Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells.
Epidemiological studies have associated coxsackie B virus (CBV) with the development of insulin-dependent diabetes mellitus (IDDM) in humans. Infections of genetically susceptible mice with CBV strain 4 (CB4) induce autoimmune diabetes. Herein, we demonstrate that in mice, CB4 infection of insulin-producing pancreatic beta cells does not directly cause beta cell death. Instead, we observed the phagocytosis of beta cells by macrophages following infection. Further, antigen-presenting cells isolated from CB4-infected mice induced diabetes upon adoptive transfer. Therefore, the specificity of CB4 for infection of beta cells leads indirectly to the development of IDDM. This generalized mechanism suggests that macrophages are the initiating pathogenic cell type during virus-mediated autoimmune diabetes and that multiple environmental agents specific for beta cells could cause IDDM.


Bleeding patterns with monophasic and triphasic low-dose ethinyl estradiol combined oral contraceptives.
This retrospective analysis evaluated the association of age and weight with cycle control in women using either of two formulations of low-estrogen-dose oral contraceptives. Data for this secondary analysis were derived from a randomized multicenter trial assessing the efficacy and safety of norgestimate (NGM) 180/215/250 mcg/ethinyl estradiol (EE) 25 mcg (n=1506) and norethindrone acetate 1 mg/EE 20 mcg (n=1057). In this retrospective analysis, the incidence of breakthrough bleeding/spotting (BTB/S) was evaluated in women stratified by age (18-24, 25-34 and >34 years) and weight (<or=123, 124-155 and >155 lb). A lower percentage of women experienced BTB/S with NGM/EE during most cycles, regardless of age or weight, compared with norethindrone acetate/EE. At Cycle 6, the incidences of BTB/S for NGM/EE versus norethindrone acetate/EE were as follows: 18-24 years, 10.9% versus 29.7% (p<.0001); 25-34 years, 10.9% versus 18.6% (p<.001); >34 years, 8.1% versus 19.1% (p<.005); <or=123 lb, 11.0% versus 25.4% (p<.0001); 124-155 lb, 10.0% versus 22.5% (p<.0001); and >155 lb, 10.0% versus 18.3% (p<.01). NGM/EE provided better cycle control as defined by BTB/S compared with norethindrone acetate/EE, regardless of subject age or weight for six cycles.


Robotic-assisted neck dissection in submandibular gland cancer: preliminary report.
Robot-assisted neck dissection (ND) in patients with head and neck cancer has been developed as a plausible substitute for conventional surgery and it provides an excellent cosmetic outcome. The authors hypothesized that surgery for submandibular gland (SMG) cancer could be achieved with a gasless retroauricular (RA) approach using the robotic system. This study evaluated the feasibility of robot-assisted ND using an RA approach for SMG cancer. Primary tumor resection with robot-assisted ND using an RA incision was performed in 6 patients with SMG cancer. All cases of robot-assisted ND combined with primary tumor resection were conducted successfully without any significant intraoperative complication, need for an additional incision, or conversion to open conventional ND. The amount and duration of drainage, length of hospital stay, number of retrieved lymph nodes, and complications were generally acceptable. The postoperative scar was completely hidden by the auricle and hair. Robot-assisted ND with primary tumor excision using an RA approach is a feasible and useful method, with excellent cosmetic results, for surgical treatment of selected cases of SMG cancer.


Measuring the power of an in situ intraocular lens with the keratometer.
A method to measure the power of an intraocular lens (IOL) in situ using an extended range keratometer and a depth measuring apparatus is described. With this method, the IOL power was measured in ten patients with an anterior chamber IOL and in ten patients with a posterior chamber IOL and compared with the labeled power. The total mean error (measured power minus labeled power) was found to be 0.01 diopters (D) with a standard deviation of 0.22 D. The largest error was 0.40 D.


Novel instrument to guide nurse-led consultations with parents of three-year-olds in school health services in Flanders: A feasibility study of SPARK36.
In the framework of new legislation on School Health Services (SHS) in Flanders (Belgium), nurses lead a preventive consultation with every three-year-old child and its parent(s), with the aim of assessing risks in child development and potential parenting problems. This study assesses the feasibility of the "Structured Problem Analysis of Raising kids aged 36 months" (SPARK36), a broad-scope structured interview to facilitate such consultations. A feasibility study was conducted with SHS nurses across Flanders, to determine need for this instrument, acceptability and practical feasibility of SPARK36 with both parents and professionals. Nurses were trained to use the instrument. Mixed methods (i.e., questionnaires for both parents and nurses, and a focus group interview with nurses) were used to evaluate the feasibility of using SPARK36. Parents were satisfied (97.0%) with what was discussed during the consultation and with the consultation's structure (98.8%). After the training, all 20 nurses felt strengthened in performing the consultation and in making a risk assessment. The interview was feasible in 20-30 min. During 561 interviews nurses gave parenting support in 88.2% of cases. SPARK36 is acceptable, practically feasible for parents and nurses, and it meets needs of both parties. The instrument supports nurses during their consultation. More research is needed to evaluate the instrument and to prepare its implementation in daily practice. SPARK36 is a promising instrument for nurse-led consultations in the SHS setting.


ATP increases head volume in capacitated human sperm via a purinergic channel.
Scanning ion-conductance microscopy allowed us to document an external Ca2+ dependent ATP driven volume increase (ATPVI) in capacitated human sperm heads. We examined the involvement of purinergic receptors (PRs) P2X2R and P2X4R in ATPVI using their co-agonists progesterone and Ivermectin (Iver), and Cu2+, which co-activates P2X2Rs and inhibits P2X4Rs. Iver enhanced ATPVI and Cu2+ and 5BDBD inhibited it, indicating P2X4Rs contributed to this response. Moreover, Cu2+ and 5BDBD inhibited the ATP-induced acrosome reaction (AR) which was enhanced by Iver. ATP increased the concentration of intracellular Ca2+ ([Ca2+]i) in >45% of individual sperm, most of which underwent AR monitored using FM4-64. Our findings suggest that human sperm P2X4R activation by ATP increases [Ca2+]i mainly due to Ca2+ influx which leads to a sperm head volume increase, likely involving acrosomal swelling, and resulting in AR.


Long-term effects of vitamin D on exacerbation rate, health care utilization and lung function in children with asthma.
Asthma exacerbations lead to unplanned health care utilization and reduced lung function in children. Sufficient vitamin D level has been found to have a short-term protective effect against asthma exacerbation in children. However, it is unclear whether this effect remains in the long term. We evaluated the long-term effects of vitamin D levels on the occurrence of asthma exacerbations, emergency department visits or hospitalizations, and lung function among children with asthma, and further investigated the temporal trends of the effects. In this retrospective cohort study, children with asthma who were admitted to the Children's Hospital of Chongqing Medical University from 2017 to 2021 were enrolled. Negative binomial, Poisson, or logistic regression model was used for the multivariable analysis, adjusting for age, sex, body mass index z-score, and severity of asthma exacerbation. Of the 370 children with asthma, 87.8% had vitamin D level less than or equal to 30 ng/mL. After adjustment for confounding factors, higher baseline vitamin D levels in asthma children were significantly associated with reduced occurrence of asthma exacerbations during the first [odds ratio 0.842, 95% confidence interval (CI): 0.805-0.881; P<0.001], second (odds ratio 0.848, 95% CI: 0.793-0.907; P<0.001) and third years (odds ratio 0.865, 95% CI: 0.811-0.922; P<0.001) of follow-up. Higher vitamin D levels in asthmatic children were also strongly associated with a reduced number of emergency department visits or hospitalizations during the first (odds ratio 0.880, 95% CI: 0.842-0.920; P<0.001), second (odds ratio 0.885, 95% CI: 0.832-0.941; P<0.001), and third years (odds ratio 0.922, 95% CI: 0.851-0.998; P=0.044) of follow-up. In addition, the vitamin D levels in asthmatic children were found to be negatively associated with the odds of large airway dysfunction (odds ratio 0.865, 95% CI: 0.771-0.970; P=0.013) and small airway dysfunction (odds ratio 0.922, 95% CI: 0.855-0.996; P=0.038) during the first year of follow-up. Sufficient vitamin D level is associated with lower risk of asthma exacerbations and health care utilization over a 3-year period, and improved lung function over 1 year. The protective effects of vitamin D on asthmatic children decreased over time.


Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development.
Using a high level of mannitol as a diluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol. The mechanical properties (Poisson's ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated. The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression. The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.


Proteomic analysis of proteins expressed by Helicobacter pylori under oxidative stress.
Helicobacter pylori is a spiral, slow growing gram-negative microaerophilic bacterium. It has been shown to be the etiological agent of gastroduodenal diseases, such as chronic gastritis, gastric and duodenal ulcers, and gastric cancer. To address the influence of oxidative stress and its underlying mechanisms, we have compared proliferation, urease activity and protein expression profile of H. pylori incubated under normal microaerophilic (5% O2) and aerobic stress (20% O2) conditions. Oxidative-stress cells displayed coccoid morphology and time-dependent decrease in proliferation. The urease activity was completely abrogated after 32 h. We have further compared the protein expression profiles of H. pylori under normal growing and oxidative-stress conditions by a global proteomic analysis, which includes high-resolution 2-DE followed by MALDI-TOF-MS and bioinformatic databases search/peptide-mass comparison. The results revealed that more than ten proteins were differentially expressed under oxidative stress. Most notably, the protein expression levels of urease accessory protein E (UreE, an essential metallochaperone for urease activity) and alkylhydroperoxide reductase (AhpC) with antioxidant potential are greatly decreased under stress conditions. Measurements of messenger RNA transcription level by performing RT-PCR on total mRNA also confirmed that gene expressions for these two proteins are consistently repressed under oxygen tension. These changes form a firm basis to account for the loss of urease activity and anti-oxidative ability of H. pylori after long-term exposure to reactive oxygen. Conceivably, UreE and AhpC may thus be listed as potential targets for the development of therapeutic drugs against H. pylori.


Single unit response of suprachiasmatic neurons to arginine vasopressin (AVP) is mediated by a V1-like receptor in the hamster.
A large population of local circuit neurons within the suprachiasmatic nucleus (SCN) exhibit immunopositive staining for arginine-vasopressin (AVP). AVP has been reported to be released from SCN neurons in a circadian pattern that peaks during the subjective day. Using an in vitro hypothalamic slice preparation, the present study investigated how SCN neurons respond to AVP over the circadian cycle and whether the response to AVP is mediated by V1- or V2-like AVP receptors. Exposure of the slice to AVP 10(-8) M produced excitatory responses in 51% of the 74 SCN neurons examined. A statistically significant day-night difference in the percentage of SCN units responding to AVP was observed (chi 2 = 15.62; P less than 0.01). During the dark phase 73% were excited by AVP, while during the light phase only 24% had excitatory responses. The threshold concentration of AVP ranged from 10(-9) to 10(-10) M and 10(-7) to 10(-8) M during the dark and light phase, respectively. In a second experiment the effects of selective V1 and V2 agonists and antagonists were determined. A V1, but not a V2 receptor antagonist was found to block the effects of AVP on single unit activity. Similarly, a V1 but not a V2 receptor agonist mimicked the effects of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)


Infusion of tumor-contaminated bone marrow for autologous rescue after high-dose therapy leading to long-term remission in a patient with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia.
We report a female patient with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia remaining in long-term second remission after high-dose radiochemotherapy followed by autologous stem cell rescue with bone marrow showing evidence of residual disease. The Philadelphia chromosome and a positive signal for the BCR/ABL p185 translocation by the polymerase chain reaction were detected in the harvested marrow. After mafosfamide-purged marrow failed to engraft, her unpurged 'back-up' bone marrow was also infused. Control marrow examinations after recovery were repeatedly positive for the BCR/ABL translocation on PCR analysis turning negative 30 months after high-dose therapy. She remains in unsustained complete clinical remission for 48+ months showing no evidence of leukemia by cytological and cytogenetic analyses.


Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia.
Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical-translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.


Cloning and characterization of the human galanin GALR2 receptor.
We present the molecular cloning and characterization of the human galanin receptor, hGALR2. hGALR2 shares 85%, 39%, and 57% amino acid identities to rGALR2, hGALR1, and hGALR3, respectively. hGALR2, along with rGALR2, can be distinguished from the other cloned galanin receptors by a tolerance for both N-terminal extension and C-terminal deletion of galanin, as well as by a primary signaling mechanism involving phosphatidyl inositol hydrolysis and calcium mobilization. By RT-PCR, GALR2 mRNA was abundant in human hippocampus, hypothalamus, heart, kidney, liver, and small intestine. A weak GALR2 mRNA signal was detected in human retina, and no signal was detected in cerebral cortex, lung, spleen, stomach, or pituitary.


Aetiology of Ludwig van Beethoven's hearing impairment: hypotheses over the past 100 years - A systematic review.
Even 250 years after Beethoven's birth, the irrevocable cause of his hearing impairment remains unclear despite multiple publications by different professional groups. This study aimed to analyse the development of the most likely aetiologies during the last 100 years by a systematic review of the relevant medical literature. A systematic review of medical literature in PubMed®, PubMed Central®, and Web of Science® for the period 1920-2020 was conducted. Medical publications between 1920 and 1935 were additionally searched manually by review of reference lists. Studies were eligible when a statement regarding the most likely aetiology of the hearing loss of Beethoven was the aimed objective of the publication. 48 publications were included. The following aetiologies were supposed: otosclerosis (n = 10), syphilis (n = 9), Paget's disease (n = 6), neural deafness (n = 5), immunopathy with inflammatory bowel disease, neural deafness with otosclerosis, sarcoidosis or lead intoxication (n = 2), and systemic lupus erythematosus, trauma, labyrinthitis or inner ear disease (n = 1). There is an ongoing effort with a mean publication frequency in this topic of 0.48/year. From 1920 to 1970, otolaryngologists were the group with the highest interest in this field (67%), whereas since 1971 most authors have belonged to non-otolaryngologic subspecialities (81%). Over the past 100 years, otosclerosis and syphilis were predominantly supposed to be the underlying causes. The hypothesis of syphilis-although rejected for a long time-has had a remarkable revival during the past 20 years. Regarding the outcome following therapeutic intervention by cochlear implantation, the differential diagnosis of neural deafness would be relevant today.


A Literature Review of Alternative Therapies for Postpartum Depression.
Postpartum depression is a debilitating disorder that requires greater awareness and treatment. Depending on severity of symptoms, standard treatment calls for individual psychotherapy and medication. Although postpartum depression can lead to negative health outcomes for women and their offspring, numerous barriers prevent women from receiving appropriate care. A review of the literature shows that nontraditional modes of psychotherapy dominate recent studies, whereas data for other complementary options are severely lacking. Further research is needed to help identify cost-effective alternative therapies for treating postpartum depression. Combined with prevention and screening, treatment options that suit women's varied situations and preferences must be explored to increase reception and adherence to treatment and, ultimately, to improve outcomes.


Animal Behavior: A Neural Basis of Individuality.
Behavior can vary greatly even between genetically identical animals, but what determines such individuality? New work reveals that inter-individual differences in wiring of visual interneurons in Drosophila, arising from stochastic developmental events, underlie fly-specific object orientation abilities.


5-Aminolevulinic acid-mediated photodynamic therapy has effective antifungal activity against Sporothrix globosa in vitro.
An alternative therapy for sporotrichosis is necessary to reduce the treatment time and raise clinical efficacy. The 5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is a promising platform with which to treat mycoses. However, despite the worldwide prevalence of Sporothrix globosa, a causative agent of sporotrichosis, the effect of ALA-PDT on this pathogen has not been validated. The aim of this study was to evaluate the effect of ALA-PDT on S globosa and the protection of melanin through an in vitro study. The mechanisms involved were also investigated. To estimate the survival rate of S globosa treated with ALA-PDT and the protection offered by melanin, the conidia and yeast cells of wild-type S globosa (Mel+), other clinical strains, tricyclazole-treated Mel+ and an albino mutant strain (Mel-) were incubated with and without ALA or irradiation. Reactive oxygen species generation by Mel+ conidia induced by ALA-PDT was assayed. SEM and TEM were conducted to obverse ultrastructural changes in the conidia. A comet assay was performed to evaluate DNA damage. The survival rate of S globosa conidia and yeast cells significantly decreased following incubation with 1.19M ALA and 162 J/cm2 irradiation in vitro. Melanin was not only capable of protecting the conidia against ALA-PDT, but also against ALA or irradiation alone. After induction by ALA-PDT, alterations in reactive oxygen species generation, DNA damage and ultrastructural changes were observed. ALA-PDT inhibits the survival of S globosa conidia in vitro and therefore has potential for the treatment of sporotrichosis.


Behavioral detection of tactile stimuli during 7-12 Hz cortical oscillations in awake rats.
Prominent 7-12 Hz oscillations in the primary somatosensory cortex (S1) of awake but immobile rats might represent a seizure-like state in which neuronal burst firing renders animals unresponsive to incoming tactile stimuli; others have proposed that these oscillations are analogous to human mu rhythm. To test whether rats can respond to tactile stimuli during 7-12 Hz oscillatory activity, we trained head-immobilized awake animals to indicate whether they could detect the occurrence of transient whisker deflections while we recorded local field potentials (LFPs) from microelectrode arrays implanted bilaterally in the S1 whisker representation area. They responded rapidly and reliably, suggesting that this brain rhythm represents normal physiological activity that does not preclude perception.


Correction: Synthesis, dynamic NMR characterization and XRD studies of novel N,N'-substituted piperazines for bioorthogonal labeling.
[This corrects the article DOI: 10.3762/bjoc.12.242.].


Decadal changes in Atlantic overturning due to the excessive 1990s Labrador Sea convection.
Changes in the Atlantic Meridional Overturning Circulation (AMOC) represent a crucial component of Northern Hemisphere climate variability. In modelling studies decadal overturning variability has been attributed to the intensity of deep winter convection in the Labrador Sea. This linkage is challenged by transport observations at sections across the subpolar gyre. Here we report simulations with an eddy-rich ocean model which captures the observed concentration of downwelling in the northeastern Atlantic and the negligible impact of interannual variations in Labrador Sea convection during the last decade. However, the exceptionally cold winters in the Labrador Sea during the first half of the 1990s induced a positive AMOC anomaly of more than 20%, mainly by augmenting the downwelling in the northeastern North Atlantic. The remote effect of excessive Labrador Sea buoyancy forcing is related to rapid spreading of mid-depth density anomalies into the Irminger Sea and their entrainment into the deep boundary current off Greenland.


Does peripheral auditory threshold correlate with brainstem auditory function at term in preterm infants?
Peripheral auditory threshold does not correlate with brainstem auditory function in preterm infants. Infants with peripheral auditory abnormality seem not to be necessarily more prone to brainstem auditory abnormality than those without the elevation, although further studies are needed in a larger number of subjects. To investigate whether peripheral auditory threshold correlates with brainstem auditory function in preterm infants and shed light on whether preterm infants with threshold elevation are prone to central auditory abnormality. Brainstem auditory evoked response (BAER) was recorded with clicks at term in preterm infants (gestation 28-36 weeks). Analysis of correlation was made between BAER threshold and various BAER components. BAER data were compared between preterm infants with thresholds < or = 20 dB nHL (n = 113) and those > 20 dB (n = 32). Although BAER threshold correlated significantly with BAER wave latencies and amplitudes, the threshold did not correlate significantly with I-V, I-III and III-V intervals. No significant differences were found between preterm infants with BAER thresholds < or = 20 dB and those > 20 dB in I-V, I-III intervals, although III-V was longer in the infants with thresholds > 20 dB nHL (p < 0.05).


Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment.
Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) possess a great therapeutical potential for osteoarthritis (OA) treatment. However, the steric and electrostatic hindrance of cartilage matrix leads to very limited distribution of MSC-sEVs in cartilage and low bioavailability of MSC-sEVs after intra-articular injection. To overcome this, a strategy to reverse the surface charge of MSC-sEVs by modifying the MSC-sEVs with a novel cationic amphiphilic macromolecule namely ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD) was developed in this study. Through incubation with 100 μg/ml PPD, positively charged MSC-sEVs (PPD-sEVs) were obtained, and the modification process showed nearly no disturbance to the integrity and contents of sEVs and exhibited good stability under the interference of anionic macromolecules. A more effective cellular uptake and homeostasis modulation ability of PPD-sEVs than unmodified MSC-sEVs to chondrocytes was demonstrated. More importantly, PPD-sEVs demonstrated significantly enhanced cartilage uptake, cartilage penetration, and joint retention capacity as compared to MSC-sEVs. Intra-articular injection of PPD-sEVs into a mouse OA model showed significantly improved bioavailability than MSC-sEVs, which resulted in enhanced therapeutic efficacy with reduced injection frequency. In general, this study provides a facile and effective strategy to improve the intra-articular bioavailability of MSC-sEVs and has a great potential to accelerate the clinical practice of MSC-sEVs based OA therapy.


Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.
Interleukin-18 (IL-18) is involved in endothelial activation and dysfunction, and in the pathogenesis and severity of acute graft-versus-host disease (aGVHD). Its relevance for patient outcome after allogeneic stem cell transplantation (alloSCT) has not yet been comprehensively addressed. Pre-transplant serum levels of free IL-18 were retrospectively assessed in a cohort of 589 patients (training cohort). Results were validated in 688 patients allografted in a different centre. The primary endpoint was overall survival (OS). Secondary endpoints included incidences of non-relapse mortality (NRM), relapse, and aGVHD. In the training cohort, higher pre-transplant levels of free IL-18 were significantly associated with worse OS (hazard ratio [HR] per 1-log2 increase, 1.25, P = 0.008) in multivariable models. This was due to a higher hazard of NRM (HR per 1-log2 increase, 1.39, P = 0.001), rather than relapse. The associations of pre-transplant free IL-18 with higher NRM (HR per 1-log2 increase, 1.24, P = 0.02) and shorter OS (HR per 1-log2 increase, 1.22, P = 0.006) were confirmed in the validation cohort. In both cohorts, the correlations of higher pre-transplant free IL-18 serum levels with increased NRM and worse OS were mainly driven by fatal infectious complications. No associations with incidence of aGVHD were observed. Higher pre-transplant levels of free IL-18 were associated with non-relapse and overall mortality after alloSCT. Our results may provide a rationale for prospective studies evaluating IL-18 status and inhibition of IL-18 activity in patients undergoing allografting.


Protective devices of early developmental stages in Pyrrhalta viburni (Coleoptera, Chrysomelidae).
Larvae and eggs of the leaf beetle Pyrrhalta viburni were investigated for protective devices against predators. The eggs are covered with faeces, which appeared to have no feeding deterrent activity against the ant Myrmica sabuleti. Chemical analyses of the material covering the eggs by gas chromatography-mass spectrometry (GC-MS) showed the triterpenes α-amyrin and β-amyrin as main components. Both compounds are also present in the hostplant Viburnum lantana. GC-MS analyses of eggs and larvae showed that 1,8-dihydroxy-3-methylanthraquinone (=chrysophanol) was present in both developmental stages. In the larvae, 1,8-dihydroxyanthraquinone (=chrysazin) and 1,8,9-trihydroxyanthracene (dithranol) were also detected. Neither hydroxylated anthraquinones nor dithranol were found in bark and leaf extracts of the hostplant. After assessing the total amounts of these compounds in a single larva, their ecological significance was studied in feeding bioassays with M. sabuleti. Both P. viburni larvae and equivalent amounts of anthraquinones and dithranol deterred feeding by the ants. The role of anthraquinones and triterpenes in P. viburni is discussed.


Individual-level predictors of inpatient childhood burn injuries: a case-control study.
Burn injuries are considered one of the most preventable public health issue among children; however, are a cause of significant morbidity and mortality in Iran. The aim of this study was to assess individual-level predictors of severe burn injuries among children leading to hospitalization, in East Azerbaijan Province, in North-West of Iran. The study was conducted through a hospital based case-control design involving 281 burn victims and 273 hospital-based controls who were frequency matched on age, gender and urbanity. Both bivariate and multivariate methods were used to analyze the data. Mean age of the participants was 40.5 months (95 % CI: 37-44) with the majority of burns occurring at ages between 2 months-13.9 years. It was demonstrated that with increase in the caregiver's age there was a decrease in the odds of burn injuries (OR = 0.94, 95 % CI: 0.92-0.97). According to the multivariate logistic regression there were independent factors associated with burn injuries including childhood ADHD (OR = 2.82, 95 % CI: 1.68 - 4.76), child's age (OR = 0.73, 95%CI: 0.67 - 0.80), flammability of clothing (OR = 1.60, 95 % CI: 1.12 - 2.28), daily length of watching television (OR = 1.31, 95 % CI: 1.06 - 1.61), playing outdoors (OR = 1.32, 95 % CI: 1.16 - 1.50) and increment in the economic status (OR = 1.37, 95 % CI: 1.18 - 1.60). Major risk predictors of burn injuries among the Iranian population included childhood ADHD, child's age, watching television, playing outdoors, high economic status and flammable clothing.


Screening problematic use of substances among young subjects attending an emergency department, and subsequent treatment seeking.
Young individuals constitute a key population for the screening of problematic use of substances (PUS), but they are not likely to seek support and are hard to reach. Targeted screening programs should thus be developed in the places of care they may attend for other reasons, including emergency departments (EDs). We aimed to explore the factors associated with PUS in young people attending an ED; we measured the subsequent access to addiction care after ED screening. This was a prospective interventional single-arm study which included any individual aged between 16 and 25 years who attended the main ED of Lyon, France. Baseline data were sociodemographic characteristics, PUS status using self-report questionnaires and biological measures, level of psychological health, and history of physical/sexual abuse. Quick medical feedback was provided to the individuals presenting a PUS; they were advised to consult an addiction unit, and contacted by phone at three months to ask whether they had sought treatment. Baseline data were used to compare PUS and non-PUS groups using multivariable logistic regressions, to provide adjusted odds ratios (aORs) and 95% confidence intervals (95% CI), with age, sex, employment status, and family environment as the adjustment variables. The characteristics of PUS subjects who subsequently sought treatment were also assessed using bivariable analyses. In total, 460 participants were included; 320 of whom (69.6%) were presenting current substance use, and 221 (48.0%) with PUS. Compared to non-PUS individuals, PUS ones were more likely to be males (aOR=2.06; 95% CI [1.39-3.07], P<0.001), to be older (per one-year increase: aOR=1.09; 95% CI [1.01-1.17], P<0.05), to have an impaired mental health status (aOR=0.87; 95% CI [0.81-0.94], P<0.001), and to have a history of sexual abuse (aOR=3.33; 95% CI [2.03-5.47], P<0.0001). Only 132 (59.7%) subjects with PUS could be reached by phone at 3 months, among whom only 15 (11.4%) reported having sought treatment. Factors associated with treatment seeking were social isolation (46.7% vs. 19.7%; P=0.019), previous consultation for psychological disorders (93.3% vs. 68.4%; P=0.044), lower mental health score (2.8±1.6 vs. 5.1±2.6; P<0.001), and post-ED hospitalization in a psychiatric unit (73.3% vs. 19.7%; P<0.0001). EDs are relevant places to screen PUS in youth, but the level of seeking further treatment needs to be substantially improved. Offering systematic screening during an emergency room visit could allow for more appropriate identification and management of youth with PUS.


Evaluation of left ventricular outflow tract area after septal reduction in obstructive hypertrophic cardiomyopathy: a real-time 3-dimensional echocardiographic study.
The comparative impact of percutaneous alcohol septal reduction (ASR) and surgical myectomy on the left ventricular outflow tract (LVOT) area in patients with obstructive hypertrophic cardiomyopathy (HC) is not well defined. Real-time 3-dimensional echocardiography (RT3DE) provides accurate information about the LVOT geometry and shape. We aimed to analyze the change in LVOT area after septal reduction interventions in patients with obstructive HC using RT3DE. Thirty-one HC patients (mean age 53 +/- 17 years) undergoing ASR (n = 14) or myectomy (n = 17) were studied at baseline and during follow-up with RT3DE. LVOT area was measured after observing the LVOT in the 3D space as the smallest area during midsystole. LVOT pressure gradients were determined by conventional continuous wave Doppler. Overall, LVOT area increased from 0.86 +/- 0.20 to 2.50 +/- 0.88 cm2 (P < .01), and the resting LVOT pressure gradient decreased from 64 +/- 41 to 16 +/- 10 mm Hg (P < .01) after a median follow-up of 3 months after intervention (range 1-24 months). A similar significant decrease in LVOT pressure gradients was seen in myectomy and ASR groups (from 62 +/- 39 to 12 +/- 5 mm Hg and from 67 +/- 43 to 21 +/- 14 mm Hg, respectively, P < .01 in between each group, and P = NS between both groups). However, the increase in LVOT area was greater in myectomy than in ASR group (from 0.81 +/- 0.22 to 2.90 +/- 0.64 cm2 and 0.93 +/- to 0.16 to 2.02 +/- 0.92 cm2, respectively, P < .01 between both groups). RT3DE demonstrated an effective increase in LVOT area after both ASR and myectomy. This technique may be useful for assessing the results of septal reduction in patients with obstructive HC.


Rheological properties of silica dispersions stabilized by stereoregular poly(methyl methacrylate).
The adsorption of stereoregular polymers and its effect on the conformation and dynamics of the polymer at interfaces are only poorly understood. 1H NMR has revealed a lowering of the peaks assigned to isotactic sequences whatever the PMMA tacticity, which provides evidence of stereospecific adsorption of the isotactic segments on silica. Entropic factors are therefore assumed to control the configuration of the adsorbed layer. Tacticity-dependent rheological behavior is revealed by dynamic investigations carried out on silica dispersions. The driving forces likely to induce the stereoselective adsorption and tacticity-dependent rheology of suspensions are discussed.


Role of AMP-activated protein kinase in autophagy and proteasome function.
In this work, we have examined the possible role of AMP-activated protein kinase (a key energy sensor) in regulating intracellular protein degradation. We have found that AICAR, a known activator of AMPK, has a dual effect. On one hand, it inhibits autophagy by a mechanism independent of AMPK activity; AICAR decreases class III PI3-kinase binding to beclin-1 and this effect counteracts and reverses the known positive effect of AMPK activity on autophagy. On the other hand, AICAR inhibits the proteasomal degradation of proteins by an AMPK-dependent mechanism. This is a novel function of AMPK that allows the regulation of proteasomal activity under conditions of energy demand.


Associations among internalized and perceived stigma, state mindfulness, self-efficacy, and depression symptoms among men who have sex with men in China: A serial mediation model.
Previous research has demonstrated that stigma is strongly related to depressive symptoms among men who have sex with men (MSM). However, data are limited regarding the associations between stigma, state mindfulness, self-efficacy, and depression symptoms. The current study aimed to analyze state mindfulness and self-efficacy as possible mediators between internalized and perceived stigma and depression symptoms. A sample of 2610 Chinese MSM (Mage = 23.99, SD = 6.09, age range: 18-68 years) was recruited from an online survey platform and completed the HIV and Homosexuality Related Stigma Scale, Patient Health Questionnaire-9, the short version of Five Facet Mindfulness Questionnaire, and the Chinese General Self-Efficacy Scale. Results indicated that state mindfulness significantly mediated the linkage between internalized and perceived stigma and depressive symptoms, and self-efficacy significantly mediated the relation between state mindfulness and depression symptoms. Furthermore, internalized and perceived stigma were associated with depression symptoms through a serial mediation of state mindfulness and self-efficacy. This study highlights that state mindfulness and self-efficacy might play important roles in the psychological response of MSM to stigmatization and psychopathology symptoms.


Electrogastrography in neonates.
Procedures for diagnosis of gastrointestinal (GI) symptoms in newborn and preterm infants should preferably be non-invasive. This study evaluates the usability of electrogastrography (EGG), a non-invasive, cutaneous recording of the gastric myoelectrical activity in newborn infants. Sixty-two randomly selected infants [27 girls and 35 boys with median gestational age of 36 weeks (range 29-42)] divided into six groups (by postconceptional age) were studied on median day 5 (range 1-24) after birth. None had GI symptoms. EGG recordings were made by Digitrapper EGG recording system. Findings were highly dispersed and without statistical difference both between pre- and postprandial periods and among the six study groups. Dominant frequency of 2.5 cycles per minute was found for 57 of 62 infants, with distribution of normal, bradygastric and tachygastric slow wave frequency uniformly dispersed around 50, 35 and 15% respectively. We find EGG unsuitable for clinical use because of significant variation in gastric slow wave frequency in normal term and preterm infants without GI symptoms.


How to prevent skin damage from air pollution. Part 1: Exposure assessment.
Both epidemiological and experimental studies have demonstrated the crucial connection between air pollution exposure and skin disorders. The exact mechanisms by which air pollutants mediate skin damage remain largely unknown. Therefore, it is very necessary to investigate the mechanism of air pollution-induced skin damage and explore some potential protective and therapeutic methods. In this review, we focus on the qualitative and quantitative skin exposure assessment methodologies-a relatively new field of interdisciplinary research.


A Near-Optimal Algorithm to Count Occurrences of Subsequences of a Given Length.
For k ∈ ℤ+, define Σ k as the set of integers {0, 1, …, k - 1}. Given an integer n and a string t of length m ≥ n over Σ k , we count the number of times that each one of the kn distinct strings of length n over Σ k occurs as a subsequence of t. Our algorithm makes only one scan of t and solves the problem in time complexity mkn-1 and space complexity m + kn . These are very close to best possible.


2D-REFINE spectroscopy: separation of overlapping hyperfine spectra.
We show on a mixture of three spectrally overlapping paramagnetic compounds TEMPO, BDPA and CuHis that it is possible to separate their field-swept and hyperfine spectra based on the difference in their longitudinal relaxation times T1. This was achieved in a two-dimensional experiment, where one dimension corresponds to the spectral domain and the second dimension encodes the relaxation behavior of the individual compound. Inverse Laplace Transform with respect to this domain separates the field-swept and hyperfine spectra of the individual compounds in the relaxation rate domain. This extends our formerly proposed Relaxation Filtered Hyperfine (REFINE) method to be applicable to more than two spectrally overlapping spectra by adding a further dimension to the chosen EPR experiment.


Management of irritable bowel syndrome in primary care: the results of an exploratory randomised controlled trial of mebeverine, methylcellulose, placebo and a self-management website.
Many patients with IBS suffer on-going symptoms. The evidence base is poor for IBS drugs but they are widely prescribed and advised in Guidelines. Cognitive Behavioural Therapy (CBT) can be helpful, but availability is poor in the NHS. We developed a web-based CBT self-management programme (Regul8) in partnership with patients and trialled it and common IBS medications in an exploratory factorial RCT to test trial procedures and provide information for a larger trial. Patients, 16 to 60 years, with IBS symptoms fulfilling Rome III criteria were recruited via GP practices and randomised to over-encapsulated mebeverine, methylcellulose or placebo for 6 weeks and to 1 of 3 website conditions: Regul8 with a nurse telephone session and email support, Regul8 with minimal email support, or no website. 135 patients recruited from 26 GP practices. Mean IBS SSS score 241.9 (sd 87.7), IBS-QOL 64 (sd 20) at baseline. 91% follow-up at 12 weeks. Mean IBS SSS decreased by 35 points from baseline to 12 weeks. There was no significant difference in IBS SSS or IBS-QOL score between medication or website groups at 12 weeks, or in medication groups at 6 weeks, or IBS-QOL in website groups at 6 weeks. However, IBS SSS at 6 weeks was lower in the No website group than the website groups (IBS SSS no website =162.8 (95% CI 137.4-188.3), website 197.0 (172.4 - 221.7), Website + telephone support 208.0 (183.1-233.0) p = 0.037). This exploratory study demonstrates feasibility and high follow-up rates and provides information for a larger trial. Primary outcomes (IBS SS and IBS QOL) did not reach significance at 6 or 12 weeks, apart from IBS SSS being lower in the no-website group at 6 weeks - this disappeared by 12 weeks. Improved Enablement suggests patients with access to the Regul8 website felt better able to cope with their symptoms than the non-website group. Improved SGA score in the Regul8 groups may indicate some overall improvement not captured on other measures. ClinicalTrials.gov Identifier (NCT number): NCT00934973.


Temperature-dependent inactivation of nucleic acid binding and aggregation of the 1,25-dihydroxyvitamin D3 receptor.
The interaction of the 1 alpha,25-dihydroxyvitamin D3 receptor with immobilized calf thymus DNA has been compared with its sedimentation properties on hypotonic sucrose gradients. Forty to sixty percent of total hormone:receptor complexes formed at 4 degrees C were retained by DNA-cellulose and could be eluted by 0.18 to 0.2 M KCl. In contrast, heating preparations to 25 degrees C rapidly and irreversibly converted receptor to a form which bound hormone and DEAE-cellulose normally, but was unable to associate with DNA. Similarly, the ability of receptor to aggregate to a 6 S species was labile at 25 degrees C. Stabilization of receptor in the DNA binding aggregating form was accomplished using Ca2+, Mg2+, Mn2+, or Na2MoO4 while several protease and phosphatase inhibitors were ineffective. An examination of DNA binding properties of aggregating and nonaggregating receptor forms revealed that only receptor competent to enter into aggregates could bind DNA suggesting that a functional nucleic acid binding site, and, hence, a nucleic acid interaction is necessary for aggregate formation. Consistent with this view, an RNA:receptor interaction appears to be involved in formation of the 6 S complex since removal of RNA by ribonuclease treatment or purification of receptor reduced aggregation, an effect that could be reversed by addition of purified RNA.


A novel composite electrode based on tungsten oxide nanoparticles and carbon nanotubes for the electrochemical determination of paracetamol.
An electrochemical sensor was prepared by the modification of a glassy carbon electrode (GCE) with a composite of nanoparticles of tungsten oxide (WO3) and carbon nanotubes (CNTs) for the quantification of paracetamol (PR). Energy dispersive X-ray analysis (EDX) and scanning electron microscopy (SEM) were performed for the characterization of the nanocomposite layer. Compared with a bare GCE and a GCE modified with CNTs, the proposed electrode (WO3NPs/CNTs/GCE) exhibited a well-defined redox couple for PR and a marked enhancement of the current response. The experimental results also showed that ascorbic acid (AA) did not interfere with the selective determination of PR. The proposed electrode was used for the determination of PR in 0.1M phosphate buffer solution (PBS) at pH7.0 using square wave voltammetry (SWV). The peak current increased linearly with the concentration of PR in the range of 1.0×10(-9)-2.0×10(-7)M. The detection limit (LOD) was 5.54×10(-11)M (based on 3Sb/m). The proposed voltammetric sensor provided long-time stability, improved voltammetric behavior and good reproducibility for PR. The selective, accurate and precise determination of PR makes the proposed electrode of great interest for monitoring its therapeutic use.


Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction. A transgenic (TG) mouse model of FHC with a mutation in tropomyosin at position 180 was employed. Adenoviral-Serca2a (Ad.Ser) was injected into the left ventricle of 1-day-old non-transgenic (NTG) and TG mice. Ad.LacZ was injected as a control. Serca2a protein expression was significantly increased in NTG and TG hearts injected with Ad.Ser for up to 6 weeks. Compared to TG-Ad.LacZ hearts, the TG-Ad.Ser hearts showed improved whole heart morphology. Moreover, there was a significant decline in ANF and β-MHC expression. Developed force in isolated papillary muscle from 2- to 3-week-old TG-Ad.Ser hearts was higher and the response to isoproterenol (ISO) improved compared to TG-Ad.LacZ muscles. In situ hemodynamic measurements showed that by 3 months the TG-Ad.Ser hearts also had a significantly improved response to ISO compared to TG-Ad.LacZ hearts. The present study strongly suggests that Serca2a expression should be considered as a potential target for gene therapy in FHC. Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth.


Novel magnetic calcium phosphate-stem cell construct with magnetic field enhances osteogenic differentiation and bone tissue engineering.
Superparamagnetic iron oxide nanoparticles (IONPs) are promising bioactive additives to fabricate magnetic scaffolds for bone tissue engineering. To date, there has been no report on osteoinductivity of IONP-incorporated calcium phosphate cement (IONP-CPC) scaffold on stem cells using an exterior static magnetic field (SMF). The objectives of this study were to: (1) develop a novel magnetic IONP-CPC construct for bone tissue engineering, and (2) investigate the effects of IONP-incorporation and SMF application on the proliferation, osteogenic differentiation and bone mineral synthesis of human dental pulp stem cells (hDPSCs) seeded on IONP-CPC scaffold for the first time. The novel magnetic IONP-CPC under SMF enhanced the cellular performance of hDPSCs, yielding greater alkaline phosphatase activities (about 3-fold), increased expressions of osteogenic marker genes, and more cell-synthesized bone minerals (about 2.5-fold), compared to CPC control and nonmagnetic IONP-CPC. In addition, IONP-CPC induced more active osteogenesis than CPC control in rat mandible defects. These results were consistent with the enhanced cellular performance by magnetic IONP in media under SMF. Moreover, nano-aggregates were detected inside the cells by transmission electron microscopy (TEM). Therefore, the enhanced cell performance was attributed to the physical forces generated by the magnetic field together with cell internalization of the released magnetic nanoparticles from IONP-CPC constructs.


Sustainable hydrogen production from bio-oil model compounds (meta-xylene) and mixtures (1-butanol, meta-xylene and furfural).
In the present work m-xylene and an equimolecular mixture of m-xylene, 1-butanol and furfural, all of them bio-oil model compounds, were studied in steam reforming (SR) conditions. Three different nickel catalysts, which showed to be active in 1-butanol SR (Ni/Al2O3, Ni/CeO2-Al2O3 and Ni/La2O3-Al2O3), were tested and compared with thermodynamic equilibrium values. Tests were carried out at temperatures from 800 to 600°C at atmospheric pressure with a steam to carbon ratio (S/C) of 5.0. Despite the different bio-oils fed, the amount of moles going through the catalytic bed was kept constant in order to obtain comparable results. After their use, catalysts were characterized by different techniques and those values were correlated with the activity results. All catalysts were deactivated during the SR of the mixture, mainly by coking. The highest hydrogen yields were obtained with Ni/Al2O3 and Ni/CeO2-Al2O3 catalysts in the SR of m-xylene and SR of the mixture, respectively.


Clinical consideration in referred muscle pain and tenderness. Connective tissue reactions.
Muscle pain and tenderness is caused either by changes in the muscle itself or by disease promoting factors outside the muscle. This paper gives a review of referred causes of muscle pain and tenderness with special emphasis on pathology in the strong supportive types of connective tissue.


Human newborns are deficient in natural killer activity.
The peripheral blood natural killer (NK) activity of newborns was found to be significantly less than that of adults. In mixing experiments newborn cells inhibited adult NK activity in only one of nine instances. Interferon treatment in vitro increased newborn NK activity to an even greater degree than adult NK activity. These findings imply that diminished newborn NK activity is due not to inhibitory cells or lack of pre-NK cells but rather to deficient in vivo activation of pre-NK cells. This deficiency may be a major factor in the increased susceptibility of newborns to certain virus infections.


LncRNA LOC101927514 regulates PM2.5-driven inflammation in human bronchial epithelial cells through binding p-STAT3 protein.
Long-term exposure to fine particulate matter (PM2.5) may cause or exacerbate many diseases, including respiratory inflammation. However, the full mechanism is not yet fully understood. The newly discovered long chain non-coding RNA, though unable to encode proteins, regulates multiple life activities and participates in the development of inflammation. In this study, we set up a cell inflammation model by using normal bronchial 16HBE cells exposed to PM2.5. High-throughput sequencing, as well as real-time fluorescent quantitative PCR detection and validation, was performed on the inflamed cells to evaluate the expression level of long chain noncoding RNA that helped us to identify the LncRNA LOC101927514. Inhibiting LncRNA LOC101927514 expression by RNAi, reflected in a reduction in inflammation, is driven by PM2.5. In addition, we identify LncRNA LOC101927514 to be located within the nucleus and binds to STAT3, altering the inflammatory state of the cells and IL6 and IL8 release. This study identifies that LncRNA LOC101927514 is a new potential target for future treatment of the inflammatory response activated by PM2.5 in the respiratory system.


Posterior Flange Cyclic Loading in a Novel Total Elbow Arthroplasty.
The goal of this study was to test the static and dynamic strength and loosening resistance of the posterior flange of a novel total elbow arthroplasty. We also examined the forces experienced by the ulnohumeral joint and the posterior olecranon during expected elbow use. Static stress analysis was performed for 3 flange sizes. Failure testing was conducted on 5 flanges (1 medium size and 4 small sizes). Loading occurred to reach 10,000 cycles. If this was accomplished, the cyclic load was increased until failure occurred. If failure occurred before 10,000 cycles, a lower force was employed. The safety factor for each implant size was calculated, and implant failure or loosening was observed. Static testing revealed a safety factor of 6.6, 5.74, and 4.53 for the small, medium, and large flanges, respectively. The medium-sized flange completed 10,000 cycles with 1,000 N at 1 Hz, and then the force was increased until it failed at 23,000 cycles. Two small-sized flanges failed at 2,345 and 2,453 cycles, respectively, when loaded with 1,000 N. Two more small flanges were loaded with 729 N for 10,000 cycles, and then the cyclic load was continued until they failed at 17,000 and 17,340 cycles, respectively. No screw loosening was noted in any specimens. This study demonstrates that the posterior flange withstood static and dynamic forces greater than what is expected during in vivo use of a novel total elbow arthroplasty design. Static strength calculation and cyclic loading demonstrate that the medium-sized posterior flange is stronger than the small-sized posterior flange. Ensuring that the ulnar body component and the posterior flange maintain secure connectivity with the polyethylene wear component may be beneficial to the proper function of a novel nonmechanically linked total elbow arthroplasty.


[Evaluation of pain in a neonatal intensive care unit during endocrine-metabolic tests].
To determine whether the pain suffered during the endocrine metabolic test can be lowered by adding skin to skin care to the use of sucrose. To establish factors that may modify the feeling of pain and evaluate the parents opinion during the extraction. Controlled clinical trial. Two groups: group 1 (n= 27), skin to skin and sucrose, and group 2 (n=27), sucrose. The pain was measured with the Neonatal Infant Pain Scale (NIPS) during the endocrine metabolic test. Patients on mechanical ventilation, with HIV III or IV and those who had been given sedative analgesics in the previous 24 hours were excluded. The average gestational age in group 1 was 35.1 +/- 3.5 weeks and 35.4 +/- 3.2 weeks for group 2. The NIPS in group 1 was 2.51 +/- 1.42 and 2.81 +/- 2.11 (NS) in group 2. On only one occasion was severe pain noticed (group 2). There was a tendency towards a higher NIPS with a higher gestational age (r=0.19) and a lower number of previous capillary (r= -0.06) and venous (r= -0.11) extractions. Group 1 parents thought that this practice contributed to decreasing their children's irritability and increased their trust in the care team. By adding skin to skin care to the sucrose during the endocrine metabolic test does not relieve the pain feeling. Parents in the skin to skin group thought that this practice contributed to decreasing their children's irritability and increased their trust in the care team.


Overall Survival is More Closely Associated with Peritoneal than Primary Appendiceal Pathological Grade in Pseudomyxoma Peritonei with Discordant Pathology.
The WHO classification of mucinous appendix neoplasms and pseudomyxoma peritonei (PMP) describes low- and high-grade histology and is of prognostic importance. The metastatic peritoneal disease grade can occasionally be different from the primary appendix tumor. This analysis aimed to report outcomes from a high-volume center in patients with pathological discordance. This was a retrospective analysis of prospective data of patients treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for PMP at a single institution between January 2016 and December 2020. Reporting was by pathologists with a special interest in peritoneal malignancy. Discordant pathology was classified as a low-grade primary appendix tumor with high-grade peritoneal disease, or a high-grade primary appendix tumor with low-grade peritoneal disease. Outcomes analyzed were overall and recurrence-free survival, and Kaplan-Meier survival curves and the log-rank test were used to analyze the outcomes. Between 2016 and 2020, 830 patients underwent CRS and HIPEC for PMP, of whom 37 (4.4%) had discordant pathology. The primary appendix tumors were low-grade in 23 patients and high-grade in 14 patients. The median Peritoneal Cancer Index (PCI) was significantly higher in patients with a low-grade primary tumor (31 vs. 16; p = 0.001), while complete cytoreduction (CC0/1) was achieved in 31/37 (83.8%) patients. The median follow-up was 19 months. Overall survival was worse in those with high-grade peritoneal disease (p = 0.029), whereas recurrence-free survival was similar in both groups (p = 0.075). In PMP with pathological discordance, the peritoneal disease grade influences prognosis and survival.


Removal of fatty acid labelled cholesterol ester, phospholipid and triglyceride from atherosclerotic rabbit aorta in vitro.
An organ culture technique was used to investigate the removal of fatty acids incorporated into various lipid fractions in intimal segments of atherosclerotic rabbit aorta. Segments of aorta were pulse-labelled in vitro with [9,10-3H]oleic acid and [1-14C]linoleic acid for 24 h. The incubation medium was replaced with non-radioactive medium and the removal of the endogenously labelled phospholipid, triglyceride and cholesterol ester was followed for a further period of 10 days. Fatty acids incorporated into phospholipid and triglyceride were removed rapidly from the aortic intima, with fractional half-times of 4--5 days. Cholesterol ester fatty acids were removed more slowly from the aortic intima with fractional half-times of 9--12 days. When the removal rate of oleic acid incorporated into phospholipid, triglyceride and cholesterol ester was compared with that of linoleic acid incorporated into the same lipid fractions, no difference between removal of the two fatty acids could be detected with respect to any of the 3 lipid fractions.


Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5.
Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild-type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders.


An approach to structural facial rejuvenation with fillers in women.
Newer understanding of volume loss as a critical component of facial aging and the integration of volume replacement into the surgical and nonsurgical therapeutic algorithm is arguably the most significant recent development in the field of facial rejuvenation. As all structural tissues play a role in the aging face, restoring youthful characteristics (or establishing them where they are congenitally absent) starts from the skeletal framework and builds progressively to the canvas of the face. The purpose of this article is to provide an introduction and brief summary of some of the current concepts concerning facial anatomy and the anatomy of facial aging, which serve as the basis for predictable and reproducible results with the use of injectable fillers. This article does not include the various types of fillers or techniques of filler injection, but covers how to decide where to use the filler and why, in different faces, as a result of the recognition and targeted correction of currently recognized specific anatomic deficiencies.


Machine learning for the early prediction of infants with electrographic seizures in neonatal hypoxic-ischemic encephalopathy.
To assess if early clinical and electroencephalography (EEG) features predict later seizure development in infants with hypoxic-ischemic encephalopathy (HIE). Clinical and EEG parameters <12 h of birth from infants with HIE across eight European Neonatal Units were used to develop seizure-prediction models. Clinical parameters included intrapartum complications, fetal distress, gestational age, delivery mode, gender, birth weight, Apgar scores, assisted ventilation, cord pH, and blood gases. The earliest EEG hour provided a qualitative analysis (discontinuity, amplitude, asymmetry/asynchrony, sleep-wake cycle [SWC]) and a quantitative analysis (power, discontinuity, spectral distribution, inter-hemispheric connectivity) from full montage and two-channel amplitude-integrated EEG (aEEG). Subgroup analysis, only including infants without anti-seizure medication (ASM) prior to EEG was also performed. Machine-learning (ML) models (random forest and gradient boosting algorithms) were developed to predict infants who would later develop seizures and assessed using Matthews correlation coefficient (MCC) and area under the receiver-operating characteristic curve (AUC). The study included 162 infants with HIE (53 had seizures). Low Apgar, need for ventilation, high lactate, low base excess, absent SWC, low EEG power, and increased EEG discontinuity were associated with seizures. The following predictive models were developed: clinical (MCC 0.368, AUC 0.681), qualitative EEG (MCC 0.467, AUC 0.729), quantitative EEG (MCC 0.473, AUC 0.730), clinical and qualitative EEG (MCC 0.470, AUC 0.721), and clinical and quantitative EEG (MCC 0.513, AUC 0.746). The clinical and qualitative-EEG model significantly outperformed the clinical model alone (MCC 0.470 vs 0.368, p-value .037). The clinical and quantitative-EEG model significantly outperformed the clinical model (MCC 0.513 vs 0.368, p-value .012). The clinical and quantitative-EEG model for infants without ASM (n = 131) had MCC 0.588, AUC 0.832. Performance for quantitative aEEG (n = 159) was MCC 0.381, AUC 0.696 and clinical and quantitative aEEG was MCC 0.384, AUC 0.720. Early EEG background analysis combined with readily available clinical data helped predict infants who were at highest risk of seizures, hours before they occur. Automated quantitative-EEG analysis was as good as expert analysis for predicting seizures, supporting the use of automated assessment tools for early evaluation of HIE.


Cold exposure aggravates pulmonary arterial hypertension through increased miR-146a-5p, miR-155-5p and cytokines TNF-α, IL-1β, and IL-6.
Cold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored. To explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model. Male Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1β, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR. The MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1β, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group. Cold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.


Hypothermia for cardiogenic encephalopathy in neonates with dextro-transposition of the great arteries.
Neonates with dextro-transposition of the great arteries (d-TGA) may experience rapid haemodynamic deterioration and profound hypoxaemia after birth. We report on d-TGA patients with severe acidosis, encephalopathy and their treatment with systemic hypothermia. This study is a single-centre retrospective cohort analysis of newborns with d-TGA. Ninety-five patients (gestational age ≥35 weeks) with d-TGA and intended arterial switch operation were included. Ten infants (10.5%) with umbilical arterial blood pH > 7.10 experienced profound acidosis (pH < 7.00) within the first 2 h of life. Six of these patients displayed signs of encephalopathy and received therapeutic hypothermia. Apgar scores at 5 min independently predicted the development of neonatal encephalopathy during postnatal transition (unit Odds Ratio 0.17, 95% confidence interval 0.06-0.49, P = 0.001). Infants treated with hypothermia had a more severe preoperative course and required more often mechanical ventilation (100% vs 35%, P = 0.003), treatment with inhaled nitric oxide (50% vs 2.4%, P = 0.002) and inotropic support (67% vs 3.5%, P < 0.001), as compared to non-acidotic controls. The median age at cardiac surgery was 12 (range 6-14) days in cooled infants and 8 (4-59) days in controls (P = 0.088). Postoperative morbidity and total duration of hospitalization were not increased in infants receiving preoperative hypothermia. Mortality in newborns with severe preoperative acidosis was zero. Newborn infants with d-TGA have a substantial risk for profound acidosis during the first hours of life. Systemic hypothermia for encephalopathic patients may delay corrective surgery without compromising perioperative outcomes.


Epidemiological profile and effectiveness of immediate postpartum contraception in Brazilian women.
To determine the epidemiological profile of women who inserted copper intrauterine device (Cu-IUD), subdermal etonogestrel implant (ENG), tubal ligation (TL), depot medroxyprogesterone acetate (DMPA) or did not choose a contraceptive method (NCM) in the immediate postpartum period and compare the contraceptive effectiveness of Cu-IUD and DPMA with non-MAC. We analyzed the epidemiological profile of women who inserted copper intrauterine device (Cu-IUD), subdermal etonogestrel implant (ENG), tubal ligation (TL), depot medroxyprogesterone acetate (DMPA) or did not choose a contraceptive method (NCM) in the immediate postpartum. The data was collected by electronic medical records of postpartum women assisted at the University Hospital of São Bernardo do Campo (HMU-SBC) from January 2016 to December 2020. Also, we compared the contraceptive effectiveness of Cu-IUD and DPMA with non-MAC by identifying women who returned for second delivery during the study period and analyzing the contraceptive method chosen in the first hospitalization. Then the pregnancies interval and the sociodemographic characteristics were analyzed according to contraceptive method type. Data from 20,896 women were collected, of which 8,183 (39%) opted for Cu-IUD, 559 (2.5%) DPMA, and 10,989 (52.5%) chose not to use contraception at the time of hospital discharge. When comparing these groups, women in the DPMA were younger (26.5 ± 7.3, p < 0.05), and NCM showed women with a lower number of pregnancies (2.2 ± 1.3, p < 0.05). Subjects in the TL group (4.6%) had the higher number of pregnancies (3.8 ± 1.2, p < 0.05), and ENG group, the highest number of miscarriages (1.6 ± 1.3, p < 0.05). Of those women who returned pregnant, 5.5% belonged to the DPMA group, 6% to the NCM group, and 2.3% to the Cu-IUD. Women who opted for Cu-IUD insertion were younger, had more pregnancies and vaginal delivery when compared to those who did not choose a method. Of those women who returned, the minority opted for Cu-IUD compared to those that opted for DPMA or no method.


Some effects of soil-moisture availability on above-ground production and reproductive allocation in Larrea tridentata (DC) Cov.
Data from the US/IBP Desert Biome validation studies indicate that above-ground production and biomass allocated to reproduction in Larrea tridentata vary from one year to another depending upon the timing and extent of soil-moisture availability. In an attempt to verify these observations and determine to what extent water availability can affect total aboveground production and reproductive allocation in this widely distributed warm desert shrub, a series of soil-moisture augmentation experiments were conducted. High levels of soil moisture had a greater effect on reproductive allocation than on total above-ground production. Enhanced soil moisture during the period of active growth increased total above-ground production and reduced the percentage of biomass allocated to reproduction. Enhanced soil moisture during the normal periods of little or no growth did not increase total above-ground production.


[Cochlear implants: state of knowledge, prospects, indications for implantation].
The authors present the development of totally deaf patients treatment program using cochlear implants. Based on leading Europeans Centers qualification basis and selection criteria are discussed for this method of treatment both for adults and children. Next given are indications for extracochlear and intracochlear implants. Summarizing, they evaluate possible results using the above implants and prospects for the development of this program in our country.


A novel multidomain polyketide synthase is essential for zeamine production and the virulence of Dickeya zeae.
Dickeya zeae is the causal agent of the rice foot rot disease, but its mechanism of infection remains largely unknown. In this study, we identified and characterized a novel gene designated as zmsA. The gene encodes a large protein of 2,346 amino acids in length, which consists of multidomains arranged in the order of N-terminus, β-ketoacyl synthase, acyl transferase, acyl carrier protein, β-ketoacyl reductase, dehydratase. This multidomain structure and sequence alignment analysis suggest that ZmsA is a member of the polyketide synthase family. Mutation of zmsA abolished antimicrobial activity and attenuated the virulence of D. zeae. To determine the relationship between antimicrobial activity and virulence, active compounds were purified from D. zeae EC1 and were structurally characterized. This led to identification of two polyamino compounds, i.e., zeamine and zeamine II, that were phytotoxins and potent antibiotics. These results have established the essential role of ZmsA in zeamine biosynthesis and presented a new insight on the molecular mechanisms of D. zeae pathogenicity.


Host serotonin axons innervate intrastriatal ventral mesencephalic grafts after implantation in newborn rats.
This study investigated the potential of immature and adult serotonin (5-HT) neurons for axonal growth into intrastriatal grafts of ventral mesencephalic tissue. Implantation of dissociated fetal (embryonic days 14-15) ventral mesencephalic tissue was carried out in immature [postnatal days (P) 5-14] and adult rat neostriatum. The brains were processed 2-6 months later for dopamine and 5-HT immunocytochemistry. A few grafts implanted into adult and P7 recipients contained small numbers of cotransplanted 5-HT cell bodies. These also displayed a rich network of 5-HT axons, even in adult rats prelesioned with 5,7-dihydroxytryptamine, indicating the graft origin of these axons. All other grafts were totally devoid of 5-HT cell bodies. After implantation in adults, such grafts contained rare 5-HT axons. In contrast, in P5-P7 recipients, they displayed many 5-HT fibres, which were uniformly distributed. Such was no longer the case after implantation in P14 recipients, which showed minimal 5-HT innervation, as in adult recipients. Processing of naïve rat brain at different ages for 5-HT immunocytochemistry showed that 5-HT axons were still clearly less numerous in the neostriatum at P21 than in adults, whereas in the substantia nigra the 5-HT innervation developed more rapidly and was comparable, at P21, to that of adults. It was concluded that 5-HT axons are able to grow into ventral mesencephalic grafts, but mainly at the fetal stage and with decreasing capacity after birth.(ABSTRACT TRUNCATED AT 250 WORDS)


Abnormalities of voluntary saccades in Gilles de la Tourette's syndrome: pathophysiological consideration.
Gilles de la Tourette's syndrome (TS) is a neurobehavioral disorder. Although the etiology and the pathophysiology of TS are still unknown, the involvement of the basal ganglia has long been postulated. On the other hand, saccadic eye movement was shown to be a useful measure to assess order and disorder of the function of the basal ganglia. To investigate the dysfunction of the basal ganglia of TS, we examined voluntary saccades in children with TS in comparison with the saccades in age-matched control children. Two kinds of saccades, visually-guided saccades (VGS) and memory-guided (MGS) saccades were evaluated. During the MGS, distracted saccades (DS), which indicate the distractibility, were examined. The results revealed the abnormalities in the parameters of the MGS, i.e. longer latencies and hypometric amplitudes, and decrease in the frequency of MGS. Whereas, the frequency of DS, the saccade to the predicted cue was significantly lower in younger patients (6-<9-years) than normal, but it was higher in the older TS children (9-<12-years). In addition, some of the patients showed large involuntary saccades, usually associated with eye blinks, during the task performance. These results suggest that in TS the basal ganglia fails to disinhibit the saccade neuron in the superior colliculus with the input of the frontal eye field to the striatum, and later allow the neurons to evoke non-goal directed saccades. In reference to abnormal saccades in other basal ganglia disorders with dopamine deficiency and to animal experiments with MPTP monkeys, these findings postulate primary hypodopaminergic state followed by upward regulation of dopamine receptors later in TS.


Silibinin exerts neuroprotective effects against cerebral hypoxia/reoxygenation injury by activating the GAS6/Axl pathway.
Ischemic stroke is regarded one of the most common causes of brain vulnerability. Silibinin (SIL), extracted from the seeds of Silybinisus laborinum L., has been found to exhibit obvious therapeutic effects on neurodegenerative diseases. GAS6 has been proven to have significant neuroprotective effects; however, the role of SIL and GAS6 in ischemic stroke remains unclear. This study aimed to investigate the protective effects of SIL against cerebral ischemia-reperfusion injury in neuroblastoma N2a cells, as well as the mechanisms involved. Firstly, the toxicity of SIL was evaluated, and safe concentrations were chosen for subsequent experiments. Then, SIL exerts significant neuroprotection against hypoxia/reoxygenation (HR) injury in N2a cells, as manifested by increased cell viability, decreased apoptotic rate, LDH, and ROS generation. Additionally, SIL was found to inhibit HR-induced apoptosis, mitochondria dysfunction, and oxidative stress. However, silencing of GAS6 inhibited the neuroprotective effects of SIL. To sum up, these results suggest that SIL may be a promising therapeutic agent for the treatment of ischemic stroke.


SH-containing compounds as allosteric effectors of glyceraldehyde-3-phosphate dehydrogenase.
The rate of hydrolysis of 3-phosphoglyceroyl-holoenzyme, a covalent intermediate of glyceraldehyde-3-phosphate dehydrogenase catalyzed reaction, is considerably decreased in the presence of micromolar concentrations of reduced glutathione, cysteine or dithiothreitol with Ki values of 0.78 microM, 0.6 microM and 10 microM, respectively. The maximal effect is achieved at a molar ratio [effector]/[tetrameric enzyme] close to unity, which points to subunit cooperatively involved in the stabilization of the covalent intermediate against hydrolysis. The effect is specific for acylholoenzyme conformation and insignificant in the case of hydrolysis of acylated apoenzyme species. The ability of the effectors to stabilize the reaction intermediate against spontaneous hydrolysis, in which water replaces inorganic phosphate as the acyl group acceptor, may be a factor contributing to the specificity and effectiveness of the enzyme catalysis.


Upward spirals of the heart: autonomic flexibility, as indexed by vagal tone, reciprocally and prospectively predicts positive emotions and social connectedness.
Vagal tone (VT), an index of autonomic flexibility, is linked to social and psychological well-being. We posit that the association between VT and well-being reflects an "upward spiral" in which autonomic flexibility, represented by VT, facilitates capitalizing on social and emotional opportunities and the resulting opportunistic gains, in turn, lead to higher VT. Community-dwelling adults were asked to monitor and report their positive emotions and the degree to which they felt socially connected each day for 9 weeks. VT was measured at the beginning and end of the 9-week period. Adults who possessed higher initial levels of VT increased in connectedness and positive emotions more rapidly than others. Furthermore, increases in connectedness and positive emotions predicted increases in VT, independent of initial VT level. This evidence is consistent with an "upward spiral" relationship of reciprocal causality, in which VT and psychosocial well-being reciprocally and prospectively predict one another.


The immunology of psoriasis and biologic immunotherapy.
In this review, we will discuss the immunological basis for psoriasis with special emphasis on the role of effector T cells. With the understanding of this immunologic process, we will present a model for the development of targeted immune response modifiers, termed biologic immunotherapies, and their potential role for the benefit of patients with psoriasis.


Aging and sperm signals alter DNA break formation and repair in the C. elegans germline.
Female reproductive aging is associated with decreased oocyte quality and fertility. The nematode Caenorhabditis elegans is a powerful system for understanding the biology of aging and exhibits age-related reproductive defects that are analogous to those observed in many mammals, including dysregulation of DNA repair. C. elegans germline function is influenced simultaneously by both reproductive aging and signals triggered by limited supplies of sperm, which are depleted over chronological time. To delineate the causes of DNA repair defects in aged C. elegans germlines, we assessed both DNA double strand break (DSB) induction and repair during meiotic prophase I progression in aged germlines which were depleted of self-sperm, mated, or never exposed to sperm. We find that germline DSB induction is dramatically reduced only in hermaphrodites which have exhausted their endogenous sperm, suggesting that a signal due specifically to sperm depletion downregulates DSB formation. We also find that DSB repair is delayed in aged germlines regardless of whether hermaphrodites had either a reduction in sperm supply or an inability to endogenously produce sperm. These results demonstrate that in contrast to DSB induction, DSB repair defects are a feature of C. elegans reproductive aging independent of sperm presence. Finally, we demonstrate that the E2 ubiquitin-conjugating enzyme variant UEV-2 is required for efficient DSB repair specifically in young germlines, implicating UEV-2 in the regulation of DNA repair during reproductive aging. In summary, our study demonstrates that DNA repair defects are a feature of C. elegans reproductive aging and uncovers parallel mechanisms regulating efficient DSB formation in the germline.


Identification of Calonectria colhounii Associated with Basal Stem Rot on Blueberry Seedlings Imported from the United States of America.
Basal stem rot symptoms were found on blueberry seedlings imported from the United States of America in 2008. The fungus obtained from the diseased seedlings was identified as Calonectria colhounii based on morphological and molecular characteristics. The consignments of the blueberry seedlings infected with C. colhounii were destroyed to prevent introduction of the fungus to Korea.


REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study- protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study.
Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable. The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period. This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants. NTR5670, EudraCT no 2016-002430-76.


Ki-67 reactivity in breast carcinoma analyzed by a computer-assisted image system: preliminary results.
The proliferative index of 63 breast carcinomas was measured on Ki-67 immunostained frozen tissue sections with a computer-assisted image analysis system. The mean proliferative index in estrogen-positive breast carcinomas was lower than in estrogen-negative carcinomas. An inverse relationship between proliferative index and short-term disease-free survival was noted.


Antifungal application of biosynthesized selenium nanoparticles with pomegranate peels and nanochitosan as edible coatings for citrus green mold protection.
Citrus production and trading are seriously affected by fungal decays worldwide; the green mold infection by Penicillium digitatum could be the most disastrous. The substitutions of chemical and synthetic fungicides with effectual natural alternatives are global demands; plant extract from pomegranates peels (PPE), biosynthesized selenium nanoparticles with PPE (PPE/SeNPs) and chitosan nanoparticles (NCT) were suggested as efficacious fungicidal agents/nanocomposites to control P. digitatum strains. PPE from Punica granatum was extracted and employed directly for synthesizing SeNPs, whereas NCT was produced using ionic gelation method of chitosan extracted from white prawn (Fenneropenaeus indicus) shells. The physiochemical, biochemical and structural characterization of generated molecules were conducted using infra-red spectroscopy, particles' size (Ps) and charge assessment and electron microscopes imaging. Antifungal potentialities were investigated in vitro and in infected fruits with P. digitatum by applying NCT nanocomposites-based edible coating. The synthesis of PPE-synthesized SeNPs and NCT was successfully achieved, the molecular bonding in synthesized agents/composites were proved with infrared spectroscopy to have both biochemical and physical interactions. The nanoparticles had 82.72, 9.41 and 85.17 nm mean diameters for NCT, PPE/SeNPs and NCT/PPE/SeNPs nanocomposites, respectively. The nanoparticles had homogenous spherical shapes and good distribution attributes. The entire agents/nanocomposites exhibited potent fungicidal potentialities toward P. digitatum isolates; NCT/PPE/SeNPs nanocomposite was the most forceful and significantly exceeded the fungicidal action of standard fungicide. The direct treatment of fungal mycelia with NCT/PPE/SeNPs nanocomposite led to remarkable lysis and deformations of P. digitatum hyphae within 12 h of treatment. The coating of infected orange with NCT-based edible coatings reduced the green mold infection signs by 91.7, 95.4 and 100%, for NCT, NCT/PPE and NCT/PPE/SeNPs based coating solutions, respectively. NCT, PPE-synthesized SeNPs, and their innovative nanocomposites NCT/PPE/SeNPs are convincingly recommended for formulating effectual antifungal and edible coatings to eliminate postharvest fungal pathogen, both with protection from their invasion or with destructing their existing infections.


Time-resolved, Cardiac-gated Computed Tomography After Endovascular Ascending Aortic and Arch Repair.
Better time-resolved imaging of stent grafts in the ascending aorta and arch accounting for cardiac motion is necessary to understand device-related complications and endoleaks. This report describes dynamic time-resolved computed tomographic angiography (d-CTA) and its combination with electrocardiography gating (d-gated CTA) to image stent grafts in the ascending aorta and to characterize endoleaks more clearly. d-CTA involves multiple scans acquired at different time points along the contrast enhancement curve. d-Gated CTA involves concomitant electrocardiography gating in a predefined cardiac phase minimizing motion-induced artifacts. This report illustrates the utility of d-CTA and d-gated CTA in 2 clinical cases. d-CTA demonstrated a type 1A endoleak in a patient with an aortic arch aneurysm treated with total arch debranching and a thoracic stent graft. d-gated CTA demonstrated a type 1A endoleak in a patient with an ascending aortic pseudoaneurysm treated with aortic cuff placement. Dynamic, cardiac-gated CTA enables time-resolved angiographic imaging of the ascending aorta and arch without any cardiac motion-related artifacts. Such advanced imaging techniques help with better characterization of endoleaks after stent graft deployment in the ascending aorta and arch.


Effect of dopamine depletion upon the K(+)-evoked release of CCK from superfused striatal slices.
The effect of a lack of dopamine (DA) in the striatum upon the K(+)-evoked release of cholecystokinin (CCK) from superfused rat striatal slices has been studied. Two pharmacological tools were used to deplete the nigrostriatal DA system: administration of alpha-methyl-p-tyrosine which competitively inhibits DA synthesis and lesions with 6-hydroxydopamine of the medial forebrain bundle. In both cases there was a significant inhibition of the K(+)-evoked release of CCK. The observed effects might be relevant on pathological conditions implying depletion of the DA system.


Transformation of bimetallic Ag-Cu thin films into plasmonically active composite nanostructures.
Formation of plasmonically active silver, copper and composite silver-copper nanostructures were studied in this paper. Metallic nanostructures were fabricated by thermal disintegration, so called dewetting, of the thin films in an argon atmosphere. The formation process of the nanostructures was in-situ observed by a novel method, based on resistance measurements. The influence of the material and thickness of the initial thin film on temperature of their disintegration was investigated. Electrical measurements were validated by scanning electron microscopy observations, while metallic the behavior of nanostructures was studied by XPS method. The formation of silver-copper nanocomposite structures was confirmed by UV-vis spectroscopy. Plasmon resonance with two characteristic peaks for nanocomposite structures was observed.


Rapid detection of six common Chinese G6PD mutations by MALDI-TOF MS.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked hereditary enzymopathy. We describe here the techniques based on matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) and multiprimer extension (multi-PEX) to detect the most common Chinese G6PD mutations, which are the single-point mutations G-->T at nt 1376, G-->A at nt 1388, A-->G at nt 95, G-->T at nt 392, C-->T at nt 1024, and C-->T at nt 1311. Fifteen samples were genotyped using this method coupled with direct sequencing, after identification of G6PD mutations by ARMS. In this study, we identified a mutation G-->T at nt 1376, which had been G-->A at nt 1388 using ARMS, while the result of sequencing corresponds with ours. This indicates the reliability of this method. Furthermore, since it can scan six common Chinese G6PD mutations simultaneously in one mass spectrum, this approach could be used to fast diagnose these G6PD mutations accurately in large-scale analysis.


Isolation and partial characterization of a cadmium-binding protein from the American oyster (Crassostrea virginica).
American oysters (Crassostrea virginica) were exposed to 0.1 ppm cadmium for 0--15 days in a flowing seawater system and then placed into clean flowing seawater for 24 h prior to sacrifice. Whole oysters were homogenized and a cadmium-binding protein isolated and purified by a process of centrifugation, heat-treatment, Sephadex G-75 chromatography, DEAE cellulose chromatography and disc gel electrophoresis. A highly anionic protein which is not present in control oysters was found to be present in cadmium-exposed animals after 3 days of treatment and to increase in concentration at succeeding time points. The protein does not extensively bind zinc or copper. Amino acid analysis of the purified protein disclosed an amino acid composition characterized by a high percentage of dicarboxylic amino acids and relatively little cysteine.


Cloning and functional analysis the first NLRC4-like gene from the sea cucumber Apostichopus japonicus.
The NOD-like receptor family member 4 (NLRC4) plays a crucial role in regulating the innate immune responses and cell apoptosis pathways in vertebrates. However, the function of the NLRC4 counterpart in invertebrates remains elusive. In this study, the first NLRC4-like gene was cloned and characterized from Apostichopus japonicus (designated as AjNLRC4-like) with RACE technology. The full-length cDNA of the AjNLRC4-like gene was 4065 bp, which consisted of a 5'-untranslated region (UTR) of 387 bp, a 3'-UTR of 159 bp, and a complete open reading frame of 3519 bp encoding a polypeptide of 1172 amino acid residues. Structural analysis revealed that AjNLRC4-like protein contained two IG domains (31-132 and 251-353 amino acids), a common NACHT (600-757 amino acids), and no LRR and CARD domains compared with the vertebrate NLRC4. Spatial expression analysis revealed that the AjNLRC4-like was ubiquitously expressed in all the examined tissues with larger magnitude in the intestine. The mRNA expression of the AjNLRC4-like was significantly upregulated by 2.86- and 2.92-fold at 24 h after the Vibrio splendidus challenge in vivo and the lipopolysaccharide (LPS) treatment in vitro, respectively, compared with that of the control group. The purified recombinant AjNLRC4-NACHT protein displayed higher binding activities to various pathogen-associated molecular patterns (PAMPs), including LPS, peptidoglycan, and mannan. Further functional analysis indicated that the apoptosis of coelomocytes was significantly inhibited by 11.37% after specific AjNLRC4-like siRNA treatment, and the inflammatory caspase Ajcaspase-1 was synchronously decreased by 0.28-fold in the same condition. Collectively, these results supported that the uncanonical AjNLRC4-like protein may share similar functions to the vertebrate NLRC4 as the pattern recognition receptor and in mediating coelomocyte apoptosis in the pathogen-challenged sea cucumber.


Mechanisms involved in postconditioning protection of cardiomyocytes against acute reperfusion injury.
Experimental and clinical studies demonstrated that postconditioning confers protection against myocardial ischemia/reperfusion injury. However the underlying cellular mechanisms responsible for the beneficial effect of postconditioning are still poorly understood. The aim of the present study was to examine the role of cytosolic and mitochondrial Ca(2+)-handling. For this purpose adult rat cardiomyocytes were subjected to simulated in vitro ischemia (glucose-free hypoxia at pH6.4) followed by simulated reperfusion with a normoxic buffer (pH7.4; 2.5 mmol/L glucose). Postconditioning, i.e., 2 repetitive cycles of normoxic (5s) and hypoxic (2.5 min) superfusion, was applied during the first 5 min of reoxygenation. Mitochondrial membrane potential (ΔΨm), cytosolic and mitochondrial Ca(2+) concentrations, cytosolic pH and necrosis were analysed applying JC-1, fura-2, fura-2/manganese, BCECF and propidium iodide, respectively. Mitochondrial permeability transition pore (MPTP) opening was detected by calcein release. Hypoxic treatment led to a reduction of ΔΨm, an increase in cytosolic and mitochondrial Ca(2+) concentration, and acidification of cardiomyocytes. During the first minutes of reoxygenation, ΔΨm transiently recovered, but irreversibly collapsed after 7 min of reoxygenation, which was accompanied by MPTP opening. Simultaneously, mitochondrial Ca(2+) increased during reperfusion and cardiomyocytes developed spontaneous cytosolic Ca(2+) oscillations and severe contracture followed by necrosis after 25 min of reoxygenation. In postconditioned cells, the collapse in ΔΨm as well as the leak of calcein, the increase in mitochondrial Ca(2+), cytosolic Ca(2+) oscillations, contracture and necrosis were significantly reduced. Furthermore postconditioning delayed cardiomyocyte pH recovery. Postconditioning by hypoxia/reoxygenation was as protective as treatment with cyclosporine A. Combining cyclosporine A and postconditioning had no additive effect. The data of the present study demonstrate that postconditioning by hypoxia/reoxygenation prevents reperfusion injury by limiting mitochondrial Ca(2+) load and thus opening of the MPTP in isolated cardiomyocytes. These effects seem to be supported by postconditioning-induced delay in pH recovery and suppression of Ca(2+) oscillations.