Brentuximab Vedotin Infusion Reaction Management: A Case Study.
We report a case of a grade 3 (Common Terminology Criteria for Adverse Events [CTCAE]) infusion reaction to brentuximab vedotin (Adcetris), in a patient with refractory Hodgkin lymphoma, at a large National Cancer Institute-designated cancer center in the Midwest (National Cancer Institute, 2010). Acute infusion reaction management and subsequent premedication strategies are outlined. Ms. R is a 30-year-old woman who presented with stage IV Hodgkin lymphoma at the age of 29. Initial staging revealed lymphadenopathy above and below the diaphragm, as well as fluorodeoxyglucose (FDG)-avid lung lesions, splenic lesions, and multiple sites of bony involvement. Bone marrow biopsy was negative. She was treated with six cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), to which she obtained a complete response by positron emission tomography-computed tomography (PET-CT) criteria. Ten months after chemotherapy completion, she presented with new PET-avid adenopathy in the cervical and paratracheal regions, and a biopsy revealed recurrent Hodgkin lymphoma. Salvage chemotherapy was administered with ifosfamide carboplatin, and etoposide (ICE). After two cycles of salvage chemotherapy, a PET-CT confirmed a complete response, and she proceeded to an autologous stem cell transplant with a preparative regimen of carmustine, etoposide, cytosine arabinoside, and melphalan (BEAM). Brentuximab vedotin consolidation therapy was prescribed in the post-transplant consolidation setting, beginning 45 days after stem cell reinfusion, given the patient's high risk for recurrence. This strategy was based upon the results of the AETHERA phase III clinical trial (Moskowitz et al., 2015), showing improvement in progression-free survival with brentuximab vedotin consolidation therapy, post autologous transplant. The first dose of brentuximab vedotin was administered without difficulty, at full dose (1.8 mg/kg) at a standard infusion time of 30 minutes. The second dose of brentuximab vedotin was complicated by nausea, chest pain, and dysphagia within 10 minutes of medication initiation. Upon the emergence of these symptoms, the brentuximab vedotin infusion was held. Vital signs were stable, with a temperature of 36.9˚C, pulse 84, respirations of 20, and blood pressure of 107/67 mm Hg. Oxygen saturations were 99% on room air. Diphenhydramine (50 mg) was administered intravenously (IV), along with 20 mg of IV famotidine. An electrocardiogram (ECG) was obtained, which was unremarkable, showing normal sinus rhythm. Fifteen minutes later, the symptoms of chest pain and shortness of breath persisted, so hydrocortisone at 100 mg IV was administered, with an additional 25 mg of IV diphenhydramine and 20 mg of IV famotidine. Intraveous granisetron was given for nausea. Thirty minutes after onset, the chest pain was persistent, and oxygen saturations were normal. Hydrocortisone (50 mg) was administered intravenously, and Ms. R's condition improved, with resolution of her symptoms within 30 minutes of the second hydrocortisone dose. The brentuximab vedotin was restarted 30 minutes after symptom resolution at a decreased infusion rate to be administered over 60 minutes. Thirty minutes later, however, Ms. R developed tingling and numbness in her feet and tongue. The brentuximab vedotin infusion was again held, and 100 mg of IV methylprednisolone was administered. Ms. R's symptoms resolved within 40 minutes, and the brentuximab vedotin infusion was able to be continued over a prolonged period of more than 4 hours. Vital signs were checked every 15 minutes during the infusion reaction and remained stable throughout. The infusion was discontinued with 40 mg of drug remaining, due to the prolonged infusion time. Given the clear benefits of brentuximab consolidation in improving progression-free survival post transplant (Moskowitz et al., 2015) in high-risk Hodgkin lymphoma, it was thought the benefit of brentuximab vedotin consolidation outweighed the possible risks of subsequent infusions. Upon reviewing the available literature regarding brentuximab vedotin hypersensitivity reactions, which will be outlined in the discussion summary, we instituted the premedication strategy for subsequent infusions outlined in the Table on p 628. Standard epinephrine and methylprednisolone were available at the bedside in the event of any anaphylactic reaction. This regimen was chosen based on the clinical rationale for H1 and H2 blockade, as well as corticosteroid and antipyretic coverage, in the prevention of hypersensitivity reactions, not classified as anaphylaxis. With the institution of the outlined premedications, Ms. R tolerated subsequent infusions well, at full dose and at standard infusion rates, with no documented infusion reactions, and was able to complete a total of 16 cycles of consolidation therapy.


[Conception, implementation and evaluation of the new general medicine continuing education curriculum in Südbaden].
Since 1994, seminars for the new curriculum in general practice are conducted by the Academy of Continuing Medical Education (consists of the regional medical board and the association of public health insurance in Südbaden). Specialists of different medical disciplines supported by general practitioners in the role of moderators are preparing and teaching a wide range of topics. The general practitioners are supervising the different courses, thus, facilitating the learning process of the participants. Furthermore, the facilitators have to work out the specific needs and requirements of general practice and family medicine. The topics are presented in a form of lessons and clinical cases discussed in small groups (problem-oriented approach). The evaluation of two seminars was carried out in 1994 and 1995 including two thirds of the complete curriculum in general practice. From the positive results of the evaluation, modification and improvement of the didactic concept for future seminars in 1996 are derived.


Probuphine® (buprenorphine implant): a promising candidate in opioid dependence.
Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits.


Exact maximal height distribution of fluctuating interfaces.
We present an exact solution for the distribution P(h(m),L) of the maximal height h(m) (measured with respect to the average spatial height) in the steady state of a fluctuating Edwards-Wilkinson interface in a one dimensional system of size L with both periodic and free boundary conditions. For the periodic case, we show that P(h(m),L)=L(-1/2)f(h(m)L(-1/2)) for all L>0, where the function f(x) is the Airy distribution function that describes the probability density of the area under a Brownian excursion over a unit interval. For the free boundary case, the same scaling holds, but the scaling function is different from that of the periodic case. Numerical simulations are in excellent agreement with our analytical results. Our results provide an exactly solvable case for the distribution of extremum of a set of strongly correlated random variables.


Functional genomics of apocarotenoids in saffron: insights from chemistry, molecular biology and therapeutic applications.
Saffron is considered to be the costliest spice of the world. It has been regarded as highly valued medicinal plant in Ayurveda to treat various ailments. Over the past few years, considerable interest has developed in saffron because of its anticancer, antimutagenic, antioxidant and immunomodulatory properties. Saffron's colour, bitter taste and aroma are its three main and peculiar characteristics, which are conferred by three chemicals namely: crocin, picrocrocin and safranal, respectively. The present review focuses on recent research/progress made in saffron in the area of functional genomics and highlights the potential of several genes and transcription factors involved in carotenoid/apocarotenoid pathway and responsible for flavour and aroma of saffron.


Involvement of the H3.3 Histone Variant in the Epigenetic Regulation of Gene Expression in the Nervous System, in Both Physiological and Pathological Conditions.
All the cells of an organism contain the same genome. However, each cell expresses only a minor fraction of its potential and, in particular, the genes encoding the proteins necessary for basal metabolism and the proteins responsible for its specific phenotype. The ability to use only the right and necessary genes involved in specific functions depends on the structural organization of the nuclear chromatin, which in turn depends on the epigenetic history of each cell, which is stored in the form of a collection of DNA and protein modifications. Among these modifications, DNA methylation and many kinds of post-translational modifications of histones play a key role in organizing the complex indexing of usable genes. In addition, non-canonical histone proteins (also known as histone variants), the synthesis of which is not directly linked with DNA replication, are used to mark specific regions of the genome. Here, we will discuss the role of the H3.3 histone variant, with particular attention to its loading into chromatin in the mammalian nervous system, both in physiological and pathological conditions. Indeed, chromatin modifications that mark cell memory seem to be of special importance for the cells involved in the complex processes of learning and memory.


Protein engineering of a nitrilase from Burkholderia cenocepacia J2315 for efficient and enantioselective production of (R)-o-chloromandelic acid.
The nitrilase-mediated pathway has significant advantages in the production of optically pure aromatic α-hydroxy carboxylic acids. However, low enantioselectivity and activity are observed on hydrolyzing o-chloromandelonitrile to produce optically pure (R)-o-chloromandelic acid. In the present study, a protein engineering approach was successfully used to enhance the performance of nitrilase obtained from Burkholderia cenocepacia strain J2315 (BCJ2315) in hydrolyzing o-chloromandelonitrile. Four hot spots (T49, I113, Y199, and T310) responsible for the enantioselectivity and activity of BCJ2315 were identified by random mutagenesis. An effective double mutant (I113M/Y199G [encoding the replacement of I with M at position 113 and Y with G at position 199]), which demonstrated remarkably enhanced enantioselectivity (99.1% enantiomeric excess [ee] compared to 89.2% ee for the wild type) and relative activity (360% of the wild type), was created by two rounds of site saturation mutagenesis, first at each of the four hot spots and subsequently at position 199 for combination with the selected beneficial mutation I113M. Notably, this mutant also demonstrated dramatically enhanced enantioselectivity and activity toward other mandelonitrile derivatives and, thus, broadened the substrate scope of this nitrilase. Using an ethyl acetate-water (1:9) biphasic system, o-chloromandelonitrile (500 mM) was completely hydrolyzed in 3 h by this mutant with a small amount of biocatalyst (10 g/liter wet cells), resulting in a high concentration of (R)-o-chloromandelic acid with 98.7% ee, to our knowledge the highest ever reported. This result highlights a promising method for industrial production of optically pure (R)-o-chloromandelic acid. Insight into the source of enantioselectivity and activity was gained by homology modeling and molecular docking experiments.


[Evaluation of neutrophile elastase and isoprostane 8epiPGF2alpha concentrations in maternal and umbilical cord blood serum and in amniotic fluid in pregnancies complicated by premature rupture of membranes].
To evaluate the total isoprostane 8-epi-PGF2alpha and neutrophil elastase (NE) concentrations in pregnancies complicated by premature rupture of membranes (PROM). 128 pregnant women were divided into four groups: pregnancies complicated by PROM between 24.-36.(PPBP-N) and between 38 a 41 weeks of gestation (PPBP-D), uncomplicated pregnancies between 24-36 gestation weeks (K1) and pregnancies delivered by cesarean section (before uterine contractions had started) after 38 weeks (K2). The concentrations of NE and isoprostane 8-epi-PGF2alpha were measured in maternal serum, cord blood serum and in the amniotic fluid. The following study revealed higher concentrations of NE in maternal serum and in the amniotic fluid than in the umbilical cord blood in PROM cases, and lower amniotic fluid than maternal serum concentrations in the control groups. Also, the levels of isoprostane differentiated between compartments in particular groups. In both groups complicated with PROM, higher maternal serum and amniotic fluid NE concentrations than in controls were found. There were no differences in isoprostane levels between the groups. 1. Higher concentrations of NE in maternal blood serum and in the amniotic fluid than in the umbilical cord blood in PROM cases, as well as lower amniotic fluid than maternal serum concentrations in the controls, may be connected with pathogenesis of PROM. 2. Differentiated maternal serum, cord serum and amniotic fluid isoprostane concentrations may suggest various intensity of oxidative stress in particular compartments. 3. Lack of differences in maternal serum, cord serum and amniotic fluid isoprostane concentrations may suggest similar intensity of oxidative stress in cases with PROM and intact membranes.


Effect of dietary protein on intake, nutrients utilization, nitrogen balance, blood metabolites, growth and puberty in growing Bhadawari buffalo (Bubalus bubalis) heifers.
Fifteen Bhadawari buffalo heifers of 207 ± 9.78 kg mean body weight were randomly distributed into three dietary groups to evaluate the effect of protein level on nutrient utilization, nitrogen (N) balance, growth rate, blood metabolites, and puberty. All animals were offered wheat straw-berseem diets supplemented with concentrate mixtures of similar energy (2.7 Mcal/kg) and different protein levels (14.3-22%). Animals of standard-protein group (SPG) were offered protein and energy as per requirement, while animals of low-protein group (LPG) and high-protein group (HPG) were fed 20% less and 20% more protein, respectively, than SPG. Feed dry matter (DM) and metabolizable energy (ME) intake (% body wt. and g/kg w(0.75)) were similar for all three diets; however, the crude protein (CP) and digestible crude protein (DCP) intake on percent body weight and per kilogram metabolic weight was higher (P < 0.05) in HPG than in SPG or LPG. Digestibility of CP, cellulose, and hemicellulose was higher (P < 0.05) in HPG versus LPG. Fecal N excretion was similar, while urinary N excretion was highest (P < 0.05) in HPG (74.83 g/day) compared with SPG (50.03 g/day) and LPG (47.88 g/day), which resulted in lower N retention in HPG than in the other dietary groups. Level of dietary N had no effect on blood metabolites viz. glucose, urea, and N. Digestible energy (DE) and ME contents of diets were identical, while DCP contents were higher (P < 0.05) in HPG than in LPG. Feed and nutrient (CP and ME) conversion efficiency to produce a unit kilogram weight gain was identical among the dietary groups. Dietary protein level had no effect on the heifer's weight and age at puberty. The mean growth rate of heifers at 240 days was higher (P > 0.05) in SPG (330.8 g/day) than in LPG (296.7 g/day), while the animals gained more weight in January to March months and the lowest weight in May to July months. Protein level had no effect on conception rate of heifers. Results revealed that 20% higher or less protein than the ICAR requirement had no significant (P > 0.05) on feed intake, nutrient conversion efficiency for weight gain, heifer growth, and puberty; however, 20% more protein increased urinary N loss.


Anesthetic management of patients with carnitine deficiency or a defect of the fatty acid β-oxidation pathway: A narrative review.
Carnitine is essential for the transport of long-chain fatty acids from the cytoplasm to the mitochondrial matrix. The carnitine shuttle transports long-chain fatty acylcarnitine to the mitochondrial matrix. Subsequently, long-chain fatty acyl CoA, which is split from long-chain fatty acylcarnitine by carnitine palmitoyltransferase II, undergoes fatty acid β-oxidation. Acetyl CoA is produced from long-chain fatty acyl CoA via fatty acid β-oxidation and aids in the synthesis of adenosine triphosphate via the tricarboxylic acid cycle and electron transport chain. In addition, in the fasting state, it leads to ketone body production in the liver and glucose production via gluconeogenesis. However, patients with compromised fatty acid β-oxidation, owing to carnitine deficiency as well as defects in carnitine transport and the fatty acid β-oxidation pathway, develop hypoglycemia, cardiomyopathy, arrhythmia, and hypotonia. These conditions are attributed to the accumulation of released fatty acids and acylcarnitine. This review aimed to shed light on the anesthetic management of patients with compromised fatty acid β-oxidation undergoing various surgeries by assessing relevant case reports associated with fatty acid β-oxidation disorder in PubMed. Pre-anesthetic and intraoperative evaluation should include monitoring of glucose and carnitine levels and specific cardiac tests, such as echocardiography. Considering that propofol is dissolved in 10% long-chain fatty acids, propofol infusion should be avoided because of increased long-chain fatty acid loading in patients with compromised fatty acid β-oxidation. Thus, anesthesia using opioids (remifentanil and fentanyl), midazolam, dexmedetomidine, etomidate, and non-depolarizing neuromuscular blocking agents would be appropriate in such patients.


Absence of sperm with rapid motility is not detrimental to IVF outcome measures when ICSI is used.
The objective of the current study was to investigate the association between rapid motility of sperm and IVF outcome when ICSI is used for insemination of oocytes. The first IVF cycle of women up to age 42 were evaluated. Patients were classified into groups by the presence/absence of sperm with rapid motility ("A" sperm) in the specimen before and after sperm preparation. Group 1 had 0% A sperm prewash and 0% A postwash (n = 45); Group 2 had 0% A sperm prewash but some A sperm postwash (n = 47); Group 3 had A sperm both pre and postwash (n = 141). Statistical analysis demonstrated no difference in the fertilization, PRs, or implantation rates in the three groups. These data suggest that absence of sperm with rapid motility postseparation of sperm from seminal plasma is not detrimental to IVF outcome when ICSI is used for insemination.


CYANOS: a data management system for natural product drug discovery efforts using cultured microorganisms.
A software package, termed "CYANOS", has been developed to facilitate the data management and mining for natural product drug discovery efforts. This system allows for the management of data associated with field collections, culture conditions, harvests, extractions, chemical separations, and biological evaluation. This software utilizes a MySQL database for data storage, which allows for reporting and data mining via third party tools. In addition, a Web-based interface was constructed to allow for multiuser access from a variety of desktop platforms. The code for this system is freely available and has been released under the Illinois Open Source license.


Intercalar satellites of human acrocentric chromosomes as a cytological manifestation of polymorphism in GC-rich material?
Fifteen unrelated individuals were found among the patients of the Cytogenetics Laboratory who possessed multiple-satellited marker chromosomes (14 with double satellites and 1 with triple satellites). Cytogenetic analysis was carried out by means of a conventional staining method and also by R, C, and Q banding and by the technique of silver staining. The intercalar structures of all 15 cases differed from the terminal satellites in their biochemical composition: they were resistant to heat denaturation, and stained heavily with the R-banding technique. Accordingly, they consisted of GC-rich material identical with that which in varying quantity is a regular constituent of the short arms of acrocentric chromosomes. The findings described indicate that any larger accumulation of such R band-positive material tends to dissociate from the basal segment of short arms by a proximal secondary constriction. We therefore assume that the formation of intercalar satellites may be interpreted as a cytological consequence of extreme natural R polymorphism.


Hemorrhage From Left Hepatic Artery Pseudoaneurysm as a Complication of Acute Pancreatitis in a Patient With Fibromuscular Dysplasia.
Hepatic artery pseudoaneurysms are a rare complication of pancreatitis, and their rupture and bleeding cause high mortality. We present the case of a 76-year-old woman with fibromuscular dysplasia who developed a new left hepatic artery pseudoaneurysm within a week of her first episode of acute pancreatitis and later suffered an acute pseudoaneurysm bleed successfully treated with transcatheter coil embolization. To the best of our knowledge, this is the first case reported of a patient with fibromuscular dysplasia with pancreatitis-related pseudoaneurysm formation. One must consider pseudoaneurysms and associated bleeding as complications of acute pancreatitis because prompt recognition can lead to timely management.


Facile Nanocasting of Dielectric Metasurfaces with Sub-100 nm Resolution.
This work presents a facile nanocasting technique to fabricate dielectric metasurfaces at low cost and high throughput. A flexible polymer mold is replicated from a master mold, and then the polymer mold is used to shape particle-embedded UV-curable polymer resin. The polymer mold is compatible with flexible and curved substrates. A hard-polydimethylsiloxane improves mechanical stability of the polymer mold providing sub-100 nm patterning resolution. The patterned resin itself can work as a metasurface without secondary operations because dielectric particles sufficiently increase the refractive index of the resin. The absence of the secondary operations allows our method to have higher productivity and cost competitiveness than those of typical nanoimprint lithography. Experimental demonstration verifies the feasibility of our method, and the replicated metasurface exhibits a conversion efficiency of 46% in the visible, which is comparable to metasurfaces based on low-loss dielectrics. Given that conventional dielectric metasurfaces have been fabricated by electron beam lithography at formidable cost due to low throughput, our method will be a promising nanofabrication platform and thereby facilitate commercialization of dielectric metasurfaces.


Imiquimod-induced ROS production disrupts the balance of mitochondrial dynamics and increases mitophagy in skin cancer cells.
Mitochondrial homeostasis is a highly dynamic process involving continuous fission and fusion cycles and mitophagy to maintain mitochondrial functionality. Imiquimod (IMQ), a Toll-like receptor (TLR) 7 ligand, is used to treat various skin malignancies. IMQ also induces apoptotic and autophagic cell death in various cancers through a TLR7-independent pathway. To investigate whether IMQ-induced ROS production is involved in mitochondrial dysfunction, mitochondrial fragmentation and mitophagy in skin cancer cells. BCC/KMC-1, B16F10 and A375 skin cancer cells, AGS gastric cancer cells and primary human keratinocytes were treated with 50 μg/mL IMQ. After 4 h, ROS were detected by CM-H2DCFDA, DHE, and MitoSOX Red staining. After 24 h, cell viability and the mitochondrial membrane potential were evaluated by a CCK-8 assay and JC-1 staining, respectively. Oxygen consumption was assessed with an Oroboros instrument. Mitochondrial morphology and mitophagy were evaluated by MitoTracker and LysoTracker staining. Mitochondrial dynamics markers, including MFN-1, DRP-1 and OPA1, and mitophagy markers, including LC3, S65-phosphorylated ubiquitin, PINK1 and TOM20, were detected by immunoblotting. IMQ not only induced severe ROS production but also resulted in increased mitochondrial membrane potential loss, mitochondrial fission and mitophagy and decreased oxygen consumption in skin cancer cells compared with normal keratinocytes. Pretreatment with the antioxidant NAC reduced IMQ-induced ROS production and attenuated IMQ-induced mitochondrial fission and mitophagy in skin cancer cells. IMQ-induced ROS might be associated with mitochondrial dysfunction, mitochondrial fission and mitophagy in cancer cells. Alleviating IMQ-induced ROS production would reduce mitochondrial fission-to-fusion skewing and further reduce IMQ-induced mitophagy.


Prevention and Management Following Complications from Endourology Procedures.
Endourologic procedures are very common in daily urologic practice for treatment of benign prostatic obstruction, stone disease, urothelial tumors, or stenosis. To characterize the complications following endoscopic procedures, to describe their management, and to gather information about their prevention in current urologic practice. A review of the literature was conducted using PubMed/Medline database to include the most relevant articles on the topic. The search focused on endoscopic approaches for treatment of prostate, bladder, or upper urinary tract disease. Percutaneous approaches and noninvasive extracorporeal techniques were excluded. Complications of endourologic procedures were identified through level 1 evidence, systematic reviews of the literature, or original articles assessing complications as the primary end point. Data about management and prevention of each type of complication were retrieved in a second round using specific keywords. Complications of endoscopic urologic procedures are specific to each surgical approach. Main complications after prostate surgery include transurethral resection of the prostate syndrome, bleeding and transfusion, acute urinary retention, urinary tract infection, clot retention, postoperative irritative symptoms, ejaculatory dysfunction, urinary incontinence, bladder neck contracture, and urethral stricture. Major complications after transurethral bladder tumor include severe bleeding, transfusion, bladder perforation, and urinary tract infection. The most frequent complications after ureteroscopy are fever and sepsis, bleeding, steinstrasse, and ureteral injury. Overall, the literature is very poor, with no systematic reporting of complications and underuse of classification systems. No clear protocols are available for management of complications, and most are based on studies with low levels of evidence. Good clinical practice recommendations and guidelines give useful support about technical issues, intraoperative safety, and prevention of urinary tract infection. The efficacy of these preventive measures remains poorly investigated. Complications following endoscopic surgery are potentially numerous and vary with patient characteristics, surgical approach, and type of medical device. Improved standardization and quality of publications are warranted to improve knowledge of these issues, which are directly linked to the level of care. We focused on the potential complications of each endoscopic approach used to treat urologic disease. We described the frequency of these complications and gathered information about how to manage them in the operating theater. We also noted caveats for the literature regarding standardization of reporting and classification systems.


Childhood systemic sclerosis.
Juvenile systemic sclerosis has a variety of clinical manifestations, sometimes different from the adult form. Early recognition, proper classification and treatment may improve the long-term outcome. A large multicenter study coordinated by the Pediatric Rheumatology European Society has yielded important information on the epidemiology and clinical manifestations of systemic sclerosis in childhood. An ad-hoc Committee on Classification Criteria for Juvenile Systemic Sclerosis developed the new classification criteria to help improve patient care by enabling earlier, more definite diagnoses and standardizing the conduct of clinical, epidemiologic, and outcome research for this rare disease. The overall outcome of children with systemic sclerosis is better than in adults but, in those cases with a fatal course, disease progression is rapid and an early involvement of internal organs is associated with poor outcome. Studies over the past few years have highlighted the peculiar clinical features and the better outcome of juvenile systemic sclerosis compared with the adult form and propose new pediatric classification criteria. Efforts have recently been made to address the definition of evidence-based recommendations for the treatment of adult and pediatric onset systemic sclerosis.


Development of a new interfacility extracorporeal membrane oxygenation transport program for pediatric lung transplantation evaluation.
Pediatric lung transplantation is a life-saving intervention for children with irreversible end-stage lung disease. Access to transplant can be limited by geographic isolation from a center or the presence of comorbidities affecting transplant eligibility. Extracorporeal membrane oxygenation (ECMO)-supported patients are an uncommon but historically high-risk cohort of patients considered for lung transplant. We report the development of a service at our center to provide transport services to our hospital for patients unable to wean from ECMO support at their local institution for the purpose of evaluation for lung transplantation by our program. We developed a process for pre-transport consultation by the lung transplant physician team, standardized hand-off tools and equipment lists, and procedures for transitioning patients to transport ECMO machinery. Four patients have been transported to date including fixed wing (FW) and helicopter transports. All patients were successfully transported with either none or minor complications. Transport of ECMO-supported patients is a feasible method to increase access of patients with irreversible lung injured patients to evaluation for lung transplant.


Vitrification of mature mouse oocytes: improved results following addition of polyethylene glycol to a dimethyl sulfoxide solution.
Oocytes have been successfully cryopreserved using rapid and slow freezing procedures; however, variability in the success of replicates has limited its practical application. We have evaluated the potentially beneficial effects of adding 1 mg/ml of the polymer polyethylene glycol (PEG) (M(r) 8000) to a 6 M dimethyl sulfoxide (Me2SO) vitrification solution. Stepwise addition of cryoprotectant, either with or without PEG, was performed at room temperature (19-21 degrees C). Oocytes were then loaded in plastic insemination straws and held in liquid nitrogen vapour at -140 degrees C for 3 min prior to storage in liquid nitrogen. Oocytes were warmed rapidly to room temperature and removal of cryoprotective agent was effected in the presence of 1 M sucrose solution. Viability was assessed by vitro fertilization. Oocytes cryopreserved after exposure to 6 M Me2SO in the absence of PEG showed 60% normality, 80% fertilization, and 55% development to blastocyst, median of 11 replicate experiments (191 oocytes). Individual replicates yield highly variable survival which ranged from 0 to 100%. The addition of PEG significantly improved oocyte normality to 95% (range 76-100%; median of 9 replicate experiments, 301 oocytes). Rates of fertilization (91%; 60-100%) and development of blastocyst (73%; 67-92) were also improved. The addition of 1 mg/ml PEG to a 6 M Me2SO solution resulted in greatly improved viability of oocytes following cryopreservation and vastly reduced the variability seen with Me2SO solution alone.


Recommendations for Choosing the Genotyping Method and Best Practices for Quality Control in Crop Genome-Wide Association Studies.
High-throughput genotyping boosts genome-wide association studies (GWAS) in crop species, leading to the identification of single-nucleotide polymorphisms (SNPs) associated with economically important traits. Choosing a cost-effective genotyping method for crop GWAS requires careful examination of several aspects, namely, the purpose and the scale of the study, crop-specific genomic features, and technical and economic matters associated with each genotyping option. Once genotypic data have been obtained, quality control (QC) procedures must be applied to avoid bias and false signals in genotype-phenotype association tests. QC for human GWAS has been extensively reviewed; however, QC for crop GWAS may require different actions, depending on the GWAS population type. Here, we review most popular genotyping methods based on next-generation sequencing (NGS) and array hybridization, and report observations that should guide the investigator in the choice of the genotyping method for crop GWAS. We provide recommendations to perform QC in crop species, and deliver an overview of bioinformatics tools that can be used to accomplish all needed tasks. Overall, this work aims to provide guidelines to harmonize those procedures leading to SNP datasets ready for crop GWAS.


Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema After Cancer Resection.
Indocyanine green lymphography has recently been used to assess lymphatic vessel function in lymphedema patients. Postoperative collateral lymphatic vessels toward ipsilateral axillary lymph nodes are rarely seen above the umbilical level in lower lymphedema patients. Between January 2012 and December 2014, we performed indocyanine green lymphography of 192 limbs in 96 lower extremity lymphedema cases. As a result, dermal back flow appeared in 95 cases, with 38 in the lower abdominal area and 31 in the genital area. We confirmed 3 cases of superficial lymphatic collateral ways extending above the umbilical level to the axillary lymph nodes. All 3 cases had similarity in lower abdominal edema, so excessive lymphatic fluid in the lower abdomen was assumed to be the cause. Lymphatic collateral ways from abdomen to axillary lymph nodes in this study was likely to be designed to prevent the progress of lymphedema.


Face Identity Recognition and the Social Difficulties Component of the Autism-Like Phenotype: Evidence for Phenotypic and Genetic Links.
Autism spectrum disorder (ASD) and autism-like traits are associated with deficits in face memory ability, although it is not yet clear whether this deficit reflects a specific aspect of the ASD/autism-like phenotype. We addressed this issue using a neurotypical sample of adolescent twins (Ncomplete pairs = 782) drawn from the Twins Early Development Study who were assessed on face and object memory performance alongside two core aspects of autism-like traits: (i) difficulties with social behavior/interactions, and (ii) attention to detail. We observed a negative association between face memory ability and difficulties with social behavior/interactions. This association reflected an overlapping genetic etiology: heritable influences acting on face memory ability are associated with the social difficulties aspects of autism-like traits.


P300 stimulus sequence effects in children and adults.
Immediate memory capability for 12 children (8 years) and 12 adults (21 years) was assessed electrophysiologically by using P300 event-related brain potential (ERP) stimulus sequences. These were derived from an auditory discrimination paradigm in which participants detected target stimuli in a series of target (T) and standard (S) tones that were varied by randomly presenting one of four sequence patterns (SSSS, TTTT, TTTS, SSST). Short-term memory capability was assessed behaviorally by recall performance of a 20-word list. Children and adults showed virtually identical P300 amplitude sequence patterns, such that for both groups component size increased systematically as the discrepancy between standard and target stimuli increased across sequence patterns. P300 latency evinced similar, albeit weaker, stimulus sequence effects, with children having longer component peak latencies. Memory recall performance was substantially weaker for the children than for adult participants, especially for recency effects. The findings suggest that immediate memory for stimulus sequences is fully developed in young children, although long-term memory is not.


A case of loss of consciousness with contralateral acute subdural haematoma during awake craniotomy.
We are reporting the case of a 56-year-old woman who developed loss of consciousness during awake craniotomy. A thin subdural haematoma in the contralateral side of the craniotomy was identified with intraoperative magnetic resonance imaging and subsequently removed. Our case indicates that contralateral acute subdural haematoma could be a cause of deterioration of the conscious level during awake craniotomy.


Evaluation of a three-year urban elementary school tobacco prevention program.
The longitudinal study compared effects of varying amounts of tobacco instruction (one, two, and three years) on the knowledge, attitudes, and behavioral intentions of urban elementary students. A three-year, fourth-through-sixth grade tobacco prevention curriculum was developed based on the Centers for Disease Control and Prevention's Guidelines for School Health Programs to Prevent Tobacco Use and Addiction. The curriculum comprised five, 45-minute lessons per year. The same trained instructor taught the curriculum all three years. Six intervention schools were taught the curriculum, and two control schools were not. A 49-item questionnaire was used to assess tobacco knowledge, attitudes, and behavioral intentions. The experimental group's posttest knowledge and attitude scores were significantly higher than the control group's posttest scores. No significant differences occurred in posttest behavioral intention scores between the control and intervention groups.


Anastomosing Haemangioma of the Kidney Involving a Segmental Branch of the Renal Vein.
Anastomosing variant of capillary haemangioma is a rare and recently described vascular tumour with a proclivity for the genitourinary tract. Here we present the case of a 64-year-old man with incidental finding of 3.4 cm renal mass on CT who had laparoscopic nephrectomy with a good postoperative recovery. Histopathological diagnosis of anastomosing haemangioma of the kidney was made and the patient was followed up for 10 months without evidence of tumour recurrence.


Orogenital ulcers of pyoderma gangrenosum resembling sexually transmitted disease.
Pyoderma gangrenosum is a non-infectious neutrophilic dermatosis that may be either idiopathic or associated with some underlying diseases like inflammatory bowel diseases, SLE, sarcoidosis, vasculitis etc. It can occur in any part of the body but pyoderma gangrenosum involving oral cavity and genital regions presenting as orogenital ulcers would be clinically quite difficult to be distinguished from Sexually Transmitted Diseases (STDS). We present such a case that was initially managed on the lines of sexually transmitted diseases, which later on came out to be pyoderma gangrenosum, after excluding all other diseases having almost same clinical presentations, on the basis of laboratory results and histopathology.


Melatonin and metformin co-loaded nanoliposomes efficiently attenuate liver damage induced by bile duct ligation in rats.
In the current study, the therapeutic effectiveness of the metformin (Met) and melatonin (Mel) co-loaded liposomes was investigated on cholestasis induced by bile duct ligation (BDL) in male rats. Histopathological analysis, biochemical analysis, and oxidative stress markers were assayed to determine the therapeutic effect of Met and Mel co-loaded liposomes on cholestasis. Histopathological analysis revealed that the simultaneous administration of Met and Mel, whether in the free (C-Mel-Met) or liposomal (C-Lipo-Mel-Met) forms, reduced inflammation as well as proliferation of bile ducts; however, results were more prominent in the liposomal form of Mel and Met. Additionaly, serum levels of aspartate aminotransferase (AST) were significantly (p < 0.001) higher in (C-Mel-Met) treated rats compared with (BDL) rats; however, (C-Lipo-Mel-Met) treated rats exhibited significant (p < 0.05) lower AST rates in comparison to (BDL) rats. Moreover, a significant (p < 0.0001) drop in bilirubin levels was detected in (C-Lipo-Mel-Met) treated rats in comparison to (BDL) rats; it is noteworthy mentioning that bilirubin levels in (C-Lipo-Mel-Met) treated rats were insignificant in comparison to sham-control (SC) rats. Furthermore, rats concomitantly administered Met and Mel, exhibited significant downregulation in the expression levels of inflammatory cytokine genes such as TNF-α and IL-1 gene expression, where the downregulation was more prominent in the liposomal from. Our findings demonestrate that the concomitant administration of metformin and melatonin in the liposomal form had more therapeutic effect on liver injury than their free forms through improving histological changes, reducing biochemical markers and favoring oxidant- antioxidant balance.


Can surface neuromuscular electrical stimulation of the wrist and hand combined with routine therapy facilitate recovery of arm function in patients with stroke?
To investigate whether treatment with surface neuromuscular electrical stimulation to the wrist extensors improves recovery of arm function in severely disabled patients with stroke. Single blinded randomized controlled trial. Acute stroke unit and stroke rehabilitation wards of a university hospital. Patients with no upper limb function (Action Research Arm Test [ARAT] score 0) (N=90; mean age ± SD, 74±11y; 49% men) were recruited to the study within 6 weeks of stroke. Only 67 participants were alive at the end of the study and data from 66 of these people were analyzed. Participants were randomized to surface neuromuscular electrical stimulation using surface electrical stimulators for 30 minutes, twice in a working day for 6 weeks in addition to standardized upper limb therapy or just standardized upper limb therapy. The primary outcome measure was the ARAT score. Assessments were made at baseline and at 6, 12, 24, and 36 weeks after recruitment. There were statistically significant improvements in measures of wrist extensor (mean difference 0.5; 95% confidence interval [CI], 0.0-1.0) and grip strength (mean difference 0.9; 95% CI, 0.1-1.7) over the treatment period. Arm function (ARAT score) was not significantly different between the groups over the treatment period at 6 weeks (mean difference 1.9; 95% CI, -2.9 to 6.8) or over the study period at 36 weeks (mean difference 6.4; 95% CI, -1.8 to 14.7), and the rate of recovery was not significantly different (mean difference 0.7; 95% CI, -0.2 to 1.6). In patients with severe stroke, with no functional arm movement, electrical stimulation of wrist extensors improves muscle strength for wrist extension and grip, and larger studies are required to study its influence on arm function.


Value of ultrasonography in the diagnosis of gout in patients presenting with acute arthritis.
To evaluate the value of ultrasonographic features of crystal deposition for diagnosing gout in patients presenting with acute arthritis. Ultrasound scanning of the most inflamed joint was performed on 89 consecutively enrolled patients with acute arthritis. Two radiologists independently reviewed the ultrasound images, and a consensus was achieved with a third radiologist when the interpretations of four key ultrasound features of gout differed. Arthrocentesis and crystal analysis using compensated polarized light microscopy of aspirates are considered the gold standards for gout diagnosis. Fifty-three (60%) patients had gout, whereas the remaining 36 (40%) had non-gout arthritis. The mean serum uric acid level was 7.1 mg/dl in patients with gout and 4.7 mg/dl in patients with non-gout arthritis. Three US features differed significantly (p < 0.001) between patients with gout and non-gout arthritis: the double contour sign (42 vs. 8%, respectively), intra-articular aggregates (58 vs. 8%), and tophi (40 vs. 0%). No statistically significant differences in detecting intra-tendinous aggregates (32 vs. 17%, p = 0.14) were observed. The sensitivity and specificity of the double contour sign were 42 and 92%, respectively; those of the intra-articular aggregates were 58 and 92%; and those of tophi were 40 and 100%. The positive predictive values for these three features ranged from 88 to 100%, whereas the negative predictive values ranged from 52 to 60%. When the prevalence is high, these three ultrasound features may be a useful adjunct in the diagnosis of acute gout, particularly when specialized microscopic techniques are not available.


Trends and determinants of change in compliance to dietary guidelines in a Swiss community-dwelling sample.
Adherence to dietary guidelines is associated with significantly better health outcomes. Studies across the world shows that compliance with the guidelines was low, but data in Switzerland are lacking. Hence, we aimed to assess the 5-year trends in dietary compliance regarding food guidelines in Switzerland in a prospective, population-based observational study. Data from 2882 participants (1591 women, 35-75 years), from the first (2009-2012) and second (2014-2017) follow-up. Dietary intake was assessed using a validated food frequency questionnaire. Compliance with the guidelines of the Swiss society of nutrition was assessed at baseline and 5.5 years afterwards. Prevalence rates for compliance were calculated using the exact Poisson method. Factors associated with changes in compliance (never, shifter or maintainer) were assessed by multinomial logistic regression using "Never compliers" as reference. Overall, improvements in compliance to fruits (42.4% to 45.1%) vegetables (6.9% to 8.6%) and fish (66.6% to 60.5%) were found, while compliance to meat decreased (61.1% to 58.5%). The prevalence of participants complying with at least three dietary recommendations did not change (24.1% to 25.2%). During follow-up, only 11.6% of participants maintained compliance to at least three dietary recommendations, and 62.4% never managed to comply. Female gender and older age were associated with maintaining compliance during the two study periods. In conclusion, compliance with dietary guidelines is a dynamic status, and only a small fraction of the population achieves sustained compliance with at least three guidelines. Almost two thirds of the population never achieve compliance with three guidelines.


Position-resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations.
Studies of insertion and interactions of amino acids in lipid membranes are pivotal to our understanding of membrane protein structure and function. Calculating the insertion cost as a function of transmembrane helix sequence is thus an important step towards improved membrane protein prediction and eventually drug design. Here, we present position-dependent free energies of solvation for all amino acid analogs along the membrane normal. The profiles cover the entire region from bulk water to hydrophobic core, and were produced from all-atom molecular dynamics simulations. Experimental differences corresponding to mutations and costs for entire segments match experimental data well, and in addition the profiles provide the spatial resolution currently not available from experiments. Polar side-chains largely maintain their hydration and assume quite ordered conformations, which indicates the solvation cost is mainly entropic. The cost of solvating charged side-chains is not only significantly lower than for implicit solvation models, but also close to experiments, meaning these could well maintain their protonation states inside the membrane. The single notable exception to the experimental agreement is proline, which is quite expensive to introduce in vivo despite its hydrophobicity--a difference possibly explained by kinks making it harder to insert helices in the translocon.


The Mediating Effect of Specific Social Anxiety Facets on Body Checking and Avoidance.
Objective: Body checking (BC) and avoidance (BA) form the behavioral component of body image disturbance. High levels of BC/BA have often been documented to hold a positive and potentially reinforcing relationship with eating pathology. While some researchers hypothesize, that patients engage in BC/BA to prevent or reduce levels of anxiety, little is known about the mediating factors. Considering the great comorbidity between eating disorders (ED) and in particular social anxieties, the present study investigated whether socially relevant types of anxiety mediate the relationship between eating pathology and BC/BA. Methods: 83 participants reporting an eating disorder and 323 healthy participants (14-25 years) took part in an online survey. Eating pathology was measured with the Eating Disorder Examination Questionnaire and Body Checking and Avoidance Questionnaire. Trait and social anxiety were assessed by means of the State Trait Anxiety Inventory (STAI-T), the Fear of Negative Evaluation (FNE) and the Social Appearance and Anxiety Scale (SAAS). Separate mediation analyses were carried out with eating pathology as independent variable, BC/BA as dependent variable and STAI, FNE, and SAAS as mediating variables. Results: Anxieties correlated highly positive with eating pathology in both groups. SAAS mediated the relationship between ED pathology and BC/BA in participants with ED and mediated the relationship between ED pathology and BA in healthy participants. FNE mediated the relationship between eating pathology and BA for participants with eating pathology. Discussion: SAAS mediated the relationship between eating pathology and BC/BA. Being afraid of bodily evaluations may represent a particular relevant fear that triggers safety behaviors.


Direct effects of diazepam on emotional processing in healthy volunteers.
Pharmacological agents used in the treatment of anxiety have been reported to decrease threat relevant processing in patients and healthy controls, suggesting a potentially relevant mechanism of action. However, the effects of the anxiolytic diazepam have typically been examined at sedative doses, which do not allow the direct actions on emotional processing to be fully separated from global effects of the drug on cognition and alertness. The aim of this study was to investigate the effect of a lower, but still clinically effective, dose of diazepam on emotional processing in healthy volunteers. Twenty-four participants were randomised to receive a single dose of diazepam (5 mg) or placebo. Sixty minutes later, participants completed a battery of psychological tests, including measures of non-emotional cognitive performance (reaction time and sustained attention) and emotional processing (affective modulation of the startle reflex, attentional dot probe, facial expression recognition, and emotional memory). Mood and subjective experience were also measured. Diazepam significantly modulated attentional vigilance to masked emotional faces and significantly decreased overall startle reactivity. Diazepam did not significantly affect mood, alertness, response times, facial expression recognition, or sustained attention. At non-sedating doses, diazepam produces effects on attentional vigilance and startle responsivity that are consistent with its anxiolytic action. This may be an underlying mechanism through which benzodiazepines exert their therapeutic effects in clinical anxiety.


The Brachyury gene encodes a novel DNA binding protein.
Brachyury (T) mutant embryos are deficient in mesoderm formation and do not complete axial development. The notochord is most strongly affected. The T gene is expressed transiently in primitive streak-derived nascent and migrating mesoderm cells and continuously in the notochord. Ectopic expression of T protein in the animal cap of Xenopus embryos results in ectopic mesoderm formation. The T protein is located in the nucleus. These and other data suggested that the T gene might be involved in the control of transcriptional regulation. In an attempt to demonstrate specific DNA binding of the T protein we have identified a consensus sequence among DNA fragments selected from a mixture of random oligomers. Under our experimental conditions T protein binds as a monomer to DNA. This property resides in the N-terminal domain of 229 amino acid residues which is strongly conserved between the mouse protein, and its Xenopus and zebrafish homologues. The latter proteins also recognize the consensus DNA binding site. We suggest that the T protein is involved in the control of genes required for mesoderm formation, and for the differentiation and function of chorda mesoderm.


Evaluation of stomatological needs of 8-year-old children connected with premature loss of deciduous teeth.
The study covered 106 eight-year-old children attending different schools in Lublin that do not provide dental care. The study evaluated decay frequency, DEF value and its components D, E, F, def value and its components d, e, f as well as treatment index for deciduous and permanent teeth. Additionally, it assessed the needs for orthodontic and prosthetic provisions connected with premature loss of deciduous teeth. The study found low treatment index, especially for deciduous teeth. Premature loss of deciduous teeth is an indication for prosthetic provision in the form of space retainers or partial dentures. Without prompt treatment different acquired facio-occlusal defects may develop.


Premicellar interaction of PEO-PPO-PEO triblock copolymers with partially hydrophobic alcohols: NMR study.
The interactions of three alcohols, namely, 2-butanol (BuOH), 3-methyl-2-butanol (MeBuOH), and 3,3-dimethyl-2-butanol (Me2BuOH) with propylene oxide octamer (PO8) and the copolymers (EO)8(PO)13(EO)8(L35) and (EO)13(PO)30(EO)13(L64) in D2O were studied using (13)C NMR spectra and relaxations and (1)H PFG NMR diffusion measurements. For L64, it was shown that the temperature at which the PO chain starts to change its conformation under dehydration decreases by 6 K for each additional methyl group in the alcohol molecule (i.e. with increasing its hydrophobicity), and the analogous conformation states are attained at temperatures approximately 10 K lower compared using ketonic analogs of the alcohols under the same conditions. Also, the first signs of L64 aggregation, according to the normalized diffusion coefficients, are at temperatures 7, 10, and 13 K lower for BuOH, MeBuOH, and Me2BuOH, respectively. These effects are much weaker for (PO)13 in L35 or nonexistent for (PO)8 in PO8, thus showing the role of cooperativity in dehydration and aggregation processes. According to diffusion measurements, the molar fraction of the alcohol hydrogen bonded to L64 increases with its hydrophobicity and, in an apparent conflict with thermodynamics, with increasing temperature at which also higher NOE can be observed. Strong hydrogen bond interaction, which is in cooperation with hydrophobic interaction, does not preclude the exchange between bound and free states of the alcohol, however. Using (13)C transverse relaxation, its correlation time is shown to be of the order of 10 ms.


Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C.
Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKT-dependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.


The Role of Immersive Virtual Reality and Augmented Reality in Medical Communication: A Scoping Review.
Communication between clinicians and patients and communication within clinical teams is widely recognized as a tool through which improved patient outcomes can be achieved. As emerging technologies, there is a notable lack of commentary on the role of immersive virtual reality (VR) and augmented reality (AR) in enhancing medical communication. This scoping review aims to map the current landscape of literature on this topic and highlights gaps in the evidence to inform future endeavors. A comprehensive search strategy was conducted across 3 databases (PubMed, Web of Science, and Embase), yielding 1000 articles, of which 623 were individually screened for relevance. Ultimately, 22 articles were selected for inclusion and review. Similarities across the cohort of studies included small sample sizes, observational study design, use of questionnaires, and more VR studies than AR. The majority of studies found these technologies to improve medical communication, although user tolerability limitations were identified. More studies are required, presenting more robust findings, in order to draw more definitive conclusions and stronger recommendations for use of immersive VR/AR in clinical environments.


Assessing the Status Quo of EHR Accessibility, Usability, and Knowledge Dissemination.
This study was performed to better characterize accessibility to electronic health records (EHRs) among informatics professionals in various roles, settings, and organizations across the United States and internationally. The EHR landscape has evolved significantly in recent years, though challenges remain in key areas such as usability. While patient access to electronic health information has gained more attention, levels of access among informatics professionals, including those conducting usability research, have not been well described in the literature. Ironically, many informatics professionals whose aim is to improve EHR design have restrictions on EHR access or publication, which interfere with broad dissemination of findings in areas of usability research. To quantify the limitations on EHR access and publication rights, we conducted a survey of informatics professionals from a broad spectrum of roles including practicing clinicians, researchers, administrators, and members of industry. Results were analyzed and levels of EHR access were stratified by role, organizational affiliation, geographic region, EHR type, and restrictions with regard to publishing results of usability testing, including screenshots. 126 respondents completed the survey, representing all major geographic regions in the United States. 71.5 percent of participants reported some level of EHR access, while 13 percent reported no access whatsoever. Rates of no-access were higher among faculty members and researchers (19 percent). Among faculty members and researchers, 72 percent could access the EHR for usability and/or research purposes, but, of those, fewer than 1 in 3 could freely publish screenshots with results of usability testing and half could not publish such data at all. Across users from all roles, only 21 percent reported the ability to publish screenshots freely without restrictions. This study offers insight into current patterns of EHR accessibility among informatics professionals, highlighting restrictions that limit dissemination of usability research and testing. Further conversations and shared responsibility among the various stakeholders in industry, government, health care organizations, and informatics professionals are vital to continued EHR optimization.


Low PD-L1 Expression Strongly Correlates with Local Recurrence in Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma after Radiation-Based Therapy.
The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080; HR = 1.88; 95% CI = 1.18⁻3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022; HR = 0.46; 95% CI = 0.24⁻0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials.


Substance use disorders among psychotic patients admitted to inpatient psychiatric care.
Previous epidemiological and clinical studies have shown high rates of substance use disorders in patients with psychotic disorders. There are few studies from the Scandinavian countries. The aim of this study was to investigate the rate of substance use disorders in a group of Norwegian psychotic inpatients from a specific catchment area. Sixty patients, aged 18-40 years, were interviewed through standardized methods: the Addiction Severity Index (EuropASI) and the Structured Clinical Interview for DSM-IV axis I disorders (SCID-I). Urine toxicology screens confirmed patients' self-report of recent substance use. The lifetime rate of substance use disorders was 70% when all psychotic disorders were included and 62.5% when substance-induced psychotic disorders were excluded. Fifty percent of all the patients studied had current substance use disorders. The majority of substance use disorders were dependence disorders. Alcohol, amphetamine and cannabis were the dominant substances. The level of comorbidity found in this study is comparable with that found in American studies, despite lower prevalence of substance use in the Norwegian population. The high rate of substance use disorders in psychotic inpatients has implications for the treatment and the organization of psychiatric care for these patients.


Fluorescence microscopic study of the architecture and structure of an adrenergic network in the plexus myentericus (Auerbach), plexus submucosus externus (Schabadasch) and plexus submucosus internus (Meissner) of the porcine small intestine.
The distribution of adrenergic fibres in the ganglionated plexuses of the porcine small intestine has been made on air-dried stretch preparations using the glyoxylic acid fluorescence method. Adrenergic fluorescent fibres occur in the ganglia and internodal strands of the three fundamental ganglionated plexuses: the myenteric plexus (Auerbach) and the two superimposed meshworks of the plexus submucosus , i.e. the plexus submucosus externus ( Schabadasch ) and the plexus submucosus internus (Meissner). The plexus Auerbach consists of densely glyoxylic acid induced fluorescent (GIF) elongated ganglia with in general a longitudinal axis running parallel to the circular muscle layer and large dense interconnecting fibre tracts with primary, secondary and tertiary subdivisions. In the ganglia, the fibres are varicose, forming large fluorescent 'baskets' which might be related to the occurrence of well defined enteric neurones. The plexus Schabadasch can be distinguished from the plexus Meissner by its size, strongly fluorescent ganglia and broad densely fluorescent internodal strands. The pattern of fluorescing ring-like formations at the margin and out of the nodes, clearly present in the Auerbach and Schabadasch plexuses, completely lack in the plexus Meissner, the latter being narrow-meshed with smaller fluorescent 'baskets', indicating that the corresponding neurones are smaller in size. In the ganglionic nodes of all three plexuses the axons display comparatively more varicosities than in the fibre tracts. Each of the three main ganglionated enteric plexuses are quite different with regard to the pattern of the adrenergic network both in the ganglia and in the strands.


[Changes in neurons and gliocytes of the rat mesoaccumbocingulate system following perinatal morphine administration].
To study the changes of neuron and gliocyte numbers and some morphometric parameters in mesoaccumbocingulate (MAC) dopaminergic system of rats after pre- and postnatal opiate treatment, 0.1 mg dose of 1% morphine hydrochloride solution was injected into the fetal amnion of Wistar female rats (n=4) at Day 17 post fertilization and intraperitoneally into newborn rats (n=4) at postnatal Day 4. Perinatal influence of morphine on MAC-system in rats resulted in the chromophilic degeneration, swelling and death of some part of neurons, decrease in the volume of the other (slightly injured) neurons. Neuronal injury was more pronounced after prenatal morphine treatment and was accompanied by the increase in both microgliocyte cell number and phagocytic activity. Morphine administration induced no changes in the satellite macrogliocyte number and in the average distance between these cells and the bodies of slightly injured neurons.


Long-term effect of amphotericin B on serum cholesterol in the rat.
Amphotericin B (1mg/kg/day) was administered intravenously to rats for 30 days, with simultaneous sham (5% dextrose in saline) injections to control animals. After four treatments, serum cholesterol concentration among treated animals demonstrated a maximum decrease of 25% (p less than 0.005) from the control level. Serum cholesterol returned to control level after three more treatments, and no significant difference (p greater than 0.05) was observed in experimental animals, despite continued treatment thereafter. Various hematological and biochemical parameters were monitored at intervals during this period. Except for significantly elevated (p less than 0.001) plasma urea nitrogen in treated animals, no significant difference was observed between the control and treated animals with regard to other parameters. Gross examination at autopsy, followed by microscopic study, showed absence of organ pathology.


Effects of insulin on wound healing: A review of animal and human evidences.
Several studies have indicated that insulin that is used in reducing blood glucose is also affective on wound healing by various mechanisms. To understand the outcomes of insulin therapy on wound healing, a meta-analysis and systematic review was performed. The Cochrane library, PubMed, and Science Direct were searched for the literature published from January the 1st 1990 to September the 30th 2016. Twelve animals and nine clinical studies were included. A quantitative and qualitative review was performed on the clinical trials and the animal studies were comprehensively overviewed. Statistical analysis for development of granulation tissue, microvessel density, and time of healing was conducted in this systematic review. The animal studies revealed that treatment with topical insulin lead to faster wound contraction and re-epithelialization. Meta-analysis of wound studies revealed that insulin therapy is significantly favored for growth of granulation tissue. Based on these findings, insulin enhanced development of granulation tissue on day 7 after treatment. The meta-analysis studies indicated significant reduction in time of healing in the patients treated with insulin. These studies also disclosed that the new vessels were observable from five days after injection in the treated group, compared to the control animals that developed significantly at later stage. Insulin is a low cost growth factor and can be considered as a therapeutic agent in wound healing. However, further studies are necessary to gain a better understanding of the role of insulin in wound healing.


[Sex specific differences in hemispheric lateralization in schizophrenia? An MEG-MRI study].
In this magnetoencephalography study the issue of hemispheric lateralisation in patients with schizophrenia was addressed using acoustically evoked neuromagnetic fields. The characteristics of dipoles in the superior temporal gyrus, the primary auditory cortex, were calculated. In contrast to other studies, alterations did not concern the localisation, but rather the orientation of dipoles. Of pathophysiological interest was that the dipoles abnormalities were found left-hemispherically in male (p = 0.02) and right-hemispherically in female patients with schizophrenia (p = 0.01) when compared to controls. The findings suggest gender-specific alterations of hemispheric lateralisation in schizophrenia.


Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma.
Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis. IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma. IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA. IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients.


Automatic recording of corneal thickness in vitro.
An addition to the specular microscope is described which allows it to record the thickness of the excised cornea automatically as a function of time. The focus of the instrument is scanned mechanically through the tissue, and the position of the reflecting surfaces is detected by a photo-electric system and marked on a chart recorder. The system is able to follow thickness changes over periods of many hours and with an accuracy greater than obtainable by manual operation. This system has been helpful in the evaluation of a new medium which considerably extends the useful lifetime of the corneal endothelial fluid pump.


Carboxyhaemoglobin concentrations, pulse oximetry and arterial blood-gas tensions during jet ventilation for Nd-YAG laser bronchoscopy.
Oxygen saturation measured with pulse oximetry (SpO2) is overestimated in the presence of carboxyhaemoglobin (COHb). Smoke produced during laser resection of tracheobronchial malignancies may increase concentrations of COHb. We have measured COHb concentrations in 14 patients undergoing laser resection and compared SpO2 with functional oxygen saturation (SaO2) to ascertain if pulse oximetry is an accurate monitor of oxygen saturation. During the procedure frequent changes occur in ventilatory mechanics. Arterial blood-gas tensions were measured to see if gas exchange was satisfactory. Mean preoperative COHb was 1.4%. There was no significant change in COHb in any patient at any stage during treatment. The highest value was 2.05%. The mean difference between SaO2 and SpO2 was 1.13% (95% confidence interval 0.70-1.56%). Oxygen saturation may therefore safely be monitored by pulse oximetry in patients managed by our technique. Empirical setting of a jet ventilator provided acceptable blood-gas tensions, although sometimes it was necessary to increase the FlO2 to greater than 0.3 to maintain oxygenation.


Clinical significance of the combined measurement of serum B7-H1 and interleukin-10 in colorectal cancer patients.
Colorectal cancer (CRC) patients have been shown to express a cytokine signature that is detectable in serum and contributes to cancer pathogenesis. The objective of this study was to evaluate the potential clinical significance of preoperative circulating cytokine levels in CRC patients.The expression of serum B7-H1 and IL-10 was assessed by ELISA in 89 patients and 64 health volunteers. As a control marker, CEA serum levels were measured by electrochemical luminescence detection. The receiver operating characteristic (ROC) curve was used to analysis to demonstrate the potential diagnostic value of these biomarkers.The expression of serum B7-H1 was significantly increased in CRC patients (P = .001) and associated with the progression of TNM stage and a positive association with serum IL-10 levels was also evident. Furthermore, serum B7-H1 and IL-10 expression was not influenced by age, gender, tumor location, or mass, whereas a relationship existed with tumor metastasis and TNM stage. The serum levels of B7-H1 and IL-10 on the 7th postoperative day were significantly decreased compared with that of preoperative serum levels (P = .001, P = .003 respectively). The area under the ROC curves (AUC) for B7-H1 and IL-10 were 0.7063 and 0.5706, respectively. The optimal sensitivity and specificity of B7-H1 for discriminating between colon cancer patients and healthy controls were 85.21% and 56.43%, respectively, using a cut-off value of 3.46 ng/mL. However, the combined ROC analysis using B7-H1 and IL-10 revealed an AUC of 0.8791, with a sensitivity of 90.63% and a specificity of 75.18%.The outcomes of the present study demonstrate the clinical significance of serum B7-H1 and IL-10 concentrations. Combined detection of B7-H1 plus IL-10 showed significantly increased sensitivity and specificity for discriminating between colorectal cancer patients and healthy controls compared these markers detection individual. The measurement of B7-H1 or IL-10 in sera following surgery may provide an additional tool for assessing the curative effects of surgery in CRC patients.


Hemodynamic and echocardiographic responses to acute interruption of left ventricular assist device support: relevance to assessment of myocardial recovery.
Assessment of myocardial recovery during left ventricular assist device (LVAD) support is difficult to perform both safely and effectively. We developed a test involving short-term interruption of LVAD support with measurements of several hemodynamic and echocardiographic parameters at rest and, whenever possible, after exercise, to investigate inotropic reserve. After full heparinization, the HeartMate I XVE device was switched off. MAP, heart rate (HR), ejection fraction (EF) and left ventricular dimensions were measured on switching off, after 5, 10 and 15 minutes, and after 6-minute walk (6MW). In total, 207 serial tests were performed on 22 patients. A total of 97.6% of the patients tolerated the tests. Of the 202 tolerated tests, 130 were performed on 16 patients who had their device explanted due to myocardial recovery (recovered group), and 72 on 6 patients who did not recover and were transplanted (non-recovered group). After device discontinuation there was an immediate drop in mean arterial blood pressure (MAP), a rise in HR, a reduction in EF and increases in ventricular dimensions. These changes tended to be more marked in the non-recovered group. After 6MW, the recovered group had a significant rise in HR and EF and a non-significant increase in MAP, whereas, the non-recovered group there was a significant drop in MAP compensated by a rise in HR. The distance walked in the recovered group was significantly higher (544 +/- 102 vs 418 +/- 109 meters, p < 0.05). MAP, pulse pressure and EF were strong predictive factors for recovery. Acute discontinuation of the device to assess recovery is safe and well tolerated and is followed by specific changes in hemodynamic and echocardiographic parameters. This helps in the assessment of recovery, particularly with regard to findings taken after exercise.


Telephone encounters in a university pediatric group practice. A 2-year analysis of after-hour calls.
The records of off-hours calls received by the University of Colorado Pediatric Group Practice from 4:30 p.m. throughout 8:00 a.m. weekdays and all day Saturday, Sunday, and holidays were audited. An answering service and pageboy system ensured 24-hour, 7-day-a-week accessibility through a single telephone number. The four practices received 2386 after-hours calls from November 1978 to October 1980. An average of 104 calls per month were received with approximately four calls per day on weekday evenings and six calls per day on Saturday, Sunday, and holidays. Five concerns accounted for 49 percent of all after hours calls: fever, vomiting and/or diarrhea, upper respiratory infection (URI), earache, and rash. While 75 percent of families made fewer than four calls per year, 4 percent made at least 12 calls per year, accounting for 18 percent of all calls. Families calling three or more times a month were defined as "frequent users" and accounted for 22 percent of a given month's calls. Most calls from the same families (55%) occurred within a 24-hour period and dealt chiefly with parental concerns about fever, vomiting and diarrhea, URIs, ear infection, accident, and rashes. The additional responsibility that residents assume in taking calls for the Pediatric Group Practice while on other off-hour assignments was not excessively demanding, and cost of the answering service was easily absorbed by group practice revenues.


Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats.
It has been shown that centrally administered neuropeptide Y (NPY) delays gastric emptying. To determine the receptor subtypes of NPY mediating the inhibitory effects on gastric emptying, effects of intracerebroventricular injection of NPY, [Leu31,Pro34]NPY (a Y1 agonist) and NPY-(3-36) (a Y2 agonist) on solid gastric emptying and postprandial antropyloric motility were studied in conscious rats. Intracerebroventricular injection of NPY and NPY-(3-36), but not [Leu31,Pro34] NPY, delayed solid gastric emptying in a dose-dependent manner (0.03-3 nmol). After the feeding (40 min), contractions with low frequency and high amplitude of the antrum were frequently observed, and the peak contraction of the antrum occurred most often 3-6 s before the peak contraction of the pylorus. Intracerebroventricular injection of NPY and NPY-(3-36) (3 nmol), but not [Leu31,Pro34]NPY, significantly reduced antral contractions and the number of antropyloric coordination events. It is suggested that centrally administered NPY impairs postprandial antral contractions and antropyloric coordination via Y2 receptors, resulting in delayed gastric emptying.


Giant bent-core mesogens in the thread forming process of marine mussels.
In marine mussels (Mytilus), byssal threads are made in minutes from prefabricated smectic polymer liquid crystals by a process resembling reaction injection molding. The mesogens in these arrays are known to be natural block copolymers with rodlike collagen cores. Using atomic force microscopy, it was shown that these collagenous mesogens are bent-core or banana-shaped in a manner that is consistent with and predictable from their amino acid sequence. The overall bend angle in preCOL-NG in Mytilus galloprovincialis is about 130 degrees. The mesogens have a center-to-center separation of approximately 22 nm and a length of 200 nm. It is evident that the smectic structure of the prefabricated mesophases remains largely intact over 1-3 microm distances in the molded fibers and is presumably locked in place during molding by cross-linking. Like the smectic liquid crystals of many synthetic banana mesogens, the collagenous mesogens of the byssal threads exhibit SmC(2) symmetry with a characteristic tilt of 24.6 degrees. At about 100% extension, this tilt is considerably reduced and the globular end domains are no longer visible presumably because they have been unraveled.


Tip-induced chemical manipulation of metal porphyrins at a liquid/solid interface.
Changing abruptly the potential between a scanning tunneling microscope tip and a graphite substrate induces "high-conductance" spots at the molecular level in a monolayer formed by a manganese chloride-porphyrin molecule. These events are attributed to the pulse-induced formation of μ-oxo-porphyrin dimers. The pulse voltage must pass a certain threshold for dimer formation, and pulse polarity determines the yield.


Nursing home deficiencies: an exploratory study of interstate variations in regulatory activity.
This study examines nursing home regulatory activity by the states, assesses interstate variations in the volume and severity of nursing home deficiencies, and explores state-level factors that may account for these differences. Nursing home deficiency citation data over a 5-year period (2000-2004) were obtained from the Centers for Medicare and Medicaid Services. We examined interstate variations in regulatory activity and identified predictors of deficiency volume and severity at the state level (demographics, elected officials, industry characteristics, etc.) using the linear mixed model. Deficiency volume remained stable across the 50 states from 2000 to 2004, while deficiency severity decreased significantly. California had the highest volume of deficiencies per nursing home; Wisconsin had the lowest. New Hampshire had the highest percentage of severe deficiencies; California had the lowest. Higher deficiency volume was found in states with lower median household income, a lower proportion of residents aged 85 and older, and a Democratic legislature. Higher deficiency severity was associated with higher median household income and a higher proportion of Medicaid nursing home residents in a state. In contrast, greater state agency funding, higher state standards for nursing home administrators, and a Democratic and more professional legislature predicted lower deficiency severity. Nursing home residents in the United States receive unequal protection from abuse and neglect, and this is partly due to their state of residence. Interstate variations in deficiency volume and severity are due to a complex set of factors beyond nursing home quality.


Reinforcing Hydrogel by Nonsolvent-Quenching-Facilitated In Situ Nanofibrosis.
Nanofibrous hydrogels are pervasive in load-bearing soft tissues, which are believed to be key to their extraordinary mechanical properties. Enlighted by this phenomenon, a novel reinforcing strategy for polymeric hydrogels is proposed, where polymer segments in the hydrogels are induced to form nanofibers in situ by bolstering their controllable aggregation at the nanoscale level. Poly(vinyl alcohol) hydrogels are chosen to demonstrate the virtue of this strategy. A nonsolvent-quenching step is introduced into the conventional solvent-exchange hydrogel preparation approach, which readily promotes the formation of nanofibrous hydrogels in the following solvent-tempering process. The resultant nanofibrous hydrogels demonstrate significantly improved mechanical properties and swelling resistance, compared to the conventional solvent-exchange hydrogels with identical compositions. This work validates the hypothesis that bundling polymer chains to form nanofibers can lead to nanofibrous hydrogels with remarkably enhanced mechanical performances, which may open a new horizon for single-component hydrogel reinforcement.


The Modular Universal Tumour And Revision System (MUTARS®) in endoprosthetic revision surgery.
The aim of this study was to present the clinical and functional results of revision surgery after failed hip endoprostheses using the Modular Universal Tumour And Revision System (MUTARS®). Functional results of the hip endoprostheses were recorded by applying the Harris hip score. The extent of the presurgical radiological bone defect was measured according to the classification system of the German orthopaedic association (DGOOC). Indications for revision surgery on 45 patients (21 female, 24 male) were aseptic loosening (19 patients), infection (16 patients), or periprosthetic fracture (Vancouver classification B2, B3 and C, in nine patients). Revision surgery was performed after 8.6 years on average (min. 0.6; max. 14.25 years). Large defects of the proximal femur (80% medial or lateral diaphysis; 20% meta-diaphysis according to DGOOC classification) were adequately reconstructed. The average follow-up was 38.6 months. Complications occurred in eight patients: one luxation, two aseptic loosenings, and five reinfections were diagnosed. The Harris hip score (presurgical 30; postsurgical 78) showed significant improvement after revision surgery. Regarding the extent of the patients' bone defects, good functional results were achieved. The comparatively low number of luxations and loosenings is due to the high modularity of the prosthesis with arbitrary antetorsion in the hip joint. However, high reinfection rates in mega-implants still constitute a problem and should be the subject of further studies.


Solvent-solute interactions in hydrofluoroalkane propellants.
Understanding solvation in hydrofluoroalkane (HFA) propellants is of great importance for the development of novel pressurized metered-dose inhaler (pMDI) formulations. HFA-based pMDIs are not only the most widely used inhalation therapy devices for delivering small drug molecules to the respiratory tract, but they also hold promise as vehicles for the delivery of therapeutic biomolecules to and through the lungs. In this work we use binding energy calculations to determine the degree of interaction between HFA propellants and candidate HFA-philes, including a methyl-based tail (isohexane, ISO), and fragments of poly(ethylene oxide) (EO), poly(propylene oxide) (PO), and poly(lactide) (LA). The distinct nature of solvation forces of the two HFA propellants approved by the FDA for use in pMDIs, 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227), is also studied. Binding energy (Ebst) calculations demonstrated that an increase in tail polarity through the addition of oxygen atoms in the fragment backbone provides for sites capable of interacting with the HFA propellant molecules, thus enhancing the stabilization energy of the complexes. The interaction energy between HFA227 and LA (EbHFA227-LA = -24.7 kJ.mol(-1)) is significantly more favorable than that between HFA227 and its hydrocarbon analog (EbHFA227-ISO = -10.0 kJ.mol(-1)). However, it was shown that not only the fragment polarity is of relevance in stabilizing the complexes. The accessibility of the oxygen atoms in the fragments of interest is also relevant. Cluster studies indicate that although both oxygen atoms in the LA fragment are available to form H-bonds with the propellant molecules, the ether oxygen in PO is accessible to only one propellant molecule, thus decreasing significantly the stabilization energy of the cluster. The results shown here serve as a guide for the design of novel HFA-philes for HFA-based pMDIs.


Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue.
Cryopreservation of the ovarian cortex with subsequent autotransplantation has, on an experimental basis, been performed to preserve fertility in women being treated for a malignant disease. The present study reports ovarian activity and pregnancies following autotransplantation of frozen/thawed ovarian tissue. One complete ovary was cryopreserved from each of six patients who were 26-35 years old prior to treatment. Tissue from three of the patients was transported 4-5 h on ice prior to cryopreservation. After a period of 17-32 months, orthotopic autotransplantation was performed replacing 20-60% of the tissue. Two patients received additional heterotopic transplants. In all cases, the tissue restored menstrual cyclicity 14-20 weeks following transplantation. Four of the six women conceived following assisted reproduction: two women (who had the tissue transported 4-5 h prior to cryopreservation) each, based on the orthotopic transplanted tissue, delivered one healthy child (February 2007 and January 2008); one woman miscarriaged in gestational Week 7; and the other had a positive hCG test but no clinical pregnancy. The remaining two women did not become pregnant. Two additional healthy children have been born as a result of the ovarian cryopreservation procedure. In both cases, the ovarian tissue was transported 4-5 h prior to freezing demonstrating that hospitals may offer cryopreservation without having the necessary expertise locally.


[Atypical mycobacteria and mycobacteriosis].
Atypical mycobacteria were isolated from 16 patients admitted to the Versailles Hospital Center over a two-years period (1981-1982). Two cases of pulmonary disease due to M. avium-intracellulare and one case of skin disease due to M. marinum were diagnosed. Pulmonary infection remained doubtful in two patients despite repeated recovery of M. Kansasii and M. chelonei.


Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.
Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U-13C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U-13C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo. Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future.


Functional role of NADPH oxidase in activation of platelets.
Involvement of phagocyte NADPH oxidase in host defense response is well established. In contrast, little is known about the functional role of NADPH oxidase in platelets. In this study, we analyzed involvement of platelet NADPH oxidase in aggregation of human platelets and in amplification of production of reactive oxygen species (ROS) by activated human neutrophils. Apocynin, a known NADPH oxidase inhibitor, as well as superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-1-pyridyl)porphyrin, inhibited ROS generation by collagen-activated platelets, collagen-induced aggregation of platelets, as well as collagen-induced release of thromboxane B2. These data suggest the key role of intracellular ROS derived from NADPH oxidase in the control of thromboxane A2 (TXA2) production in platelets stimulated by collagen. Apocynin also inhibited thrombin-induced ROS production and thrombin-induced platelet aggregation. Activation of neutrophils with latex resulted in an outburst of ROS that was inhibited by apocynin. ROS production by latex-stimulated platelets was modest and also inhibited by apocynin. However, when a mixture of platelets and neutrophils was stimulated with latex, ROS production was three to six times higher in comparison with activation of neutrophils alone. Platelet-dependent augmentation of neutrophil ROS production was abrogated by TXA2 synthase inhibitor (furegrelate, 1 microM) or by aspirin (300 microM). In summary, NADPH oxidase in platelets seems to play a major role as an intracellular signaling mechanism in the activation of platelets. However, in host defense response involving neutrophils and platelets, platelets enhance ROS production by neutrophils and possibly their cytotoxic potential via the release of TXA2, which in turn in platelets is not affected by the extracellular release of free radicals.


The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90.
Tetratricopeptide (TPR) domains are known protein interaction domains. We show that the TPR domain of FKBP8 selectively binds Hsp90, and interactions upstream of the conserved MEEVD motif are critical for tight binding. In contrast FKBP8 failed to bind intact Hsp70. The PPIase domain was not essential for the interaction with Hsp90 and binding was completely encompassed by the TPR domain alone. The conformation adopted by Hsp90 peptides, containing the conserved MEEVD motif, in the crystal structure were similar to that seen for the TPR domains of CHIP, AIP and Tah1. The carboxylate clamp interactions with bound Hsp90 peptide were a critical component of the interaction and mutation of Lys 307, involved in the carboxylate clamp, completely disrupted the interaction with Hsp90. FKBP8 binding to Hsp90 did not substantially influence its ATPase activity.


Concurrent exposure to microbial products and food antigens triggers initiation of food allergy.
It is estimated that as much as 6-8% population suffers from food allergy or food antigen-related disorders. The prevalence keeps rising. So far we do not have identified remedy to treat food allergy. Avoidance of the offending food is the only effective method currently. Skewed T helper 2 polarization is one of the major feature in the pathogenesis of food allergy. However, the causative mechanism in the initiation of food allergy remains to be further understood. Research in food allergy has got giant advance in recent years. Several animal models have been established and used in food allergy study. One of the common features of these food allergy animal models is that most of them require using microbial products as adjuvant to sensitize animals. This review documents the recent advance in the mechanistic study on concurrent use of microbial products and food antigens to study food allergy.