Assessing the impact of denitrifier-produced nitric oxide on other bacteria.
A series of experiments was undertaken to learn more about the impact on other bacteria of nitric oxide (NO) produced during denitrification. The denitrifier Rhodobacter sphaeroides 2.4.3 was chosen as a denitrifier for these experiments. To learn more about NO production by this bacterium, NO levels during denitrification were measured by using differential mass spectrometry. This revealed that NO levels produced during nitrate respiration by this bacterium were in the low muM range. This concentration of NO is higher than that previously measured in denitrifiers, including Achromobacter cycloclastes and Paracoccus denitrificans. Therefore, both 2.4.3 and A. cycloclastes were used in this work to compare the effects of various NO levels on nondenitrifying bacteria. By use of bacterial overlays, it was found that the NO generated by A. cycloclastes and 2.4.3 cells during denitrification inhibited the growth of both Bacillus subtilis and R. sphaeroides 2.4.1 but that R. sphaeroides 2.4.3 caused larger zones of inhibition in the overlays than A. cycloclastes. Both R. sphaeroides 2.4.3 and A. cycloclastes induced the expression of the NO stress response gene hmp in B. subtilis. Taken together, these results indicate that there is variability in the NO concentrations produced by denitrifiers, but, irrespective of the NO levels produced, microbes in the surrounding environment were responsive to the NO produced during denitrification.


Efficacy of bacteriophage treatment in murine burn wound infection induced by klebsiella pneumoniae.
In the present study, the therapeutic potential of purified and well-characterized bacteriophages was evaluated in thermally injured mice infected with Klebsiella pneumoniae B5055. The efficacy of five Klebsiella phages (Kpn5, Kpn12, Kpn13, Kpn17, and Kpn22) was evaluated on the basis of survival rate, decrease in bacterial counts in different organs of phage-treated animals, and regeneration of skin cells as observed by histopathological examination of phage-treated skin. Toxicity studies performed with all the phages showed them to be non-toxic, as no signs of morbidity and mortality were observed in phage-treated mice. The results of the study indicate that a single dose of phages, intraperitoneally (i.p.) at an MOI of 1.0, resulted in significant decrease in mortality, and this dose was found to be sufficient to completely cure K. pneumoniae infection in the burn wound model. Maximum decrease in bacterial counts in different organs was observed at 72 h post infection. Histopathological examination of skin of phage-treated mice showed complete recovery of burn infection. Kpn5 phage was found to be highly effective among all the phages and equally effective when compared with a cocktail of all the phages. From these results, it can be concluded that phase therapy may have the potential to be used as stand-alone therapy for K.pneumoniae induces burn wound infection, especially in situations where multiple antibiotic-resistant organisms are encountered.


Circadian variations in the risk of urinary calcium oxalate stone formation.
To evaluate the circadian fluctuations in the risk of urinary calcium oxalate stone formation with regard to critical periods of crystallization. Over a given time period, the Tiselius index depends on urine volume and urinary excretion of oxalate, calcium, citrate and magnesium. This crystallization potential was evaluated during three successive periods spread over 24 h for 25 recurrent stone-formers aged 16-76 years (mean 50) and 25 control subjects aged 27-71 years (mean 44). There was no significant difference in the value of the Tiselius index for all equivalent time periods in both groups of patients. The minimum value was recorded in the afternoon and the circadian pattern of the index illustrated the predominant importance of urinary output in its determination. Morning urinary concentrations and excretions of citrate, and nocturnal levels of magnesium were significantly higher in the stone-formers when compared with the control subjects. The lithogenic risk for calcium oxalate stones was maximal at the end of the night or during the early morning, when urinary output was minimal. This circadian study revealed abnormalities that are not apparent from non-fractionated 24 h urine samples, and which were potentially relevant to therapy.


Risk Factors of Anaemia among Children under Five Years in the Hohoe Municipality, Ghana: A Case Control Study.
Anaemia is one of the major causes of death among children under five years in Ghana. We examined the risk factors of anaemia among children under five years in the Hohoe Municipality, Ghana. This facility-based matched case control study recruited 210 children (70 cases and 140 controls) aged 6 to 59 months. Stratified and simple random sampling techniques were used to select mothers attending Child Welfare Clinic (CWC) for the screening of their children. Data were collected using a semistructured questionnaire. Finger prick blood was collected to estimate the haemoglobin (Hb) level and thick film was prepared to determine malaria parasitaemia. Axillary temperature was measured using an +electronic thermometer and anthropometric measurements were done using a weighing scale and inelastic tape measure. Continuous variables were presented as means and standard deviations and categorical variables as frequencies and proportions. Conditional logistic regression was used to determine the strength of association between the dependent and the independent variables. Statistical significance was considered at p value of <0.05. The prevalence of anaemia was high (53.8%), while children whose mothers received iron supplementation during pregnancy were 7.64 times more likely to be anaemic compared with those who did not [AOR=7.64 (95% CI:1.41-41.20.93); p=0.018]. Children with poor dietary diversity were 9.15 times more likely to have anaemia [AOR=9.15 (95% CI: 3.13-26.82); p< 0.001]; and children whose mothers were farmers and traders were 83% [AOR = 0.17 (95% CI: 0.05-0.60); p=0.006] and 79% [AOR=0.21 (95% CI: 0.06-0.74); p=0.014], respectively, less likely to have anaemia. The biologic, intermediate, and underlying factors that were significantly associated with anaemia comprised maternal iron supplementation, poor dietary diversity, farmers, and traders. Given that iron supplementation during pregnancy did not protect children against anaemia, we recommend the child's nutritional dietary diversity is encouraged.


Heliospheric X-ray Emission Associated with Charge Transfer of the Solar Wind with Interstellar Neutrals.
X-rays should be generated throughout the heliosphere as a consequence of charge transfer collisions between heavy (Z>2) solar wind ions and interstellar neutrals. The high charge state solar wind ions resulting from these collisions are left in highly excited states and emit extreme ultraviolet or soft X-ray photons. This solar wind charge exchange mechanism applied to cometary neutrals has been used to explain the soft X-ray emission observed from comets. A simple model demonstrates that heliospheric X-ray emission can account for about 25%-50% of the observed soft X-ray background intensities. The spatial and temporal variations of heliospheric X-ray emission should reflect variations in the solar wind flux and composition as well as variations in the distribution of interstellar neutrals within the heliosphere. The heliospheric X-ray "background" can perhaps be identified with the "long-term enhancements" in the soft X-ray background measured by ROSAT.


Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma.
To the authors' knowledge, there are no other published clinical studies that have employed either systemic or local biologic response modifiers in the treatment of patients with pancreatic carcinoma. The purpose of this study was to determine the feasibility and safety of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound (EUS)-guided fine-needle injection (FNI) in patients with advanced pancreatic carcinoma. Eight patients with unresectable adenocarcinoma of the pancreas were enrolled: 4 patients in Stage II, 3 in Stage III, and 1 in Stage IV. Cytoimplants were delivered locally into the tumor using a novel EUS-guided FNI technique. Escalating doses of 3, 6, or 9 billion cells were implanted into the pancreatic tumor by a single EUS-guided FNI. Toxicity (modified National Cancer Institute criteria) was assessed at Day 1, Week 1, and Months 1 and 3. Clinical endpoints included Karnofsky performance status (KPS), CA 19-9, tumor response (computed tomography and/or EUS), and survival with follow-up examinations and imaging tests on months 3, 6, 9, 12, and 24. There were no bone marrow, hemorrhagic, infectious, renal, cardiac, or pulmonary toxicities. There were 3 transient Grade 3 gastrointestinal toxicities, and 3 patients had transient episodes of hyperbilirubinemia that were reversed by replacement of biliary stents. Seven of 8 patients (86%) experienced low grade fever that responded to acetaminophen, and all fever was resolved within the first 4 weeks. There were no procedure-related complications. There were 2 partial responses and 1 minor response, with a median survival of 13.2 months. A single injection of cytoimplant immunotherapy by EUS-guided FNI appears to be feasible and is not associated with substantial toxicity.


Efficacy of combined transbronchial lung cryobiopsy and conventional forceps biopsy for lung malignancies: a prospective cohort study.
There are few prospective reports of transbronchial lung cryobiopsy (TBLC) for malignant tumors in combination with forceps biopsy. We investigated the clinical parameters in which TBLC is superior to forceps biopsy. This is a prospective cohort study to analyse the efficacy of TBLC for suspected malignancy. TBLC was performed after brushing cytology and forceps biopsy, and the diagnostic yield for TBLC, brushing cytology, and forceps biopsy were examined. Adverse events were defined as those requiring additional procedures. Next-generation sequencing (NGS) analysis was performed in each case of non-small cell lung cancer. Of the 100 patients, malignancy was confirmed in 94 cases. The diagnostic yield for TBLC/forceps biopsy/brushing cytology was 86/81/82% respectively, while the diagnostic yield for all procedures combined was 94%. There was no significant difference in the diagnostic yield between TBLC and forceps biopsy. When comparing the biopsy site, the diagnostic yield for TBLC at the lower lobe was significantly higher than forceps biopsy (P < 0.01). Endobronchial ultrasonography imaging using a guide-sheath did not significantly differ in the diagnostic yield of TBLC. The success rate of NGS for TBLC specimens was 100% (26 cases). Adverse events included two cases of severe bleeding. TBLC of peripheral lesions may improve the diagnostic yield when combined with forceps biopsy and brushing cytology. The diagnostic yield of TBLC was higher at the lower lobes. Furthermore, TBLC provided sufficient specimen quality for NGS.


Manual lymphatic drainage with or without fluoroscopy guidance did not substantially improve the effect of decongestive lymphatic therapy in people with breast cancer-related lymphoedema (EFforT-BCRL trial): a multicentre randomised trial.
When added to decongestive lymphatic therapy (DLT), what is the effect of fluoroscopy-guided manual lymphatic drainage (MLD) versus traditional MLD or placebo MLD for the treatment of breast cancer-related lymphoedema (BCRL)? Multicentre, three-arm, randomised controlled trial with concealed allocation, intention-to-treat analysis and blinding of assessors and participants. At five hospitals in Belgium, 194 participants with unilateral chronic BCRL were recruited. All participants received standard DLT (education, skin care, compression therapy and exercises). Participants were randomised to also receive fluoroscopy-guided MLD (n = 65), traditional MLD (n = 64) or placebo MLD (n = 65). Participants received 14 sessions of physiotherapy during the 3-week intensive phase and 17 sessions during the 6-month maintenance phase. Participants performed self-management on the other days. All outcomes were measured: at baseline; after the intensive phase; after 1, 3 and 6 months of maintenance phase; and after 6 months of follow-up. The primary outcomes were reduction in excess volume of the arm/hand and accumulation of excess volume at the shoulder/trunk, with the end of the intensive phase as the primary endpoint. Secondary outcomes included daily functioning, quality of life, erysipelas and satisfaction. Excess lymphoedema volume decreased after 3 weeks of intensive treatment in each group: 5.3 percentage points of percent excessive volume (representing a relative reduction of 23.3%) in the fluoroscopy-guided MLD group, 5.2% (relative reduction 20.9%) in the traditional MLD group and 5.4% (relative reduction 24.8%) in the placebo MLD group. The effect of fluoroscopy-guided MLD was very similar to traditional MLD (between-group difference 0.0 percentage points, 95% CI -2.0 to 2.1) and placebo MLD (-0.2 percentage points, 95% CI -2.1 to 1.8). Fluid accumulated at the shoulder/trunk in all groups. The average accumulation with fluoroscopy-guided MLD was negligibly less than with traditional MLD (-3.6 percentage points, 95% CI -6.4 to -0.8) and placebo MLD (-2.4 percentage points, 95% CI -5.2 to 0.4). The secondary outcomes also showed no clinically important between-group differences. In patients with chronic BCRL, MLD did not provide clinically important additional benefit when added to other components of DLT. NCT02609724.


Influence of risk-organ-based tube current modulation on CT-induced DNA double-strand breaks in a biological phantom model.
Techniques for dose reduction in computed tomography (CT) are receiving increasing attention. Lowering the tube current in front of the patient, known as risk-organ-based tube current modulation (RTM), represents a new approach. Physical dose parameters can determine the exposure but are not able to assess the biological-X-ray interactions. The purpose of this study was to establish a biological phantom model to evaluate the effect of RTM on X-ray-induced DNA double-strand breaks (DSBs). In breast phantoms and in the location of the spine in an Alderson phantom, isolated human blood lymphocytes were irradiated using a 128-slice CT scanner. A standard thoracic CT protocol (120 kV, 110 ref. mAs, anatomy-based tube current modulation, pitch 0.6, scan length 30 cm) with and without RTM was used. X-ray-induced DSBs were quantified in isolated blood lymphocytes using immunofluorescence microscopy after staining for the phosphorylated histone variant γ-H2AX. Using RTM, the resulting DNA damage reduction was 41% in superficial breast locations (P = 0.0001), 28% in middle breast locations (P = 0.0003) and 29% in lower breast locations (P = 0.0001), but we found a DNA damage increase of 36% in superficial spine locations (P = 0.0001) and of 26% in deep spine locations (P = 0.0001). In summary, we established a biological phantom model that is suitable for detecting DNA damage in distinct organs. In addition, we were able to show that, using RTM, X-ray-induced DNA damage in the breast can be significantly reduced; however, there is a significant increase in DSBs in the location of the spine.


Life on arginine for Mycoplasma hominis: clues from its minimal genome and comparison with other human urogenital mycoplasmas.
Mycoplasma hominis is an opportunistic human mycoplasma. Two other pathogenic human species, M. genitalium and Ureaplasma parvum, reside within the same natural niche as M. hominis: the urogenital tract. These three species have overlapping, but distinct, pathogenic roles. They have minimal genomes and, thus, reduced metabolic capabilities characterized by distinct energy-generating pathways. Analysis of the M. hominis PG21 genome sequence revealed that it is the second smallest genome among self-replicating free living organisms (665,445 bp, 537 coding sequences (CDSs)). Five clusters of genes were predicted to have undergone horizontal gene transfer (HGT) between M. hominis and the phylogenetically distant U. parvum species. We reconstructed M. hominis metabolic pathways from the predicted genes, with particular emphasis on energy-generating pathways. The Embden-Meyerhoff-Parnas pathway was incomplete, with a single enzyme absent. We identified the three proteins constituting the arginine dihydrolase pathway. This pathway was found essential to promote growth in vivo. The predicted presence of dimethylarginine dimethylaminohydrolase suggested that arginine catabolism is more complex than initially described. This enzyme may have been acquired by HGT from non-mollicute bacteria. Comparison of the three minimal mollicute genomes showed that 247 CDSs were common to all three genomes, whereas 220 CDSs were specific to M. hominis, 172 CDSs were specific to M. genitalium, and 280 CDSs were specific to U. parvum. Within these species-specific genes, two major sets of genes could be identified: one including genes involved in various energy-generating pathways, depending on the energy source used (glucose, urea, or arginine) and another involved in cytadherence and virulence. Therefore, a minimal mycoplasma cell, not including cytadherence and virulence-related genes, could be envisaged containing a core genome (247 genes), plus a set of genes required for providing energy. For M. hominis, this set would include 247+9 genes, resulting in a theoretical minimal genome of 256 genes.


Developing a common bean core collection suitable for association mapping studies.
Because of the continuous introduction of germplasm from abroad, some collections have a high number of accessions, making it difficult to explore the genetic variability present in a germplasm bank for conservation and breeding purposes. Therefore, the aim of this study was to quantify and analyze the structure of genetic variability among 500 common bean accessions to construct a core collection. A total of 58 SSRs were used for this purpose. The polymorphism information content (PIC) in the 180 common bean accessions selected to compose the core collection ranged from 0.17 to 0.86, and the discriminatory power (DP) ranged from 0.21 to 0.90. The 500 accessions were clustered into 15 distinct groups and the 180 accessions into four distinct groups in the Structure analysis. According to analysis of molecular variance, the most divergent accessions comprised 97.2% of the observed genetic variability present within the base collection, confirming the efficiency of the selection criterion. The 180 selected accessions will be used for association mapping in future studies and could be potentially used by breeders to direct new crosses and generate elite cultivars that meet current and future global market needs.


Pharmacological analysis of vasodilator responses to alpha 2-adrenoceptor agonists in isolated rat common carotid arteries.
Using the cannula inserting method, vasodilator responses to alpha 2-adrenoceptor agonists (clonidine, guanabenz, DJ7141 and xylazine) were investigated in isolated and perfused rat common carotid arteries. Alpha 2-adrenoceptor agonists dose-dependently induced a vasodilation in preparations preconstricted by noradrenaline. The potencies were in the order of clonidine greater than guanabenz greater than DJ-7141 greater than or equal to xylazine. Removal of the endothelium inhibited ACh-induced vasodilation, but not the alpha 2-agonist-induced dilation. Atropine treatment inhibited ACh-induced vasodilation, but not the alpha 2-agonist-induced dilation. Alpha 2-agonist-induced dilations were not modified by beta-blockade, which significantly suppressed isoprenaline-induced vasodilations. The potent alpha 2-adrenoceptor antagonist DG5128 did not influence the alpha 2-agonist-induced vasodilation. In preparations preconstricted by PGF2 alpha, clonidine and xylazine never induced a vasodilation, and clonidine frequently induced vasoconstrictions that were completely blocked by bunazosin. It is concluded that alpha 2-adrenoceptor agonist-induced vasodilation is independent from the existence of the endothelium, and that it is not related to vascular beta- and alpha 2-adrenoceptors and muscarinic receptors, suggesting that the alpha 2-adrenoceptor agonist-induced vasodilation is due to an antagonistic activity towards the vascular alpha 1-adrenoceptors.


Prophylactic preoperative levosimendan for off-pump coronary artery bypass grafting in patients with left ventricular dysfunction: Single-centered randomized prospective study.
Off-pump coronary artery bypass surgery (OPCAB) is often complicated by hemodynamic instability, especially in patients with prior left ventricular (LV) dysfunction and appropriate choice of inotrope plays a vital role in perioperative management of these patients. To study hemodynamic effects and immediate outcome of prophylactic infusion of levosimendan in patients with the LV dysfunction undergoing OPCAB surgery and whether this strategy helps in successful conduct of OPCAB surgery. After Institutional Ethics Committee approval, 60 patients posted for elective OPCAB surgery were randomly divided into two groups (n = 30 each). Patients with the LV ejection fraction <30% were included. Study group was started on injection levosimendan (@ 0.1 μg/kg/min) in the previous night before surgery and continued for 24 h including intraoperative period. Hemodynamic monitoring included heart rate, invasive blood pressure, cardiac index (CI), pulmonary capillary wedge pressure (PCWP), pulse oximetry, and arterial blood gases with serum lactates at as T0 (baseline), T1 (15 min after obtuse marginal and/or PDA anastomoses), T2 (at end of surgery), T3 (6 h after surgery in Intensive Care Unit [ICU]), T4 (12 h after surgery), and T5 (24 h after surgery in ICU). Vasopressor was added to maintain mean arterial pressure >60 mmHg. Chi-square/Fisher's exact/Mid P exact test and Student's t-tests were applied for categorical and continuous data. CI was greater and PCWP reduced significantly in Group L during intraoperative and early postoperative period. Serum lactate concentration was lower in patients pretreated with levosimendan. Incidence of postoperative atrial fibrillation (POAF) (36.6 vs. 6.6%; P = 0.01), low cardiac output syndrome (LCOS) (30% vs. 6%; P = 0.02), and acute kidney injury (23.3% vs. 6.7%; P = 0.04) was less in Group L. Three patients (10%) in control group required conversion to cardiopulmonary bypass (CPB) as compared to none in the study group. There was no difference regarding ICU or hospital stay and mortality in both groups. Preoperative levosimendan helps in successful conduct of OPCAB and reduces the incidence of LCOS, POAF, conversion to CPB, and requirement of intra-aortic balloon pump.


[Hormone replacement therapy and osteoporosis].
Estrogen deficiency is one significant cause of accelerated bone loss in women during and after menopause. Postmenopausal osteoporosis is a major health problem, primarily because of the severe morbidity and mortality associated with osteoporotic fractures. The Women's Health Initiative Study (WHI) reported that hormone replacement therapy (HRT) prevented osteoporotic fractures. The risks and benefits of HRT are complex and require the individual assessment of each woman considering taking HRT. Use of HRT can be considered as a treatment option for osteoporosis but the risks and benefits should be discussed with each individual woman before starting treatment.


Conducting polymer-coated electrode as a reference/counter electrode in an organic phase and its application to a two-electrode type thin-layer cell for voltammetry at the liquid | liquid interface.
An indium tin oxide glass electrode coated with poly(3,4-ethylenedioxythiophene), PEDOT, PEDOT-ITOE, was proposed as an electrode workable as both a reference electrode and a counter one, a reference/counter electrode, in an organic phase and applied to a thin-layer cell of a two-electrode system for voltammetry at the liquid | liquid interface. By oxidizing the PEDOT film by 50% and doping a supporting electrolyte anion in an organic phase into the PEDOT film, a suitable depolarization was realized at the PEDOT | organic phase interface. The partially oxidized PEDOT-ITOE showed a Nerntian response to the supporting electrolyte anion concentration in the organic phase. The electrode potential was stable within +/-3 mV for 12 h, and showed a consistent value among the PEDOT-ITOEs prepared under the same procedure (the error range was about 7 mV, n = 8).


Persistent ventricular bigeminy during anesthesia in pediatric patients: a case report of an 11-year-old child.
An 11-year-old male child with fractures in both bones in his left forearm presented for open reduction and internal fixation. The pre-anesthetic check-up and investigations did not reveal any pre-existing underlying cardio-respiratory disease. The patient had an uneventful peri-operative period during the operation and was comfortable without any anxiety or restlessness. After an uneventful induction and intubation as per routine protocol, the patient received 600 mg of amoxicillin+clavunate intravenously as an antibiotic. After 3 min, the patient developed persistent ventricular bigeminy with intermittent sinus rhythm, which returned to normal after 20 min. Open reduction and internal fixation of the fractures in both bones were done. Extubation and the post-op course were uneventful. To rule out the cause of arrhythmia, ECG, 2D-ECHO and serum electrolyte evaluation were done, however the results came back as normal. Many days later, the patient fell again on the same arm and revisited the ortho operation theatre for revision surgery. As the child was very cooperative and calm, he was given a supraclavicular block after proper counseling. Thirty minutes before tourniquet inflation as a routine method, 600 mg of amoxicillin+clavunate was administered. After 5 min, the patient developed persistent ventricular bigeminy. After 1 h, the child complained of chest pain and had redness of eyes and was restless. This was managed with 100% oxygen and an injection of 150 mg amiodarone intravenously. Surgery was postponed for further stabilization and optimization. Serum electrolytes were normal. The child was observed in the surgical intensive care unit with continuous ECG monitoring. Ventricular bigeminy with intermittent sinus rhythm persisted for 3 days. This was managed with metoprolol 12.5 mg BD and amiodarone 100 mg OD tablets. The opinion of a pediatric cardiologist was obtained and repeated 2D-ECHO results revealed no abnormality. After 5 days, the patient was discharged and surgery was rescheduled for 2 weeks later with continuation of metaprolol and amiodarone tablets. On the fourth occasion we avoided the injection of amoxicillin+clavunate and all anesthetic drugs, which might contribute to cardiac arrhythmia. The peri-operative period was uneventful. An in-depth discussion of the case and ventricular dysrhythmias in the pediatric population is emphasized in this case report.


Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women.
While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. Thirty-four, obese (body mass index, BMI > 30 kg m(-2)) women of reproductive age (18-35 years old) were placed on a COC pill containing 20 µg ethinylestradiol/100 µg levonorgestrel for 21 days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21 days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3 l h(-1) vs. 53.9 l h(-1), P < 0.05). A median decrease of 5.6 l h(-1) (95% CI -4.1, 13.3 l h(-1)) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.


Influence of atomistic physics on electro-osmotic flow: an analysis based on density functional theory.
Molecular density profiles and charge distributions determined by density functional theory (DFT) are used in conjunction with the continuum Navier-Stokes equations to compute electro-osmotic flows in nanoscale channels. The ion species of the electrolyte are represented as centrally charged hard spheres, and the solvent is treated as a dense fluid of neutral hard spheres having a uniform dielectric constant. The model explicitly accounts for Lennard-Jones interactions among fluid and wall molecules, hard sphere repulsions, and short range electrical interactions, as well as long range Coulombic interactions. Only the last of these interactions is included in classical Poisson-Boltzmann (PB) modeling of the electric field. Although the proposed DFT approach is quite general, the sample calculations presented here are limited to symmetric monovalent electrolytes. For a prescribed surface charge, this DFT model predicts larger counterion concentrations near charged channel walls, relative to classical PB modeling, and hence smaller concentrations in the channel center. This shifting of counterions toward the walls reduces the effective thickness of the Debye layer and reduces electro-osmotic velocities as compared to classical PB modeling. Zeta potentials and fluid speeds computed by the DFT model are as much as two or three times smaller than corresponding PB results. This disparity generally increases with increasing electrolyte concentration, increasing surface charge density and decreasing channel width. The DFT results are found to be comparable to those obtained by molecular dynamics simulation, but require considerably less computing time.


A Dynamic Algorithm for Interference Management in D2D-Enabled Heterogeneous Cellular Networks: Modeling and Analysis.
To supporting a wider and diverse range of applications, device-to-device (D2D) communication is a key enabler in heterogeneous cellular networks (HetCNets). It plays an important role in fulfilling the performance and quality of service (QoS) requirements for 5G networks and beyond. D2D-enabled cellular networks enable user equipment (UE) to communicate directly, without any or with a partial association with base stations (eNBs). Interference management is one of the critical and complex issues in D2D-enabled HetCNets. Despite the wide adoption of D2D communications, there are very few researchers addressing the problems of mode selection (MS), as well as resource allocation for mutual interference in three-tier cellular networks. In this paper, we first identify and analyze three key factors, namely outage probability, signal-to-interference and noise ratio (SINR), and cell density that influence the performance of D2D-enabled HetCNets. We then propose a dynamic algorithm based on a distance-based approach to minimize the interference and to guarantee QoS for both cellular and D2D communication links. Results obtained show that outage probability is improved by 35% and 49% in eNB and SCeNB links, respectively, when compared with traditional neighbor-based methods. The findings reported in this paper provide some insights into interference management in D2D communications that can help network researchers and engineers contribute to further developing next-generation cellular networks.


Rates of gonorrhea and Chlamydia in U.S. military personnel deployed to Iraq and Afghanistan (2004-2009).
The increased incidence of sexually transmitted infections has historically been associated with military personnel at war. The incidence of gonorrhea and Chlamydia in personnel deployed in the current wars in Iraq and Afghanistan has not been reported. An electronic records' review of testing done from January 2004 to September 2009 revealed higher rates of Chlamydia than gonorrhea, especially among females who deploy to Iraq. Additionally, increasing Chlamydia rates were noted over the study. Overall, the rates of gonorrhea and Chlamydia were the same or lower than age- and year-matched U.S. rates reported by the Center for Disease Control and Prevention. Ongoing education with emphasis on prevention and treatment are needed, as are development of specific projects to define the risk factors and timing of acquisition of sexually transmitted infections in combat zones.


Carcinogenesis associated with parasites other than Schistosoma, Opisthorchis and Clonorchis: A systematic review.
Only three helminths (Schistosoma haematobium, Opisthorchis viverrini and Clonorchis sinensis) are directly associated with carcinogenesis in humans whereas the role of other parasites in cancer remains unclear. This study aimed to perform a systematic review to identify recent insights in the role of other parasite infections in carcinogenesis. We conducted systematic searches of MEDLINE and EMBASE on July 2015. Our primary outcome was the association between parasitic infections and carcinogenesis. Out of 1,266 studies, 19 were selected for detailed evaluation (eight for helminths and 11 for protozoa). The mechanisms of helminth-induced cancer included chronic inflammation, sustained proliferation, modulation of the host immune system, reprogramming of glucose metabolism and redox signaling, induction of genomic instability and destabilization of suppressor tumor proteins, stimulation of angiogenesis, resisting cell death, and activation of invasion and metastasis. In addition to the current knowledge, the following parasites were found in cancers or tumors: Echinococcus, Strongyloides, Fasciola, Heterakis, Platynosomum and Trichuris. Additional parasites were found in this systematic review that could potentially be associated with cancers or tumors but further evidence is needed to elaborate a cause-effect relationship.


Boat and Chair Shaped Hexahalogen Synthons.
Non-covalent halogen bonding interactions are quintessential in crystal engineering for the construction of distinctive supramolecular synthons. Here, we report the first crystalline evidences of unique boat and chair shaped cyclic hexahalogen synthons in the crystal structures of α,α,α',α',4-pentabromo-o-xylene (PBX) and α,α,α',α',4,5-hexabromo-o-xylene (HBX) respectively. Nature and stability of constituent interactions in the supramolecular synthons are scrutinized with the help of quantum-chemical calculations. Pendás' interacting quantum atoms approach confirmed the stability of Br⋅⋅⋅Br interactions leading to boat and chair shaped synthons with major contribution from exchange-correlation. Although both the molecules are achiral in nature, the packing forces guide PBX to crystallize in the chiral space group P21 with a helix-like orientation while HBX packs in a centrosymmetric P21 /n space group. The extended furcations in the pentabromo derivative construct a molecular framework consisting of macrocycles realized through halogen bonding.


Theoretical study of the H/D isotope effect of CH4/CD4 adsorption on a Rh(111) surface using a combined plane wave and localized basis sets method.
We analysed the H/D isotope effect of CH4/CD4 adsorption on a Rh(111) surface using our combined plane wave and localized basis sets method, that we proposed for the consideration of delocalized electrons on a surface and the quantum effect of protons (deuterons) in metal-molecule interactions. We observed that the adsorption distance and energy of CD4 were larger and lower than those of CH4, respectively. This is in reasonable agreement with the corresponding experimental results of cyclohexane adsorption. We clearly found that the trend of the H/D isotope effect in the geometrical and energetic difference was similar to that of the hydrogen-bonded systems.


Solutions to the home healthcare nursing shortage.
Effective management in home healthcare is the key to successful recruitment, orientation, and assistance for staff nurses and safe nursing practice. Networking with healthcare providers at all levels provides the home health nurse with feelings of inclusion, self-worth, and job satisfaction.


Downregulation of pancreatic-duodenal homeobox 1 expression in breast cancer patients: a mechanism of proliferation and apoptosis in cancer.
Pancreatic-duodenal homeobox 1 (PDX-1) is a transcription factor that regulates embryological pancreas development and insulin expression in adult islets. The current study investigated the expression profile and potential role of PDX-1 in breast cancer. Immunohistochemistry was performed to determine the expression pattern of PDX-1 in breast cancer and adjacent benign breast tissues. In addition, cell proliferation and the cell cycle were evaluated following the transient inhibition of PDX-1 with antisense oligonucleotides in MCF-7 human breast cancer cells. Real-time PCR and western blotting were conducted to investigate the correlation between PDX-1, P53, Ki-67, Caspase 3 and Caspase 8. These experiments demonstrated that PDX-1 was downregulated in human breast cancer tissue compared with adjacent normal breast tissue. Knockdown of PDX-1 expression in vitro in MCF-7 breast cancer cells promoted cell proliferation and disrupted the cell cycle, as demonstrated by the overexpression of P53 and Ki-67 at the mRNA and protein levels. In conclusion, the current study shows that PDX-1 regulates cell proliferation and the cell cycle in human breast cancer cells by altering the expression of the cell cycle-related genes, P53 and Ki-67. These data suggest that PDX-1 is a putative tumor suppressor in breast cancer.


Changing Beliefs and Behaviors Related to Sexually Transmitted Diseases in Vulnerable Women: A Qualitative Study.
The first step in health education is awareness of the people and their acceptance to change their behavior. Therefore, the aim of this study was to investigate the effects of empowerment program towards the concept of self-care and prevention of sexually transmitted diseases (STDs) in women at risk of STDs. The present study was conducted as a qualitative approach (step of action and observation of an action) by using conventional content analysis method. An empowerment program regarding STDs (Action) was performed among 32 (with convenient sample) drug user women with addicted husbands referring to the counseling center for vulnerable women (drop in enter) in Isfahan in 2015. The knowledge of quiddity, transmission, and prevention of STDs, as well as some items of life skills such as self-awareness, interpersonal communication, and assertive behavior were taught in an educational program. Teaching methods were lectures, group, and individual training and role play. The impact of the program on modified belief and behavior change regarding STDs was evaluated with structured interviews. Analysis of the obtained results yielded three categories. The categories were awareness of STD, believing in being at risk, and decision and change. Promoting self-care and prevention through education programs based on action research can make a significant reduction in the incidence of problems and cause a behavior change in women with the disease or those at risk for STDs.


Out-of-hospital endotracheal intubation experience and patient outcomes.
Previous studies suggest improved patient outcomes for providers who perform high volumes of complex medical procedures. Out-of-hospital tracheal intubation is a difficult procedure. We seek to determine the association between rescuer procedural experience and patient survival after out-of-hospital tracheal intubation. We analyzed probabilistically linked Pennsylvania statewide emergency medicine services, hospital discharge, and death data of patients receiving out-of-hospital tracheal intubation. We defined tracheal intubation experience as cumulative tracheal intubation during 2000 to 2005; low=1 to 10 tracheal intubations, medium=11 to 25 tracheal intubations, high=26 to 50 tracheal intubations, and very high=greater than 50 tracheal intubations. We identified survival on hospital discharge of patients intubated during 2003 to 2005. Using generalized estimating equations, we evaluated the association between patient survival and out-of-hospital rescuer cumulative tracheal intubation experience, adjusted for clinical covariates. During 2003 to 2005, 4,846 rescuers performed tracheal intubation. These individuals performed tracheal intubation on 33,117 patients during 2003 to 2005 and 62,586 patients during 2000 to 2005. Among 21,753 cardiac arrests, adjusted odds of survival was higher for patients intubated by rescuers with very high tracheal intubation experience; adjusted odds ratio (OR) versus low tracheal intubation experience: very high 1.48 (95% confidence interval [CI] 1.15 to 1.89), high 1.13 (95% CI 0.98 to 1.31), and medium 1.02 (95% CI 0.91 to 1.15). Among 8,162 medical nonarrests, adjusted odds of survival were higher for patients intubated by rescuers with high and very high tracheal intubation experience; adjusted OR versus low tracheal intubation experience: very high 1.55 (95% CI 1.08 to 2.22), high 1.29 (95% CI 1.04 to 1.59), and medium 1.16 (95% CI 0.97 to 1.38). Among 3,202 trauma nonarrests, survival was not associated with rescuer tracheal intubation experience; adjusted OR versus low tracheal intubation experience: very high 1.84 (95% CI 0.89 to 3.81), high 1.25 (95% CI 0.85 to 1.85), and medium 0.92 (95% CI 0.67 to 1.26). Rescuer procedural experience is associated with improved patient survival after out-of-hospital tracheal intubation of cardiac arrest and medical nonarrest patients. Rescuer procedural experience is not associated with patient survival after out-of-hospital tracheal intubation of trauma nonarrest patients.


Anti-tumor activity of Gastrodia elata Blume is closely associated with a GTP-Ras-dependent pathway.
Gastrodia elata Blume (GEB) is an important medicinal plant in Korea. In order to confirm the anti-tumor activities of GEB extracts, we carried out various in vitro anti-tumor assays, including a wound assay and an invasion assay using an ethyl ether extract of GEB. The results showed that the GEB extract exhibits potent anti-tumor activity in vitro in a dose-dependent manner. The expression of CD44, cdc42, Timp-2 or RhoA mRNA did not change by GEB treatment, compared to that of the control. GTP-Ras, an active form of a G-coupled protein family, however, is associated with the anti-tumor activity of GEB extracts. We examined various molecular markers related to metastasis by reverse transcriptase-polymerase chain reaction with the extract of GEB-treated B16 cells. There was an increase in GTP-Ras expression by the Gastrodia elata Blume extract. Together, these results suggest that the Gastrodia elata Blume extract could have potential in alleviating tumorigenesis, by a GTP-Ras-dependent pathway; although the precise molecular mechanisms are still being examined.


Pure Autonomic Failure-A Localized Alpha Synucleinopathy with a Potential for Conversion to More Extensive Alpha Synucleinopathies.
Pure autonomic failure (PAF) is an alpha synucleinopathy with predominant involvement of the autonomic ganglia and peripheral nerves. The hallmark clinical feature is orthostatic hypotension. However, genitourinary, sudomotor, and cardiac involvement is also common. Many patients also develop supine hypertension. Almost a quarter of patients can phenoconvert or evolve into Parkinson's disease, multiple system atrophy, and Lewy body dementia in the future. Early severe bladder involvement, higher supine noradrenaline level, early motor involvement, and dream enactment behavior increase the risk of phenoconversion. The diagnosis is confirmed via autonomic function testing and serum noradrenaline measurement. The treatment is mainly supportive. The non-pharmacological treatment includes adequate fluid, dietary salt, compression stockings, and abdominal binders. The drug therapies to improve blood pressure include midodrine, fludrocortisone, pyridostigmine, and droxidopa. The diagnostic criteria need to be updated to incorporate the recent understandings. The treatment of orthostatic hypotension and supine hypertension is mainly based on case series and anecdotal reports. Randomized control trials are needed to ascertain the best treatment strategies for PAF.


Computed tomographic venography is specific but not sensitive for diagnosis of acute lower-extremity deep venous thrombosis in patients with suspected pulmonary embolus.
Duplex ultrasound scanning (US) is the accepted standard means of diagnosis for lower-extremity suprageniculate deep venous thrombosis (LE-DVT). Computed tomographic venography (CTV) has been proposed as an alternative modality for diagnosis of LE-DVT in patients with suspected pulmonary embolism (PE). This study compared CTV with US as a means of diagnosing acute LE-DVT. A retrospective review of US and CTV scans from 136 patients with suspected PE who underwent both studies to exclude acute LE-DVT at a single institution was performed. Studies were reviewed and coded in a blinded manner. US was considered to be the reference test. Direct costs of each study were determined by using commercial software. The sensitivity and specificity rates of CTV were 71% and 93%, respectively. The positive predictive value, negative predictive value, and accuracy rates of CTV were 53%, 97%, and 90%, respectively. DVT localization was the same in eight of 10 cases in which the results of both US and CTV were positive. CTV costs and charges per study were greater than those of US by $46.88 and $602.00, respectively. CTV is specific, but has a lower sensitivity rate and positive predictive value for the diagnosis of acute LE-DVT compared with US. Additionally, CTV is more costly than US scanning. Because of the lower sensitivity rate and positive predictive value and the increased cost of CTV, US remains the screening study of choice in cases of suspected acute LE-DVT.


US artifacts.
Image artifacts are commonly encountered in clinical ultrasonography (US) and may be a source of confusion for the interpreting physician. Some artifacts may be avoidable and arise secondary to improper scanning technique. Other artifacts are generated by the physical limitations of the modality. US artifacts can be understood with a basic appreciation of the physical properties of the ultrasound beam, the propagation of sound in matter, and the assumptions of image processing. US artifacts arise secondary to errors inherent to the ultrasound beam characteristics, the presence of multiple echo paths, velocity errors, and attenuation errors. The beam width, side lobe, reverberation, comet tail, ring-down, mirror image, speed displacement, refraction, attenuation, shadowing, and increased through-transmission artifacts are encountered routinely in clinical practice. Recognition of these artifacts is important because they may be clues to tissue composition and aid in diagnosis. The ability to recognize and remedy potentially correctable US artifacts is important for image quality improvement and optimal patient care.


Avoidable deaths in the first 24 hours of life: health care reflexes.
to analyze the risks of deaths in the first 24 hours of life and their preventable causes. cross-sectional study carried out in Pernambuco, Northeast of Brazil, between 2000-2019, with mortality and live birth data. The avoidability was analyzed through the Brazilian List of Avoidable Causes of Deaths due to Interventions of the Unified Health System. For the statistical analyses, Pearson's chi-squared test and relative and attributable risks were used. 13,601 deaths were registered, of which 10,497 (77.19%) were from preventable causes. Of the total, 5,513 (40.53%) were reducible through adequate care for women during pregnancy. The lower the gestational age, birth weight and education level, the higher the relative and attributable risk of death in the first 24 hours of life. most of the deaths were considered avoidable and with high relative and attributable risks. These early deaths suggest care failures and the need to reinforce prevention and treatment measures.


Total synthesis of two novel 5,6,7,8-tetrahydroindolizine alkaloids, polygonatines A and B.
The structures of polygonatines A and B, two simple but structurally novel alkaloids, have been substantiated by synthesis. Cyclisation of 4-(1H-pyrrol-1-yl)butanoic acid or its ethyl ester produced 6,7-dihydroindolizin-8(5H)-one , formylation of which at C-3 followed by reduction afforded polygonatine A . Acetylation of this alkaloid followed by displacement of the acetate with ethanol yielded polygonatine B , possibly via an azafulvenium cation.


Newborns' perception of left-right spatial relations.
Five experiments examined 79 newborns' ability to discriminate and categorize a spatial relation, defined by the left-right spatial position of a blinking object-target with respect to a vertical landmark-bar. Three-day-old infants discriminated the up versus low position of an object located on the same side of the landmark-bar (Experiment 1) and recognized a basic left-right spatial invariance of the object-target and the landmark-bar in conditions of low (Experiment 2) and high (Experiment 3) perceptual variability of the object's positions. Additional evidence ruled out the possibility that newborns were unable to discriminate the within-category left-right spatial positions of the object-target (Experiment 4) or made a categorical distinction based on spatial distance rather than on categorical spatial relations of left of and right of (Experiment 5).


A first step towards a framework for interventions for individual working practice to prevent work-related musculoskeletal disorders: a scoping review.
Work-related musculoskeletal disorders (WMSDs) are a key topic in occupational health. In the primary prevention of these disorders, interventions to minimize exposure to work-related physical risk factors are widely advocated. Besides interventions aimed at the work organisation and the workplace, interventions are also aimed at the behaviour of workers, the so-called individual working practice (IWP). At the moment, no conceptual framework for interventions for IWP exists. This study is a first step towards such a framework. A scoping review was carried out starting with a systematic search in Ovid Medline, Ovid Embase, Ovid APA PsycInfo, and Web of Science. Intervention studies aimed at reducing exposure to physical ergonomic risk factors involving the worker were included. The content of these interventions for IWP was extracted and coded in order to arrive at distinguishing and overarching categories of these interventions for IWP. More than 12.000 papers were found and 110 intervention studies were included, describing 810 topics for IWP. Eventually eight overarching categories of interventions for IWP were distinguished: (1) Workplace adjustment, (2) Variation, (3) Exercising, (4) Use of aids, (5) Professional skills, (6) Professional manners, (7) Task content & task organisation and (8) Motoric skills. Eight categories of interventions for IWP are described in the literature. These categories are a starting point for developing and evaluating effective interventions performed by workers to prevent WMSDs. In order to reach consensus on these categories, an international expert consultation is a necessary next step.


Effects of reproductive factors on risk of breast cancer: a literature review.
Breast cancer is the leading women's cancer worldwide. However, there are geographical considerable differences with high rates of disease in North America and North Europe and relatively low rates in Africa and Asia. This article reviews the effects of reproductive factors on risk of breast cancer: early menarche, nulliparity or late age at first birth, late menopause, as well as hormonal factors. Knowing risk factors of breast cancer could significantly contribute to an improved prevention of this cancer. Furthermore, this review aimed to highlight potentially controversial conditions in the Asian countries compared to other parts of the world which could in the future improve early prevention of breast cancer in Asian women.


Cutaneous manifestations and massive genital involvement in Hennekam syndrome.
We describe a 16-year-old boy with intestinal lymphangiectasia, lymphedema of the limbs and genitalia, mild mental retardation, and facial anomalies (Hennekam syndrome) and cutaneous lesions. Severe edema in the genital area created a gigantic mass that included the scrotum and penis. Numerous grouped red-violaceous pseudo-vesicular lesions and plaques, as well as verrucous brown papules, were present on the penis and scrotum. The prepuce was hypertrophic, with severe phimosis. Histologic analysis revealed dilated lymphatic vessels lined by a discontinuous layer of flat endothelial cells in the papillary dermis and extending down to the reticular dermis. Dilated blood vessels were also present but no cellular abnormalities were identified. A diagnosis of superficial cutaneous lymphatic malformations was made. To the best of our knowledge, this is the first detailed cutaneous histologic investigation in a patient with Hennekam syndrome. We assume that the onset of cutaneous lesions in our patient was likely triggered by a generalized worsening of his lymphedema.


[Clinical significance of CEA levels in lung cancer].
Serum concentrations of CEA, Ferritin, beta 2-MG, TPA and IAP were measured in patients with lung cancer. Significant difference of positive rate between lung cancer and benign chest disease was observed only in CEA and TPA. CEA elevations occurred most frequently with stage IV and histologically with adenocarcinoma. Positive CEA levels (greater than or equal to 5 ng/ml) of pleural effusion were observed in 75% of all patients with lung cancer and increased to 94% in patients with positive cytology of effusion. There was not significant difference of bronchial washings CEA levels between lung cancer and benign chest disease. Furthermore, serial measurement of postoperative CEA levels had considerable value in monitoring the course of disease following resection.


Eigenmobilities in background electrolytes for CZE. V. Intensity (amplitudes) of system peaks.
We present a mathematical model of CZE based on the concept of eigenmobilities - the eigenvalues of matrix M tied to the linearized governing equations of electromigration, and the spectral decomposition of matrix M into matrices of amplitudes P(j). Any peak in an electropherogram, regardless of whether it is an analyte peak or a system peak (system zone), is matched with its matrix P(j). This enables calculation of the peak parameters, such as the transfer ratio and the molar conductivity detection response (which give the indirect detection signal and the conductivity detection signal, respectively), when the initial disturbance caused by the injection of the sample is known. We also introduce new quantities, such as the generalized transfer ratio and the conductivity response of system zones, and show how the amplitude (intensity, area) of the analyte peaks and the system peaks can be calculated. We offer a free software, PeakMaster (http://www.natur.cuni.cz/gas), which yields this information in a user-friendly way.


Implementing Benefit-Risk Assessment for the Periodic Benefit-Risk Evaluation Report.
In 2012, the International Conference on Harmonisation (ICH) E2C (R1) guideline for periodic safety update reporting (PSUR) for medicines was revised. Several new concepts that expanded the scope of the report were added, including a new section focused on benefits and an additional section focused on integrated benefit-risk (B-R) assessment. These changes are reflected in the new title of the report, namely, the Periodic Benefit-Risk Evaluation Report (PBRER). Recently, structured frameworks have been developed by the pharmaceutical industry and regulatory agencies to facilitate B-R analysis for medicines. This manuscript provides suggestions for incorporating the elements of a structured B-R assessment into the PBRER and also includes practical approaches for implementing the ICH guidelines for the B-R analysis section. The main components of a B-R assessment for the PBRER include decision context; key benefits and key risks; strengths, limitations, and uncertainties of the evidence; risk management; and the overall B-R conclusions. A structured, systematic approach to defining a medicine's B-R profile will help ensure compliance with this ICH objective for the PBRER.


Comparing High-Frequency With Monophasic Electroporation Protocols in an In Vivo Beating Heart Model.
This study compared monophasic 100-μs pulses with high-frequency electroporation (HF-EP) bursts using an in vivo animal model. Myocardial damage was evaluated by histologic analysis. Compared with 10 monophasic pulses, 20 bursts of HF-EP at 100 and 150 kHz were associated with less damage. However, when the number of HF-EP bursts was increased to 60, myocardial damage was comparable to that of the monophasic group. HF-EP protocols were associated with attenuated collateral muscle contractions. This study shows that HF-EP is feasible and effective and that pulse frequency has a significant effect on extent of ablation.


Coronary atherosclerosis in sudden cardiac death: an autopsy study.
The incidence of ischemic heart disease (IHD) has markedly increased in India over the past few years. Considering the variations in racial, dietary and lifestyle patterns in our population, it is essential to study the biology of coronary atherosclerosis in our patients. Vulnerable plaques have a large number of foam cells, extracellular lipid, thin fibrous caps and clusters of inflammatory cells and are more prone to rupture. These plaques are nourished by the microvessels arising from the vasa vasorum of the blood vessels and by lumen-derived microvessels through the fibrous cap. This autopsy study was designed to analyse the coronary arterial tree in cases of sudden cardiac death, classify coronary atherosclerotic plaques and to assess the factors contributing to vulnerability of the plaques including inflammation, calcification and microvascular density. Seven cases of sudden cardiac death were included in the study. The hearts were perfusion-fixed and the coronary arteries along with their main branches were dissected and studied. The location of the plaques, type of plaques, presence of inflammation and calcification were assessed. The cap thickness and microvessel density per 1000 um 2 were assessed. The statistical significance was estimated. Extensive high-grade coronary atherosclerotic disease was seen in all sudden cardiac death cases. Majority of the plaques were vulnerable. High-grade inflammation was seen in most of the vulnerable and ruptured plaques. All the ruptured plaques were uncalcified indicating that calcification probably stabilizes the plaques and protects against rupture. Increased microvessel density was noted in ruptured plaques compared to vulnerable plaques. However, it was not statistically significant.


Dynamic Network Biomarker Analysis Reveals the Critical Phase Transition of Fruit Ripening in Grapevine.
Grapevine (Vitisvinifera L.) fruit ripening is a complex biological process involving a phase transition from immature to mature. Understanding the molecular mechanism of fruit ripening is critical for grapevine fruit storage and quality improvement. However, the regulatory mechanism for the critical phase transition of fruit ripening from immature to mature in grapevine remains poorly understood. In this work, to identify the key molecular events controlling the critical phase transition of grapevine fruit ripening, we performed an integrated dynamic network analysis on time-series transcriptomic data of grapevine berry development and ripening. As a result, we identified the third time point as a critical transition point in grapevine fruit ripening, which is consistent with the onset of veraison reported in previous studies. In addition, we detected 68 genes as being key regulators involved in controlling fruit ripening. The GO (Gene Ontology) analysis showed that some of these genes participate in fruit development and seed development. This study provided dynamic network biomarkers for marking the initial transcriptional events that characterizes the transition process of fruit ripening, as well as new insights into fruit development and ripening.


[Causes of encephalopathy: descriptive study at Abidjan (Cote-d'Ivoire)].
Assess the etiology and course of cases of encephalopathy seen in the neurology department of the Cocody University Hospital in Abidjan (Côte-d'Ivoire), a city of more than three million inhabitants. Retrospective analysis of patients admitted to the hospital neurology unit from 1 December, 1998, through 31 December, 2000; with a lesion of the brain, brainstem, cerebellum or meninges. Lesions were either confirmed by computed tomography or clinically obvious; MRI was unavailable. Overall, 1011 subjects met the inclusion criteria: 58% were male; their median age was 45 years (range: 1 to 93 years); more than 40% were not working, and 92% had a medical history. The etiology was vascular (445), infectious (380) or undetermined (125); rare cases were degenerative (5) or traumatic (4). Of 35 cases of metabolic encephalopathy, half were associated with another etiology. Pathological confirmation of cerebral tumors (22) was unavailable. All cases of toxic encephalopathy (11) involved adults and alcohol. Global lethality was 26% and did not differ significantly according to whether or not the etiology was identified (26% vs 28.8%). Another 13% were lost to follow-up (left without discharge), and 61% patients recovered and were discharged after a median hospitalization of 12.5 days. The proportion of cases with an undetermined etiology is worrisome. Better knowledge would be useful to develop indicators to evaluate improvements in the medical management of these diseases.


Multicellular tumor spheroids from human gliomas maintained in organ culture.
Tumor tissue from seven human gliomas was maintained in long-term agar overlay culture as multicellular organotypic spheroids. Light microscopic and ultrastructural observation of the spheroids displayed morphological features similar to those of the original tumor tissue in vivo; in this respect they were different from spheroids obtained from permanent cell lines. The spheroids contained preserved vessels, connective tissue, and macrophages, revealing a close resemblance to the conditions in the original tumor. Flow cytometric deoxyribonucleic acid measurements of cells from the tumor spheroids and from biopsy material obtained directly from the operation revealed the same ploidy and the same amount of proliferating cells in the spheroids as in the original tumor. Fluorescence microscopy using bromodeoxyuridine (BUdR) incorporation and anti-BUdR monoclonal antibody confirmed the proliferative potential of tumor cells in the spheroids. Diameter measurements showed that the size of the spheroids from two of the tumors increased over time while in three other cases it decreased. Spheroids from the remaining two tumors showed no change in size, even after 80 days in culture. These growth data and the relatively high number of proliferating cells, as measured by flow cytometry, indicate that the degree of cell proliferation and cell loss from the spheroids are closely linked, as is the case for tumors in vivo. The culture system presented provides a valuable alternative to propagation of human tumors in animals.


Sm antibodies increase risk of death in systemic lupus erythematosus.
The importance of ethnicity, socioeconomic status (SES), and autoantibodies as prognostic indicators in lupus were evaluated in a Canadian cohort. A retrospective review of 330 lupus patients identified demographic features including age and self reported ethnicity, SES, lupus features, antibodies to extractable nuclear antigens (ENAs), organ damage (SDI score), and mortality. ENA (Sm, RNP, Ro, La) associations with lupus features, predictors of final visit SDI score and the contributions of ethnicity, autoantibodies and SES on overall mortality were determined. Three ethnic groups [Caucasians (C), Asian-Orientals (AO), Native American First Nations (FN)] differed in disease severity and SES. FN and AO patients had similarly severe lupus, developing lupus at an earlier age, with more renal and neurological involvement, greater SDI scores at last visit, and more frequently had Sm or RNP antibodies than C. FN had the highest mortality and lowest SES. Sm and RNP antibodies were associated with renal and neurologic involvement. RNP, education and duration of follow-up predicted SDI score. Sm increased risk of death. In conclusion, RNP and lower SES are associated with lupus related organ damage and the presence of Sm is a predictor of mortality in lupus, independent of ethnicity, renal involvement or socioeconomic status.


Intimate partner violence and other partner-related factors: correlates of sexually transmissible infections and risky sexual behaviours among young adult African American women.
Intimate partner violence and other partner-related factors have been associated with acquiring sexually transmissible infections (STIs) and engaging in risky sexual behaviour. The present study examined partner-related risk factors for STIs and risky sexual behaviours among an urban sample of African American women. African American women, between 18 and 29 years (n = 848), participated in the study at baseline. Participants completed a 40-min Audio Computer Assisted Survey Interview assessing sociodemographics, partner-related factors and HIV/STI-associated sexual risk behaviours. Subsequently, participants provided two vaginal swab specimens for STIs. The findings indicated that risky sexual behaviours and STIs were prevalent in this sample: 35.6% reported a risky sexual partner, 65.4% reported inconsistent condom use and 17% tested positive for a laboratory-confirmed STI. Women reporting a history of intimate partner violence were more likely to report risky sexual partners (adjusted odds ratio (AOR) = 2.00; 95% confidence interval (CI) = 1.5-2.8), inconsistent condom use (AOR = 1.60; 95% CI = 1.1-2.3) and test positive for an STI (AOR = 1.46; 95% CI = 0.99-2.1). Women reporting high partner-related barriers to condom use were more likely to report risky sexual partners (AOR = 1.69; 95% CI = 1.2-2.3), inconsistent condom use (AOR = 2.13; 95% CI = 1.5-3.0) and test positive for an STI (AOR = 1.98; 95% CI = 1.3-3.0). Finally, women with older partners were more likely to report risky sexual partners (AOR = 1.53; 95% CI = 1.1-2.1) and test positive for an STI (AOR = 1.46; 95% CI = 1.0-2.2). This study examines partner-related risk factors for STIs and risky sexual behaviours among African American women. These findings underscore the need for combined intimate partner violence and HIV/STI prevention programs for this disproportionately affected high-risk group.


Impact of multiple joint impairments on the energetics and mechanics of walking in patients with haemophilia.
Few studies have assessed the changes produced by multiple joint impairments (MJI) of the lower limbs on gait in patients with haemophilia (PWH). In patients with MJI, quantifiable outcome measures are necessary if treatment benefits are to be compared. This study was aimed at observing the metabolic cost, mechanical work and efficiency of walking among PWH with MJI and to investigate the relationship between joint damage and any changes in mechanical and energetic variables. This study used three-dimensional gait analysis to investigate the kinematics, cost, mechanical work and efficiency of walking in 31 PWH with MJI, with the results being compared with speed-matched values from a database of healthy subjects. Regarding energetics, the mass-specific net cost of transport (C(net)) was significantly higher for PWH with MJI compared with control and directly related to a loss in dynamic joint range of motion. Surprisingly, however, there was no substantial increase in mechanical work, with PWH being able to adopt a walking strategy to improve energy recovery via the pendulum mechanism. This probable compensatory mechanism to economize energy likely counterbalances the supplementary work associated with an increased vertical excursion of centre of mass (CoM) and lower muscle efficiency of locomotion. Metabolic variables were probably the most representative variables of gait disability for these subjects with complex orthopaedic degenerative disorders.


Iron(III) complex of a crown ether-porphyrin conjugate and reversible binding of superoxide to its Iron(II) form.
The synthesis and characterization of the Fe(III) complex of a novel crown ether-porphyrin conjugate, 52-N-(4-aza-18-crown-6)methyl-54,104,154,204-tetra-tert-butyl-56-methyl-5,10,15,20-tetraphenylporphyrin (H2Porph), as well as the corresponding hydroxo, dimeric, Fe(II), and peroxo species are reported. The crystal structure of [FeIII(Porph)Cl].H3O+.FeCl4-.C6H6.EtOH is also reported. [FeIII(Porph)(DMSO)2]+ and K[FeIII(Porph)(O22-)] are high-spin species (Mössbauer data: delta = 0.38 mm s(-1), DeltaEq = 0.83 mm s(-1) and delta = 0.41 mm s(-1), DeltaEq = 0.51 mm s(-1), respectively), whereas in a solution of reduced [FeIII(Porph)(DMSO)2]+ complex the low-spin [FeII(Porph)(DMSO)2] (delta = 0.44 mm s(-1), DeltaEq = 1.32 mm s(-1)) and high-spin [FeII(Porph)(DMSO)] (delta = 1.27 mm s(-1), DeltaEq = 3.13 mm s(-1)) iron(II) species are observed. The reaction of [FeIII(Porph)(DMSO)2]+ with KO2 in DMSO has been investigated. The first reaction step, involving reduction to [FeII(Porph)(DMSO)2], was not investigated in detail because of parallel formation of an Fe(III)-hydroxo species. The kinetics and thermodynamics of the second reaction step, reversible binding of superoxide to the Fe(II) complex and formation of an Fe(III)-peroxo species, were studied in detail (by stopped-flow time-resolved UV/vis measurements in DMSO at 25 degrees C), resulting in kon = 36 500 +/- 500 M(-1) s(-1), koff = 0.21 +/- 0.01 s(-1) (direct measurements using an acid as a superoxide scavenger), and KO2- = (1.7 +/- 0.2) x 10(5) (superoxide binding constant kinetically obtained as kon/koff), (1.4 +/- 0.1) x 10(5), and (9.0 +/- 0.1) x 10(4) M(-1) (thermodynamically obtained in the absence and in the presence of 0.1 M NBu4PF6, respectively). Temperature-dependent kinetic measurements for kon (-40 to 25 degrees C in 3:7 DMSO/CH3CN mixture) yielded the activation parameters DeltaH = 61.2 +/- 0.9 kJ mol(-1) and DeltaS = +48 +/- 3 J K(-1) mol(-1). The observed reversible binding of superoxide to the metal center and the obtained kinetic and thermodynamic parameters are unique. The finding that fine-tuning of the proton concentration can cause the Fe(III)-peroxo species to release O2- and form an Fe(II) species is of biological interest, since this process might occur under very specific physiological conditions.


Immobilizing Enzymes on Noble Metal Hydrogel Nanozymes with Synergistically Enhanced Peroxidase Activity for Ultrasensitive Immunoassays by Cascade Signal Amplification.
Enzyme immobilization plays an essential role in solving the problems of the inherently fragile nature of enzymes. Although prominent stability and reuse of enzymes can be achieved by enzyme immobilization, their bioactivity and catalytic efficiency will be adversely affected. Herein, PdCu hydrogel nanozymes with a hierarchically porous structure were used to immobilize horseradish peroxidase (HRP) to obtain PdCu@HRP. In addition to the improvement of stability and reusability, PdCu@HRP displayed synergistically enhanced activities than native HRP and PdCu hydrogels. Not only the specific interactions between PdCu hydrogel nanozymes and enzymes but also the enrichment of substrates around enzymes by electrostatic adsorption of hydrogels was proposed to expound the enhanced catalytic activity. Accordingly, by taking advantage of the excellent catalytic performance of the PdCu@HRP and the glucose oxidase encapsulated in zeolitic imidazolate framework-8, colorimetric biosensing of the carcinoembryonic antigen via catalytic cascade reactions for achieving signal amplification was performed. The obtained biosensor enhanced the detection sensitivity by approximately 6.1-fold as compared to the conventional HRP-based enzyme-linked immunosorbent assay, demonstrating the promising potential in clinical diagnosis.


Reducing PAH emissions from the iron ore sintering process by optimizing its operation parameters.
This study set out to reduce polycyclic aromatic hydrocarbon (PAH) emissions from the iron ore sintering process by optimizing its operation parameters obtained from the Taguchi experimental design. Four operating parameters, including the water content (Wc; range = 6.0-7.0 wt %), suction pressure (Ps; range = 1000-1400 mmH2O), bed height (Hb; range = 500-600 mm), and type of hearth layer (HL; including sinter, hematite, and limonite) were selected and conducted on a pilot-scale sinter pot to simulate various sintering operating conditions of a real-scale sinter plant. We found that the resultant optimal combination (Wc = 6.5 wt %, Hb = 600 mm, Ps = 1400 mmH2O, and HL = limonite) could reduce the emission factor of total BaP equivalent concentration (EF(BaPeq)) up to 57.6% in comparison with the current operating condition of a real-scale sinter plant (Wc = 6.5 wt %, Hb = 550 mm, Ps = 1200 mmH2O, and HL = sinter). Through the ANOVA analysis, we found that Ps and Hb were the top two parameters affecting total EF(BaPeq) (accounting, respectively, for 70.9% and 21.2% of the total contribution of the four selected parameters). By examining both the sinter productivity and sinter strength, the values obtained from the optimal combination were quite comparable to those of the current operating condition. The above results further confirm the applicability of the obtained optimal combination for the real-scale sinter plant.


Hydroxyfasudil, an active metabolite of fasudil hydrochloride, relaxes the rabbit basilar artery by disinhibition of myosin light chain phosphatase.
Fasudil hydrochloride (AT877, hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, identical to HA1077) inhibits cerebral vasospasm after subarachnoid hemorrhage in experimental animals and humans. In the current study, the vasorelaxing mechanism of hydroxyfasudil, a hydroxylated metabolite of fasudil hydrochloride, was determined in the rabbit basilar artery. The effects of hydroxyfasudil on tension, intracellular Ca2+ concentration ([Ca2+]i), and phosphorylation of the myosin light chain were examined using the isolated and intact or permeabilized rabbit basilar artery without endothelium in vitro. In the intact rabbit basilar artery, hydroxyfasudil elicited a concentration-dependent relaxation of the artery precontracted with 1 nmol/L endothelin-1 (ET-1) plus 20 mmol/L KCl without any significant decrease in [Ca2+]i as determined by fura-2 microfluorometry (IC50: 5.1 +/- 4.6 micromol/L). The relaxation induced by hydroxyfasudil was accompanied with dephosphorylation of the myosin light chain. In the permeabilized preparation, hydroxyfasudil inhibited the contraction induced by ET-1, guanosine 5'-O-(3-thiotriphosphate), or the catalytic subunit of rho-associated kinase, but it did not inhibit Ca2+-induced contraction under the condition of inhibited myosin light chain phosphatase. Hydroxyfasudil showed a greater relaxant effect under decreased adenosine triphosphate (ATP) levels. The present study indicated that hydroxyfasudil relaxes the rabbit basilar artery mainly by disinhibiting myosin light chain phosphatase through the inhibition of rho-associated kinase and that this effect depends on the intracellular ATP concentration.


[Embryonic genome organization after fertilization in mammals].
In mammals, the embryonic genome is first transcriptionally inactive after fertilization. Embryonic development is then strictly dependent on the maternally inherited RNA and proteins accumulated before ovulation and present in the oocyte cytoplasm. The onset of embryonic gene expression is initiated later during development, i.e. during the "embryonic genome activation (EGA)". EGA takes place at various preimplantation stages according to species and is dependent on the presence of the basal transcriptional machinery components but also on parental genomes reorganizations after fertilization. Indeed, during the first embryonic cycles, nuclei undergo intense remodeling that could be a key regulator of embryonic development.


Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.
Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.


The kinesin KIF1C and microtubule plus ends regulate podosome dynamics in macrophages.
Microtubules are important for the turnover of podosomes, dynamic, actin-rich adhesions implicated in migration and invasion of monocytic cells. The molecular basis for this functional dependency, however, remained unclear. Here, we show that contact by microtubule plus ends critically influences the cellular fate of podosomes in primary human macrophages. In particular, we identify the kinesin KIF1C, a member of the Kinesin-3 family, as a plus-end-enriched motor that targets regions of podosome turnover. Expression of mutation constructs or small interfering RNA-/short hairpin RNA-based depletion of KIF1C resulted in decreased podosome dynamics and ultimately in podosome deficiency. Importantly, protein interaction studies showed that KIF1C binds to nonmuscle myosin IIA via its PTPD-binding domain, thus providing an interface between the actin and tubulin cytoskeletons, which may facilitate the subcellular targeting of podosomes by microtubules. This is the first report to implicate a kinesin in podosome regulation and also the first to describe a function for KIF1C in human cells.


Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily. It has been suggested that it plays a pivotal role in various physiological and pathological conditions due to its proinflammatory properties. Fibroblast growth-inducible 14 (Fn14) has been identified as a TWEAK receptor. A number of studies have suggested that TWEAK-Fn14 interaction results in the promotion of apoptosis, cell growth as well as angiogenesis. Although recent studies have indicated that TWEAK and Fn14 are expressed in a number of tumor lines and tissues, the therapeutic potential of this pathway has yet to be elucidated. This study investigated the potential of TWEAK and Fn14 in esophageal and pancreatic cancer as novel molecular targets for anti-cancer therapy. TWEAK and Fn14 protein expression was evaluated in 43 patients with esophageal cancer and 51 patients with pancreatic cancer by immunohistochemistry. As a result, either TWEAK or Fn14 expression was observed in 58.1% of the cases with esophageal cancer and 74.5% of the cases with pancreatic cancer. Furthermore, TWEAK/Fn14 gene expression was identified in the majority of the human esophageal and pancreatic cancer cell lines. Therapeutic efficacies of blocking TWEAK and Fn14 were evaluated by tumor growth inhibition assay in TWEAK- and Fn14-expressing human esophageal and pancreatic cancer cell lines. Coculture with anti-TWEAK or -Fn14 mAb was found to induce a 22-65% cell growth inhibition of these cells. Finally, the significant therapeutic effect of targeting this pathway under in vivo physiological conditions was confirmed using a murine gastrointestinal cancer model. In conclusion, the TWEAK/Fn14 pathway may be functional and critical in intractable gastrointestinal cancers. Therefore, TWEAK and/or Fn14 may be novel molecular targets for anti-cancer therapy.


Compared peripheral H1 inhibiting effects of cetirizine 2 HCl and loratadine.
Histamine-induced wheals and flares were measured in seven healthy volunteers zero, four, and eight hours after oral intake of cetirizine, 2.5, 5, and 10 mg; loratadine, 10, 20, and 40 mg; and placebo. Cetirizine (2.5, 5, and 10 mg) and loratadine (20 and 40 mg) significantly inhibited the histamine-induced wheals at all experimental times and with all histamine concentrations. This was not always the case with loratadine, 10 mg. Cetirizine, 2.5 mg, was as potent in inhibiting the histamine skin reactivity as loratadine, 10 mg.


Anti-inflammatory activity of azithromycin as measured by its NF-kappaB, inhibitory activity.
Growing data suggest that the antibiotic azithromycin mediates anti-inflammatory activity through the inhibition of the transcription factor NF-kappaB. The purpose of this study was to compare azithromycin's anti-inflammatory potency with that of hydrocortisone and dexamethasone as measured in an activated NF-kappaB assay. Dose-response curves and the corresponding inhibitory potencies (IC(50)) of azithromycin, hydrocortisone, and dexamethasone were evaluated in a fluorescence assay using A549 cells. All three compounds inhibited TNFalpha stimulated NF-kappaB activity in a dose-dependent manner. IC(50) values of azithromycin, hydrocortisone and dexamethasone were 56 microM, 2.6 nM, and 0.18 nM, respectively. Hydrocortisone was approximately 4 orders of magnitude more potent than azithromycin, while dexamethasone was approximately 14 times as potent as hydrocortisone. In relative terms the anti-inflammatory potency of azithromycin was about 4 orders of magnitude weaker than that of hydrocortisone.


A preliminary study of Patient Dignity Inventory validation among patients hospitalized in an acute psychiatric ward.
To investigate the perception of dignity among patients hospitalized in a psychiatric setting using the Patient Dignity Inventory (PDI), which had been first validated in oncologic field among terminally ill patients. After having modified two items, we administered the Italian version of PDI to all patients hospitalized in a public psychiatric ward (Service of Psychiatric Diagnosis and Treatment of a northern Italian town), who provided their consent and completed it at discharge, from October 21, 2015 to May 31, 2016. We excluded minors and patients with moderate/severe dementia, with poor knowledge of Italian language, who completed PDI in previous hospitalizations and/or were hospitalized for <72 hours. We collected the demographic and clinical variables of our sample (n=135). We statistically analyzed PDI scores, performing Cronbach's alpha coefficient and principal factor analysis, followed by orthogonal and oblique rotation. We concomitantly administered to our sample other scales (Hamilton Rating Scales for Depression and Anxiety, Global Assessment of Functioning and Health of the Nation Outcome Scales) to analyze the PDI concurrent validity. With a response rate of 93%, we obtained a mean PDI score of 48.27 (±19.59 SD) with excellent internal consistency (Cronbach's alpha coefficient =0.93). The factorial analysis showed the following three factors with eigenvalue >1 (Kaiser's criterion), which explained >80% of total variance with good internal consistency: 1) "Loss of self-identity and social role", 2) "Anxiety and uncertainty for future" and 3) "Loss of personal autonomy". The PDI and the three-factor scores were statistically significantly positively correlated with the Hamilton Scales for Depression and Anxiety but not with other scale scores. Our preliminary research suggests that PDI can be a reliable tool to assess patients' dignity perception in a psychiatric setting, until now little investigated, helping professionals to improve quality of care and patients to accept treatments.


Characterizing the acute heat stress response in gilts: I. Thermoregulatory and production variables.
Identifying traits associated with susceptibility or tolerance to heat stress (HS) is a prerequisite for developing strategies to improve efficient pork production during the summer months. Study objectives were to determine the relationship between the thermoregulatory and production responses to acute HS in pigs. Prepubertal gilts (n = 235; 77.9 ± 1.2 kg BW) were exposed to a thermoneutral (TN) period (P1, 24 h; 21.9 ± 0.5 °C, 62 ± 13% RH; fed ad libitum) followed immediately by a subsequent acute HS period (P2, 24 h; 29.7 ± 1.3 °C, 49 ± 8% RH; fed ad libitum). Rectal temperature (TR), skin temperature (TS), and respiration rate (RR) were monitored and BW and feed intake (FI) were determined. All pigs had increased TR, TS, and RR (0.80 °C, 5.65 °C, and 61.2 bpm, respectively; P < 0.01) and decreased FI and BW (29% and 1.10 kg, respectively; P < 0.01) during P2 compared to P1. Interestingly, body temperature indices did not explain variation in FI during P2 (R2 ≤ 0.02). Further, the percent change in BW during P2 was only marginally explained by each body temperature index (R2 ≤ 0.06) or percent change in FI (R2 = 0.14). During HS, TR was strongly correlated with P1 TR (r = 0.72, P < 0.01), indicating a pig's body temperature during TN conditions predicts the severity of hyperthermia during HS. Additionally, the change in TR (ΔTR, HS TR - TN TR) was larger in pigs retrospectively classified as susceptible (SUS) as compared to tolerant (TOL) pigs (1.05 vs. 0.51 °C, respectively; P < 0.01). In summary, thermoregulatory responses and production variables during acute HS are only marginally related. Further, changes in BW and FI were unexpectedly poorly correlated during acute HS (r = 0.34; P < 0.01). Collectively, suboptimal growth is largely independent on the thermoregulatory response and hypophagia during acute HS. Consequently, incorporating solely body temperature indices into a genetic index is likely insufficient for substantial progress in selecting HS tolerant pigs.


A Flexible Triboelectric Nanogenerator Based on Multilayer MXene/Cellulose Nanofibril Composite Film for Patterned Electroluminescence Display.
The flexible self-powered display system integrating a flexible triboelectric nanogenerator (TENG) and flexible alternating current electroluminescence (ACEL) has attracted increasing attention for its promising potential in human-machine interaction applications. In this work, a performance-enhanced MXene/cellulose nanofibril (CNF)/MXene-based TENG (MCM-TENG) is reported for powering a flexible patterned ACEL device in order to realize self-powered display. The MCM multilayer composite film was self-assembled through the layer-by-layer method. The MCM film concurrently acted as a triboelectric layer and electrode layer due to its high conductivity and strength. Moreover, the effect of CNF concentration and number of layers on the output performance of TENG was investigated. It was found that the MCM-TENG realized the optimum output performance. Finally, a flexible self-powered display device was realized by integrating the flexible TENG and ACEL. The MCM-TENG with an output voltage of ≈90 V at a frequency of 2 Hz was found to be efficient enough to power the ACEL device. Therefore, the as-fabricated flexible TENG demonstrates a promising potential in terms of self-powered displays and human-machine interaction.


Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence.
Oxidative stress-induced DNA damage, the senescence-associated secretory phenotype (SASP), and impaired autophagy all are general features of senescent cells. However, the cross-talk among these events and processes is not fully understood. Here, using NIH3T3 cells exposed to hydrogen peroxide stress, we show that stress-induced DNA damage provokes the SASP largely via cytosolic chromatin fragment (CCF) formation, which activates a cascade comprising cGMP-AMP synthase (cGAS), stimulator of interferon genes protein (STING), NF-κB, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-κB signaling, promoting SASP and cellular senescence. We also present evidence that the persistent accumulation of CCFs in prematurely senescent cells is partially associated with a defect in DNA-degrading activity in autolysosomes and reduced abundance of activated DNase 2α. Intriguingly, we found that metformin- or rapamycin-induced activation of autophagy significantly lessened the size and levels of CCFs and repressed the activation of the cGAS-STING-NF-κB-SASP cascade and cellular senescence. These effects of autophagy activators indicated that autolysosomal function contributes to CCF clearance and SASP suppression, further supported by the fact that the lysosome inhibitor bafilomycin A1 blocked the role of autophagy-mediated CCF clearance and senescence repression.


Renal subcapsular haematoma: an unusual complication of renal artery stenting.
After successful renal artery angioplasty and stent placement, a patient in a fully anticoagulated state developed hypotension and flank pain. Computed tomography (CT) of the abdomen revealed a large renal subcapsular haematoma which was successfully managed conservatively without embolotherapy and surgical intervention. To prevent hemorrhage after renal artery stenting, it is necessary to underscore the importance of reducing the contrast volume and pressure of angiography, controlling systemic blood pressure, and monitoring guide wire position at all times.


[Gross tumor volume and clinical target volume in brachytherapy of malignant tumors].
Tumours treated with radioactive implants are in most cases small and accessible to clinical examination or endoscopy. Gross tumour volume is consequently mainly determined clinically or with endoscopy. Imaging may also be useful, with classical techniques, as mammography, or with CT-scan or MRI. Clinical target volume includes gross tumour volume and a 5-10 mm margin. Distribution of dose is estimated on the basis of images performed after implantation, classically with two orthogonal films of the implant. It can then be optimised. Dose-volume histogram of gross tumour volume and critical organs can be obtained with a CT-scan or a MRI of the implant, which may be difficult to perform because of implantation material and dummy sources.


Development of a novel loop-mediated isothermal amplification assay for rapid detection of Mycobacterium leprae in clinical samples.
Sensitive and definitive diagnostic tests are required for timely treatment of leprosy and to control its transmission. In the present study, we report the development of loop-mediated isothermal amplification assay using six primers targeting the RLEP gene sequence uniquely present in Mycobacterium leprae. Tissue punch samples (n = 50) and slit aspirates (n = 50) from confirmed cases of leprosy (M. leprae positive by quantitative polymerase chain reaction), reporting at the Department of Dermatology, Safdarjung Hospital, New Delhi, were analyzed using newly developed closed tube loop-mediated isothermal amplification assay. The sensitivity and specificity; positive predictive value, negative predictive value and accuracy were calculated using MedCalc statistical software. The loop-mediated isothermal amplification assay specifically amplified M. leprae genomic DNA with an analytical sensitivity of 100 fg. About 47 Out of the 50 quantitative polymerase chain reactions confirmed M. leprae positive tissue samples, 47 were positive by loop-mediated isothermal amplification assay (sensitivity 94%; 95% confidence interval 83.5%-98.8%) while only 31/50 were positive by histopathology (sensitivity 62%; 95% confidence interval 47.2%-75.4%) . Using slit aspirate samples of these 50 patients, 42 were positive by both quantitative polymerase chain reaction and loop-mediated isothermal amplification assay (sensitivity 84%; 95% confidence interval 70.9%-92.8%) while only 23/50 (sensitivity 46%; 95% confidence interval 31.8%-60.7%) were positive by microscopy. In the present study, the leprosy patient cohort was not uniform, as it comprised a lower number of paucibacillary cases (22%) compared to multibacillary (78%) cases. Loop-mediated isothermal amplification assay established here provides a rapid and accurate diagnostic test for leprosy in terms of sensitivity and specificity. The assay is simple to perform in comparison with other molecular techniques (polymerase chain reaction/quantitative polymerase chain reaction) and has potential for field applicability.


Validation of a microRNA liquid biopsy assay for diagnosis and risk stratification of invasive cutaneous melanoma.
Noninvasive molecular biomarkers are needed to improve the early, accurate and precise diagnosis of invasive cutaneous melanoma. To independently validate a previously identified circulating microRNA signature of melanoma (MEL38), and, secondly, to develop a complementary microRNA signature, optimized for prognostication. MicroRNA expression profiling was performed on plasma samples from a multicentre observational case-control study, involving patients with primary or metastatic melanoma, melanoma in situ, nonmelanoma skin cancer, or benign naevi. MicroRNA profiles from patients with length of survival, treatment and sentinel lymph node biopsy (SLNB) data were used to develop the prognostic signature. The primary outcome of interest for MEL38 was its association with melanoma status, including area under the curve, binary diagnostic sensitivity and specificity, and incidence-adjusted positive and negative predictive values. The prognostic signature was assessed using rates of survival per risk group and relationship to conventional predictors of outcome. Circulating microRNA profiles of 372 patients with invasive melanoma and 210 control individuals were generated. The average age of all participants was 59 years; 49% were male. A MEL38 score > 5.5 indicated the presence of invasive melanoma. Overall, 551/582 (95%) of patients were correctly diagnosed, with 93% sensitivity and 98% specificity. MEL38 score ranged from 0 to 10 with an area under the curve of 0.98 (95% confidence interval 0.97-0.99, P < 0.001). A novel prognostic 12-microRNA signature (MEL12) developed from 232 patients identified low-, standard- or high-risk groups, with 94%, 78% and 58% rates of 10-year melanoma-specific survival, respectively (log-rank P < 0.001). MEL12 prognostic risk groups were significantly associated with clinical staging (χ2, P < 0.001) and SLNB status (P = 0.027). Patients who were classified as high risk by MEL12 were approximately three times more likely to have melanoma detected in their sentinel lymph nodes compared to low-risk patients. The circulating MEL38 signature may assist in diagnosing patients with invasive melanoma vs. other conditions associated with a lower - or negligible - risk of mortality. A complementary and prognostic MEL12 signature is predictive of SLNB status, clinical stage and probability of survival. Plasma microRNA profiling may help to optimize existing diagnostic pathways as well as enable personalized, risk-informed melanoma treatment decisions.


Mechanics Underpinning Phase Separation of Hydrogels.
This paper reveals the underpinning role of mechanical constraints and dynamic loading in triggering volume phase transitions and phase separation of hydrogels. Using the Flory-Rehner free energy that does not predict phase separation of hydrogels under equilibrium free swelling, we show that mechanical constraints can lead to coexistence of multiple phases. We systematically obtain the states of equilibrium for hydrogels under various mechanical constraints and unravel how mechanical constraints change the convexity of the free energy and monotonicity of the stress-stretch curves, leading to phase coexistence. Using a phase-field model, we predict the pattern evolution of phase coexistence and show that many features cannot be captured by the homogeneous states of equilibrium due to large mismatch stretch between the coexisting phases. We further reveal that the system size, quenching rate, and loading rate can significantly influence the phase behavior, which provides insights for experimental studies related to morphological patterns of hydrogels.