did not differ to healthy control for slope (p>0.05) but did have a lower intercept (p<0.001). The linear FGD group modulated gait speed by adjusting stride length and cadence similar to controls whereas the nonlinear FGD participants adjusted stride length but not cadence similar to controls. The non-linear FGD group had greater disturbance to their gait, poorer postural control and greater fear of falling compared to the linear FGD group. Investigation of the SLCrel resulted in new insights into the underlying mechanisms responsible for the gait changes found in FGD. The findings suggest stride length regulation was disrupted in milder FGD but as the disorder worsened, cadence control also became disordered resulting in a break down in the relationship between stride length and cadence.


Accounting for quiescent cells in tumour growth and cancer treatment.
A four-state cell-cycle model with explicit G1-phase representation, termed the quiescent-cell model (QCM), has been proposed to represent biologically the G1-phase specific effect of the chemotherapeutic tamoxifen. The QCM was used to model untreated and tamoxifen-treated tumour xenograft data from the literature with equivalent accuracy to previously developed tumour growth models. Open-loop analysis demonstrated that perturbations to the two newly introduced parameters, kG01 and kG10, significantly altered untreated tumour growth predictions. However, the sensitivity did not carry over to closed-loop simulations, where alterations to kD and kGS proved most significant in determining overall controller performance. Additional mismatch studies comparing controllers designed using the QCM to controllers designed with the Gompertz model and saturating-rate, cell-cycle model returned similar performance for a step-wise tumour reduction case study, but the quiescent-cell controller delivered a more aggressive treatment regimen. More importantly, the Gompertz and saturating-rate, cell-cycle controllers were unable to follow a reference trajectory when measurement updates were made biweekly, with both controllers returning tamoxifen dose schedules alternating between the maximum and minimum allowable dose.


Differential protein expression profile in the hypothalamic GT1-7 cell line after exposure to anabolic androgenic steroids.
The abuse of anabolic androgenic steroids (AAS) has been considered a major public health problem during decades. Supraphysiological doses of AAS may lead to a variety of neuroendocrine problems. Precisely, the hypothalamic-pituitary-gonadal (HPG) axis is one of the body systems that is mainly influenced by steroidal hormones. Fluctuations of the hormonal milieu result in alterations of reproductive function, which are made through changes in hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH). In fact, previous studies have shown that AAS modulate the activity of these neurons through steroid-sensitive afferents. To increase knowledge about the cellular mechanisms induced by AAS in GnRH neurons, we performed proteomic analyses of the murine hypothalamic GT1-7 cell line after exposure to 17α-methyltestosterone (17α-meT; 1 μM). These cells represent a good model for studying regulatory processes because they exhibit the typical characteristics of GnRH neurons, and respond to compounds that modulate GnRH in vivo. Two-dimensional difference in gel electrophoresis (2D-DIGE) and mass spectrometry analyses identified a total of 17 different proteins that were significantly affected by supraphysiological levels of AAS. Furthermore, pathway analyses showed that modulated proteins were mainly associated to glucose metabolism, drug detoxification, stress response and cell cycle. Validation of many of these proteins, such as GSTM1, ERH, GAPDH, PEBP1 and PDIA6, were confirmed by western blotting. We further demonstrated that AAS exposure decreased expression of estrogen receptors and GnRH, while two important signaling pathway proteins p-ERK, and p-p38, were modulated. Our results suggest that steroids have the capacity to directly affect the neuroendocrine system by modulating key cellular processes for the control of reproductive function.


Design of Microporous Material HUS-10 with Tunable Hydrophilicity, Molecular Sieving, and CO2 Adsorption Ability Derived from Interlayer Silylation of Layered Silicate HUS-2.
The attractive properties of zeolites, which make them suitable for numerous applications for the energy and chemical industries and for life sciences, are derived from their crystalline framework structures. Herein, we describe the rational synthesis of a microporous material, HUS-10, utilizing a layered silicate precursor, HUS-2, as a structural building unit. For the ordered micropores to be formed, interlayer pillars that supported the original silicate layer of HUS-2 were immobilized through the interlayer silylation of silanol groups with trichloromethylsilane and a subsequent dehydration-condensation reaction of the hydroxyl groups on the preintroduced tetrahedral units. An actual molecular sieving ability, enabling the adsorption of molecules smaller than ethane, was confirmed in the ordered micropores of HUS-10. The hydrophilic adsorption could also be controlled by changing the number of methyl and hydroxyl groups in the immobilized interlayer pillars. In addition, when the adsorption behaviors of CO2, CH4, and N2 on HUS-10 were compared to those on siliceous MFI and CDO zeolites with approximately the same pore diameter, the CO2 adsorption capacity of HUS-10 was comparable. Conversely, because of the adsorption inhibition of CH4 and N2, HUS-10 exhibited larger CO2/CH4 and CO2/N2 adsorption ratios relative to those of MFI and CDO zeolites. These results reveal that the unique microporous framework structure presented by the rational structural design using the layered silicate precursor HUS-2 has the potential to separate CO2 from gas mixtures.


Decreases in retinal nerve fiber layer thickness correlates with cumulative alcohol intake.
Alcohol and illicit drugs affect neurons through various mechanisms and are detected by neuroimaging techniques. The optical coherence tomography device has just been used in research on substance use disorders. In this study, we compared the retinal nerve fiber layer (RNFL), the ganglion cell layer (GCL), the inner plexiform layer (IPL), and choroid layer of alcohol use disorder (AUD) and healthy subjects. We included 38 male patients and 38 male healthy controls of similar age (p = .714) in the study, prospectively. Monthly income (p = .001) and stable employment (p = .001) were lower in the patient group. There was a significant difference between patient and control groups in terms of RNFL sectors, choroid, GCL, IPL values of both eyes were significantly different (p < .05). When the effect of age and liver damage was controlled in the patient group, a correlation was found between alcohol unit/year and nasal superior (r = -0.474, p = .004), temporal (r = -0.402, p = .015) sectors of the RNFL. The regression analysis indicated that the sensitivity and specificity of mean N (p = .060), mean choroidal thickness (p < .001), mean GCL (p = .013), and mean IPL (p = .017) related to the diagnosis of AUD were 78.9% and 81.6% (-2 Log likelihood = 57.57, Nagelkerke R2=0.622), respectively. Alcohol has neurotoxic effects, either directly or indirectly, with withdrawal. Our study results suggest that RNFL, the non-myelinated white matter tissue, can be a follow-up marker of neuronal damage due to cumulative alcohol intake.


Host immunity modulates transcriptional changes in a multigene family (yir) of rodent malaria.
Variant antigens, encoded by multigene families, and expressed at the surface of erythrocytes infected with the human malaria parasite Plasmodium falciparum and the simian parasite Plasmodium knowlesi, are important in evasion of host immunity. The vir multigene family, encoding a very large number of variant antigens, has been identified in the human parasite Plasmodium vivax and homologues (yir) of this family exist in the rodent parasite Plasmodium yoelii. These genes are part of a superfamily (pir) which are found in Plasmodium species infecting rodents, monkeys and humans (P. yoelii, P. berghei, P. chabaudi, P. knowlesi and P. vivax). Here, we show that YIR proteins are expressed on the surface of erythrocytes infected with late-stage asexual parasites, and that host immunity modulates transcription of yir genes. The surface location and expression pattern of YIR is consistent with a role in antigenic variation. This provides a unique opportunity to study the regulation and expression of the pir superfamily, and its role in both protective immunity and antigenic variation, in an easily accessible animal model system.


MSK1 functions as a transcriptional coactivator of p53 in the regulation of p21 gene expression.
Mitogen- and stress-activated kinase 1 (MSK1) is a chromatin kinase that facilitates activator-dependent transcription by altering chromatin structure through histone H3 phosphorylation. The kinase activity of MSK1 is activated by intramolecular autophosphorylation, which is initially triggered by the activation of upstream mitogen-activated protein kinases (MAPKs), such as p38 and ERK1/2. MSK1 has been implicated in the expression of p21, a p53 target gene; however, the precise connection between MSK1 and p53 has not been clearly elucidated. Here, using in vitro and cell-based transcription assays, we show that MSK1 functions as a transcriptional coactivator of p53 in p21 expression, an action associated with MAPK-dependent phosphorylation of MSK1 and elevated kinase activity. Of special significance, we show that MSK1 directly interacts with p53 and is recruited to the p21 promoter, where it phosphorylates histone H3 in a p53-dependent manner. In addition, phosphomimetic mutant analysis demonstrated that negative charges in the hydrophobic motif are critical for serine 212 phosphorylation in the N-terminal kinase domain, which renders MSK1 competent for histone kinase activity. These studies suggest that MSK1 acts through a direct interaction with p53 to function as a transcriptional coactivator and that MSK1 activation by upstream MAPK signaling is important for efficient p21 gene expression.


Multicopy plasmid with a structure related to the polyoma virus genome.
In a subclone derived from mouse L(tk-) cells, we found a plasmid present in a high copy number (greater than 5000 copies per cell) that was stably maintained extrachromosomally without any cytopathic effect to the host cells. This plasmid, termed L factor, has two forms: 5.3 and 5.5 kilobase pairs. DNA sequencing and restriction enzyme mapping showed that, although the structure contains DNA sequences common to polyoma virus, plasmid sequences belonging to the regulatory region (the enhancer region) and other regions are quite different from those in polyoma. In cells bearing the plasmid, we detected a low level of material that cross-reacts with antibody to polyoma tumor antigens, suggesting that the plasmids replicate and are maintained in the cells by a mechanism different from that functioning during propagation following infection of papovaviruses.


Therapeutic aspects of mucociliary clearance.
Measurements of mucociliary activity are still very approximate. It is therefore difficult to determine the particular effect of certain drugs on patients and on experimental animals. Adrenergic drugs increase ciliary efficiency; local anesthetics, barbiturates and narcotics strongly depress ciliary action. Further research is required on mucociliary clearance mechanisms.


Climate change mitigation potential of Louisiana's coastal area: Current estimates and future projections.
Coastal habitats can play an important role in climate change mitigation. As Louisiana implements its climate action plan and the restoration and risk-reduction projects outlined in its 2017 Louisiana Coastal Master Plan, it is critical to consider potential greenhouse gas (GHG) fluxes in coastal habitats. This study estimated the potential climate mitigation role of existing, converted, and restored coastal habitats for years 2005, 2020, 2025, 2030, and 2050, which align with the Governor of Louisiana's GHG reduction targets. An analytical framework was developed that considered (1) available scientific data on net ecosystem carbon balance fluxes per habitat and (2) habitat areas projected from modeling efforts used for the 2017 Louisiana Coastal Master Plan to estimate the net GHG flux of coastal area. The coastal area was estimated as net GHG sinks of -38.4 ± 10.6 and -43.2 ± 12.0 Tg CO2 equivalents (CO2 e) in 2005 and 2020, respectively. The coastal area was projected to remain a net GHG sink in 2025 and 2030, both with and without the implementation of Coastal Master Plan projects (means ranged from -25.3 to -34.2 Tg CO2 e). By 2050, with model-projected wetland loss and conversion of coastal habitats to open water due to coastal erosion and relative sea level rise, Louisiana's coastal area was projected to become a net source of GHG emissions both with and without the Coastal Master Plan projects. However, in the year 2050, the Louisiana Coastal Master Plan project implementation was projected to avoid the release of +8.8 ± 1.3 Tg CO2 e compared with an alternative with no action. Reduction in current and future stressors to coastal habitats, including impacts from sea level rise, as well as the implementation of restoration projects could help to ensure coastal areas remain a natural climate solution.


The Role of Chromoendoscopy in Evaluating Colorectal Dysplasia.
Chromoendoscopy pertains to image-enhanced endoscopic techniques such as dye-based chromoendoscopy and electronic chromoendoscopy using narrow-band imaging, flexible spectral imaging color enhancement, and i-scan. Dye-based chromoendoscopy has been demonstrated to improve colorectal dysplasia detection in high-risk patients with long-term inflammatory bowel disease, and electronic chromoendoscopy techniques have been shown to improve characterization of diminutive colorectal lesions, allowing for optical diagnosis during a colonoscopy examination. This article reviews endoscopic imaging using chromoendoscopy techniques for colorectal dysplasia evaluation.


Spatial bridges for the importation of gonorrhea and chlamydial infection.
A study of heterosexuals with gonorrhea and/or chlamydial infection in King County, Washington, found that 5.2% of study participants had both local and geographically distant sex partners in the 60 days before diagnosis. Individuals who served as spatial bridges were of higher socioeconomic status and older than other patients. Sexual mixing between distant geographic areas (spatial bridging) is important in the spread of antimicrobial resistance and new sexually transmitted disease pathogens. The goal was to define the extent of sexual mixing between persons with gonorrhea or chlamydial infection in King County, Washington, and persons outside the Seattle area, and to identify characteristics of persons and partnerships associated with spatial bridging. Patients contacted for purposes of partner notification were interviewed regarding demographics, sexual behavior, and the characteristics of their sex partners. Of 2912 participants, 150 (5.2%) were spatial bridgers. Bridgers were of higher socioeconomic status than nonbridgers and more often reported concurrent partnerships. Over a 39-month period, bridgers and potential bridgers linked King County with 35 states and 13 foreign countries. Spatial bridging could represent an important channel of transmission between geographic areas. These results highlight the need for linkage of prevention efforts across geographic boundaries.


Firework-related ocular trauma in Pernambuco, Brazil.
This study aimed to describe the demographic and clinical characteristics of victims of fireworkrelated ocular trauma treated at the ophthalmologic emergency de partments of two reference centers in Pernambuco, Brazil, and to identify risk factors related to poor visual prognosis. We retrospectively evaluated the medical records of patients admitted in emergency departments with a report of firework-related trauma between January 2012 and December 2018. Data collected included patient's age, sex, place of origin, month and year of the accident, ocular structures affected, characteristics of the injuries, and type of treatment that patients received. For patients who were followed for >30 days, the final visual acuity and patient's origin were analyzed. Three hundred and seventy eyes from 314 patients were included, of which 248 (79.0%) were male and 160 (51.0%) were from the metropolitan region of Recife. The mean patient age was 25.6 ± 18.8 years. In 56 (17.8%) patients, the ocular trauma was bilateral. A total of 152 (48.4%) cases occurred in June. The most affected sites were the eyelids in 91 (24.6%) eyes and ocular surface in 252 (68.1%). Surgical treatment was required in 87 (23.5%) eyes. After clinical and surgical management, 37 (10.0%) eyes presented final visual acuity of <20/400. Of these, 34 (91.9%) eyes were from patients from the countryside or from another state. Patients from the countryside presented higher risk of developing blindness after a firework trauma than those from the metropolitan area (odds ratio of 5.46). Victims of firework-related ocular trauma were mostly male, from the metropolitan region of Pernambuco state and mainly pediatric patients or economically active. Those coming from the countryside and other states had higher risk of developing blindness.


The binding of anti-pseudomonal antibiotics to macromolecules from cystic fibrosis sputum.
Antibiotics are known to bind to whole cystic fibrosis sputum. However, the composition of sputum varies from one patient to another, making the interpretation of binding studies difficult. This problem has been examined by standardising the macromolecule concentration of sputum from four cystic fibrosis patients and adding tobramycin or ceftazidime directly to the sputum components. Binding to mucin-rich and DNA-rich fractions of sputum was also studied before and after DNase treatment of these fractions. These studies indicated that (i) the degree of tobramycin binding is dependent on the sputum macromolecule concentration, (ii) a significant proportion of tobramycin is bound even at concentrations of 100 mg/l of drug, (iii) tobramycin binds to both the mucin rich fraction and the DNA rich fraction of sputum and (iv) ceftazidime binding to sputum is negligible. Our data indicate that there is a need to standardise sputum in antibiotic binding studies and they provide another rationale for favouring the use of ceftazidime over aminoglycosides in infectious exacerbations of cystic fibrosis caused by Pseudomonas aeruginosa.


A unique DNA binding domain converts T-cell factors into strong Wnt effectors.
Wnt regulation of gene expression requires binding of LEF/T-cell factor (LEF/TCF) transcription factors to Wnt response elements (WREs) and recruitment of the activator beta-catenin. There are significant differences in the abilities of LEF/TCF family members to regulate Wnt target genes. For example, alternatively spliced isoforms of TCF-1 and TCF-4 with a C-terminal "E" tail are uniquely potent in their activation of LEF1 and CDX1. Here we report that the mechanism responsible for this unique activity is an auxiliary 30-amino-acid DNA interaction motif referred to here as the "cysteine clamp" (or C-clamp). The C-clamp contains invariant cysteine, aromatic, and basic residues, and surface plasmon resonance (SPR) studies with recombinant C-clamp protein showed that it binds double-stranded DNA but not single-stranded DNA or RNA (equilibrium dissociation constant = 16 nM). CASTing (Cyclic Amplification and Selection of Targets) experiments were used to test whether this motif influences WRE recognition. Full-length LEF-1, TCF-1E, and TCF-1E with a mutated C-clamp all bind nearly identical WREs (TYYCTTTGATSTT), showing that the C-clamp does not alter WRE specificity. However, a GC element downstream of the WRE (RCCG) is enriched in wild-type TCF-1E binding sites but not in mutant TCF-1E binding sites. We conclude that the C-clamp is a sequence-specific DNA binding motif. C-clamp mutations destroy the ability of beta-catenin to regulate the LEF1 promoter, and they severely impair the ability of TCF-1 to regulate growth in colon cancer cells. Thus, E-tail isoforms of TCFs utilize two DNA binding activities to access a subset of Wnt targets important for cell growth.


Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase.
Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken a particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Herein, we report the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. Top compounds, exemplified by 35 and 36, display nM potency against 12-LOX, excellent selectivity over related lipoxygenases and cyclooxygenases, and possess favorable ADME properties. In addition, both compounds inhibit PAR-4 induced aggregation and calcium mobilization in human platelets and reduce 12-HETE in β-cells.


Genetics. Motivating hotspots.
Only recently have we begun to characterize fine-scale recombination rates in mammals. In her Perspective, Przeworski discusses the work by Myers et al. in which linkage disequilibrium data have been used to produce a high-resolution recombination map for most of the human genome. More than 25,000 putative hotspots have been identified, as well as the first motifs that appear to influence their intensity.


Molecular approaches to the treatment of Fanconi anemia: recent advances.
Fanconi anemia (FA) is an autosomal recessive disorder that leads to aplastic anemia. Cells from FA patients are abnormally sensitive to DNA cross-linking agents such as mitomycin C. FA consists of at least five subgroups (FA-A through-E). The genes defective in the FA-C and FA-A groups have recently been cloned. Transfection of the normal FA gene into mutant cells corrects the hypersensitivity to DNA cross-linking agents and improves cell viability in vitro. The function of the FA gene products is still unclear, however. For patients lacking a compatible bone marrow transplantation donor, an experimental trial of gene therapy for group C FA is ongoing at the National Institutes of Health.


Evaluation of microRNA responses in ARPE-19 cells against the oxidative stress.
This study aimed to determine microRNA (miRNA) expression profile of human retinal pigment epithelium cell (ARPE-19) against the oxidative stress induced by hydrogen peroxide (H2O2). ARPE-19 cells were incubated with different concentrations of H2O2 (200, 600 and 800 μM) for 18 h, and then cell viability, vascular endothelial growth factor levels and total oxidant status were evaluated. Expressions of 1152 miRNA were determined by quantitative real-time PCR in each group. Expressions of 90 miRNA were significantly changed in the ARPE-19 cells incubated with H2O2 compared to control group. However, miR-143-3p was only found to be expressed in groups incubated with H2O2. While 24 miRNA (hsa-miR-200c-3p, miR-192-5p, miR-194-5p, miR-141-3p, miR-658, miR-18 b-5p, miR-486-5p, miR-525-3p, miR-493-3p, miR-518d-3p, miR-29 b-1-5p, miR-675-3p, miR-1238-3p, miR-195-3p, miR-1539, miR-490-5p, miR-3200-5p, miR-1273d, miR-130a-5p, miR-30 b-5p, miR-1247-5p, miR-1910-5p, miR27a-5p and miR-200 b-3p) upregulated due to the increased dose of H2O2, nine miRNA (hsa-miR-96-5p, miR-33a-5p, miR-345-5p, miR-106 b-3p, miR-1285-3p, miR-23 b-5p, miR-27 b-5p, miR-103a-3p and miR-4289) were also found to be downregulated. This study suggests that oxidative stress may be an important factor on expression of miRNAs in ARPE-19 cells. These miRNAs may have a role in the pathogenesis of age-related macular degeneration related to oxidative stress. However, this relationship needs to be examined in new studies by evaluation of pathways and target genes.


Regional pulmonary function before and after pneumonectomy using 133xenon.
Regional pulmonary function studies using 133xenon gas, spirometry, and arterial blood gas levels were performed before and 1 to 47 months after pneumonectomy for bronchogenic carcinoma in 27 patients. The mean loss in forced vital capacity was more after right pneumonectomy (44.9 percent of preoperative value) than after left lung resection (41.4 percent). There was no significant change in regional pulmonary function distribution within the remaining lung in 24 patients. Two patients developed significant changes in regional pulmonary blood flow; one had hepatic cirrhosis, and the other sustained a myocardial infarction after pneumonectomy. The third patient with significant apical hyperperfusion before pneumonectomy gradually developed abnormal distribution of ventilation concomitant with electrocardiographic evidence of cor pulmonale within two years after pneumonectomy. The mean ventilation of the apical zones was significantly lower than the mean of 14 healthy subjects. This finding and the higher incidence of ventilatory defects were related to old age and heavy smoking. Seven patients with marked reduction of pulmonary blood flow to the tumor-bearing lung (9 to 33 percent of cardiac output) had technically successful pneumonectomy. A formula and nomogram were developed to estimate the prognostically significant forced expiratory volume in one second after pneumonectomy from the preoperative studies.


Histological Features of Oral Cavity Mucous Membrane Epithelium in Six-Month-Old Experimental Animals Born with Macrosomia.
We examined the histological features of the mucobuccal fold of oral cavity mucous membrane from the area of the masticatory teeth roots' projection in 6-month-old Wistar Albino Glaxo rats with fetal macrosomia. The animals were divided into groups according to the body weight, the body length, and the Quetelet index at birth. A morphological study was performed using the Leica SP8 AOBS laser scanning confocal microscope and a conventional light (Axiostar, Zeiss) microscopy. Morphometric parameters were used to estimate the degree of acanthosis development in the epithelium of the oral mucosa, which indicates the intensity of its proliferation. Numerous narrow and deep acanthotic outgrowths and densely located 'juvenile' epitheliocytes in the basal layer on the apex of the acanthotic protrusions were found in animals with fetal macrosomia that was due to intrauterine obesity. In these animals, the morphometric index, which we used, was maximally different from that in the control group. In animals with fetal macrosomia that was due to intrauterine growth acceleration of the body, the hyperproliferation of the mucous membrane epithelium of the oral cavity was absent or little pronounced. It can be assumed that fetal macrocosmia with obesity causes instability in the epithelium of the oral cavity mucosa, its rapid death, and therefore, a more active stimulation of proliferation.


[8-oxo-7,8-dihydro-2'-deoxyguanosine as a marker of DNA oxidative stress in individuals with combined familiar hyperlipidemia].
To compare 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) value as an indicator of oxidative stress situation between healthy and familial combined hyperlipidemic (FCH) subjects as a mixed dislipidemia with insulin resistance model and early coronary heart disease, and to study its relationship with clinical-biologic parameters of insulin resistance. 40 non-related FCH patients (15 women) and 20 normolipidemic and nondiabetic healthy subjects (8 women) were studied. Clinical, anthropometric and biochemical parameters (lipidic profile, glucemia, insulinemia and 8-oxo-dG) were measured in fasting state in all. Both groups had similar age, body mass index blood pressure and waist perimeter values. Insulin and 8-oxo-dG values were significantly higher in FHC subjects. These differences were maintained after correcting by waist perimeter. 8-oxo-dG correlated positively with insulin and trygliceride; and negatively with high density lipoprotein cholesterol in FCH subjects. Insulin values are independently correlated with oxidative stress degree measured as 8-oxo-dG.


A novel mutation in PRPF31, causative of autosomal dominant retinitis pigmentosa, using the BGISEQ-500 sequencer.
To study the genes responsible for retinitis pigmentosa. A total of 15 Chinese families with retinitis pigmentosa, containing 94 sporadically afflicted cases, were recruited. The targeted sequences were captured using the Target_Eye_365_V3 chip and sequenced using the BGISEQ-500 sequencer, according to the manufacturer's instructions. Data were aligned to UCSC Genome Browser build hg19, using the Burroughs Wheeler Aligner MEM algorithm. Local realignment was performed with the Genome Analysis Toolkit (GATK v.3.3.0) IndelRealigner, and variants were called with the Genome Analysis Toolkit Haplotypecaller, without any use of imputation. Variants were filtered against a panel derived from 1000 Genomes Project, 1000G_ASN, ESP6500, ExAC and dbSNP138. In all members of Family ONE and Family TWO with available DNA samples, the genetic variant was validated using Sanger sequencing. A novel, pathogenic variant of retinitis pigmentosa, c.357_358delAA (p.Ser119SerfsX5) was identified in PRPF31 in 2 of 15 autosomal-dominant retinitis pigmentosa (ADRP) families, as well as in one, sporadic case. Sanger sequencing was performed upon probands, as well as upon other family members. This novel, pathogenic genotype co-segregated with retinitis pigmentosa phenotype in these two families. ADRP is a subtype of retinitis pigmentosa, defined by its genotype, which accounts for 20%-40% of the retinitis pigmentosa patients. Our study thus expands the spectrum of PRPF31 mutations known to occur in ADRP, and provides further demonstration of the applicability of the BGISEQ500 sequencer for genomics research.


Management outcome of pulmonary tuberculosis: a nine year review in Ilorin.
This study evaluates the management outcome of patients with pulmonary tuberculosis (PTB) over a nine year period. Essentially the cure rate, rate of default and fatality rate were all estimated. Factors predisposing to poor drug compliance were also reviewed. This was conducted by analysing the medical records of all newly diagnosed cases of PTB. Patients' demographic data, their social and past medical histories were obtained from their records. The extents of the lung lesions were determined from their chest X-rays. Criteria were set to define those that were (a) cured, (b) defaulted (c) transferred (d) had treatment failure and (e) died. The chi-square test of significance was used to estimate the difference between those that were cured and those that defaulted therapy. Multiple regression models were used to determine the level of interplay among the various factors contributing to patients' poor therapy compliance; the best of these was recorded. Out of the 1,741 cases of PTB treated over the studied period, 43.7% were cured, 0.3% had treatment failure, 44.2% defaulted therapy, 0.2% were transferred to other treatment centers while a fatality rate of 11.6% was recorded. Male gender, old age (> or =) 65 years), unmarried status, and previous default from therapy were found associated with poor therapy compliance. Others were unemployment, cigarette smoking and the use of alcohol. The cure rate of PTB in this study was very low, while the rate of default from therapy was quite high. These are in contrast to WHO target for TB control. To improve on these, directly observed therapy short course (DOTS) strategy for treating TB has to be adopted and implemented at all our treatment points for PTB. There should be emphasis on the Primary health Care (PHC) centers, because majority of PTB patients are grass root people and PHC set-ups are closer to them.


Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc.
Extracellular vesicles (EVs) are lipid membrane particles carrying proteins, lipids, DNA, and various types of RNA that are involved in intercellular communication. EVs derived from mesenchymal stem cells (MSCs) have been investigated extensively in many different fields due to their crucial role as regeneration drivers, but research for their use in degenerative diseases of the intervertebral disc (IVD) has only started recently. MSC-derived EVs not only promote extracellular matrix synthesis and proliferation in IVD cells, but also reduce apoptosis and inflammation, hence having multifunctional beneficial effects that seem to be mediated by specific miRNAs (such as miR-233 and miR-21) within the EVs. Aside from MSC-derived EVs, IVD-derived EVs (e.g., stemming from notochordal cells) also have important functions in IVD health and disease. This article will summarize the current knowledge on MSC-derived and IVD-derived EVs and will highlight areas of future research, including the isolation and analysis of EV subpopulations or exposure of MSCs to cues that may enhance the therapeutic potential of released EVs.


[Current state of the attention deficit hyperactivity disorder approach in neuropediatrics].
To know the current state of the approach of attention deficit hyperactivity disorder (ADHD) in neuropediatricians. A telematic survey was carried out to collect preliminary information on the interest, difficulties in the management and treatment of ADHD to the 437 fellowship of the Neuropediactric Spanish Society (SENEP). Only 32.49% of the sent questionnaires were answered, with important geographic variability. 97.89% stated that 50% of their consultations were children with learning disabilities and ADHD. Regarding who started treatment for ADHD in their area, the majority answered that the neuropediatrician (57.97%), followed by the child psychiatrist (34.78%) and the primary care pediatrician (5.31%). The lack of a psycho-pedagogical study by the school (49.79%), followed by the lack of time in the consultation (29.11%), was cited as the greatest difficulty in the initial assessment of children with suspected ADHD. Concerning the difficulties in the follow-up, the biggest complaint was the lack of coordination between professionals, the school and parents. And, lastly, regarding the type of treatment use, most patients were on prolonged-release methylphenidate, a stable percentage using immediate release methylphenidate as a single or combined treatment, and in a lower range was the use of clonidine and atomoxetine, and an incipient use of lisdexamphetamine were observed. 80% of the patient showed adherence to pharmacological treatment after one year. It is necessary to advance in the training and continuous education of our neuropediatric specialists in ADHD and to homogenize the clinical practice and coordination with education system in the Spanish territory.


Mathematical solutions in internal dose assessment: A comparison of Python-based differential equation solvers in biokinetic modeling.
In biokinetic modeling systems employed for radiation protection, biological retention and excretion have been modeled as a series of discretized compartments representing the organs and tissues of the human body. Fractional retention and excretion in these organ and tissue systems have been mathematically governed by a series of coupled first-order ordinary differential equations (ODEs). The coupled ODE systems comprising the biokinetic models are usually stiff due to the severe difference between rapid and slow transfers between compartments. In this study, the capabilities of solving a complex coupled system of ODEs for biokinetic modeling were evaluated by comparing different Python programming language solvers and solving methods with the motivation of establishing a framework that enables multi-level analysis. The stability of the solvers was analyzed to select the best performers for solving the biokinetic problems. A Python-based linear algebraic method was also explored to examine how the numerical methods deviated from an analytical or semi-analytical method. Results demonstrated that customized implicit methods resulted in an enhanced stable solution for the inhaled60Co (Type M) and131I (Type F) exposure scenarios for the inhalation pathway of the International Commission on Radiological Protection (ICRP) Publication 130 Human Respiratory Tract Model (HRTM). The customized implementation of the Python-based implicit solvers resulted in approximately consistent solutions with the Python-based matrix exponential method (expm). The differences generally observed between the implicit solvers andexpmare attributable to numerical precision and the order of numerical approximation of the numerical solvers. This study provides the first analysis of a list of Python ODE solvers and methods by comparing their usage for solving biokinetic models using the ICRP Publication 130 HRTM and provides a framework for the selection of the most appropriate ODE solvers and methods in Python language to implement for modeling the distribution of internal radioactivity.


Intrahepatic and systemic therapy with oxaliplatin combined with capecitabine in patients with hepatic metastases from breast cancer.
The aim was to evaluate activity and toxicity of hepatic arterial infusion of oxaliplatin in combination with capecitabine in patients with metastatic breast cancer with liver metastases and limited extrahepatic disease. Sixteen consecutive patients received capecitabine 13 00mg/m(2) daily combined with oxaliplatin 85 mg/m(2) every two weeks. Seven patients alternated between intrahepatic and systemic oxaliplatin, and in 9 oxaliplatin was primarily given intrahepatic. Five patients had liver-only metastases and 11 had additionally bone metastases. The patients had received median two previous chemotherapeutic regimens for metastatic disease. The response rate was 50% and the stable disease (≥6 months) rate 44%. Median progression free and overall survival was 7.9 and 19.2 months, respectively. The toxicity was moderate with abdominal pain, neuropathy, and hand foot syndrome as the most common adverse events. The combination of capecitabine and intrahepatic/systemic therapy with oxaliplatin was active in pretreated patients with liver metastasis from breast cancer.


Neuritic growth from a new subline of PC12 pheochromocytoma cells: cyclic AMP mimics the action of nerve growth factor.
We have identified a new subline of PC12 pheochromocytoma cells (PC12D cells) in which neurites are extended within 24 hr in response to cAMP-enhancing reagents as well as in response to nerve growth factor (NGF), but not in response to epidermal growth factor or phorbol diester. Anti-NGF antiserum did not affect forskolin (FRK)-induced neuritic recruitment. FRK-induced neurites exhibited growth cones and contained secretion granules and many parallel arrays of microtubules as was the case with NGF-induced neurites. FRK, but not NGF, increased the levels of intracellular cAMP and activated adenylate cyclase in the membrane fraction. Both NGF and FRK enhanced the activities of tyrosine hydroxylase (TH), acetylcholinesterase (AchE), and ornithine decarboxylase (ODC), but not the levels of neuron-specific enolase. Enhanced levels of intracellular cAMP mimicked the effects of NGF on neuritic growth, TH, AchE, and ODC activities in PC12D cells, even though NGF does not act through elevation of levels of cAMP.


Preventative Health and Risk Behaviors Among Adolescent Girls With and Without Family Histories of Breast Cancer.
To compare health behaviors (smoking, alcohol use, fruit and vegetable intake, and exercise frequency) and breast self-exam (BSE) between girls with breast cancer family history (BCFH+) and without (BCFH-) and assess associates of behaviors across all girls. A total of 208 BCFH+ girls (11-19 years old), with first- or second-degree relatives with breast cancer or a mother with a BRCA1/2 mutation, and 112 BCFH- peers reported their health behaviors, beliefs, and psychosocial function. Despite higher BCFH+ girls' greater perceived breast cancer risk, there were no differences between BCFH+ and BCFH- girls on diet, exercise, alcohol initiation, or BSE. BCFH+ girls were slightly more likely to report trying cigarettes (11% vs. 5%, p = .04). In multivariable models with all girls, categorical associations with behaviors included the following: developmental and demographic factors with smoking, alcohol, diet, and exercise; family breast cancer history and experience with smoking, alcohol, and diet; psychosocial factors with smoking; girls perceptions of cancer controllability and mother support for health behaviors with alcohol, diet, exercise, and BSE; and mother behaviors with diet. Adolescent girls from BCFH+ families reported similar health behaviors to BCFH- peers, signaling that they are not translating their higher perceived risk into cancer control behaviors. Both uncontrollable (i.e., breast cancer experiences) and modifiable factors relate to health behaviors and warrant further investigation. Results indicate that interventions with teens and parents that target modifiable variables such as controllability perceptions, maternal modeling, and communication may relate to better health behaviors and reduced future breast cancer risk.


First evaluation of the NHS direct online clinical enquiry service: a nurse-led web chat triage service for the public.
NHS Direct is a telephone triage service used by the UK public to contact a nurse for any kind of health problem. NHS Direct Online (NHSDO) extends NHS Direct, allowing the telephone to be replaced by the Internet, and introducing new opportunities for informing patients about their health. One NHSDO service under development is the Clinical Enquiry Service (CES), which uses Web chat as the communication medium. To identify the opportunities and possible risks of such a service by exploring its safety, feasibility, and patient perceptions about using Web chat to contact a nurse. During a six-day pilot performed in an inner-city general practice in Coventry, non-urgent patients attending their GP were asked to test the service. After filling out three Web forms, patients used a simple Web chat application to communicate with trained NHS Direct triage nurses, who responded with appropriate triage advice. All patients were seen by their GP immediately after using the Web chat service. Safety was explored by comparing the nurse triage end point with the GP's recommended end point. In order to check the feasibility of the service, we measured the duration of the chat session. Patient perceptions were measured before and after using the service through a modified Telemedicine Perception Questionnaire (TMPQ) instrument. All patients were observed by a researcher who captured any comments and, if necessary, to assisted with the process. A total of 25 patients (mean age 48 years; 57% female) agreed to participate in the study. An exact match between the nurse and the GP end point was found in 45% (10/22) of cases. In two cases, the CES nurse proposed a less urgent end point than the GP. The median duration of Web chat sessions was 30 minutes, twice the median for NHS Direct telephone calls for 360 patients with similar presenting problems. There was a significant improvement in patients' perception of CES after using the service (mean pre-test TMPQ score 44/60, post-test 49/60; p=0.008 (2-tailed)). Patients volunteered several potential advantages of CES, such as the ability to re-read the answers from the nurse. Patients consider CES a useful addition to regular care, but not a replacement for it. Based on this pilot, we can conclude that CES was sufficiently safe to continue piloting, but in order to make further judgments about safety, more tests with urgent cases should be performed. The Web chat sessions as conducted were too long and therefore too expensive to be sustainable in the NHS. However, the positive reaction from patients and the potential of CES for specific patient groups (the deaf, shy, or socially isolated) encourage us to continue with piloting such innovative communication methods with the public.


Two cases of sarcoidosis-lymphoma syndrome.
An association between sarcoidosis and lymphoproliferative diseases (LD), the sarcoidosis-lymphoma syndrome, has been previously described, and may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. We report two patients who developed Hodgkin's disease and diffuse large B-cell non-Hodgkin's lymphoma (NHL) subsequent to their diagnosis of sarcoidosis after latency periods of 6 years and 18 years respectively. Both patients developed histologically-proven sarcoidosis late in life, at 46 years and 58 years, and had differing clinical courses. The first had radiographically staged II chronic progressive respiratory sarcoidosis (RS) and required long-term methotrexate to control the disease, while the second achieved a spontaneous remission of her stage I intrathoracic RS. After treatment, the patient with Hodgkin's disease remains in remission 2.5 years following six cycles of ABVD protocol chemotherapy and involved-field radiotherapy, while the NHL patient remains in remission at 3 years following six cycles of R-COP protocol chemotherapy. Clinicians should be aware of the potential risks of malignancy, and especially of LD in sarcoidosis patients. They should be alerted to the possibility of additional pathology by any atypical clinical features, and should biopsy new lesions and adenopathy to exclude any coexistent neoplasm.


Comparative analyses of ion release, pH and multispecies biofilm formation between conventional and bioactive gutta-percha.
To analyse the effect of commercial and experimental gutta-percha with the addition of niobium phosphate glass on biofilm formation by oral bacteria from human dental plaque. Additional pH and elemental release of the materials were analysed. The multispecies biofilm was grown anaerobically from plaque bacteria on standardized discs of each material: hydroxyapatite (HA), gutta-percha pellets (OBT) (Obtura pellets, Shoreline, CT, USA), ProTaper gutta-percha (PTP) (ProTaper Universal Gutta-Percha Points, Dentsply Maillefer, Ballaigues, Switzerland), EndoSequence BC gutta-percha (GBC) (Brasseler USA, Savannah, GA, USA), experimental gutta-percha associated with niobium phosphate glass (GNB) and niobium phosphate glass (NPG). Specimens (n = 5 per group and per incubation period) were incubated in brain-heart infusion broth for 3, 14 and 30 days, at 37 °C, and stained using live/dead viability assay. Images were analysed by confocal laser scanning microscopy (CLSM) and the total biovolume (mm3 ), viable bacteria biovolume (mm3 ), and live percentage (%) were quantified. For pH measurement, specimens of each material (n = 3) were immersed in phosphate-buffered saline at 37 °C, and pH was monitored in multiple intervals, up to 30 days. For elemental analysis, additional specimens (n = 3) were immersed in deionized water and elemental release was analysed by ICP-OES (inductively coupled plasma - optical emission spectrometry) at time intervals of 3, 14 and 30 days. Differences between groups were evaluated by the two-way analysis of variation (anova) with Tukey's post hoc test (P < 0.05). The lowest total biovolume at 30 days was found in GNB, GBC and NPG. GNB had the lowest viable bacteria biovolume (mean value) at 30 days (P < 0.05), and the lowest live percentage of bacteria at 3 and 30 days (P < 0.05), whilst NPG had the lowest live percentage at 14 days (P < 0.05). GNB had the highest pH (8.45) after 30 days (P < 0.05), and the greatest Zn and Na release at all time intervals (P < 0.05). Both GBC and GNB had significantly higher Ca release at 14 and 30 days. GNB and GBC reduced biofilm formation, GNB had the lowest amount of viable bacteria in biofilms with the highest pH, and high Zn and Na release values after 30 days.


Efficacy of estradiol topical patch in the treatment of symptoms of depression following mini-gastric bypass in women.
Obesity is associated with elevated levels of estrogen. Gastric bypass causes rapid weight loss and decreased levels of estrogen. Patients after gastric bypass can suffer from anxiety and depression out of proportion to the surgical outcome. This study reports the efficacy of a short-term empiric trial of topical estradiol for the treatment of mild to moderate depression and anxiety following mini-gastric bypass (MGB) in women. Postoperative MGB women were surveyed for the presence of depressive symptoms before and after MGB. The results of an empiric trial of transdermal patches of estradiol-17beta were assessed. Outcome measures were the self-reported efficacy of the patch. 711 women who had undergone MGB and had functioning e-mail addresses made up the study. 62% of patients reported depression prior to surgery. 156 patients (22%) reported depression after the operation. 130 women were treated empirically with the patch, and remission of depression was observed in 92 (71%). In response to the question "Did the estrogen patch help?", subjects reported responses of 1) Yes, fantastic, 2) Yes, somewhat, 3) Hard to say, 4) No, in 36%, 31%, 20%, 13% of respondents respectively. Patients treated with estradiol sustained antidepressant benefit of treatment after the patch was discontinued. Treatment lasted <1 month, 1-3 months, and >3 months, in 48%, 32% and 20% respectively. Treatment was well-tolerated and adverse events were rare. Depression is common in obese patients and remains a problem in a subset following the MGB operation. Transdermal estradiol replacement appears to be an effective treatment of symptoms of depression in women following MGB.


Research-based Analytical Procedures to Evaluate Diabetic Biomarkers and Related Parameters: In Vitro and In Vivo Methods.
The degenerative tendency of diabetes leads to micro- and macrovascular complications due to abnormal levels of biochemicals, particularly in patients with poor diabetic control. Diabetes is supposed to be treated by reducing blood glucose levels, scavenging free radicals, and maintaining other relevant parameters close to normal ranges. In preclinical studies, numerous in vivo trials on animals as well as in vitro tests are used to assess the antidiabetic and antioxidant effects of the test substances. Since a substance that performs poorly in vitro won't perform better in vivo, the outcomes of in vitro studies can be utilized as a direct indicator of in vivo activities. The objective of the present study is to provide research scholars with a comprehensive overview of laboratory methods and procedures for a few selected diabetic biomarkers and related parameters. The search was conducted on scientific database portals such as ScienceDirect, PubMed, Google Scholar, BASE, DOAJ, etc. Conclusion: The development of new biomarkers is greatly facilitated by modern technology such as cell culture research, lipidomics study, microRNA biomarkers, machine learning techniques, and improved electron microscopies. These biomarkers do, however, have some usage restrictions. There is a critical need to find more accurate and sensitive biomarkers. With a few modifications, these biomarkers can be used with or even replace conventional markers of diabetes.


Expression of p53 and proliferating cell nuclear antigen in lichen sclerosus et atrophicus with different histological features.
In this study, immunohistochemistry was used to investigate p53 and proliferating cell nuclear antigen (PCNA) expression in 40 cases of lichen sclerosus et atrophicus (LSA). Nuclear immunoreactivity for both p53 and PCNA was found in the basal and parabasal keratinocytes in the majority (91%) of the lesions. Typically, there was a widely varying positivity for PCNA, suggesting a wide range of proliferative capacity in individual LSA lesions. Lesions with p53 positivity in 5% or more of the basal cells also presented a strong (> 14% of basal cells positive) PCNA positivity (p = 0.030) and exhibited a higher mitotic rate (p = 0.002), suggesting a causal relationship between enhanced p53 expression and elevated cell proliferation. Lesions with a low number of PCNA-positive cells (< 15% of basal and parabasal cells positive) exhibited a wider subepithelial edematous zone and a thinner epithelium than in the lesions with a higher number of PCNA-positive cells. The results show that later stages of LSA, typified by subepithelial edema and epithelial atrophy, are associated with decreased proliferative activity of the basal and parabasal cells.


Assessing the Predictive Validity of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) in Alaska Native and American Indian People.
The objective of this study was to examine the predictive validity of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) among Alaska Native and American Indian (ANAI) people with an alcohol use disorder. The sample was 170 ANAI adults with an alcohol use disorder living in Anchorage, Alaska who were part of a larger alcohol intervention study. The primary outcome of this study was alcohol use as measured by mean urinary ethyl glucuronide (EtG). EtG urine tests were collected at baseline and then up to twice a week for four weeks. We conducted bivariate linear regression analyses to evaluate associations between mean EtG value and each of the three SOCRATES subscales (Recognition, Ambivalence, and Taking Steps) and other covariates such as demographic characteristics, alcohol use history, and chemical dependency service utilization. We then performed multivariable linear regression modeling to examine these associations after adjusting for covariates. After adjusting for covariates, mean EtG values were negatively associated with the Taking Steps (P = 0.017) and Recognition (P = 0.005) subscales of the SOCRATES among ANAI people living in Alaska. We did not find an association between mean EtG values and the Ambivalence subscale (P = 0.129) of the SOCRATES after adjusting for covariates. Higher scores on the Taking Steps and Recognition subscales of the SOCRATES at baseline among ANAI people predicted lower mean EtG values. This study has important implications for communities and clinicians who need tools to assist ANAI clients in initiating behavior changes related to alcohol use.


Palmoplantar pustulosis - a cross-sectional analysis in Germany.
Palmoplantar pustulosis (PPP) is a recalcitrant chronic inflammatory skin disease. Data relevant for the medical care of patients with PPP are scarce. Thus, the aim of this work was to investigate the disease burden, clinical characteristics, and comorbidity of PPP patients in Germany. PPP patients were examined in a crosssectional study at seven specialized psoriasis centers in Germany. Of the 172 included patients with PPP, 79.1% were female and 69.8% were smokers.In addition, 25.0% suffered from psoriasis vulgaris, 28.2% had documented psoriatic arthritis, and 30.2% had a family history of psoriasis. In 77 patients the mean Dermatology Life Quality Index (DLQI) was 12.2 ± 7.7 (mean ± SD). The mean Psoriasis Palmoplantar Pustulosis Area and Severity Index (PPPASI) was 12.6 ± 8.6. Mean body mass index was above average at 27.1 ± 5.5. The PPP patients had previously received an average of 2.6 ± 2.1 different anti-psoriatic systemic drugs or UV-therapies. The systemic drugs that had been used most frequently were corticosteroids in 40.1% of patients, followed by acitretin (37.8%), and methotrexate (27.9%). The PPPASI was 13.4 ± 8.9 in patients without current systemic therapy and 10.4 ± 7.9 in patients with systemic therapy. Many PPP patients had a concomitant diagnosis of psoriasis vulgaris and/or psoriatic arthritis or had a family history of psoriasis. Despite the fact that many of the patients were using anti-psoriatic therapies, there was still a high burden of disease within this PPP cohort. This insufficient control of symptoms demonstrates the urgent need for new PPP treatments.


A prospective multicenter cohort study of frailty in younger critically ill patients.
Frailty is a multidimensional syndrome characterized by loss of physiologic and cognitive reserve that heightens vulnerability. Frailty has been well described among elderly patients (i.e., 65 years of age or older), but few studies have evaluated frailty in nonelderly patients with critical illness. We aimed to describe the prevalence, correlates, and outcomes associated with frailty among younger critically ill patients. We conducted a prospective cohort study of 197 consecutive critically ill patients aged 50-64.9 years admitted to intensive care units (ICUs) at six hospitals across Alberta, Canada. Frailty was defined as a score ≥5 on the Clinical Frailty Scale before hospitalization. Multivariable analyses were used to evaluate factors independently associated with frailty before ICU admission and the independent association between frailty and outcome. In the 197 patients in the study, mean (SD) age was 58.5 (4.1) years, 37 % were female, 73 % had three or more comorbid illnesses, and 28 % (n = 55; 95 % CI 22-35) were frail. Factors independently associated with frailty included not being completely independent (adjusted OR [aOR] 4.4, 95 % CI 1.8-11.1), connective tissue disease (aOR 6.0, 95 % CI 2.1-17.0), and hospitalization within the preceding year (aOR 3.3, 95 % CI 1.3-8.1). There were no significant differences between frail and nonfrail patients in reason for admission, Acute Physiology and Chronic Health Evaluation II score, preference for life support, or treatment intensity. Younger frail patients did not have significantly longer (median [interquartile range]) hospital stay (26 [9-68] days vs. 19 [10-43] days; p = 0.4), but they had greater 1-year rehospitalization rates (61 % vs. 40 %; p = 0.02) and higher 1-year mortality (33 % vs. 20 %; adjusted HR 1.8, 95 % CI 1.0-3.3; p = 0.039). Prehospital frailty is common among younger critically ill patients, and in this study it was associated with higher rates of mortality at 1 year and with rehospitalization. Our data suggest that frailty should be considered in younger adults admitted to the ICU, not just in the elderly. Additional research is needed to further characterize frailty in younger critically ill patients, along with the ideal instruments for identification.


Periodic knolls and valleys: coexistence of solid and liquid states in granular suspensions.
We report the spontaneous emergence of a doubly periodic train of sedimented knolls in a dense suspension. These solidified knolls rise out of, and coexist alongside, a sea of freely flowing liquid in a slowly rotating horizontal bottle. We apply a variable viscosity model that permits simultaneous analysis of fluidlike and solidlike behaviors that are ubiquitous in a variety of sedimenting flows. The model generates qualitative agreement with experiments, and produces new insights into mechanisms by which sedimented structures form.


Systemic Lupus Erythematosus and Secondary Antiphospholipid Syndrome after Thymectomy for Myasthenia Gravis - A Case Report.
Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) are autoimmune diseases that show some similarities: a higher incidence in young women, relapsing-remitting course and positive anti-nuclear antibodies (ANA). However, they are two different clinical syndromes, which can coexist or precede each other. Thymectomy is a therapeutic option for patients with severe MG or thymoma. There are many cases of SLE after thymectomy described in the literature, so the question arises whether thymectomy predisposes patients to SLE and what are imunopathogenetic mechanisms behind this process. We report a case of a patient who was diagnosed with SLE and secondary antiphospholipid syndrome (APS) 28 years after thymectomy for MG. Clinical picture of SLE was characterized by cutaneous and articular manifestations, polyserositis, lupus nephritis and immunological parameters showed positive ANA, anti-ds-DNA, excessive consumption of complement components, positive cryoglobulins. Clinical and laboratory immunological parameters for the diagnosis of secondary APS where also present. The patient was initially treated with glucocorticoids followed by mycophenolate mofetil. During one year follow-up patient was in a stable remission of SLE. Thymectomy for MG may predispose SLE development in some patients. Further studies are needed to better understand the connection between these two autoimmune diseases.


The incidence of invasion and metastasis of nasopharyngeal carcinoma at different anatomic sites in the skull base.
This study aimed to investigate the incidence of direct invasion and metastasis of nasopharyngeal carcinoma (NPC) at different anatomic sites in the skull base using magnetic resonance imaging (MRI). MRI data from 101 NPC patients with skull base invasion were collected and we analyzed the incidence and anatomic sites of invasion of NPC in the skull base. Of the 101 NPC patients, 84 had direct invasion at the skull base (83.2%), and 17 had skull base metastasis (16.8%). Affected sites with direct invasion in the skull base included sphenoid sinus and sella base, cavernous sinus, internal carotid canal, and clivus blumenbachii. Skull base metastasis sites included the internal carotid canal and jugular foramen area. Because of early lymphatic metastasis of NPC to the skull base, MRI examination can be helpful in increasing the accuracy of diagnostic imaging for skull base invasion of NPC and selecting appropriate target sites, radiotherapy techniques, and operative approaches.


Vortex phases and glassy dynamics in the highly anisotropic superconductor HgBa2CuO4+δ.
We present an extensive study of vortex dynamics in a high-quality single crystal of HgBa2CuO4+δ, a highly anisotropic superconductor that is a model system for studying the effects of anisotropy. From magnetization M measurements over a wide range of temperatures T and fields H, we construct a detailed vortex phase diagram. We find that the temperature-dependent vortex penetration field Hp(T), second magnetization peak Hsmp(T), and irreversibility field Hirr(T) all decay exponentially at low temperatures and exhibit an abrupt change in behavior at high temperatures T/Tc >~ 0.5. By measuring the rates of thermally activated vortex motion (creep) S(T, H) = |dlnM(T, H)/dlnt|, we reveal glassy behavior involving collective creep of bundles of 2D pancake vortices as well as temperature- and time-tuned crossovers from elastic (collective) dynamics to plastic flow. Based on the creep results, we show that the second magnetization peak coincides with the elastic-to-plastic crossover at low T, yet the mechanism changes at higher temperatures.


Opinion formation and the collective dynamics of risk perception.
The formation of collective opinion is a complex phenomenon that results from the combined effects of mass media exposure and social influence between individuals. The present work introduces a model of opinion formation specifically designed to address risk judgments, such as attitudes towards climate change, terrorist threats, or children vaccination. The model assumes that people collect risk information from the media environment and exchange them locally with other individuals. Even though individuals are initially exposed to the same sample of information, the model predicts the emergence of opinion polarization and clustering. In particular, numerical simulations highlight two crucial factors that determine the collective outcome: the propensity of individuals to search for independent information, and the strength of social influence. This work provides a quantitative framework to anticipate and manage how the public responds to a given risk, and could help understanding the systemic amplification of fears and worries, or the underestimation of real dangers.


The effects of electrode position on the detection of the transvenous cardiac electrogram.
Adequate sensing of the cardiac electrogram is a necessary requisite for all demand cardiac pacemakers. In order to define better the effects of position of the sensing electrode on the ability of the pacer to detect the electrogram, a specially designed lead system with a movable, large surface area (50 mm2) proximal ring electrode and a small surface area distal tip electrode was placed transvenously in 12 mongrel dogs. As the sensing electrode was moved away from the right ventricular apex, there were slight but insignificant decreases in R wave amplitude. When the electrode was moved retrograde through the tricuspid valve into the atria there was a marked decrease in R wave sensing; however, this was accompanied by a significant increase in P wave amplitude. Therefore, with a large surface area electrode, direct contact with the myocardium is not needed for the detection of adequate P and R waves. In addition, a pacer lead system utilizing this sliding sensing electrode design could be used to optimize sensing position, either for atrial or ventricular sensing pacemakers.


Acoustic radiation force on a heated spherical particle in a fluid including scattering and microstreaming from a standing ultrasound wave.
Analytical expressions are derived for the time-averaged, quasisteady, acoustic radiation force on a heated, spherical, elastic, solid microparticle suspended in a fluid and located in an axisymmetric incident acoustic wave. The heating is assumed to be spherically symmetric, and the effects of particle vibrations, sound scattering, and acoustic microstreaming are included in the calculations of the acoustic radiation force. It is found that changes in the speed of sound of the fluid due to temperature gradients can significantly change the force on the particle, particularly through perturbations to the microstreaming pattern surrounding the particle. For some fluid-solid combinations, the effects of particle heating even reverse the direction of the force on the particle for a temperature increase at the particle surface as small as 1 K.


Cell-type- and developmental-stage-specific metabolism and storage of retinoids by embryonic chick retinal cells in culture.
Biological functions of retinoids in the vertebrate retina include the role of 11-cis retinaldehyde as visual pigment chromophore, and possible effects of retinoic acid in histogenesis and cell survival. Qualitative and quantitative regulation of retinoid availability for these complex processes could involve several cell types, including retinal pigment epithelium, Müller glia and retinal photoreceptors and non-photoreceptor neurons; their relative contributions, however, have not been fully elucidated. Using purified cultures, we have carried out a study of cell-type-specific metabolism and storage of retinoids in chick embryo retinal photoreceptors and other neuronal cells, as compared to those of retinal glia. Retinal glia were found to synthesize both retinoic acid and retinyl esters, and to hydrolyse the latter; they also displayed retinol dehydrogenase activities. Cultured neurons and photoreceptors also synthesized and hydrolysed retinyl esters; their capacity for retinaldehyde synthesis from a retinol or retinyl ester substrate suggested the presence of retinol dehydrogenase activity. Retinoic acid was not synthesized in differentiated neuronal cultures, although some synthesis was detectable at early culture stages when the cells were still morphologically undifferentiated. These findings indicate that cell-type-specific metabolic activities are expressed during retinal cell differentiation in vitro, and that embryonic retinal photoreceptors and nonphotoreceptor neurons are active participants in the metabolism and storage of retinoids.