Hippocampal morphology and spatially related behavior in Long-Evans and CFY rats.
Behavioral responses to novelty in an open field and spatial learning in a radial maze with four arms out of eight reinforced were tested in male and female CFY and Long-Evans rats. Subsequently, the sizes of the total hippocampi and of various hippocampal cell layers and terminal fields at the midseptotemporal level were measured in Timm-stained sections. No strain differences were found in the open field (except for defecation). In the radial maze, Long-Evans rats showed better spatial reference memory capabilities than rats of the CFY strain. The relative sizes of the intra- and infrapyramidal mossy fiber (IIP-MF) projections did not differ between the strains. Within the more variable CFY strain, a positive correlation between the size of the IIP-MF projection and radial maze performance was found. The absolute sizes of the entire hippocampi and all hippocampal layers at the midseptotemporal level were larger in the CFY strain. The size of the suprapyramidal mossy fiber projection was related to the number of granule cells and to the ratio between granule and CA3 pyramidal cells. In contrast, the size of the IIP-MF projection did not correlate with either of these variables. The results indicate that the size of the mossy fiber projection may be determined mainly by the available postsynaptic surface on the dendrites of CA3 pyramidal neurons. Furthermore, an increased number of granule cells and their larger projection to the apical dendrites of pyramidal neurons does not appear to result in physiological changes with behavioral consequences.(ABSTRACT TRUNCATED AT 250 WORDS)


Adherence to French nutritional guidelines is associated with lower risk of metabolic syndrome.
A decrease in metabolic syndrome (MetS) prevalence may lower the cardiovascular disease (CVD) burden. The predictive value of nutritional recommendations for the incidence of MetS has not yet been evaluated. We assessed, in a population-based study, the association between the French National Nutrition and Health Program Guideline Score (PNNS-GS) and 6-y risk of MetS. Participants in the Supplémentation en Vitamines et Minéraux Antioxydants study were followed-up from 1994-1996 to 2001-2002. MetS was defined according to International Diabetes Federation criteria. We also defined "mild" and "severe" MetS as waist criteria plus 2, or more than 2, other criteria. Prospective associations between the PNNS-GS at baseline (either as a continuous variable or in quartiles) and incident MetS were assessed using binary or multinomial logistic regression to provide OR and 95% CI in participants free of MetS at baseline (n = 2763). In multivariate models, each unit increase in the PNNS-GS score was associated with a 9% lower risk of MetS (OR = 0.91; 95% CI = 0.83-1.00). This association was even stronger with the risk of severe MetS (OR = 0.76; 95% CI = 0.63-0.91). After adjustment for baseline and change in BMI, this association remained significant for severe MetS but did not reach significance for overall MetS. These findings support a potential beneficial impact of nutritional guidelines upon primary prevention of MetS. Improvement in compliance with nutritional recommendations may help to reduce the burden of CVD disease in the general population.


Mobilization and homing of peripheral blood progenitors is related to reversible downregulation of alpha4 beta1 integrin expression and function.
Despite the wide use of mobilized peripheral blood (PB) progenitor cells (PBPC) for clinical transplantation the mechanism(s) underlying their mobilization and subsequent engraftment are still unknown. We compared the adhesive phenotype of CD34(+) colony-forming cells (CFC) in bone marrow (BM) and PB of normal donors before and after administration of granulocyte colony-stimulating factor (G-CSF) for 5 d. G-CSF-mobilized PB CFC cells adhered significantly less to BM stroma, fibronectin, and to the alpha4 beta1 binding fibronectin peptide, CS1, because of decreased expression of the alpha4 integrin. Since incubation of BM CD34(+) cells for 4 d with G-CSF at concentrations found in serum of G-CSF- treated individuals did not affect alpha4-dependent adhesion, G-CSF may not be directly responsible for the decreased alpha4-mediated adhesion of PB CFC. Culture of G-CSF-mobilized PB CD34(+) cells with cytokines at concentrations found in BM stromal cultures upregulated alpha4 expression and restored adhesion of mobilized PB CFC to stroma, fibronectin, and CS1. Adhesion of cultured, mobilized PB CFC to stroma and CS1 could not be further upregulated by the beta1 activating antibody, 8A2. This indicates acquisition of a maximally activated alpha4 beta1 integrin once PB CFC have been removed from the in vivo mobilizing milieu. Thus, decreased alpha4 expression on CD34(+) CFC in PB may be responsible for the aberrant circulation of mobilized PB CD34(+) cells. Reexpression of a maximally activated alpha4 beta1 integrin on mobilized PB CFC removed from the mobilizing in vivo milieu may contribute to the early engraftment of mobilized PBPC.


Metabolic and Lipidomic Markers Differentiate COVID-19 From Non-Hospitalized and Other Intensive Care Patients.
Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus, there is increasing interest in metabolic and lipoprotein signatures of the disease, and early analyses have demonstrated a metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether this is specific for COVID-19 and whether the observed signature is caused by the disease or rather represents an underlying risk factor. To answer this question, we have analyzed 482 serum samples using nuclear magnetic resonance metabolomics, including longitudinally collected samples from 12 COVID-19 and 20 cardiogenic shock intensive care patients, samples from 18 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody-positive individuals, and single time point samples from 58 healthy controls. COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared with healthy controls. Specifically, very-low-density lipoprotein and intermediate-density lipoprotein particles and associated apolipoprotein B and intermediate-density lipoprotein cholesterol were significantly increased, whereas cholesterol and apolipoprotein A2 were decreased. Moreover, a similarly perturbed profile was apparent when compared with other patients with cardiogenic shock who are in the intensive care unit when looking at a 1-week time course, highlighting close links between COVID-19 and lipid metabolism. The metabolic profile of COVID-19 patients distinguishes those from healthy controls and also from patients with cardiogenic shock. In contrast, anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared with age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized low- and high-density lipoprotein subfractions. Our data suggest that COVID-19 is associated with dyslipidemia, which is not observed in anti-SARS-CoV-2 antibody-positive individuals who have not developed severe courses of the disease. This suggests that lipoprotein profiles may represent a confounding risk factor for COVID-19 with potential for patient stratification.


Parental reports of health-related quality of life in young children with neurofibromatosis type 1: influence of condition specific determinants.
To assess the health-related quality of life of 34 Dutch children 12 to 72 months of age with neurofibromatosis type 1 (NF1) using the Infant/Toddler Quality of Life Questionnaire (ITQOL) and to investigate the potential impact of clinical factors on parental reports of health-related quality of life. A parent-completed form including the ITQOL, NF1-specific questions, and sociodemographic questions was sent. ITQOL scale scores were compared for the study population against Dutch reference values. The influence of general and clinical characteristics on ITQOL scale scores was evaluated with multivariate analysis. A significant impact was observed on most aspects of quality of life, particularly for growth and development, general health perceptions and parental impact. The lowest scores were observed in children with complications because of NF1. ITQOL scale scores were affected by parental educational level, familial NF1, and parental reports of complications of NF1 and perceived disease severity. Important aspects of health-related quality of life were observed to be negatively affected in children with NF1, as measured by the ITQOL. Family-related and disease-related variables appeared to influence the quality of life in children with NF1.


Conversion of pepsinogen into pepsin is not a one-step process.
By incubation of pepsinogen with pepstatin at pH2.5, the first 'active' protein generated on activation is trapped in an inactive complex. The first activation peptide liberated has been identified as residues 1-16 from the pepsinogen sequence. This suggests a sequential mechanism rather than a one-step formation of pepsin.


Feasibility and outcomes of the Berg Balance Scale in older adults with intellectual disabilities.
High incidence of falls and increased risk of fall-related injuries are seen in individuals with intellectual disabilities (ID). The Berg Balance Scale (BBS) is a reliable instrument for balance assessment in the population of (older) adults with ID. The aims of this study were to assess the balance capacities of a large group of older adults with ID with the BBS and look for gender and age effects, as well as reasons for drop-out on separate items, and to identify feasible subtests for subgroups in which the complete BBS is not feasible. The balance capacities of 1050 older clients with borderline to profound ID of three Dutch care-provider services (mean age 61.6 [sd=8.0]) were assessed with the BBS. The participants who completed all items of the BBS (n=508) were the functionally more able part of the study sample. Results showed that even this functionally more able part had poor balance capacities, with a mean BBS score of 47.2, 95% CI [46.3, 48.0], similar to adults in the general population aged around 20 years older. Balance capacities decreased with increasing age and females had poorer balance capacities than males. Difficulties understanding the task and physical limitations were most often the reasons for drop-out. Feasible subtests were identified for the subgroups with very low cognitive levels and wheelchair users. Low balance capacities of older adults with ID show the need for regular screening and the urge for fall prevention programs for individuals with ID.


COVID-19 and the impact on blood availability and transfusion practices in low- and middle-income countries.
The coronavirus disease 2019 (COVID-19) pandemic disrupted the global blood supply. Low- and middle-income countries (LMICs) already experienced blood supply deficits that preceded the pandemic. We sought to characterize the challenges experienced during the pandemic, and adaptations, such as COVID-19 convalescent plasma (CCP). A cross-sectional survey explored blood availability, challenges, and adaptations. The survey contained 31 questions, e-mailed in English, French, or Spanish, to selected LMIC blood transfusion practitioners. Data acquisition occurred between October 28 and December 28, 2020. A mixed methods analysis followed. A total of 31 responses from 111 invitations represented 26 LMIC countries. Languages included English (22, 71%), Spanish (7, 22.6%), and French (2, 6.4%). Most respondents (29/31, 93.5%) collected blood; 58% also transfused blood (18/31). The supply of blood came from hospital-based blood donations (61%, 11/18); blood suppliers (17%, 3/18); and both sources (22%, 4/18). Collectively, 77.4% (24/31) of respondents experienced a decline in blood availability, ranging from 10% to 50%. Contributing factors included public fear of COVID-19 (21/24); stay-at-home measures (18/24); logistics (14/24); and canceled blood drives (16/24). Adaptations included increased collaboration within and between institutions (17/27), donor eligibility changes (21/31); social media or phone promotion (22/39); and replacement donation (3/27). Fifteen of 31 responses reported CCP donation (48.4%); CCP transfusion occurred in 6 (19.4%). The primary barrier was engaging recovered patients for donation (7/15). Our survey describes challenges experienced by LMIC blood systems during the COVID-19 pandemic. While the decline in blood supplies was severe, adaptive measures included collaboration, outreach, and CCP programs.


Quality of life for veterans and servicemembers with major traumatic limb loss from Vietnam and OIF/OEF conflicts.
The goals of rehabilitation after major limb loss include not only functional restoration but also a return to a high quality of life (QOL). Few studies have identified which factors are associated with QOL in veterans and servicemembers with combat-associated major limb loss. We enrolled Vietnam and Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans and servicemembers in a national survey on prosthetic device use. In the Vietnam group, multivariate analysis found multiple limb loss (adjusted odds ratio [aOR] = 3.1, 95% confidence interval [CI] = 1.57-6.02) and satisfaction with current prostheses (aOR = 1.2, 95% CI = 1.05-1.38) are associated with better overall QOL, while a higher amputation impact rank (aOR = 0.66, 95% CI = 0.59-0.74) and depression (aOR = 0.21, 95% CI = 0.08-0.54) are associated with worse overall QOL. In the OIF/OEF group, three factors are significantly associated with worse overall QOL: combat-associated head injury (aOR = 0.78, 95% CI = 0.61-0.99), combat-associated injury to the nonamputated limb (aOR = 0.71, 95% CI = 0.57-0.88), and assistance needed in daily living (aOR = 0.12, 95% CI = 0.02-0.72). Improving satisfaction with prosthetic devices, improving mental health care, and treating other combat-associated injuries may significantly improve the overall QOL for these veterans and servicemembers.


Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.
We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS. Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years. Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL. Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.


Cigarette smoking and e-cigarette use among university students in Queensland, Australia and New Zealand: results of two cross-sectional surveys.
Examine the patterns of cigarette smoking and e-cigarette use (vaping), the perceived harm of e-cigarettes compared with tobacco cigarettes, and associations between smoking and vaping with student characteristics. Cross-sectional studies. The University of Queensland (UQ), Australia and eight New Zealand (NZ) universities. Students at UQ: 4957 (70.8% aged <25 years, 63.0% women) and NZ: 1854 (82.5% aged <25 years, 60.1% women). Χ2 tests compared smoking by age and gender, and vaping by age, gender and smoking status. Two-sided p<0.05 was considered significant and 95% CIs reported where appropriate. Multinomial logistic regression examined associations between smoking and vaping (exclusive smoking, exclusive vaping, dual use and non-use) with age, gender and student type (domestic vs international). Smoking (UQ vs NZ, 95% CI): ever 45.2% (43.8% to 46.6%) vs 50.0% (47.7% to 52.3%), current 8.9% (8.1% to 9.7%) vs 10.4% (9.1% to 11.9%) and daily 5.2% (4.6% to 5.8%) vs 5.6% (4.6% to 6.7%), and not smoking in indoor 98.3% vs 87.7% or outdoor smoke-free spaces 83.8% vs 65.3%.Vaping (UQ vs NZ, 95% CI): ever 20.9% (19.8% to 22.1%) vs 37.6% (35.4% to 39.9%), current 1.8% (1.5% to 2.2%) vs 6.5% (5.4% to 7.7%) and daily 0.7% (0.5% to 1.0%) vs 2.5% (1.9% to 3.4%), and not vaping in indoor 91.4% vs 79.6% or outdoor smoke-free spaces 84.4% vs 71.3%. Of respondents, 71.7% (70.3% to 73.2%) vs 75.3% (72.9% to 77.6%) perceived e-cigarettes as less harmful than tobacco cigarettes.Men were more likely than women to smoke and vape, and to believe that e-cigarettes are less harmful. Regression models containing all predictors for smoking and vaping were significant and the effect of gender was significant for dual use, exclusive smoking and exclusive vaping (all p<0.01). Men had higher odds for smoking, vaping or dual use. Results suggest significant differences in patterns of smoking and vaping of university students in Australia and NZ, and a strong influence of gender on smoking and vaping.


Reduced fluence versus standard photodynamic therapy in combination with intravitreal triamcinolone: short-term results of a randomised study.
To compare early treatment effect of reduced fluence versus standard photodynamic therapy (rPDT, sPDT, respectively) in combination with intravitreal triamcinolone (IVTA) in neovascular age-related macular degeneration. Forty patients received either sPDT (group A, n = 20) or rPDT (group B, n = 20) each followed by same-day 4 mg IVTA. Patients were examined at baseline, day 1, week 1, 4 and 12. Main outcomes were visual acuity, central retinal thickness (CRT), choroidal perfusion and macular sensitivity (MS). Baseline characteristics were well balanced in both groups (p>0.05). At week 12, patients in group A had a mean loss of -3.7 letters compared with a gain of 3.4 letters in group B (p = 0.04, between both groups). Both treatment groups showed a similar course regarding CRT as well as MS (p>0.05). In 70% (14/20) of group A and 15% (3/20) of group B, a choroidal hypoperfusion in the area of treatment was observed after treatment (p<0.001). In 70% of group A and 55% of group B, a repeat treatment was indicated at week 12 (p = 0.55). At month 3, the rPDT+IVTA group showed a significantly better visual outcome, less alteration of the choroid and a trend for lower recurrence rate than the sPDT+IVTA group. Further follow-up of this study will provide information on long-term functional results and treatment durability.


Diffusion with partial resetting.
Inspired by many examples in nature, stochastic resetting of random processes has been studied extensively in the past decade. In particular, various models of stochastic particle motion were considered where, upon resetting, the particle is returned to its initial position. Here we generalize the model of diffusion with resetting to account for situations where a particle is returned only a fraction of its distance to the origin, e.g., half way. We show that this model always attains a steady-state distribution which can be written as an infinite sum of independent, but not identical, Laplace random variables. As a result, we find that the steady-state transitions from the known Laplace form which is obtained in the limit of full resetting to a Gaussian form, which is obtained close to the limit of no resetting. A similar transition is shown to be displayed by drift diffusion whose steady state can also be expressed as an infinite sum of independent random variables. Finally, we extend our analysis to capture the temporal evolution of drift diffusion with partial resetting, providing a bottom-up probabilistic construction that yields a closed-form solution for the time-dependent distribution of this process in Fourier-Laplace space. Possible extensions and applications of diffusion with partial resetting are discussed.


Effects of bradykinin on venous capacitance in health and treated chronic heart failure.
In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3+/-2.1%, P<0.001 compared with baseline; ARB-treated CHF patients maximum 9.3+/-3.3%, P<0.05 compared with baseline; P=not significant for difference between groups), but the increase in unstressed volume in ACEI-treated CHF patients was higher (maximum 28.8+/-7.8%, P<0.001 compared with baseline; P<0.05 for the difference between groups). In contrast, while the increase in blood flow in healthy volunteers (maximum 362+/-9%, P<0.001) and in ACEI-treated CHF patients (maximum 376+/-12%, P<0.001) was similar (P=not significant for the difference between groups), the increase in ARB-treated CHF patients was less (maximum 335+/-7%, P<0.001; P<0.05 for the difference between groups). Infusion of each receptor antagonist alone similarly reduced basal unstressed volume and blood flow in ACEI-treated CHF patients, but not in healthy volunteers or ARB-treated CHF patients. In conclusion, bradykinin does not contribute to basal venous tone in health, but in ACEI-treated chronic heart failure it does. In ARB-treated heart failure, venous responses to bradykinin are preserved but arterial responses are reduced compared with healthy controls. Bradykinin-mediated vascular responses in both health and heart failure are mediated by the B2, rather than the B1, receptor.


A screening study of antidepressant treatment rates and mood symptoms in pregnancy.
As part of a large screening study of perinatal depression, pregnant women were screened for demographic, depression and treatment variables in obstetrics clinics. Women taking antidepressant medication prior to conception were included in the sample as the study aimed to document rates of antidepressant medication use, and relationship to depressive symptomatology. Among women who reported using antidepressant medications within 2 years prior to screening (n = 390, or 11% of all women), 22% reported current use of these medications. Women who reported using antidepressant medications (52%) and those who discontinued them (49%) evidenced elevated depressive symptoms during pregnancy. Both women who discontinue and some who continue antidepressants during pregnancy demonstrate depressive symptoms, suggesting sub-optimal management of both groups. Future studies should carefully assess the adequacy of treatments prescribed as well as the monitoring and adherence of recommended treatments. Full symptom remission should be the goal for antenatal and postnatal depression in order to minimize risk to mother and baby.


Differential mapping spiking neural network for sensor-based robot control.
In this work, a spiking neural network (SNN) is proposed for approximating differential sensorimotor maps of robotic systems. The computed model is used as a local Jacobian-like projection that relates changes in sensor space to changes in motor space. The SNN consists of an input (sensory) layer and an output (motor) layer connected through plastic synapses, with inter-inhibitory connections at the output layer. Spiking neurons are modeled as Izhikevich neurons with a synaptic learning rule based on spike timing-dependent plasticity. Feedback data from proprioceptive and exteroceptive sensors are encoded and fed into the input layer through a motor babbling process. A guideline for tuning the network parameters is proposed and applied along with the particle swarm optimization technique. Our proposed control architecture takes advantage of biologically plausible tools of an SNN to achieve the target reaching task while minimizing deviations from the desired path, and consequently minimizing the execution time. Thanks to the chosen architecture and optimization of the parameters, the number of neurons and the amount of data required for training are considerably low. The SNN is capable of handling noisy sensor readings to guide the robot movements in real-time. Experimental results are presented to validate the control methodology with a vision-guided robot.


Moving Forward on Consent Practices in Australia.
Allowing persons to make an informed choice about their participation in research is a pre-eminent ethical and legal requirement. Almost universally, this requirement has been addressed through the provision of written patient information sheets and consent forms. Researchers and others have raised concerns about the extent to which such forms-particularly given their frequent lengthiness and complexity-provide participants with the tools and knowledge necessary for autonomous decision-making. Concerns are especially pronounced for certain participant groups, such as persons with low literacy and Indigenous persons. Multimedia strategies have the potential to usefully supplement current consent practices in Australia; however, information is needed about the need for supplementary consent practices, along with drivers for and barriers against adoption. This study initiates the required evidence base through an audit of informed consent practices for medical research in the Australian state of Tasmania to assess the need for, and current uptake of, supplementary consent strategies. Drivers for and barriers against adoption of multimedia consent practices were explored in detail through interviews with key stakeholders, including researchers, HREC chairs and members, and research participants, including Indigenous participants.


Early use of CO2 lasers and silicone gel on surgical scars: Prospective study.
Some publications have shown good aesthetic results for scars through the early application of fractional CO2 lasers on elective surgery scars. The aim of this randomized, double-blinded clinical trial was to compare the aesthetic quality of the scar from a group of patients submitted to super-pulsed fractional CO2 laser applications (10,600 nm fractional CO2 , set at a density of 20% and an energy of 10 mJ, a scanner of 03 × 03 mm, and a pulse repetition time of 0.3 seconds) in contrast with the other group that used only the silicone gel on the scar after plastic surgery. A prospective study was conducted by analyzing 42 patients with recent scars of up to three weeks in patients with a I-IV Fitz-Patrick skin phototype. The scars were evaluated aesthetically in the second and sixth months by applying the Vancouver scale. At 2 months of treatment, the statistical data showed a discrete superiority in the LASER group's treatment, as compared to that of the SILICONE group, in both percentage and significance concerning flexibility (P = 0.05) and pigmentation (P = 0.01). Laser group presented better results in the sixth month (P = 0,03). The early use of the fractional CO2 laser contributed to improving the aesthetic quality of scars from elective surgeries in the second and in the 6th months. Lasers Surg. Med. 49:570-576, 2017. © 2017 Wiley Periodicals, Inc.


Effects of rapid versus slow infusion of sodium bicarbonate on cerebral hemodynamics and oxygenation in preterm infants.
Sodium bicarbonate (NaHCO3) is often used for correction of metabolic acidosis in preterm infants. The effects of NaHCO3 administration on cerebral hemodynamics and oxygenation are not well known. Furthermore, there is no consensus on infusion rate of NaHCO3. To evaluate the effects of rapid versus slow infusion of NaHCO3 on cerebral hemodynamics and oxygenation in preterm infants. Twenty-nine preterm infants with metabolic acidosis were randomized into two groups (values are mean +/-SD): In group A (GA 30.5 +/- 1.7 weeks, b.w. 1,254 +/- 425 g) NaHCO3 4.2% was injected as a bolus. In group B (GA 30.3 +/- 1.8 weeks, b.w. 1,179 +/- 318 g) NaHCO3 4.2% was administered over a 30-min period. Concentration changes of oxyhemoglobin (cO2Hb) and deoxyhemoglobin (cHHb) were assessed using near infrared spectrophotometry. Changes in HbD (= cO2Hb - cHHb) represent changes in cerebral blood oxygenation and changes in ctHb (= cO2Hb + cHHb) reflect changes in cerebral blood volume. Cerebral blood flow velocity was intermittently measured using Doppler ultrasound. Longitudinal data analysis was performed using linear mixed models (SAS procedure MIXED), to account for the fact that the repeated observations in each individual were correlated. Administration of NaHCO3 resulted in an increase of cerebral blood volume which was more evident if NaHCO3 was injected rapidly than when infused slowly. HbD and cerebral blood flow velocity did not show significant changes in either group. To minimize fluctuations in cerebral hemodynamics, slow infusion of sodium bicarbonate is preferable to rapid injection.


CLINICAL OPHTHALMIC PARAMETERS OF THE TEXAS TORTOISE (GOPHERUS BERLANDIERI).
Ophthalmic studies of the Texas tortoise (Gopherus berlandieri) established normal ophthalmic parameters for select diagnostic tests in captive tortoises and assessment of differences among individuals of differing size and health status. Sixty-one tortoises of varying weight, shell size, Mycoplasma seroprevalence, and herpesvirus exposure were included. Complete ophthalmic examinations, including neuro-ophthalmic reflexes, phenol red thread test, rebound tonometry, fluorescein staining, palpebral fissure length measurement, slit lamp biomicroscopy, indirect fundoscopy, and ocular ultrasound measurements of axial globe length, anterior chamber depth, lens thickness, and vitreous length, were recorded. All tortoises had negative dazzle and pupillary light reflexes, inconsistent menace responses, and positive palpebral reflexes. Mean ± SD tear production and intraocular pressure (IOP) were 14.2 ± 5.6 mm/15 sec and 13.8 ± 2.4 mm Hg in healthy tortoises, respectively. Mycoplasma-seropositive tortoises (with or without herpesvirus exposure) had significantly increased tear production (20.2 ± 8.1 and 19.9 ± 8.9 mm/15 sec, respectively) compared with healthy seronegative tortoises (14.2 ± 5.6 mm/15 sec; P = 0.02). As body size decreased, so too did palpebral fissure length and ocular ultrasound measurements, while IOP increased. Overall, palpebral fissure length appeared relatively small, and tear production relatively increased compared with other chelonian species, likely on the basis of the relatively arid native habitat. Further work is recommended to establish baseline values in related species, as well as comparison in aquatic versus terrestrial chelonians. The authors further suggest that the finding of relatively increased tear production in tortoises may indicate the need to rule out mycoplasmosis as a cause of upper respiratory tract disease.


Hyperbaric oxygen treatment during pregnancy in acute carbon monoxide poisoning. A case report.
Carbon monoxide poisoning in pregnancy is a relatively rare occurrence, with potentially serious complications for both mother and fetus. Controversy regarding treatment during pregnancy exists primarily due to the concern for oxygen toxicity in the fetus. However, rapid oxygen dissociation and prolonged clearance of carbon monoxide in the fetal circulation emphasize the importance of adhering to aggressive treatment protocols. A 22-year-old employee at an office undergoing repairs on the heating and ventilation systems presented with neurologic symptoms, tachycardia, tachypnea, signs of preterm labor and a carboxyhemoglobin level that was mildly elevated. Fetal monitoring demonstrated a reactive nonstress test with mild to moderate repetitive variable decelerations. The patient underwent hyperbaric oxygen treatment, with complete resolution of her neurologic symptoms, tachycardia and tachypnea as well as fetal variable decelerations. She was additionally treated with intravenous magnesium sulfate tocolysis, with cessation of contractions. The patient subsequently delivered at term; the viable infant had no sequelae of in utero carbon monoxide poisoning. This case supports previously published recommendations for treating acute carbon monoxide poisoning during pregnancy with hyperbaric oxygen. As more cases are gathered, a more widely accepted set of standards can be established.


Targeting angiogenesis in small cell lung cancer.
Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year. Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.


Dealing with cancer screening in the COVID-19 era.
This article aims to alert health professionals for cancer screening in the face of the possibility of new waves of disease. A narrative review was conducted through a search in MEDLINE, Lilacs, Chinese Biomedical Literature Database, and international medical societies publications. Breast cancer: in high-risk patients (confirmed familial cancer syndrome or with high-risk tools scores), clinicians should act according to usual recommendations; in average-risk individuals, consider screening with mammography with a longer time span (maximum of two years). Cervical cancer: women turning 25 years old who have already been immunized and with no previous Pap test can have the test postponed during the pandemic; if there is no previous dose of Human Papillomavirus vaccination, initiation of screening should be recommended following a more rigid approach for COVID prevention; in women over 30 years of age who have never participated in cervical screening, the first screening exam is also essential. Colorectal cancer: if the individual is at elevated risk for familial cancer, the screening with colonoscopy according to usual recommendations should be supported; if at average risk consider screening with Fecal Occult Blood Test. Prostate cancer: there is a trend to postpone routine prostate cancer screening until the pandemic subsides. The decision to keep cancer screening must be discussed and individualized, considering the possibility of new waves of COVID-19.


Night shift work characteristics and risk of incident coronary heart disease among health care workers: national cohort study.
Night work has been associated with coronary heart disease. The present study examined exposure-response relations between quantitative night work characteristics and coronary heart disease (angina pectoris or myocardial infarction) with the aim to contribute to evidence-based recommendations for low-risk night work schedules. We followed 100 149 night workers (80% women) and 153 882 day workers (78% women), all health care workers in Denmark with day by day payroll information on night shifts from 2007 to 2015. We analysed data with Poisson regression stratified by sex and adjusted for age, calendar year, diabetes, family history of cardiovascular disease, educational level, occupation, indicators for obesity, hypercholesterolaemia, and hypertension. Female and male night workers worked on average 1.7 and 1.8 night shifts per month for an average duration of less than 4 years. During follow-up, 1198 night and 2128 day workers were hospitalized with first-time coronary heart disease. When compared with day workers, the overall incidence rate ratios for female and male night workers were 1.06 [95% confidence interval (CI): 0.97, 1.17] and 1.22 (95% CI 1.07, 1.39). Highest risks were observed in top exposure categories for several night work characteristics. However, no consistent exposure-response relations by number of monthly night shifts, cumulative night shifts, years with rotating night shifts, years with any night shift and consecutive night shifts were observed among the night workers of either sex. This study of a population with low exposure to night work does not indicate that reducing extent of monthly night shifts, cumulative night shifts, years with rotating night shifts, years with any night shift and consecutive night shifts would reduce the risk of coronary heart disease.


A split-luciferase lysate-based approach to identify small-molecule modulators of phosphatase subunit interactions.
An emerging strategy for the therapeutic targeting of protein phosphatases involves the use of compounds that interfere with the binding of regulatory subunits or substrates. However, high-throughput screening strategies for such interfering molecules are scarce. Here, we report on the conversion of the NanoBiT split-luciferase system into a robust assay for the quantification of phosphatase subunit and substrate interactions in cell lysates. The assay is suitable to screen small-molecule libraries for interfering compounds. We designed and validated split-luciferase sensors for a broad range of PP1 and PP2A holoenzymes, including sensors that selectively report on weak interaction sites. To facilitate efficient hit triaging in large-scale screening campaigns, deselection procedures were developed to eliminate assay-interfering molecules with high fidelity. As a proof-of-principle, we successfully applied the split-luciferase screening tool to identify small-molecule disruptors of the interaction between the C-terminus of PP1β and the ankyrin-repeat domain of the myosin-phosphatase targeting subunit MYPT1.


Bilberry and Sea Buckthorn Leaves and Their Subcritical Water Extracts Prevent Lipid Oxidation in Meat Products.
The aim of this study was to find new sustainable, Nordic natural antioxidant sources, develop subcritical water extraction (SWE) process for recovering the antioxidant compounds from the most potential raw materials, and to test their antioxidative effects in meat products. The antioxidant capacities of water and 50% ethanol (aq) extracts of 13 berry, grain, and horticultural plant materials as well as hexane/ethanol extracted stilbene fractions from pine heartwood and spruce inner bark were measured in hydrophilic and lipophilic systems. Tree, bilberry leaf (BL), and sea buckthorn leaf (SBL) extracts showed the highest antioxidant capacities. BL and SBL were selected for the development of SWE. The optimal conditions for recovering maximal antioxidative capacities were 110 °C/1 min for SBL and 120 °C/1 min for BL. Dried BL and SBL and the respective optimized subcritical water extracts were applied in chicken slices and pork sausage, and their ability to prevent lipid oxidation was evaluated during 8 and 20 days storage, respectively, at 6 °C. All tested plant ingredients effectively prevented lipid oxidation in the products compared to the control samples. Sensory acceptance of the plant ingredients was good, especially in the chicken product. To our knowledge, this is the first study to assess the antioxidant effects of SW extracted berry leaves in meat products.


Angiogenic efficacy of ASC spheroids filtrated on porous nanosheets for the treatment of a diabetic skin ulcer.
Stem cell transplantation is expected to be an effective treatment for intractable skin ulcers by promoting angiogenesis; however, it is challenging to quickly realize a sufficient bloodstream for the ulcers. For this treatment, sheet-like materials with monolayer cells such as cell sheets have been investigated. However, they have a limitation of cell number that can be transplanted at one time due to the two-dimensional, monolayer cell structure, and sufficient secretion of growth factors cannot be expected. In this regard, cellular aggregates, such as spheroids, can reproduce three-dimensional cell-cell interactions that cause biological functions of living tissues more representative than monolayer cells, which is important to achieving efficient secretion of growth factors. In this study, we focused on free-standing porous polymer ultrathin films ("porous nanosheets") comprising poly(d,l-lactic acid) (PDLLA) and succeeded in developing a spheroid-covered nanosheet, on which more than 1000 spheroids from adipose-tissue derived stem cells (ASCs) were loaded. The porous structure with an average pore diameter of 4 μm allowed for facile filtration and carrying spheroids on the nanosheet, as well as sufficient oxygen and nutrients inflow to the cells. The spheroid-covered nanosheet achieved homogeneous transference of spheroids to a whole skin defect in diabetic model mice. Given the continuous release of vascular endothelial growth factor (VEGF) from the spheroids, the transplanted spheroids promoted healing with more accelerated angiogenesis than a nanosheet with a monolayer of cells. The spheroid-covered nanosheet may be a new regenerative material for promoting intractable skin ulcer healing.


Comparison of Pediatric Dentistry Under General Anesthesia in a Surgery Center vs a Hospital.
Pediatric patients who undergo general anesthesia (GA) for dentistry may be treated in different venues. This retrospective study compared patients treated in an ambulatory surgery center (ASC) to those treated in a hospital operating room (H-OR). The 2-venue model was also compared with a historical hospital-only model. Twelve months of data were collected via records review: patient demographics, American Society of Anesthesiology (ASA) classification, and medical comorbidities. Data from patients treated at the H-OR 10 years prior were referenced for comparison. Between July 2017 and June 2018, 1148 patients were treated: 635 at the ASC and 513 at the H-OR. The most common age range for both venues was 3 to 8 years. Of all the ASC patients, 78% were ASA I, while 48% of H-OR patients were ASA III (P < .001). The number of patients treated with the 2-venue model represented a 240% annual increase compared with those treated historically using the hospital-only model. Because of differences in patient medical comorbidities, both the ASC and H-OR are needed to adequately address the needs of pediatric dental patients who require GA. Treating healthy patients in an ASC also creates increased capacity in the H-OR to better accommodate those with higher medical acuity.


[Alveolar deposition of inhaled radio-aerosol particles in central and peripheral airway obstruction. Methodologic conditions and clinical results].
The degree of alveolar deposition of inhaled microparticles, which is affected by airway patency, was studied in 16 asymptomatic smokers with small airways disease. Compared to healthy subjects (n = 12) as well as to patients with chronic obstructive lung disease (COLD, n = 14) significant differences in mean alveolar particle deposition were encountered. The results indicate that in both patient groups the lower-lung regions were most affected by airway obstruction. In patients with peripheral airways disease there was no difference in the degree of right- and left-lung aerosol deposition whereas in patients with COLD obstructive airway alteration was found to affect preferably the right lung region.


Cancer Fatalism and Preferred Sources of Cancer Information: an Assessment Using 2012 HINTS Data.
Cancer fatalism is associated with lower participation in cancer screening, nonadherence to cancer screening guidelines, and avoidance of medical care. Few studies, however, have examined the relationship between cancer fatalism and health information seeking. The purpose of this study was to examine the relationship between endorsement of fatalistic beliefs regarding cancer and preferred sources of cancer information. We analyzed data from the Health Information National Trends Survey 4 Cycle 2, which were collected in late 2012 and early 2013 (N = 3630). When weighted, the data are representative of the non-institutionalized US population aged 18 or older. In bivariate and multivariate analyses, we assessed three cancer fatalism beliefs as predictors of preferred use of healthcare provider versus preferred use of the Internet for cancer information. Results indicate the majority of US adults endorse one or more fatalistic beliefs about cancer. Unadjusted results indicate endorsing the fatalistic belief that "there's not much you can do to lower your chances of getting cancer" was significantly associated with lower odds of preferring the Internet (versus healthcare providers) as the source of cancer information (OR: 0.70; CI: 0.50, 0.98). In the adjusted model, however, none of the three cancer fatalism measures were significantly associated with preferred source of cancer information. In conclusion, fatalistic beliefs about cancer are common, and further research is warranted to understand cancer fatalism and whether and how it may impact health information-seeking behaviors.


Federated Learning for Diabetic Retinopathy Detection in a Multi-center Fundus Screening Network.
Federated learning (FL) is a machine learning framework that allows remote clients to collaboratively learn a global model while keeping their training data localized. It has emerged as an effective tool to solve the problem of data privacy protection. In particular, in the medical field, it is gaining relevance for achieving collaborative learning while protecting sensitive data. In this work, we demonstrate the feasibility of FL in the development of a deep learning model for screening diabetic retinopathy (DR) in fundus photographs. To this end, we conduct a simulated FL framework using nearly 700,000 fundus photographs collected from OPHDIAT, a French multi-center screening network for detecting DR. We develop two FL algorithms: 1) a cross-center FL algorithm using data distributed across the OPHDIAT centers and 2) a cross-grader FL algorithm using data distributed across the OPHDIAT graders. We explore and assess different FL strategies and compare them to a conventional learning algorithm, namely centralized learning (CL), where all the data is stored in a centralized repository. For the task of referable DR detection, our simulated FL algorithms achieved similar performance to CL, in terms of area under the ROC curve (AUC): AUC =0.9482 for CL, AUC = 0.9317 for cross-center FL and AUC = 0.9522 for cross-grader FL. Our work indicates that the FL algorithm is a viable and reliable framework that can be applied in a screening network.Clinical relevance- Given that data sharing is regarded as an essential component of modern medical research, achieving collaborative learning while protecting sensitive data is key.


Correlates of HIV infection among young adult short-term injection drug users.
To identify risks associated with HIV infection among young adult short-term injection drug users. Current injection drug users, between 18 and 29 years of age, were recruited through street outreach to participate in a cross-sectional survey of HIV prevalence by circumstances of drug injection initiation, HIV-related risk behaviors, and a follow-up to estimate HIV incidence. At enrollment, 33 (14.4%) of 229 participants were HIV-seropositive. Significant bivariate associations with HIV at the time injection drug use was initiated included age less than or equal to 18 years, having receptive anal sex with the person who assisted with initiation, and having two or more 'trainers' before being able to self-inject. Injecting risks positively associated with HIV included cocaine or speedball (heroin and cocaine together) injection versus heroin or amphetamine injection, injecting five or more times per day, daily crack smoking, backloading, sharing needles at peak drug use, and not using a new needle for every injection. Sexual practices associated with HIV included reporting > 100 lifetime sex partners, a history of sexual assault, being gay or bisexual, and trading sex for money or drugs after starting to inject. In a multivariate model, trading anal sex for money or drugs after initiating injection drug use [odds ratio (OR), 14.2; 95% confidence interval (CI) 3.2-62.3], cocaine/speedball injection (OR, 10.3; 95% CI, 2.2-47.9), daily crack smoking (OR, 4.2; 95% CI, 1.7-10.5), and having two or more trainers (OR, 2.6; 95% CI, 1.1 - 5.9) were independently associated with HIV. During 12 months of follow-up, four persons seroconverted for HIV (annual incidence: 2.6%; 95% CI, 1.1 -5.9%) Among short-term injectors, both sexual and injecting practices were important predictors of HIV infection, indicating that a proportion of HIV infections among young injection drug users can be attributed to sexual transmission. The incidence rate for HIV infection suggests that immediate steps should be taken to prevent new infections among young injection drug users.


Different spatial and temporal interactions between Notch, wingless, and vestigial specify proximal and distal pattern elements of the wing in Drosophila.
The wing of Drosophila is composed of a proximal element, the hinge, which attaches it to the thorax, and a distal one, the wing blade. The development of the wing is a complex process that requires the integration of cellular responses to two signaling systems centered along the anteroposterior and the dorsoventral axes. The genes Notch (N) and wingless (wg) play an important role in generating the information from the dorsoventral axis. The vestigial (vg) gene is necessary for the development of the wing and is a target of these signaling systems during the growth of the wing. Here we examine the roles that N, wg, and vg play during the initial stages of wing development. Our results reveal that vg is involved in the specification of the wing primordium under the combined control of Notch and wingless signaling. Furthermore, we show that once cells are assigned to the wing fate, their development relies on a sequence of regulatory loops that involve N, wg, and vg. During this process, cells that are exposed to the activity of both wg and vg will become wing blade and those that are continuously under the influence of wg alone will develop as hinge. Our results also indicate that the growth of the cells in the wing blade results from a synergistic effect of the three genes N, wg, and vg on the cells that have been specified as wing blade.


Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors.
Three glycosyltransferases are involved in tylosin biosynthesis in Streptomyces fradiae. The first sugar to be added to the polyketide aglycone (tylactone) is mycaminose and the gene encoding mycaminosyltransferase is orf2* (tylM2). However, targeted disruption of orf2* did not lead to the accumulation of tylactone under conditions that normally favour tylosin production; instead, the synthesis of tylactone was virtually abolished. This may, in part, have resulted from a polar effect on the expression of genes downstream of orf2*, particularly orf4* (ccr) which encodes crotonyl-CoA reductase, an enzyme that supplies 4-carbon extender units for polyketide metabolism. However, that cannot be the entire explanation, since tylosin production was restored at about 10% of the wild-type level when orf2* was re-introduced into the disrupted strain. When glycosylated precursors of tylosin were fed to the disrupted strain, they were converted to tylosin, confirming that two of the three glycosyltransferase activities associated with tylosin biosynthesis were still intact. Interestingly, however, tylactone also accumulated under such conditions and, to a much lesser extent, when tylosin was added to similar fermentations. It is concluded that glycosylated macrolides exert a pronounced positive effect on polyketide metabolism in S. fradiae.


A Clinical Practice Guideline for the Emergency Management of Anaphylaxis (2020).
Background: For anaphylaxis, a life-threatening allergic reaction, the incidence rate was presented to have increased from the beginning of the 21st century. Underdiagnosis and undertreatment of anaphylaxis are public health concerns. Objective: This guideline aimed to provide high-quality and evidence-based recommendations for the emergency management of anaphylaxis. Method: The panel of health professionals from fifteen medical areas selected twenty-five clinical questions and formulated the recommendations with the supervision of four methodologists. We collected evidence by conducting systematic literature retrieval and using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: This guideline made twenty-five recommendations that covered the diagnosis, preparation, emergency treatment, and post-emergency management of anaphylaxis. We recommended the use of a set of adapted diagnostic criteria from the American National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network (NIAID/FAAN), and developed a severity grading system that classified anaphylaxis into four grades. We recommended epinephrine as the first-line treatment, with specific doses and routes of administration for different severity of anaphylaxis or different conditions. Proper dosage is critical in the administration of epinephrine, and the monitor is important in the IV administration. Though there was only very low or low-quality evidence supported the use of glucocorticoids and H1 antagonists, we still weakly recommended them as second-line medications. We could not make a well-directed recommendation regarding premedication for preventing anaphylaxis since it is difficult to weigh the concerns and potential effects. Conclusion: For the emergency management of anaphylaxis we conclude that: • NIAID/FAAN diagnostic criteria and the four-tier grading system should be used for the diagnosis • Prompt and proper administration of epinephrine is critical.


Phase behavior of diblock copolymer/star-shaped polymer thin film mixtures.
We investigated the phase behavior of thin film, thickness h≈ 100 nm, mixtures of a polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) diblock copolymer with star-shaped polystyrene (SPS) molecules of varying functionalities f, where 4 ≤f≤ 64, and molecular weights per arm Marm. The miscibility of the system and the surface composition varied appreciably with Marm and f. For large values of Marm, regardless of f, the miscibility of the system was qualitatively similar to that of linear chain PS/PS-b-P2VP mixtures - the copolymer chains aggregate to form micelles, each composed of an inner P2VP core and PS corona, which preferentially segregate to the free surface. On the other hand, for large f and small Marm, SPS molecules preferentially resided at the free surface. Moreover, blends containing SPS molecules with the highest values of f and lowest values of Marm were phase separated. These observations are rationalized in terms of competing entropic interactions and the dependence of the surface tension of the star-shaped molecules on Marm and f.


World Health Organization (WHO) and the World Heart Federation (WHF) Pathobiological Determinants of Atherosclerosis in Youth (PBDAY) Study. Lipid and raised lesion distribution in the right coronary artery of young people.
As part of the WHO-WHF PBDAY Study, we examined the proximal segment of the right coronary artery (RCA) (n = 469) of 5-34 yr-old otherwise healthy trauma victims from 15 countries to establish the topographical relation of atherosclerotic lesions to age, sex and geographical location. Topography and extent of lesions were analyzed by image processing and probability-of-occurrence maps of lipid lesions (mostly fatty streaks) and raised lesions on the intimal surface of the RCA were produced. Extension of lesions varied considerably between the groups and between individuals in the same group. The prevalence of lipid lesions was 68% (319/469) compared with 100% in the aorta. The prevalence of raised lesions was 22% (102/469) compared with 7% and 26% in the thoracic and abdominal aorta. Females had more lipid lesions, whereas raised lesions prevailed in males. Lipid lesion extent increased with age in both sexes. High probability-of-occurrence areas for lipid and raised lesions prevailed in the proximal 5 cm of the intimal surface of the RCA (myocardial side) and were greatly overlapping. Regression analysis between lipid and raised lesion extent in the thoracic or abdominal aorta and the RCA showed no correlations between the lipid lesion extent, whereas significant correlations were found between the raised lesion extent in the RCA and the thoracic aorta only, showing that the two types of lesion behave differently in different anatomical locations.


Five years' experience with a right atrial catheter for prolonged parenteral nutrition at home.
The results with a cuffed silicon rubber right atrial catheter for prolonged parenteral nutrition are reported. In 43 patients, 78 catheters were inserted; of these, 52 were removed for various reasons. The mean duration of catheter patency in 26 patients currently infusing at home is 9.4 months. The high incidence of catheter-related septicemia previously reported by others has been reduced to one for every 5.5 patient years. The combination of soft Silastic material, catheter design, localization and easy handling by the patient have all contributed to its longer life span. It can be used with impunity whenever long term access to the circulation is needed.


Tuning Inner-Sphere Electron Transfer in a Series of Copper/Nitrosoarene Adducts.
A series of copper/nitrosoarene complexes was created that mimics several steps in biomimetic O2 activation by copper(I). The reaction of the copper(I) complex of N,N,N',N'-tetramethypropylenediamine with a series of para-substituted nitrosobenzene derivatives leads to adducts in which the nitrosoarene (ArNO) is reduced by zero, one, or two electrons, akin to the isovalent species dioxygen, superoxide, and peroxide, respectively. The geometric and electronic structures of these adducts were characterized by means of X-ray diffraction, vibrational analysis, ultraviolet-visible spectroscopy, NMR, electrochemistry, and density functional theory (DFT) calculations. The bonding mode of the NO moiety depends on the oxidation state of the ArNO moiety: κN for ArNO, mononuclear η2-NO and dinuclear μ-η2:η1 for ArNO•-, and dinuclear μ-η2:η2 for ArNO2-. 15N isotopic labeling confirms the reduction state by measuring the NO stretching frequency (1392 cm-1 for κN-ArNO, 1226 cm-1 for η2-ArNO•-, 1133 cm-1 for dinuclear μ-η2:η1-ArNO•-, and 875 cm-1 for dinuclear μ-η2:η2 for ArNO2-). The 15N NMR signal disappears for the ArNO•- species, establishing a unique diagnostic for the radical state. Electrochemical studies indicate reduction waves that are consistent with one-electron reduction of the adducts and are compared with studies performed on Cu-O2 analogues. DFT calculations were undertaken to confirm our experimental findings, notably to establish the nature of the charge-transfer transitions responsible for the intense green color of the complexes. In fine, this family of complexes is unique in that it walks through three redox states of the ArNO moiety while keeping the metal and its supporting ligand the same. This work provides snapshots of the reactivity of the toxic nitrosoarene molecules with the biologically relevant Cu(I) ion.


Angiotensin AT(2) receptor contributes towards gender bias in weight gain.
Obesity is a major disease condition, in turn leading to pathological changes collectively recognized as metabolic syndrome. Recently angiotensin receptor AT(2)R has been associated negatively with body weight (BW) gain in male mice. However, the gender differences in AT(2)R and BW changes have not been studied. To understand the gender based role of AT(2)R involving BW changes, we fed male and female wild type (WT) and AT(2)R knock out (AT(2)KO) mice with C57BL6 background with high fat diet (HFD) for 16 weeks. The male AT(2)KO had higher HFD calorie intake (WT: 1280±80; AT(2)KO:1680±80 kcal) but gained less BW compared with the WT (WT: 13; AT(2)KO: 6 g). Contrary to the male animals, the female AT(2)KO mice with equivalent caloric intake (WT: 1424±48; AT(2)KO:1456±80 kcal) gained significantly more BW than the WT mice (WT: 9 g; AT(2)KO: 15 g). The male AT(2)KO on HFD displayed lower plasma insulin level, less impaired glucose tolerance (GT), and higher plasma T3 compared with WT males on HFD; whereas the female AT(2)KO mice on HFD showed elevated levels of plasma insulin, more impaired GT, lower plasma T3 and higher free fatty acid and hepatic triglycerides compared with WT females on HFD. Interestingly, compared with WT, AT(2)KO female mice had significantly lower estrogen, which was further reduced by HFD. These results suggest that AT(2)R in female mice via potentially regulating estrogen may have protective role against BW gain and impaired glucose tolerance and lipid metabolism.


Heart failure with preserved ejection fraction in outpatients with unexplained dyspnea: a pressure-volume loop analysis.
The aim of the present study was to diagnose heart failure with preserved ejection fraction (HFPEF) in outpatients with unexplained chronic dyspnea and to elucidate its underlying mechanisms in this population using invasive pressure-volume loop analysis. The diagnosis of HFPEF in stable outpatients with unexplained dyspnea is difficult. Thirty patients (age 67 +/- 8.6 years, 27% males) with preserved left ventricular (LV) ejection fraction (>50%) and unexplained chronic New York Heart Association functional class II to III dyspnea underwent heart catheterization. Patients with significant coronary artery stenosis (>50%) were excluded. Pressure-volume loops were assessed using a conductance catheter at rest, hand-grip exercise, leg lifting, and nitroprusside and dobutamine infusion. Twenty (66%) patients showed LV end-diastolic pressure >16 mm Hg (HFPEF), whereas the remaining 10 patients served as controls. Patients with HFPEF had significantly higher end-diastolic stiffness (0.205 +/- 0.074 vs. 0.102 +/- 0.017, p < 0.001) at rest, and their end-diastolic pressure-volume relationship showed a consistent upward and leftward shift during all hemodynamic interventions compared with controls. Regarding the underlying mechanism of HFPEF, 14 (70%) patients had markedly increased end-diastolic stiffness, which was considered a sufficient single pathology to induce increased LV end-diastolic pressure. Four (20%) patients showed a concomitant presence of moderately increased stiffness and severe LV dyssynchrony, and the remaining 2 (10%) patients, with normal stiffness, showed significant exercise-induced mitral regurgitation at hand-grip exercise. If the invasive pressure measurements were absent, only 5 (25%) of the outpatients with HFPEF fulfilled the European Society of Cardiology definition of HFPEF. A significant proportion of stable outpatients with unexplained chronic dyspnea may have HFPEF. In the patients whom we studied, increased LV stiffness, dyssynchrony, and dynamic mitral regurgitation were the major mechanisms underlying development of HFPEF.


Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial.
Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of "responders" in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron's mechanisms of action we hope to better identify patients with IBS-D who are likely to respond. ISRCTN, ISRCTN17508514 , Registered on 2 October 2017.


Combination of arsenic and interferon-α inhibits expression of KSHV latent transcripts and synergistically improves survival of mice with primary effusion lymphomas.
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice. These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.


Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease.
Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10(-5)). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10(-6) according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10(-8) according to the replication study; beta = 3.97 and p = 1.11 × 10(-13) according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in KD.


[On pathogenesis of primary open-angle glaucoma].
The article comprises data on the pathogenesis of primary open-angle glaucoma. Accepted theories and risk factors of glaucoma development are considered from a historical perspective as well as in the light of modern understanding of the essence of glaucomatous optic neuropathy. The impact of different independent factors on particular pathogenetic events and their interrelation is shown. Data on possible mechanisms involved in the neurogenerative process that yet lack substantiation are presented.


[Indications for percutaneous screw fixation of scaphoid fractures].
A total of 198 patients with scaphoid fracture who were treated by percutaneous screw fixation were reexamined after a mean postoperative time of 82 months. Sound radiological union and clinical healing were found in 89% of the recent fractures, 81.8% of fractures with delayed or nonunion and in 42.8% with sclerotic nonunion. Based on our experience, good results can be anticipated if the fracture is anatomically reduced and the screw correctly placed. In cases of carpal collapse, sclerotic nonunion, and or a very small proximal fragment, an open fixation method should be used.


Job Burnout Reduces Hand Hygiene Compliance Among Nursing Staff.
Health professional burnout has been associated with suboptimal care and reduced patient safety. However, the extent to which burnout influences hand hygiene compliance among health professionals has yet to be explored. The aim of the study was to examine whether job burnout reduces hand washing compliance among nursing staff. A diary study was conducted. Forty registered nurses working in a general city hospital in Thessaloniki, Greece, completed a questionnaire, while they were monitored for hand hygiene compliance following the World Health Organization protocol for hand hygiene assessment. Burnout was measured using validated items from the Maslach Burnout Inventory. Data were collected from September to October 2015. Multiple regression analysis showed that controlling for years in practice, burnout was negatively associated with hand hygiene compliance (R = 0.322, F(3,36) = 5.704, P < 0.01). Nurses reporting higher levels of burnout were less likely to comply with hand hygiene opportunities (b = - 3.72, 95% confidence interval = -5.94 to -1.51). This study showed that burnout contributes to suboptimal care by reducing compliance to hand hygiene among nurses. Given the crucial role of hand hygiene compliance for the prevention of in-hospital infections, this study highlights the need for interventions targeting the prevention of burnout among nursing staff.


Evidences for the Involvement of Monoaminergic and GABAergic Systems in Antidepressant-like Activity of Tinospora cordifolia in Mice.
The present study was taken up to investigate the effect of petroleum ether extract of Tinospora cordifolia (Wild.) Miers, on depression in mice. The extract (50, 100 and 200 mg/kg, p.o.) was administered for 14 successive days to Swiss young albino mice (either sex) and evaluated for antidepressant-like activity using tail suspension test and forced swim test. Petroleum ether extract at all three doses produced significant antidepressant-like effect in tail suspension test as well as in forced swim test and their efficacies were found to be comparable to imipramine (15 mg/kg, p.o.) and sertraline (20 mg/kg, p.o.). The extract at a dose of 50 mg/kg showed most potent effect and did not show any significant change in locomotor functions of mice as compared to control. The antidepressant-like effect of the extract was significantly reversed by pretreatment of animals with prazosin (a α(1)-adrenoceptor antagonist), sulpiride (a selective dopamine D(2)-receptor antagonist), p-CPA (a serotonin synthesis inhibitor) and baclofen (GABA-B agonist), when tested in tail suspension test. Moreover, petroleum ether extract also reduced the mouse whole brain monoamine oxidase (MAO-A and MAO-B) activities as compared to control, resulting in increase in the levels of brain monoamines. Therefore, the extract may have potential therapeutic value for the management of depressive disorders.


Prevalence of lumbar high-intensity zone: assessment using a screening tool independent of spinal symptoms.
High-intensity zone is an area of high-intensity signal within the posterior annulus fibrosus observed in magnetic resonance imaging; initially described in painful discs, recent studies have described similar prevalence in symptomatic and asymptomatic subjects. Since its' prevalence in the general population has not been established, we used a screening tool independent of spinal symptoms to determine high-intensity zone prevalence. We studied 217 patients evaluated with abdominal-pelvic magnetic resonance imaging; we looked for high-intensity zone, disc degeneration, spondylolysis, spondylolisthesis, Modic changes and scoliosis. We determined if these variables, age and sex affected the presence of high-intensity zone; through a logistic regression analysis we evaluated their independent effect. Patients' mean age was 56.3±17.4 years; 66.8% were females. Prevalence of high-intensity zone (11.06%) was larger in males (18.06%) than females (7.59%), p = 0.02. Patients with and without high-intensity zone did not differ in age or presence of scoliosis. High-intensity zone was more frequent in degenerated discs, but not in levels with spondylolisis, spondylolisthesis or Modic changes. Male sex (OR = 2.3, 1.04-5.38) and disc degeneration (OR = 6.76, 1.77-25.81) independently influenced the presence of high-intensity zone. The prevalence of high-intensity zone in this sample of the general population, including 217 subjects, was 11.06%. Similarly, a recent meta-analysis mentioned a 9.5% prevalence in asymptomatic subjects; on the other hand it stressed a 10.4% prevalence in symptomatic subjects. All these data do not plead for a strict correlation between high-intensity zone and low back pain complaints.


Joint larval development of Cystocaulus ocreatus/Muellerius capillaris and C. ocreatus/Neostrongylus linearis (Nematoda) in six species of Helicidae (Mollusca) experimentally infected).
This is the first study on the experimental susceptibility of the following species of molluscs: Cernuella (X.) cespitum arigonis, Helicella (H.) itala, Helicella ordunensis, Cochlicella barbara, Cepaea nemoralis and Helix (C.) aspersa, as intermediate hosts for the combination of both C. ocreatus and M. capillaris, pulmonary parasites in ruminants. Furthermore, the larval development of C. ocreatus and N. linearis, the two taken together, has been followed in Cernuella (X.) cespitum arigonis, H. ordunensis and C. nemoralis. Approximately 40 specimens of each of the above-mentioned species of molluscs were infected with the parasites listed. Bearing in mind the results obtained, we believe that while Cernuella (X.) cespitum arigonis, H. ordunensis, C. nemoralis, C. barbara and Helicella (H.) itala are suitable intermediate hosts for the larval combination of C. ocreatus and M. capillaris, the same cannot be said of Helix (C.) aspersa. Likewise, the first 3 species of molluscs quoted are ideal for the joint larval development of C. ocreatus and N. linearis. It seems that double infections favour larval development.


The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.
One of the most important tumor suppressor proteins in eukaryotic cells is the transcription factor called p53. The importance of this protein in cells comes from the fact that it regulates a wide variety of cellular processes including the cell cycle, metabolism, DNA repair, senescence and apoptosis. In cancer cells, p53 is a major target as the most mutated protein, which has led to the search for potential activators of the mutant protein. Currently, the only mutated-p53 activator in clinical trials is a small molecule called APR-246. There is evidence that the active metabolite of APR-246 binds covalently to mutant p53 and restores its wild-type (wt) activity. In this work, we created atomistic in silico models of the wt, mutant and drugged mutant p53 proteins each in complex with DNA. Using molecular dynamics simulations we generated equilibrated models of the complexes. Detailed analysis revealed that the binding of the APR-246 active metabolite to the mutant proteins alters their interaction with DNA. In particular, the binding of the molecule at loop L1 of the protein allows the loop to anchor the protein to DNA similarly to wt p53. Several important p53-DNA interactions lost due to mutation were also restored in the drugged mutants. These findings, not only provide a possible mechanism of action of this drug, but also criteria to use in virtual screening campaigns for other p53 activators.


The incidence of end-stage renal disease in two regions of kingdom of saudi arabia.
Maintaining patients with end-stage renal disease (ESRD) on renal replacement therapy is expensive and it is important to increase efforts towards reducing the incidence of ESRD. For this, a sound knowledge of the magnitude of the problem is necessary. This study was undertaken to estimate the incidence of ESRD in two regions of Saudi Arabia namely: Gizan, situated in the Southern area with a population of 654,685; and Al-Madinah, situated in the North Western area with a population of 828,477. All general hospitals and primary care centers under the Ministry of Health in the two regions were included in the study. Those patients in whom two consecutive serum creatinine values above 265 micromol/L were recorded were recruited into the study. There were no non governmental centers offering care for patients with renal failure in the study regions at the time of the study. A total of 108 patients in Al-Madinah region and 187 patients in Gizan fulfilled the criteria of the study. Sex distribution was similar in both regions, 61% male and 39% female. There were 71.3% Saudi and 28.7% Non-Saudi patients in Al-Madinah and 65.2% Saudis and 34.7% Non-Saudi patients in Gizan. Analysis of age distribution showed that the highest prevalence occurred among patients between 41 and 60 years of age in Al-Madinah whereas in Gizan it was between 21 to 50 years. The annual incidence of ESRD in Al-Madinah was 65.2 per million population (PMP) and in Gizan 189 PMP. The higher incidence in Gizan may be due to ethnic, socio-economic and environmental factors. A large scale study covering all parts of the Kingdom is needed to throw more light on such variations in the incidence of ESRD in the Kingdom.


The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort.
Choline is the precursor to the neurotransmitter acetylcholine. Loss of cholinergic neurons is associated with impaired cognitive function, particularly memory loss and Alzheimer disease (AD). Brain atrophy and white-matter hyperintensity (WMH) are also associated with impaired cognitive function and AD. The objective was to determine whether a relation exists between dietary choline intake, cognitive function, and brain morphology in a large, nondemented community-based cohort. A dementia-free cohort of 1391 subjects (744 women, 647 men; age range: 36-83 y; mean ± SD age: 60.9 ± 9.29 y) from the Framingham Offspring population completed a food-frequency questionnaire administered from 1991 to 1995 (exam 5; remote intake) and from 1998 to 2001 (exam 7; concurrent intake). Participants underwent neuropsychological evaluation and brain MRI at exam 7. Four neuropsychological factors were constructed: verbal memory (VM), visual memory (VsM), verbal learning, and executive function. MRI measures included WMH volume (WMHV). Performance on the VM and VsM factors was better with higher concurrent choline intake in multivariable-adjusted models for VM (average change in neuropsychological factor per 1-unit change in choline = 0.60; 95% CI: 0.29, 0.91; P < 0.01) and VsM (0.66; 95% CI: 0.19, 1.13; P < 0.01). Remote choline intake was inversely related to log-transformed WMHV (average change in log WMHV per 1-unit change in choline = -0.05; 95% CI: -0.10, -0.01; P = 0.02). Furthermore, an inverse association was observed between remote higher choline intake and presence of large WMVH (OR: 0.56; 95% CI: 0.34, 0.92; P = 0.01). In this community-based population of nondemented individuals, higher concurrent choline intake was related to better cognitive performance, whereas higher remote choline intake was associated with little to no WMHV.


Inside information on xenon adsorption in porous organic cages by NMR.
A solid porous molecular crystal formed from an organic cage, CC3, has unprecedented performance for the separation of rare gases. Here, xenon was used as an internal reporter providing extraordinarily versatile information about the gas adsorption phenomena in the cage and window cavities of the material. 129Xe NMR measurements combined with state-of-the-art quantum chemical calculations allowed the determination of the occupancies of the cavities, binding constants, thermodynamic parameters as well as the exchange rates of Xe between the cavities. Chemical exchange saturation transfer (CEST) experiments revealed a minor window cavity site with a significantly lower exchange rate than other sites. Diffusion measurements showed significantly reduced mobility of xenon with loading. 129Xe spectra also revealed that the cage cavity sites are preferred at lower loading levels, due to more favourable binding, whereas window sites come to dominate closer to saturation because of their greater prevalence.


Multiphoton fluorescent images with a spatially varying background signal: a ML deconvolution method.
By means of multiphoton laser scanning microscopy, neuroscientists can look inside the brain deeper than has ever been possible before. Multiphoton fluorescent images, as all optical images, suffer from degradation caused by a variety of sources (e.g. light dispersion and absorption in the tissue, laser fluctuations, spurious photodetection and staining deficiency). From a modelling perspective, such degradations can be considered the sum of stochastic noise and a background signal. Among the methods proposed in the literature to perform image deconvolution in either confocal or multiphoton fluorescent microscopy, Vicidomini et al. (2009) were the first to incorporate models for noise (a Poisson process) and background signal (spatially constant) in the context of regularized inverse problems. Unfortunately, the so-called split-gradient deconvolution method (SGM) they used did not consider possible spatial variations in the background signal. In this paper, we extend the SGM by adding a maximum-likelihood estimation step for the determination of a spatially varying background signal. We demonstrate that the assumption of a constant background is not always valid in multiphoton laser microscopy and by using synthetic and actual multiphoton fluorescent images, we evaluate the face of validity of the proposed method, and compare its accuracy with the previously introduced SGM algorithm.


Spatial variation in abundance, size and orientation of juvenile corals related to the biomass of parrotfishes on the Great Barrier Reef, Australia.
For species with complex life histories such as scleractinian corals, processes occurring early in life can greatly influence the number of individuals entering the adult population. A plethora of studies have examined settlement patterns of coral larvae, mostly on artificial substrata, and the composition of adult corals across multiple spatial and temporal scales. However, relatively few studies have examined the spatial distribution of small (≤50 mm diameter) sexually immature corals on natural reef substrata. We, therefore, quantified the variation in the abundance, composition and size of juvenile corals (≤50 mm diameter) among 27 sites, nine reefs, and three latitudes spanning over 1000 km on Australia's Great Barrier Reef. Overall, 2801 juveniles were recorded with a mean density of 6.9 (±0.3 SE) ind.m(-2), with Acropora, Pocillopora, and Porites accounting for 84.1% of all juvenile corals surveyed. Size-class structure, orientation on the substrate and taxonomic composition of juvenile corals varied significantly among latitudinal sectors. The abundance of juvenile corals varied both within (6-13 ind.m(-2)) and among reefs (2.8-11.1 ind.m(-2)) but was fairly similar among latitudes (6.1-8.2 ind.m(-2)), despite marked latitudinal variation in larval supply and settlement rates previously found at this scale. Furthermore, the density of juvenile corals was negatively correlated with the biomass of scraping and excavating parrotfishes across all sites, revealing a potentially important role of parrotfishes in determining distribution patterns of juvenile corals on the Great Barrier Reef. While numerous studies have advocated the importance of parrotfishes for clearing space on the substrate to facilitate coral settlement, our results suggest that at high biomass they may have a detrimental effect on juvenile coral assemblages. There is, however, a clear need to directly quantify rates of mortality and growth of juvenile corals to understand the relative importance of these mechanisms in shaping juvenile, and consequently adult, coral assemblages.


New aspects of regulatory signaling pathways and novel therapies in pancreatic cancer.
Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to higher resistance of pancreatic tumor cells to conventional approaches including surgery, radiation and/or chemotherapy. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple signaling pathways to induce responsiveness of pancreatic cancer cells to death signals. Although crucial advances in our understanding of the molecular pathogenesis of the disease have been made, the exceptional aggressiveness of pancreatic cancer remains largely unexplained. Investigators have actively investigated to elucidate molecular mechanisms involved in the oncogenesis, growth, invasion and metastasis of this malignancy. Pancreatic tumor cells have developed remarkable defense mechanisms to evade apoptosis and to increase their resistance to several drugs. All the typical signs of apoptosis are the final results of a complex biochemical cascade of events, whose proper function is regulated by growth and transcriptional factors, hormones and other molecules affecting the intracellular signal transduction. Understanding these complex mechanisms has created new hopes concerning pancreatic cancer in the last years and has evoked new therapeutic approaches, many of which undergo clinical trials with promising results to date. The present review provides a comprehensive description of the molecular signaling mainly of the apoptotic pathways implicated in the pathogenesis of pancreatic cancer, an incentive on the potential pathogenetic role of Helicobacter pylori infection and an appraisal of the most recent therapeutic strategies aiming at the repair of molecular lesions and applied at a cell biochemical level.


Evaluation of pyrethrin aerial ultra-low volume applications for adult Culex tarsalis control in the desert environments of the Coachella Valley, Riverside County, California.
Eliminating infected female mosquitoes by aerial applications of ultra-low volume adulticides is the intervention strategy currently recommended to interrupt the epidemic transmission of encephalitis viruses, including West Nile. The current research optimized pyrethrin formulations and evaluated their efficacy in the desert environment of the Coachella Valley, Riverside County, California. After seven trials during 2004, a 1:2 by volume mixture of Pyrenone 25-5 in BVA oil optimized particle size, droplet descent to ground level, and kill of sentinel mosquitoes. Three subsequent experiments used 3 aerial applications of the 1:2 Pyrenone 25-5:BVA oil mixture on alternate nights to suppress Culex tarsalis Coquillett host-seeking abundance over a 1-square-mile target area. Mortality patterns among caged sentinel mosquitoes varied among sites and replicate sprays, indicating variable particle dispersion at ground level within the target area. In addition, mortality was observed for sentinels up to 1 mile downwind from the target area, indicating considerable particle drift. Geometric mean abundance of host-seeking Cx. tarsalis females collected at dry ice-baited traps within each of 3 sprayed and 2 unsprayed negative control strata varied similarly over time, indicating that our sprays minimally impacted the target population or that drift combined with other factors led to widespread area control. Experiments during March and June when recruitment rates were minimal showed general area-wide suppression of abundance following spray, whereas an experiment during September when recruitment rates were high from newly flooded marshes failed to prevent an area-wide increase in abundance. Clearly additional research is needed to standardize the efficacy of aerial applications of pyrethrins in hot dry desert environments.


A permissive chromatin structure is adopted prior to site-specific DNA demethylation of developmentally expressed genes involved in macronuclear differentiation.
DNA methylation and demethylation are important epigenetic regulatory mechanisms in eukaryotic cells and, so far, only partially understood. We exploit the minimalistic biological ciliate system to understand the crosstalk between DNA modification and chromatin structure. In the macronucleus of these cells, the DNA is fragmented into individual short DNA molecules, each representing a functional expression and replication unit. Therefore, long range epigenomic interaction can be excluded in this system. In the stichotrichous ciliate Stylonychia lemnae, cytosine methylation occurs in a small subset of macronuclear nanochromosomes expressed only during sexual reproduction. Methylation pattern shows similarity to that observed in fungi and Drosophila. Cytosine methylation correlates with gene activity and chromatin structure. Upon gene activation, cytosines become demethylated and a redistribution of histone post-translational modifications (PTMs) takes place. Evidence is presented that the formation of a permissive chromatin structure in the vicinity of the 5meCs precedes cytosine methylation and is probably a necessary prerequisite for their demethylation. Shortly after demethylation of cytosines occurs, the parental macronucleus degenerates, a new macronucleus is formed from a micronuclear derivative and the specific methylation pattern is transmitted from the germline micronucleus to the new macronucleus. We show that very few, or even only one, discrete methylated cytosines are required to assign regulatory functions at a specific locus. Furthermore, evidence is provided that a permissive chromatin structure is probably a necessary prerequisite for the demethylation of specific cytosines. Our results allow us to propose a mechanistic model for the biological function of cytosine methylation in the ciliate cell and its regulation during the cell cycle.


Fibrous histiocytoma of the orbit. A clinicopathologic study of 150 cases.
This is a clinicopathologic study of 150 cases of fibrous histiocytoma of the orbit. The tumors occurred in adults (median age, 43 years). The upper and nasal portions of the orbit were the most common sites of involvement. The most common signs and symptoms were proptosis (60 per cent), mass (46 per cent), and decreased vision (25 per cent). Based on the histopathologic features, the tumors were classified in three groups: benign (94 cases), locally aggressive (39 cases), and malignant (17 cases). The biological behavior correlated well with the duration of symptoms, the size and margins of the mass, and the histologic classification. The rate of recurrence was 31 per cent for the benign tumors, 57 per cent for the locally aggressive tumors, and 64 per cent for the malignant tumors. Follow-up data were obtained for 123 patients, with a mean duration of seven years. The ten-year survival of patients with benign, locally aggressive, and malignant fibrous histiocytoma was 100 per cent, 92 per cent, and 23 per cent, respectively. Nine patients died as a result of the tumor, six from local invasion of adjacent structures and three from metastatic disease. Fibrous histiocytoma is the most common primary mesenchymal orbital tumor of adults. The origin of the neoplasm is probably a primitive mesenchymal cell. Complete surgical excision appears to be the treatment of choice.


Purification of labeled cyanogen bromide peptides of the alpha polypeptide from sodium ion and potassium ion activated adenosinetriphosphatase modified with N-[3H]ethylmaleimide.
Sodium ion and potassium ion activated adenosinetriphosphatase, isolated from canine kidney, was reacted with N-[3H]ethylmaleimide while it was poised in three different conformations, ostensibly E2-P, E2, and E1, respectively. These assignments were made from a consideration of the particular concentrations of ligands in the respective alkylation mixtures. After a 30-min reaction, the remaining enzymatic activity was found to vary among these three different samples from 90 to 30% of that of unalkylated controls. In all cases, the alpha polypeptide was purified and subjected to digestion with cyanogen bromide, and in each digest the same two distinct radioactive peptides were identified and purified by gel filtration on a column of Sephadex LH-60. The incorporation of N-[3H]ethylmaleimide into one of these two peptides correlated closely with enzymatic inactivation, while the incorporation into the other was most extensive when the portion of the active site to which ATP binds was unoccupied. Alkylation of the residue within the latter peptide, however, does not result in inactivation of the enzyme. Both peptides were further purified by high-pressure liquid chromatography, and their amino-terminal sequences were determined by manual dansyl Edman or solid-phase techniques. The peptide containing the sulfhydryl protected by ATP has, as its amino terminus, the lysine that reacts exclusively with fluoresceinyl 5'-isothiocyanate [Farley, R. A., Tran, C. M., Carilli, C. T., Hawke, D., & Shively, J. E. (1984) J. Biol. Chem. 259, 9532-9535].


My first 20 years in neuroscience.
Intriguing facts were obtained in the first electrophysiological investigations (1964) that the action potentials (AP) produced by direct depolarization of the cell membrane in different species of mollusks showed specific relations to changes in external ionic composition. In Helix neurons, the generation of AP was well maintained in sodium-free solutions with high calcium or barium content. The amplitude of the spike overshoot in the case was linearly related to the logarithm of calcium concentration. It is interesting that increase in external calcium ions decreased the ionic conductance of the resting membrane (R0) also in linear relation to the logarithm of Ca2+ or Ba2+ concentration. It was found for the first time (1965) that addition of Ba2+ to the external solution produced in the neurons well-developed prolonged (protracted) APs in all cases. However, the excitability of Planorbis and Limnea neurons was rapidly (during 3 min) reversibly depressed in sodium-free solutions. We found that, after injections of horse radish peroxidase (HRP) in the spinal cord of cats, the enzyme was transported retrogradely to brain stem neurons in the bulbar medial reticular formation, the vestibular complex, and the red nucleus. We obtained (1975) intriguing facts in our investigations: we recorded the labeled neurons in the locus coeruleus and subcoeruleus, as well as in the paraventricular hypothalamic nucleus. The existence of straight pathways from hypothalamus to the spinal cord has not been demonstrated earlier. The next step of our study was to determine the corresponding spinal funiculi where descending fibers (from various brain stem cell groups) are located. Indeed, in our pioneer studies (1977), we found that the fibers from the hypothalamus, which descend throughout the spinal cord, are located mainly in the lateral funiculus, ipsilaterally.