Syringomyelia and cervical spondylosis: a clinicoradiological investigation.
Eighty eight patients with proven syringomyelia have been studied retrospectively to explore the relationship between syringomyelia and spondylotic degeneration of the cervical spine. When compared with age and sex matched control subjects, they showed no significant increase in incidence or severity of spondylosis or of vertebral subluxation. Duration of symptoms, degree of disability, and the pattern of analgesia or lower motor neurone lesions in the arms did not appear to be related to the development of spondylosis. The onset of moderate spondylosis was, however, earlier than in the controls, and individual cases with a remarkably early onset or unusual site and/or severity of spondylosis and subluxation were encountered, particularly following laminectomy. It was also noted that in a small number of patients the concomitant development of spondylosis contributed to clinical deterioration. It is concluded that while syringomyelia does not have a consistent, major role in the development of cervical spondylosis or vertebral luxation, it may contribute to progression of spinal degenerative disease in some patients.


Attributes of analgesics for emergency pain relief: results of the Consensus on Management of Pain Caused by Trauma Delphi initiative.
Management of pain is suboptimal in many prehospital and emergency department settings, and European guidelines are lacking. We carried out the Consensus On Management of PAin Caused by Trauma (COMPACT) Delphi initiative to gain insights into the factors physicians consider important when selecting analgesics for trauma pain. A pan-European panel of experts in emergency medicine or pain (N = 31) was recruited to participate in the COMPACT Delphi initiative. In round 1, panelists supplied free-text responses to an open question about the attributes of analgesics for emergency pain relief favored by physicians. Common themes were consolidated into factors. In round 2, factors rated important by more than 75% of the panel were taken forward into round 3. In round 3, the point at which the consensus was achieved was defined a priori as at least 75% of panelists agreeing or strongly agreeing that a factor was important. Twenty-nine experts participated, representing 12 European countries and with a mean (SD) of 20 (8.6) years of clinical experience. Most worked in an emergency department (79.3%). The consensus was achieved for 10 factors that were important to consider when selecting analgesics for trauma pain relief. The highest level of consensus was achieved for 'efficacy' (100%), followed by 'safety and tolerability' (96.6%), and 'ease of use' (93.1%). These findings may facilitate the development of evidence-based guidelines supporting the provision of pain management in prehospital, emergency department, and critical care settings.


Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with alpha-blocking agent doxazosin; versus placebo.
The efficacy of doxazosin monotherapy in chronic non-bacterial prostatitis was investigated in terms of urinary symptom, pain and quality of life assessment versus placebo. A total of 60 men with chronic non-bacterial prostatitis were randomised to daily supplement of 4 mg doxazosin or a placebo, for 3 months. International Prostate Symptom Score (IPSS) questionnaire was self administered at the entry and at 3 months after the cessation of the treatment. In addition, patients were asked to complete 2-item questionnaire on pain related symptoms of chronic prostatitis. Quality of life was assessed with a single item included in IPSS. Three months after cessation of the treatment there was a significant difference between the overall mean IPSS, pain and quality of life scores of the two groups in favour of alpha-blocking agent use (p = 0.001, p < 0.001 and p < 0.001, respectively). In patients undergone doxazosin treatment; symptom, pain and quality of life status revealed 32.94 +/- 5.27%, 36.57 +/- 5.67% and 36.78 +/- 4.75% overall improvement, respectively. IPSS appeared to be a valuable tool in assessing treatment outcome of chronic non-bacterial prostatitis.


Effect of High-Dose Statin Therapy on Drug-Eluting Stent Strut Coverage.
The influence of high-dose statin therapy on the serial stent healing process has not been fully investigated. Using optical coherence tomography, the effect of high-dose statin therapy on stent strut coverage was evaluated in drug-eluting stent-treated patients. Sixty patients were randomly assigned to 2 groups according to the statin dose (atorvastatin 40 mg as high-dose statin therapy [n=29] versus pravastatin 20 mg as low-dose statin therapy [n=31]). Serial optical coherence tomographic evaluation post procedure and at the 3-month and 12-month follow-ups was performed in 50 patients with 54 stents (23 atorvastatin-treated patients versus 27 pravastatin-treated patients). The percentage of uncovered struts was defined as the ratio of uncovered struts/total struts. The primary end point was the percentage of uncovered struts at the 12-month follow-up. The secondary end point was the percentage of uncovered struts at the 3-month follow-up and the comparative percentage change (Δ) of uncovered struts at the 3- and 12-month follow-ups between the different dose statin therapies. The percentage of uncovered struts was 7.4% (range, 4.3%-10.4%) in atorvastatin-treated patients versus 10.6% (range, 5.7%-22.6%) in pravastatin-treated patients at the 3-month follow-up (P=0.13) and 1.3% (0.3%-3.8%) versus 2.5% (0.9%-9.7%), respectively, at the 12-month follow-up (P=0.01). The percentage Δ of uncovered struts from 3 to 12 months of follow-up was -7.9±8.5% in atorvastatin-treated patients versus -9.3±12.5% in pravastatin-treated patients (P=0.67). This study suggested that high-dose statin therapy might provide a beneficial effect for the vascular healing process after drug-eluting stent implantation.


Whole-Genome Sequences of Seven Strains of Bacillus cereus Isolated from Foodstuff or Poisoning Incidents.
We present here the whole shotgun genome sequences of seven strains of Bacillus cereus isolated from foodstuff samples or food poisoning incidents.


A low-cost, open-source evolutionary bioreactor and its educational use.
A morbidostat is a bioreactor that uses antibiotics to control the growth of bacteria, making it well-suited for studying the evolution of antibiotic resistance. However, morbidostats are often too expensive to be used in educational settings. Here we present a low-cost morbidostat called the EVolutionary biorEactor (EVE) that can be built by students with minimal engineering and programming experience. We describe how we validated EVE in a real classroom setting by evolving replicate Escherichia coli populations under chloramphenicol challenge, thereby enabling students to learn about bacterial growth and antibiotic resistance.


Food, nutrients and nutraceuticals affecting the course of inflammatory bowel disease.
Inflammatory bowel diseases (ulcerative colitis; Crohn's disease) are debilitating relapsing inflammatory disorders affecting the gastrointestinal tract, with deleterious effect on quality of life, and increasing incidence and prevalence. Mucosal inflammation, due to altered microbiota, increased intestinal permeability and immune system dysfunction underlies the symptoms and may be caused in susceptible individuals by different factors (or a combination of them), including dietary habits and components. In this review we describe the influence of the Western diet, obesity, and different nutraceuticals/functional foods (bioactive peptides, phytochemicals, omega 3-polyunsaturated fatty acids, vitamin D, probiotics and prebiotics) on the course of IBD, and provide some hints that could be useful for nutritional guidance. Hopefully, research will soon offer enough reliable data to slow down the spread of the disease and to make diet a cornerstone in IBD therapy.


Characteristics and information searched for by French patients with systemic lupus erythematosus: A web-community data-driven online survey.
To provide information about the needs of patients with systemic lupus erythematosus (SLE) using Carenity, the first European online platform for patients with chronic diseases. At one year after its creation, all posts from the Carenity SLE community were collected and analysed. A focused cross-sectional online survey was performed. The SLE community included 521 people (93% females; mean age: 39.8 years). Among a total of 6702 posts, 2232 were classified according to disease-related topics. The 10 most common topics were 'lupus and …' either 'treatment', 'fatigue', 'entourage', 'sun exposure', 'diagnosis', 'autoimmune diseases', 'pregnancy', 'contraception', 'symptoms' or 'sexuality'. 112 SLE patients participated in the online survey. At the time of diagnosis, only 17 (15%) patients had heard of SLE and 84 (75%) expressed a need for more information on outcomes (27%), treatments (27%), daily life (14%), patients' associations (11%), symptoms (8%), the disease (8%) and psychosocial aspects (7%). When treatment was initiated, 48 patients (43%) would have liked more information about side effects (46%), long-term effects (21%), treatment duration/cessation (12.5%) and type (10%) and mechanism of action (8%) of treatments. All participants except one had used the internet to find information about SLE. Sources of information included healthcare providers (51%/61%/67%), journals/magazines (7%/12%/6%), lupus Websites (51%/77%/40%), web forums/blogs (34%/53%/19%), patients' associations (11%/23%/9%) accessed at 'just before diagnosis', 'just after diagnosis' and 'before treatment initiation'. Online patient communities provide original unbiased information that can help improve provision of information to SLE patients.


Origin of mitochondrial enzymes. V. The polypeptide character and the biosynthesis of rat liver cytochrome c oxidase polypeptides by mitochondria.
Isolated rat liver mitochondria were labeled in vitro with L-[14C]leucine. Sixty percent of the incorporated radioactivity was found to reside in subunits 1, 2, and 3 of cytochrome c oxidase with apparent molecular weights of approximately 33,000, 25,000, and 20,000, respectively. The results indicate that these are the predominant products of protein synthesis under the conditions employed. The enzyme complex, as derived by immunoprecipitation, was found to contain four additional polypeptides with apparent molecular weights of 17,000, 12,500, 7000, and 3500. A comparison of electrophoretic profiles of the rat liver and beef heart enzyme reveals that the apparent molecular weights of all polypeptides are remarkably similar.


Airway inflammation and cough sensitivity in cough-variant asthma.
Mechanisms underlying cough and bronchoconstriction in patients with cough-variant asthma (CVA) are not well established. Differences in location or degree of activation of eosinophils and allergic cytokines have been suggested as the likely causes. To address this issue, we have carried out a comparative study of airway inflammatory markers between patients with CVA and classic asthma (CA). The relationship between these markers with airway hyperresponsiveness (AHR) and cough sensitivity has also been studied. Twenty-seven non-smokers and steroid-naive patients with CVA (12) and CA (15) were examined. Capsaicin challenge, histamine bronchoprovocation test, nitric oxide levels in exhaled air and sputum induction were performed in all of them. Differential cell sputum recount and supernatant concentrations of eosinophil granule-derived cationic proteins (ECP), interleukin (IL)5, IL8 and tumour necrosis factor (TNF)-alpha were also measured. There were no significant differences in either the inflammatory pattern of soluble markers or differential cell counts between CA and CVA. Histamine PC20 was correlated with IL-5 in CVA, whereas it was associated with sputum eosinophilia in CA. Cough sensitivity (log C5) and histamine PC20 were inversely related in CA. Although the pattern of inflammatory sputum markers in patients with asthma and cough-variant asthma is similar, its relation with bronchial hyperreactivity and cough sensitivity is different in each group.


Gastric atony complicating pharyngo-gastric anastomosis.
We have presented two cases of gastric atony complicating the gastric 'pull-up' procedure in pharyngo-laryngo-oesophagectomy.


Developmental alteration of rat brain synaptic membranes. Reaction of glycoproteins with plant lectins.
Synaptic membranes were isolated from the forebrains of rats of increasing postnatal ages. Developmentally related changes in the structure and concnetration of synaptic membrane glycoproteins were indicated by: (1) a 2--3 fold increase in glycoprotein sialic acid between 5 and 60 days; (2) a similar increase in the number of membrane receptors for the lectins concanavalin A and wheat germ agglutinin; (3) transient increases between 10 and 17 days in the receptors for lentil and castor bean lectins and (4) an age dependent stimulation of castor bean lectin binding by neuraminidase. Labelling of SDS polysacrylamide gels of synaptic membranes with [125I]concanavalin A or wheat germ agglutinin revealed specific, age dependent changes in the lectin binding properties of individual molecular weight classes of glycoproteins. Differences in the glycoproteins composition of synaptic junctional complexes isolated from 10 and 28-day-old brains were also revealed by lectin binding studies. The results indicate that the number and structure of oligosaccharides associated with synaptic membrane glycoproteins are under developmental regulation.


Recombinant Swinepox Virus for Veterinary Vaccine Development.
Poxvirus-vectors have been widely used in vaccine development for several important human and animal diseases; some of these vaccines have been licensed and used extensively. Swinepox virus (SPV) is well suited to develop recombinant vaccines because of its large packaging capacity for recombinant DNA, its host range specificity, and its ability to induce appropriate immune responses.


Emerging various environmental threats to brain and overview of surveillance system with zebrafish model.
Pathologies related to neurotoxicity represent an important percentage of the diseases that determine the global burden of diseases. Neurotoxicity may be related to the increasing levels of potentially neurotoxic agents that pollute the environment, which generates concern, since agents that affect children may increase the incidence of neurodevelopmental disorders, affecting the quality of life of future citizens. Many environmental contaminants have been detected, and many of them derive from several human activities, including the mining, agriculture, manufacturing, pharmaceutical, beverage and food industries. These problems are more acute in third world countries, where environmental regulations are lax or non-existent. An additional major emerging problem is drug contamination. Periodic monitoring should be performed to identify potential neurotoxic substances using biological tests capable of identifying the risk. In this sense the fish embryo test (FET), which is performed on zebrafish embryos, is a useful, reliable and economical alternative that can be implemented in developing countries.


Discoidin domain receptor 1 (ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice.
Collagens are abundant within the atherosclerotic plaque, where they contribute to lesion volume and mechanical stability and influence cell signaling. The discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds to collagen, is expressed in blood vessels, but evidence for a functional role during atherogenesis is incomplete. In the present study, we generated Ddr1(+/+);Ldlr(-/-) and Ddr1(-/-);Ldlr(-/-) mice and fed them an atherogenic diet for 12 or 24 weeks. Targeted deletion of Ddr1 resulted in a 50% to 60% reduction in atherosclerotic lesion area in the descending aorta at both 12 and 24 weeks. Ddr1(-/-);Ldlr(-/-) plaques exhibited accelerated deposition of fibrillar collagen and elastin at 12 weeks compared with Ddr1(+/+);Ldlr(-/-) plaques. Expression analysis of laser microdissected lesions in vivo, and of Ddr1(-/-) smooth muscle cells in vitro, revealed increased mRNA levels for procollagen alpha1(I) and alpha1(III) and tropoelastin, suggesting an enhancement of matrix synthesis in the absence of DDR1. Furthermore, whereas plaque smooth muscle cell content was unchanged, Ddr1(-/-);Ldlr(-/-) plaques had a 49% decrease in macrophage content at 12 weeks, with a concomitant reduction of in situ gelatinolytic activity. Moreover, mRNA expression of both monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 was reduced in vivo, and Ddr1(-/-);Ldlr(-/-) macrophages demonstrated impaired matrix metalloproteinase expression in vitro. These data suggest novel roles for DDR1 in macrophage recruitment and invasion during atherogenesis. In conclusion, our data support a role for DDR1 in the regulation of both inflammation and fibrosis early in plaque development. Deletion of DDR1 attenuated atherogenesis and resulted in the formation of matrix-rich plaques.


[Certification criteria in pre-employment interviews of candidates for operators of mechanical saws].
The work of the motor-saw operator is very hard and dangerous because of the exposure to noxious factors as vibration, noise, combustion gases and variable atmospheric conditions. The authors discuss the certification criteria including the medical contraindications and propose the range of the pre-employment examinations.


[The distribution of frequent premature ventricular contractions originated from left/right ventricular and characteristics of radiofrequency ablation].
The aim of this study was to investigate the differences on origin distribution and radiofrequency ablation characteristics between premature ventricular contractions (PVC) from left and right ventricular. A total of 354 frequent PVC patients were enrolled. Two hundred and eighty patients were PVCs with right ventricular origin (group RV) and 74 patients with left ventricular origin (group LV). The age, gender, ablation power, temperature and duration, time of target potential before QRS onset, fluoroscopic time, procedure time and success rate were compared between the two groups. Majority PVCs (79.10%) were of right ventricular origin, in which the most common site was at right ventricular outflow tract (RVOT) (55.93%); whereas, only 20.90% were of left ventricular. There were significantly differences between group RV and group LV in age [(44.7±13.6) yrs vs (49.6±15.9) yrs, P=0.017], gender [male: 35.4%(99) vs 55.4%(41), P=0.002], time of target potential before QRS onset [(37.9±16.2) ms vs (31.3±11.7) ms, P=0.008], procedure time [(85.1±36.9) min vs (100.8±45.5) min, P=0.017], fluoroscopic time [(12.3±9.2) min vs (15.9±10.8) min, P=0.028] and success rate (96.4% vs 89.2%, P=0.012). Radiofrequency ablation of PVCs was a safe and effective method. Subjects with RV PVCs are younger and more females than subjects with LV PVCs. The radiofrequency ablation for RV PVCs was easier, and the success rate was higher than that for LV PVCs.


Epidemiology, prognostic factors, and management of malignant odontogenic tumors: an analysis of 295 cases.
To determine the demographic characteristics, prognostic factors, and management for patients diagnosed with a malignant odontogenic tumor (MOT). The Surveillance, Epidemiology, and End Results (SEER) registry was reviewed for patients diagnosed with MOT from 1973 to 2011. Kaplan-Meier and multivariate Cox regression analyses were performed on patient demographic characteristics and pathologic variables. The SEER database identified 295 MOT patients. The mean age at diagnosis was 50.5 years (range 5-89 years). Of these patients, 61.7% were male and 38.3% were female. The racial composition was 66.4% White, 22% Black, 6.1% Asian, 3.1% Pacific Islander, 0.3% Native American, and 2.1% Other/Unknown. Kaplan-Meier analysis found an overall survival (OS) and disease-specific survival (DSS) at 5 years of 54% and 67%, respectively. Multivariate analysis of the entire cohort found that age and stage were predictors of OS and that age was a predictor for DSS. For stage I/II MOTs, age and surgical therapy were predictors of OS and DSS, respectively. Here we report the largest study to date investigating demographic characteristics, prognostic factors, and management of MOT patients. Determinants of survival for OS and DSS include age, stage, and surgical therapy.


A new classification for quadrilateral plate fracture of acetabulum.
Recently, quadrilateral plate (QLP) fractures of acetabulum have attracted increasing attention. However, evidence for the appropriate classification of QLP fractures is still lacking, making it difficult to understand and manage these fractures. This study aimed to introduce a new classification for QLP fractures and evaluate its reproducibility. A series of 1101 consecutive patients with acetabular fractures from 8 level-I trauma centers were enrolled in this study. All patients underwent preoperative radiograph and computed tomography imaging. QLP fractures were identified and classified using the new and Judet-Letournel classification system. The inter- and intra-observer reliabilities (kappa coefficients, κ) of these two systems were investigated by 4 observers. Furthermore, surgical approaches and fixation methods for each fracture type are described. In total, 243 (243/1101, 22%) patients with QLP fractures were identified and included in this analysis. The mean κ value of the intra-observer reliability was 0.84 (range, 0.763-0.919) for the new classification, indicating excellent agreement, and the inter-observer reliability was 0.762 (range, 0.625-0.876), indicating substantial agreement. The values were 0.649 (range, 0.523-0.708) and 0.584 (0.497-0.646), respectively, according to the Judet-Letournel classification. Six cases (6/243, 2.5%) could not be classified using the Judet-Letournel classification. The selection of surgical approaches and fixation methods depends on the fracture type; however, an anterior intra-pelvic approach and buttressing fixation using the plate or screw are preferred for QLP fractures. This study presents a new classification for QLP fractures, showing higher intra- and inter-observer reliabilities than those obtained using the Judet-Letournel classification. This allowed us to obtain an in-depth and comprehensive understanding of QLP fractures. Additionally, the new classification might guide further studies on surgical strategies for QLP fractures. Level II.


Expression, purification and characterization of a catalytic domain of human protein tyrosine phosphatase non-receptor 12 (PTPN12) in Escherichia coli with FKBP-type PPIase as a chaperon.
Protein tyrosine phosphatase non-receptor type 12 (PTPN12), also known as PTP-PEST, was broadly expressed in hemopoietic cells. Recent research has shown that this enzyme is involved in tumorigenesis, as well as in tumor progression and transfer, as it can suppress multiple oncogenic tyrosine kinases. However, the difficulty of soluble expression of PTP-PEST in prokaryotic cells has resulted in great limitations in investigating its structure and functions. In this study, we successfully carried out soluble expression of the catalytic domain of PTP-PEST (ΔPTP-PEST) in Escherichia coli and performed an enzymatic characterization and kinetics. To confirm expression efficiency, we also induced the expression of the chaperon, FKBP_C. FKBP_C expression indicated efficacious prokaryotic expression of ΔPTP-PEST. In conclusion, our work yielded a practical expression system and two-step chromatography purification method that may serve as a valuable tool for the structural and functional analysis of proteins that are difficult to express in the soluble form in prokaryotic cells.


A fresh look at an ancient receptor family: emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation.
The well-known family of low-density lipoprotein receptors represents a collection of ancient membrane receptors that have been remarkably conserved throughout evolution. These multifunctional receptors, known to regulate cholesterol transport, are becoming increasingly interesting to the neuroscience community due to their ability to transduce a diversity of extracellular signals across the membrane in the adult CNS. Their roles in modulating synaptic plasticity and necessity in hippocampus-specific learning and memory have recently come to light. In addition, genetic, biochemical and behavioral studies have implicated these signaling systems in a number of human neurodegenerative and neuropsychiatric disorders involving loss of cognitive ability, such as Alzheimer's disease, schizophrenia and autism. This review describes the known functions of these receptors and discusses their potential role in processes of synaptic regulation and memory formation.


Role of supraspinal serotonin receptors for micturition in normal conscious rats.
Serotonin (5-HT) receptors are widely distributed in the central nervous system, including several areas involved in the control of micturition reflex pathways. However, the roles of the different subtypes of 5-HT receptors are not well known. We studied in normal, conscious rats, the effects on the cystometrogram of intracerebroventricular (i.c.v.) administration of 5-HT, 8-hydroxy-2-(di-N-propylaminotetralin) (8-OH-DPAT; agonist at 5-HT(1A) receptors), alpha-methyl-5-hydroxytryptamine maleate (agonist at 5-HT(2) receptors), 2-methyl-5-hydroxytryptamine hydrochloride (agonist at 5-HT(3) receptors), and 1-(4-amino-5-chloro-2methoxyphenyl)-3-(1-n-butyl-4piperidinyl)-1-propanone hydrochloride (RS67506; agonist at 5-HT(4) receptors). Female Sprague-Dawley rats, weighing approximately 230 g, were used. A polyethylene catheter was inserted into the bladder through the dome for cystometric investigations. For administration of drugs, a catheter was implanted into the right cerebral ventricle. Three days after implantation of the bladder catheter, continuous cystometry was performed. Administration of 5-HT (6 nmol/kg i.c.v.), 8-OH-DPAT (6 nmol/kg), alpha-methyl-5-hydroxytryptamine maleate (6 nmol/kg), or RS67506 hydrochloride (6 nmol/kg) significantly (P < 0.05) increased micturition pressure and decreased bladder capacity and micturition volume. The effects increased in a dose-dependent manner (18, 60 nmol/kg). Intracerebroventricular administration of 2-methyl-5-hydroxytryptamine hydrochloride (60 nmol/kg) caused no change in the cystometric parameters. The results suggest that in normal conscious rats, at the supraspinal level, 5-HT (via 5-HT(1A), 5-HT(2), and 5-HT(4) receptors) can enhance the micturition reflex induced by bladder filling. Whether this means that 5-HT(1A), 5-HT(2), and 5-HT(4) receptors can be targets for drugs meant for treatment of bladder hyperactivity, should be explored.


Right-left orientation and significance of systematic reversal in children.
Shortly before the acquisition of right and left, which generally occurs around age 6-7 years, a very simple right/left discrimination task makes it possible to distinguish groups of children with strikingly different cognitive abilities. Preschool children aged from 5 to 6.4 years were asked to show their left hand, right eye, left ear and right hand. On a variety of simple cognitive tasks exploring verbal fluency, syntactic comprehension, working memory, visuo-spatial ability and number processing, children who made from 1 to 3 errors (14% of the sample) performed significantly worse than those who showed systematic reversal (30%) and those who made no error. Differential use of logical thinking can partially explain these differences. Neuropsychological implications of these developmental findings are discussed.


[Calculation of the structure of the serotonin-antibiotic lasalocid A complex by conformation analysis and the Monte Carlo method].
The conformational aspects of interaction of the antibiotic X537A at complexation with serotonin, hydration of molecules and their complex were studied by the methods of theoretical conformational analysis and Monte-Carlo.


Complicated Iatrogenic Pneumopericardium in a Patient With Suspected Multiple Myeloma.
Pneumopericardium is the presence of air within the pericardial cavity. Though several etiologies and pathological mechanisms for this have been described, there is no clear consensus. Most resolve spontaneously, but others may develop severe complications such as cardiac tamponade which may lead to cardiorespiratory arrest. We report a rare case of a patient who developed a tension pneumopericardium requiring emergent aspiration following a therapeutic pericardiocentesis. Radiological and echocardiographic findings of this rare iatrogenic pneumopericardium are reviewed.


Effects of lysergic acid diethylamide on autonomic post-ganglionic transmission.
1. Six sites of autonomic post-ganglionic transmission were examined for susceptibility to LSD. Inhibition of transmission by LSD was confined to the three sympathetic junctions. 2. Inhibition of sympathetic transmission was maximal with short trains of pulses and declined considerably as train length was increased. 3. Evidence for a presynaptic mode of action was obtained. This was the predominant effect of LSD in the rat anococcygeus and dog retractor penis because alpha-adrenoceptor-blocking properties were feeble or absent; but in dog splenic strips LSD produced marked post-synaptic alpha-blockade. 4. The presynaptic inhibitory effect of LSD was unrelated to its 5-hydroxytryptamine-blocking property because it was not shared by methysergide. Neither was it mediated by prostaglandin release because it was unaltered by indomethacin, which suppresses prostaglandin synthesis. 5. In the rat anococcygeus and dog retractor penis larger doses of LSD induced slow contractions and, as a result of the concurrent block of motor transmission, revealed relaxation responses on transmural stimulation, caused by the excitation of sacral inhibitory fibres present in these muscles. 6. The LSD contractions were due to stimulation of post-synaptic alpha-adrenoceptors because they were abolished by phentolamine or yohimbine but were present as usual in preparations taken from reserpinized animals. 7. LSD blocked presynaptic alpha-adrenoceptors in the cholinergic motor fibres to the longitudinal muscle of the guinea-pig ileum.


Influence of psychosocial risk factors on the trajectory of mental health problems from childhood to adolescence: a longitudinal study.
Longitudinal epidemiological studies involving child/adolescent mental health problems are scarce in developing countries, particularly in regions characterized by adverse living conditions. We examined the influence of psychosocial factors on the trajectory of child/adolescent mental health problems (CAMHP) over time. A population-based sample of 6- to 13-year-olds with CAMHP was followed-up from 2002-2003 (Time 1/T1) to 2007-2008 (Time 2/T2), with 86 out of 124 eligible children/adolescents at T1 being reassessed at T2 (sample loss: 30.6%). CAMHP at T2 according to the Child Behavior Checklist/CBCL's total problem scale. Psychosocial factors: T1 variables (child/adolescent's age, family socioeconomic status); trajectory of variables from T1 to T2 (child/adolescent exposure to severe physical punishment, mother exposure to severe physical marital violence, maternal anxiety/depression); and T2 variables (maternal education, child/adolescent's social support and pro-social activities). Multivariate analysis identified two risk factors for child/adolescent MHP at T2: aggravation of child/adolescent physical punishment and aggravation of maternal anxiety/depression. The current study shows the importance of considering child/adolescent physical punishment and maternal anxiety/depression in intervention models and mental health care policies.


Diffusion tensor imaging tractography and reliability analysis for limbic and paralimbic white matter tracts.
Diffusion tensor imaging (DTI) provides the opportunity to study white matter tracts in vivo. The goal was to estimate the reliability of DTI tractography for the analysis of limbic and paralimbic white matter. Normative data from 24 healthy subjects and reliability data from four healthy and four depressed subjects were acquired at 1.5 Tesla, using twice-refocused spin-echo, echoplanar DTI and Fluid-Attenuated Inversion Recovery (FLAIR) DTI sequences. Fiber tracking was performed using the Fiber Assignment by Continuous Tracking algorithm. Fractional Anisotropy (FA), trace Apparent Diffusion Coefficient and tract volumes were calculated. The inter-rater (and intra-rater) intraclass correlation coefficients for FA values were as follows: rostral cingulum 0.89 (0.87), dorsal cingulum 0.85 (0.90), parahippocampal cingulum 0.85 (0.95), uncinate fasciculus 0.85 (0.87), medial prefrontal white matter 0.97 (0.99), ventromedial prefrontal white matter 0.92 (0.93), crus of fornix 0.80 (0.81). The reported DTI protocol provides a reliable method to analyze limbic and paralimbic white matter tracts relevant to psychiatric disorders.


Differential uptake of herpes zoster vaccination associated with socioeconomic status: A population-based study in Stockholm County, Sweden.
To investigate whether herpes zoster vaccine (HZV) was associated with socioeconomic status in Stockholm, when the vaccine was reimbursed in Sweden. This was an observational retrospective case-control study, using population-based health care registers. During the study period, September 2013 to November 2014, the HZV was reimbursed as part of the National Pharmaceutical Benefits Scheme in Sweden and recommended for individuals over 50 years. A case was any person, living in Stockholm County, who received HZV during the study period. For each case, 10 (unvaccinated) controls living in Stockholm County were selected and matched by age and sex. In total, 9099 cases and 89 736 controls were included. Socioeconomic variables investigated included education, income, immigration status, and marital status. We also investigated whether HZV was associated with the Charlson Comorbidity Index (CCI), and/or previous herpes zoster diagnosis. Mean age at vaccination was 69.8 years, and 65.8% of vaccinees were women. There was a positive association between vaccination and higher education (OR = 3.4 (95% CI 3.0-3.8) for men and OR = 2.8 (95% CI 2.6-3.0) for women, respectively) in comparison to primary education. Higher income and being married were positively associated with vaccination, particularly for men, whereas being an immigrant was negatively associated. There was a negative association between a higher CCI score and HZV, indicating that healthier individuals were more likely to have been vaccinated. Despite the vaccine being part of the National Pharmaceutical Benefit Scheme, receipt of the HZV was significantly associated with socioeconomic factors.


Losing CD45 and various B-cell markers in a case of MYC-driven pediatric high-grade B-cell lymphoma, not otherwise specified that transformed from Burkitt's lymphoma during rituximab-containing treatments: a case report.
In this study, we reported a seldom case of pediatric high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS) with loss of B-cell markers (CD19, CD20, CD22, CD79a, CD38, Pax5, OCT2, and BOB1) and CD45, which bring great challenges to exclude a non-lymphomatous neoplasm. However, no evidence was found to support the diagnosis of sarcoma and carcinoma. Thus, due to the patient's prior history of Burkitt's lymphoma treated by rituximab-containing therapies, we carefully searched for any indication of B-cell differentiation. Eventually, NGS results revealed the monoclonal rearrangement of IGH (IGHD2-8-IGHJ6 and IGHV4-30-2-IGHJ4) in both pre-treatment and present tumors, confirming the same B-cell lineage. Moreover, both tumors exhibited the same IGHA1-MYC translocation and somatic mutations of c-MYC, TP53, ID3, and CCND3. Therefore, in addition to strong expression of BCL2 in the present tumor, we finally arrived at a diagnosis of pediatric HGBL, NOS with loss of B-cell lineage markers and CD45.


Assessment of Quality of Life in Children With Pulmonary Hypertension Using Parent and Self-report Questionnaires.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevation of pulmonary vascular resistance and right ventricular failure. By using advanced therapies to reduce mortality, clinicians focus on improving functional status and quality of life (QOL). The aim of our study was to assess health-related QOL of pediatric patients with PAH. Parents of all children (aged 2-18 years) and patients aged 5-18 years with an appropriate level of intellectual development completed general and cardiac-specific validated surveys (Pediatric Quality of Life Inventory 4.0 and Pediatric Quality of Life Inventory 3.0, respectively). Demographic and clinical information was collected to grade disease severity. Twenty-five children were enrolled, yielding 25 parent reports and 15 patient self-reports. The PAH group had significantly lower scores than healthy children in all domains. Patients with World Health Organization Functional Class I had significantly higher parent proxy scores in School Functioning (P = .029) and in Heart Problems and Symptoms domain (P = .014) Patients with tricuspid annular plane systolic excursion below -2 z score showed impairment in each parent proxy general domain and in the Cognitive Problems score of the Cardiac module (P = .006). In conclusion the QOL of patients with PAH was impaired in every domain compared with healthy children. Patients with reduced right ventricle systolic function showed significantly lower QOL in all core domains. These results point to the need for psychosocial rehabilitation in addition to somatic care to improve the QOL in this severely ill population.


Digitalis cardiotoxicity.
Clinical manifestations of digitalis toxicity were clearly described by Withering in 1785. One hundred years later, certain digitalis-induced arrhythmias were inscribed on the smoked drum, and shortly thereafter with the introduction of the electrocardiograph, manifestations of digitalis toxicity as recognized today were recorded in animals and human beings. With popularization of the direct-writing electrocardiograph in the late 1940s and the introduction of digitoxin in recommended doses (that in retrospect appear inappropriately high), the documented prevalence of digitalis toxicity increased rapidly. With increased understanding of the interaction of electrolytes and digitalis and perhaps, and more importantly, the widespread use of digoxin in doses derived largely from its inotropic action and, thus, inappropriately low for the management of many of the arrhythmias, the prevalence of digitalis toxicity began to decline again. In addition, the advent of serum level determinations and the widespread acceptance of the concept of "therapeutic" levels which, although frequently falling short of the desired clinical end point, served to preclude digitalis toxicity. With the decline in the incidence of digitalis toxicity consequent to these factors, some of the digitalis-related arrhythmias that were common are now rarely observed. This report focuses on arrhythmias that are highly specific for digitalis toxicity and on those that now are less commonly encountered. The discussion and classification of the arrhythmias are based on their most probable electrophysiologic mechanism.


IPI59: An Actionable Biomarker to Improve Treatment Response in Serous Ovarian Carcinoma Patients.
Despite improvements in operative management and therapies, overall survival rates in advanced ovarian cancer have remained largely unchanged over the past three decades. Although it is possible to identify high-risk patients following surgery, the knowledge does not provide information about the genomic aberrations conferring risk, or the implications for treatment. To address these challenges, we developed an integrative pathway-index model and applied it to messenger RNA expression from 458 patients with serous ovarian carcinoma from the Cancer Genome Atlas project. The biomarker derived from this approach, IPI59, contains 59 genes from six pathways. As we demonstrate using independent datasets from six studies, IPI59 is strongly associated with overall and progression-free survival, and also identifies high-risk patients who may benefit from enhanced adjuvant therapy.


Surgical Management of Female Voiding Dysfunction.
Surgical intervention for female voiding dysfunction is common, involving a single or multifaceted approach affecting multiple organ systems in the pelvis. Surgical success relies on knowledge of surgical history, anatomic approaches, and judicious use of supports or materials. Owing to the varied repairs used over the last few decades, it is important for the general surgeon to understand both current and historic approaches. This understanding will help in planning future pelvic surgery as well as in evaluating current ramifications of prior surgery.


Genetic and environmental associations between insulin resistance and weight-related traits and future weight change.
The aims of this study were to investigate the association between initial insulin resistance (IR), weight status, and precedent weight change (PWC) and future weight change and the genetic and environmental contributions affecting these relationships in a prospective cohort of Korean twins and their family members. The PWC (weight change from 20 y of age), baseline body mass index (BMI), baseline homeostasis model assessment of IR (HOMA-IR) score, and future weight change (follow-up interval 3.28 ± 1.32 y) of 1565 adults were assessed. The mixed linear model was applied after adjusting for intrafamilial relationship, age, education, health behaviors, chronic diseases, dietary intake, eating restraint, and menopausal status of women at baseline. A bivariate genetic analysis was performed after adjusting for age and sex. In the model that simultaneously included all predictors and confounding factors, inverse associations were observed between PWC and baseline HOMA-IR score and future weight change in men, and only baseline BMI was inversely associated with future weight change in women. Men and women with BMI ≥25 kg/m2, HOMA-IR score ≥2.5, and PWC greater than or the same as the sex-specific median of PWC were more likely to lose weight than those with the combination of the counterparts. Approximately 63.6% of the correlation between the baseline HOMA-IR score and future weight change was attributed to genetic effects, and 68.4% to 91.3% of the correlations between weight-related traits and future weight change were correlated to environmental effects. An inverse association was observed between the initial IR, weight status, and PWC and future weight change, and genetic or environmental factors contributed to these relationships.


Effects of Verbal Priming With Acute Exercise on Convergent Creativity.
The acute effects of moderate-intensity treadmill exercise during anagram problem solving on subsequent creativity performance has yet to be empirically investigated, which was this study's purpose. A two-visit (counterbalanced order), within-subject experiment was conducted among individuals aged 18-35. For the acute exercise visit, participants engaged in a 15-minute bout of moderate-intensity treadmill exercise while solving anagram problems. For the anagram only visit, participants engaged in 15 minutes of seated rest while solving anagram problems. Average RAT performance was higher for the exercise + anagram problem-solving visit (M = 10.51, SD = 3.25) compared to anagram-solving + seated rest (M = 9.29, SD = 4.12). The difference between conditions was statistically significant, t(44) = 2.385, p = .021, Cohen's d = 0.36. These findings demonstrate that acute exercise coupled with anagram problem-solving, prior to RAT completion, is a potential strategy for enhancing verbal convergent creative thinking.


The nucleotide excision repair proteins through the lens of molecular dynamics simulations.
Mutations that affect the proteins responsible for the nucleotide excision repair (NER) pathway can lead to diseases such as xeroderma pigmentosum, trichothiodystrophy, Cockayne syndrome, and Cerebro-oculo-facio-skeletal syndrome. Hence, understanding their molecular behavior is needed to elucidate these diseases' phenotypes and how the NER pathway is organized and coordinated. Molecular dynamics techniques enable the study of different protein conformations, adaptable to any research question, shedding light on the dynamics of biomolecules. However, as important as they are, molecular dynamics studies focused on DNA repair pathways are still becoming more widespread. Currently, there are no review articles compiling the advancements made in molecular dynamics approaches applied to NER and discussing: (i) how this technique is currently employed in the field of DNA repair, focusing on NER proteins; (ii) which technical setups are being employed, their strengths and limitations; (iii) which insights or information are they providing to understand the NER pathway or NER-associated proteins; (iv) which open questions would be suited for this technique to answer; and (v) where can we go from here. These questions become even more crucial considering the numerous 3D structures published regarding the NER pathway's proteins in recent years. In this work, we tackle each one of these questions, revising and critically discussing the results published in the context of the NER pathway.


Endoscopic Enucleation of the Prostate Is Better than Robot-assisted Simple Prostatectomy.
In 2022, endoscopic enucleation of the prostate (EEP) is the treatment of choice for benign prostatic obstruction (BPO) for glands >80 ml and is a valid alternative for patients with bleeding disorders. Unlike robot-assisted radical prostatectomy, EEP has no additional access-related trauma and can be performed using the same instruments as for bipolar enucleoresection. With favorable costs, EEP can serve as a global solution for BPO treatment.


The roles of the Moran effect and dispersal in synchronizing oscillating populations.
Patterns of spatial synchrony of population dynamics are dramatic phenomena that provide the potential for unraveling forces controlling the dynamics of natural populations in time and space. Prior ecological research has focused on attention to either deterministic or stochastic forces acting separately, with an emphasis on long term behavior, or on small systems consisting often of two interacting spatial locations. Using ideas from the dynamics of weakly coupled oscillators with an emphasis on the temporal dynamics of synchrony we develop a synthetic approach that explains patterns of synchrony as the result of an interplay between deterministic and stochastic forces. The temporal scale of convergence can provide a useful tool for determining the relative importance of deterministic and stochastic influences. Our approach applies both to specific systems that have been previously analyzed such as disease dynamics, and to a range of exploiter victim systems.


Secondary causes of premacular fibrosis.
The records of 187 consecutive patients (206 eyes) with a diagnosis of secondary premacular fibrosis were reviewed. The mean patient age was 63.2 years; 96 (51.3%) patients were men. The most common surgical causes in 175 eyes were cataract extraction with or without implant, 73 (41.7%); scleral buckle, 33 (18.9%); both cataract extraction with implant and scleral buckle (in separate surgical sessions), 20 (11.4%); argon laser procedures, 17 (9.7%); and retinal cryopexy, 14 (8.0%). The most common nonsurgical causes in 31 eyes were blunt ocular trauma, 12 (38.7%); uveitis, 9 (29.0%); and retinal vein occlusion, 5 (16.1%). Initial visual acuity was 20/100 or better in 120 of the 206 eyes (58.3%). After a minimum follow-up period of 6 months (mean, 44.2 months), 72 of 101 eyes (71.3%) had stable or improved visual acuity without surgical intervention. Of 32 eyes that underwent vitrectomy with membrane stripping, 25 of 26 eyes (96.2%) followed for a mean period of 24 months (minimum, 6 months) had stable or improved visual acuity. Of 157 eyes that did not undergo vitrectomy, 143 (91.1%) had partial or complete posterior detachment. Fifty-eight of 148 eyes (39.2%) had angiographic cystoid macular edema; however, vitreous traction at the macula was not a significant cause of cystoid macular edema (CME) in these eyes.(ABSTRACT TRUNCATED AT 250 WORDS)


Signal detection behavior in humans and rats: a comparison with matched tasks.
Animal models of human cognitive processes are essential for studying the neurobiological mechanisms of these processes and for developing therapies for intoxication and neurodegenerative diseases. A discrete-trial signal detection task was developed for assessing sustained attention in rats; a previous study showed that rats perform as predicted from the human sustained attention literature. In this study, we measured the behavior of humans in a task formally homologous to the task for rats, varying two of the three parameters previously shown to affect performance in rats. Signal quality was manipulated by varying the increment in the intensity of a lamp. Trial rate was varied among values of 4, 7, and 10 trials/min. Accuracy of signal detection was quantified by the proportion of correct detections of the signal (P(hit)) and the proportion of false alarms (P(fa), i.e. incorrect responses on non-signal trials). As with rats, P(hit) in humans increased with increasing signal intensity whereas P(fa) did not. Like rats, humans were sensitive to the trial rate, though the change in behavior depended on the sex of the subject. These data show that visual signal detection behavior in rats and humans is controlled similarly by two important parameters, and suggest that this task assesses similar processes of sustained attention in the two species.


[The expression of FasL and ICAM-1 on the HEVs in the hypertrophic tonsils].
To investigate the expression of FasL and ICAM-1 on the HEVs in the hypertrophic tonsils and its clinical significance. Under the light microscopy, HE and immunohistochemistry methods were used to show the morphology of HEVs, the number of T, B lymphocytes, the expression intensity of FasL and ICAM-1 in 17 patients with the idiopathic tonsillar hypertrophy (ITH) and in 20 patients with the chronic hypertrophic tonsillitis (CHT). The expression intensity of ICAM-1 on the tonsillar HEVs in ITH group was significantly lower than that in CTH group (P < 0.05), but the intensity of FasL in ITH group was significantly higher than that in CHT group (P < 0.05). FasL and ICAM-1 expression in the tonsillar HEVs contribute to the CHT and ITH. The former mainly makes IHT developed, and the latter promotes the process of the inflammation.


[Disadvantageous course of ophthalmological changes in young women with long-lasting diabetes mellitus followed by the symptoms of anorexia nervosa].
To present the course and progression of very severe proliferative retinopathy in young women with long lasting diabetes mellitus and symptoms of anorexia nervosa. The data of 5 young women, in age 25-32 years, suffering from diabetes mellitus 15 to 29 years with intended weight lose. The progression of ophthalmological changes was observed, followed by considerable fluctuations of glucose blood. In the time of weight lose in all patients, the worsening of the visual acuity was observed and it was the first reason for ophthalmological check-up. The initial best corrected visual acuity was 0.1-0.9. The rubeosis of the iris, cataracts and proliferative retinopathy with intravitreal hemorrhage and tractional retinal detachment were observed. Despite the immediate ophthalmological treatment (lasertherapy, pars plana vitrectomy, criopexy and retinopexy) the useful visual acuity (>0.1) was maintained only in one eye. 1. In case of significant exacerbation of progression of ophthalmological changes in patients with long lasting diabetes mellitus and anorexia nervosa the monitoring of their psychological and physical conditions is essential. 2. In the case of weight lose in patients with long lasting diabetes mellitus the rigorous ophtalmological monthly consultations are obligate.


Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese.
We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.


Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy.
Prednisolone and methylprednisolone pharmacokinetic parameters were evaluated in asthmatic children receiving concomitant anticonvulsant therapy. On separate study days, 15 children receiving either phenobarbital, carbamazepine, phenytoin, or combination anticonvulsant therapy were administered an intravenous dose of prednisolone or methylprednisolone and compared with a pediatric population not receiving anticonvulsant therapy. Plasma clearance of prednisolone in subjects receiving phenobarbital, carbamazepine, and phenytoin and in control subjects was 302.7 +/- 74.6, 383.2 +/- 53.8, 378.9 +/- 50.7, and 214.0 +/- 28.8 ml/min/1.73 m2 (mean +/- 1 SD), whereas plasma clearance of methylprednisolone was 1179.1 +/- 519.4, 1687.0 +/- 109.9, 2209.5 +/- 473.8, and 381.7 +/- 98.4 ml/min/1.73 m2, respectively. Bioavailability of prednisolone after the oral administration of prednisone and methylprednisolone ranged from 86% to 104% during anticonvulsant therapy. Three individuals reevaluated 13 to 20 days after discontinuing anticonvulsant therapy demonstrated pharmacokinetic parameters similar to those of the control group. Limited studies performed in patients receiving combination anticonvulsant therapy did not demonstrate an additive effect on prednisolone elimination. Differences in the degree of enhancement of prednisolone and methylprednisolone disposition in all three anticonvulsant study groups suggest that different metabolic pathways may be involved.


Community preceptors' views of their identities as teachers.
Community physicians are increasingly being recruited to teach medical students and residents, yet there has been little research about how they think of themselves as teachers or what factors contribute to "teacher identity." Physicians who think of themselves as teachers may be more likely to enjoy teaching, to teach more, and to be recognized by students and other faculty as good teachers. Identifying factors that enhance teacher identity may be helpful for the recruitment and retention of high-quality community faculty. Thirty-five experienced community preceptors were audiotaped in five structured focus groups in April 2001, answering a series of questions about their teacher identity. Responses were qualitatively analyzed for evidence of themes. "Feeling intrinsic satisfaction" was the most common theme that emerged from the tapes. Preceptors also identified that "having knowledge and skill about teaching" and "belonging to a group of teacher" enhanced their roles as teachers. "Being a physician means being a teacher," "feeling a responsibility to teach medicine," and "sharing clinical expertise" also emerged as important themes. Although a group of participants were interested in "receiving rewards for teaching," rewards did not need to be financial compensation. For some, genuine recognition for their efforts by the medical school, particularly in the form of faculty development opportunities, constituted reward and recognition for teaching. Community physicians described a variety of factors that contribute to their identity as teachers. Faculty development programs offer opportunities to strengthen teacher identity and foster relationships between teaching programs and community-based faculty.


Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO®) in subjects with haemophilia A (SWIFT-HA study).
VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate® P (CSL Behring). The pharmacokinetic, efficacy and safety profiles of VONCENTO® were investigated in this multicentre,double-blind, randomised study. Subjects aged ≥ 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO® only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for ≥ 6 months and ≥ 50 exposure days, respectively. Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.


Altered endothelium-dependent and -independent hyperpolarization and endothelium-dependent relaxation in carotid arteries isolated from streptozotocin-induced diabetic rats.
We examined endothelium-dependent and -independent hyperpolarizations and endothelium-dependent relaxation responses in carotid arteries isolated from streptozotocin-induced diabetic rats and age-matched controls. The resting membrane potentials were not significantly different between control and diabetic carotid arteries. The endothelium-dependent hyperpolarization induced by acetylcholine, which was inhibited by TEA but not by glibenclamide or by treatment with either a high concentration of glucose or pertussis toxin, was significantly weaker in diabetic arteries than in the controls. The relaxation responses to acetylcholine in carotid artery rings were significantly decreased in streptozotocin-diabetic rats. Treatment with NG-nitro-L-arginine (L-NOARG) inhibited the acetylcholine-induced maximal relaxation by 80% and 30% in control and streptozotocin-diabetic rats, respectively, and the simultaneous application of L-NOARG and indomethacin had a more potent inhibitory effect on this relaxation in both groups. The release of 6-keto-prostaglandin F1alpha and that of thromboxane A2 in response to methoxamine or methoxamine plus acetylcholine were both markedly decreased in diabetic rats. The cromakalim-induced hyperpolarization of the carotid artery, which was completely prevented by glibenclamide, was also significantly weaker in diabetic arteries than in the controls. These results suggest that changes in (1) various K+ channels on smooth muscle, (2) the biosynthesis of cyclooxygenase products and (3) endothelium-dependent relaxation may be important factors in the development of diabetic complications in the carotid artery.


The structure of oriented sphingomyelin bilayers.
X-ray diffraction from oriented bilayers of sphingomyelin gave up to 14 orders of diffraction of a lamellar repeat of 68.5 A on the merididan and up to eight reflections, including a strong reflection at 4.2 A, on the equator. The diffraction spacings did not change when the sphingomyelin bilayers were exposed to different humidities. A direct analysis of the low resolution X-ray data, using deconvolution is presented. A comparison of the Patterson functions of sphingomyelin with those of phosphatidylcholine and phosphatidylethanolamine suggests that the molecular structure of sphingomyelin in oriented bilayers resembles the structure of both phosphatidylcholine and phosphatidylethanolamine. Molecular model calculations for sphingomyelin bilayers have also been performed. Electron density profiles of sphingomyelin bilayers at resolution of about 6 A and about 2.5 A are presented. Our results indicate that the phosphorylcholine head group of sphingomyelin is in the plane of the membrane and at right angles to the hydrocarbon chains, the hydrocarbon chains are nearly parallel to each other, and there is only a limited, if any, interdigitation of the hydrocarbon chains of the adjacent sphingomyelin molecules in the bilayer.


Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.
Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.


"I listened with my eyes": writing speech and reading deafness in the fiction of Charles Dickens and Wilkie Collins.
While characters with disabilities appear frequently in Victorian fiction, deaf characters, specifically, are almost entirely absent. In fact, the only deaf characters who use sign language in Victorian fiction are Madonna Blyth in Wilkie Collins's Hide and Seek and Sophy Marigold in Charles Dickens's "Doctor Marigold." Grounding its analysis in these two texts, this article contends that it is, in particular, a deaf character's relationship to language that disqualifies him or her from conventional representation in Victorian fiction. Through reading Hide and Seek and "Doctor Marigold" in the context of Victorian deaf history, Collins and Dickens's realist aims, and Victorian generic conventions rooted in transcribing orality, this essay argues that the absence of deaf characters reveals the investment of mid-Victorian fiction in a particular and normativized relationship between bodies, spoken language, and textuality.


Guidelines for the Management of Atopic Dermatitis in Children: A Systematic Review.
Numerous guidelines have been published for atopic dermatitis management in children in recent years. To date, the quality of the newest guidelines has not been appraised. This study aimed to identify and evaluate guidelines for the management of atopic dermatitis in children. We reviewed the literature retrieved from PubMed, Web of Science, Ovid, ScienceDirect, Embase, China National Knowledge Infrastructure, WanFang Data, and guidelines websites. Search period from January 1, 2016, to December 31, 2021. The following keywords were used for searching: "atopic dermatitis," "atopic eczema," "eczema," "guideline," and "consensus." The quality of the guidelines was assessed by two assessors using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument independently, and domain scores >60% were considered to have sufficient quality. The guideline recommendations were reviewed. Nineteen guidelines were included in the study. Three guidelines had a graded A level, which was recommended for use in practice. Eleven guidelines had a graded B level, which was recommended for use in revision. The remaining five guidelines were rated with C level, which was not recommended. The average score of six domains of AGREE II was 64.76%, 48.53%, 42.35%, 73.83%, 32.23%, and 70.17%, respectively. A consistency test showed an intraclass correlation coefficient range of 0.497 (95% CI: 0.105, 0.705) to 0.970 (95% CI: 0.93, 0.987) based on the two assessors' test results for the guidelines. Most guidelines were recommended for use with revision. No significant changes were observed in the primary management of atopic dermatitis in children compared to previous evidence. New biological agents and complementary alternative medicine are increasingly available, but the evidence for the treatment of atopic dermatitis in children is still limited.


Evaluation of bee venom and hyaluronic acid in the intra-articular treatment of osteoarthritis in an experimental rabbit model.
The aim of this study was to investigate bee venom and hyaluronic acid in the intra-articular treatment of osteoarthritis in an experimental rabbit model. Forty-five rabbits were used and they were randomly divided into three groups (BVI, BVII, and HA) and each group was divided to two subgroups to evaluate the radiologic, magnetic resonance imaging, histopathologic, and biochemical evaluation in post treatment second week (a) and twelfth week (b). Radiologically, a significant difference was observed in the HA group (P<0.05). The MRI evaluation of at any time in group BVI(b) was found to be different. No significant differences were seen between the groups, biochemically. Histopathologically, cellularity, and orthochromasia was evident with Safranin-O in the BVI(b) and BVII(a); adhesions were seen in the BVII(a) group and clustering of chondrocyte in the HA(b) group were found to be different. Consequently, intra-articular application of HA and BV for experimental model of osteoarthritis has no significant influence upon recovery after therapy.


Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro.
Adult mesenchymal stem cells (MSCs) have the capacity to differentiate into various connective tissues such as cartilage and bone following stimulation with certain growth factors. However, less is known about the capacity of these cells to undergo chondrogenesis when these proteins are delivered via gene transfer. In this study, we investigated chondrogenesis of primary, bone marrow-derived MSCs in aggregate cultures following genetic modification with adenoviral vectors encoding chondrogenic growth factors. We found that adenoviral-mediated expression of TGF-beta1 and BMP-2, but not IGF-1, induced chondrogenesis of MSCs as evidenced by toluidine blue metachromasia and immunohistochemical detection of type II collagen. Chondrogenesis correlated with the level and duration of expressed protein and was strongest in aggregates expressing 10-100 ng/ml transgene product. Transgene expression in all aggregates was highly transient, showing a marked decrease after 7 days. Chondrogenesis was inhibited in aggregates modified to express >100 ng/ml TGF-beta1 or BMP-2; however, this was found to be partly due to the inhibitory effect of exposure to high adenoviral loads. Our findings indicate that parameters such as these are important functional considerations for adapting gene transfer technologies to induce chondrogenesis of MSCs.


Elemental analyses of soil and sediment fused with lithium borate using isotope dilution laser ablation-inductively coupled plasma-mass spectrometry.
Quantitative analysis using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) remains challenging primarily due to the lack of appropriate reference materials available for the wide variety of samples of interest and to elemental fractionation effects. Isotopic dilution mass spectrometry (IDMS) is becoming the methodology of choice to address these issues because the different isotopes of an element represent near-perfect internal standards. In this work, we investigated the lithium borate fusion of powdered solid samples, including soils, sediments, rock mine waste and a meteorite, as a strategy to homogenously distribute, i.e. equilibrate the elements and the added isotopically enriched standards. A comparison of this methodology using two pulsed laser ablation systems (ArF* excimer and Nd:YAG) with different wavelengths as well as two ICP-MS instruments (quadrupole and double-focusing sector field) was performed. Emphasis was put on using standard equipment to show the potential of the proposed strategy for its application in routine laboratories. Cr, Zn, Ba, Sr and Pb were successfully determined by LA-ICP-IDMS in six Standard Reference Materials (SRMs) representing different matrices of environmental interest. Experimental results showed the SRM fused glasses exhibited a low level of heterogeneity (intra- and inter-sample) for both natural abundance and isotopically enriched samples (RSD <3%, n=3, 1σ). A good agreement between experimental results and the certified values was also observed.


Rapid and sensitive quantitation of the antiproliferative agent mitoguazone in small volumes of plasma by high-performance liquid chromatography with ultraviolet detection.
Mitoguazone is an antiproliferative agent used in chemotherapy. This study describes a simple and sensitive high-performance liquid chromatographic method for the determination of mitoguazone in 100 microl of plasma. Samples were deproteinized with 100 microl of a solution of internal standard (amiloride, 10 microg/ml) in acetonitrile. An aliquot of the supernatant was injected onto the column. HPLC separation was achieved on a silica column with the mobile phase of methanol-50 mM potassium phosphate buffer (pH 3)-triethylamine (80:20:0.3, v/v), at a flow-rate of 1 ml/min. The eluent was detected at 320 nm. The retention time was about 5.5 min for amiloride and 12 min for mitoguazone. No endogenous substances were found to interfere. Calibration curves were linear from 0.25 to 50 microg/ml. The absolute recoveries of mitoguazone and amiloride were both greater than 84%. The limit of quantitation was 0.25 microg/ml. The intra- and inter-day precision (expressed as RSD) was 5.8%, or less, and the accuracy was 94.7% of the nominal concentration. The method is suitable in pharmacokinetic investigation and monitoring mitoguazone concentration.


Detecting hidden spatial and spatio-temporal structures in glasses and complex physical systems by multiresolution network clustering.
We elaborate on a general method that we recently introduced for characterizing the "natural" structures in complex physical systems via multi-scale network analysis. The method is based on "community detection" wherein interacting particles are partitioned into an "ideal gas" of optimally decoupled groups of particles. Specifically, we construct a set of network representations ("replicas") of the physical system based on interatomic potentials and apply a multiscale clustering ("multiresolution community detection") analysis using information-based correlations among the replicas. Replicas may i) be different representations of an identical static system, ii) embody dynamics by considering replicas to be time separated snapshots of the system (with a tunable time separation), or iii) encode general correlations when different replicas correspond to different representations of the entire history of the system as it evolves in space-time. Inputs for our method are the inter-particle potentials or experimentally measured two (or higher order) particle correlations. We apply our method to computer simulations of a binary Kob-Andersen Lennard-Jones system in a mixture ratio of A(80)B(20) , a ternary model system with components "A", "B", and "C" in ratios of A(88)B(7)C(5) (as in Al(88)Y(7)Fe(5) , and to atomic coordinates in a Zr(80)Pt(20) system as gleaned by reverse Monte Carlo analysis of experimentally determined structure factors. We identify the dominant structures (disjoint or overlapping) and general length scales by analyzing extrema of the information theory measures. We speculate on possible links between i) physical transitions or crossovers and ii) changes in structures found by this method as well as phase transitions associated with the computational complexity of the community detection problem. We also briefly consider continuum approaches and discuss rigidity and the shear penetration depth in amorphous systems; this latter length scale increases as the system becomes progressively rigid.


XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells.
X-chromosome inactivation (XCI) in mammals relies on XIST, a long noncoding transcript that coats and silences the X chromosome in cis. Here we report the discovery of a long noncoding RNA, XACT, that is expressed from and coats the active X chromosome specifically in human pluripotent cells. In the absence of XIST, XACT is expressed from both X chromosomes in humans but not in mice, suggesting a unique role for XACT in the control of human XCI initiation.


Passive donor-to-recipient transfer of antiphospholipid syndrome following allogeneic stem-cell transplantation.
Autoantibody production following allogeneic stem-cell transplantation is common and is often ascribed to the immune dysregulation associated with graft-versus-host disease. Recent data suggests that donor-memory B cells can be reactivated on exposure to antigen and result in antibody production in the recipient identical to that seen in the donor. Here we describe the production of autoantibodies in a recipient of bone marrow from a donor with systemic lupus erythematosus and antiphospholipid syndrome. Autoantibody appearance was precipitated by the onset of graft-versus-host disease, was identical to that of the donor, and ultimately lead to cerebrovascular thrombosis, which was successfully treated with antiplatelet and anticoagulant therapy.


Changes in protein expression in testes of L2 strain Taiwan country chickens in response to acute heat stress.
Heat stress causes a decrease of fertility in roosters. Yet, the way acute heat stress affects protein expression remains poorly understood. This study investigated differential protein expression in testes of the L2 strain of Taiwan country chickens following acute heat stress. Twelve 45-week-old roosters were allocated into four groups, including control roosters kept at 25 °C, roosters subjected to 38 °C acute heat stress for 4 hours without recovery, with 2 hours of recovery, and with 6 hours of recovery. Testis samples were collected for morphologic assay and protein analysis. Some of the differentially expressed proteins were validated by Western blot and immunohistochemistry. Abnormal and apoptotic spermatogenic cells were observed at 2 hours of recovery after acute heat stress, especially among the spermatocytes. Two-dimensional difference gel electrophoresis revealed that 119 protein spots were differentially expressed in chicken testes following heat stress, and peptide mass fingerprinting revealed that these spots contained 92 distinct proteins. In the heat-stressed samples, the heat shock proteins, chaperonin containing t-complex, and proteasome subunits were downregulated, and glutathione S-transferase, transgelin, and DJ-1 were upregulated. Our results demonstrate that acute heat stress impairs the processes of translation, protein folding, and protein degradation, and thus results in apoptosis and interferes with spermatogenesis. On the other hand, the increased expression of antioxidant enzymes, including glutathione S-transferase and DJ-1, may attenuate heat-induced damage. These findings may have implications for breeding chickens that can tolerate more extreme conditions.


The limited importance of size-asymmetric light competition and growth of pioneer species in early secondary forest succession in Vietnam.
It is generally believed that asymmetric competition for light plays a predominant role in determining the course of succession by increasing size inequalities between plants. Size-related growth is the product of size-related light capture and light-use efficiency (LUE). We have used a canopy model to calculate light capture and photosynthetic rates of pioneer species in sequential vegetation stages of a young secondary forest stand. Growth of the same saplings was followed in time as succession proceeded. Photosynthetic rate per unit plant mass (P(mass): mol C g(-1) day(-1)), a proxy for plant growth, was calculated as the product of light capture efficiency [Phi(mass): mol photosynthetic photon flux density (PPFD) g(-1) day(-1)] and LUE (mol C mol PPFD(-1)). Species showed different morphologies and photosynthetic characteristics, but their light-capturing and light-use efficiencies, and thus P (mass), did not differ much. This was also observed in the field: plant growth was not size-asymmetric. The size hierarchy that was present from the very early beginning of succession remained for at least the first 5 years. We conclude, therefore, that in slow-growing regenerating vegetation stands, the importance of asymmetric competition for light and growth can be much less than is often assumed.


Phosphorus removal by application of natural and semi-natural materials for possible recovery according to assumptions of circular economy and closed circuit of P.
In the last few years the idea of circular economy has become essential. Thus, designing methods of nutrients removal should be based on using materials that make it possible to recover those nutrients. Recently, methods applied in wastewater treatment plants cannot provide optimal results; moreover, the application of commercial coagulants like ferric chloride and polyaluminum chloride can cause difficulties in potential recovery of phosphorus from sludge. Sorption materials, both natural and modified, are appearing as successful for wastewater treatment, especially for treatment wetland effluent. To pursue circular economy principles, the capacity of waste materials needs to be tested with regard to nutrients removal. If in addition a possibility to recover them appears, it will be possible to close the circuit. The aim of the investigation, according to HELCOM and EU Water Framework Directive recommendations, was to explore the possibility of ensuring good and stable quality of effluent by the application of natural materials for phosphorous removal with possible minimum energy and material consumption. The objective was to determine the sorption capacity of two selected materials (waste material and chemically modified material) in steady conditions. The research focused also on the time of mixing, a period of sedimentation of absorbent materials, and the influence of used materials on the basic parameters of the solution: pH, temperature, total suspended solids, conductivity, turbidity, and color. M1 was a waste material after thermal treatment of carbonate-siliceous rock in temperature above 700 °C (Rockfos®). Material M2 was lanthanum-modified bentonite, a material of anthropogenic origin. Both selected materials have shown a high ability to reduce phosphates concentration in synthetic wastewater. Sorption capacity of materials M1 and M2 were 45.6 mg/g and 5.6 mg/g, respectively.


Quantitative aspects of enzyme histochemistry on sections of freeze-substituted glycol methacrylate-embedded rat liver.
Freeze-substituted rat liver embedded in glycol methacrylate (GMA) has been used to demonstrate the activities of several enzymes. The following enzymes could be detected in GMA-sections by the indicated histochemical procedure(s): 5'-nucleotidase (lead salt, cerium-diaminobenzidine), alkaline phosphatase (indoxyl-tetrazolium salt), catalase (diaminobenzidine), acid phosphatase (diazonium salt), lactate dehydrogenase (tetrazolium salt) and glutamate dehydrogenase (tetrazolium salt). The activities of all these enzymes were dramatically decreased compared with the activities demonstrated in unfixed cryostat sections, with the exception of catalase. The activities of the following enzymes could not be detected in GMA-sections: glucose-6-phosphate dehydrogenase (tetrazolium salt), xanthine oxidoreductase (tetrazolium salt), D-amino acid oxidase (cerium-diaminobenzidine-cobalt-hydrogen peroxide) and glucose-6-phosphatase (cerium-diaminobenzidine). The possible role of restricted penetration of reagents into the resin was studied by measuring cytophotometrically the enzyme activities in GMA-sections of 3 and 6 microns in thickness. For all the enzymes that could be detected, the 6 microns:3 microns ratio varied from 1.4 to 2.7. An eventual retarded penetration of reagents into the resin was investigated by measuring cytophotometrically the amount of final reaction product during incubation for acid phosphatase and glutamate dehydrogenase activities. In both cases linear relationships without a lag phase were found for the specific enzyme activities with incubation time. Chemical denaturation of proteins or masking of active sites in proteins due to embedding in the resin monomer may be considered to be the main cause of decreased enzyme activities.


Detectability of choledocholithiasis on CT: The effect of positive intraduodenal enteric contrast on portovenous contrast-enhanced studies.
To retrospectively assess the accuracy of intravenous (IV) contrast-enhanced multidetector CT (MDCT) in choledocholithiasis detectability, in the presence and absence of positive intraduodenal contrast. Over a 3-year period, patients in whom endoscopic retrograde cholangiopancreatography (ERCP) was performed within a week from a portovenous (PV)-enhanced abdominal CT were identified. The final cohort consisted of 48 CT studies in which the entire common bile duct (CBD) length was visualized (19 males, 29 females; mean age, 68 years). We identified two groups according to the absence (n = 31) or presence (n = 17) of positive intraduodenal contrast. CT section thickness ranged from 1.25 to 5 mm. Two radiologists, blinded to clinical information and ERCP results, independently evaluated the CT images. Direct CBD stone visualization was assessed according to previously predefined criteria, correlating with original electronic CT reports and using ERCP findings as the reference standard. A third reader retrospectively reviewed all discordant results. The diagnostic performances of both observers and interobserver agreement were calculated for both groups. 77%-88% sensitivity, 50%-71% specificity, and 71%-74% accuracy were obtained in the group without positive intraduodenal contrast, versus 50%-80% sensitivity, 57%-71% specificity, and 59%-71% accuracy in the group with positive intraduodenal contrast. With the exception of the positive predictive value (PPV), all diagnostic performance parameters decreased in the positive intraduodenal contrast group, mostly affecting the negative predictive value (NPV) (71%-78% vs 50%-67%). PV-enhanced MDCT has moderate diagnostic performance in choledocholithiasis detection. A trend of decreasing accuracy was noted in the presence of positive intraduodenal contrast.


Assessing the atrial electromechanical coupling during atrial focal tachycardia, flutter, and fibrillation using electromechanical wave imaging in humans.
Minimally-invasive treatments of cardiac arrhythmias such as radio-frequency ablation are gradually gaining importance in clinical practice but still lack a noninvasive imaging modality which provides insight into the source or focus of an arrhythmia. Cardiac deformations imaged at high temporal and spatial resolution can be used to elucidate the electrical activation sequence in normal and paced human subjects non-invasively and could potentially aid to better plan and monitor ablation-based arrhythmia treatments. In this study, a novel ultrasound-based method is presented that can be used to quantitatively characterize focal and reentrant arrhythmias. Spatio-temporal maps of the full-view of the atrial and ventricular mechanics were obtained in a single heartbeat, revealing with otherwise unobtainable detail the electromechanical patterns of atrial flutter, fibrillation, and tachycardia in humans. During focal arrhythmias such as premature ventricular complex and focal atrial tachycardia, the previously developed electromechanical wave imaging methodology is hereby shown capable of identifying the location of the focal zone and the subsequent propagation of cardiac activation. During reentrant arrhythmias such as atrial flutter and fibrillation, Fourier analysis of the strains revealed highly correlated mechanical and electrical cycle lengths and propagation patterns. High frame rate ultrasound imaging of the heart can be used non-invasively and in real time, to characterize the lesser-known mechanical aspects of atrial and ventricular arrhythmias, also potentially assisting treatment planning for intraoperative and longitudinal monitoring of arrhythmias.


Successful treatment of severe acute antibody-mediated rejection of renal allografts with bortezomib--a report of two pediatric cases.
aAMR in renal allografts is uncommon and remains a challenge as it is often refractory to treatment modalities. Aggressive therapy is essential to reverse the rejection as it results in renal allograft loss in approximately 27-40% of cases. There are anecdotal case reports of use of bortezomib, a proteasome inhibitor in the treatment of resistant AMR cases in solid organ transplant recipients; however, the experience is limited. We herein report successful reversal of resistant aAMR in two pediatric patients with bortezomib. Patients were initially treated with IV methylprednisolone pulse therapy with IVIG and PP three times weekly for a total of 10 treatments. After the standard therapy used at our institution persistence of DSA associated with graft dysfunction prompted the use of bortezomib to further treat the rejection. We did not have any neurologic side effects, but one patient did experience significant infections after bortezomib infusions requiring prolonged antimicrobial therapy. The long-term outcome of both children was excellent with preservation of normal renal function and persistent reduction in DSA titers.


A high-affinity monoclonal anti-IgE antibody for depletion of IgE and IgE-bearing cells.
We have identified a monoclonal anti-human immunoglobulin E (IgE) antibody, which recognizes FcepsilonRI-bound IgE and prevents binding of IgE to FcepsilonRI. In this study, we assessed the binding kinetics and affinity of monoclonal antibody 12 (mAb12) for IgE and investigated whether mAb12 can be used for depletion of IgE and isolation of IgE-bearing cells from peripheral blood. Binding kinetics and affinity for IgE were studied using Biacore surface plasmon resonance technique experiments. IgE antibodies were depleted from serum using sepharose-coupled mAb12 and IgE-bearing cells were enriched from heparinized blood samples with mAb12. The extent and biological relevance of IgE depletion were studied by quantitative IgE measurements and basophil histamine release experiments. Specific binding of mAb12 to IgE-bearing cells (basophils, mast cells, IgE-secreting plasma cells) was demonstrated by FACS. Monoclonal antibody 12 shows rapid association (k(a) = 5.46e5/Ms) with IgE, almost no dissociation (k(d) = 8.8e-5/s) and an affinity for IgE (K(D) = 1.61e-10 M), which is as high as that of FcepsilonRI. Immobilized mAb12 could be used to deplete IgE antibodies and isolate IgE-bearing cells from peripheral blood in a single-step procedure. Monoclonal antibody 12 is a high affinity anti-human IgE antibody, which efficiently removes IgE and IgE-bearing cells from peripheral blood and may thus be used for extracorporeal depletion of IgE and IgE-bearing cells.


Current Perspectives of Anticoagulation in Patients With COVID-19.
Thromboembolism and myocardial injury is common in patients with COVID-19. Low-molecular-weight heparin appears to be associated with a good prognosis in patients with COVID-19 and has the ability to reduce coagulation and inflammation markers. Hospitalized patients with COVID-19 should be placed on thromboprophylaxis with the option of full therapeutic anticoagulation or tissue plasminogen activator in high-risk or mechanically ventilated patients. Thromboprophylaxis should also be considered at hospital discharge for high-risk patients. Clinical judgment should be used to evaluate the bleeding and safety risk of anticoagulation in patients with COVID-19 without confirmed data.


Evaluation of Automated Sample Preparation for Mycotoxin Analysis in Foods.
In the present study, we developed a novel automated sample preparation workflow for the determination of mycotoxins in foods. This workflow integrates off-line devices such as a centrifuge, shaker, liquid and solid dispensing units into a unified platform to perform gravimetric and volumetric dispensing, capping/decapping, extraction, shaking, filtration, and centrifugation. Two robotic arms provide sample transportation without human assistance. Critical method performance attributes were characterized using spiked corn, milk and peanut butter containing aflatoxins, deoxynivalenol, fumonisins, ochratoxin A, HT-2 and T-2 toxins and zearalenone and certified reference materials. Prepared samples were analyzed by liquid chromatography mass spectrometry (LC-MS). Recoveries of spiked samples range 100-120% with RSD<20% and the majority of measured values of certified reference materials are consistent with certified values within ±20%. Within- and between-batch variabilities of QC samples range 5-9% and 7-12% respectively. Our workflow introduces a straightforward and automated sample preparation procedure for LC-MS-based multimycotoxin analysis. Further, it demonstrates how individual sample preparation devices, that are conventionally used off-line, can be integrated together. This study shows automated sample preparation will replace manual operations and significantly increase the degree of automation and standardization for sample preparation.


Clinical response to lifestyle counseling for dyslipidemia and elevated blood pressure in childhood cancer survivors.
Childhood cancer survivors (CCS) have increased risk of premature cardiovascular disease. Whether they respond similarly to lifestyle changes for elevated blood pressure (BP), body mass index (BMI), and dyslipidemia to those without history of childhood cancer is unknown. This retrospective cohort study included CCS and 3:1 age- and sex-matched controls treated at Boston Children's Hospital Preventive Cardiology (2010-2019) using lifestyle management based on National Heart, Lung, and Blood Institute (NHLBI) guidelines. Change in BMI, BP, and lipids were analyzed. We included 52 CCS and 162 controls with a median age of approximately 16 years. More CCS (84.3%) had elevated baseline fasting triglycerides (TG) than controls (49.4%) (p < .001). More CCS (62.5%) also had abnormal baseline high-density lipoprotein cholesterol (HDL-C) compared to controls (35.2%) (p = .001). Baseline BMI, BP, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were similar between groups. Over 15 weeks [IQR: 10.5-26], CCS had greater decrease in TG than controls (72.5 vs. 17 mg/dl decrease, p = .095). BP improved in 5% of CCS versus 38% of controls (p = .008). For both, BMI, TC, LDL-C, and HDL-C remained stable. CCS with stem cell transplantation (SCT) had a TC increase of 5% (6 mg/dl) compared to a decrease of 9% (19 mg/dl) among CCS without SCT (p = .02). CCS demonstrated similar improvement in lipids, but impaired BP lowering in response to lifestyle management compared to controls. Further prospective studies are needed to determine if earlier pharmaceutical treatment is warranted in this higher risk population and for the long-term risk reductions of these approaches.


Nutrients, Infectious and Inflammatory Diseases.
A balanced diet with sufficient essential nutritional elements is critical for maintaining a healthy body.[...].


Calcium and muscarinic agonist stimulation of type I adenylylcyclase in whole cells.
The type I adenylylcyclase which was originally purified and cloned from bovine brain is stimulated by Ca2+ and calmodulin in vitro. Although it has been proposed that this enzyme may couple elevations in intracellular Ca2+ to increases in cAMP in whole cells, this has not been demonstrated in vivo. In this study, the type I adenylylcyclase was expressed in human 293 cells, and the influence of extracellular Ca2+ and Ca2+ ionophore on intracellular cAMP levels was examined. The cAMP levels of control cells were unaffected by Ca2+ and A23187. In contrast, intracellular cAMP in 293 cells expressing type I adenylylcyclase was markedly elevated by addition of A23187 and extracellular Ca2+. In the presence of forskolin, the muscarinic agonist carbachol also increased cAMP in 293 cells expressing the type I adenylylcyclase. These data indicate that the type I adenylylcyclase can be stimulated by Ca2+ in vivo, and that muscarinic agonists may indirectly stimulate the enzyme by increasing intracellular free Ca2+.


Subterranean transport of microplastics as evidenced in karst springs and their characterization using Raman spectroscopy.
The increasing use of plastic materials has led to accumulation of large amounts of plastic waste in environment and a global challenge to be tackled with. The natural process of macro-plastics aging generates a multitude of secondary microplastic fragments accumulating in all areas of the planet. The pollution with microplastics of large water bodies, such as rivers, seas and oceans was already proven, but the presence of microplastics even in karst spring water was not reported yet. In this study, Raman micro-spectroscopy was used to confirm the presence of microplastics in the spring water samples collected from two rural karst springs in the Apuseni Mountains (Țarina and Josani), North-Western Romania. Two sets of water samples of 1000 L collected in spring time 2021 and one in autumn 2021 were filtered and analyzed. Using the Python programming language and combining two separate Raman databases, one for plastics and the other for pigments, we established a customized database to unambiguously identify the type of plastic and pigment present in the discovered micro-fragments. The generated reference pigment-plastic spectra were compared to those of potential microplastics found on filters and Pearson's coefficient was used to measure the level of similarity. The presence of microplastics in karst spring waters was confirmed and a quantitative estimation expressed as number of fragments or fibers per liter was 0.034 in Josani and 0.06 in Țarina karst spring. Five months later sampling (autumn 2021) revealed 0.05 microplastics per liter. The spectral results revealed that most microplastics found were dominated by polyethylene terephthalate (PET), followed by polypropylene and interestingly, abundant blue micro-fragments were identified according to their copper phthalocyanine pigments (pigment Blue 15) or indigo carmine (pigment Blue 63) characteristic spectral fingerprints, which surpassed the inherent spectral background level characteristic for the Raman spectra of naturally contaminated waste micro-samples. Their origin in mountain karst spring waters and potential decrease in time is discussed.


Achieving polyhydroxyalkanoate production from rubber wood waste using mixed microbial cultures and anaerobic-aerobic feeding regime.
In the past few years, creating value-added products has become the best choice to pretreat biomass waste. For instance, the fermentable sugar obtained after pretreatment bioconversion into valuable bioproducts, biopolymer as a typical representative, has become a potential strategy. In particular, the production of biopolymer polyhydroxyalkanoate (PHA) by mixed microbial cultures in waste activated sludge can be regarded as a promising alternative to traditional petrochemical plastics. In this study, the enzymatic hydrolysate of rubber wood was utilized as substrate to explore the optimal process conditions for the accumulation of PHA under anaerobic-aerobic mode. The results showed that longer operation cycle (24 h), suitable anaerobic duration (3.5 h) and secondary feeding regimen (secondary addition without draining liquid) were more beneficial to PHA production. After accumulation, the highest PHA production, PHA storage yield (YPHA/S) and ratio to cell dry weight (CDW) reached 929.8 mg COD·L-1, 0.24 g COD/g COD and 0.31 g PHA/g CDW, respectively. The YPHA/S values were similar to the previous reported 0.22 ∼ 0.24 g COD/g COD. The results demonstrated that the secondary feeding regimen was an effective approach to improve the production of PHA with rubber wood enzymatic hydrolysate as substrate.