Electrodeposited submicron thermocouples with microsecond response times.
We describe a procedure for preparing submicron scale silver-nickel thermocouples (TCs) using electrochemical step edge decoration on graphite surfaces. Each fabrication operation produced ensembles of 2-20 TCs with diameters in the 1.0 microm to 500 nm range. These "sub-mum TCs" (SMTCs) produced linear voltage versus temperature output over the range from 20 to 100 degrees C characterized by a Seebeck coefficient of 20 +/- 1 microV/degrees C, equal to the 21 microV/degrees C that is theoretically expected for a junction between these two metals. The time response of SMTCs was evaluated using two different laser-heating methods and compared with the smallest mechanically robust commercially available type J TCs. Electrochemical etching of the silver wire introduced constrictions at grain boundaries that reduced the thermal mass of the junction without altering its integrity or its overall diameter, producing a decrease of the measured rise time for SMTCs up to 96%.


Gape drives regional variation in temporalis architectural dynamics in tufted capuchins.
Dynamic changes in jaw movements and bite forces depend on muscle architectural and neural factors that have rarely been compared within the same muscle. Here we investigate how regional muscle architecture dynamics-fascicle rotation, shortening, lengthening and architectural gear ratio (AGR)-vary during chewing across a functionally heterogeneous muscle. We evaluate whether timing in architecture dynamics relates to gape, food material properties and/or muscle activation. We also examine whether static estimates of temporalis fibre architecture track variation in dynamic architecture. Fascicle-level architecture dynamics were measured in three regions of the superficial temporalis of three adult tufted capuchins (Sapajus apella) using biplanar videoradiography and the XROMM workflow. Architecture dynamics data were paired with regional fine-wire electromyography data from four adult tufted capuchins. Gape accounted for most architectural change across the temporalis, but architectural dynamics varied between regions. Mechanically challenging foods were associated with lower AGRs in the anterior region. The timing of most dynamic architectural changes did not vary between regions and differed from regional variation in static architecture. Collectively these findings suggest that, when modelling temporalis muscle force production in extant and fossil primates, it is important to account for the effects of gape, regionalization and food material properties. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.


The role of body mass index and diabetes in the development of acute organ failure and subsequent mortality in an observational cohort.
Several studies have shown a correlation between body mass index (BMI) and both the development of critical illness and adverse outcomes in critically ill patients. The goal of our study was to examine this relationship prospectively with particular attention to the influence of concomitant diabetes mellitus (DM). We analyzed data from 15,408 participants in the Atherosclerosis Risk in Communities (ARIC) study for this analysis. BMI and the presence of DM were defined at baseline. We defined 'acute organ failure' as those subjects who met a standard definition with diagnostic codes abstracted from hospitalization records. Outcomes assessed included the following: risk of the development of acute organ failure within three years of the baseline examination; in-hospital death while ill with acute organ failure; and death at three years among all subjects and among those with acute organ failure. At baseline, participants with a BMI of at least 30 were more likely than those in lower BMI categories to have DM (22.4% versus 7.9%, p < 0.01). Overall, BMI was not a significant predictor of developing acute organ failure. The risk for developing acute organ failure was increased among subjects with DM in comparison with those without DM (2.4% versus 0.7%, p < 0.01). Among subjects with organ failure, both in-hospital mortality (46.5% versus 12.2%, p < 0.01) and 3-year mortality (51.2% versus 21.1%, p < 0.01) was higher in subjects with DM. Our findings suggest that obesity by itself is not a significant predictor of either acute organ failure or death during or after acute organ failure in this cohort. However, the presence of DM, which is related to obesity, is a strong predictor of both acute organ failure and death after acute organ failure.


A Surface Plasmon Resonance Spectroscopy Method for Characterizing Small-Molecule Binding to Nerve Growth Factor.
Small-molecule inhibitors have been previously investigated to identify possible therapeutics for the treatment of chronic pain. In the present study, known nerve growth factor (NGF) inhibitors identified by (125)I-NGF binding were characterized using affinity and binding evaluations by surface plasmon resonance (SPR) spectroscopy. A novel strategy for characterizing NGF inhibitors was used to determine the binding affinity (KD) and saturation ability of each compound with immobilized NGF. Seventy-four percent of compounds screened demonstrated a positive binding event to NGF. A KD less than 10 μM and a percent saturation greater than 50% were used as thresholds to identify inhibitors that would warrant further investigation. This study details for the first time a methodology that can be used to directly characterize the binding event between small-molecule inhibitors and NGF.


Sites hypersensitive to, and protected from, nuclease digestion in the regulatory region of wild-type and mutant polyoma chromatin.
It has been shown that the untranscribed regulatory region of polyoma virus (Py) is hypersensitive (Hs) to DNase I treatment, and that this hypersensitivity is located in two areas which correspond to the A and B domains of the enhancer. We mapped the DNase I hypersensitive sites in the Py regulatory region of wild-type (PyA2) and of mutants, selected in neuroblastoma cells (PyNB), which are characterized by an extensive duplication involving the A domain, with or without deletion of the B domain. The experiments were performed in both a permissive host (3T6 mouse fibroblasts) and in a restrictive host (41A3 mouse neuroblasts). No significant differences were observed between the two hosts. Our results show that four sites, in addition to the ones already described, can be identified in the wild-type A2 strain. These newly identified sites coincide with the domains of the enhancer region as they have recently been established. In PyNB mutants duplications and deletions are generally correlated to the gain or loss of the corresponding hypersensitive sites. However, a new site is formed in one of the duplicated sequences, even if no corresponding hypersensitive site is present in the other identical sequence. A region protected from DNase I digestion occurs in the PyNB mutants which corresponds to the junction of the duplication which is absent in the wild-type strain. In this region, as a consequence of the rearrangement, a GGCGGG motif which is very similar to the one (GGGCGG) present at the binding sites of the cellular regulatory protein SP1, is found.(ABSTRACT TRUNCATED AT 250 WORDS)


A scoping review of preprocessing methods for unstructured text data to assess data quality.
Unstructured text data (UTD) are increasingly found in many databases that were never intended to be used for research, including electronic medical record (EMR) databases. Data quality can impact the usefulness of UTD for research. UTD are typically prepared for analysis (i.e., preprocessed) and analyzed using natural language processing (NLP) techniques. Different NLP methods are used to preprocess UTD and may affect data quality. Our objective was to systematically document current research and practices about NLP preprocessing methods to describe or improve the quality of UTD, including UTD found in EMR databases. A scoping review was undertaken of peer-reviewed studies published between December 2002 and January 2021. Scopus, Web of Science, ProQuest, and EBSCOhost were searched for literature relevant to the study objective. Information extracted from the studies included article characteristics (i.e., year of publication, journal discipline), data characteristics, types of preprocessing methods, and data quality topics. Study data were presented using a narrative synthesis. A total of 41 articles were included in the scoping review; over 50% were published between 2016 and 2021. Almost 20% of the articles were published in health science journals. Common preprocessing methods included removal of extraneous text elements such as stop words, punctuation, and numbers, word tokenization, and parts of speech tagging. Data quality topics for articles about EMR data included misspelled words, security (i.e., de-identification), word variability, sources of noise, quality of annotations, and ambiguity of abbreviations. Multiple NLP techniques have been proposed to preprocess UTD, with some differences in techniques applied to EMR data. There are similarities in the data quality dimensions used to characterize structured data and UTD. While a few general-purpose measures of data quality that do not require external data; most of these focus on the measurement of noise.


Effect of protein supply on hepatic synthesis of plasma and constitutive proteins in lactating dairy cows.
The effects of metabolizable protein (MP) supply on the synthesis of plasma total proteins and albumin, as well as total hepatic protein synthesis, were determined in 6 multicatheterized lactating Holstein cows. Three TMR formulated to supply the same amount of energy but different amounts of MP, 1,922 (low), 2,264 (medium), and 2,517 g of MP/d (high), were fed every 2 h according to a double 3 x 3 Latin square design. For the low and high MP treatments, the cows were continuously infused with [(2)H(5)]Phe (d5-Phe) into a jugular vein for 8 h (1.3 mmol/h) on d 21 of each period. Concentration and isotopic enrichment of d5-Phe were measured for free plasma Phe, plasma total proteins, and albumin on hourly samples collected between 3 and 8 h. Low MP decreased the plasma albumin concentration (32.3 vs. 33.7 +/- 0.11 g/L) but the plasma total protein concentration was unchanged (74.1 vs. 75.6 +/- 1.13 g/L). Incorporation of d5-Phe over time into both plasma total proteins and albumin was linear (R(2) > 0.98). Neither fractional nor absolute synthesis rates of plasma total proteins (6.8 vs. 6.5 +/- 0.65%/d; 168 vs. 154 +/- 19.9 g/d) or albumin (3.4 vs. 3.4 +/- 0.10%/d; 36.3 vs. 36.5 +/- 1.11 g/d) were affected by the MP supply. Net hepatic removal of Phe was lower with the low-MP diet (-12.3 vs. -20.2 +/- 1.98 mmol/h). As a result, net hepatic Phe removal used for total export protein synthesis (17.9 vs. 11.1 +/- 1.83%) and albumin synthesis (4.6 vs. 2.9 +/- 0.54%) tended to be greater at low MP. These results suggest that hepatic synthesis of plasma proteins, including albumin, is maintained in lactating dairy cows even when the protein supply is reduced.


Influence of learning styles on the practical performance after the four-step basic life support training approach - An observational cohort study.
Learning and training basic life support (BLS)-especially external chest compressions (ECC) within the BLS-algorithm-are essential resuscitation training for laypersons as well as for health care professionals. The objective of this study was to evaluate the influence of learning styles on the performance of BLS and to identify whether all types of learners are sufficiently addressed by Peyton's four-step approach for BLS training. A study group of first-year medical students (n = 334) without previous medical knowledge was categorized according to learning styles using the German Lernstilinventar questionnaire based on Kolb's Learning Styles Inventory. Students' BLS performances were assessed before and after a four-step BLS training approach lasting 4 hours. Standardized BLS training was provided by an educational staff consisting of European Resuscitation Council-certified advanced life support providers and instructors. Pre- and post-intervention BLS performance was evaluated using a single-rescuer-scenario and standardized questionnaires (6-point-Likert-scales: 1 = completely agree, 6 = completely disagree). The recorded points of measurement were the time to start, depth, and frequency of ECC. The study population was categorized according to learning styles: diverging (5%, n = 16), assimilating (36%, n = 121), converging (41%, n = 138), and accommodating (18%, n = 59). Independent of learning styles, both male and female participants showed significant improvement in cardiopulmonary resuscitation (CPR) performance. Based on the Kolb learning styles, no significant differences between the four groups were observed in compression depth, frequency, time to start CPR, or the checklist-based assessment within the baseline assessment. A significant sex effect on the difference between pre- and post-interventional assessment points was observed for mean compression depth and mean compression frequency. The findings of this work show that the four-step-approach for BLS training addresses all types of learners independent of their learning styles and does not lead to significant differences in the performance of CPR.


Technique for secondary tracheo-oesophageal puncture in difficult necks.
A secondary tracheo-oesophageal puncture is required for voice restoration post-laryngectomy either for reasons of closure of the primary fistula or as a planned secondary procedure. A method of doing this safely is described using an endotracheal tube and a flexible nasopharyngoscope in especially difficult cases.


The ventral tegmental area dopamine to lateral amygdala projection supports cocaine cue associative learning.
Learning and memory mechanisms are critically involved in drug craving and relapse. Environmental cues paired with repeated drug use acquire incentive value such that exposure to the cues alone can trigger craving and relapse. The amygdala, particularly the lateral amygdala (LA), underlies cue-related learning processes that assign valence to environmental stimuli including drug-paired cues. Evidence suggests that the ventral tegmental area (VTA) dopamine (DA) projection to the LA participates in encoding reinforcing effects that act as a US in conditioned cue reward-seeking as DA released in the amygdala is important for emotional and behavioral functions. Here we used chemogenetics to manipulate these VTA DA inputs to the LA to determine the role of this projection for acquisition of drug-cue associations and reinstatement of drug-seeking. We found inhibiting DA input to the LA during cocaine self-administration slowed acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with DA input to the LA had no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Overall, we show that manipulation of projections underlying DA signaling in the LA may be useful for developing therapeutic interventions for substance use disorders.


Clinical Application of the Fluid Challenge Approach in Goal-Directed Fluid Therapy: What Can We Learn From Human Studies?
Resuscitative fluid therapy aims to increase stroke volume (SV) and cardiac output (CO) and restore/improve tissue oxygen delivery in patients with circulatory failure. In individualized goal-directed fluid therapy (GDFT), fluids are titrated based on the assessment of responsiveness status (i.e., the ability of an individual to increase SV and CO in response to volume expansion). Fluid administration may increase venous return, SV and CO, but these effects may not be predictable in the clinical setting. The fluid challenge (FC) approach, which consists on the intravenous administration of small aliquots of fluids, over a relatively short period of time, to test if a patient has a preload reserve (i.e., the relative position on the Frank-Starling curve), has been used to guide fluid administration in critically ill humans. In responders to volume expansion (defined as individuals where SV or CO increases ≥10-15% from pre FC values), FC administration is repeated until the individual no longer presents a preload reserve (i.e., until increases in SV or CO are <10-15% from values preceding each FC) or until other signs of shock are resolved (e.g., hypotension). Even with the most recent technological developments, reliable and practical measurement of the response variable (SV or CO changes induced by a FC) has posed a challenge in GDFT. Among the methods used to evaluate fluid responsiveness in the human medical field, measurement of aortic flow velocity time integral by point-of-care echocardiography has been implemented as a surrogate of SV changes induced by a FC and seems a promising non-invasive tool to guide FC administration in animals with signs of circulatory failure. This narrative review discusses the development of GDFT based on the FC approach and the response variables used to assess fluid responsiveness status in humans and animals, aiming to open new perspectives on the application of this concept to the veterinary field.


DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression.
Ferritins, an ancient family of protein nanocages, concentrate iron in iron-oxy minerals for iron-protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert-butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE/ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE/ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE/ARE or IRE alone. Regulation of ferritin-L by a MARE/ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.


Sorbitol dehydrogenase (EC.184.108.40.206) polymorphism in human seminal plasma.
Sorbitol dehydrogenase was electrophoretically determined in 173 different samples of human seminal plasma in cellulose acetate as support media. This method permitted the identification of three phenotypes : one with a slow band, one with a fast band and the third with both slow and fast bands. These findings can be explained either by the presence of two alleles at a different SORD locus determining the enzyme in seminal plasma or by the formation of secondary isozymes.


Intraportal transplantation of pancreatic islets into livers of diabetic rats. Reinnervation of islets and regulation of insulin secretion by the hepatic sympathetic nerves.
Two weeks after intraportal transplantation of 2,000 neonatal pancreatic islets, recipient rats completely recovered from streptozotocin-induced diabetes. The reversal of diabetes could be documented by the normalization of blood glucose levels, by a restored weight gain, by normal glucagon and insulin levels in blood, and by a disappearance of polyuria and polydipsia. The reversal remained stable for at least 9 months. This study determined whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin and glucagon from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Predominantly catecholaminergic but also cholinergic nerve fibers were detected not only within the portal tracts around hepatic arteries, portal veins, and bile ducts, but also at the borderline of hepatocytes and beta-cells and in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Isolated livers were single pass perfused via both the hepatic artery and the portal vein. An increase in glucose level from 5 to 14 mmol/l enhanced hepatic glucose uptake and increased insulin secretion from transplanted islets with a biphasic secretion profile but had no effect on glucagon output. Stimulation of the nerve plexus around the hepatic artery and the portal vein (7.5 Hz, 2 min), which activates primarily the sympathetic system, not only reduced glucose uptake and perfusion flow but also completely reversed the glucose-stimulated increase in insulin secretion. Nerve stimulation did not influence glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)


Complexity and Controversies over the Cytokine Profiles of T Helper Cell Subpopulations in Tuberculosis.
Tuberculosis (TB) is a contagious infectious disease caused by the TB-causing bacillus Mycobacterium tuberculosis and is considered a public health problem with enormous social impact. Disease progression is determined mainly by the balance between the microorganism and the host defense systems. Although the immune system controls the infection, this control does not necessarily lead to sterilization. Over recent decades, the patterns of CD4+ T cell responses have been studied with a goal of complete understanding of the immunological mechanisms involved in the maintenance of latent or active tuberculosis infection and of the clinical cure after treatment. Conflicting results have been suggested over the years, particularly in studies comparing experimental models and human disease. In recent years, in addition to Th1, Th2, and Th17 profiles, new standards of cellular immune responses, such as Th9, Th22, and IFN-γ-IL-10 double-producing Th cells, discussed here, have also been described. Additionally, many new roles and cellular sources have been described for IL-10, demonstrating a critical role for this cytokine as regulatory, rather than merely pathogenic cytokine, involved in the establishment of chronic latent infection, in the clinical cure after treatment and in keeping antibacillary effector mechanisms active to prevent immune-mediated damage.


Rapid crystallization of glycine using metal-assisted and microwave-accelerated evaporative crystallization: the effect of engineered surfaces and sample volume.
Metal-Assisted and Microwave-Accelerated Evaporative Crystallization (MA-MAEC), is a new approach to crystallization of drug compounds, amino acids, DNA and proteins. In this work, we report our additional findings on the effect of engineered surfaces and sample volume on the rapid crystallization of glycine. With the use of hydrophilic functionalized surfaces and the MA-MAEC technique, glycine crystals ~1 mm in size were grown in 35 seconds with 100% selectivity for the α-form.The use of moderately hydrophobic surfaces resulted in the growth of glycine crystals only at room temperature. An increase in volume of initial glycine solution (5-100 μL) resulted in an increase in crystal size without a significant increase in total crystallization time. Raman spectroscopy and powder X-ray diffraction results demonstrated that the glycine crystals grown on engineered surfaces were structurally identical to those grown using conventional evaporative crystallization.


The impact of the 2006 Scottish smoke-free legislation on sales of nicotine replacement therapy.
This study used over-the-counter (OTC) sales of nicotine replacement therapy (NRT) to investigate the impact of the introduction of smoke-free legislation in Scotland in March 2006 on smoking cessation behaviour. The time series of NRT sales (units and value) in Scotland from 2004 to 2006 were compared with the same period for the rest of the UK, and analysed using an ARIMA time series model. There was a significant increase in units and value of NRT sales in Scotland in the first 6 months of 2006 (p< or =0.001), apparent from January and prior to the introduction of the smoking ban, with no comparable increase for the rest of the UK. There was no significant increase in NRT sales for the second half of 2006. These data suggest an increase in smoking cessation behaviour in the period immediately before the introduction of smoke-free legislation, but this was not sustained beyond the first few months of the post-legislation period.


Investigations for the diagnostic recording of nasal wing collapse.
The inspiratory medial movement of the nasal wing at high flow velocities is a protective physiologic mechanism. If this collapse of the nasal wing occurs at lower flow velocities, it may result in nasal obstruction. "Nasal wing collapse" is generally a clinical diagnosis. However, in the pressure-flow relationship of rhinomanometry, the medial movement of the nasal wing can be documented in the inspiratory arm of the graph. The diagnostic impact of this hysteresis was investigated. The pressure-flow curves of three box models and three nasal models with a moveable valve (analogous to the nasal wing) in the entrance area as well as three volunteers with unstable nasal wings were investigated. We recorded synchronously the pressure-flow relationship and by endoscopy the movement of the valve in the box models and the nasal wing in the volunteers on video. For evaluation, we used the frame by frame analysis of the tape. The medial movement of the nasal wing causes a hysteresis in the inspiratory arm of the pressure-flow curve. At this point, the graph runs on or between two border curves, termed the "no collapse curve" (for the maximally opened valve or a stable nasal wing) and the "collapse curve" (for the subtotally closed valve or a collapsed nasal wing), respectively. Analogous to the nasal wing motion, the descending course of hysteresis runs in two phases, and the ascending course runs in three phases. The medial movement of the nasal wing is expressed by a deviation of the graph from the "no collapse curve." The flow, at which the graph leaves this curve, depends on the elasticity module of the nasal wing. The extent of nasal wing collapse is reflected by the approximation of the pressure-flow curve to the "collapse curve" of the graph. The hysteresis appears because of a late opening of the collapsed nasal wing.


Saxagliptin, a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Saxagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, is currently under development by Bristol-Myers Squibb Co, AstraZeneca plc and Otsuka Pharmaceutical Co Ltd for the treatment of type 2 diabetes. The compound has high selectivity for DPP-IV compared with other dipeptidyl peptidases and a duration profile designed for once-daily dosing. DPP-IV inhibitors act by increasing levels of glucagon-like peptide-1, which stimulates insulin secretion. In animal studies, saxagliptin improved glucose clearance and raised insulin levels in rodents. Clinical trials have demonstrated a dose-dependent inhibition of DPP-IV by saxagliptin without serious side effects. Results have demonstrated that treatment with saxagliptin lowers blood glucose levels, with good tolerability and safety. The specific advantages of saxagliptin over other DPP-IV inhibitors may lie in its long-lived, effective and highly specific inhibition of DPP-IV, making once-daily treatment feasible, effective and safe.


Total Knee Arthroplasty in Paget's Disease using 3D-Printed Patient-Specific Femoral Jig - A Case Report.
Patients with Paget's disease develop abnormal bony anatomy which can result in significantly altered lower limb alignment predisposing them to early secondary osteoarthritis. Due to the severe extra-articular deformity, total knee arthroplasty (TKA) in these patients is challenging. Conventional knee arthroplasty using intramedullary guides is not an option and can lead to erroneous limb alignment postoperatively. Patient-specific instrumentation (PSI) is a simple solution in such complex primary knee arthroplasty. A 70-year-old male patient presented with a severe left femur deformity and left knee pain. He was diagnosed to have monostotic Paget's disease of the left femur with tricompartmental osteoarthritis of the left knee. After reduction in pathological bone turnover, the patient was planned for a total knee replacement. As a standard intramedullary femoral jig was not applicable due to the femoral deformity, a computed topography-based 3D-printed patient-specific instrument was used. This custom jig was used to define and perform the distal femur cut at 90 degrees to the mechanical axis of the femur in the coronal and sagittal plane. Postoperatively, the patient did well and achieved good function and pain relief. The use of a 3D-printed PSI for complex primary knee arthroplasty is an excellent option with no additional operative time than a conventional knee arthroplasty. Although a robotic or computer-navigated TKA would be an excellent option in this case, we restored the limb alignment using a cost-effective patient-specific femoral jig. This could be a viable option in centers without navigation or robotic arthroplasty.


Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive-Compulsive Disorder.
Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive-compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.


Clinical efficacy of casein derivatives: a systematic review of the literature.
The objective of this article was to review systematically the clinical trials of casein derivatives (specifically casein phosphopeptide-amorphous calcium phosphate [CPP-ACP] complex) used in dentistry. The authors included clinical studies that examined the efficacy of casein derivatives in dentistry. They excluded in vitro studies, case series, case reports, letters to editors (not containing primary data), editorials, review articles and commentaries, but read them to identify any potential studies. The authors searched 98 articles for relevance, determined according to title, abstract and full text, resulting in a yield of 12 original studies. Nine were clinical trials that focused on caries prevention, seven of which showed that CPP-ACP (as found in sugar-free pellet or slab chewing gum, lozenges, milk or mouthrinse) was effective in preventing dental caries by remineralizing subsurface carious lesions in situ in a dose-response fashion. One was a clinical trial with conflicting results regarding the effect of CPP-ACP on the regression of white-spot lesions; one was a survey of the relief of dry-mouth symptoms; and one was an uncontrolled clinical study that showed the lack of effectiveness and lack of short-term therapeutic effect in treating dentin hypersensitivity. The quantity and quality of clinical trial evidence are insufficient to make conclusions regarding the long-term effectiveness of casein derivatives, specifically CPP-ACP, in preventing caries in vivo and treating dentin hypersensitivity or dry mouth.


Effect of current reproduction on apparent survival, breeding dispersal, and future reproduction in barn swallows assessed by multistate capture-recapture models.
1. Theoretical models predict a negative effect of current reproduction on breeding dispersal, survival and future reproduction, and many studies confirm these predictions. Yet, results of most previous studies may be difficult to interpret because the fate of the affected individuals cannot always be observed. Detection is almost always imperfect and some individuals emigrate from the study area, resulting in biased estimates of both survival and dispersal. 2. Most studies bypass these problems with strong assumptions. We use a multistate capture-recapture model that does not require these assumptions. States are defined based on classes of reproductive success and on observed dispersal events within the study area. By accounting for imperfect detection within the study area, the model allows estimation of the effect of reproductive success on apparent survival, dispersal probabilities within the study area and the annual transition probabilities among classes of reproductive success. Based on an assumption about the estimate of real survival, the model allows the estimation of total dispersal that is not specific to a fixed study area. 3. We applied this model to capture-recapture data of 2262 adult barn swallows (Hirundo rustica) sampled from 1997-2004 in eight local populations in Switzerland. 4. We found that dispersal within the study area decreased with increasing reproductive success in both sexes, that reproductive success was not affected by preceding dispersal and that apparent survival of females but not of males increased with increasing reproductive success. Apparent survival of females with high reproductive success was identical to apparent survival of males suggesting that this estimate of apparent survival (0.48) was close to true survival. Total breeding dispersal was generally higher in females and it increased with decreasing reproductive success in both sexes. Current reproductive success depended on reproductive success in the preceding year suggesting that individual differences were of importance. 5. Our study highlights that reproductive success was an important factor affecting breeding dispersal and population turnover. While unsuccessful males mainly remained in the local populations, many unsuccessful females left them. Population turnover of adult swallows was mainly due to unsuccessful females.


Insights into the relationships of Palearctic and Nearctic lymnaeids (Mollusca: Gastropoda) by rDNA ITS-2 sequencing and phylogeny of stagnicoline intermediate host species of Fasciola hepatica.
Fascioliasis by Fasciola hepatica is the vector-borne disease presenting the widest latitudinal, longitudinal and altitudinal distribution known. F. hepatica shows a great adaptation power to new environmental conditions which is the consequence of its own capacities together with the adaptation and colonization abilities of its specific vector hosts, freshwater snails of the family Lymnaeidae. Several lymnaeid species only considered as secondary contributors to the liver fluke transmission have, however, played a very important role in the geographic expansion of this disease. Many of them belong to the so-called "stagnicoline" type group. Stagnicolines have, therefore, a very important applied interest in the Holarctic region, to which they are geographically restricted. The present knowledge on the genetics of stagnicolines and on their parasite-host interrelationships is, however, far from being sufficient. The present paper analyses the relationships between Palaearctic and Nearctic stagnicoline species on the base of the new light furnished by the results obtained in nuclear rDNA ITS-2 sequencing and corresponding phylogenetic studies of the lymnaeid taxa Lymnaea (Stagnicola) occulta, L. (S.) palustris palustris (topotype specimens) and L. (S.) p. turricula from Europe. Natural infections with F. hepatica have been reported in all of them. Surprisingly, ITS-2 length and GC content of L. occulta were similar and perfectly fitted within the respective ranges known in North American stagnicolines. Nucleotide differences and genetic distances were higher between L. occulta and the other European stagnicolines than between L. occulta and the North American ones. The ITS-2 sequence of L. p. turricula from Poland differed from the other genotypes known from turricula in Europe. The phylogenetic trees using the maximum-parsimony, distance and maximum-likelihood methods confirmed (i) the inclusion of L. occulta in the branch of North American stagnicolines, (ii) the link between the North American stagnicolines-L. occulta group with Galba truncatula, and (iii) the location of the L. p. turricula genotype from Poland closer to L. p. palustris than to other European L. p. turricula genotypes. The Palaearctic species occulta is included in the genus Catascopia, together with the Nearctic species catascopium, emarginata and elodes. The results suggest a potential of transmission capacity for C. occulta higher than that of other European stagnicolines or Omphiscola glabra. The relatively low genetic distances between C. occulta and G. truncatula and the clustering of both species in the same clade suggest that C. occulta may be potentially considered as the second lymnaeid intermediate host species of F. hepatica in importance in eastern and northern Europe, and probably also western and central Asia, after G. truncatula. L. p. turricula may be considered as a potential secondary vector of F. hepatica, at a level similar to that of L. p. palustris.


Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.
Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.


Systematic Review of Extended Reality Digital Therapy for Enhancing Mental Health Among South Korean Adolescents and Young Adults.
Digital therapy using extended reality (XR) holds great promise for addressing the mental health needs of adolescents and young adults. This study addresses a notable research gap in South Korea by systematically reviewing XR-based digital therapy for the mental health of South Korean adolescents and young adults. We analyzed 26 studies encompassing various aspects, including study type, publication date, research field, research methodology, data sources, program types, program content, sample characteristics, target population, assessment tools, and program effectiveness. Notably, 46.15% of the studies employed an experimental design, whereas over 53% utilized non-experimental approaches. Experimental studies lacked a genuine design, standardized questionnaires, and control variables. Similarly, non-experimental studies failed to report specific literature selection criteria. Consequently, future studies should adopt rigorous methodologies to enhance reliability and validity. Moreover, over 85% of the 26 studies focused solely on virtual reality and did not incorporate augmented or mixed reality. This study identifies the limitations of the previous research. These findings emphasize the need for structured investigations to advance the development of XR-based digital therapy to promote mental health in adolescents and young adults in South Korea.


Structure-Activity Relationship Studies To Identify Affinity Probes in Bis-aryl Sulfonamides That Prolong Immune Stimuli.
Agents that safely induce, enhance, or sustain multiple innate immune signaling pathways could be developed as potent vaccine adjuvants or coadjuvants. Using high-throughput screens with cell-based nuclear factor κB (NF-κB) and interferon stimulating response element (ISRE) reporter assays, we identified a bis-aryl sulfonamide bearing compound 1 that demonstrated sustained NF-κB and ISRE activation after a primary stimulus with lipopolysaccharide or interferon-α, respectively. Here, we present systematic structure-activity relationship (SAR) studies on the two phenyl rings and amide nitrogen of the sulfonamide group of compound 1 focused toward identification of affinity probes. The murine vaccination studies showed that compounds 1 and 33 when used as coadjuvants with monophosphoryl lipid A (MPLA) showed significant enhancement in antigen ovalbumin-specific immunoglobulin responses compared to MPLA alone. SAR studies pointed to the sites on the scaffold that can tolerate the introduction of aryl azide, biotin, and fluorescent rhodamine substituents to obtain several affinity and photoaffinity probes which will be utilized in concert for future target identification and mechanism of action studies.


Uric Acid Is a Risk Indicator for Metabolic Syndrome-related Colorectal Adenoma: Results in a Korean Population Receiving Screening Colonoscopy.
An association between serum uric acid and cancer risk has been noted over the past few decades. There is ongoing debate about whether hyperuricemia represents an independent risk factor for colorectal neoplasm. We investigated the association between serum uric acid and prevalence of colorectal adenoma considering numerous confounding factors. A cross-sectional study was performed with individuals who underwent a routine health check-up examination, including a screening colonoscopy and blood chemistry. The association between serum uric acid and prevalence of colorectal adenoma was estimated from the results of a logistic regression analysis. Of the 1,066 participants, 402 had colorectal adenoma (37.7%). In univariate models, the prevalence of colorectal adenoma was higher in participants in the fourth quartile uric acid level, compared to those in the first quartile uric acid level (OR, 1.67; 95% CI, 1.17-2.42; p=0.004). However, no significant association was detected between serum uric acid and prevalence of colorectal adenoma in multiple logistic regression analysis. A number of metabolic syndrome components exhibited a strong association with the prevalence of colorectal adenoma in the multivariate model (OR, 3.46 for highest vs. lowest; 95% CI, 1.30-9.20; p=0.021). Moreover, serum uric acid was strongly associated with metabolic syndrome-associated variables, including waist circumference, fasting blood glucose, systolic blood pressure, diastolic blood pressure, triglyceride, and high-density lipoprotein. Uric acid is not an independent risk factor for colorectal adenoma but is a risk indicator for metabolic syndrome-related colorectal adenoma.


Glass transition and relaxation processes of nanocomposite polymer electrolytes.
This study focus on the effect of δ-Al(2)O(3) nanofillers on the dc-conductivity, glass transition, and dielectric relaxations in the polymer electrolyte (PEO)(4):LiClO(4). The results show that there are three dielectric relaxation processes, α, β, and γ, in the systems, although the structural α-relaxation is hidden in the strong conductivity contribution and could therefore not be directly observed. However, by comparing an enhanced dc-conductivity, by approximately 2 orders of magnitude with 4 wt % δ-Al(2)O(3) added, with a decrease in calorimetric glass transition temperature, we are able to conclude that the dc-conductivity is directly coupled to the hidden α-relaxation, even in the presence of nanofillers (at least in the case of δ-Al(2)O(3) nanofillers at concentrations up to 4 wt %). This filler induced speeding up of the segmental polymer dynamics, i.e., the α-relaxation, can be explained by the nonattractive nature of the polymer-filler interactions, which enhance the "free volume" and mobility of polymer segments in the vicinity of filler surfaces.


[Scutellarin starch microspheres' permeability through nasal mucosa of different animals in vitro].
To study scutellarin starch microspheres' permeability through nasal mucosa of different animals in vitro. The Franz diffusion cell method was used to experiment the permeability test (n = 4), taking fresh nasal mucosa of dog, swine and domestica in vitro as permeation barrier separately, with scutellarin starch microspheres (scutellarin 0.25 mg) above them, and blank pH 6.8 PBS as absorption liquid to detemine the scutellarin by HPLC. The permeability coefficient of scutellarin starch microspheres through nasal mucosa of dog, swine and domestica in vitro were (5.295 +/- 0.637) x 10(-3) (4.065 +/- 1.140) x 10(-3), (1.855 +/- 0.150) x 10(-3) cm x mL(-1) separately. The permeability coefficient order of scutellarin starch microspheres through nasal mucosa of different animals in vitro is dog > swine > domestica, and there are significant differences between the permeability coefficient of scutellarin starch microspheres through nasal mucosa of dog, swine in vitro, and that through nasal mucosa of swine and domestica in vitro. Drugs in scutellarin starch microspheres could permeate through the above-mentioned nasal mucosa in vitro. There might be different permeability coefficient among different species.


Trajectories of Youth's Helping From Adolescence into Adulthood: The Importance of Social Relations and Values.
Helping behaviors (e.g., helping a sick friend, volunteering) are important forms of community involvement and likely change with age and life context. Yet, trajectories of community helping from adolescence through early adulthood have rarely been examined. It is also unclear how the roles of family, friends, and social attitudes might foster the development of helping behaviors across these years. We report on a study of community helping in a Canadian youth sample, across five intervals over a 15-year span, beginning at age 17 (N = 416). Helping displayed a quadratic trend, decreasing into the mid-20s, and then rebounding somewhat by 32. Social responsibility and salience of friends' prosocial moral values positively predicted age 17 community helping, whereas parents' moral values predicted less decrease in helping over this timeline. These findings add to an understanding of moral influences and social responsibility, in the potential shaping of youths' community helping behaviors.


N6-Methyladenosine mRNA Modification: From Modification Site Selectivity to Neurological Functions.
The development of various chemical methods has enabled scientists to decipher the distribution features and biological functions of RNA modifications in the past decade. In addition to modifying noncoding RNAs such as tRNAs and rRNAs, N6-methyladenosine (m6A) has been proven to be the most abundant internal chemical modification on mRNAs in eukaryotic cells and is also the most widely studied mRNA modification to date. Extensive studies have repeatedly demonstrated the important functions of m6A in various biological conditions, ranging from embryonic organ development to adult organ function and pathogenesis. Unlike DNA methylation which is relatively stable, the reversible m6A modification on mRNA is highly dynamic and easily influenced by various internal or external factors, such as cell type, developmental stage, nutrient supply, circadian rhythm, and environmental stresses.In this Account, we review our previous findings on the site selectivity mechanisms regulating m6A formation, as well as the physiological roles of m6A modification in cerebellum development and long-term memory consolidation. In our initial efforts to profile m6A in various types of mouse and human cells, we surprisingly found that the sequence motifs surrounding m6A sites were often complementary with the seed sequences of miRNAs. By manipulating the abundance of the miRNA biogenesis enzyme Dicer or individual miRNAs or mutating miRNA sequences, we were able to reveal a new role of nucleus localized miRNAs, which is to guide the m6A methyltransferase METTL3 to bind to mRNAs and to promote m6A formation. As a result, we partially answered the question of why only a small proportion of m6A motifs within an mRNA could have m6A modification at a certain time point. We further explored the functions of m6A modification in regulating brain development and brain functions. We found that cerebellum had the most severe defects when Mettl3 was knocked out in developing mouse embryonic brain and revealed that the underlying mechanisms could be attributed to aberrant mRNA splicing and enhanced cell apoptosis under m6A deficit conditions. On the other hand, knocking out Mettl3 in postnatal hippocampus did not cause morphological defects in the mouse brain but impaired the efficacy of long-term memory consolidation. Under learning stimuli, formation of m6A modifications could be detected on transcripts encoding proteins related to dendrite growth, synapse formation, and other memory related functions. Loss of m6A modifications on these transcripts would result in translation deficiency and reduced protein production, particularly in the translation of early response genes, and therefore would compromise the efficacy of long-term memory consolidation. Interestingly, excessive training sessions or increased training intensity could overcome such m6A deficiency related memory defects, which is likely due to the longer turnover cycle and the cumulative abundance of proteins throughout the training process. In addition to revealing the roles of m6A modification in regulating long-term memory formation, our work also demonstrated an effective method for studying memory formation efficacy. As the lack of an appropriate model for studying memory formation efficacy has been a long-lasting problem in the field of neural science, our hippocampus-specific postnatal m6A knockout model could also be utilized to study other questions related to memory formation efficacy.


Analysis of the effect of apex-base wall curvature on the vectorial representation of ventricular depolarization: a model study.
A computer model of propagated activation study is presented to investigate the possible effect of the ventricular wall curvature on the vectorial representation of its activation. The shape of the ventricle is changed by gradually decreasing the value of the input parameter determining the relative apex-base curvature of the ventricular wall (rvc) from 1.0 to 0.5. Two series of simulation experiments were accomplished. In the first series all input parameters of the model were held constant, except for rvc. In the second series, the height of the ventricles was altered simultaneously with the value of rvc in order to hold the volumes of the ventricular walls and cavities constant. In both series, the gradual increase of the apex-base curvature of the ventricular walls led to a slight decrease of initial heart vectors and an increase of laterally oriented vectors accompanied with their downward deviation. In addition, this increase caused a decrease in the terminal heart vectors along with their rotation to the left. The degree of this changes was proportional to the difference in the relative apex-base curvature of the two ventricles compared. The apex-base curvature of ventricular walls was found to be an effective factor influencing the cardiac electric field and consequently its representative quantitative parameters.


Spleen stiffness: a new tool to predict high-risk varices in cirrhotic patients.
Cirrhosis is one of the major causes of morbidity and mortality worldwide. Portal hypertension is the major contributor of cirrhosis-related complications and is defined as a hepatic venous pressure gradient (HVPG) > 5 mmHg. Measurement of HVPG is an invasive, difficult, and costly procedure. Therefore, it is only performed in specialized centers. Liver stiffness measured with transient elastography is one of the most studied noninvasive markers of portal hypertension, and spleen elastography has recently emerged as an important adjuvant tool. The development of a new probe (100 Hz) that more reliably reflect the grade of portal hypertension evaluated by spleen stiffness measurement has improved the accuracy of this technique. The aim of this work was to evaluate the accuracy of spleen stiffness with the new dedicated probe to predict the presence of high-risk varices, as well as to determine the ideal cutoff to predict it. Prospective study of cirrhotic patients admitted to upper endoscopy that were also submitted to liver and spleen elastography with the 100-Hz probe by the same blinded operator in a tertiary center. We included 209 cirrhotic patients, with mean age of 61.9 years (±9.9), 77.0% male. The most common etiology was alcoholic liver disease (72.7%). The median value of liver elastography was 25.3 [4.5-75] kPa, and the median value of spleen elastography was 42.4 [7.6-100] kPa. At the cutoff of 53.25 kPa, we obtained sensitivity of 100% and specificity of 72.6% to predict high-risk varices, and, according to this cutoff, 133/175 of esophagogastroduodenoscopy could have been spared (76.0%), while according to Baveno guidelines, only 51/175 would have been spared (29.1%). In the era of noninvasive exams, spleen elastography with the 100-Hz probe emerges as an excellent tool for prediction of presence of high-risk varices. At the cutoff of 53.25 kPa, spleen elastography avoids upper endoscopy for screening for high-risk varices, promising to be become part of the hepatologists' daily routine.


The promise of RNA-based therapeutics in revolutionizing heart failure management - a narrative review of current evidence.
This review elucidates the potential of RNA-based therapeutics to revolutionize heart failure (HF) management. Through a comprehensive analysis of relevant studies, this review reveals the promising prospects of these novel interventions in personalized treatment strategies, targeted modulation of specific molecular pathways, and the attainment of synergistic effects via combination therapies. Moreover, the regenerative capacity of RNA-based therapeutics for cardiac repair and the inherent advantages associated with noninvasive routes of administration are explored. Additionally, the studies accentuate the significance of diligent monitoring of disease progression and treatment response, ensuring safety and considering long-term outcomes. While ongoing research endeavours and technological advancements persist in addressing extant challenges and limitations, the transformative potential of RNA-based therapeutics in HF management offers a beacon of hope for enhanced patient outcomes.


"Diabodies": small bivalent and bispecific antibody fragments.
Bivalent and bispecific antibodies and their fragments have immense potential for practical application. Here we describe the design of small antibody fragments with two antigen-binding sites. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) on the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. As indicated by a computer graphic model of the dimers, the two pairs of domains can pack together with the antigen-binding sites pointing in opposite directions. The dimeric antibody fragments, or "diabodies," can be designed for bivalent or bispecific interactions. Starting from the monoclonal antibodies NQ11.7.22 (NQ11) and D1.3 directed against the hapten phenyloxazolone and hen egg lysozyme, respectively, we built bivalent fragments (VHNQ11-VLNQ11)2 and (VHD1.3-VLD1.3)2 and bispecific fragments VHNQ11-VLD1.3 and VHD1.3-VLNQ11. The fragments were expressed by secretion from bacteria and shown to bind specifically to the hapten and/or antigen. Those with 5- and 15-residue linkers had similar binding affinities to the parent antibodies, but a fragment with the VH domain joined directly to the VL domain was found to have slower dissociation kinetics and an improved affinity for hapten. Diabodies offer a ready means of constructing small bivalent and bispecific antibody fragments in bacteria.


[Prognostic factors of myasthenic crisis after extended thymectomy in patients with generalized myasthenia gravis].
To investigate the prognostic factors of myasthenic crisis after extended thymectomy in patients with generalized myasthenia gravis (MG). Extended thymectomy was performed on 176 patients with generalized MG, 74 males and 102 females, aged 4 - 67, of which 36 experienced postoperative myasthenic crisis and required prolonged mechanical ventilation. The relations among the age, sex, preoperative course of disease, pathologic type of thymus, Osserman classification, history of infection during 1 month preoperatively, history of myasthenic crisis 1 month preoperatively, thymoma, preoperative daily dose of pyridostigmine, preoperative steroid use, operation time, intra-operative blood loss, and intra-operative pleura injury and postoperative myasthenia crisis were analyzed. Univariate analysis showed that bulbar symptoms (OR = 8.494, P = 0.001), history of myasthenic crisis 1 month preoperatively (OR = 5.667, P = 0.000), thymoma (OR = 2.147, P = 0.047), Osserman types III and IV (OR = 0.459, P = 0.000), history of infection during 1 month preoperatively (OR = 3.30, P = 0.038), large pre-operative dose of pyridostigmine (OR = 1.019, P = 0.001), long operation time (OR = 1.012, P = 0.034), and more blood loss (186 ml +/- 163 ml) (OR = 1.004, P = 0.012), were all prognostic factors or postoperative myasthenic crisis. However, multivariate logistic regression analysis revealed that preoperative bulbar symptoms (OR = 7.709, P = 0.003), history of infection during 1 month preoperatively (OR = 4.582, P = 0.037), history of myasthenic crisis 1 month preoperatively (OR = 4.526, P = 0.001, large pre-operative dose of pyridostigmine (OR = 1.016, P = 0.001) were prognostic factors of postoperative myasthenic crisis. Preoperative bulbar symptoms, history of preoperative myasthenic crisis, history of preoperative infection, and large preoperative dose of, pyridostigmine are all independent influencing factors of postoperative myasthenic crisis. Ample preoperative care may prevent postoperative myasthenic crisis in the patients with such factors.


Stereoselective ligand-exchange reaction of planar-chiral cyclopentadienyl-ruthenium complexes: thermodynamic control of configuration at a stereogenic metal center.
The reaction of planar-chiral cyclopentadienyl-ruthenium complexes with Bu4NI resulted in the formation of iodo complexes with high diastereoselectivity (up to >99%de). The stereochemistry of the ruthenium center in the starting material did not influence the diastereoselectivity of the products. Epimerization of a diastereomerically pure sample gave a mixture of two diastereomers in the same ratio as with the ligand-exchange reaction, suggesting that the selectivity is determined by the difference in thermodynamic stability between the diastereomeric pair of iodo complexes. The ratio of the products depends on the nature of the substituent on the cyclopentadienyl ring and P ligands on the ruthenium atom. A combination of small substituents on the cyclopentadienyl group and small P ligands with strong electron-donating ability favored the formation of 2-I. The bulkiness of the substituents on the cyclopentadienyl group or of the P ligands, and low electron-donating ability of the P ligands increased the ratio of 2-II complexes to 2-I isomer.


Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome status.
To assess the long-term health outcomes and quality of life of patients with juvenile rheumatoid arthritis (JRA) using health and functional assessment questionnaires in 2 populations, one from the USA and one from Italy. Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 during the first 6 months after onset of symptoms, (2) diagnosis of JRA by the American College of Rheumatology criteria, (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form, or childhood HAQ (CHAQ), and (2) Quality of Life Scales (QOLS, adults only). Eligible patients were identified by computer search and chart review and were then mailed a packet containing a consent/assent form and the assessment instruments. Of 346 patients who met the eligibility criteria were able to locate 301, and 290 verbally agreed to participate and were mailed packets. Signed consent and complete information were received from 227 of the 290 (78%), 178 from the USA and 49 from Italy. Mean duration of disease at the time of outcome assessment was 15 yrs. 127 had pauciarticular, 55 polyarticular, and 45 systemic onset disease. Mean and (median) scores of the outcomes are shown in the table. [table: see text] Long-term outcome, as assessed by the instruments used, is very favorable in most patients with JRA 5 years or more after onset of symptoms.


Idiopathic photosensitive occipital epilepsy: clinical and electroencephalographic (EEG) features.
Idiopathic photosensitive occipital lobe epilepsy is a reflex, age- and localization-related syndrome. We describe the clinical and electroencephalographic features, therapy, and outcome of 16 children/adolescents with this syndrome. The cohort included 2 sets of siblings and 7 patients with other first- or second-degree relatives with a seizure history. All patients had occipital onset seizures and 15 had secondarily generalized tonic-clonic seizures. Seizure frequency was relatively low in all patients but one. Myoclonic seizures later developed in 2 patients with juvenile myoclonic epilepsy. Eight patients achieved full seizure control with monotherapy, and 5 required a second drug; 3 patients had rare seizures and were not treated with antiepileptics. Seven patients required special education or developmental assistance. This interesting syndrome sheds light on the pathophysiology and genetic etiology of common phenomena such as photosensitivity and headache. Further large prospective studies are required to better define this unique syndrome and its implications.


Edmonton Symptom Assessment System for outpatient symptom monitoring of sickle cell disease.
Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD.


The multi-centre assessment of quality of life: the Interdisciplinary Group for Cancer Care Evaluation (GIVIO) experience in Italy.
One of the main issues to be considered in conducting clinical trials concerns the presence of missing data. This aspect is particularly relevant in oncology longitudinal studies, characterized by a long follow-up, and especially in quality of life studies where there is still little knowledge about patients' characteristics that predict loss of data. Since the middle of the 1980s the GIVIO (Interdisciplinary Group for Cancer Care Evaluation) co-operative group has been involved in conducting quality of life assessment studies, also focusing on the development of some strategies aimed at the minimization of missing data. In this paper we report on the results of two trials, which are now completed, concerning the quality of life assessment in a sample of breast and colon cancer patients. In order to cope with the problem of missing data, in both the trials the strategy of follow-up mailing was adopted, which proved to be an effective way to increase the response rate by nearly 50 per cent at each time point.


Comparison of the EuroSCORE II and Society of Thoracic Surgeons 2008 risk tools.
Risk stratification in cardiac surgery is uniquely detailed, led latterly by the EuroSCORE and the Society of Thoracic Surgeons (STS) risk calculators. The recently published EuroSCORE II (ES2) algorithms update estimated mortality in a broad spectrum of cardiac procedures. The 2008 STS tool, in comparison, predicts multiple outcomes for specific procedures. We sought to identify and compare the external validity of both contemporaneous tools in our population. Data from our hospital database were collated for the period February 2001 to March 2010. Logistic regression coefficients from the risk calculations were applied to the data and the results presented as receiver-operating characteristic (ROC) curves. Statistical analyses were performed using the area under the ROC curve (AUROC) and the Hosmer-Lemeshow (H-L) goodness-of-fit test, with comparisons using the DeLong method. A total of 15 497 procedures were identified, of which 14 432 were appropriate for STS risk scoring (i.e. valve and/or graft procedures with no tricuspid valve operations etc.). For all procedures, ES2 and STS were equivalent (AUROC 0.818 vs 0.805, respectively, P = 0.343). For procedures appropriate for STS risk scoring, results were similar (AUROC ES2 vs STS, 0.816 vs 0.810, P = 0.714), whereas for procedures excluded by STS, the result was marginally worse (AUROC ES2 vs STS, 0.773 vs 0.784, P = 0.751). Goodness of fit in all cases was poor, primarily where risk was higher than 15% (H-L P < 0.0001). EuroSCORE II and STS both provide equivalent discrimination in predicting mortality in a British population, including those undergoing procedures for which the STS does not normally predict. Accounting for decile-grouped Hosmer-Lemeshow tests not being ideal for the assessment of calibration, both tools show good calibration for patients with low to moderate risk, with divergence from ~15% predicted risk.


Study of secondary relaxation in disordered plastic crystals of isocyanocyclohexane, cyanocyclohexane, and 1-cyanoadamantane.
In the present communication, dielectric relaxation investigations on three interesting supercooled plastic crystalline substances, i.e., isocyanocyclohexane (ICNCH), cyanocyclohexane (CNCH), and 1-cyanoadamantane (CNADM) are reported. All of these have the main dipole moment situated in their side group- C[Triple Bond]N or- N[Triple Bond]C. Differential scanning calorimetry (DSC) was also employed as a supporting technique. Glassy crystal were easily formed in the first two samples by slowly cooling the plastic phase, but in CNADM it was formed by rapidly quenching the room temperature plastic phase. In addition to the so called alpha process that can reasonably be described by a Havriliak-Negami (HN) shape function, a secondary (or beta) relaxation process is found in all the materials. The beta process in CNADM has an activation energy (DeltaE(beta)) of about approximately 13.8+/-1 kJmol, and is present even in the corresponding ordered crystalline phase, i.e., in its monoclinic phase. On the other hand, the magnitude of DeltaE(beta) in both the isomers of cyanocyclohexane, i.e., ICNCH and CNCH, is similar and is about 21.1 and 23.4 kJmol, respectively. Unlike CNADM, the cyclohexane derivatives are capable of exhibiting additional intramolecular process due to chair-chair conversion (i.e., in addition to the rotational motion of the side group- C[Triple Bond]N or- N[Triple Bond]C). Therefore, the secondary process of these systems is compared to that occuring in the binary liquid glass formed by dispersing a small quantity of these dipolar liquids in nearly nonpolar orthoterphenyl (OTP). Measurements were also made in the supercooled binary mixures of other cyclohexyl derivatives like cyclohexylchloride and cyclohexylbromide with OTP which lack a flexible side group. The sub-T(g) relaxation process exhibited in all these cases have almost similar activation energy as in case of pure ICNCH and CNCH. These observations together with the fact that the activation energy for this process is much below that of chair-chair conversion which is about 43 kJmol leads us to the conclusion that sub-T(g) relaxation process in the binary mixtures is JG type, and perhaps beta relaxation process in phase I of ICNCH and CNCH is also similar. With the help of semiemperical calculations of the dipolemoments for the axial and equitorial confirmers, it is concluded that the process associated with the chair-chair may not be dielectrically very active and, hence, should be relatively weaker in magnitude. The beta process in CNADM has an activation energy (DeltaE(beta)) of about 13.8+/-1 kJmol, and is present even in the corresponding ordered crystalline phase indicating that it may not be characteristic of the glass formation of phase I. The molecular structure of CNADM is such that it does not possess other intramolecular degrees of freedom of the type equitorial to axial (or chair-chair) transformation. Our experimental finding that JG relaxation for CNADM dispersed in glassy OTP matrix is about 31 kJmol, indicating that the well resolved sub-T(g) process in CNADM is due to the small side group, i.e., -C[Triple Bond]N and JG relaxation in phase I of CNADM is perhaps not resolvable or too small to be detected.


Multisensory integration in schizophrenia: a behavioural and event-related potential study.
Successful processing of multisensory stimuli increases the likelihood of detection or identification of salient, biologically significant events faster and more efficiently than unisensory inputs. Schizophrenia (SZ) patients show deficits in unisensory processing, but it is unclear whether impairments are seen to multisensory stimuli, a process known as multisensory integration (MSI). We used behavioural and event-related potential (ERP) measures to examine MSI in SZ and healthy controls (HC). Thirty-three SZ and 30 HC completed a target detection task with unisensory and multisensory stimuli. Reaction times (RT) were measured while their electroencephalogram (EEG) was recorded. Two auditory (N100 and P200) and visual (P100 and N160) ERPs were examined. MSI was analysed in terms of violations of RT to the race model and by comparing ERPs in the MSI condition to the sum of the unisensory ERPs. Both groups showed faster RT in MSI compared to unisensory conditions. SZ had non-significantly fewer violations of the race model compared to HC. SZ had significantly smaller amplitudes to unisensory visual N160 and auditory P100 relative to HC; there were no significant group differences on any ERP measure of MSI. SZ showed relatively intact MSI with subtle (non-significant) differences at the neural and behavioural levels compared to HC. Our results suggest that neural processes associated with MSI are not an additional source of impairment in SZ.


The perceived position shift of a pattern that contains internal motion is accompanied by a change in the pattern's apparent size and shape.
When the sinusoidal grating of a "Gabor pattern" is drifted, the apparent position of the pattern shifts in the direction of motion [De Valois, R. L., & De Valois, K. K. (1991). Vernier acuity with stationary moving Gabors. Vision Research, 31, 1619-1626]. We investigated the underlying cause of this illusion by determining whether the effect is a consequence of the internal motion shifting the perceived position of the whole pattern, or a consequence of a shift in the perceived location of the centroid (centre of mass) of the Gabor envelope. While each of these two possible distortions can account for a perceived positional offset, they give different predictions for the apparent size of the stimulus. A simple shift in perceived position results in no change in apparent size, while a centroid shift will likely result in either a decrease or an increase in the pattern's apparent size, depending on whether the trailing or leading edge of the Gabor stimulus is most affected by motion. We examined whether there is a change in the apparent size of Gabor patterns containing a range of grating motion speeds. We found that the perceived size of the pattern increased in the presence of motion as a function of speed, and is thus consistent with a centroid-shift explanation. We verified that this size change is a consequence of an increase in contrast at the leading edge, since the leading edge appears elongated relative to the trailing edge. We furthermore showed that the apparent-position shifts due to motion can be negated by displacing the centroid in the opposite direction to the motion.


Host-specific thermal profiles affect fitness of a widespread pathogen.
Host behavior can interact with environmental context to influence outcomes of pathogen exposure and the impact of disease on species and populations. Determining whether the thermal behaviors of individual species influence susceptibility to disease can help enhance our ability to explain and predict how and when disease outbreaks are likely to occur. The widespread disease chytridiomycosis (caused by the fungal pathogen Batrachochytrium dendrobatidis, Bd) often has species-specific impacts on amphibian communities; some host species are asymptomatic, whereas others experience mass mortalities and population extirpation. We determined whether the average natural thermal regimes experienced by sympatric frog species in nature, in and of themselves, can account for differences in vulnerability to disease. We did this by growing Bd under temperatures mimicking those experienced by frogs in the wild. At low and high elevations, the rainforest frogs Litoria nannotis, L. rheocola, and L. serrata maintained mean thermal regimes within the optimal range for pathogen growth (15-25°C). Thermal regimes for L. serrata, which has recovered from Bd-related declines, resulted in slower pathogen growth than the cooler and less variable thermal regimes for the other two species, which have experienced more long-lasting declines. For L. rheocola and L. serrata, pathogen growth was faster in thermal regimes corresponding to high elevations than in those corresponding to low elevations, where temperatures were warmer. For L. nannotis, which prefers moist and thermally stable microenvironments, pathogen growth was fastest for low-elevation thermal regimes. All of the thermal regimes we tested resulted in pathogen growth rates equivalent to, or significantly faster than, rates expected from constant-temperature experiments. The effects of host body temperature on Bd can explain many of the broad ecological patterns of population declines in our focal species, via direct effects on pathogen fitness. Understanding the functional response of pathogens to conditions experienced by the host is important for determining the ecological drivers of disease outbreaks.


Relationship between cellular ATP content and cellular functions of primary cultured rat hepatocytes in hypoxia.
The importance of oxygen in maintaining the functional integrity of hepatocytes has been well established in a variety of experimental models, such as in vivo, perfused liver and isolated hepatocytes. However, one of the shortcomings of these systems is their short life span. Therefore, we have examined the effects of long-term hypoxia on cellular adenine nucleotide content and cellular functions, such as albumin production, urea production and DNA synthesis, in adult rat hepatocytes in primary culture. Hepatocytes were cultured at a density of 11 x 10(4) and 5 x 10(4) cells/0.18 mL per cm2 for the study of albumin and urea production and DNA synthesis, respectively, at various oxygen tensions (20, 12, 8 and 5%) for 24 h. Cellular ATP content in cultured hepatocytes in hypoxia gradually declined, corresponding to the decrease in oxygen tension, and the cellular ATP level at 5% oxygen was approximately 20% of that at 20% oxygen. Albumin production also decreased in parallel with the decrease in cellular ATP content in cultured hepatocytes in hypoxia. However, even when cellular ATP content gradually declined corresponding with the decrease in oxygen tension in cultured hepatocytes in hypoxia, such as at 8 or 5% oxygen, urea production remained at a high level; in contrast, DNA synthesis was completely suppressed. These results suggest that the cellular ATP content decreases in cultured hepatocytes during long-term hypoxia in relation to oxygen tension and that the relationship between decreased ATP levels and liver function in cultured hepatocytes during hypoxia differs for albumin production, urea production and DNA synthesis.


Nasal reconstruction: the state of the art.
Cutaneous malignancies of the nose are common problems and create the need for nasal reconstruction within many otolaryngology practices. In spite of the fact that such reconstruction is an ancient art, there continue to be innovations and advances that allow for more predictable and functional long-term results. Analyzing the nasal defect through an organized algorithm can be useful in many circumstances, especially when one needs to consider vectors of tension, minimizing alar base asymmetry, resultant scars, and preservation of the intranasal airway. Application of the principle of aesthetic subunits has greatly improved the cosmetic results for many large nasal defects, and there have been some proposals to modify the original definitions and concept. Structural reconstruction is paramount with complex defects that involve the nasal framework or with those that are located in functionally critical areas. Autogenous cartilage grafting remains the gold standard, but the use of alloplastic and homograft materials for grafting continues to be reported as an alternative. Internal lining repair is essential with larger defects and the versatility of intranasal flaps is understood, but at times not available. Other flaps have been described and may be useful on such occasions. There are many considerations during nasal reconstruction, and the surgeon must be facile with a variety of options within his/her armamentarium.


[Effects of video work on the ocular vascular hemodynamic and visual of the operators].
Objective: To investigate the effects of long time video display terminal (VDT) operation on the ocular vascular hemodynamic and visual acuity. Methods: During March and October 2015, 120 cases of video monitoring warriors were selected as study group, another 155 cases of logistics personnel as the control group. The low vision of the two groups was calculated and compared, and the color Doppler flow imaging was used to measure the central retinal artery (CRA) , short posterior ciliary artery (SPCA) , anterior ciliary artery (ACA) , (peak systolic velocity, PSV) , end diastolic velocity (EDV) and (resistance index (RI) . The differences of hemodynamic parameters between these two groups were evaluated, and the relationship between the visual acuity and each hemodynamic parameter was analyzed. Results: The visual acuity of the study group was[0.8 (0.4-1.2) ], much lower than the control group, and the rate of low version in the study group was 40.00%, much higher than that of the control group. Compared with the control group, both of ACA and CRA of SPCA, PSV and EDV in the study group were decreased, while RI of CRA, ACA were increased (P<0.05) ; Compared with the control group, no statistical significance was found in the RI of SPCA in the study group (P>0.05) . The PSV and EDV were negatively correlated with visual acuity (r value of PSV and visual acuity were -0.352, -0.265 and -0.304; r value of EDV and visual acuity were -0.324, -0.348 and -0.365, while RI was positively correlated with visual acuity (r value were 0.363, 0.326 and 0.344) . Conclusion: Our data suggest that long time video operation may be associated with changes of ocular vascular hemodynamic parameters and raise the incidence of low vision.


Localized linear IgA disease induced by ampicillin/sulbactam.
We describe a patient who developed an exclusively perianal-intergluteal vesicular eruption after receiving a course of ampicillin/sulbactam. Direct immunofluorescence microscopy of perilesional skin demonstrated linear deposits of IgA along the dermal-epidermal junction. Circulating IgA autoantibodies against the 120-kd soluble ectodomain of bullous pemphigoid antigen 180 (LAD-1 autoantigen) were detected by immunoblotting. Discontinuation of the antibiotics resulted in a rapid resolution of the skin lesions. This is a most unusual case of localized drug-induced linear IgA disease.


Hospital-acquired anemia: prevalence, outcomes, and healthcare implications.
Evidence suggests that patients with normal hemoglobin (Hgb) levels on hospital admission who subsequently develop hospital-acquired anemia (HAA) may be at risk for adverse outcomes. Our objectives were to (1) determine the prevalence of HAA and (2) examine whether HAA is associated with increased mortality, length of stay (LOS), and total hospital charges. The population consisted of 417,301 adult hospitalizations from January 1, 2009 to August 31, 2011, in an academic medical center and 9 community hospitals. Patients with anemia on admission, and hospitals in the health system without available laboratory data were excluded; 188,447 hospitalizations were included in the analysis. Demographics, comorbidities, and outcomes were retrieved from administrative data; Hgb values were taken from the electronic medical record. Regression modeling was used to examine the association between demographics, comorbidity, hospitalization type, and HAA variables (mild: Hgb >11 and <12 g/dL for women, and >11 and <13 g/dL for men; moderate: Hgb 9.1 to ≤ 11.0 g/dL; severe: Hgb ≤ 9.0 g/dL) on mortality, LOS, and hospital charges. Among 188,447 hospitalizations, 139,807 patients (74%) developed HAA: mild, 40,828 (29%); moderate, 57,184 (41%); and severe, 41,795 (30%). Risk-adjusted odds ratios and 95% confidence intervals for in-hospital mortality with HAA were: mild, 1.0 (0.88-1.17; P = 0.8); moderate, 1.51 (1.33-1.71, P < 0.001); and severe, 3.28 (2.90-3.72, P < 0.001). Risk-adjusted relative mean LOS and hospital charges relative to no HAA were higher with HAA: LOS: mild, 1.08 (1.08-1.10, P < 0.001); moderate, 1.28 (1.26-1.29, P < 0.001); severe, 1.88 (1.86-1.89, P < 0.001). Hospital charges: mild, 1.06 (1.06-1.07, P < 0.001); moderate, 1.18 (1.17-1.19, P < 0.001); severe, 1.80 (1.79-1.82, P < 0.001). HAA is common and associated with increased mortality and resource utilization. Factors related to its development necessitate further study.


A thermostable transketolase evolved for aliphatic aldehyde acceptors.
Directed evolution of the thermostable transketolase from Geobacillus stearothermophilus based on a pH-based colorimetric screening of smart libraries yielded several mutants with up to 16-fold higher activity for aliphatic aldehydes and high enantioselectivity (>95% ee) in the asymmetric carboligation step.


Structural basis for differential activities of enantiomeric PPARγ agonists: Binding of S35 to the alternate site.
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARγ agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARγ LBD; it is located beside the Ω loop between the helices H2' and H3. We reported previously that the chirality of two optimized enantiomeric PPARγ ligands (S35 and R35) differentiates their PPARγ transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). S35 is a PPARγ phosphorylation inhibitor with promising glucose uptake potential, whereas R35 behaves as a potent conventional PPARγ agonist. To provide a structural basis for understanding the differential activities of these enantiomeric ligands, we have determined crystal structures of the PPARγ LBD in complex with either S35 or R35. S35 and R35 bind to the PPARγ LBD in significantly different manners. The partial agonist S35 occupies the alternate site near the Ω loop, whereas the full agonist R35 binds entirely to the canonical LBP. Alternate site binding of S35 affects the PPARγ transactivation and the inhibitory effect on PPARγ Ser245 phosphorylation. This study provides a useful platform for the development of a new generation of PPARγ ligands as anti-diabetic drug candidates.


Chronic osteomyelitis of the tibia: treatment with hyperbaric oxygen and autogenous microsurgical muscle transplantation.
To establish the success rate of combined therapy for tibial osteomyelitis, we reviewed all cases of this infection treated with surgery, antibiotics, and hyperbaric oxygen (HBO) between 1974 and 1991 at Duke University Medical Center. The median delay from diagnosis of osteomyelitis to initiation of HBO was 12.5 months (range, 1 month to 684 months). Of 34 patients in whom follow-up data were complete, 27 (79%) were male and 7 (21%) female, with a mean age of 37.9 years (range, 20 years to 77 years). Patients received an average of 8.3 surgical procedures (range, 2 to 19) and 35 HBO treatments (range, 6 to 99). Twenty patients (59%) received free vascularized muscle flaps as part of therapy. Actuarial analysis was used to examine the effect of free vascularized flap procedures. Of 26 patients with 24 months of follow-up after treatment, 21 (81%) remained drainage free. At 60 months and 84 months after treatment, 12 of 15 (80%) and 5 of 8 (63%), respectively, were drainage free. After more than 84 months, patients who had received muscle flaps were more likely to be drainage free than patients who had received only debridement, and this difference approached statistical significance.


Effect of busulphan treatment and elevated temperature on the expression of the beta-pol gene in rat testis.
Changes in the expression pattern of the DNA polymerase beta gene during inhibition of spermatogenesis by busulphan and by temperature (artificial cryptorchidism) have been studied. Transient arrest of spermatogenesis in two-month-old rats after injection of a single dose of busulphan (10 mg/kg) resulted in parallel but transient decrease in the 1.4 kb of beta-pol mRNA level to an undetectable value, followed by its reappearance after resumption of spermatogenesis. An artificial cryptorchidism also caused a drastic decrease of beta-pol mRNA level. Both results as well as morphological examination of testis after busulphan injection and artificial cryptorchidism revealed that spermatocytes and spermatids represent the testicular cell fraction containing the elevated amount of beta-pol mRNA. Involvement of DNA polymerase beta in meiotic recombination is discussed.


Opportunities to strengthen resilience of health care workers regarding patient safety.
The COVID-19 pandemic endangered the quality of health care and the safety of patients and health care workers (HCWs). This provided challenges for HCWs' resilience and for hospital management and probably increased risks for patient safety incidents (PSI). HCWs may also have experienced psychological consequences as second victims of PSI, but evidence on this is lacking. Therefore, we mapped HCWs' experiences with PSI during the second wave of COVID-19, the associations of these experiences with the hospital management of patient safety culture and HCWs' interests in receiving further training. We obtained data from 193 HCWs working at the COVID-related departments of one large hospital in eastern Slovakia via a questionnaire developed in direct collaboration with them. We measured PSI experiences as various HCWs' experiences with near miss and adverse events and the hospital management of patient safety culture using indicators such as risk of recurrence, open disclosure and second victim experiences. For analysis, we used logistic regression models adjusted for age and gender of the HCWs. One-third of the hospital HCWs had experienced PSI; these were more likely to expect adverse events to recur (odds ratio, OR = 2.7-3.5). Regarding the hospital management of patient safety culture, the HCWs' experiencing openly disclosed PSI was associated with one negative outcome, i.e. conflicts among colleagues (OR = 2.8), and one positive outcome, i.e. patients' acceptance of their explanation and apologies (OR = 2.3). We found no associations for any other essential domains after disclosure. PSI experiences were strongly associated with psychological indicators of second victimhood, such as sadness, irritability, anxiety and depression (OR = 2.2-4.3), while providing support was not. The majority of the HCWs would like to participate in the suggested trainings (83.4%). HCWs with PSI experiences reported poor hospital management of the patient safety culture, which might reflect they missed the opportunities to strengthen their resilience, especially during the COVID-19 pandemic.


Volatile anesthetic facilitation of in vitro desensitization of membrane-bound acetylcholine receptor from Torpedo californica.
Incubation of membrane fragments bearing acetylcholine receptors from Torpedo californica under an atmosphere of 3% halothane, 1% chloroform, or 6% diethyl ether greatly facilitates the carbamoylcholine-induced structural transition of the acetylcholine receptor reflected by alterations in the rate of binding of (125)I-labeled alpha-bungarotoxin. The half-time of this ligand-induced conformational change is decreased to 10% of the original value after incubation of the membranes with these volatile anesthetics at or near their clinical concentrations. The synergistic effects observed with the general anesthetics and carbamoylcholine are abolished if the membranes are incubated under a stream of air after exposure to the inhalational agents. The antagonist d-tubocurarine exerts a smaller yet measurable time-dependent effect on the toxin-binding properties of the membrane fragments. Treatment of membranes with general anesthetics facilitates this antagonist-induced conversion of the receptor protein as well. The synergism between ligands and general anesthetics may be due to the disruption by these inhalational agents of interactions at the protein-lipid interface, which may play a significant role in determination of receptor conformation. In addition, if the conformational change induced by carbamoylcholine observed in the snake toxin binding assay corresponds to desensitization of the receptor in vivo, facilitation of this conformational change by volatile anesthetics provides an attractive model for the pharmacological action of these compounds.


microRNAs as players and signals in the metastatic cascade: Implications for the development of novel anti-metastatic therapies.
microRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Increasing evidence emerging from human tumor preclinical models clearly indicates that specific miRNAs, collectively termed "metastamirs," play a functional role in different steps of the metastatic cascade, by exerting either pro- or anti-metastatic functions, and behave as signaling mediators to enable tumor cell to colonize a specific organ. miRNAs also actively participate in the proficient interaction of cancer cells with tumor microenvironment, either at the primary or at the metastatic site. Circulating miRNAs, released by multiple cell types, following binding to proteins or encapsulation in extracellular vesicles, play a main role in this cross-talk by acting as transferrable messages. The documented involvement of specific miRNAs in the dissemination process has aroused interest in the development of miRNA-based strategies for the treatment of metastasis. Preclinical research carried out in tumor experimental models, using both miRNA replacement and miRNA inhibitory approaches, is encouraging towards translating miRNA-based strategies into human cancer therapy, based on the observed therapeutic activity in the absence of main toxicity. However, to accelerate their adoption in the clinic, further improvements in terms of efficacy and targeted delivery to the tumor are still necessary.


Stimulus-related gamma oscillations in primate auditory cortex.
With a multielectrode system, we explored neuronal activity in the gamma range (>40 Hz) in the primary and caudomedial auditory cortex of six anesthetized macaque monkeys. Stimuli were tone bursts of 100- to 500-ms duration that were presented at sound pressure levels of 40-60 dB and were varied over a wide range of frequencies. These stimuli induced gamma oscillations, not phase-locked to the onset of stimulation, in 465 of 616 multiunit clusters and at 321 of 422 sites at which field potentials were recorded. Occurrence of gamma activity was stimulus dependent. It was mostly seen when the stimulus was at the units' preferred frequency. The incidence of gamma activity decreased with increasing difference between stimulus frequency and preferred frequency. gamma activity emerged 100-900 ms after stimulus onset with highest incidence ~120 ms. Amplitudes of stimulus-induced gamma oscillations in field potentials were, on average, almost twice the amplitude of spontaneously occurring gamma oscillations. gamma activity at different sites within the primary and the caudomedial auditory field could be synchronized at near-zero phase. Synchrony depended on the spatial distance and on the receptive fields similarity of pairs of units. It decreased with increasing distance between recording sites and increased with similarity of preferred frequencies of the pairs of units. The results indicate that stimulus-induced gamma oscillations originate from sources in the auditory cortex. They further suggest that gamma oscillations may provide a mechanism utilized in many parts of the sensory cortex, including the auditory cortex, to integrate neurons according to the similarity of their receptive fields.