[Sevoflurane anesthesia in a patient with multiple sclerosis].
Multiple sclerosis (MS) is a disorder of the nervous system in which myelin breakdown is a prominent feature. We report a 65-yr-old woman scheduled for femoral neck prosthetic replacement under sevoflurane anesthesia, who had been suffering from a progressive type of MS for 27 years. Previously she had a history of exacerbation of symptoms after caudal block done for sciatic neuralgia. Stress such as surgery, anesthesia, emotional distress and variable body temperature can exacerbate the disease. Spinal and epidural block are relatively contraindicated in MS. Thiopental was reported to worsen MS. But there is no evidence that any of the volatile anesthetic agents has a deleterious effect on MS. Sevoflurane can be used to induce anesthesia quickly. To avoid thiopental, we chose slow induction with sevoflurane (GOS). Anesthesia was maintained with GOS. It seems that intraoperative hypotension which resists to ephedrine administration is partly due to autonomic abnormality. Yet, there is no report of sevoflurane anesthesia in MS patient. We consider that in this case sevoflurane is a safe anesthetic because of its less effect on postopreative neurological symptoms than that of epidural block.


An increased tendency in fibrinogen activity and its association with a hypo-fibrinolytic state in early stages after injury in patients without acute traumatic coagulopathy (ATC).
Acute traumatic coagulopathy (ATC) diagnosed by prolongation of APTT and/or PT/INR involves alterations in platelet activity, coagulation and fibrinolysis. However, data showing the haemostatic situation in injured patients without ATC are scarce. To assess whether haemostatic impairment is also present in injured patients without ATC, ten injured patients without ATC and ten normal individuals were examined. The patients were sampled on arrival at the emergency department 0, 2, 12 h after surgical or other intervention. Thrombin generation, fibrin formation and fibrin proteolysis were determined via several laboratory methods, using tissue factor as the coagulation trigger. Thrombograms demonstrated that trauma accelerated both thrombin generation and decay. In the presence of unaffected peak thrombin levels, these two contradictory effects cancelled each other out, leading to the global endogenous thrombin potential (ETP) remaining normal. Under the mediation of normal ETP, fibrin network permeability (Ks) kept the reference levels in the two groups of subjects. Fibrinogen (FBG) activity (Clauss) rose with time from 0 to 2 h and 12 h, which significantly slowed down Clot Lysis Potential as determined by an in vitro method with exogenous t-PA. the main haemostatic impairment in the present patients concerned an increased tendency in FBG activity. Since an increase in FBG is a biomarker of acute inflammation and also predicts greater fibrin production which down-regulates fibrinolysis, we suggest that during early stages after injury, patients without ATC may suffer from worsening inflammation and confront enhancement of thrombosis risk due to dysfunction of fibrinolysis.


Biologics in Asthma: A Molecular Perspective to Precision Medicine.
Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40-60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.


Recurrent Syncope, a Clue in Amyloid Cardiomyopathy.
Infiltrative cardiomyopathies include a variety of disorders that lead to myocardial thickening resulting in a constellation of clinical manifestations and eventually heart failure that could be the first clue to reach the diagnosis. Among the more described infiltrative diseases of the heart is amyloid cardiomyopathy. The disease usually presents with subtle, nonspecific symptoms. Herein, we illustrate a case of recurrent syncope as the initial presenting symptom for systemic amyloid with polyneuropathy and cardiomyopathy as a cause of syncope. The article illustrates the role of advanced cardiac imaging in the diagnosis of the disease with a focused literature review. We also highlight the role of early, shared decision-making between patient, family, and medical team in the management of cardiac amyloidosis.


The use of vesical irrigation system dual pump Endo FMS urology in the endoscopic therapy of the vesical neoplasms.
The objective of this study was to determine whether vesical irrigation during transurethral resection of bladder tumours (TURBT) with the dual pump system for the intracavitary irrigation Endo FMS Urology is more efficient than the standard gravity technique. One hundred patients suffering from vesical neoplasms underwent TURBT using the Endo FMS Urology (group A). They were compared to 100 patients previously (2002-2003) treated endoscopically for vesical tumours with the standard endovesical irrigation method (group B). We demonstrated a reduction of the average time of resection of 10% in favour of patients of group A, a reduction of 39% of the amount of fluid of vesical irrigated in favour of patients of group A. No differences were observed in the recurrence rate of tumours at 3 months and in need of endoscopic revision in the 48 hours following TURBT. Two patients required blood transfusion after TURBT in group B, none in group A. The average time of hospitalisation in group A was less than one day. On the basis of this experience the use of Endo FMS Urology Irrigation System in TURBT is strongly recommended.


The impact of resident involvement in breast reconstruction surgery outcomes by modality: An analysis of 4,500 cases.
The goal of this study was to determine the impact of resident involvement on various methods of breast reconstruction via an American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) retrospective analysis. We performed a retrospective analysis of the ACS NSQIP database to identify patients undergoing breast reconstruction by free flap, implant, latissimus dorsi (LD), and transverse rectus abdominis myocutaneous (TRAM) flap reconstruction modalities. Primary outcomes measured include major and wound complications. A total of 4,500 cases were included in this analysis, of which residents participated in 1,743 (38.7%). Major complications occurred in 7.2% of all cases, and wound complications occurred in 3.3% of all cases. BMI was positively correlated with major complications in free flap, implant, and TRAM reconstruction groups. Wound complications were associated with BMI in free flap, implant, and TRAM reconstruction, with steroid use in implant and TRAM reconstruction, and with a history of bleeding disorder in LD reconstruction. Resident involvement did not reach significance in any reconstruction group as an independent factor for major or wound complications. Resident involvement is safe and effective across implant, free flap, LD, and TRAM based methods of breast reconstruction with similar major and wound complication rates. Participation of trainees in these surgical cases is imperative for future patient care.


Metal-mediated reactions between dialkylcyanamides and acetamidoxime generate unusual (nitrosoguanidinate)nickel(ii) complexes.
The nitrosoguanidinate complexes [Ni{NH[double bond, length as m-dash]C(NR2)NN(O)}2] (R2 = Me21, (CH2)4O 2, (CH2)43, (CH2)54, (Me)Ph 5, Ph26, (p-MeC6H4)27) were obtained in low-to-moderate (12-26%) yields but reproducible yields in an unexpected metal-mediated reaction in MeOH between the nickel salt NiCl2·2H2O, N,N-disubstituted cyanamides NCNR2, and the amidoxime MeC([double bond, length as m-dash]NOH)NH2. These complexes were formed along with a spectrum of cyanamide-oxime coupling products. The IR and X-ray data indicate the delocalization within the NNO and NCN systems of the nitrosoguanidinate ligand. This delocalization was additionally confirmed by inspection of Wiberg bond indices for the selected bonds. In the X-ray structure of 5, the rare metallophilic contacts NiNi between stacks of the square-planar complexes were detected and these non-covalent interactions were studied by non-relativistic and relativistic DFT calculations and topological analysis of the electron density distribution within the framework of Bader's theory (QTAIM method). The estimated strength of the NiNi interactions is 1.3-1.9 kcal mol-1 and they are mostly determined by crystal packing effects and weak attractive interactions between adjacent metal centers due to the overlapping of their dz2 and pz orbitals.


[The prevalence of dementia in Denmark].
The exact prevalence of dementia in Denmark is unknown. Based on epidemiological data we have calculated possible estimates for the present Danish prevalence of dementia and prevalence projections through to 2030. The discrepancy between estimates based on epidemiological studies and the number of dementia diagnoses in registers indicates that dementia may be underdiagnosed. Even though results from recent epidemiological studies point to a possible decline in incidence we expect the future prevalence of dementia to increase due to an expected increase of the elderly population.


Chroococcidiopsis and heterocyst-differentiating cyanobacteria are each other's closest living relatives.
Many filamentous cyanobacteria reduce atmospheric nitrogen in specialized differentiated cells called heterocysts. Here we present evidence that shows that members of the unicellular non-heterocyst-differentiating genus Chroococcidiopsis and the filamentous heterocyst-differentiating cyanobacteria are each other's closest living relatives. Distance, maximum-parsimony, and maximum-likelihood analyses of complete small subunit ribosomal RNA gene sequences yielded highly congruent support for the monophyly of Chroococcidiopsis and the heterocyst-differentiating cyanobacteria. Our results demonstrate that the order Pleurocapsales, which traditionally contains Chroococcidiopsis, is a polyphyletic assemblage with the ability to reproduce by multiple fission having arisen independently at least twice during the cyanobacterial radiation. Our data also reject Myxosarcina as a sister taxon to Chroococcidiopsis, indicating that the numerous presumed shared derived characters thought to unite the two genera evolved independently. The sequence divergence within the Chroococcidiopsis lineage is comparable to and probably exceeds that in the entire heterocyst-differentiating lineage. Chroococcidiopsis forms unique survival cells under nitrogen-limiting conditions, and the sister group relationship with the heterocystous cyanobacteria shown here suggests that differentiation of these cells and heterocysts may be related processes.


Outbreak of Salmonella Typhimurium associated with feeder rodents.
In December 2012, an increase in human Salmonella Typhimurium cases was identified in the province of Ontario, Canada launching an outbreak investigation. The outbreak spanned 3 years (2012-2014), with 134 cases reported from five Canadian provinces. There was a substantial burden of illness among children: 45% of cases were children 12 years old or under, and 23% of cases were under 5 years old. Epidemiologic, traceback and laboratory findings linked this outbreak to feeder rodents (used to feed snakes) supplied by a network of rodent breeders in Ontario. Cases likely acquired their illness through either direct or indirect contact with feeder rodents. This investigation not only contributes to the weight of evidence on the risk that feeder rodents pose, but also underscores the importance of investigating indirect animal contact and associated risks, especially for high-risk individuals.


Natriuretic hormones, endogenous ouabain, and related sodium transport inhibitors.
The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NHs). In addition to the atrial peptides (APs), the circulation contains unidentified physiologically relevant NHs. One NH is controlled by the central nervous system (CNS) and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide (NO). Both NHs have short (<35 min) circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS) including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress NO in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain-like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority.


Resolving the mechanisms underlying epithelial-to-mesenchymal transition of the lateral plate mesoderm.
Formation of the vertebrate limb buds begins with a localized epithelial-to-mesenchymal transition (EMT) of the somatic lateral plate mesoderm (LPM). While the processes that drive proliferation and outgrowth of the limb mesenchyme are well established, the fundamental mechanisms that precede this process and initiate EMT are less understood. In this review, we outline putative drivers of EMT of the LPM, drawing from analyses across a range of vertebrates and developmental models. We detail the expression patterns of key EMT transcriptional regulators in the somatic LPM of the presumptive limb fields, and their potential role in producing a mesenchymal cell fate. These include a putative cooperative role between the EMT inducers PRRX1 and TWIST1, supported by evidence in zebrafish and chicken models but unconfirmed data from mice. As such, additional functional data are required to definitively determine the mechanisms that initiate and drive EMT of the somatic LPM, a critical transition preceding formation of the limb bud mesenchyme.


Shape mode analysis exposes movement patterns in biology: flagella and flatworms as case studies.
We illustrate shape mode analysis as a simple, yet powerful technique to concisely describe complex biological shapes and their dynamics. We characterize undulatory bending waves of beating flagella and reconstruct a limit cycle of flagellar oscillations, paying particular attention to the periodicity of angular data. As a second example, we analyze non-convex boundary outlines of gliding flatworms, which allows us to expose stereotypic body postures that can be related to two different locomotion mechanisms. Further, shape mode analysis based on principal component analysis allows to discriminate different flatworm species, despite large motion-associated shape variability. Thus, complex shape dynamics is characterized by a small number of shape scores that change in time. We present this method using descriptive examples, explaining abstract mathematics in a graphic way.


Ultrathin 2D Cerium-Based Metal-Organic Framework Nanosheet That Boosts Selective Oxidation of Inert C(sp3 )H Bond through Multiphoton Excitation.
The development of methodologies for inducing and tailoring activities of catalysts is an important issue in various catalysis. The ultrathin 2D monolayer metal-organic framework (MOF) nanosheets with more accessible active sites and faster diffusion obtained by exfoliating 3D layered MOFs are of great potential as heterogeneous catalysts, but the rational design and preparation of 3D layered MOFs remains a grand challenge. Herein, a novel weak electrostatic interaction strategy to construct a 3D layered cerium-bearing MOF by coordinating chlorine-capped cerium nodes and linear photoactive methyl viologen (MV+ ) organic linkers is used. Under multiphoton excitation, the MV+ ligands and CeCl chromophores are triggered consecutively to form the high activity chlorine radical (Cl• ) for activation of inert C(sp3 )H bond through a hydrogen atom transfer. Benefiting from framework confinement effects, synergistic effects of two active sites and/or flexibility of the ultrathin framework nanosheets with high surface utilization, the observed activities increase in the order CeCl3 /MV+ < bulk 3D MOF crystals < 2D MOF nanosheets in photocatalysis. This work not only contributes a new strategy to construct 3D layered MOFs and their ultrathin nanosheets but also paves the way to use nanostructured MOFs to handle synergy of multiple molecular catalysts.


Adrenergic Reprogramming of Preexisting Adipogenic Trajectories Steer Naïve Mural Cells Toward Beige Differentiation.
In adult white adipose tissue, cold or β3-adrenoceptor activation promotes the appearance of thermogenic beige adipocytes. Our comprehensive single-cell analysis revealed that these cells arise through the reprogramming of existing adipogenic trajectories, rather than from a single precursor. These trajectories predominantly arise from SM22-expressing vascular mural progenitor cells. Central in this transition is the activation of Adrb3 in mature adipocytes, leading to subsequent upregulation of Adrb1 in primed progenitors. Under thermoneutral conditions, synergistic activation of both Adrb3 and Adrb1 recapitulates the pattern of cold-induced SM22+ cell recruitment. Lipolysis-derived eicosanoids, specifically docosahexaenoic acid (DHA) and arachidonic acid (AA) prime these processes and in vitro, were sufficient to recapitulate progenitor cells priming. Collectively, our findings provide a robust model for cold-induced beige adipogenesis, emphasizing a profound relationship between mature adipocytes and mural cells during cold acclimation, and revealing the metabolic potential of this unique cellular reservoir.


Gaussian kinetic model for granular gases.
A kinetic model for the Boltzmann equation is proposed and explored as a practical means to investigate the properties of a dilute granular gas. It is shown that all spatially homogeneous initial distributions approach a universal "homogeneous cooling solution" after a few collisions. The homogeneous cooling solution (HCS) is studied in some detail and the exact solution is compared with known results for the hard sphere Boltzmann equation. It is shown that all qualitative features of the HCS, including the nature of overpopulation at large velocities, are reproduced by the kinetic model. It is also shown that all the transport coefficients are in excellent agreement with those from the Boltzmann equation. Also, the model is specialized to one having a velocity independent collision frequency and the resulting HCS and transport coefficients are compared to known results for the Maxwell model. The potential of the model for the study of more complex spatially inhomogeneous states is discussed.


Promoting interprofessional collaboration in oncology through a teamwork skills simulation programme.
Outcomes in clinical oncology can be improved when care is delivered by high-performance teams. The purpose of the initiative described in this article was to develop interprofessional team training opportunities using simulated cancer care scenarios to enhance collaborative practice skills within clinical oncology. Scenarios were developed based on internal needs assessment and review of patient safety data. Paired teams of haematology-oncology nurses and fellows completed the patient management scenarios, followed by debriefing and performance feedback. Research design consisted of an observational case study and questionnaire of participants in a cross-sectional analysis. Twenty-three learners participated in two separate sessions. All participants responded with scores of 4-5 on a 5-point Likert scale regarding the perceived value of the training programme and its effectiveness in developing skills in teamwork and communication. Simulation-based team training scenarios were successfully implemented into an interprofessional curriculum for haematology-oncology nurses and fellows. Participants valued the experience and indicated that they acquired new knowledge, skills, and attitudes to enhance interprofessional collaboration in cancer care. These types of training programmes have the potential to transform cancer care by creating high-performing teams resulting in improved patient outcomes, enhanced clinical effectiveness, and higher levels of satisfaction among patients, families, and healthcare providers.


Epidemiologic and laboratory observations of Chlamydia psittaci infection in pet birds.
Psittacosis was diagnosed in 13 (24%) of 55 pet bird submissions in the first 3 months of 1983, compared with 18 (17%) of 103 in 1982, 4 (4.6%) of 87 in 1981, and 3 (8%) of 36 in 1980. The numbers and types of birds in which psittacosis was diagnosed were 2 of 47 budgerigars, 8 of 45 cockatiels , 3 of 11 small parrots ( lovebirds , conures ), 20 of 116 medium-sized parrots (African Grays, Amazons ), 2 of 21 macaws , and 3 of 21 cockatoos . Thirty-nine percent of psittacosis-positive birds were received from pet bird owners, compared with 21% from pet shops, 18% from pet bird breeders and fanciers, and 13% from pet bird jobbers and retailers . Most frequently observed clinical signs were anorexia, weight loss, and diarrhea or yellowish droppings. Major gross lesions were splenohepatomegaly (77%), followed by enteritis (53%), sinusitis (47%), airsacculitis (37%), pneumonitis (23%), and pericarditis (10%). Regarding the 38 cases of confirmed psittacosis in pet birds since 1980, transmission of the disease to human beings was confirmed in 2 cases and suspected in 4 cases.


Traveller's diarrhoea.
Dietary indiscretion is penalized by an increased risk of diarrhoea. Severe dehydration is seldom encountered, and fluid losses are easily corrected with readily available fluids. Drug treatment is either directed at suppressing the pathogen or for its anti-secretory effect.


Making the case: using case studies for staff development.
The case study is a popular teaching strategy frequently used in academic settings. Currently, little evidence is found to support hospital-based educators using case studies to promote enhanced problem-solving, decision-making, and critical-thinking abilities. Department orientation and the improvement of patient outcomes are two examples of the use of case studies discussed in this article. Criteria for choosing and implementing an effective case study also are reviewed.


CEA vs. stent in patients with acute strokes: are they equally effective?
Stroke is the 3rd leading cause of death worldwide with 15 million strokes annually. Extracranial carotid stenosis contributes to major stroke morbidity and mortality as a significant etiology of ischemic strokes. For acute stroke, in addition to optimal medical management, patients may be candidates for carotid endarterectomy and/or carotid stenting for secondary stroke reduction. This paper set out to review the data currently available regarding equivalency of the two intervention options. A comprehensive literature review was performed through PubMed and other sources using the key words carotid endarterectomy, carotid artery stent, acute stroke, symptomatic carotid stenosis, flow reversal, TCAR. Studies which solely evaluated patients with asymptomatic disease were ineligible for the study. Review of landmark trials such as NASCET and CREST in addition to more recent studies demonstrates the effectiveness of surgical management with carotid endarterectomy of acute stroke. Carotid stenting has also been shown to have acceptable outcomes in certain patient populations. Carotid endarterectomy continues to demonstrate effectiveness and safety for management of acute stroke, while carotid stenting has limitations. Carotid artery stenting has been shown to be non-inferior in some patient populations, but more recent and future technologic developments may expand the potential acceptable patient selection criteria.


[Pneumococcal vaccine and influenza vaccine for prevention of exacerbation in patients with COPD].
Patients with chronic obstructive pulmonary diseases (COPD) are frequently exposed to infectious agents including influenza virus and Streptococcus pneumoniae. These infectious agents cause pneumonia and exacerbation of COPD. Prevention as well as anti-microbial treatments is critical for COPD. International guideline recommends that all COPD patients should be vaccinated against influenza virus. While pneumococcal vaccine is recommended for older and severe cases at present. Recently additive effect of pneumococcal vaccine and influenza vaccine are shown.


Characteristics of TCRζ, ZAP-70, and FcɛRIγ gene expression in patients with T- and NK/T-cell lymphoma.
Abnormal expression of key signaling molecules and defective T-cell function play a crucial role in the pathogenesis of T-cell immunodeficiency in hematological malignancies. To understand the molecular basis of T-cell signaling abnormalities and TCRζ chain deficiencies in T- and NK/T-cell lymphoma, the expression level of the TCRζ, ZAP-70, and FcɛRIγ genes in peripheral blood mononuclear cells from 25 patients with T-cell lymphoma, 16 patients with NK/T-cell lymphoma (NK/T-CL), and 26 healthy individuals was determined. In addition, their relationship with disease stage and TCRζ 3' untranslated region (3'UTR) splice variants was analyzed in this study. The expression level of all three genes was significantly altered with disease progression, and a decreasing trend was found in patients compared with healthy controls. TCRζ and ZAP-70 were significantly positively related in all samples, and a negative relationship between TCRζ and FcɛRIγ was significantly lost in NK/T-CL patients. Moreover, distinct expression patterns were defined for patient groups with different TCRζ 3'UTR isoforms. In conclusion, a lower expression pattern for all three genes may indicate a weaker immune status based on reduced TCRζ and ZAP-70 expression without the complementary effects of FcɛRIγ, while aberrant TCRζ 3'UTR splicing may contribute to T-cell receptor (TCR) signaling regulation in T cells from patients with T- and NK/T-cell lymphoma.


Gastroesophageal reflux: how much imaging is required?
The authors present a protocol for the selection of imaging studies for infants suspected of gastroesophageal reflux. In most cases, only a single imaging procedure is required. Three groups of patients are considered: those suspected of an esophageal or postgastric obstruction who require a barium GI series; those who appear to have reflux and a possible gastric obstruction in whom sonographic study of the gastric outlet is advised; and those suspected of aspirating in whom the possibility of reflux is studied by scintigraphy. Esophagoscopy and other studies are reserved for those refractory to therapy.


Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate.
Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection.


Platelets and plasma stimulate sheep rotator cuff tendon tenocytes when cultured in an extracellular matrix scaffold.
The addition of platelet-rich plasma (PRP) to rotator cuff repair has not translated into improved outcomes after surgery. However, recent work stimulating ligament healing has demonstrated improved outcomes when PRP or whole blood is combined with an extracellular matrix carrier. The objective of this study was to evaluate the effect of three components of blood (plasma, platelets, and macrophages) on the in vitro activity of ovine rotator cuff cells cultured in an extracellular matrix environment. Tenocytes were obtained from six ovine infraspinatus tendons and cultured over 14 days in an extracellular matrix scaffold with the following additives: (1) plasma (PPP), (2) plasma and platelets (PAP), (3) plasma and macrophages (PPPM), (4) plasma, platelets and macrophages (PAPM), (5) phosphate buffered saline (PBS), and (6) PBS with macrophages (PBSM). Assays measuring cellular metabolism (AlamarBlue), proliferation (Quantitative DNA assay), synthesis of collagen and cytokines (SIRCOL, TNF-α and IL-10 ELISA, and MMP assay), and collagen gene expression (qPCR) were performed over the duration of the experiment, as well as histology at the conclusion. Plasma was found to stimulate cell attachment and spreading on the scaffold, as well as cellular proliferation. Platelets also stimulated cell proliferation, cellular metabolism, transition of cells to a myofibroblast phenotype, and contraction of the scaffolds. The addition of macrophages did not have any significant effect on the sheep rotator cuff cells in vitro. In vivo studies are needed to determine whether these changes in cellular function will translate into improved tendon healing.


The Effect of WeChat on Parental Care Burden, Anxiety, and Depression in Children after CHD Surgery during COVID-19 Pandemic.
This study aimed to explore the effect of applying WeChat in the follow-up and health education of children after congenital heart disease (CHD) surgery during the coronavirus disease 2019 (COVID-19) epidemic. Data from 135 children were retrospectively analyzed. The care burden, anxiety, depression, and satisfaction of the parents of patients at home were analyzed and compared. One month after discharge, the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Zarit Burden Interview (ZBI), and Patient Satisfaction Questionnaire-18 scores of the WeChat follow-up group were significantly better than those of the outpatient follow-up group (p < 0.05). Compared with the discharge time, the SAS, SDS, and ZBI scores were significantly improved in the WeChat follow-up group but not in the outpatient follow-up group (p < 0.05). During the COVID-19 epidemic, the application of WeChat to the follow-up management of children after CHD surgery can effectively reduce care burden and relieve anxiety and depression in parents at home. It can also improve the satisfaction of parents with medical treatment.


On-chip coherent detection with quantum limited sensitivity.
While single photon detectors provide superior intensity sensitivity, spectral resolution is usually lost after the detection event. Yet for applications in low signal infrared spectroscopy recovering information about the photon's frequency contributions is essential. Here we use highly efficient waveguide integrated superconducting single-photon detectors for on-chip coherent detection. In a single nanophotonic device, we demonstrate both single-photon counting with up to 86% on-chip detection efficiency, as well as heterodyne coherent detection with spectral resolution f/∆f exceeding 1011. By mixing a local oscillator with the single photon signal field, we observe frequency modulation at the intermediate frequency with ultra-low local oscillator power in the femto-Watt range. By optimizing the nanowire geometry and the working parameters of the detection scheme, we reach quantum-limited sensitivity. Our approach enables to realize matrix integrated heterodyne nanophotonic devices in the C-band wavelength range, for classical and quantum optics applications where single-photon counting as well as high spectral resolution are required simultaneously.


Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways.
Azithromycin is effective at controlling exaggerated inflammation and slowing the long-term decline of lung function in patients with cystic fibrosis. We previously demonstrated that the drug shifts macrophage polarization toward an alternative, anti-inflammatory phenotype. In this study we investigated the immunomodulatory mechanism of azithromycin through its alteration of signaling via the NF-κB and STAT1 pathways. J774 murine macrophages were plated, polarized (with IFN-γ, IL-4/-13, or with azithromycin plus IFN-γ) and stimulated with LPS. The effect of azithromycin on NF-κB and STAT1 signaling mediators was assessed by Western blot, homogeneous time-resolved fluorescence assay, nuclear translocation assay, and immunofluorescence. The drug's effect on gene and protein expression of arginase was evaluated as a marker of alternative macrophage activation. Azithromycin blocked NF-κB activation by decreasing p65 nuclear translocation, although blunting the degradation of IκBα was due, at least in part, to a decrease in IKKβ kinase activity. A direct correlation was observed between increasing azithromycin concentrations and increased IKKβ protein expression. Moreover, incubation with the IKKβ inhibitor IKK16 decreased arginase expression and activity in azithromycin-treated cells but not in cells treated with IL-4 and IL-13. Importantly, azithromycin treatment also decreased STAT1 phosphorylation in a concentration-dependent manner, an effect that was reversed with IKK16 treatment. We conclude that azithromycin anti-inflammatory mechanisms involve inhibition of the STAT1 and NF-κB signaling pathways through the drug's effect on p65 nuclear translocation and IKKβ.


In vitro antibacterial activity of trovafloxacin and five other fluoroquinolones.
The in vitro inhibitory and bactericidal activities of the investigational fluoroquinolone trovafloxacin were studied and compared with those of five other fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin, rufloxacin and sparfloxacin) against a wide range of clinical isolates from Italian hospitals. Against gram-positive bacteria, trovafloxacin was overall more active than the other antibiotics tested, including sparfloxacin, another gram-positive-oriented fluoroquinolone, and was active against all ciprofloxacin-resistant streptococci, enterococci, and listeriae, all ciprofloxacin-resistant Staphylococcus aureus isolates and most ciprofloxacin-resistant coagulase-negative staphylococci. Its antistaphylococcal activity was not affected by oxacillin resistance or susceptibility of the isolates, nor was its antipneumococcal activity affected by whether isolates were susceptible or resistant to penicillin. Against gram-negative bacteria, trovafloxacin retained a high potency mostly comparable with that of ciprofloxacin. Rufloxacin and pefloxacin were less active than the other fluoroquinolones against most test strains of both gram-positive and gram-negative organisms. Trovafloxacin minimal bactericidal concentrations usually equalled or exceeded by 2-4 times the minimal inhibitory concentration values, indicating that the compound is overall highly bactericidal.


Carbon-13 nuclear magnetic resonance studies of the selectively isotope-labeled reactive site peptide bond of the basic pancreatic trypsin inhibitor in the complexes with trypsin, trypsinogen, and anhydrotrypsin.
A previously characterized modification of the basic pancreatic trypsin inhibitor (BPTI), with the carbonyl carbon atom of Lys-15 selectively enriched in 13C, the peptide bond Arg-39--Ala-40 cleaved, and Arg-39 removed, was used for 13C NMR studies of the reactive site peptide bond Lys-15--Ala-16 in the complexes with trypsin, trypsinogen, and anhydrotrypsin. The chemical shift of [1-13C]Lys-15 was 175.7 ppm in the free inhibitor, 176.4 ppm in the complexes with trypsin and anhydrotrypsin and the ternary complex with trypsinogen and H-Ile-Val-OH, and 175.7 ppm in a neutral solution containing the inhibitor and trypsinogen. These data show that the trypsin--BPTI complex does not contain a covalent tetrahedral carbon atom in the position of the reactive site peptide carbonyl of the inhibitor. They would be consistent with the formation of a noncovalent complex but cannot at present be used to further characterize the degree of a possible pyramidalization of the carbonyl carbon of Lys-15 in such a complex. The identical chemical shifts in the complexes with trypsin and anhydrotrypsin indicate that the gamma-hydroxyl group of Ser-195 of trypsin does not have an important role in the binding of the inhibitor. The previously described [Perkins, S. J. & Wüthrich, K. (1980) J. Mol. Biol. 138, 43--64] stepwise transition from the trypsinogen conformation to an intermediate conformational state in the trypsinogen--BPTI complex and a trypsin-like conformation in the ternary complex trypsinogen--BPTI--H-Ile-Val-OH appears to be manifested also in the chemical shift of [1-13C]Lys-15 of labeled BPTI.


Oncological outcomes of laparoscopic versus open gastrectomy after neoadjuvant chemotherapy for locally advanced gastric cancer: a retrospective multicenter study.
The oncological outcomes of laparoscopic gastrectomy (LG) and open gastrectomy (OG) following neoadjuvant chemotherapy have been investigated in a few studies. Our purpose was to evaluate the oncological outcomes of LG and OG after neoadjuvant chemotherapy in patients with locally advanced gastric cancer (GC) and to determine the advantages, preferences, and ease of use of the two techniques after chemotherapy. We conducted a retrospective chart review of all patients who underwent either OG (n = 43) or LG (n = 41). The neoadjuvant treatment regimen consisted of capecitabine plus oxaliplatin for three cycles, which was then repeated 6 to 12 weeks after the operation for four cycles. The hospital stay time and intraoperative blood loss in the LG group were significantly lower than those in the OG group. The mortality rate and the 3-year survival rate for patients in the LG group were comparable to those of patients in the OG group (4.6% vs. 9.7% and 68.3% vs. 58.1%, respectively). Similar trends were observed regarding the 3-year recurrence rate and metastasis. The mean survival time was 52.9 months (95% confidence interval [CI], 44.2-61.6) in the OG group compared with 43.3 (95% CI, 36.6-49.8) in the LG group. Likewise, the mean disease-free survival was 56.1 months (95% CI, 46.36-65.8) in the LG group compared with 50.9 months (95% CI, 44.6-57.2) in the OG group. LG is a feasible and safe alternative to OG for patients with locally advanced GC receiving neoadjuvant chemotherapy.


Assessment of glucagon-like peptide-1 analogue and renin inhibitor on the binding and regulation of GLP-1 receptor in type 1 diabetic rat hearts.
This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with (125)I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.


The Collapse and Expansion of Liquid-Filled Elastic Channels and Cracks.
The rate at which fluid drains from a collapsing channel or crack depends on the interaction between the elastic properties of the solid and the fluid flow. The same interaction controls the rate at which a pressurized fluid can flow into a crack. In this paper, we present an analysis for the interaction between the viscous flow and the elastic field associated with an expanding or collapsing fluid-filled channel. We first examine an axisymmetric problem for which a completely analytical solution can be developed. A thick-walled elastic cylinder is opened by external surface tractions, and its core is filled by a fluid. When the applied tractions are relaxed, a hydrostatic pressure gradient drives the fluid to the mouth of the cylinder. The relationship between the change in dimensions, time, and position along the cylinder is given by the diffusion equation, with the diffusion coefficient being dependent on the modulus of the substrate, the viscosity of the fluid, and the ratio of the core radius to the exterior radius of the cylinder. The second part of the paper examines the collapse of elliptical channels with arbitrary aspect ratios, so as to model the behavior of fluid-filled cracks. The channels are opened by a uniaxial tension parallel to their minor axes, filled with a fluid, and then allowed to collapse. The form of the analysis follows that of the axisymmetric calculations, but is complicated by the fact that the aspect ratio of the ellipse changes in response to the local pressure. Approximate analytical solutions in the form of the diffusion equation can be found for small aspect ratios. Numerical solutions are given for more extreme aspect ratios, such as those appropriate for cracks. Of particular note is that, for a given cross-sectional area, the rate of collapse is slower for larger aspect ratios. With minor modifications to the initial conditions and the boundary conditions, the analysis is also valid for cracks being opened by a pressurized fluid.


Massive myocardial calcification of right and left ventricles following acute myocarditis complicated with rhabdomyolysis-induced acute renal failure.
A 26-year-old man was admitted with a high fever, oliguria, skeletal muscle weakness, and cardiogenic shock which led to a diagnosis of acute myocarditis and acute rhabdomyolysis. During treatment with hemodialysis and calcium supplementation, because of severe hypocalcemia, a massive calcification of both right and left ventricular myocardium gradually became apparent with repeated computed tomographic (CT) examinations. Technetium-99m scannings more clearly delineated the markedly accumulated calcium in the myocardium, while significant activity was not detected in other soft tissues. Histopathological examinations by myocardial biopsy revealed a large amount of fibrosis and calcium deposits, and serial CT scans showed a gradual regression of the calcium deposition, suggesting that this rare form of massive dystrophic calcification may parallel changes in the severity of myocarditis, and may be associated with abnormalities in calcium metabolism secondary to rhabdomyolysis-induced acute renal failure.


Lung cysts associated with Pneumocystis carinii pneumonia: radiographic characteristics, natural history, and complications.
The purpose of our study was to characterize the radiographic features of thin-walled air-filled structures (cysts) related to Pneumocystis carinii pneumonia in a large series of patients, determine the natural history of the cysts, and test the hypothesis that the cysts are associated with an increased risk of pneumothorax. Of 100 patients with proved pneumocystis pneumonia, 34 (34%) had cysts shown on chest radiographs. The size, number, and location of the cysts and their natural history and association with pneumothorax were determined. A control group consisting of a random sample of 30 patients was selected from the 66 patients who had pneumocystis pneumonia but no cysts to assess the frequency of pneumothorax in this population. Of 34 patients with cysts, 32 (94%) had multiple cysts that were 1.0-5.0 cm in diameter. Most cysts were in the upper part of the lungs. Most patients had complete or partial resolution of the cysts after the acute episode of pneumonia. Pneumothoraces occurred in 12 (35%) of the 34 patients with cysts, but in only two (7%) of the 30 who did not have cysts (p = .007). Cysts related to pneumocystis pneumonia are usually multiple, occur most often in the upper parts of the lungs, and tend to decrease in size or resolve after the acute stage of the infection. In patients with pneumocystis pneumonia, the prevalence of pneumothorax is significantly higher in those who have cysts than in those who do not. The cysts are similar to pneumatoceles and the high prevalence of pneumothorax may be due to the subpleural location of some cysts.


Administration of intravenous fluids and medicines in children and young people.
Managing intravenous (IV) access is a standard proficiency for UK nurses, enabling them to administer IV injections and IV infusions and to manage injection equipment and infusion pumps and devices. In this article the author describes various types of venous access devices that are commonly seen in practice and details the preparation, checking and administration of IV fluids and medicines, including some complications that may arise. The author also discusses the calculation of fluid requirements, types of IV fluids, displacement values and ongoing care of venous access devices.


Genotypic distribution of multidrug-resistant and extensively drug-resistant tuberculosis in northern Thailand.
Multidrug/extensively drug-resistant tuberculosis (M/XDR-TB) is a major public health problem, and early detection is important for preventing its spread. This study aimed to demonstrate the distribution of genetic site mutation associated with drug resistance in M/XDR-TB in the northern Thai population. Thirty-four clinical MTB isolates from M/XDR-TB patients in the upper northern region of Thailand, who had been identified for drug susceptibility using the indirect agar proportion method from 2005 to 2012, were examined for genetic site mutations of katG, inhA, and ahpC for isoniazid (INH) drug resistance and rpoB for rifampicin (RIF) drug resistance. The variables included the baseline characteristics of the resistant gene, genetic site mutations, and drug susceptibility test results. All 34 isolates resisted both INH and RIF. Thirty-two isolates (94.1%) showed a mutation of at least 1 codon for katG, inhA, and ahpC genes. Twenty-eight isolates (82.4%) had a mutation of at least 1 codon of rpoB gene. The katG, inhA, ahpC, and rpoB mutations were detected in 20 (58.7%), 27 (79.4%), 13 (38.2%), and 28 (82.3%) of 34 isolates. The 3 most common mutation codons were katG 315 (11/34, 35.3%), inhA 14 (11/34, 32.4%), and inhA 114 (11/34, 32.4%). For this population, the best genetic mutation test panels for INH resistance included 8 codons (katG 310, katG 340, katG 343, inhA 14, inhA 84, inhA 86, inhA 114, and ahpC 75), and for RIF resistance included 6 codons (rpoB 445, rpoB 450, rpoB 464, rpoB 490, rpoB 507, and rpoB 508) with a sensitivity of 94.1% and 82.4%, respectively. The genetic mutation sites for drug resistance in M/XDR-TB are quite variable. The distribution of these mutations in a certain population must be studied before developing the specific mutation test panels for each area. The results of this study can be applied for further molecular M/XDR-TB diagnosis in the upper northern region of Thailand.


Hydrogen sulfide protects against amyloid beta-peptide induced neuronal injury via attenuating inflammatory responses in a rat model.
Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides (Aβ). In the present study, we examined the neuroprotective effects of hydrogen sulfide (H2S) on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS (a donor of H2S, 5.6 mg/kg/d, i.p.) treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aβ-induced rat model and has potential value for AD therapy.


In vivo pharmacokinetics and pharmacodynamics of the lantibiotic NAI-107 in a neutropenic murine thigh infection model.
NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose fractionation included total doses ranging from 1.56 to 400 mg/kg/72 h, divided into 1, 2, 3, or 6 doses. Studies of treatment effects against 9 S. aureus strains (4 methicillin-susceptible Staphylococcus aureus [MSSA] and 5 MRSA) using a 12-h dosing interval and total dose range of 1.56 to 400 mg/kg/72 h were also performed. A maximum effect (Emax) model was used to determine the pharmacokinetic/pharmacodynamic (PK/PD) index that best described the dose-response data and to estimate the doses required to achieve a net bacteriostatic dose (SD) and a 1-log reduction in CFU/thigh. The pharmacokinetic studies demonstrated an area under the concentration-time curve (AUC) range of 26.8 to 276 mg·h/liter and half-lives of 4.2 to 8.2 h. MICs ranged from 0.125 to 0.5 μg/ml. The 2 highest single doses produced more than a 2-log kill and prolonged postantibiotic effects (PAEs) ranging from 36 to >72 h. The dose fractionation-response curves were similar, and the AUC/MIC ratio was the most predictive PD index (AUC/MIC, coefficient of determination [R2]=0.89; maximum concentration of drug in serum [Cmax]/MIC, R2=0.79; time [T]>MIC, R2=0.63). A ≥2-log kill was observed against all 9 S. aureus strains. The total drug 24-h AUC/MIC values associated with stasis and a 1-log kill for the 9 S. aureus strains were 371±130 and 510±227, respectively. NAI-107 demonstrated concentration-dependent killing and prolonged PAEs. The AUC/MIC ratio was the predictive PD index. Extensive killing was observed for S. aureus organisms, independent of the MRSA status. The AUC/MIC target should be useful for the design of clinical dosing regimens.


A lymphokine distinct from interferon-gamma that activates human monocytes to kill Leishmania donovani in vitro.
Human interferon-gamma (IFN-gamma), a T cell lymphokine (LK), activates monocytes to kill many intra- and extracellular pathogens. In fact, previous reports assert that all activity in LK for macrophage activation is due to IFN-gamma. To test this assertion, we examined monocyte interactions with amastigotes of Leishmania donovani after treatment with recombinant DNA or affinity-purified leukocyte IFN-gamma and IFN-gamma containing LK. Cells treated with at least 200 IU/ml IFN-gamma were microbicidal for L. donovani. Analysis of IFN-gamma dose responses for induction of microbicidal activity by recombinant IFN-gamma (r-IFN-gamma) and LK, however, documented a striking difference: LK was 25-fold more efficient than r-IFN-gamma at equivalent IFN-gamma titers. This large difference suggested that monocyte activation factor(s) in LK may not be IFN-gamma. Rabbit anti-IFN-gamma completely inhibited antiviral activity in LK but did not abrogate the ability to induce monocyte cytotoxicity against leishmania. Furthermore, removal of IFN-gamma from LK by monoclonal anti-IFN-gamma affinity chromatography or by treatment with anti-IFN-gamma followed by staphylococcal protein A chromatography also did not inhibit LK activity. Fractionation of LK on Sephadex G-100 revealed two activity peaks: one in the 50,000 to 60,000 m.w. range coincident with IFN-gamma, and the other at 25,000 to 30,000 daltons with no IFN-gamma. These studies document LK physicochemically and antigenically distinct from IFN-gamma that activate monocytes to kill L. donovani. Such novel factors may have broad import for the study of macrophage-mediated host defenses and for development of immunotherapeutic regimens.


Growth hormone in musculoskeletal pain states.
Growth hormone is essential for normal linear growth and the attainment of an adult mature height. It also plays an important role in cartilage growth and the attainment of normal bone mass. There is only one rheumatic disorder, namely acromegaly, in which abnormalities of growth hormone production play a major etiologic role. However, there is increasing appreciation that suboptimal growth hormone secretion, leading to a state of adult growth hormone deficiency, may occur in the setting of chronic inflammatory disease, chronic corticosteroid use, and fibromyalgia. Therefore, the evaluation and effective management of growth hormone oversecretion and undersecretion is relevant to practicing rheumatologists.


Allogeneic skin grafting for extensive skin chronic graft-versus-host disease.
A 35-year-old female with chronic myelogenous leukemia in chronic phase underwent allogeneic bone marrow transplantation from her genotypically-matched brother in 1990. The extensive chronic graft-versus-host skin disease supervened with skin ulcers on both lower legs in 1992. Conservative therapy was unsuccessful for these lesions. Therefore, not only autologous skin grafting but also allogeneic skin grafting from the marrow donor was successfully performed. She has been maintaining her daily activities (Karnofsky performance status 90%) with little limitation for 17 months after the final skin grafting.


Designing compound subsets: comparison of random and rational approaches using statistical simulation.
Compound subsets, which may be screened where it is not feasible or desirable to screen all available compounds, may be designed using rational or random selection. Literature on the relative performance of random versus rational selection reports conflicting observations, possibly because some random subsets might be more representative than others and perform better than subsets designed by rational means, or vice versa. In order to address this likelihood, we simulated a large number of rationally designed subsets for evaluation against an equally large number of randomly generated subsets. We found that our rationally designed subsets give higher mean hit rates compared to those of the random ones. We also compared subsets comprising random plates with subsets of random compounds and found that, while the mean hit rate of both is the same, the former demonstrates more variation in the hit rate. The choice of compound file, rational subset method, and ratio of the subset size to the compound file size are key factors in the relative performance of random and rational selection, and statistical simulation is a viable way to identify the selection approach appropriate for a subset.


Cadmium tolerance in six poplar species.
Selection of poplar species with greater Cd tolerance and exploiting the physiological mechanisms involved in Cd tolerance are crucial for application of these species to phyto-remediation. The aim of this study is to investigate variation in Cd tolerance among the six poplar species and its underlying physiological mechanisms. Cuttings of six Populus species were cultivated for 10 weeks before exposure to either 0 or 200 μM CdSO(4) for 20 days. Gas exchange in mature leaves was determined by a portable photosynthesis system. Cd concentrations in tissues were analyzed by a flame atomic absorbance spectrometry. Subsequently, Cd amount per plant, bio-concentration factor (BCF) and translocation factor (T (f)) were calculated. Nonenzymatic compounds and activities of antioxidative enzymes in tissues were analyzed spectrophotometrically. Cd exposure caused decline in photosynthesis in four poplar species including Populus cathayana (zhonghua 1). Among the six species, P. cathayana (zhonghua 1) displayed the highest Cd concentrations in tissues, the largest Cd amount in aerial parts, the highest BCF in aerial parts and T (f) under Cd exposure. Under Cd stress, increases in total soluble sugars in roots but decreases in starch in roots, wood, and leaves of P. cathayana (zhonghua 1) were found. Induced O (2) (•-) and H(2)O(2) production in roots and leaves, and increases in free proline, soluble phenolics, and activities of antioxidative enzymes were observed in P. cathayana (zhonghua 1). Based on results of this pot experiment, it is concluded that P. cathayana (zhonghua 1) is superior to other five species for Cd phyto-remediation, and its well-coordinated physiological changes under Cd exposure confer the great Cd tolerance of this species.


Hereditary angioedema.
Hereditary angioedema is an autosomal-dominant deficiency of C1 inhibitor--a serpin inhibitor of kallikrein, C1r, C1s, factor XII, and plasmin. Quantitative or qualitative deficiency of C1 inhibitor leads to the generation of vasoactive mediators, most likely bradykinin. The clinical syndrome is repeated bouts of nonpruritic, nonpitting edema of the face, larynx, extermities, and intestinal viscera. Recently, investigators, physicians, and industry have demonstrated a renewed interest in the biology and treatment of hereditary angioedema. Investigators have generated a C1INH-/- mouse model that has demonstrated the importance of the contact activation system for hereditary angioedema-related vascular permeability. An interactive database of mutations is available electronically. Investigators have continued exploration into mRNA/protein levels. The proceedings of a recent workshop have been impressive in the scope and depth. Clinicians have produced consensus documents and expert reviews. The pharmaceutical industry has initiated clinical trails with novel agents. Hereditary angioedema is often misdiagnosed and poorly treated. Diagnosis requires careful medical and family history and the measurement of functional C1 inhibitor and C4 levels. Attenuated androgens, anti-fibrinolytics, and C1 inhibitor concentrates are used for long-term and preprocedure prophylaxis, but have significant drawbacks. C1 inhibitor concentrates and fresh frozen plasma are available for acute intervention. The mainstays of supportive care are airway monitoring, pain relief, hydration, and control of nausea. New agents such as recombinant C1 inhibitor, kallikrein inhibitors, and bradykinin inhibitors may offer safer and more tolerable treatments.


The akaike information criterion (AIC) is not a sufficient condition to determine the number of ion channel states from single channel recordings.
The Akaike information criterion (AIC) and other criteria that trade off the goodness-of-fit against the number of parameters have been used to determine the number of ion channel states from single channel recordings. We show that, in general, such criteria are not valid. This is illustrated by an elementary example in which the AIC yields an incorrect result. The implications of these findings for the discrimination of different kinetic models of ion channels are discussed.


Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings.
Pregabalin is a gamma-aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in 2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse. Population-based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012-February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004-2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005-2016). A total of 122 572 people dispensed pregabalin, people with intentional pregabalin overdoses managed by NSWPIC and the toxicology services and pregabalin-associated deaths referred to the NSW coroner. Trends in dispensing, poisoning, death; demographics and patient characteristics, proportion of users at high risk of misuse (latent class analysis, LCA) and characteristics of high-risk users. Pregabalin dispensing increased by 73 424 per year [95% confidence interval (CI) = 61726-85 121 P < 0.001] between 2013 and 2016. NSWPIC received 1158 reports of intentional pregabalin poisonings, with a 53.8% increase per year, 2005-2016 (95% CI = 44.0-64.2%, P < 0.001). We identified 88 pregabalin-associated deaths, 57.8% yearly increase (95% CI = 30.0-91.6%, P < 0.001). Patients overdosing on pregabalin commonly co-ingested opioids, benzodiazepines and illicit drugs, and had high rates of psychiatric and substance use comorbidities; 14.7% of pregabalin users were classed by the LCA as at high risk of misuse, and were more likely to be younger, male, co-prescribed benzodiazepines or opioids, have more individual prescribers and higher pregabalin strengths dispensed. There has been a dramatic increase in pregabalin use, poisonings and deaths in Australia since it became subsidized publicly in 2013. One in seven Australians dispensed pregabalin appears to be at high risk of misuse.


Identification and characterization of human UDP-glucuronosyltransferases responsible for xanthotoxol glucuronidation.
1. Xanthotoxol is a furanocoumarin that possesses many pharmacological activities and in this study its in vitro glucuronidation was studied. 2. Xanthotoxol can be rapidly metabolized to a mono-glucuronide in both human intestine microsomes (HIM) and human liver microsomes (HLM); the structure of the metabolite was confirmed by NMR spectroscopy. 3. Reaction phenotyping with 12 commercial recombinant human UGTs, as well as with the Helsinki laboratory UGT1A10 that carry a C-terminal His-tag (UGT1A10-H), revealed that UGT1A10-H catalyzes xanthotoxol glucuronidation at the highest rate, followed by UGT1A8. The other enzymes, namely UGT1A3, UGT1A1, UGT1A6, UGT1A10 (commercial), and UGT2B7 displayed moderate-to-low reaction rates. 4. In kinetic analyses, HIM exhibited much higher affinity for xanthotoxol, along with high Vmax and mild substrate inhibition, whereas the kinetics in HLM was biphasic. UGT1A1 (high Km value), UGT1A10-H (low Km value), and UGT1A8 exhibited mild substrate inhibition. 5. Considering the above findings and the current knowledge on UGTs expression in HIM, it is likely that UGT1A10 is mainly responsible for xanthotoxol glucuronidation in the human small intestine, with some contribution from UGT1A1. In the liver, this reaction is mainly catalyzed by UGT1A1 and UGT2B7. 6. Glucuronidation appears to be the major metabolic pathway of xanthotoxol in human.


Classification Performance of Neural Networks Versus Logistic Regression Models: Evidence From Healthcare Practice.
Machine learning encompasses statistical approaches such as logistic regression (LR) through to more computationally complex models such as neural networks (NN). The aim of this study is to review current published evidence for performance from studies directly comparing logistic regression, and neural network classification approaches in medicine. A literature review was carried out to identify primary research studies which provided information regarding comparative area under the curve (AUC) values for the overall performance of both LR and NN for a defined clinical healthcare-related problem. Following an initial search, articles were reviewed to remove those that did not meet the criteria and performance metrics were extracted from the included articles. Teh initial search revealed 114 articles; 21 studies were included in the study. In 13/21 (62%) of cases, NN had a greater AUC compared to LR, but in most the difference was small and unlikely to be of clinical significance; (unweighted mean difference in AUC 0.03 (95% CI 0-0.06) in favour of NN versus LR. In the majority of cases examined across a range of clinical settings, LR models provide reasonable performance that is only marginally improved using more complex methods such as NN. In many circumstances, the use of a relatively simple LR model is likely to be adequate for real-world needs but in specific circumstances in which large amounts of data are available, and where even small increases in performance would provide significant management value, the application of advanced analytic tools such as NNs may be indicated.


Polyphenolic Profiling, Quantitative Assessment and Biological Activities of Tunisian Native Mentha rotundifolia (L.) Huds.
Phenolic profiling of ten plant samples of Mentha rotundifolia (L.) Huds. collected from different bioclimatic areas of Tunisia, was for the first time carried out by using a fast ultra-high-performance liquid chromatography (UHPLC)-high resolution tandem mass spectrometry (HRMS/MS) method on a Q Exactive platform equipped with an electrospray ionization (ESI) source. An intraspecific, interpopulation variability was evidenced and a total of 17 polyphenolic metabolites were identified and quantified by using the UHPLC-HRESIMS/MS method, here validated for specificity, linearity, limit of detection, limit of quantitation, accuracy and precision. The quantitative method resulted sensitive at the nM level and reliable for rapid polyphenol quantification in vegetal matrices. The metabolomic study allowed us to identify a new compound, named salvianolic acid W, which was isolated and characterized mainly by NMR and MS analysis. A statistical correlation of the phenolic composition with antioxidant and anti-acetylcholinesterase activities was provided.


Analyses of TCR clustering at the T cell-antigen-presenting cell interface and its impact on the activation of naive CD4+ T cells.
The role of micrometer-scale clustering of TCRs at the T cell-antigen-presenting cell (APC) interface in T cell activation is an area of active investigation. Here we have investigated the impact of variations in the extent of TCR clustering on the activation of naive CD4+ T cells. These T cells are derived from transgenic (tg) mice expressing TCRs (172.10 and 1934.4) specific for the N-terminal nonapeptide of MBP bound to I-A(u), and are associated with murine experimental autoimmune encephalomyelitis (EAE). The 172.10 TCR has a approximately 4-fold higher affinity for antigen relative to the 1934.4 TCR, allowing us to compare the properties of two tg T cells of different avidities. We observe that variations in large-scale TCR clustering at the T cell-APC interface do not correlate well with the extent of activation (CD25 or CD69 up-regulation and IL-2 or IFN-gamma production). Efficient activation can also be achieved in the absence of micrometer-scale TCR clustering, indicating that this is not a prerequisite for the effective stimulation of naive T cells.


Thermogenic ability of uncoupling protein 1 in beige adipocytes in mice.
Chronic adrenergic activation leads to the emergence of beige adipocytes in some depots of white adipose tissue in mice. Despite their morphological similarities to brown adipocytes and their expression of uncoupling protein 1 (UCP1), a thermogenic protein exclusively expressed in brown adipocytes, the beige adipocytes have a gene expression pattern distinct from that of brown adipocytes. However, it is unclear whether the thermogenic function of beige adipocytes is different from that of classical brown adipocytes existing in brown adipose tissue. To examine the thermogenic ability of UCP1 expressed in beige and brown adipocytes, the adipocytes were isolated from the fat depots of C57BL/6J mice housed at 24°C (control group) or 10°C (cold-acclimated group) for 3 weeks. Morphological and gene expression analyses revealed that the adipocytes isolated from brown adipose tissue of both the control and cold-acclimated groups consisted mainly of brown adipocytes. These brown adipocytes contained large amounts of UCP1 and increased their oxygen consumption when stimulated with norepinephirine. Adipocytes isolated from the perigonadal white adipose tissues of both groups and the inguinal white adipose tissue of the control group were white adipocytes that showed no increase in oxygen consumption after norepinephrine stimulation. Adipocytes isolated from the inguinal white adipose tissue of the cold-acclimated group were a mixture of white and beige adipocytes, which expressed UCP1 and increased their oxygen consumption in response to norepinephrine. The UCP1 content and thermogenic ability of beige adipocytes estimated on the basis of their abundance in the cell mixture were similar to those of brown adipocytes. These results revealed that the inducible beige adipocytes have potent thermogenic ability comparable to classical brown adipocytes.


PbS Nanoparticles Prepared Using 1, 10-Phenanthroline Adduct of Lead(II) Bis(N-alkyl-N-phenyl dithiocarbamate) as Single Source Precursors.
Dithiocarbamate complexes have remained prominent as single source precursors for the synthesis of clean metal sulfide nanoparticles. This study reports the synthesis of lead sulfide (PbS) nanoparticles using some novel complexes of 1, 10-phenanthroline lead(II) bis(N-alkyl-N-phenyl dithiocarbamate), represented as [Pb(L1)2phen] (1) and [Pb(L2)2phen] (2) (where L1 = bis(N-ethyl-N-phenyldithiocarbamate; L2 = bis(N-butyl-N-phenyldithiocarbamate); phen = 1, 10 phenanthroline) as a single source precursors. The complexes (1 and 2) were synthesized and characterized using various spectroscopic techniques and elemental analysis. The nanoparticles were synthesized via a solvothermal approach in oleylamine, used as a capping agent, and were given as PbS(1) and PbS(2) from [Pb(L1)2phen] (1) and [Pb(L2)2phen] (2), respectively, which were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), and absorption spectroscopy. The diffraction patterns confirmed the formation of face-centered cubic phase PbS nanoparticles with a preferential growth orientation along the (200) plane. The TEM images showed that PbS(1) were of a spherical morphology, while the morphology of PbS(2) tended to produce short rods. This was due to variation in the functional group on the precursor compounds. This variation also resulted in the different band gap energies found such as 1.148 and 1.107 eV for PbS(1) and PbS(2), respectively, indicating a blue shift from the bulk.


Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe!
Many different population groups throughout the world have thiamine deficiency and are at risk of developing severe neurological and cardiac disorders. Alcoholics are most at risk but other important clinical groups should be monitored carefully. The most severe, potentially fatal disease caused by thiamine deficiency is the neurological disorder Wernicke-Korsakoff syndrome. This can be difficult to diagnose and many cases remain undiagnosed. Treatment with thiamine generally results in a dramatic clinical improvement. Thiamine supplementation of stable food products like flour is an effective, simple and safe public health measure that can improve the thiamine status of all population groups.


Quantification of permitted synthetic colours in food by liquid chromatographic methods: A review on analytical methods and theirperformance.
Colours, natural and synthetic, are substances which add or restore colour to a food after processing or storage. They are widely used by food manufacturers but may pose a potential risk to human health. Most food safety authorities set up regulations to limit the use of synthetic colours, and monitor their levels and consumption by the general public. Therefore, validated analytical methods are needed to fulfil this requirement. This review presents a comprehensive overview of various liquid chromatographic methods used for quantification of permitted synthetic colours in foods. Available analytical methods have been assessed for their fitness for purpose in terms of extraction, clean-up, liquid chromatographic separation, quantification and method performance. The advantages and disadvantages are given of available analytical methods for analysing 24 synthetic colours, permitted for use by different jurisdictions. Gaps in the knowledge and levels of validation are identified and recommendations made on further research to develop suitable methods for routine monitoring of these permitted synthetic colours.


[Clinical problems in fracture of the scaphoid bone].
The following specific characteristics of injury cause the problems that occur in scaphoid bone fractures: 1. Mechanisms of accident: There are only a few typical circumstances that cause the injury: as there are false winding of a shrankshaft handle or a fall on the extended hand. In all the other cases the accident is neither realized by the injured person himself or by the physician. As a consequence the possibility of injury of the scaphoid bone is not taken into consideration. 2. In a stable fracture the symptoms do not appear directly but may be clearly delayed or they may disappear very quickly after a short period of intensity, so that the accident is no longer taken any notice of. 3. Radiodiagnostics: Because of the anatomic position of the scaphoid bone any X-raying from a lateral view is difficult because the scaphoid is covered by other carpal bones. In case of an undisplaced fracture you often only see very fine fracture lines, which are only to be seen from a direct orthograde view. It is necessary to X-ray the carpus in different positions. 4. If there is the slightest chance of a scaphoid bone fracture an intensive therapy must be directly started. An immobilisation for a too short period may lead to a delayed union and end in a pseudarthrosis. This is also the case if you start the therapy too late. Then the fracture line is already filled up by fibrous tissue. The latest period of time to begin a conservative treatment is six to eight weeks after the day of the accident.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence & risk factors of anaemia among women of reproductive age in Bursa, Turkey.
The control of anaemia in women of childbearing age is essential to prevent low birth weight and perinatal and maternal mortality. The aim of this study was to determine the anaemia prevalence and risk factors in women of reproductive age group in Nilufer Public Health Training and Research Area, Bursa, Turkey. In this cross-sectional study, 530 women were selected using stratified random sampling among 6,506 women in 15-49 age group and 488 women (92.1%) participated in the study. Pregnant women or women who were not sure of their pregnancy were not included in the study. The data collected were analysed by multivariate logistic regression analysis to determine the risk factors related to anaemia. The prevalence of anaemia was 32.8 per cent (haemoglobin level < 12 g/dl). Usage of more than 2 sanitary pads in a day during menstruation (OR=3.67, 95% CI 2.30-5.88; P=0.000) and duration of menstrual bleeding more than 5 days (OR=3.01, 95% CI 1.94-4.66; P=0.000) were found to be risk factors for anaemia. Approximately 1 of 3 women in the study area was diagnosed to be anaemic. These data indicated the necessity of a public health programme for prevention and early diagnosis of anaemia. Starting from adolescence, all non pregnant women should be screened for anaemia every 5-10 yr throughout their childbearing years during routine health examinations. The follow up service provided by midwives at the primary health care can be used as a suitable tool for anaemia prevention.


Role of the p-Coumaroyl Moiety in the Antioxidant and Cytoprotective Effects of Flavonoid Glycosides: Comparison of Astragalin and Tiliroside.
The aim of this study was to explore the role of p-coumaroyl in the antioxidant and cytoprotective effects of flavonoid glycosides. The antioxidant effects of astragalin and tiliroside were compared using ferric ion reducing antioxidant power, DPPH• scavenging, ABTS•⁺ scavenging, •O₂- scavenging, and Fe2+-chelating assays. The results of these assays revealed that astragalin and tiliroside both exhibited dose-dependent activities; however, tiliroside exhibited lower IC50 values than astragalin. In the Fe2+-chelating assay, tiliroside gave a larger shoulder-peak at 510 nm than astragalin, and was also found to be darker in color. Both of these compounds were subsequently evaluated in a Fenton-induced mesenchymal stem cell (MSC) damaged assay, where tiliroside performed more effectively as a cytoprotective agent than astragalin. Tiliroside bearing a 6''-O-p-coumaroyl moiety exhibits higher antioxidant and cytoprotective effects than astragalin. The 6''-O-p-coumaroyl moiety of tiliroside not only enhances the possibility of electron-transfer and hydrogen-atom-transfer-based multi-pathways, but also enhances the likelihood of Fe-chelating. The p-coumaroylation of the 6"-OH position could therefore be regarded as a potential approach for improving the antioxidant and cytoprotective effects of flavonoid glycosides in MSC implantation therapy.


The cumulative effect of multiple dimensions of lifestyle on risky drinking during the Covid-19 pandemic.
Lifestyle impacts morbidity and mortality worldwide. Herein, we evaluated the association of a multidimensional lifestyle measure and its domains (diet/nutrition, substance use, physical activity, social, stress management, sleep, environmental exposure) with risky drinking. Also, we analyzed the cumulative effect of unhealthy domains in the likelihood of presenting risky drinking. To reach these objectives, data from a web survey conducted in Brazil and Spain was analyzed. The main outcome was risky drinking assessed by the AUDIT-C. Lifestyle was measured using the Short Multidimensional Inventory Lifestyle Evaluation (SMILE). Fixed logistic models were used to evaluate associations between lifestyle and risky drinking. Between April and May 2020, 22,785 individuals answered the survey. The prevalence of risky drinking was 45.6% in Brazil and 30.8% in Spain. The SMILE score was lower (unhealthier lifestyle) among at-risk drinkers. Worse scores on Diet, Substance use, Stress management and Environment were associated with an increased likelihood of risky drinking. The higher the number of unhealthy domains, the higher the likelihood of presenting risky drinking: adjusted odds ratio (aOR) for risky drinking was 1.15 (IC95% 0.98-1.35) and 23.42 (IC95% 3.08-178.02) for those presenting worse lifestyle in 1 and 5 domains, respectively. Finally, interactions suggest that improvement in lifestyle domains would have a larger effect in Spain than in Brazil. Our results suggest that future interventions aiming at reducing Risky drinking may benefit from strategies targeting multiple domains of lifestyle.


Normative developmental vs. reverse developmental trends in memory distortion: a framework to investigate the impact of internal and external influences on memory and their relevance to legal decisions.
There are two opposing positions regarding the development of memory: the normative developmental position, and the reverse developmental position. The normative position, which has long been the default presupposition, supports the notion that susceptibility to memory distortion, including false memories, decreases with age. In contrast, the concept of "developmental reversals" supports the notion that susceptibility to memory distortion and false memories increases with age. Each perspective finds support from existing theories as well as from research on endogenous and exogenous sources of influence. In a legal context, having an accurate understanding of the developmental course of false memory can contribute on the one hand to mitigating wrongful convictions and, on the other hand, to appreciating the accuracy of children's statements when warranted. This review aims to integrate the existing literature regarding these seemingly opposite developmental courses and construct a framework outlining the conditions under which we may observe one age trend over the other. This entails an examination of the paradigms that have been invoked to support these competing positions, specifically developmental responses to internal vs. external sources of distortion.


Wilms tumor in monozygous twins: clinical, pathological, cytogenetic and molecular case report.
The concomitant occurrence of Wilms tumor (WT) was observed in two monozygotic twin sisters without evidence of congenital malformations. Twin 1 was diagnosed with a stage I WT at 11 months of age, whereas twin 2 developed a bilateral (stage V) WT at 13 months of age. In both cases pathologic examination showed a nonanaplastic stromal type WT, with marked rhabdomyomatous elements. Cytogenetic analyses performed on blood samples and on tumor specimens revealed no karyotypic abnormality. No alteration of the WT1 and POU6F2 genes was identified in constitutional and tumor DNA of both sisters, and no anomaly in WT1 expression was evidenced in the normal kidney of one of them. However, loss of heterozygosity on chromosome 11p, involving the alleles of maternal origin, was detected both in the single tumor of twin 1 and in the two distinct tumors of twin 2, thus suggesting a common etiology of the diseases. To the authors' knowledge, this is the first report describing at both the clinical and genetic level a couple of monozygotic twins concordant for WT development.


Scrapie-Responsive Gene 1 Promotes Chondrogenic Differentiation of Umbilical Cord Mesenchymal Stem Cells via Wnt5a.
Repair of cartilage defects, a common condition resulting from many factors, is still a great challenge. Based on their chondrogenic differentiation ability, mesenchymal stem cell- (MSC-) based cartilage regeneration is a promising approach for cartilage defect repair. However, MSC differentiation into chondroblasts or related cell lineages is elaborately controlled by stem cell differentiation stage factors and affected by an array of bioactive elements, which may impede the efficient production of target cells. Thus, identifying a single transcription factor to promote chondrogenic differentiation is critical. Herein, we explored the mechanism by which scrapie-responsive gene 1 (SCRG1), a candidate gene for cartilage regeneration promotion, regulates chondrogenic differentiation of MSCs. Expression of SCRG1 was detected in umbilical cord-derived MSCs (UCMSCs) by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis during chondrogenic differentiation. The function of SCRG1 in chondrogenic potential was evaluated after gene knockdown or overexpression by lentiviral vectors. Finally, a rabbit cartilage defect model was established to evaluate the effect of SCRG1 on cartilage repair in vivo. Expression of SCRG1 was upregulated during in vitro chondrogenic differentiation of UCMSCs. SCRG1 knockdown inhibited chondrogenic differentiation of UCMSCs, while SCRG1 overexpression promoted chondrogenic differentiation of UCMSCs in vitro. In addition, UCMSC overexpressing SCRG1 promoted cartilage repair in vivo. Mechanistically, SCRG1 promoted chondrogenic differentiation via upregulation of Wnt5a expression and subsequent inhibition of β-catenin. Our results showed that SCRG1 promotes chondrogenic differentiation of UCMSCs by inhibiting canonical Wnt/β-catenin signaling through Wnt5a. Our findings provide a future target for chondrogenic differentiation and cartilage regeneration.


Dietary protein levels regulated antibacterial activity, inflammatory response and structural integrity in the head kidney, spleen and skin of grass carp (Ctenopharyngodon idella) after challenged with Aeromonas hydrophila.
This study investigated the effects of dietary protein levels on disease resistance, immune function and structural integrity in the head kidney, spleen and skin of grass carp (Ctenopharyngodon idella). A total of 540 grass carp (264.11 ± 0.76 g) were fed six diets containing graded levels of protein (143.1, 176.7, 217.2, 257.5, 292.2 and 322.8 g digestible protein kg-1 diet) for 8 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila for 14 days. The results indicated that optimal levels of dietary protein: (1) (1) increased the lysozyme (LA) and acid phosphatase (ACP) activities and the complement 3 (C3) and C4 contents, up-regulated antimicrobial peptides, anti-inflammatory cytokines, inhibitor of κBα, target of rapamycin and ribosomal protein S6 kinases 1 mRNA levels, whereas down-regulated pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) P65, IKKβ, IKKγ, eIF4E-binding proteins (4E-BP) 1 and 4E-BP2 mRNA levels in the head kidney, spleen and skin of grass carp (P < 0.05), suggesting that optimal level of dietary protein could enhance immune function in the head kidney, spleen and skin of fish; (2) increased the activities and mRNA levels of antioxidant enzymes, enhanced the glutathione content, decreased reactive oxygen species, malondialdehyde (MDA) and protein carbonyl contents, and up-regulated the mRNA levels of NF-E2-related factor 2, B-cell lymphoma protein-2, inhibitor of apoptosis proteins, myeloid cell leukemia-1 and tight junction complexes, whereas down-regulated Kelch-like-ECH-associated protein (Keap) 1b, cysteinyl aspartic acid-protease 3, 8, 9, Fas ligand, apoptotic protease activating factor-1, Bcl-2 associated X protein and myosin light chain kinase mRNA levels in the head kidney, spleen and skin of grass carp (P < 0.05), indicating that optimal level of dietary protein could improve structural integrity in the head kidney, spleen and skin of fish. Finally, based on the skin hemorrhage and lesion morbidity, LA activity and MDA content, the optimal levels of dietary protein for grass carp (264 g-787 g) were estimated to be 241.45 g kg-1 diet (217.68 g digestible protein kg-1 diet), 301.68 g kg-1 diet (265.48 g digestible protein kg-1 diet) and 307.84 g kg-1 diet (272.71 g digestible protein kg-1 diet), respectively.


Inhibition of integrin receptors reduces extracellular matrix levels, ameliorating benign prostate hyperplasia.
Although a high prevalence of benign prostate hyperplasia (BPH) has been documented, the risk factors are poorly understood. Metabolic syndrome increases the risk of BPH. Succinylation, a type of posttranslational modification, mostly targets metabolic processes. The level of succinylation was investigated in 4 BPH patients and 4 healthy controls. Additionally, 176 patients with BPH were analyzed by using pan-antisuccinyllysine antibody blotting. TMT-labeling proteomic and sc-RNAseq Cellchat analyses were employed to identify key signaling factors involved in the development of BPH. In vivo and in vitro experiments were used to confirm the role of integrin receptors. The global succinylation level in BPH was higher than that in the healthy prostate. Positive correlations of prostate volume with IHC score sand urodynamics testing were found in large clinical cohorts. The extracellular matrix (ECM), metabolic processes and immune signaling were involved in succinylation in BPH, as indicated by using TMT-labeling proteomic analysis, and this finding was also confirmed by sc-RNAseq CellChat analysis. The proteins upregulated in SIRT5 knockout WPMY-1 cells were also enriched in the extracellular matrix and metabolic processes. More importantly, integrin receptor inhibition in a mouse model of BPH significantly ameliorated prostate hyperplasia. High levels of succinylation modifications were found in BPH, and succinylated proteins influenced the activation of the ECM. Inhibition of ECM signaling further ameliorated prostate hyperplasia in mice.


Viability of transgenic rat embryos after freezing and thawing.
In-vivo viability of frozen-thawed embryos derived from transgenic rats, as well as the transmission and the expression of transgenes in the resultant newborn rats, was investigated. Three strains of transgenic rats, carrying human growth hormone gene connected downstream to the promoter region of the bovine alpha-lactalbumin gene (alpha LA/hGH), bovine beta-casein gene (beta CN/hGH) or bovine alpha-S1 casein gene (alpha S1CN/hGH), were used. Two-cell stage embryos (non-transgenic Wistar female x heterozygous transgenic male) were placed in 10% (v/v) dimethylsulfoxide (DMSO) solution and cooled from -7 to -30 degrees C at -0.5 degree C/min before being plunged into liquid nitrogen. After 2 to 4 years storage, the embryos were thawed by rapid warming. The intact embryos were transferred into the oviducts of Day 1 pseudopregnant recipients. The postthaw survival rate of frozen embryos was high in all 3 transgenic strains (88 to 92%), which was similar to that of control (non-transgenic) frozen embryos (95%). Development to newborn rats following transfer of embryos derived from the 3 strains (64 to 68%) was also similar to that of control embryos (60%). These transgenes (alpha LA/hGH, beta CN/hGH and alpha S1CN/hGH) were detected in the DNA extracts from tail tissue of the newborn rats, but the transmission rates (41, 23 and 32%, respectively) were lower than 50% which is expected in the Mendelian fashion. In a transgenic line carrying alpha S1CN/hGH, hGH levels of secretion into the milk of transgenic newborn rats derived from frozen-thawed embryos and her transgenic offspring were the same mg/ml-level as that of their founder rat. Two-step freezing of embryos derived from transgenic rats was therefore an effective method for the long-term cryopreservation of transgene.


Regulation of the 5-lipoxygenase pathway in human leucocytes.
Local levels of 5-lipoxygenase pathway products are the net result of stimulus-induced local synthesis and subsequent degradation. These events are regulated by the interaction of leucocytes with stromal cells and locally produced cytokines and growth factors, and may be modulated by the fatty acid composition of cellular membrane phospholipids and extracellular fluid unesterified fatty acids. A more comprehensive understanding of the regulation and modulation of the 5-lipoxygenase pathway may result in more effective management of inflammatory and immune disorders.


Differential scanning calorimetric study of the thermal denaturation of aspartate transcarbamoylase of Escherichia coli.
The thermal denaturation of Escherichia coli aspartate transcarbamoylase (c6r6) in the absence and presence of various ligands has been studied by means of high-sensitivity differential scanning calorimetry (DSC). As previously reported [Vickers, K.P., Donovan, J.W., & Schachman, H.K. (1978) J. Biol. Chem. 253, 8493-8498], the denaturational endotherm consists of two peaks, the lower of which is due to denaturation of the three regulatory, r2, subunits while the upper involves the two catalytic, c3, subunits. The temperature of maximal excess apparent specific heat, tm, of the lower peak is raised from the value of 51.4 degrees C for the isolated subunit to 66.8 degrees C as a result of subunit interactions, whereas tm for the c3 peak is essentially the same in the isolated subunit and in the holoenzyme, indicating that the denatured r2 subunits do not interact with the c3 subunits. The total specific denaturational enthalpy for c6r6, 4.83 +/- 0.16 cal g-1, is significantly larger than the weighted mean, 4.08 cal g-1, of the enthalpies for c3 and r2. The fact that no endotherm is observed when previously scanned protein is rescanned indicates that the denaturation is irreversible, as is also the case with the r2 and c3 subunits. Empirical justification for analyzing the data in terms of equilibrium thermodynamics is cited. The observed DSC curves can be expressed within experimental uncertainty as the sum of five sequential two-state steps. The value of t 1/2, the temperature of half-completion, for each step increases with increasing protein concentration, indicating that some dissociation of the protein takes place during denaturation.(ABSTRACT TRUNCATED AT 250 WORDS)


Citrate anticoagulation and adverse events.
Several patients with heparin intolerance were dialysed with tri-sodium citrate as anticoagulant without acute clinical problems (good tolerance). After some weeks however problems arose. In all patients an alkalosis developed: the pre dialysis bicarbonate level rose progressively from 27 mmol/l to 40 mmol/l. This could be tempered by lowering the dialysis fluid bicarbonate concentration from 37 mmol/l to 25 mmol/l. A second problem was a progressive rise in pre dialysis sodium level from a mean of 136 mmol/l to 150 mmol/l. Adapting the dialysis fluid sodium concentration from 140 mmol/l towards 132 mmol/l could solve this. The third problem was a progressive rise in serum aluminium level in patients from 3 microg/l to 38 microg/l. After excluding water, concentrate, dialysis fluid, drug intake, etc... as possible sources, we controlled the aluminium level in the glass bottle containing tri-sodium citrate. We noted the very high value of 35,300 microg/l. After replacing the glass bottles with polyvinylchloride bags with a negligible aluminium content, the serum aluminium levels returned back to normal. It is known that citrate chelates the aluminium present in the glass of bottles or vials.


Food and water intake in gold thioglucose-induced obese Charles River mice.
Food and water intake have been measured during the dynamic phase of gold thioglucose-induced obesity in Charles River mice. Regressions of gain in weight with food and water consumption were calculated in young growing animals and in adults fed ad libitum. The influence of fat content in the diet (2.5 and 8% fat) and environmental temperature (68degrees or 79degrees F) was estimated on the regressions. Excessive gain in weight without hyperphagia was observed in growing animals, in adults fed on a fat-enriched diet or maintained within a thermoneutral environment (79degrees F). But a significant hyperphagia was observed in adults fed with a conventional diet and maintained at 68degrees F or in growing animals as a sequela of food deprivation.


[Challenges for health-care professionals in the treatment of ethnic minorities with type 2 diabetes].
This literature review describes health-care professionals' perspective on roles and approaches in encounters with ethnic minorities with type 2 diabetes, including perceived barriers and potentials. They shift between roles in encounters with ethnic minority patients and they consider language and cultural barriers to have an impact on roles, communication as well as time consumption. They emphasise the importance of patient-centeredness and insight into patients' cultural background; however, they report lack of competences to provide good quality in diabetes care to ethnic minority patients.