Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
Direct new oral anticoagulants (NOACs) - inhibitors of thrombin or factor Xa - are intended to be used largely in the treatment of venous thromboembolic disease or the prevention of systematic embolism in atrial fibrillation, instead of vitamin K antagonists. Like any anticoagulant treatment, they are associated with spontaneous or provoked haemorrhagic risk. Furthermore, a significant proportion of treated patients are likely to be exposed to emergency surgery or invasive procedures. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The lack of data means that it is only possible to issue proposals rather than recommendations, which will evolve according to accumulated experience. The proposals presented here apply to dabigatran (Pradaxa(®)) and rivaroxaban (Xarelto(®)); data for apixaban and edoxaban are still scarce. For urgent surgery with haemorrhagic risk, the drug plasma concentration should be less or equal to 30ng/mL for dabigatran and rivaroxaban should enable surgery associated with a high bleeding risk. Beyond that, if possible, the intervention should be postponed by monitoring the drug concentration. The course to follow is then defined according to the NOAC and its concentration. If the anticoagulant dosage is not immediately available, worse propositions, based on the usual tests (prothrombin time and activated partial thromboplastin time), are presented. However, these tests do not really assess drug concentration or the risk of bleeding that depends on it. In case of serious bleeding in a critical organ, the effect of anticoagulant therapy should be reduced using a non-specific procoagulant drug as a first-line approach: activated prothrombin complex concentrate (aPCC) (FEIBA(®) 30-50U/kg) or non-activated PCC (50U/kg). In addition, for any other type of severe haemorrhage, the administration of a procoagulant drug, which is potentially thrombogenic in these patients, is discussed according to the NOAC concentration and the possibilities of mechanical haemostasis.


ATYPICAL LINEAR CONFIGURATION OF BEDBUG BITES IN AN EIGHT-YEAR-OLD BOY: A Case Report and Overview of Cimicosis.
At the beginning of the 21st century, the prevalence of Cimex species (bedbugs) infestation in human dwellings rose exponentially, particularly in the United States. Although there is no evidence that bedbugs transmit diseases to their hosts, they are difficult to eradicate, making them a source of psychological and physical distress and a socioeconomic burden to society. Here, the author describes the case of an eight-year-old boy who presented with widespread, multiple, itchy, red papules surrounded by round patches of erythematous, edematous skin, and was eventually diagnosed with cimicosis (bedbug infestation). Other family members living with the boy showed no clinical signs of bedbug infestation, and the bites on the boy were not in the typical three-row linear configuration associated with bedbug bites-which made this case compelling. Clinical diagnostic characteristics, symptom management, and suggestions on infestation eradication are provided. Biological and epidemiological characteristics of bedbug infestation are also described. Currently, evidence of simple, safe, and effective means of bedbug eradication is lacking.


Facilitating adherence to physical activity: exercise professionals' experiences of the National Exercise Referral Scheme in Wales: a qualitative study.
Although implementers' experiences of exercise referral schemes (ERS) may provide valuable insights into how their reach and effectiveness might be improved, most qualitative research has included only views of patients. This paper explores exercise professionals' experiences of engaging diverse clinical populations in an ERS, and emergence of local practices to support uptake and adherence in the National Exercise Referral Scheme (NERS) in Wales. Thirty-eight exercise professionals involved in the delivery of NERS in 12 local health board (LHB) areas in Wales took part in a semi-structured telephone interview. Thematic analysis was conducted. Professionals' accounts offered insights into how perceived needs and responses to NERS varied by patient characteristics. Adherence was described as more likely where the patient sought referral from a health professional rather than being advised to attend. Hence, professionals sometimes described a need for the referral process to identify patients for whom change was already internally motivated. In addition, mental health patients were seen as facing additional barriers, such as increased anxieties about the exercise environment. Professionals described their role as involving helping patients to overcome anxieties about the exercise environment, whilst providing education and interpersonal support to assist patients' confidence and motivation. However, some concerns were raised regarding the levels of support that the professional should offer whilst avoiding dependence. Patient-only group activities were described as supporting adherence by creating an empathic environment, social support and modelling. Furthermore, effectively fostering social support networks was identified as a key mechanism for reducing dependence and maintaining changes in the longer term. Whether ERS should identify motivated patients, or incorporate activities to support internalisation of motivation amongst less motivated patients deserves attention. As well as providing the knowledge to advise patients on how to exercise safely given their conditions, professionals' training should focus on providing the skills to meet the interpersonal support needs of patients, particularly where ERS are used as a means of improving mental health outcomes. The effectiveness of emerging activities, such as post-scheme maintenance classes, in fostering long-term social networks supportive of physical activity deserve attention. Current Controlled Trials: ISRCTN47680448.


Breast-feeding and Infant Hospitalization for Infections: Large Cohort and Sibling Analysis.
Breast-feeding may protect against infections, but its optimal duration remains controversial. We aimed to study the association of the duration of full and any breast-feeding with infections the first 18 months of life. The Norwegian Mother and Child study (MoBa) is a prospective birth cohort which recruited expecting mothers giving birth from 2000 to 2009. We analyzed data from the full cohort (n = 70,511) and sibling sets (n = 21,220) with parental report of breast-feeding and infections. The main outcome measures were the relative risks (RRs) for hospitalization for infections from 0 to 18 months by age at introduction of complementary foods and duration of any breast-feeding. Although we found some evidence for an overall association between longer duration of full breast-feeding and lower risk of hospitalizations for infections, 7.3% of breast-fed children who received complementary foods at 4 to 6 months of age compared to 7.7% of those receiving complementary foods after 6 months were hospitalized (adjusted RR 0.95, 95% confidence interval 0.88-1.03). Higher risk of hospitalization was observed in those breast-fed 6 months or less (10.0%) compared to ≥12 months (7.6%, adjusted RR 1.22, 95% confidence interval 1.14-1.31), but with similar risks for 6 to 11 months versus ≥12 months. Matched sibling analyses, minimizing the confounding from shared maternal factors, showed nonsignificant associations and were generally weaker compared with the cohort analyses. Our results support the recommendation to fully breast-feed for 4 months and to continue breast-feeding beyond 6 months, and suggest that protection against infections is limited to the first 12 months.


The metabolism of acetamidothiazoles in the rat. 2-Acetamido-, 2-acetamido-4-methyl- and 2-acetamido-4-phenyl-thiazole.
The metabolism of some anti-inflammatory acetamidothiazoles was studied in the rat. The main metabolites were the corresponding acetylthiohydantoic acids, produced by fission of the thiazole ring. Minor metabolites arising from oxidation of the methyl or phenyl substituents were also identified. The structures of metabolites were established spectroscopically (u.v., i.r., n.m.r. and mass spectroscopy) and by identification with authentic specimens. The excretion of the original compounds and of metabolites, labelled with (14)C is also reported.


45 GyRBE for group III orbital embryonal rhabdomyosarcoma.
Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.


[Pathological patterns of reperfused myocardial infarction. Experimental study (author's transl)].
The effect of the reperfusion on the pathological appearance of experimental myocardial infarction has been studied in the rat (87 animals). Following permanent ischemia (33 animals sacrified after 1, 6, 24 and 48 hours), there appeared a reproducible extended transversal infarction marked by an uniform sequence of histologic, histoenzymatic and ultrastructural changes. Following temporary ischemia (54 animals), the pathological patterns were marked by myofibrillar degeneration (contraction band necrosis), cellular edema, calcium deposits and interstitial hemorrhages. These changes appeared after reperfusion of short duration (10 minutes). Sarcolemmal and capillary permeability alterations could be the main factor involved in the reperfusion injury. Similar tissue damage have been found in clinical conditions in subendocardial hemorrhagic necrosis after cardiopulmonary by-pass, and in reperfused infarction.


Relebactam Is a Potent Inhibitor of the KPC-2 β-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae.
The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the Klebsiella pneumoniae carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing Enterobacteriaceae (K. pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Citrobacter koseri, and Escherichia coli) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/liter). Relebactam inhibited KPC-2 with a second-order onset of acylation rate constant (k2/K) value of 24,750 M-1 s-1 and demonstrated a slow off-rate constant (koff) of 0.0002 s-1 Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2-relebactam acyl-enzyme complex was stable for up to 24 h. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation have been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that the positioning of active-site water molecules is less favorable for desulfation in the KPC-2 active site than it is in the KPC-2-avibactam complex. In the acyl complexes, the water molecules are within 2.5 to 3 Å of the avibactam sulfate; however, they are more than 5 to 6 Å from the relebactam sulfate. As a result, we propose that the KPC-2-relebactam acyl complex is more stable than the KPC-2-avibactam complex. The clinical implications of this difference are not currently known.


The role and relevance of phospholipase D1 during growth and dimorphism of Candida albicans.
The phosphatidylcholine-specific phospholipase D1 (PLD1) in Saccharomyces cerevisiae is involved in vesicle transport and is essential for sporulation. The gene encoding the homologous phospholipase D1 from Candida albicans (PLD1) was used to study the role of PLD1 in this pathogenic fungus. In vitro and in vivo expression studies using Northern blots and reverse transcriptase-PCR showed low PLD1 mRNA levels in defined media supporting yeast growth and during experimental infection, while enhanced levels of PLD1 transcripts were detected during the yeast to hyphal transition. To study the relevance of PLD1 during yeast and hyphal growth, an essential part of the gene was deleted in both alleles of two isogenic strains. In vitro PLD1 activity assays showed that pld1 mutants produced no detectable levels of phosphatidic acid, the hydrolytic product of PLD1 activity, and strongly reduced levels of diacylglycerol, the product of lipid phosphate phosphohydrolase, suggesting no or a negligible background PLD1 activity in the pld1 mutants. The pld1 mutants showed no growth differences compared to the parental wild-type in liquid complex and minimal media, independent of the growth temperature. In addition, growth rates of pld1 mutants in media with protein as the sole source of nitrogen were similar to growth rates of the wild-type, indicating that secretion of proteinases was not reduced. Chlamydospore formation was normal in pld1 mutants. When germ tube formation was induced in liquid media, pld1 mutants showed similar rates of yeast to hyphal transition compared to the wild-type. However, no hyphae formation was observed on solid Spider medium, and cell growth on cornmeal/Tween 80 medium indicated aberrant morphogenesis. In addition, pld1 mutants growing on solid media had an attenuated ability to invade the agar. In a model of oral candidosis, pld1 mutants showed no attenuation of virulence. In contrast, the mutant was less virulent in two different mouse models. These data suggest that PLD1 is not essential for growth and oral infections. However, they also suggest that a prominent part of the phosphatidic acid and diacylglycerol pools is produced by PLD1 and that the level of these components is important for morphological transitions under certain conditions in C. albicans.


Clinical Significance of Contrast-Enhanced Ultrasound Galactography in Pre-operative Diagnosis of Patients With Pathologic Nipple Discharge.
The aim of the work described here was to investigate the feasibility and diagnostic value of using contrast-enhanced ultrasound (CEUS) galactography with SonoVue in patients with pathologic nipple discharge (PND). Twenty-eight patients who underwent breast surgery for PND from May 2019 to August 2021 were included. Routine ultrasound, ductoscopy and CEUS galactography were performed successively. Lesions were diagnosed and localized. The sensitivity, specificity and pre-operative localization value of each examination method were evaluated on post-operative pathology. CEUS galactography was successfully conducted in all 28 patients and revealed negative ductal ectasia, filling stop and filling defect. Ductoscopy revealed positive nodules in 21 cases and negative nodules in 7 cases. A total of 18 nodules were found by routine ultrasound, and the relationship between all nodules and the discharge duct was confirmed after CEUS galactography. Compared with the other two methods, CEUS galactography had higher sensitivity, positive predictive value and negative predictive value (100%, 81.82% and 100%, respectively), while it has the same specificity as routine ultrasound (both 60%). The pre-operative location of the nipple duct was consistent with the intra-operative findings in 28 patients after CEUS galactography. The ultrasound contrast agent SonoVue can be used for CEUS galactography in patients with PND. CEUS galactography can improve the detection of ductal nodules and locate the nipple discharge duct pre-operatively. As the technique does not emit radiation and SonoVue is easily metabolized and safe, CEUS galactography is better than conventional imaging for PND patients.


Plasmid-mediated fluoroquinolone-resistance QnrA and QnrB genes among Escherichia coli from cattle in Ado-Ekiti, Nigeria.
This is to investigate the implication of fluoroquinolone usage in veterinary practice and the food chain system. Five hundred isolates of commensal E coli were recovered from the faeces of apparently healthy cattle in Ado-Ekiti, Nigeria. The susceptibility of the bacteria was tested using standard laboratory procedures. Polymerase chain reaction (PCR) was carried out to detect the presence of qnrA and qnrB genes, which were selected on the basis of their fluoroquinolone-resistant patterns. The agar disc diffusion technique revealed that the representative isolates showed multiple fluoroquinolone-resistance and this formed the basis for their selection for PCR amplification. The PCR revealed that ten of the 17 quinolone-resistant representative isolates showed distinct bands which are specific for the qnrB gene; in addition, only one strain of the 20 representative isolates of commensal E coli carried plasmids on which the qnrA gene was detected. This study has confirmed that plasmid-mediated quinolone resistance is a possible mechanism among the fluoroquinolone-resistant commensal E coli isolated from faeces of apparently healthy cattle in the study location.


A prospective observational study to investigate utility of the Delirium Observational Screening Scale (DOSS) to detect delirium in care home residents.
care home residents are particularly at risk of delirium due to high prevalence of dementia. The Delirium Observation Screening Scale (DOSS) identifies behavioural changes associated delirium onset that nursing staff are uniquely placed to recognise. We tested the psychometric properties of the DOSS in UK care homes compared with the Confusion Assessment Method (CAM). prospective observational cohort study performed between 1 March 2015 and 30 June 2016. nine UK residential and nursing care homes. residents over 65 years except those approaching end of life or unable to complete delirium assessments. the 25-item DOSS was completed daily by care home staff and compared with the temporally closest CAM performed twice per week by trained researchers. Sensitivity, specificity, positive and negative predictive values, diagnostic odds and likelihood ratios were calculated. 216 residents participated; mean age 84.9 (SD 7.9); 50% had cognitive impairment (median AMTS 7 (IQR 3-9)). Half of all expected DOSS assessments occurred (30,201); of these, 11,659 (39%) were complete. 78 positive CAM measurements were made during 71 delirium episodes in 45 residents over 70 weeks. Sensitivity and specificity for delirium detection were optimised at a DOSS cut point of ≥5 (sensitivity 0.61 (95% CI: 0.39-0.80) and specificity (0.71 95% CI: 0.70-0.73)). Positive and negative predictive values were 1.6 and 99.5%, respectively. the low sensitivity of the DOSS limits clinical utility for detection of delirium as part of routine care for care home residents, although a negative DOSS affords confidence that delirium is not present.


Arterio-Biliary Fistula as a Rare Life-Threatening Complication of Transjugular Intrahepatic Portosystemic Shunt: A Case Report.
A 46-year-old male with alcoholic liver cirrhosis underwent a transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites. On the 9th day after the procedure, he presented with melena and decreasing hemoglobin levels. Hemobilia due to fistula formation between the right intrahepatic bile duct and right hepatic artery was suspected on computed tomography. Angiography revealed a fistula of the small branches of the hepatic segmental arteries, and right intrahepatic bile duct was confirmed; embolization was successfully performed with a coil for the eighth segmental hepatic artery, a glue-lipiodol mixture for the fifth segmental hepatic artery, and gelfoam slurry for the right anterior hepatic artery. However, 2 days after embolization, the patient died owing to aggravated disseminated intravascular coagulopathy. When gastrointestinal bleeding occurs after TIPS, careful evaluation is immediately required, and hemobilia should be considered.


Does a magnetic blanket induce changes in muscular blood flow, skin temperature and muscular tension in horses?
Static magnetic blankets are often claimed to induce increases in blood flow, reduce muscle tension and tenderness, and be beneficial in both prevention and treatment of musculoskeletal injuries in horses. However, there are no studies that confirm alleged beneficial effects of magnets on muscles of the back in healthy horses. To investigate whether static magnets sewn into a blanket affect back muscle blood flow, skin temperature, mechanical nociceptive threshold (MNT) and behaviour in healthy horses. Prospective, randomised, blinded, placebo-controlled crossover study. The following outcome measurements of the back of 10 healthy horses were performed; blood flow by photoplethysmography, skin temperature by use of thermistors in conjunction with digital infrared thermography, and MNTs by algometry. The horses' behaviour was filmed during the procedure and scored on an ethogram. Measurements were performed repeatedly for a 30 min baseline period. Thereafter a blanket with active, static magnets (900 gauss) or placebo magnets was placed on the horse and measurements were performed for a 60 min treatment period and a 30 min post treatment period. The study procedure was repeated on the consecutive day, when the horse received the alternative treatment. Blood flow in muscle, skin temperatures, MNTs and behavioural traits did not differ between active and placebo magnetic blankets. Skin temperature increased similarly during both active and placebo blanket treatment. In healthy horses, magnetic blankets did not induce additional significant effects on muscle blood flow, skin temperature, MNTs and behaviour when compared with nonmagnetic blankets.


Harmonic phase angle as a concentration-independent measure of nanoparticle dynamics.
The harmonic spectrum of magnetic nanoparticles contains valuable information about the quantity and environment of the particles. Harmonic amplitudes have been used to produce quantitative images and ratios of these amplitudes have been used to monitor changes in the particle environment. Harmonic phase angles have not yet been utilized in these pursuits. The authors explore harmonic phase angle as a concentration-independent means of remotely monitoring the dynamic magnetization of nanoparticles. A magnetic nanoparticle spectrometer was used to explore the impacts of viscosity and excitation frequency and amplitude on the phase angle of magnetization harmonics. A dynamic model, which accounts for particle relaxation times, was used to model some results. Harmonic phase angle can undergo large changes when a nanoparticle's Brownian motion is altered. Excitation parameters and particle characteristics have a profound effect on the extent of these changes. Phase angle can allow for monitoring of various impacts on a nanoparticle's Brownian motion. When combined with other concentration-independent metrics, such as ratios of harmonic amplitudes, valuable information about the particle's environment can be gathered.


Underperformance of clinical risk scores in identifying vascular ultrasound-based high cardiovascular risk in systemic lupus erythematosus.
The aim of this study was to assess the performance of eight clinical risk prediction scores to identify individuals with systemic lupus erythematosus (SLE) at high cardiovascular disease (CVD) risk, as defined by the presence of atherosclerotic plaques. CVD risk was estimated in 210 eligible SLE patients without prior CVD or diabetes mellitus (female: 93.3%, mean age: 44.8 ± 12 years) using five generic (Systematic Coronary Risk Evaluation (SCORE), Framingham Risk Score (FRS), Pooled Cohort Risk Equations (ASCVD), Globorisk, Prospective Cardiovascular Münster Study risk calculator (PROCAM)) and three 'SLE-adapted' (modified-SCORE, modified-FRS, QRESEARCH risk estimator, version 3 (QRISK3)) CVD risk scores, as well as ultrasound examination of the carotid and femoral arteries. Calibration, discrimination and classification measures to identify high CVD risk based on the presence of atherosclerotic plaques were assessed for all risk models. CVD risk reclassification was applied for all scores by incorporating ultrasound results. Moderate calibration (p-value range from 0.38 to 0.63) and discrimination (area under the curve 0.73-0.84), and low-to-moderate sensitivity (8.3-71.4%) and classification ability (Matthews correlation coefficient (MCC) 0.25-0.47) were observed for all risk models to identify patients with plaques at any arterial site as high-risk. MCC was improved for modified-FRS versus FRS (0.43 vs 0.36), but not for modified-SCORE versus SCORE (0.25 vs 0.25). Based on plaque presence, CVD risk was upgraded to high-risk in 10%, 16.1%, 20.5%, 21.5%, 24%, 28.2% and 28.6% of cases classified as non-high-risk by QRISK3, modified-FRS, Globorisk, FRS/PROCAM, ASCVD, modified-SCORE and SCORE, respectively. Most of the five generic and three 'SLE-adapted' clinical risk scores underestimated high CVD risk defined by atherosclerotic plaque presence in patients with SLE.


Visual scanpaths and facial affect recognition in delusion-prone individuals: Increased sensitivity to threat?
Using visual scanpaths as a measure of directed attention, we investigated whether delusion-prone individuals would exhibit reduced visual appraisal, and impaired recognition accuracy, for threat-related facial expressions. 47 psychiatrically healthy individuals completed the Peters et al. Delusions Inventory (PDI) as an index of delusion-proneness; experimental groups of high and low PDI scorers were formed on the basis of a median split. Visual scanpaths were recorded while participants viewed photographs of faces displaying anger, fear, happy, sad, and neutral expressions under a free-viewing condition. Affect recognition accuracy was assessed using a forced-choice response format. The high PDI group displayed generally "extended" scanpaths, characterised by increased distances between fixations, for angry, fearful, and happy faces, but exhibited a distinctive pattern of reduced foveal attention (fewer fixations) for facial expressions of anger and fear. Impaired affect recognition accuracy in the high PDI group was most pronounced for fearful faces. Reduced recognition accuracy for fearful faces was associated with longer distances between fixations in the entire group. Delusion-prone individuals displayed a bias of directing attention away from threat-related faces, and a trend toward reduced recognition accuracy for fearful faces, suggesting that these individuals may be particularly sensitive to facial threat.


A review of epidemiology of paediatric elbow injuries in sports.
The elbow is a common site of orthopaedic injury in the paediatric population. The number of these injuries continues to rise following increased levels of participation in paediatric recreational and competitive sport. Injuries to the paediatric elbow can be classified as either overuse or acute. Delineating injury patterns to the elbow in children can be challenging, given the cartilaginous composition of the distal humerus and the multiple secondary ossification centres that appear and unite with the epiphysis at defined ages. Pitching in baseball, serving in tennis, spiking in volleyball, passing in American football and launching in javelin-throwing can all produce elbow pathology by forceful valgus stress, with medial stretching, lateral compression and posterior impingement. In children and adolescents, the epiphyseal plate is weaker than the surrounding ligaments, predisposing them to epiphyseal plate injuries. On the other hand, post-pubescent or skeletally mature athletes are more prone to tendinous or ligamentous injury. Injuries may cause significant impact on the athlete, parents and healthcare system. With the exception of baseball, there are few prospective cohort studies on the epidemiological trends of childhood elbow injuries in other sports. This paper aims to describe the epidemiological trends in paediatric elbow injuries related to sports, suggests prevention strategies and discusses the scope for further research. A web-based search of existing articles pertaining to paediatric elbow injuries in sports was performed. The implications of acute and overuse injuries and the possibility of permanent damage should be understood by parents, coaches and the athletes. Proper understanding of the intrinsic and extrinsic risk factors that could lead to elbow injuries is thus required. Measures to prevent elbow injuries should include proper coaching, warm-up, officiation, legislation, medical expertise and protective gear. There are still many opportunities for prospective studies and other research projects among young athletes in various sports. Current studies will serve as a baseline for future research to assess the success of specific interventions in reducing the incidence of elbow injury in the paediatric athlete. Further epidemiological studies in various sports will help expand our knowledge and prevent potential disability and deformity in the paediatric elbow.


Attentional capture by working memory contents.
There has been controversy on whether working memory (WM) contents automatically guide attention. The present study tried to replicate the effect of WM-based attentional capture using an adaption of Downing's (2000) paradigm, in which WM and attentional capture were combined. Subjects were presented with an attention display containing two objects, one of which could be precued by a matching item being held in WM. As measured by a probe discrimination task, the memory-matching object had a privileged status to capture attention regardless of the stimulus onset asynchronies between the memory cue and the attention display, even when there was absolutely no benefit for subjects to bias attention in favour of the memory match. These results suggest that WM contents guide attention in an involuntary manner. The implications of current findings for understanding of WM effects on visual selection are discussed.


Intrathecal liposomal cytarabine (lipoCIT) administration in patients with leukemic or lymphomatous meningitis: efficacy and long-term safety in a single institution.
There is limited information regarding the efficacy and long term safety of intrathecal injection of liposomal cytarabine in leukemic or lymphomatous meningitis. We studied 20 consecutive HIV-negative patients with leukemic or lymphomatous meningitis who were treated with intrathecal liposomal cytarabine between 2004 and 2007. We focused on efficacy and on any late effects of the drug. Twenty patients who received intrathecal liposomal cytarabine injection as part of their treatment; of these, 9 were alive and in complete remission at the end of the study. Median survival from the time of the first injection was 22.7 months (range, 0.5 to 64 months). Short-term toxicity related to intrathecal of liposomal cytarabine was observed in 2 cases; headache in 1 case and regressive facial palsy and diplopy in 1 case. Long-term toxicity was seen in 2 cases; clinical symptoms were urinary and fecal dysfunction with confusion in 1 case, and urinary dysfunction in 1 case. Both patients had been heavily pre-treated with neurotoxic drugs and neuraxis irradiation. In our experience, intrathecal liposomal cytarabine injections were convenient in the management of leukemic and lymphomatous meningitis, and can lead to long-term survival. Although neurotoxicity was rare, clinicians should exercise caution when retreatment is required in relapsing patients.


Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis.
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.


The rate-determining step is dead. Long live the rate-determining state!
The concept of a rate-determining step (RD-Step) is central to the kinetics community, and it is basic knowledge even for the undergraduate chemical student. In spite of this, too many different definitions of the RD-Step appear in the literature, all of them with drawbacks. This dilemma has been thoroughly studied by several authors in the attempt to "patch" the drawbacks and bring the RD-Step to a correct physical meaning. Herein we review with simple models the most notable definitions and some challengers of the RD-Step concept, to conclude with the deduction that there are no rate-determining steps, only rate-determining states.


Altered communication between L-type calcium channels and ryanodine receptors in heart failure.
Heart failure (HF) is a progressive syndrome that appears as the final phase of most cardiac diseases and is manifested as a decreased contractile function. Contraction in cardiomyocytes arises by the Ca2+ induced Ca2+ release mechanism, where Ca2+ entry (ICa) through Ca2+ channels (DHPRs) activates Ca2+ release channels (RyRs) in the junctional sarcoplasmic reticulum (SR). This is the base of cardiac excitation-contraction (EC) coupling. To elucidate the mechanisms underlying depressed function of the failing heart, analysis of EC coupling main elements have been undertaken. ICa density is usually maintained in HF. However, failing myocytes show a reduced SR Ca2+ release. Then, if the trigger of SR Ca2+ release is maintained, why is SR Ca2+ release depressed in HF? Analyses of the DHPR-RyR coupling efficiency have revealed a decrease in the ICa efficacy to trigger Ca2+ release in failing myocytes. In terminal heart failure without hypertrophy, a decrease in SR Ca2+ load can account for the decreased SR Ca2+ release. Fewer Ca2+ sparks (elementary units of SR Ca2+ release) are triggered by an equivalent ICa in hypertrophied failing myocytes, suggesting a functional or spatial reorganization of the space T-tubule junctional SR. This theory is supported by new data showing that the T-tubule density is reduced in failing cells.


Longitudinal Legendre polynomial expansion of electromagnetic fields for analysis of arbitrary-shaped gratings.
The Legendre polynomial expansion method (LPEM), which has been successfully applied to homogenous and longitudinally inhomogeneous gratings [J. Opt. Soc. Am. B24, 2676 (2007)], is now generalized for the efficient analysis of arbitrary-shaped surface relief gratings. The modulated region is cut into a few sufficiently thin arbitrary-shaped subgratings of equal spatial period, where electromagnetic field dependence is now smooth enough to be approximated by keeping fewer Legendre basis functions. The R-matrix propagation algorithm is then employed to match the Legendre polynomial expansions of the transverse electric and magnetic fields across the upper and lower interfaces of every slice. The proposed strategy then enhances the overall computational efficiency, reduces the required memory size, and permits the efficient study of arbitrary-shaped gratings. Here the rigorous approach is followed, and analytical formulas of the involved matrices are given.


De novo enhancer deletion of LMX1B produces a mild nail-patella clinical phenotype.
Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss-of-function sequence variants and deletions cause Nail-Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%-10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B-binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail-Patella phenotype that includes ophthalmological and renal manifestations.


Use of a semipermeable glove during treatment of hand dermatitis.
Forty-six subjects with hand dermatitis participated in a pilot study comparing a new semipermeable glove to a standard cotton glove. A variety of diagnoses were represented. Each subject received treatment with topical steroids and/or moisturizers and used one each of the experimental and cotton gloves for approximately one month. Physicians scored skin condition before and after treatment. Subjects evaluated skin comfort and practical aspects of using each type of glove. Thirty subjects completed the study protocol. The type of glove used had no impact on skin condition at follow up, with both groups of hands improving. Patients expressed a preference for the experimental gloves, noting improvements in skin and hand comfort, dexterity, cleanliness, and ease of use. Feedback suggested that the gloves will be well tolerated and patient compliance in using the gloves will be high. Evaluation of the gloves' value for prevention and chronic management of hand dermatitis is warranted.


Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis.
PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%-8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6-10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4-10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.


Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits.
Among the many approaches to Coronavirus disease 2019 (COVID-19) prevention, the possible role of nutrition has so far been rather underestimated. Foods are very rich in substances, with a potential beneficial effect on health, and some of these could have an antiviral action or be important in modulating the immune system and in defending cells from the oxidative stress associated with infection. This short review draws the attention on some components of citrus fruits, and especially of the orange (Citrus sinensis), well known for its vitamin and flavonoid content. Among the flavonoids, hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy, both with the coronavirus "spike" protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The binding energy of hesperidin to these important components is lower than that of lopinavir, ritonavir, and indinavir, suggesting that it could perform an effective antiviral action. Furthermore, both hesperidin and ascorbic acid counteract the cell damaging effects of the oxygen free radicals triggered by virus infection and inflammation. There is discussion about the preventive efficacy of vitamin C, at the dose achievable by the diet, but recent reviews suggest that this substance can be useful in the case of strong immune system burden caused by viral disease. Computational methods and laboratory studies support the need to undertake apposite preclinical, epidemiological, and experimental studies on the potential benefits of citrus fruit components for the prevention of infectious diseases, including COVID-19.


Translating the Canadian Occupational Performance Measure to Danish, addressing face and content validity.
The Canadian Occupational Performance Measure (COPM) is a recognized assessment tool within Danish occupational therapy (OT), and translated versions of the COPM have been implemented in Danish OT practice. However, a rigorous translation and cross-cultural validation process has not been applied to these versions. To produce a new Danish translation of the COPM evaluating its semantic, conceptual, operational and item equivalence while addressing its face and content validity. An iterative, multistage translation process was undertaken with (1) forward translation involving professional translators and bilingual OTs, (2) pilot testing and cognitive debriefing interviews with 15 OTs and 37 clients which were analyzed quantitatively and qualitatively, and (3) finalization with adaptations, back translation and approval. Content validity of COPM in terms of appropriateness, acceptability, intelligibility and comprehensiveness was found in 78-100% of the cases, and its ability to ensure a client-centred focus in the assessment process was confirmed. However, issues concerning the administration and content of the COPM were identified. Subsequently, two recommendations regarding the administration of the COPM were added to the Danish version. Semantic, conceptual, operational and aspects of item equivalence of the COPM into Danish were achieved and supported by face and content validity.


The influence of hyperthermia on intracranial pressure, cerebral oximetry and cerebral metabolism in traumatic brain injury.
Hyperthermia is a common secondary insult in traumatic brain injury (TBI). The aim was to evaluate the relationship between hyperthermia and intracranial pressure (ICP), and if intracranial compliance and cerebral blood flow (CBF) pressure autoregulation affected that relationship. The relationships between hyperthermia and cerebral oximetry (BtipO2) and cerebral metabolism were also studied. A computerized multimodality monitoring system was used for data collection at the neurointensive care unit. Demographic and monitoring data (temperature, ICP, blood pressure, microdialysis, BtipO2) were analyzed from 87 consecutive TBI patients. ICP amplitude was used as measure of compliance, and CBF pressure autoregulation status was calculated using collected blood pressure and ICP values. Mixed models and comparison between groups were used. The influence of hyperthermia on intracranial dynamics (ICP, brain energy metabolism, and BtipO2) was small, but individual differences were seen. Linear mixed models showed that hyperthermia raises ICP slightly more when temperature increases in the groups with low compliance and impaired CBF pressure autoregulation. There was also a tendency (not statistically significant) for increased BtipO2, and for increased pyruvate and lactate, with higher temperature, while the lactate/pyruvate ratio and glucose were stable. The major finding was that the effects of hyperthermia on intracranial dynamics (ICP, brain energy metabolism, and BtipO2) were not extensive in general, but there were exceptional cases. Hyperthermia treatment has many side effects, so it is desirable to identify cases in which hyperthermia is dangerous. Information from multimodality monitoring may be used to guide treatment in individual patients.


Antibiograms of streptococci isolated from bovine intramammary infections.
A total of 455 streptococcal cultures from bovine intramammary infection in 72 herds were studied to determine their sensitivity to 17 antimicrobial agents. More than 90% of the cultures were sensitive to carbenicillin, chloramphenicol, erythromycin, and penicillin. Gentamicin, neomycin, nitrofurazone, polymyxin, and streptomycin were ineffective in the in vitro inhibition of streptococci.


Molecular biology of the kallikrein-kinin system: from structure to function.
The participation of the kallikrein-kinin system, comprising the serine proteases kallikreins, the protein substrates kininogens and the effective peptides kinins, in some pathological processes like hypertension and cardiovascular diseases is still a matter of controversy. The use of different experimental set-ups in concert with the development of potent and specific inhibitors and antagonists for the system has highlighted its importance but the results still lack conclusivity. Over the last few years, transgenic and gene-targeting technologies associated with molecular biology tools have provided specific information about the elusive role of the kallikrein-kinin system in the control of blood pressure and electrolyte homeostasis. cDNA and genomic sequences for kinin receptors B2 and B1 from different species were isolated and shown to encode G-protein-coupled receptors and the structure and pharmacology of the receptors were characterized. Transgenic animals expressing an overactive kallikrein-kinin system were established to study the cardiovascular effects of these alterations and the results of these investigations further corroborate the importance of this system in the maintenance of normal blood pressure. Knockout animals for B2 and B1 receptors are available and their analysis also points to the role of these receptors in cardiovascular regulation and inflammatory processes. In this paper the most recent and relevant genetic animal models developed for the study of the kallikrein-kinin system are reviewed, and the advances they brought to the understanding of the biological role of this system are discussed.


Prolonged instability prior to a regime shift.
Regime shifts are generally defined as the point of 'abrupt' change in the state of a system. However, a seemingly abrupt transition can be the product of a system reorganization that has been ongoing much longer than is evident in statistical analysis of a single component of the system. Using both univariate and multivariate statistical methods, we tested a long-term high-resolution paleoecological dataset with a known change in species assemblage for a regime shift. Analysis of this dataset with Fisher Information and multivariate time series modeling showed that there was a∼2000 year period of instability prior to the regime shift. This period of instability and the subsequent regime shift coincide with regional climate change, indicating that the system is undergoing extrinsic forcing. Paleoecological records offer a unique opportunity to test tools for the detection of thresholds and stable-states, and thus to examine the long-term stability of ecosystems over periods of multiple millennia.


Biocommunicability and the biopolitics of pandemic threats.
In this article we assess accounts of the H1N1 virus or "swine flu" to draw attention to the ways in which discourse about biosecurity and global health citizenship during times of pandemic alarms supports calls for the creation of global surveillance systems and naturalizes forms of governance. We propose a medical anthropology of epidemics to complement an engaged anthropology aimed at better and more critical forms of epidemic surveillance. A medical anthropology of epidemics provides insights into factors and actors that shape the ongoing production of knowledge about epidemics, how dominant and competing accounts circulate and interact, how different stakeholders (citizens, politicians, journalists, and policymakers) access and interpret information available from different sources-including through a variety of new digital venues-and what they do with it. These insights together provide a compelling agenda for medical anthropology and anyone working in health-related fields.


Exercise training prevents the exaggerated exercise pressor reflex in rats with chronic heart failure.
An exaggerated exercise pressor reflex (EPR) occurs in the chronic heart failure (CHF) state, which contributes to exercise intolerance and excessive sympathoexcitation during exercise. Exercise training (ExT) improves abnormal cardiovascular reflexes in CHF. Whether ExT can normalize the exaggerated EPR function remains to be determined. This study was designed to investigate the effects of ExT on the EPR and on the mechanical or metabolic components of this reflex in sham-operated and CHF rats. The EPR was activated by static contraction induced by electrical stimulation of L4/L5 ventral roots. The afferent fibers associated with the mechanoreflex and metaboreflex were activated by passive stretch and hindlimb arterial injection of capsaicin (0.1 and 1 microg/kg, 0.2 ml), respectively. Heart rate, blood pressure, and sympathoexcitatory responses during the activation of these reflexes were compared in sham+sedentary (Sed), sham+ExT, CHF+Sed, and CHF+ExT rats. Compared with sham+Sed rats, CHF+Sed rats exhibited exaggerated heart rate and pressor and sympathoexcitatory responses to either static contraction or passive stretch, whereas the cardiovascular responses to injection of capsaicin were blunted. Eight to ten weeks of ExT normalized the exaggerated responses induced by static contraction or passive stretch and partially improved the blunted responses due to intra-arterial capsaicin in CHF rats. ExT had no significant effect on the EPR and mechanoreflex and metaboreflex functions in sham rats. These findings suggest a potential therapeutic role for ExT in minimizing arterial pressure and sympathetic outflow following activation of the EPR in the CHF state.


Analysis of subcellular localization and function of the yeast Rab6 homologue, Ypt6p, using a novel amino-terminal tagging strategy.
Ypt6p, the yeast homologue of mammalian Rab6, is involved in the multiple processes regulated by membrane trafficking such as vacuole maturation and membrane protein recycling. Although several lines of evidence suggest that Ypt6p is possibly localized to multiple membrane compartments, the precise localization of endogenous Ypt6p remains to be elucidated. In this study, we developed a novel method for N-terminal tagging of endogenous protein based on homologous recombination and investigated the subcellular localization and function of Ypt6p. Ypt6p and its GTP-bound form were predominantly localized to the cis- to medial-Golgi compartments whereas the GDP-bound form of Ypt6p was localized to the cytosol. Ric1p, a component of the specific GEF complex for Ypt6p, largely colocalized with Ypt6p in the early Golgi, and localization of Ypt6p changed to the cytosol in ric1Δ cells. On the other hand, Gyp6p, a putative GAP for Ypt6p, was localized to the trans-Golgi compartment and deletion of GYP6 increased the localization of Ypt6p at the trans-Golgi, suggesting that Gyp6p promotes the dissociation of Ypt6p from the Golgi when arriving at the trans-Golgi compartment. Additionally, we demonstrated that overexpression of the GDP-bound form of Ypt6p caused defective vacuole formation and recycling of Snc1p to the plasma membrane. These results suggest that the GTP-binding activity of Ypt6p is necessary for intra-Golgi trafficking and protein recycling in the early Golgi compartment.


Intensive lifestyle changes for reversal of coronary heart disease.
The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year. To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes (without lipid-lowering drugs) on coronary heart disease. Randomized controlled trial conducted from 1986 to 1992 using a randomized invitational design. Forty-eight patients with moderate to severe coronary heart disease were randomized to an intensive lifestyle change group or to a usual-care control group, and 35 completed the 5-year follow-up quantitative coronary arteriography. Two tertiary care university medical centers. Intensive lifestyle changes (10% fat whole foods vegetarian diet, aerobic exercise, stress management training, smoking cessation, group psychosocial support) for 5 years. Adherence to intensive lifestyle changes, changes in coronary artery percent diameter stenosis, and cardiac events. Experimental group patients (20 [71%] of 28 patients completed 5-year follow-up) made and maintained comprehensive lifestyle changes for 5 years, whereas control group patients (15 [75%] of 20 patients completed 5-year follow-up) made more moderate changes. In the experimental group, the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year (a 4.5% relative improvement) and by 3.1 absolute percentage points after 5 years (a 7.9% relative improvement). In contrast, the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year (a 5.4% relative worsening) and by 11.8 percentage points after 5 years (a 27.7% relative worsening) (P=.001 between groups. Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up (risk ratio for any event for the control group, 2.47 [95% confidence interval, 1.48-4.20]). More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group. In contrast, in the control group, coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred.


Fluid shear stress induces osteoblast differentiation and arrests the cell cycle at the G0 phase via the ERK1/2 pathway.
Numerous studies have demonstrated that fluid shear stress (FSS) may promote the proliferation and differentiation of osteoblast cells. However, proliferation and differentiation are mutually exclusive processes and are unlikely to be promoted by FSS simultaneously. Cell proliferation and differentiation induced by FSS has rarely been reported. In order to provide an insight into this process, the present study investigated the effects of FSS on osteoblast‑like MC3T3 cells in the G0/G1 phase, the period during which the fate of a cell is determined. The results of the present study demonstrated that FSS promoted alkaline phosphatase (ALP) activity, and the mRNA expression and protein expression of osteocalcin, collagen type I and runt‑related transcription factor 2 (Runx2), while inhibiting DNA synthesis and arresting the cell cycle at the G0/G1 phase. The increase in Runx2 and ALP activity was accompanied by the activation of calcium/calmodulin‑dependent protein kinase type II (CaMK II) and extracellular signal‑regulated kinases 1/2 (ERK1/2), which was completely abolished by treatment with KN93 and U0126, respectively. In addition, the inhibition of ERK1/2, although not CaMK II, decreased p21Cip/Kip activity, resulting in an increase in cell number and S phase re‑entry. The results of the present study indicated that in the G0/G1 phase, FSS promoted osteoblast differentiation via the CaMK II and ERK1/2 signaling pathways, and blocked the cell cycle at the G0/G1 phase via the ERK1/2 pathway only. The present findings provided an increased understanding of osteoblastic mechanobiology.


Pain: its physiology and rationale for management. Part I. Neuroanatomical substrate of pain.
Pain, one of man's most worrisome afflictions, is also one of neurobiology's most challenging problems. Even its definition is beset with controversy. The origin and current resolution of this controversy are presented in this paper, but the major purpose of Part I is to review the anatomical substrate of the peripheral and central nervous systems involved in pain. Structural and functional characteristics of pain receptors and their afferent fibers are described, with emphasis upon current hypotheses regarding putative neural transmitters and possible mechanisms for signal transduction. Hitherto unrecognized details of the cytoarchitecture, anatomical organization, and circuitry of the dorsal horns are reviewed. The paper concludes with a consideration of the major components of the ascending and descending systems of subserving pain.


The highest incidence of out-of-hospital cardiac arrest during a circadian period in survivors.
Health care associated with cardiac arrest exhibits a significant economic burden, rather than effectiveness. The time of the out-of-hospital cardiac arrest (OHCA) onset during a diurnal period alters the survival chance. Professionally resuscitated patients for witnessed OHCA (n = 495) from the study were prospectively followed for 12 months. The distribution of the onset of cardiac arrest during the 24-hour period was tested in the survivors (the total group, the other groups). In the ultrashort-term survivors (n = 136, follow-up = admission to hospital) the highest incidence was seen between 18:01-22:00 h. The same trend was seen in both the short-term (n = 48, follow-up = discharge from hospital) and the long-term survivors (n = 39, follow-up = 1 year). Furthermore, when the ultrashort-, short-, and long-term survivors were analysed according to indicators of prehospital care (early electrical defibrillation < or =5 min, bystander cardiopulmonary resuscitation, ambulance response time < or =10 min; locations of arrest; initial cardiac rhythms) an OHCA peak was observed for early defibrillation and ambulance response time (ultrashort-term survivors, 18:01-22:00 h) and/or in the case of OHCA that occurred in a public place (short-term survivors, 18:01-22:00 h). The lowest incidence of cardiac arrest was between 22:01-06:00 h in all groups. The evening incidence of OHCA reflects a higher chance of survival in our study area (East Bohemian region).


Combinatorial liquid-phase synthesis of structurally diverse benzimidazole libraries.
An expedient liquid-phase synthesis for construction of the diverse benzimidazole libraries is described. Nucleophilic aryl substitution of poly(ethylene glycol)-supported 4-fluoro-3-nitrobenzoic acid 3 with several primary amines under basic conditions, followed by Zn/NH(4)Cl mediated nitro group reduction, gave the PEG bound diamines 5. Subsequent cyclization of immobilized o-phenylenediamine 5 using thiocarbonyldiimidazole (TCD) or thiophosgene in dichloromethane furnished benzimidazole-2-thiones 6. Treatment of 6 with alkyl halides and benzylic halides in the presence of triethylamine provided 1-substituted-2-alkylthio-5-carbamoylbenzimidazoles on the support. The desired products 8 were severed from the PEG under mild conditions in high yield and high purity.


Iron deficiency anemia and educational achievement.
The present study investigates the effect of iron supplementation on measures of school performance among 78 iron-deficient anemic and 41 nonanemic children in an economically deprived rural area in Central Java, Indonesia. All the subjects were treated for ancylostomiasis before iron supplementation. They were randomly assigned to either an iron or placebo group. Hematological and behavioral measurements were obtained immediately before (T1) and after (T2) the iron and placebo treatments. Iron treatment for a 3-mo period resulted in substantive increases in mean Hgb, Hct, and transferrin saturation among the iron-deficient anemic children. Furthermore, changes in the iron status of iron-deficient anemic children were associated with significant changes in the school achievement test scores of iron-deficient anemic children. T2 evaluation of achievement test scores indicated that the difference between iron-treated anemic and nonanemic children was still statistically significant. However, when T1 scores were entered as a covariate, iron-deficient anemic subjects treated with iron obtained significantly higher delta achievement scores. Findings from the present study indicate that iron supplementation among iron-deficient anemic children benefits learning processes as measured by the school achievement test scores.


Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication.
The study aimed at determining the effect of melatonin on the activity of protective antioxidative enzymes in the heart and of lipid peroxidation products in the course of intoxication with doxorubicin (DOX). The rats were categorized into four groups, receiving: 0.9% NaCl i.p. (NaCl control); melatonin [20 mg/kg body weight (b.w.)] s.c. (control Mel); DOX (2.5 mg/kg b.w.) i.p.; melatonin plus DOX in doses as above. All the substances were administered once in a week for four consecutive weeks. Homogenates of heart tissue were examined for activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), levels of reduced glutathione (GSH) and of lipid peroxidation indices (MDA + 4-HDA). Administration of melatonin alone did not induce alterations in levels of MDA + 4-HDA, GSH, or in activity of GPx, SOD or CAT, as compared to the group receiving 0.9% NaCl. GSH levels decreased following DOX but remained at normal levels following DOX and melatonin. The level of MDA + 4-HDA increased following DOX, as compared with the control, a change prevented by the combination of DOX + melatonin. Activities of GPx, SOD and CAT were higher in groups receiving DOX and/or DOX plus melatonin than in control groups. Activity of CAT and the level of GSH in the group receiving DOX plus melatonin were significantly higher than in the group intoxicated with DOX alone. The obtained results demonstrate that, when given in parallel with DOX, melatonin protects cardiomyocytes from damaging effects of the cytostatic drug (reflected by the levels of MDA + 4-HDA). The protective effect resulted, in part from the augmented levels of GSH and from stimulation of CAT activity by melatonin in cardiomyocytes subjected to the action of DOX.


Arch-width and perimeter changes in patients with borderline Class I malocclusion treated with extractions or without extractions with air-rotor stripping.
The aim of this study was to compare dental arch-width and perimeter changes in patients with borderline Class I occlusion, treated with extractions or without extractions with air-rotor stripping (ARS). The study was conducted with 26 sets of pretreatment and posttreatment dental models of patients with borderline Class I occlusion. Thirteen patients (mean age, 18.1 +/- 3.7 years) were treated with 4 premolar extractions, and 13 (mean age, 17.8 +/- 2.4 years) were treated without extractions but with the ARS technique. Mean maxillary and mandibular crowding values were 5.7 +/- 1.5 and 5.9 +/- 1.4 mm in the extraction group, and 5.0 +/- 1.3 and 5.9 +/- 1.3 mm in the nonextraction group, respectively. A digital caliper was used to measure maxillary and mandibular intercanine and intermolar arch widths and arch perimeters. The Wilcoxon test was used to evaluate treatment changes in each group. The Mann-Whitney U test was used to compare the pretreatment and posttreatment values and the treatment changes between the 2 groups. At the start of treatment, the maxillary and mandibular intercanine and intermolar widths and the arch perimeters of both groups did not differ statistically. The maxillary intercanine widths were maintained in both groups. The maxillary and mandibular intermolar widths and arch perimeters decreased in the extraction group. In the nonextraction group, intermolar widths decreased, but arch perimeters did not change significantly. After treatment, the maxillary and mandibular intercanine widths were not different between the groups. In Class I borderline patients with moderate crowding, extraction therapy with minimum anchorage did not result in narrower dental arches, and nonextraction treatment with ARS preserved the intercanine arch widths and arch perimeters.


Optimization of Picrosirius red staining protocol to determine collagen fiber orientations in vaginal and uterine cervical tissues by Mueller polarized microscopy.
Polarized microscopy provides unique information on anisotropic samples. In its most complete implementation, namely Mueller microscopy, this technique is well suited for the visualization of fibrillar proteins orientations, with collagen in the first place. However, the intrinsic optical anisotropy of unstained tissues has to be enhanced by Picrosirius Red (PR) staining to enable Mueller measurements. In this work, we compared the orientation mapping provided by Mueller and second harmonic generation (SHG) microscopies on PR stained samples of vaginal and uterine cervix tissues. SHG is a multiphoton technique that is highly specific to fibrillar collagen, and was taken as the "gold standard" for its visualization. We showed that Mueller microscopy can be safely used to determine collagen orientation in PR stained cervical tissue. In contrast, in vaginal samples, Mueller microscopy revealed orientations not only of collagen but also of other anisotropic structures. Thus PR is not fully specific to collagen, which necessitates comparison to SHG microscopy in every type of tissue. In addition to this study of PR specificity, we determined the optimal values of the staining parameters. We found that staining times of 5 min, and sample thicknesses of 5 µm were sufficient in cervical and vaginal tissues.


Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation.
The type 2 iodothyronine deiodinase (D2) is an integral membrane ER-resident selenoenzyme that activates the pro-hormone thyroxine (T4) and supplies most of the 3,5,3'-triiodothyronine (T3) that is essential for brain development. D2 is inactivated by selective conjugation to ubiquitin, a process accelerated by T4 catalysis and essential for the maintenance of T3 homeostasis. A yeast two-hybrid screen of a human-brain library with D2 as bait identified von Hippel-Lindau protein-interacting deubiquitinating enzyme-1 (VDU1). D2 interaction with VDU1 and VDU2, a closely related deubiquitinase, was confirmed in mammalian cells. Both VDU proteins colocalize with D2 in the ER, and their coexpression prolongs D2 half-life and activity by D2 deubiquitination. VDU1, but not VDU2, is markedly increased in brown adipocytes by norepinephrine or cold exposure, further amplifying the increase in D2 activity that results from catecholamine-stimulated de novo synthesis. Thus, deubiquitination regulates the supply of active thyroid hormone to brown adipocytes and other D2-expressing cells.


Variation in lycopene and lycopenoates, antioxidant capacity, and fruit quality of buffaloberry (Shepherdia argentea [Pursh]Nutt.).
Buffaloberry (Shepherdia argentea [Pursh] Nutt.) has historically been used as an important food source by North American indigenous peoples, but its commercial production has been limited. These plants produce fruits rich in carotenoid and phenolic antioxidants, which may have health benefits that may make buffaloberry commercially valuable. Here, we examined these constituents in the fruit of 7 Dakota-grown buffaloberry selections. Primary carotenoids were determined by liquid chromatography-mass spectral analysis and by nuclear magnetic resonance spectroscopy to be lycopene (0.27 ± 0.02 g/kg FW) and methyl apo-6'-lycopenoate (MA6L; 0.32 ± 0.03/kg FW). MA6L comprised the greatest proportion (55%) of carotenoid antioxidants, but its role in human nutrition is still to be evaluated. The fruit contained high total phenolics concentrations (9.06 ± 0.71 g gallic acid equivalents/kg FW). Hydrophilic antioxidant capacity among the 7 selections averaged 49.0 ± 6.6 mmol trolox equivalents/kg FW, respectively, as measured by ferric reducing ability of plasma assay. The soluble solids and titratable acids concentrations were 21% and 2.2%, respectively. This species is adapted to poor soils and can tolerate drier climates. In the Dakotas, buffaloberry flourishes on the American Indian Tribal Reservations, yielding copious amounts of health-beneficial fruit for fresh and processing markets, making it a potentially valuable new crop for marginal lands.


[Determination of the degree of similarity of cholera and NAG vibrios].
The numeric taxonomy taking into account 80 signs has demonstrated the similarity of NAG and cholera vibrios, the average similarity coefficient exceeding 80 %. Among NAG vibrios, 53 % of the strains have been found to deviate from the central strain of V. cholerae mainly with regard to their utilization of the sources of carbon. The use of the citrate sign for the study of the biological properties of NAG vibrios is proposed.


Evaluation of a community-based inner-city disease management program for postmyocardial infarction patients: a randomized controlled trial.
Disease management programs (DMPs) that use multidisciplinary teams and specialized clinics reduce hospital admissions and improve quality of life and functional status. Evaluations of cardiac DMPs delivered by home health nurses are required. Between August 1999 and August 2000 we identified consecutive patients admitted to hospital with elevated cardiac enzymes. Patients who agreed were randomly assigned to participate in a DMP or to receive usual care. The DMP included 6 home visits by a cardiac-trained nurse, a standardized nurses' checklist, referral criteria for specialty care, communication with the family physician and patient education. We measured readmission days per 1000 follow-up days for angina, congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD); all-cause readmission days; and provincial claims for emergency department visits, physician visits, diagnostic or therapeutic services and laboratory services. We screened 715 consecutive patients admitted with elevated cardiac markers between August 1999 and August 2000. Of those screened 71 DMP and 75 usual care patients met the diagnostic criteria for myocardial infarction, were eligible for visits from a home health nurse and consented to participate in the study. Readmission days for angina, CHF and COPD per 1000 follow-up days were significantly higher for usual care patients than for DMP patients (incidence density ratio [IDR] = 1.59, 95% confidence interval [CI] 1.27-2.00, p < 0.001). All-cause readmission days per 1000 follow-up days were significantly higher for usual care patients than for DMP patients (IDR = 1.53, 95% CI 1.37-1.71, p < 0.001). The difference in emergency department encounters per 1000 follow-up days was significant (IDR = 2.08, 95% CI 1.56-2.77, p < 0.001). During the first 25 days after discharge, there were significantly fewer provincial claims submitted for DMP patients than for usual care patients for emergency department visits (p = 0.007), diagnostic or therapeutic services (p = 0.012) and laboratory services (p = 0.007). The results provide evidence that an appropriately developed and implemented community-based inner-city DMP delivered by home health nurses has a positive impact on patient outcomes.


Real-World Evidence of the Cambridge Hybrid Closed-Loop App With a Novel Real-Time Continuous Glucose Monitoring System.
We evaluated the performance of the interoperable Cambridge hybrid closed-loop app with FreeStyle Libre 3 glucose sensor, and YpsoPump insulin pump in a real-world setting. Data from 100 users (63 adults [mean ± SD age 41.9 ± 14.0 years], 15 children [8.6 ± 5.2 years)] and 22 users of unreported age) for a period of 28 days were analyzed. Time in range (3.91- 10.0mmol/L) was 72.6 ± 11.1% overall. Time below range (<3.9mmol/L) was 3.1% (1.4-5.1) (median [interquartile range]). Auto-mode was active for 95.8% (91.8-97.9) of time. This real-world analysis suggests that the performance of Cambridge hybrid closed-loop app with this glucose sensor is comparable to other commercially available hybrid closed-loop systems.


Optimal Sedation in Patients Who Receive Neuromuscular Blocking Agent Infusions for Treatment of Acute Respiratory Distress Syndrome-A Retrospective Cohort Study From a New England Health Care Network.
Two previously published trials (ARDS et Curarisation Systematique [ACURASYS] and Reevaluation of Systemic Early Neuromuscular Blockade [ROSE]) presented equivocal evidence on the effect of neuromuscular blocking agent infusions in patients with acute respiratory distress syndrome (acute respiratory distress syndrome). The sedation regimen differed between these trials and also within the ROSE trial between treatment and control groups. We hypothesized that the proportion of deeper sedation is a mediator of the effect of neuromuscular blocking agent infusions on mortality. Retrospective cohort study. Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA). Intubated and mechanically ventilated ICU patients with acute respiratory distress syndrome (Berlin definition) admitted between January 2008 until June 2019. None. The proportion of deeper sedation was defined as days with nonlight sedation as a fraction of mechanical ventilation days in the ICU after acute respiratory distress syndrome diagnosis. Using clinical data obtained from a hospital network registry, 3,419 patients with acute respiratory distress syndrome were included, of whom 577 (16.9%) were treated with neuromuscular blocking agent infusions, for a mean (sd) duration of 1.8 (±1.9) days. The duration of deeper sedation was prolonged in patients receiving neuromuscular blocking agent infusions (4.6 ± 2.2 d) compared with patients without neuromuscular blocking agent infusions (2.4 ± 2.2 d; p < 0.001). The proportion of deeper sedation completely mediated the negative effect of neuromuscular blocking agent infusions on in-hospital mortality (p < 0.001). Exploratory analysis in patients who received deeper sedation revealed a beneficial effect of neuromuscular blocking agent infusions on mortality (49% vs 51%; adjusted odds ratio, 0.80; 95% CI, 0.63-0.99, adjusted absolute risk difference, -0.05; p = 0.048). In acute respiratory distress syndrome patients who receive neuromuscular blocking agent infusions, a prolonged, high proportion of deeper sedation is associated with increased mortality. Our data support the view that clinicians should minimize the duration of deeper sedation after recovery from neuromuscular blocking agent infusion.


A nonswellable gradient hydrogel with tunable mechanical properties.
Susceptibility of traditional hydrogels to water leads to the deterioration of their mechanical properties and dimensional instability. Inspired by bone tissues, here, we report a nonswellable gradient hydrogel with adjustable mechanical properties via a simple acid-heat treatment of polyamide-based hydrogels. Both the hydrophilicity/hydrophobicity and crosslinking degree of the gel can be simultaneously regulated by taking advantage of the conversion of amide groups to imide groups in the hydrogel. A gradient imide structure is formed with a dense layer near the surface of the gel. The resultant hydrogel has no size change both in water and 0.9 wt% NaCl solution while it shows high strength with a compressive stress of 70 MPa at 70% strain at a higher imidization degree. At a lower imidization degree, the gel has excellent fatigue resistance and resilience and can return to its original state after 5 cycles of 90% strain.


Rutaecarpine inhibited imiquimod-induced psoriasis-like dermatitis via inhibiting the NF-κB and TLR7 pathways in mice.
Psoriasis is a chronic, immune-mediated inflammatory skin disease. As psoriasis rarely occurs in nonhuman animals, the lack of an ideal animal model reflecting the histopathological and molecular immunological characteristics of psoriasis remains an urgent issue. In the present study, an imiquimod-induced psoriasis-like dermatitis mouse model was constructed under natural immune conditions and verified by evaluations of the Psoriasis Area and Severity Index (PASI) score and Baker score, H&E staining, immunohistochemical examination of the CD3 and Gr1 levels, measurement of plasmacytoid dendritic cell- (pDC) and Th17-associated cytokine levels, and evaluation of p65 phosphorylation and TLR7 expression. Moreover, rutaecarpine (RUT), the main active ingredient in the traditional Chinese medicine Wu-Zhu-Yu, could improve psoriasis-like dermatitis through effects on pDC- and Th17-associated cytokines through NF-κB and toll-like receptor 7 (TLR7) signaling. Taken together, the imiquimod-induced psoriasis-like dermatitis mouse model can be regarded as an ideal model for evaluating psoriasis pathogenesis and antipsoriatic drugs. We provided theoretical and experimental evidence for the clinical application of RUT in psoriasis.


Is Intraoperative Opioids Avoidance A Utopia? A Matched Study in Laparoscopic Hysterectomy.
Opioid-sparing strategies are recommended, and Opioid-Free Anaesthesia (OFA) is proposed in the literature. But few data exist about the feasibility of OFA in the routine practice. From a larger series of 21,463 patients receiving OFA, this work investigates the postoperative pain and related outcomes in patients undergoing laparoscopic hysterectomy. This matched retrospective study concerned 521 patients scheduled for a laparoscopic hysterectomy between 2010 and 2015 (118 receiving OFA and 403 receiving anaesthesia with opioids, AO). Primary outcome was pain in the Post-Anaesthetic Care Unit (PACU). Among the 521 included patients, 403 received sufentanil (mean±SD: 0.1±0.05 mcg/kg), the only synthetic opioid used to balance anaesthesia. Concerning the 118 patients receiving OFA, most of them received an association of clonidine (97%) and ketamine (95%). Most of the patients in both groups received non-steroidal anti-inflammatory drugs. No difference in pain scores was observed between AO and OFA (median [IQR], respectively: 4 [0-5] vs. 4.5 [0-6], P=0.74). A difference in the perioperative morphine equivalent use was observed (mean±SD: 0.18±0.06 mg/kg vs. 0.09±0.06 mg/kg, P<0.001). No difference was observed regarding the nausea/vomiting incidences, use of anti-emetics, sedation scores, or time spent at the PACU. Coming from an extensive daily practice, these data show that OFA is feasible and not associated with higher pain scores or longer PACU stay, suggesting the absence of specific immediate complications.


A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome--a randomized controlled trial with primary care physicians.
Therapy trials with bacterial compounds in irritable bowel syndrome (IBS) have produced conflicting results. This study was performed in 1988 and 1989, and was re-analysed according to current IBS standards. Two hundred ninety-seven patients with lower abdominal symptoms diagnosed as IBS were treated for 8 weeks by the compound ProSymbioflor((R)) (Symbiopharm GmbH, Herborn, Germany), an autolysate of cells and cell fragments of Enterococcus faecalis and Escherichia coli, or placebo in a double-blinded, randomized fashion. Patients were seen weekly by the physician, who assessed the presence of core IBS symptoms. Responders had at least a 50% decrease in global symptom score (GSS) and in abdominal pain score (APS) reports at >/=1 visit during treatment. The responder rate in GSS to the drug was 102/149 (68.5%) in comparison to placebo with 56/148 (37.8%) (P < 0.001), the improvement in APS was 108/149 (72.5%) and 66/148 (44.6%) respectively (P = 0.001). The number-needed-to-treat was 3.27 for GSS and 3.59 for the APS report. Kaplan-Meier analysis revealed a mean response time of 4-5 weeks for active treatment and more than 8 weeks for placebo (P < 0.0001). Treatment of IBS with the bacterial lysate ProSymbioflor is effective and superior to placebo in reducing typical symptoms of IBS patients seen by general practitioners.


Identification of the Acidobacterium capsulatum LexA box reveals a lateral acquisition of the Alphaproteobacteria lexA gene.
Acidobacterium capsulatum is the most thoroughly studied species of a new bacterial phylogenetic group designated the phylum Acidobacteria. Through a tblastn search, the A. capsulatum lexA gene has been identified, and its product purified. Electrophoretic mobility shift assays have shown that A. capsulatum LexA protein binds specifically to the direct repeat GTTCN(7)GTTC motif. Strikingly, this is also the LexA box of the Alphaproteobacteria, but had not previously been described outside this subclass of the Proteobacteria. In addition, a phylogenetic analysis of the LexA protein clusters together Acidobacterium and the Alphaproteobacteria, moving the latter away from their established phylogenetic position as a subclass of the Proteobacteria, and pointing to a lateral gene transfer of the lexA gene from the phylum Acidobacteria, or an immediate ancestor, to the Alphaproteobacteria. Lastly, in vivo experiments demonstrate that the A. capsulatum recA gene is DNA-damage inducible, despite the fact that a LexA-binding sequence is not present in its promoter region.


Extracellular targeting of an active endoxylanase by a TolB negative mutant of Gluconobacter oxydans.
Gluconobacter (G.) oxydans strains have great industrial potential due to their ability to incompletely oxidize a wide range of carbohydrates. But there is one major limitation preventing their full production potential. Hydrolysis of polysaccharides is not possible because extracellular hydrolases are not encoded in the genome of Gluconobacter species. Therefore, as a first step for the generation of exoenzyme producing G. oxydans, a leaky outer membrane mutant was created by deleting the TolB encoding gene gox1687. As a second step the xynA gene encoding an endo-1,4-β-xylanase from Bacillus subtilis was expressed in G. oxydans ΔtolB. More than 70 % of the total XynA activity (0.91 mmol h(-1) l culture(-1)) was detected in the culture supernatant of the TolB mutant and only 10 % of endoxylanase activity was observed in the supernatant of G. oxydans xynA. These results showed that a G. oxydans strain with an increased substrate spectrum that is able to use the renewable polysaccharide xylan as a substrate to produce the prebiotic compounds xylobiose and xylooligosaccharides was generated. This is the first report about the combination of the process of incomplete oxidation with the degradation of renewable organic materials from plants for the production of value-added products.


Effect of strontium ranelate on bone remodeling.
Osteoporosis is a disease in which the microarchitecture of bone tissue deteriorates, with consequent loss of bone mass. Strontium ranelate (SrR) is currently used for treatment of the condition. SrR may have a dual effect: anabolic (stimulating pre-osteoblast replication) and anti-catabolic (reducing osteoclastic activity). However, its mechanism of action has not yet been completely elucidated. The aim of this study is to evaluate the effect of SrR on bone remodeling in healthy Wistar rats. Two-month old female Wistar rats were administered SrR (2 g/L) in drinking water for 30 weeks. Oriented histological sections were prepared from lower jaw and tibia and stained with H&E, and the following histomorphometric parameters were evaluated: a) in interradicular bone: bone volume, and percentages of bone-formation, quiescent and bone-resorption surfaces; and b) in tibia: bone volume, total thickness of growth cartilage, thickness of hypertrophic cartilage zone and number of megakaryocytes. No significant difference was found in the parameters between the control animals and those treated with SrR. The results would therefore show that SrR does not alter the bone parameters studied in this experimental design.


Differential chemotactic behavior of developing T cells in response to thymic chemokines.
Differentiation-dependent thymocyte migration in the thymus may be important for T lymphopoiesis and might be regulated by thymic chemoattractants. We examined modulation of chemotactic responsiveness of thymocyte subsets during their early to late stages of development in response to 2 thymus-expressed chemokines, SDF-1 and CKbeta-11/MIP-3beta/ELC. SDF-1 shows chemotactic preference for immature thymocytes (subsets of triple negative thymocytes and double positive [DP] subset) over mature single positive (SP) thymocytes. CKbeta-11/MIP-3beta/ELC shows low chemotactic activity on the immature thymocytes, but it strongly attracts mature SP thymocytes, effects opposite to that of SDF-1. SDF-1-dependent chemoattraction of immature thymocytes is not significantly desensitized by a negative concentration gradient of CKbeta-11/MIP-3beta/ELC, and chemoattraction of mature SP thymocytes to CKbeta-11/MIP-3beta/ELC is not antagonized by SDF-1, demonstrating that these two chemokines have different chemoattractant preferences for thymocyte subsets and would probably not inhibit each other's chemotaxis in the event of microenvironmental coexpression. The chemotactic responsiveness of thymocytes and mature T cells to the 2 chemokines is respectively enhanced after selection process and migration to the spleen. These studies demonstrate the presence of thymocyte chemoattractants with differential chemotactic preference for thymocytes, a possible mechanism for thymocyte migration in the thymus.


Effect of head and neck positioning on cerebral perfusion during shoulder arthroscopy in beach chair position.
The aim of this prospective cohort study was to investigate the effect of head and neck positioning on cerebral perfusion during shoulder arthroscopy in the beach chair position. Regional cerebral tissue oxygen saturation (rSO2) was monitored intraoperatively using near-infrared spectroscopy on 51 consecutive patients undergoing arthroscopic shoulder surgery in the beach chair position. The head of each subject was manipulated by the examiner and sequentially positioned for 45 seconds in terminal flexion, extension, bilateral rotation, and bilateral lateral bending. Decreases in rSO2 of 20% or greater from baseline were defined as a cerebral desaturation event (CDE). The association between head and neck position and cerebral perfusion was assessed. Eight percent of patients (4/51) experienced CDE during head and neck positioning. Body mass index was found to be a risk factor for CDE (p = .05). When comparing preoperative baseline rSO2 to intraoperative supine and intraoperative upright rSO2, there was no significant decrease in saturation levels for any of the six tested positions. Frequent intraoperative evaluations of the head and neck position as well as careful preoperative positioning may reduce the risk of position-related complications in patients undergoing elective shoulder arthroscopy in the beach chair position. In this study's patient population, however, head and neck position was not found to cause significant cerebral desaturation for the time period tested compared to preoperative baselines.


The Role of pHi in Intestinal Epithelial Proliferation-Transport Mechanisms, Regulatory Pathways, and Consequences.
During the maturation of intestinal epithelial cells along the crypt/surface axis, a multitude of acid/base transporters are differentially expressed in their apical and basolateral membranes, enabling processes of electrolyte, macromolecule, nutrient, acid/base and fluid secretion, and absorption. An intracellular pH (pHi)-gradient is generated along the epithelial crypt/surface axis, either as a consequence of the sum of the ion transport activities or as a distinctly regulated entity. While the role of pHi on proliferation, migration, and tumorigenesis has been explored in cancer cells for some time, emerging evidence suggests an important role of the pHi in the intestinal stem cells (ISCs) proliferative rate under physiological conditions. The present review highlights the current state of knowledge about the potential regulatory role of pHi on intestinal proliferation and differentiation.


Bacillus subtilis MraY in detergent-free system of nanodiscs wrapped by styrene-maleic acid copolymers.
As an integral membrane protein, purification and characterization of phospho-N- acetylmuramyl- pentapeptide translocase MraY have proven difficult. Low yield and concerns of retaining stability and activity after detergent solubilization have hampered the structure-function analysis. The recently developed detergent-free styrene-maleic acid (SMA) co-polymer system offers an alternative approach that may overcome these disadvantages. In this study, we used the detergent free system to purify MraY from Bacillus subtilis. This allowed efficient extraction of MraY that was heterologously produced in Escherichia coli membranes into SMA-wrapped nanodiscs. The purified MraY embedded in these nanodiscs (SMA-MraY) was comparable to the micellar MraY extracted with a conventional detergent (DDM) with regard to the yield and the purity of the recombinant protein but required significantly less time. The predominantly alpha-helical secondary structure of the protein in SMA-wrapped nanodiscs was also more stable against heat denaturation compared to the micellar protein. Thus, this detergent-free system is amenable to extract MraY efficiently and effectively while maintaining the biophysical properties of the protein. However, the apparent activity of the SMA-MraY was reduced compared to that of the detergent-solubilized protein. The present data indicates that this is caused by a lower accessibility of the enzyme in SMA-wrapped nanodiscs towards its polyisoprenoid substrate.


Elbow Biomechanics, Radiocapitellar Joint Pressure, and Interosseous Membrane Strain Before and After Radial Head Arthroplasty.
Complex radial head fracture and elbow instability can be treated with radial head arthroplasty. Good clinical results have been described after this surgical treatment. However, the revision and complication rate reported in the literature is concerning. This might be due to altered kinematics after radial head arthroplasty. Eight human native elbows were examined with dynamic radiostereometric analysis and compared with a radial head arthroplasty. Translations of the radial head in the x-, y-, and z-directions relative to the humerus and the ulna were measured. The radiocapitellar joint pressure was measured using a pressure sensor. The tension within the interosseous membrane was measured using a custom-made strain gauge. After radial head arthroplasty, the radial head was displaced approximately 1.8 mm medially and 1.4 mm distally at the starting point. During unloaded flexion motion the difference in all translations between the native radial head and the radial head arthroplasty was less than 1 mm (95% confidence interval [CI] ± 0.5 mm) (p = 0.001). With loading the difference was less than 1.5 mm (95% CI ± 1.5 mm) (p = 0.001). The mean difference in radiocapitellar joint contact pressure was less than 0.30 MPa (95% CI ± 0.40 MPa) (p = 0.001) during unloaded flexion motion. There were only submillimetre kinematic changes and small changes in joint pressure and interosseous membrane tension after the insertion of a radial head arthroplasty in an experimental setting. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:510-522, 2020.


Chapter 27: Approach to primary immunodeficiency.
Primary immunodeficiency diseases (PID) are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections. There may be defects in the adaptive arm of the immune system that include combined immunodeficiency and antibody deficiency syndromes or by abnormalities in innate immunity such as disorders of phagocytes, the complement pathway, or Toll-Like receptor (TLR) mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenza type B or Streptococcus pneumoniae may be characteristic of an IgG antibody deficiency or dysfunction. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte dysfunction. Multiple staphylococcal skin infections and fungal infections may imply neutrophil dysfunction or the hyper-IgE syndrome, and recurrent neisserial infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections often without the presence of a significant inflammatory response suggest a defect in TLR signaling. Mycobacterial infections are characteristic of defects in interleukin (IL)-12, interferon (IFN) gamma, or their receptors. Screening of newborns for T-cell lymphopenia using a polymerase chain reaction to amplify T-cell receptor excision circles (TRECs), which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naïve T cells. Because of very low numbers of TRECs, severe combined immunodeficiency, DiGeorge syndrome, and other causes of T-cell lymphopenia have been identified in newborns.


Self-medication with antibiotics in Europe: a case for action.
Unlike most other drugs that only affect individual patients if used incorrectly for self-medication, misused antibiotics add to the global risk of increased spread of bacterial resistance. This review focuses on self-medication with antibiotics in Europe and its determinants. High prevalence of self-medication with antibiotics has been repeatedly found in Southern and Eastern European countries that also report high levels of antibiotic resistance. Despite being illegal, over the counter dispensation of systemic antibiotics occurs in several European Union Member States. A second major source of self-medication is the availability of "leftover" antibiotics which results from either patient non-compliance or dispensation of a larger number of tablets than needed for one single course. The potentially modifiable factors associated with self-medication are: availability of antibiotics without prescription, pack-based antibiotic dispensing system, misconceptions of the general public about the efficacy of antibiotics for minor illnesses and prescribing of antibiotics for minor ailments by physicians. Measures that may reduce and prevent self-medication include dispensation of exact tablet quantities in pharmacies as already implemented e.g. in the UK, Netherlands, the Czech Republic and the United States, and enforcement of existing laws prohibiting over-the-counter sales of antibiotics. Such measures should be embedded in a general policy to change the culture of antibiotic use by improving awareness of the general public and professionals about antibiotics and the risks associated with their use as well as reducing misconceptions about the need for antibiotics for minor ailments.