Changes in quantitative bone histomorphometry in aging healthy men.
Changes in bone mineral metabolism with aging in healthy men and the roles of various factors in the pathogenesis of age-related changes in quantitative bone histomorphometry in men are poorly defined. To clarify these changes and factors, serum and urinary biochemical parameters and iliac crest bone biopsies were evaluated in 43 healthy men, aged 20-80 yr. The static histomorphometric parameters, cancellous bone volume and osteoblast-osteoid interface, decreased by 40.0% and 19.2%, respectively, between 20-80 yr of age. The dynamic histomorphometric parameters, double and single labeled osteoid, also decreased by 18.6% and 18.0%, respectively, over this period. None of the other static or dynamic histomorphometric parameters changed with age in this population sample of healthy men. Univariate analysis of static bone histomorphometric parameters and biochemical parameters revealed significant correlations between osteoid surface and intact PTH (r = 0.37; P = 0.015); osteoclast surface and serum total testosterone (r = 0.36; P = 0.016), estradiol (r = 0.40; P = 0.009), and FSH (r = 0.49; P = 0.001); osteoblast-osteoid interface and serum phosphate (r = 0.31; P = 0.046); and cortical thickness and serum total calcium (r = 0.38; P = 0.013). Univariate analysis of dynamic bone histomorphometric parameters and biochemical parameters revealed correlations between mineral apposition rate and serum total testosterone (r = 0.32; P = 0.037); total volume-referent bone formation rate and serum osteocalcin (r = 0.43; P = 0.004), total testosterone (r = 0.47; P = 0.001), estradiol (r = 0.35; P = 0.023), and dehydroepinadrosterone sulfate (r = 0.31; P = 0.045); and mean wall thickness and serum total calcium (r = 0.36; P = 0.019) and creatinine clearance (r = 0.42; P = 010). Mineralization lag time and serum phosphate (r = -0.39; P = 0.012) and urinary total pyridinoline (r = 0.36; P = 0.023), and mean wall thickness and urinary total pyridinoline (r = -0.38; P = 0.013), were inversely correlated. Multiple regression analysis using all-subset analysis comparing cancellous bone volume to serum and urinary biochemical parameters in these men indicated that the log free androgen index and body weight best predicted the age-related decline in iliac crest cancellous bone volume (r2 = 0.19; P = 0.015). Multiple regression analysis by the same method, comparing bone density at different skeletal sites to bone histomorphometric parameters, indicated that lumbar spine bone mineral density (BMD) was best predicted by cancellous bone volume and mineral apposition rate (r2 = 0.31; P = 0.001), femoral neck BMD by cancellous bone volume and osteoid surface (r2 = 0.19; P = 0.020), femoral greater trochanter BMD by cortical thickness and single labeled osteoid surface (r2 = 0.13; P = 0.060), and total body BMD by cancellous bone volume and surface-based bone formation rate (r2 = 0.31; P = 0.001). In summary, cancellous bone volume, osteoblast-osteoid interface, and double and single labeled osteoid decreased with age in this sample of healthy men. The lack of detectable change in bone density at some skeletal sites in these men may be due to the small sample size or other confounding factors. Multivariate analysis suggests that different combinations of histomorphometric parameters predict bone density at different skeletal sites, and that cancellous bone volume predicts bone density at the lumbar spine, femoral neck, and total body, but not at the femoral greater trochanter. We conclude that alterations in several biochemical parameters are important in the pathogenesis of age-related bone loss in healthy men.


Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease.
A single embryonic stem cell (ESC) line can be repetitively cryopreserved, thawed, expanded, and differentiated into various cellular components serving as a potentially renewable and well-characterized stem cell source. Therefore, we determined whether ESCs could be used to reconstitute marrow and blood in major histocompatibility complex (MHC)-mismatched mice. To induce differentiation toward hematopoietic stem cells (HSCs) in vitro, ESCs were cultured in methylcellulose with stem cell factor, interleukin (IL)-3, and IL-6. ESC-derived, cytokine-induced HSCs (c-kit+/CD45+) were isolated by flow cytometry and injected either intra bone marrow or intravenously into lethally irradiated MHC-mismatched recipient mice. From 2 wk to 6 mo after injection, the peripheral blood demonstrated increasing ESC-derived mononuclear cells that included donor-derived T and B lymphocytes, monocytes, and granulocytes without clinical or histologic evidence of graft-versus-host disease (GVHD). Mixed lymphocyte culture assays demonstrated T cell tolerance to both recipient and donor but intact third party proliferative responses and interferon gamma production. ESCs might be used as a renewable alternate marrow donor source that reconstitutes hematopoiesis with intact immune responsiveness without GVHD despite crossing MHC barriers.


Effectiveness of a multidimensional home nurse led heart failure disease management program--a French nationwide time-series comparison.
The purpose of this study was to assess the effectiveness of a disease management program (DMP) in heart failure (HF) on the incidence of HF hospitalizations and related costs in a real-world population-based setting. Insuffisance CArdiaque en LORraine (ICALOR), a DMP for HF was established in 2006 in the French region of Lorraine. Patients were enrolled after an index HF hospitalization. They received educational and home-visit monitoring programs by HF-trained nurses. General physicians received automatic alerts about patients' significant clinical or biological changes. We used the ICALOR and the national diagnostic related group databases to conduct a comparison of time-series trends in HF hospitalizations in France. The economic impact was obtained using the national scale of costs in France. The median age of the 1222 patients recruited before 2010 was 76 years, and 65% were male. Upon enrollment, patients essentially presented with NYHA class II (n=537, 48%) or class III (n=359, 32%) symptoms. One-year mortality rate was 20.3%. The implementation of the ICALOR program was associated with a reduction in HF hospitalizations in Lorraine estimated by an absolute difference between the number of hospitalizations observed in the Lorraine region and that expected had it been similar to that observed in the whole country of -7.19% in 2010. The estimated annual hospital cost saved by ICALOR was €1,927,648 in 2010. Coordinated DMP of HF might improve outcome cost-effectively when implemented in a real-world population setting, and was associated in Lorraine with a substantial modification of the trend of HF hospitalizations.


Using high-resolution contact networks to evaluate SARS-CoV-2 transmission and control in large-scale multi-day events.
The emergence of highly transmissible SARS-CoV-2 variants has created a need to reassess the risk posed by increasing social contacts as countries resume pre-pandemic activities, particularly in the context of resuming large-scale events over multiple days. To examine how social contacts formed in different activity settings influences interventions required to control Delta variant outbreaks, we collected high-resolution data on contacts among passengers and crew on cruise ships and combined the data with network transmission models. We found passengers had a median of 20 (IQR 10-36) unique close contacts per day, and over 60% of their contact episodes were made in dining or sports areas where mask wearing is typically limited. In simulated outbreaks, we found that vaccination coverage and rapid antigen tests had a larger effect than mask mandates alone, indicating the importance of combined interventions against Delta to reduce event risk in the vaccine era.


Bayesian blind source separation for data with network structure.
In biology, more and more information about the interactions in regulatory systems becomes accessible, and this often leads to prior knowledge for recent data interpretations. In this work we focus on multivariate signaling data, where the structure of the data is induced by a known regulatory network. To extract signals of interest we assume a blind source separation (BSS) model, and we capture the structure of the source signals in terms of a Bayesian network. To keep the parameter space small, we consider stationary signals, and we introduce the new algorithm emGrade, where model parameters and source signals are estimated using expectation maximization. For network data, we find an improved estimation performance compared to other BSS algorithms, and the flexible Bayesian modeling enables us to deal with repeated and missing observation values. The main advantage of our method is the statistically interpretable likelihood, and we can use model selection criteria to determine the (in general unknown) number of source signals or decide between different given networks. In simulations we demonstrate the recovery of the source signals dependent on the graph structure and the dimensionality of the data.


PTSD in a one year old girl after the Wenchuan earthquake in Sichuan, China.
On May 12, 2008, at 2:28 PM, an earthquake measuring 8.0 on the Richter Scale struck Southwest China, with the epicenter in Wenchuan, a county about 92 km (about 58 miles) north-west of the Sichuan provincial capital of Chengdu. The earthquake destroyed about 6.5 million homes, leaving 4.8 million people homeless. Official figures stated that 69,196 are confirmed dead, including some 5,335 school children, while an additional 18,379 are listed as missing (Sina.com, 2009). An epidemiological survey conducted 2.5 months after the earthquake in two counties affected by the earthquake found the prevalence of post-traumatic disorder (PTSD) to be 45.5% in the heavily damaged county and 9.4% in the moderately damaged one (Kun et al., 2009).


Effects of Hovenia dulcis fruit and peduncle extract on alcohol metabolism.
The dried fruit and peduncle of Hovenia dulcis Thunberg (Rhamnaceae) (HD) has been used as a folk medicine to treat liver disease, detoxify alcoholism, and prevent and cure hangovers. We investigated the pharmacology of HD on the kinetics of EtOH and on the enzymes related to alcohol metabolism to seek the scientific evidence of HD to prevent hangover, the effectiveness as a folk medicine. EtOH was orally administered 30 min after oral administration of HD boiling water extract in rats. Then, the profiles of blood EtOH concentrations were measured. Mice were reared with food containing powdered HD for 7 days, and the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in liver were measured. Hepa1c1c7 cells were cultured with the medium containing HD extract, and the activities of ADH and ALDH were measured. HD extract reduced the blood EtOH concentrations in rats and induced the activities of ADH and ALDH and mRNA and protein expressions of ADH1B, ALDH1A1, and ALDH2 in the liver of mice and Hepa1c1c7 cells. Dihydromyricetin, one of the ingredients of HD, significantly induced the activities of ADH and ALDH in Hepa1c1c7 cells, however, the fractions containing hydrophilic organic compounds with small molecular weight contributed the most of the activities of HD extract. We clarified the experimental pharmacological evidences of HD as a folk medicine to detoxify alcoholism and prevent hangovers.


Isolation, Characterization, and Antimicrobial Activity of Bacterial and Fungal Representatives Associated With Particulate Matter During Haze and Non-haze Days.
Particulate matter (PM) has been a threat to the environment and public health in the metropolises of developing industrial countries such as Beijing. The microorganisms associated with PM have an impact on human health if they are exposed to the respiratory tract persistently. There are few reports on the microbial resources collected from PM and their antimicrobial activities. In this study, we greatly expanded the diversity of available commensal organisms by collecting 1,258 bacterial and 456 fungal isolates from 63 PM samples. A total of 77 bacterial genera and 35 fungal genera were included in our pure cultures, with Bacillus as the most prevalent cultured bacterial genus, Aspergillus, and Penicillium as the most prevalent fungal ones. During heavy-haze days, the numbers of colony-forming units (CFUs) and isolates of bacteria and fungi were decreased. Bacillus, Paenibacillus, and Chaetomium were found to be enriched during haze days, while Kocuria, Microbacterium, and Penicillium were found to be enriched during non-haze days. Antimicrobial activity against common pathogens have been found in 40 bacterial representatives and 1 fungal representative. The collection of airborne strains will provide a basis to greatly increase our understanding of the relationship between bacteria and fungi associated with PM and human health.


The course of fear of cancer recurrence: Different patterns by age in breast cancer survivors.
To examine the time course and predictors of fear of cancer recurrence (FCR) in breast cancer survivors over a period of 18 months after initial surgery. Breast cancer patients (n = 267) were followed until 18 months after primary breast surgery. Shortly after surgery, participants completed the Life Orientation Test-Revised to measure optimism and the Concerns about Recurrence Scale to measure FCR. Mixed regression analysis was performed with age, optimism, marital status, education, type of surgery, with or without lymphectomy, chemotherapy, hormonal therapy, or radiotherapy, time since surgery, and all interactions with time as predictors of FCR. The final model included a significant interaction between age and time since surgery and a main effect for optimism. These results suggest that the course of FCR depends on the age of breast cancer survivors. Younger survivors showed an increase of fear during the first 1.5 years after breast surgery, whereas older survivors showed stable levels during the first 6 months after which it declined. Also, less optimistic survivors reported higher levels of FCR. Health care providers should pay (extra) attention to FCR in younger and less optimistic patients and offer psychological help when needed.


Learning from our international colleagues: a US plastic surgeon's perspective.
With growing contribution to plastic surgery by our international colleagues, one may be wondering about what US plastic surgeons have learned from them. The purpose of this study was to evaluate a single surgeon's experience to identify any specific areas of plastic surgery that one has learned substantially from our international colleagues. All plastic surgical procedures performed by a single US plastic surgeon at an academic medical center with an active plastic surgery residency training program during the past 10 years were reviewed. More frequently performed procedures by the author were identified. In each identified procedure, critical references used by the author were examined to find out whether these references were from domestic or international sources. More frequently performed procedures by the author were (1) free anterolateral thigh perforator flap and free-style free flap, (2) deep inferior epigastric perforator flap breast reconstruction, (3) implant-based breast reconstruction, (4) oncoplastic breast reduction or mastopexy for breast reconstruction, (5) vertical scar breast reduction, and (6) fat grafting for correction of contour deformity after breast reconstruction. Much more innovative procedures that the author had learned after his residency were published primarily by our international colleagues. The author has learned substantially from our international colleagues because many new procedures may be either first described by them or they have more extensive clinical experience. It is important to fully appreciate the significance of international scientific exchange in plastic surgery and its impact on a US plastic surgeon's clinical practice.


Expression of a novel lacrimal gland gene lacritin in human breast tissues.
The purpose of this study was to examine breast tumors and normal breast tissues for the expression of the glycoprotein lacritin. The mRNA and protein expression of lacritin has been reported to be restricted to the lacrimal gland. We investigated 37 human primary invasive breast tumors, seven breast cancer cell lines and 16 normal breast tissues by quantitative real-time PCR for lacritin expression. We detected lacritin transcripts in 51% (19/37) of the primary invasive breast tumors, in 71% (5/7) of the breast cancer cell lines, and also in 56% (9/16) of the normal breast tissues. No lacritin mRNA was detectable in peripheral blood of healthy individuals. Here we show by quantitative real-time PCR that lacritin is expressed in human breast tumors, breast cancer cell lines, and normal breast. The previously reported restricted expression pattern of lacritin is therefore incorrect. Lacritin transcripts were not detected in peripheral blood which makes lacritin a potential candidate as a breast cancer marker gene.


The Magnitude of the Warfarin-Amiodarone Drug-Drug Interaction Varies With Renal Function: A Propensity-Matched Cohort Study.
Amiodarone inhibits warfarin metabolism and is associated with major bleeding during warfarin therapy. Managing this drug-drug interaction (DDI) is challenging because of substantial interpatient variability in DDI magnitude. Because renal dysfunction induces changes in drug metabolism and protein binding that could alter cytochrome P450 inhibition mechanisms, we hypothesized that renal dysfunction alters the impact of the warfarin-amiodarone DDI. We tested this question in a propensity-matched cohort study of hospitalized patients with atrial fibrillation. Patients were queried from an electronic health record database. Renal function was estimated with creatinine clearance (CrCl). Warfarin response was measured with the warfarin sensitivity index (WSI), a dose-normalized international normalized ratio (INR) measure, and was modeled with multilevel mixed-effects linear regression. Time to supratherapeutic INR (> 4) was modeled using Cox regression. Propensity score matching resulted in 4,518 patients administered amiodarone and 4,518 controls. Amiodarone's effect on warfarin response varied threefold across the renal function range, increasing WSI by 36% in patients with normal renal function (CrCl 115 mL/minute), but by only 11.8% in patients with severe renal dysfunction (CrCl 15 mL/minute). Similarly, amiodarone had a strong effect in patients with normal renal function (hazard ratio (HR) 1.80; 1.23, 2.64), but a negligible effect on supratherapeutic INR hazard in patients with severe renal dysfunction (HR 1.01; 0.75, 1.37). These results suggest that renal function is a novel factor that explains substantial variability in the warfarin-amiodarone DDI. This information could inform warfarin dosage adjustment and monitoring and may have implications for the selection of oral anticoagulation agents in patients treated with amiodarone.


Hypocalcemia, morbidity, and mortality in end-stage renal disease.
Hypocalcemia and hyperphosphatemia with secondary hyper-parathyroidism are characteristic of end-stage renal disease (ESRD). Although calcium levels critically affect almost all cellular processes, the impact of chronic hypocalcemia and other abnormalities of calcium-phosphate homeostasis on the prognosis of ESRD patients is unknown. An inception cohort of 433 patients starting ESRD therapy was followed prospectively for an average of 41 months. Serum calcium and other parameters were measured monthly. The mean calcium levels were 9.4 +/- 0.7 mg/dl. 23% of the patients had mean calcium levels < 8.8 mg/dl. After adjusting for baseline age, diabetes mellitus, ischemic heart disease, smoking and cholesterol levels, as well as serial albumin, hemoglobin, mean arterial blood pressure, phosphate and alkaline phosphatase levels, chronic hypocalcemia was strongly associated with mortality (RR 2.10, p = 0.006 for a mean calcium level < 8.8 mg/dl). The association with mortality was similar in hemodialysis (RR 2.10, p = 0.006) and peritoneal dialysis patients (2.67, p = 0.034). Using similar covariate adjustment, chronic hypocalcemia was associated with de novo ischemic heart disease (RR 5.23, p < 0.001), recurrent ischemic heart disease (RR 2.46, p = 0.006), de novo cardiac failure (RR 2.64, p < 0.001), and recurrent cardiac failure (RR 3.30, p < 0.001). Hypocalcemia retained its independent impact on morbidity and mortality when analyzed as a time-dependent covariate. Chronic hypocalcemia, a very common, reversible feature of chronic uremia, is independently associated with morbidity and mortality in ESRD patients.


Ocean Aerobiology.
Ocean aerobiology is defined here as the study of biological particles of marine origin, including living organisms, present in the atmosphere and their role in ecological, biogeochemical, and climate processes. Hundreds of trillions of microorganisms are exchanged between ocean and atmosphere daily. Within a few days, tropospheric transport potentially disperses microorganisms over continents and between oceans. There is a need to better identify and quantify marine aerobiota, characterize the time spans and distances of marine microorganisms' atmospheric transport, and determine whether microorganisms acclimate to atmospheric conditions and remain viable, or even grow. Exploring the atmosphere as a microbial habitat is fundamental for understanding the consequences of dispersal and will expand our knowledge of biodiversity, biogeography, and ecosystem connectivity across different marine environments. Marine organic matter is chemically transformed in the atmosphere, including remineralization back to CO2. The magnitude of these transformations is insignificant in the context of the annual marine carbon cycle, but may be a significant sink for marine recalcitrant organic matter over long (∼104 years) timescales. In addition, organic matter in sea spray aerosol plays a significant role in the Earth's radiative budget by scattering solar radiation, and indirectly by affecting cloud properties. Marine organic matter is generally a poor source of cloud condensation nuclei (CCN), but a significant source of ice nucleating particles (INPs), affecting the formation of mixed-phase and ice clouds. This review will show that marine biogenic aerosol plays an impactful, but poorly constrained, role in marine ecosystems, biogeochemical processes, and the Earth's climate system. Further work is needed to characterize the connectivity and feedbacks between the atmosphere and ocean ecosystems in order to integrate this complexity into Earth System models, facilitating future climate and biogeochemical predictions.


Quantum bits with polyacetylene.
The dynamics of a polyacetylene single chain as a system for possible physical implementations of quantum bits is determined. This novel proposition is studied by varying intensity and duration of application of an electric field as well as the intensity, number, and position in the polymer chain of impurity molecules. The behavior of soliton pairs, whose associated energy levels form the quantum bit, is analyzed. The chain is modeled by a modified Pariser-Parr-Pople Hamiltonian extended to include the effects of an external electric field and the parameters of the impurity molecules. The effect of the variation of the field and impurities on the separation of the energy levels associated with soliton pairs is analyzed by numerical integration of the equations of motion. Two different approaches for controlling the separation of levels are presented, and their features compared. First, the use of changes in the electric field to control the distance (and ultimately coupling) between two solitons moving freely on the chain or captured by the potential generated by the impurity molecules. Second, the change in the intensity of the impurities alone, with no application of an external field. We have found that the effect of the use of the field on the separation of levels is much smaller than the one obtained by changes in the parameters of the impurity molecules, which eventually led us to achieve quantum bit behavior in a polyacetylene chain. The influence of the field and impurity parameters in the energy levels is determined, as well as their role in the coupling of the two solitons on the chain. Critical values for distance between solitons, intensity of field, and impurities that determine whether a pair of solitons can work as a quantum bit are obtained.


Granule formation and structure from single drop impact on heterogeneous powder beds.
Single drop impact of liquid on a static powder bed was studied to investigate the granule formation mechanism, droplet penetration time, as well as the characterization of granules (morphology, surface structure and internal structure). Water was used as the liquid and two pharmaceutical powders, microcrystalline cellulose (MCC) and acetaminophen (APAP), were mixed to make heterogeneous powder beds. The complete drop impact and penetration was recorded by a high speed camera. Two granule formation mechanisms that have been identified previously occurred: Spreading and Tunneling. Spreading occurred for mixtures with an APAP amount of less than 20%, while Tunneling started to occur when the APAP amount increased above 20%. With an increase of APAP concentration, the mean particle size decreased, drop penetration time increased, and the granules formed became smaller in size, which was in good agreement with previous literature. The granule morphology, surface structure, and internal structure were characterized by a prism method with image analysis, scanning electron microscopy (SEM), and X-ray microtomography, respectively. The Spreading mechanism produced flat disks with a porous internal structure, while the Tunneling mechanism produced round granules with a dense internal structure. There is a clear trend of decreasing porosity and increasing roundness of granules made from heterogeneous mixtures within the transition from Spreading to Tunneling. It is believed that the mean particle size of the powder bed and the powder-liquid contact angle are the predominant factors in influencing the formation mechanism, drop penetration time, and granule properties.


European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update.
Advances in the management of respiratory distress syndrome (RDS) ensure that clinicians must continue to revise current practice. We report the third update of the European Guidelines for the Management of RDS by a European panel of expert neonatologists including input from an expert perinatal obstetrician based on available literature up to the beginning of 2016. Optimizing the outcome for babies with RDS includes consideration of when to use antenatal steroids, and good obstetric practice includes methods of predicting the risk of preterm delivery and also consideration of whether transfer to a perinatal centre is necessary and safe. Methods for optimal delivery room management have become more evidence based, and protocols for lung protection, including initiation of continuous positive airway pressure and titration of oxygen, should be implemented from soon after birth. Surfactant replacement therapy is a crucial part of the management of RDS, and newer protocols for surfactant administration are aimed at avoiding exposure to mechanical ventilation, and there is more evidence of differences among various surfactants in clinical use. Newer methods of maintaining babies on non-invasive respiratory support have been developed and offer potential for greater comfort and less chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease although minimizing the time spent on mechanical ventilation using caffeine and if necessary postnatal steroids are also important considerations. Protocols for optimizing the general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome.


Epidemiology and pathogenicity of M. equirhinis in equine respiratory disorders.
Mycoplasmas are pathogens involved in respiratory disorders of various animal hosts. In horses, Mycoplasma (M.) equirhinis is the species most frequently detected in clinical respiratory specimens, with a prevalence of 12-16%, but its clinical implication in equine respiratory disorders remains unclear. Here we screened 1948 clinical specimens for the presence of M. equirhinis. The samples were both tracheal washes (TW) and bronchoalveolar lavages (BAL) collected by veterinarians in France in day-to-day work between 2020 and 2022. The samples were associated with a standardized form that served to collect key general and clinical information, such as horse age, breed, and living environment. M. equirhinis was detected using a combination of culture and post-enrichment PCR. Other diagnostic data included virology and bacteriology as well as neutrophil counts, when available. Prevalence of M. equirhinis was examined as a function of a clinical score based on four significant clinical signs (nasal discharge, cough, dyspnoea, and hyperthermia). Multivariate logistic regression analysis was run to identify risk factors for the presence of M. equirhinis, and comparative prevalence analysis was used to test for association with other bacteria and viruses. TW and BAL were analysed independently, as we found that TW samples were associated with a higher prevalence of M. equirhinis. As prevalence remained steady whatever the clinical score, M. equirhinis cannot be considered a primary pathogen. M. equirhinis was more frequently isolated in thoroughbreds and trotters and in horses living exclusively stabled compared to other horses or other living environments. M. equirhinis was never detected in BAL specimens with a 'normal' neutrophil count, i.e. 5%, suggesting it could be associated with an inflammatory response, similar to that observed in equine asthma. Prevalence of M. equirhinis was shown to increase in the presence of other bacteria such as Streptococcus equi subsp. zooepidemicus (S. zoo) or viruses, and S. zoo load was higher in M. equirhinis-positive samples, suggesting a potential increase of clinical signs in the event of co-infection.


Distinct functions of BMP4 during different stages of mouse ES cell neural commitment.
Bone morphogenetic protein (BMP) signaling plays a crucial role in maintaining the pluripotency of mouse embryonic stem cells (ESCs) and has negative effects on ESC neural differentiation. However, it remains unclear when and how BMP signaling executes those different functions during neural commitment. Here, we show that a BMP4-sensitive window exists during ESC neural differentiation. Cells at this specific period correspond to the egg cylinder stage epiblast and can be maintained as ESC-derived epiblast stem cells (ESD-EpiSCs), which have the same characteristics as EpiSCs derived from mouse embryos. We propose that ESC neural differentiation occurs in two stages: first from ESCs to ESD-EpiSCs and then from ESD-EpiSCs to neural precursor cells (NPCs). We further show that BMP4 inhibits the conversion of ESCs into ESD-EpiSCs during the first stage, and suppresses ESD-EpiSC neural commitment and promotes non-neural lineage differentiation during the second stage. Mechanistic studies show that BMP4 inhibits FGF/ERK activity at the first stage but not at the second stage; and IDs, as important downstream genes of BMP signaling, partially substitute for BMP4 functions at both stages. We conclude that BMP signaling has distinct functions during different stages of ESC neural commitment.


Neuroimmune interaction in the gut: from bench to bedside.
The enteric nervous system plays a crucial role in the control of gastrointestinal motility and coordinates relaxation and contraction of the smooth muscle cells. Relaxation of the gut is mainly mediated by inhibitory non-adrenergic non-cholinergic (NANC) neurons, a subpopulation of enteric neurons which release a neurotransmitter different from acetylcholine and noradrenaline. Via in vitro work performed in Antwerp, we demonstrated in 1990 that these neurons release nitric oxide. Thereafter, my research has focused on the role of the inhibitory NANC neurons in the pathophysiology of postoperative ileus. This iatrogenic condition is characterized by general hypomotility of the entire gastrointestinal tract. In a rat model, we have confirmed that manipulation of the bowel indeed leads to activation of inhibitory NANC neurons during and immediately after abdominal surgery. However, this neuronal component is short lasting and does not explain the observation that ileus lasts several days. Based on this consideration, our research in recent years rather focused on this late phase of postoperative ileus. In Amsterdam, we developed a mouse model studying gastric emptying 24 hours after surgery as read out of postoperative ileus. This research provided new insights regarding the interaction between the immune system and the innervation of the gut. Manipulation of the bowel induced mast cell degranulation and activation of macrophages present in the gut wall leading to influx of inflammatory cells in the vicinity of the myenteric plexus. This local infiltrate subsequently activates inhibitory spinal pathways paralyzing the entire gastrointestinal tract. Conversely, we showed that stimulation of the vagus nerve before and during abdominal surgery prevents this infiltrate. Both in vitro and in vivo studies showed that acetylcholine release prevents activation of macrophages via nicotinic receptors. This finding illustrates the bidirectional communication between the immune system and the enteric nervous system. Next we showed that pharmacological interventions with mast cell stabilizers, antibodies against adhesion molecules and nicotinic agonists can prevent the influx of inflammatory cells and thereby shorten postoperative ileus. Especially as we also demonstrated mast cell activation and intestinal inflammation following surgery in man, these findings provide opportunities to develop new therapeutic strategies for the treatment of postoperative ileus. In summary, our work illustrates that the innervation of the intestine intensely communicates with the immune system. Inflammation activates inhibitory neural pathways whereas vagus nerve stimulation can suppress the immune system, in particular macrophages. These findings have led to the identification of new "targets" for the development of new treatments, not only for postoperative ileus, but possibly also for other gastrointestinal inflammatory diseases.


Mobile technologies in medical education: AMEE Guide No. 105.
Mobile technologies (including handheld and wearable devices) have the potential to enhance learning activities from basic medical undergraduate education through residency and beyond. In order to use these technologies successfully, medical educators need to be aware of the underpinning socio-theoretical concepts that influence their usage, the pre-clinical and clinical educational environment in which the educational activities occur, and the practical possibilities and limitations of their usage. This Guide builds upon the previous AMEE Guide to e-Learning in medical education by providing medical teachers with conceptual frameworks and practical examples of using mobile technologies in medical education. The goal is to help medical teachers to use these concepts and technologies at all levels of medical education to improve the education of medical and healthcare personnel, and ultimately contribute to improved patient healthcare. This Guide begins by reviewing some of the technological changes that have occurred in recent years, and then examines the theoretical basis (both social and educational) for understanding mobile technology usage. From there, the Guide progresses through a hierarchy of institutional, teacher and learner needs, identifying issues, problems and solutions for the effective use of mobile technology in medical education. This Guide ends with a brief look to the future.


Altered glucose kinetics in diabetic rats during gram-negative infection.
The present study examined the purported exacerbating effect of sepsis on glucose metabolism in diabetes. Diabetes was induced in rats by an intravenous injection of 70 or 45 mg/kg streptozotocin. The higher dose produced "severe" diabetes, whereas the lower dose of streptozotocin produced a milder, "latent" diabetes. After a chronic diabetic state had developed for 4 wk, rats had catheters implanted and sepsis induced by intraperitoneal injections of live Escherichia coli. After 24 h of sepsis the blood glucose concentration was unchanged in nondiabetics and latent diabetics, but glucose decreased from 15 to 8 mM in the septic severe diabetic group. This decrease in blood glucose was not accompanied by alterations in the plasma insulin concentration. Glucose turnover, assessed by the constant intravenous infusion of [6-3H]- and [U-14C]glucose, was elevated in the severe diabetic group, compared with either latent diabetics or nondiabetics. Induction of sepsis produced a slight decrease in the glucose turnover in the severe diabetic group but did not alter turnover in the latent diabetics. The rate of glucose disappearance, used to quantitate the alterations in plasma glucose after an intravenous glucose tolerance test, was decreased in both groups of diabetics and was proportional to the severity of the diabetic state. Sepsis increased the rate of glucose disappearance in nondiabetic rats but had no effect in either group of diabetic animals. Sepsis also failed to alter the insulinogenic index, used to estimate the insulin secretory capacity, in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)


A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival. We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension. Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.


Synergistic growth inhibition of YM529 with biologic response modifiers (BRMs) in myeloma cells.
Bisphosphonates (BPs) are effective in the management of bone disease in patients with multiple myeloma. Recent reports have suggested that they may also have an antitumor activity. YM529 is a new synthetic BP with more than 1000 times the bone resorption inhibitory activity of pamidronate. To clarify the direct effects of YM529 on myeloma cells, the cell proliferation and cell cycle perturbation were analyzed using 12 myeloma cell lines established in our laboratory. The growth inhibition was dose dependent. The cells accumulated in [2n<<4n] of the cell cycle and subsequently formed an apoptotic sub-G1 fraction. Combined treatment with all-trans retinoic acid, thalidomide, or interferon-alpha enhanced the growth inhibitory effects of YM529 on these cells. However, there were no remarkable effects of YM529 on the messenger RNA expression for angiogenic factors, cell cycle regulators, or cytokines related to myeloma cells. These results indicate that YM529 is beneficial not only to bone lesions but also for its direct antitumor effects on myeloma cells.


The Coumarin Glucoside, Esculin, Reveals Rapid Changes in Phloem-Transport Velocity in Response to Environmental Cues.
The study of phloem transport and its vital roles in long-distance communication and carbon allocation have been hampered by a lack of suitable tools that allow high-throughput, real-time studies. Esculin, a fluorescent coumarin glucoside, is recognized by Suc transporters, including AtSUC2, which loads it into the phloem for translocation to sink tissues. These properties make it an ideal tool for use in live-imaging experiments, where it acts as a surrogate for Suc. Here, we show that esculin is translocated with a similar efficiency to Suc and, because of its ease of application and detection, demonstrate that it is an ideal tool for in vivo studies of phloem transport. We used esculin to determine the effect of different environmental cues on the velocity of phloem transport. We provide evidence that fluctuations in cotyledon Suc levels influence phloem velocity rapidly, supporting the pressure-flow model of phloem transport. Under acute changes in light levels, the phloem velocity mirrored changes in the expression of AtSUC2 This observation suggests that under certain environmental conditions, transcriptional regulation may affect the abundance of AtSUC2 and thus regulate the phloem transport velocity.


Rickettsia parkeri invasion of diverse host cells involves an Arp2/3 complex, WAVE complex and Rho-family GTPase-dependent pathway.
Rickettsiae are obligate intracellular pathogens that are transmitted to humans by arthropod vectors and cause diseases such as spotted fever and typhus. Although rickettsiae require the host cell actin cytoskeleton for invasion, the cytoskeletal proteins that mediate this process have not been completely described. To identify the host factors important during cell invasion by Rickettsia parkeri, a member of the spotted fever group (SFG), we performed an RNAi screen targeting 105 proteins in Drosophila melanogaster S2R+ cells. The screen identified 21 core proteins important for invasion, including the GTPases Rac1 and Rac2, the WAVE nucleation-promoting factor complex and the Arp2/3 complex. In mammalian cells, including endothelial cells, the natural targets of R. parkeri, the Arp2/3 complex was also crucial for invasion, while requirements for WAVE2 as well as Rho GTPases depended on the particular cell type. We propose that R. parkeri invades S2R+ arthropod cells through a primary pathway leading to actin nucleation, whereas invasion of mammalian endothelial cells occurs via redundant pathways that converge on the host Arp2/3 complex. Our results reveal a key role for the WAVE and Arp2/3 complexes, as well as a higher degree of variation than previously appreciated in actin nucleation pathways activated during Rickettsia invasion.


Exposure assessment of electromagnetic fields near electrosurgical units.
Electrosurgical units (ESU) are widely used in medical health services. By applying sinusoidal or pulsed voltage in the frequency range of 0.3-5 MHz to the electrode tip, the desired mixture of coagulation and cutting are achieved. Due to the high voltage and current in the cable, strong electromagnetic fields appear near the ESU. The surgeon and others inside the operating room such as nurses, anesthesiologists, etc., will be highly exposed to these fields. The stray fields surrounding the ESU have previously been measured, but now a deeper analysis has been made of the curve shape of the field and the implication of this when assessing exposure from a commonly used ESU in accordance with the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. The result showed that for some of the modes, especially those using high-pulsed voltage with only a few sinusoidal periods, the E-field close to the cable could reach linear spatially averaged values of 20 kV/m compared to the 2.1 kV/m stated in ICNIRP guidelines. Assessing the E- and B-field from ESU is not straightforward since in this frequency range, both induced current density and specific absorption rate are restricted by the ICNIRP guidelines. Nevertheless, work needs to be done to reduce the stray fields from ESU.


Long-term breast-feeding in women with type 1 diabetes.
Breast-feeding may be more difficult in women with diabetes because of neonatal morbidity and fluctuating maternal blood glucose values. The frequency of long-term breast-feeding and the possible predictors for successful breast-feeding were investigated. One hundred two consecutive women with type 1 diabetes were interviewed about breast-feeding using a semistructured questionnaire 5 days and 4 months after delivery. Clinical data were collected from the medical records. Five days after delivery, 86% of the women were breast-feeding. Four months after delivery, 55 (54%) women were exclusively, 14 (14%) were partly, and 33 (32%) were not breast-feeding compared with 50, 26, and 24% in the background population (NS). Mothers exclusively breast-feeding at 4 months were characterized by previous experience with breast-feeding, a higher educational level, and vaginal delivery and included a high proportion of nonsmokers, whereas there were no associations with diabetes-related parameters such as white classes, duration of diabetes, HbA(1c), and insulin dose at conception. Breast-fed offspring had a significantly higher birth weight and gestational age and were less often receiving glucose intravenously compared with the remaining offspring. Independent predictors of exclusive breast-feeding at 4 months were previous experience with breast-feeding (odds ratio 6.3 [95% CI 2.4-17]) and higher educational level (7.1 [2.4-21]). Cessation of breast-feeding was mainly due to common nursing problems, such as perceived milk supply, and not related to maternal diabetes status. The majority of the women with type 1 diabetes initiated breast-feeding, and the prevalence of breast-feeding at 4 months was comparable to that in the background population. Independent predictors of exclusive breast-feeding at 4 months were previous experience with breast-feeding and higher educational level.


Transposable Element Expression and Regulation Profile in Gonads of Interspecific Hybrids of Drosophila arizonae and Drosophila mojavensis wrigleyi.
Interspecific hybridization may lead to sterility and/or inviability through differential expression of genes and transposable elements (TEs). In Drosophila, studies have reported massive TE mobilization in hybrids from interspecific crosses of species presenting high divergence times. However, few studies have examined the consequences of TE mobilization upon hybridization in recently diverged species, such as Drosophila arizonae and D. mojavensis. We have sequenced transcriptomes of D. arizonae and the subspecies D. m. wrigleyi and their reciprocal hybrids, as well as piRNAs, to analyze the impact of genomic stress on TE regulation. Our results revealed that the differential expression in both gonadal tissues of parental species was similar. Globally, ovaries and testes showed few deregulated TEs compared with both parental lines. Analyses of small RNA data showed that in ovaries, the TE upregulation is likely due to divergence of copies inherited from parental genomes and lack of piRNAs mapping to them. Nevertheless, in testes, the divergent expression of genes associated with chromatin state and piRNA pathway potentially indicates that TE differential expression is related to the divergence of regulatory genes that play a role in modulating transcriptional and post-transcriptional mechanisms.


High Prevalence of Sarcopenia in HIV-Infected Individuals.
Sarcopenia is a geriatric syndrome that leads to a loss of functionality and mortality. We assessed the prevalence of sarcopenia in HIV-infected patients attended in our HIV Unit who had at least two DXA scans from 2000 to 2016 (1,720 DXA scans from 860 individuals). Sarcopenia was determinate according to appendicular skeletal muscle mass index (ASM) calculated as the ratio between skeletal muscle mass index (SMI) by DXA and height2 (kg/m2). We stratified patients by gender and age (<40, 41-50, and >50 years) and according to the interval between DXAs (≤3, 3-7, 7-10, >10 years). The statistical analysis was performed using SPSS version 19. Median (IQR) age was 52 (47; 57) years, and 76% were male. The median (IQR) time with HIV infection was 8 (3; 15) years. The prevalence of sarcopenia was 25.7% (95% CI, 22.8-28.7), more prevalent in those aged >50 years (27.8%). Stratifying by gender, 43% of women aged >50 years presented sarcopenia compared with 8.8% of men. The frequency of sarcopenia increased from 37.6% to 49.4% when interval between DXA was 7-10 years (n=109), significantly higher in women than in men (p=0.016). In addition to the traditional risk factors, time with HIV infection was associated with sarcopenia [RR 1.780 (95% CI, 1.314-2.411), p=0.001]. The prevalence and progression of sarcopenia in HIV-infected patients were high, mainly among women. Further studies are necessary to assess the best approaches to prevent this condition and its consequences.


Peer support for discharge from inpatient to community mental health services: Study protocol clinical trial (SPIRIT Compliant).
In the period shortly after discharge from inpatient to community mental health care, people are at increased risk of self-harm, suicide, and readmission to hospital. Discharge interventions including peer support have shown potential, and there is some evidence that community-based peer support reduces readmissions. However, systematic reviews of peer support in mental health services indicate poor trial quality and a lack of reporting of how peer support is distinctive from other mental health support. This study is designed to establish the clinical and cost effectiveness of a peer worker intervention to support discharge from inpatient to community mental health care, and to address issues of trial quality and clarity of reporting of peer support interventions. This protocol describes an individually randomized controlled superiority trial, hypothesizing that people offered a peer worker discharge intervention in addition to usual follow-up care in the community are less likely to be readmitted in the 12 months post discharge than people receiving usual care alone. A total of 590 people will be recruited shortly before discharge from hospital and randomly allocated to care as usual plus the peer worker intervention or care as usual alone. Manualized peer support provided by trained peer workers begins in hospital and continues for 4 months in the community post discharge. Secondary psychosocial outcomes are assessed at 4 months post discharge, and service use and cost outcomes at 12 months post discharge, alongside a mixed methods process evaluation. Clearly specified procedures for sequencing participant allocation and for blinding assessors to allocation, plus full reporting of outcomes, should reduce risk of bias in trial findings and contribute to improved quality in the peer support evidence base. The involvement of members of the study team with direct experience of peer support, mental distress, and using mental health services, in coproducing the intervention and designing the trial, ensures that we theorize and clearly describe the peer worker intervention, and evaluate how peer support is related to any change in outcome. This is an important methodological contribution to the evidence base. This study was prospectively registered as ISRCTN 10043328 on November 28, 2016.


Mesenchymal Stromal Cell Secretome for Severe COVID-19 Infections: Premises for the Therapeutic Use.
From the end of 2019, the world population has been faced the spread of the novel coronavirus SARS-CoV-2 responsible for COVID-19 infection. In approximately 14% of the patients affected by the novel coronavirus, the infection progresses with the development of pneumonia that requires mechanical ventilation. At the moment, there is no specific antiviral treatment recommended for the COVID-19 pandemic and the therapeutic strategies to deal with the infection are only supportive. In our opinion, mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 pneumonia, due to the broad pharmacological effects it shows, including anti-inflammatory, immunomodulatory, regenerative, pro-angiogenic and anti-fibrotic properties.


Effect of different catching practices during manual upright handling on broiler welfare and behavior.
The aim of this study was to identify the influence of different catching practices during manual upright handling on broiler welfare and behavior. Catching was examined in a total of 4,595 Cobb broilers with average live weight of 3.2 kg and 42 days old. Six catching practices were evaluated: shed curtain position, loading time, catching method, catching team, height of the crates from the floor, and placement of the bird in the crate. Behavioral welfare indicators were defined as follows: 1) broiler agitation in the catcher's hands, measured when the birds flapped their wings, kicked, or wriggled in the hands; 2) broiler striking the crate entrance as it was being placed in the crate, measured when the birds get the head, wings, or legs, hit at the crate entrance; and 3) broiler agitation in the crate, measured when birds flapped the wings or jumped inside the crate for 3 s or more after placement in the crate. A logistic regression model was used to calculate the chance of occurrence of each behavioral welfare indicator due to the handling factors. All catching practices evaluated in the present study influenced the birds' welfare and behavior. Thus, some procedures during broiler catching potentially improved their behavior, making them less prone to accidents, and consequently improved their welfare. The catching process should be performed with the curtains in the closed position, carrying one broiler per catcher in an upright position while containing its wings, carefully placing the birds inside the crates, and with the crates being positioned at a height of at least 21 cm from the ground. Additionally, it was concluded that more attention should be given to the broiler catchers, since the position of the curtain, loading time, and position of the crate during handling can influence the work done by them, affecting the welfare and behavior of both humans and birds.


Ethical and Practical Realities of Using Letters for Recruitment in Bereavement Research.
Recruitment of participants into bereavement research may present many challenges for the research team. At present, there is little consensus for researchers and ethics committees on the most appropriate method of recruitment. There is some evidence that participants prefer to be contacted about research studies via letters. However, recruitment involving the use of a letter can occur in a number of ways, each with ethical and practical benefits and limitations. In a study of the experiences of bereaved parents, we used letters in three ways: direct mailing from the research team with an opt-out option; permission to mail letters obtained by social workers from a hospital-based follow-up program during routine contact; and letters mailed from the hospital's PICU research nurse at the hospital with instruction on how to opt in. In this paper, the practical and ethical realities of each method are highlighted, using examples from our own experiences. Nineteen parents also provided reflections in follow-up phone calls. While direct researcher contact is perhaps the most feasible for researchers, ethical concerns may render it unacceptable. While contact via a known member of a follow-up program is more ethically appropriate for participants, it also presents significant practical issues. We suggest that contact via a representative of the healthcare institution provides the best balance of ethical and practical acceptability for both participants and the research team, but responsiveness to the ethical and practical requirements of the study is crucial in ensuring it can be successfully undertaken. © 2017 Wiley Periodicals, Inc.


Evaluation of the additive effects of volatile fatty acids and moderate heat treatment for enhancing the inactivation of vegetative cells and spores of Clostridium perfringens by flow cytometry.
Clostridium perfringens is a well-known spore-forming bacterium that can resist the environment. A mixture of volatile fatty acids or thermal treatments can interact with these bacteria. The aim of this study was to evaluate the effects of different volatile fatty acid concentrations and moderate heat treatment on Clostridium perfringens sporulation. A pure culture of Clostridium perfringens type A in Duncan Strong medium was treated with a mixture of volatile fatty acids at several concentrations. A thermal treatment was also tested. To evaluate the effects, a double staining method was employed, and treatments on Clostridium perfringens were analysed by flow cytometry. Moderate heat treatment destroyed vegetative forms but had no effect on sporulating forms. Volatile fatty acids combined with moderate heat treatment inhibited Clostridium perfringens sporulation. The use of flow cytometry as an original method for evaluating the treatment of Clostridium perfringens is of interest because of its simplicity, short time to obtain results, and the level of information provided on the microbial population (impact on metabolism). A combination of mild treatments (moderate heat treatment + volatile fatty acids) to decrease the Clostridium perfringens concentration when these bacteria sporulate is a very promising finding for inhibiting Clostridium perfringens propagation.


User experiences using FLAME: A Case study modelling conflict in large enterprise system implementations.
The complexity of systems now under consideration (be they biological, physical, chemical, social, etc), together with the technicalities of experimentation in the real-world and the non-linear nature of system dynamics, means that computational modelling is indispensible in the pursuit of furthering our understanding of complex systems. Agent-based modelling and simulation is rapidly increasing in its popularity, in part due to the increased appreciation of the paradigm by the non-computer science community, but also due to the increase in the usability, sophistication and number of modelling frameworks that use the approach. The Flexible Large-scale Agent-based Modelling Environment (FLAME) is a relatively recent addition to the list. FLAME was designed and developed from the outset to deal with massive simulations, and to ensure that the simulation code is portable across different scales of computing and across different operating systems. In this study, we report our experiences when using FLAME to model the development and propagation of conflict within large multi-partner enterprise system implementations, which acts as an example of a complex dynamical social system. We believe FLAME is an excellent choice for experienced modellers, who will be able to fully harness the capabilities that it has to offer, and also be competent in diagnosing and solving any limitations that are encountered. Conversely, because FLAME requires considerable development of instrumentation tools, along with development of statistical analysis scripts, we believe that it is not suitable for the novice modeller, who may be better suited to using a graphical user interface driven framework until their experience with modelling and competence in programming increases.


The Effect of a Nurse Initiated Therapeutic Conversation Compared to Standard Care for Patients With Acute Pain in the ED: A Randomized Controlled Trial.
Acute pain is a common presenting complaint in the emergency department (ED) and is most often treated with opioid or nonopioid analgesia. However, studies have shown that receiving analgesia alone does not always influence patient satisfaction with pain management in the ED. Pain anxiety and catastrophizing have been shown to affect pain intensity and patients' response to analgesia. The objective of this study was to determine whether a brief therapeutic conversation would improve patient satisfaction with pain management compared with standard care for adult patients presenting to the ED with moderate to severe acute pain. Adult (18 years or older) patients presenting to the ED with moderate to severe acute pain were randomized to either the standard care group or the intervention group. Patients in the intervention group participated in a brief therapeutic conversation with an ED nurse to discuss their perceived cause of pain, level of anxiety, and expectations of their pain management. Prior to discharge, all patients were asked to complete a self-reported, 9-item questionnaire to assess their level of satisfaction with their overall ED experience. A total of 166 patients (83 in each group) were enrolled. Patient satisfaction with ED pain management and the proportion of patients who received analgesia in the ED were similar in both the control (n = 57; 68.7%) and intervention (n = 58; 69.9%) groups (Δ 1.2%; 95% CI [12.6, 15]). Qualitative findings demonstrate that patients place high importance on acknowledgment from ED staff and worry about the unknown cause of pain. This study suggests that patient satisfaction with pain management in the ED is multifactorial and complex. Further research should investigate additional methods of integrating nurse-led interventions into the care of patients in acute pain.


Tubal abnormalities in patients with intrauterine adhesion: evaluation using hysterosalpingography.
Intrauterine adhesion (IUA) represents scar tissue inside the uterine cavity. Many patients may experience recurrent miscarriages, menstrual dysfunction, and may also be unable to achieve pregnancy. Tubal abnormalities are a significant cause of infertility in women. Hysterosalpingography (HSG) is a useful screening test for the evaluation of the uterine cavity and provides information relating to the assessment of tubal morphology and patency. The HSG radiographs of 92 patients with intrauterine adhesions, between November 2008 and October 2011, in the Lagos State University Teaching Hospital, were assessed and analyzed for tubal abnormality. Out of the 92 patients studied, 12 (13.04%) were diagnosed with primary infertility, while the rest of the 80 (86.96%) were referred for secondary infertility. The age range of the patients was between 27 and 42 years, with a mean age of 34.58 ± SD years. The mean infertile period of all the study subjects was 5.78 ± SD years. The prevalence of tubal abnormalities demonstrated in the study was 67.39%. Sixty-six (71.73%) patients presented with minor adhesions, while 26 (28.27%) patients presented with moderate adhesions. Conclusion : The prevalence of tubal abnormalities demonstrated in patients with intrauterine adhesion was 67.39%.


Polymeric membranes: surface modification for minimizing (bio)colloidal fouling.
This paper presents an overview on recent developments in surface modification of polymer membranes for reduction of their fouling with biocolloids and organic colloids in pressure driven membrane processes. First, colloidal interactions such as London-van der Waals, electrical, hydration, hydrophobic, steric forces and membrane surface properties such as hydrophilicity, charge and surface roughness, which affect membrane fouling, have been discussed and the main goals of the membrane surface modification for fouling reduction have been outlined. Thereafter the recent studies on reduction of (bio)colloidal of polymer membranes using ultraviolet/redox initiated surface grafting, physical coating/adsorption of a protective layer on the membrane surface, chemical reactions or surface modification of polymer membranes with nanoparticles as well as using of advanced atomic force microscopy to characterize (bio)colloidal fouling have been critically summarized.


Ultrasound-guided compression repair of femoral pseudoaneurysms complicating cardiac catheterization.
Femoral pseudoaneurysms complicate cardiac catheterizations in up to 3.2% of cases. Ultrasound-guided compression repair (UGCR) is a known valid alternative therapy to surgical and percutaneous repair. We evaluated its safety and efficacy in a series of patients. Patients with clinical findings suggesting pseudoaneurysm after cardiac catheterization, underwent echo-color and duplex studies. When a pseudoaneurysm was diagnosed, the patient underwent UGCR until closure or for 50 min. A groin compression bandage was applied after the procedure and patients were put on bed rest for 12-18 hours; a new ultrasound study was performed the day after the procedure: when the UGCR procedure failed, patients were referred to a vascular surgeon or interventional radiologist. When possible, a third ultrasound study was performed 1 month after the procedure. Between January 2001 and June 2003, 15 pseudoaneurysms were diagnosed and treated by means of UGCR. The UGCR procedure (UGCR followed by groin bandage) was successful in 13 cases (87%); 1 patient underwent surgical repair and 1 patient underwent percutaneous repair. No local or systemic complications were observed following UGCR. Pseudoaneurysm UGCR constitutes a safe and valid procedure; it is less invasive and easier to perform than percutaneous and surgical repair.


GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor.
In the last decade, accumulated evidence highlighted that GPR55 might be activated by several classical cannabinoid ligands, making this orphan receptor the main candidate to be considered as the "third" cannabinoid receptor. The investigation of its pharmacology has often provided divergent and more intricate results that have complicated the understanding of the physiological role of GPR55. Nevertheless, the patent analysis regarding GPR55 outlines the fair interest of big pharmaceutical companies, especially in the first years of this decade. This investigation provides a brief overview of the current "state of the art" of our knowledge of GPR55, giving particular emphasis to its functional selectivity. This property could account for controversial roles of GPR55, whose pharmacology and downstream signaling is known to vary significantly both in ligand- and system-dependent manners. In addition, we gain insights into the challenging aspect of finding out novel GPR55 modulators, by analyzing conserved structural and functional motifs that, together with future studies, could help to elucidate its mechanism of action and to design more selective and potent small-molecules directed towards GPR55. Preliminary data highlight remarkable differences, but also intriguing commonalities, between GPR55 and other members of class A G protein-coupled receptors. It is anticipated that, in the next future, novel lead candidates targeting GPR55 could represent new tools to better understand GPR55-mediated human diseases and, hopefully, generate an innovative class of effective next-generation therapeutics.


Gouty arthropathy of the acromioclavicular joint.
Gouty arthropathy of the acromioclavicular joint is uncommon, with only two previously reported cases in the literature. The authors report a case in a 54-year-old man. The differential diagnosis of acromioclavicular arthropathy is reviewed, emphasizing that a high index of suspicion and aspiration of joint fluid are needed to make an accurate diagnosis.


Computational analysis of base composition pattern and promoter elements in the putative promoter regions in relation to expression profiles of 682 human genes on chromosome 22.
Abstract The base composition pattern (BCP) in the putative promoter region (PPRs) up to 5 Kb lengths of 682 human genes on Chromosome 22 (Chr22) was examined. Two-dimensional (2D) and three-dimensional (3D) functions were designed to delineate the DNA base composition, with four major patterns identified. It is found that 17.6% genes include TATA box, 28.0% GC box, 18.9% CAAT box and 38.4% CpG islands, and approximately 10% genes have one of four putative initiator (Inr) motifs. The occurrence of the promoter elements is tightly associated with the base composition features in the promoter regions, and the associations of the base composition features with occurrence of the promoter elements in the promoter regions mediate tissue-wide expression of the genes in human. The occurrence of two or more promoter elements in the promoter regions is required for the medium- and wide-range expression profiles of the human genes on Chr22. Thus, the reported data shed light on the characteristics of the PPRs of the human genes on Chr22, which may improve our understanding of regulatory roles of the PPRs with occurrence of the promoter elements in gene expression.


Interpretable Machine Learning Methods for Monitoring Polymer Degradation in Extrusion of Polylactic Acid.
This work investigates real-time monitoring of extrusion-induced degradation in different grades of PLA across a range of process conditions and machine set-ups. Data on machine settings together with in-process sensor data, including temperature, pressure, and near-infrared (NIR) spectra, are used as inputs to predict the molecular weight and mechanical properties of the product. Many soft sensor approaches based on complex spectral data are essentially 'black-box' in nature, which can limit industrial acceptability. Hence, the focus here is on identifying an optimal approach to developing interpretable models while achieving high predictive accuracy and robustness across different process settings. The performance of a Recursive Feature Elimination (RFE) approach was compared to more common dimension reduction and regression approaches including Partial Least Squares (PLS), iterative PLS (i-PLS), Principal Component Regression (PCR), ridge regression, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest (RF). It is shown that for medical-grade PLA processed under moisture-controlled conditions, accurate prediction of molecular weight is possible over a wide range of process conditions and different machine settings (different nozzle types for downstream fibre spinning) with an RFE-RF algorithm. Similarly, for the prediction of yield stress, RFE-RF achieved excellent predictive performance, outperforming the other approaches in terms of simplicity, interpretability, and accuracy. The features selected by the RFE model provide important insights to the process. It was found that change in molecular weight was not an important factor affecting the mechanical properties of the PLA, which is primarily related to the pressure and temperature at the latter stages of the extrusion process. The temperature at the extruder exit was also the most important predictor of degradation of the polymer molecular weight, highlighting the importance of accurate melt temperature control in the process. RFE not only outperforms more established methods as a soft sensor method, but also has significant advantages in terms of computational efficiency, simplicity, and interpretability. RFE-based soft sensors are promising for better quality control in processing thermally sensitive polymers such as PLA, in particular demonstrating for the first time the ability to monitor molecular weight degradation during processing across various machine settings.


The utility of virtual reality and augmented reality in spine surgery.
As the number of advances in surgical techniques increases, it becomes increasingly important to assess and research the technology regarding spine surgery techniques in order to increase surgical accuracy, decrease overall length of surgery, and minimize overall radiation exposure. Currently, augmented reality and virtual reality have shown promising results in regard to their applicability beyond their current functions. At present, VR has been generally applied to a teaching and preparatory role, while AR has been utilized in surgical settings. As such, the following review attempts to provide an overview of both virtual reality and augmented reality, followed by a discussion of their current applications and future direction.


Prevention of Ventilator-Associated Pneumonia: The Multimodal Approach of the Spanish ICU "Pneumonia Zero" Program.
The "Pneumonia Zero" project is a nationwide multimodal intervention based on the simultaneous implementation of a comprehensive evidence-based bundle measures to prevent ventilator-associated pneumonia in critically ill patients admitted to the ICU. Prospective, interventional, and multicenter study. A total of 181 ICUs throughout Spain. All patients admitted for more than 24 hours to the participating ICUs between April 1, 2011, and December 31, 2012. Ten ventilator-associated pneumonia prevention measures were implemented (seven were mandatory and three highly recommended). The database of the National ICU-Acquired Infections Surveillance Study (Estudio Nacional de Vigilancia de Infecciones Nosocomiales [ENVIN]) was used for data collection. Ventilator-associated pneumonia rate was expressed as incidence density per 1,000 ventilator days. Ventilator-associated pneumonia rates from the incorporation of the ICUs to the project, every 3 months, were compared with data of the ENVIN registry (April-June 2010) as the baseline period. Ventilator-associated pneumonia rates were adjusted by characteristics of the hospital, including size, type (public or private), and teaching (postgraduate) or university-affiliated (undergraduate) status. The 181 participating ICUs accounted for 75% of all ICUs in Spain. In a total of 171,237 ICU admissions, an artificial airway was present on 505,802 days (50.0% of days of stay in the ICU). A total of 3,474 ventilator-associated pneumonia episodes were diagnosed in 3,186 patients. The adjusted ventilator-associated pneumonia incidence density rate decreased from 9.83 (95% CI, 8.42-11.48) per 1,000 ventilator days in the baseline period to 4.34 (95% CI, 3.22-5.84) after 19-21 months of participation. Implementation of the bundle measures included in the "Pneumonia Zero" project resulted in a significant reduction of more than 50% of the incidence of ventilator-associated pneumonia in Spanish ICUs. This reduction was sustained 21 months after implementation.


Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine.
To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1) isolated from an extract of herbal medicine Sorbaria sorbifolia. Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM) method. Microvessel density (MVD) was determined by staining tissue sections immunohistochemically for CD34 using the Weidner capillary counting method. The mRNA and protein levels of vascular endothelial growth factor (VEGF), vascular endothelialgrowth factor receptor 2 (VEGFR2, Flk-1/KDR), basic fibroblast growth factor (bFGF), cyclo-oxygenase (COX)-2 and hypoxia-inducible factor (HIF)-1α were detected by quantitative real-time polymerase chain reaction and Western blotting analysis. The TTF1 inhibition rates for CAM were 30.8%, 38.2% and 47.5% with treatment concentrations of 25, 50 and 100 μg/embryo × 5 d, respectively. The inhibitory rates for tumor size were 43.8%, 49.4% and 59.6% at TTF1 treatment concentrations of 5, 10, and 20 μmol/kg, respectively. The average MVD was 14.2, 11.2 and 8.5 at treatment concentrations of 5 μmol/kg, 10 μmol/kg and 20 μmol/kg TTF1, respectively. The mRNA and protein levels of VEGF, KDR, bFGF, COX-2 and HIF-1α in mice treated with TTF1 were significantly decreased. TTF1 can inhibit tumor angiogenesis, and the mechanism may be associated with the down-regulation of VEGF, KDR, bFGF, HIF-1α and COX-2.


Whole-body imaging of infection using bioluminescence.
Bioluminescence imaging is a powerful technique to visualize and monitor biological processes in numerous systems. This unit describes two strategies for bioluminescence imaging that can be used to study bacterial infection in mice. One method is to express a luciferase gene in the bacteria; the second method is to use bacteria that express both a luciferase and β-lactamase along with a substrate containing caged luciferin, which is released by β-lactamase hydrolysis and reacts with luciferase to generate light. For both strategies, bioluminescent signals are imaged using an IVIS live animal imaging system (Caliper Life Sciences). The bioluminescence images are analyzed to localize bioluminescent bacteria, quantify signal, and determine the wavelengths of the signals produced. The correlation of bacterial numbers with signal intensity in vivo can be determined, allowing a quantitative measure of bacterial numbers in mice in real time. Methods are described in detail to facilitate successful application of these emerging technologies in nearly any experimental system.


Ductal carcinoma in situ in a 25-year-old man presenting with apparent unilateral gynecomastia.
Ductal carcinoma in situ (DCIS) in a young man is rarely reported. Our patient, a 25-year-old man, presented with apparent symptomatic unilateral gynecomastia. He has a strong history of cancer on both the maternal and paternal sides of his family, including breast and lung (maternal) and melanoma, colon, and pancreatic (paternal). His mother tested negative for BRCA1 and BRCA2. There is no information on paternal genetic testing.The patient was treated with left subcutaneous mastectomy. Upon histologic review of the sample, concurrent gynecomastia and DCIS were discovered. To date, only 4 cases of gynecomastia and DCIS have been described in younger male patients. Because only 30%-50% of patients with DCIS eventually develop invasive cancer in the subsequent 10-20 years, DCIS prevalence in the general population may be higher than predicted. This case underscores the importance of family history in any patient presenting with a breast mass. Patients must be made aware of the risk, however small it may be, and physicians must remain cautious of cancer in young men with gynecomastia.


It Takes Two to Tango-Double-Layer Selective Contacts in Perovskite Solar Cells for Improved Device Performance and Reduced Hysteresis.
Solar cells made from inorganic-organic perovskites have gradually approached market requirements as their efficiency and stability have improved tremendously in recent years. Planar low-temperature processed perovskite solar cells are advantageous for possible large-scale production but are more prone to exhibiting photocurrent hysteresis, especially in the regular n-i-p structure. Here, a systematic characterization of different electron selective contacts with a variety of chemical and electrical properties in planar n-i-p devices processed below 180 °C is presented. The inorganic metal oxides TiO2 and SnO2, the organic fullerene derivatives C60, PCBM, and ICMA, as well as double-layers with a metal oxide/PCBM structure are used as electron transport materials (ETMs). Perovskite layers deposited atop the different ETMs with the herein applied fabrication method show a similar morphology according to scanning electron microscopy. Further, surface photovoltage spectroscopy measurements indicate comparable perovskite absorber qualities on all ETMs, except TiO2, which shows a more prominent influence of defect states. Transient photoluminescence studies together with current-voltage scans over a broad range of scan speeds reveal faster charge extraction, less pronounced hysteresis effects, and higher efficiencies for devices with fullerene compared to those with metal oxide ETMs. Beyond this, only double-layer ETM structures substantially diminish hysteresis effects for all performed scan speeds and strongly enhance the power conversion efficiency up to a champion stabilized value of 18.0%. The results indicate reduced recombination losses for a double-layer TiO2/PCBM contact design: First, a reduction of shunt paths through the fullerene to the ITO layer. Second, an improved hole blocking by the wide band gap metal oxide. Third, decreased transport losses due to an energetically more favorable contact, as implied by photoelectron spectroscopy measurements. The herein demonstrated improvements of multilayer selective contacts may serve as a general design guideline for perovskite solar cells.


Grapheme-colour synaesthesia yields an ordinary rather than extraordinary memory advantage: evidence from a group study.
In synaesthesia, the input of one sensory modality automatically triggers an additional experience, not normally triggered by the input of that modality. Therefore, compared to non-synaesthetes, additional experiences exist and these may be used as retrieval cues when memory is tested. Previous case studies have suggested that synaesthesia may yield even extraordinary memory abilities. However, group studies found either a task-specific memory advantage or no performance advantage at all. The aim of the present study was to test whether grapheme-colour synaesthesia gives rise to a general memory benefit using a standardised memory test (Wechsler Memory Scale). The synaesthetes showed a performance advantage in episodic memory tests, but not in short-term memory tests. However, performance was still within the ordinary range. The results support the hypothesis that synaesthesia provides for a richer world of experience and as a consequence additional retrieval cues may be available and beneficial but not to the point of extraordinary memory ability.


Oxidative stress and metabolic syndrome: Effects of a natural antioxidants enriched diet on insulin resistance.
Oxidative stress (OS) could play a role in metabolic syndrome-related manifestations contributing to insulin resistance (IR). The aim of the present study was to gain insight the relationships between OS, IR and other hormones involved in caloric balance, explaining the effects of a natural antioxidant-enriched diet in patients affected by metabolic syndrome. We investigated the effects of dietary antioxidants on IR, studying 53 obese (20 males and 33 females, 18-66 years old, BMI 36.3 ± 5.5 kg/m2), with IR evaluated by Homeostasis Model Assessment (HOMA)-index, comparing 4 treatments: hypocaloric diet alone (group A) or plus metformin 1000 mg/daily (group B), natural antioxidants-enriched hypocaloric diet alone (group C) or plus metformin (group D). A personalized program, with calculated antioxidant intake of 800-1000 mg/daily, from fruit and vegetables, was administered to group C and D. The glycemic and insulinemic response to oral glucose load, and concentrations of total-, LDL- and HDL-cholesterol, triglycerides, uric acid, C reactive protein, fT3, fT4, TSH, insulin-like growth factor 1 were evaluated before and after 3-months. Plasma Total antioxidant capacity was determined by H2O2-metmyoglobin system, which interacting with the chromogen ABTS generates a radical with latency time (LAG) proportional to antioxidant content. Despite a similar BMI decrease, we found a significant decrease of HOMA and insulin peak only in group B and D. Insulin response (AUC) showed the greatest decrease in group D (25.60 ± 8.96%) and was significantly lower in group D vs B. No differences were observed in glucose response, lipid metabolism and TAC (expressed as LAG values). TSH values were significantly suppressed in group D vs B. These data suggest that dietary antioxidants ameliorate insulin-sensitivity in obese subjects with IR by enhancing the effect of insulin-sensitizing drugs albeit with molecular mechanisms which remain yet to be elucidated.


HHLA2 Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma.
Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a member of the B7 family; however, little is known regarding its expression and clinical relevance in hepatocellular carcinoma (HCC). To better characterize HHLA2 expression in HCC, we analyzed its expression by in situ staining and further investigated its correlation with immune infiltration and patient prognosis. HHLA2 was primarily expressed in the peri-tumor region of HCC tissues and co-localized with CD68+ monocytes/macrophages. In vitro analysis and multi-immunofluorescence staining showed up-regulated HHLA2 expression in tumor-activated monocytes/macrophages, and HHLA2+ monocytes/macrophages expressed high levels of HLA-DR in HCC tissue. A correlation analysis showed that samples displaying high HHLA2 expression in the peri-tumor region had significant tumor infiltration of CD204+ and CD11b+ cells, and low expression of genes associated with an anti-tumor immune response. The high level of peri-tumoral HHLA2 expression was associated with a poor patient overall survival (OS; P = 0.008). A multivariate analysis revealed that HHLA2 expression in the peri-tumor region was an independent prognostic factor for OS (hazard ratio = 1.872, p = 0.003). Moreover, the expression of HHLA2 was negatively correlated with PD-L1, and patients exhibiting HHLA2 and programmed cell death-ligand 1(PD-L1) co-expression had the shortest survival time. HHLA2 expression represented an immunosuppressive microenvironment in HCC, and may serve as a potential target for immunotherapy.


The N-of-1 Clinical Trial: A Timely Research Opportunity in Homeopathy.
The randomised controlled trial (RCT) is considered the 'gold standard' for establishing treatment efficacy or effectiveness of an intervention, but its data do not infer response in an individual patient. Individualised clinical care, a fundamental principle in complementary and alternative medicine (CAM), including homeopathy, seems well disposed in principle to being researched by single-patient (N-of-1) study design. Guidelines for reporting N-of-1 trials have recently been developed. To overview the current status in the literature of the N-of-1 method and its application in medicine, including CAM. To consider whether the N-of-1 trial design offers an opportunity for novel research in homeopathy. N-OF-1 TRIAL DESIGN: The N-of-1 trial applies the principles of the conventional crossover, blinded, RCT design. The treatment under study and the comparator are repeated in a randomised order, and with suitable washout time, over a defined period. N-of-1 design is constrained for use in chronic stable conditions, and for interventions that have quick onset and cessation of effect, with modest or negligible carryover. Outcome data can be aggregated and interpreted for the individual subject; they can also be pooled with data from several similar N-of-1 trials, enabling more generalisable conclusions. THE N-OF-1 TRIAL IN CAM: The typical individualisation of patient care can be accommodated in N-of-1 study design if the patient and the specific therapeutic intervention are selected within the constraints of the method. Application of the N-of-1 method in CAM has been advocated but has been mainly limited, in practice, to a small number of studies in herbal and traditional Chinese medicine. THE N-OF-1 TRIAL IN HOMEOPATHY: Individualised homeopathy can be accommodated for investigation within the same methodological constraints; less in-depth homeopathic approaches to prescribing are also amendable to investigation using the N-of-1 method. No such studies have been published. We identify three main targets in its ready applicability to homeopathy: (1) to optimise clinical care in an individual patient; (2) to investigate whether the outcomes of treatment using homeopathy differ from those of placebo; (3) to aggregate data from a series of N-of-1 trials to enable broader conclusions about a group of patients or intervention. The N-of-1 trial design offers important new investigative possibilities in homeopathy and should be explored as a means to optimise individualised health care or investigate effectiveness of the homeopathic intervention compared with placebo in individual subjects.


Mechanosensitive gating of Kv channels.
K-selective voltage-gated channels (Kv) are multi-conformation bilayer-embedded proteins whose mechanosensitive (MS) Popen(V) implies that at least one conformational transition requires the restructuring of the channel-bilayer interface. Unlike Morris and colleagues, who attributed MS-Kv responses to a cooperative V-dependent closed-closed expansion↔compaction transition near the open state, Mackinnon and colleagues invoke expansion during a V-independent closed↔open transition. With increasing membrane tension, they suggest, the closed↔open equilibrium constant, L, can increase >100-fold, thereby taking steady-state Popen from 0→1; "exquisite sensitivity to small…mechanical perturbations", they state, makes a Kv "as much a mechanosensitive…as…a voltage-dependent channel". Devised to explain successive gK(V) curves in excised patches where tension spontaneously increased until lysis, their L-based model falters in part because of an overlooked IK feature; with recovery from slow inactivation factored in, their g(V) datasets are fully explained by the earlier model (a MS V-dependent closed-closed transition, invariant L≥4). An L-based MS-Kv predicts neither known Kv time courses nor the distinctive MS responses of Kv-ILT. It predicts Kv densities (hence gating charge per V-sensor) several-fold different from established values. If opening depended on elevated tension (L-based model), standard gK(V) operation would be compromised by animal cells' membrane flaccidity. A MS V-dependent transition is, by contrast, unproblematic on all counts. Since these issues bear directly on recent findings that mechanically-modulated Kv channels subtly tune pain-related excitability in peripheral mechanoreceptor neurons we undertook excitability modeling (evoked action potentials). Kvs with MS V-dependent closed-closed transitions produce nuanced mechanically-modulated excitability whereas an L-based MS-Kv yields extreme, possibly excessive (physiologically-speaking) inhibition.


A genome-wide cis-regulatory element discovery method based on promoter sequences and gene co-expression networks.
Deciphering cis-regulatory networks has become an attractive yet challenging task. This paper presents a simple method for cis-regulatory network discovery which aims to avoid some of the common problems of previous approaches. Using promoter sequences and gene expression profiles as input, rather than clustering the genes by the expression data, our method utilizes co-expression neighborhood information for each individual gene, thereby overcoming the disadvantages of current clustering based models which may miss specific information for individual genes. In addition, rather than using a motif database as an input, it implements a simple motif count table for each enumerated k-mer for each gene promoter sequence. Thus, it can be used for species where previous knowledge of cis-regulatory motifs is unknown and has the potential to discover new transcription factor binding sites. Applications on Saccharomyces cerevisiae and Arabidopsis have shown that our method has a good prediction accuracy and outperforms a phylogenetic footprinting approach. Furthermore, the top ranked gene-motif regulatory clusters are evidently functionally co-regulated, and the regulatory relationships between the motifs and the enriched biological functions can often be confirmed by literature. Since this method is simple and gene-specific, it can be readily utilized for insufficiently studied species or flexibly used as an additional step or data source for previous transcription regulatory networks discovery models.


Adverse Effects of GLP-1 Receptor Agonists.
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.


Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients.
Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy.


[Psychological aspects of increased patient participation in prophylactic programs on treating arterial hypertension].
The MMPI and 16-PF scales were used in assessing 146 patients with first- and second-stage essential hypertension, according to the WHO classification. It was shown that the degree of patients' compliance was related to their personality features. The results of the study may be useful in determining differential psychotherapeutic approaches, geared specifically to the patients who declined or discontinued treatment. The practicability of a more active psychotherapeutic influence and individual psychotropic therapy for hypertensive patients involved in large-scale preventive programs is pointed out.