PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation.
Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process. We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019. This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor. Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.


An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort.
Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson's disease (PD) subjects from the Parkinson's Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03-1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.


Lymphoma of the head and neck.
The natural history of 88 cases of non-Hodgkin's lymphoma of the head and neck were reviewed. An analysis is presented of the histopathologic, clinical, and prognostic features of these patients which presented to the Washington University Affiliated Hospitals between 1955-1975. All biopsies were histologically classified according to the criteria of Rappaport and staged accordingly to the Ann Arbor Classification. There were 38 histiocytic lymphomas, 29 poorly differentiated lymphocytic lymphomas, 16 well differentiated lymphocytic lymphomas, and 5 mixed lymphomas. The lesions were equally divided between Waldeyer's ring and other head and neck sites. Most of the lymphomas were extranodal in presentation. Sixty-one percent of all cases presented with disease localized to the site of origin; 17% had extension to regional nodes and 21% had generalized disease (Stage III and IV). In terms of treatment, localized well differentiated lymphocytic lymphoma was treated with radiation therapy. Generalized well differentiated lymphocytic lymphomas were treated with radiation and chemotherapy. Most patients with histiocytic and poorly differentiated lymphocytic lymphoma limited to the site of origin were treated with radiation and all others with combined therapy. Over 90% of patients with Stage I disease were considered cured at the end of three years while the overall survival was 72%.


Bacteria alone establish the chemical basis of the wood-fall chemosynthetic ecosystem in the deep-sea.
Wood-fall ecosystems host chemosynthetic bacteria that use hydrogen sulfide as an electron donor. The production of hydrogen sulfide from decaying wood in the deep-sea has long been suspected to rely on the activity of wood-boring bivalves, Xylophaga spp. However, recent mesocosm experiments have shown hydrogen sulfide production in the absence of wood borers. Here, we combined in situ chemical measurements, amplicon sequencing and metagenomics to test whether the presence of Xylophaga spp.-affected hydrogen sulfide production and wood microbial community assemblages. During a short-term experiment conducted in a deep-sea canyon, we found that wood-fall microbial communities could produce hydrogen sulfide in the absence of Xylophaga spp. The presence of wood borers had a strong impact on the microbial community composition on the wood surface but not in the wood centre, where communities were observed to be homogeneous among different samples. When wood borers were excluded, the wood centre community did not have the genetic potential to degrade cellulose or hemicellulose but could use shorter carbohydrates such as sucrose. We conclude that wood centre communities produce fermentation products that can be used by the sulfate-reducing bacteria detected near the wood surface. We thus demonstrate that microorganisms alone could establish the chemical basis essential for the recruitment of chemolithotrophic organisms in deep-sea wood falls.


Probiotics in microbiome ecological balance providing a therapeutic window against cancer.
The gut microbiota composition and dietary factors in our food along with the use of prebiotics and probiotics play an important role in the maintenance of human health. A well-balanced gut microbial population is necessary for the host and the microbiota to coexist in a mutually beneficial relationship maintaining homeostasis. Considering the potential of modern technological tools, it is possible nowadays to engineer prebiotic bacteria having a positive influence on the microbiome on one hand while on the other one may have the ease to get rid of the pathogenic proinflammatory microbes or elements causing dysbiosis. Past studies have seen that in cancer there is a loss of inter-microbial relationship cum interactions within microbiota members, the metabolic products produced by them and the host immune system in a microbial ecosystem, leading to dysbiosis. Current review highlights the importance of probiotics in the management of cancer by bringing together majority of the studies together at a single platform and moreover, stresses upon the need to maintain eubiosis in order to evade and inhibit the progression of cancer. Continuous expansion in knowledge about probiotics, their effect on various cancers and the underlying mechanism of action has raised the global scientific interest towards their possible use against different cancers. Furthermore, the article emphasizes upon the need to explore newer therapeutic targets comprising of the microbiome which could further pave the way to the concept of personalized medicines for various kinds of malignancies so as to derive maximum benefits of a treatment modality and to preserve the microbial homeostasis.


Icariin synergizes with arsenic trioxide to suppress human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with high chemoresistance to chemotherapeutics. Arsenic trioxide (ATO) is of therapeutic potential for the treatment of HCC; however, the therapeutic benefit of ATO is very limited due to narrow therapeutic window. Icariin is a natural compound which inhibits tumour cell growth and induces apoptotic cell death in a variety of cancer cells. This study was designed to determine whether Icariin can potentiate the antitumour activity of ATO in HCC treatment. Cell proliferation and apoptosis were measured using an MTT assay and flow cytometry respectively. Changes in reactive oxygen species (ROS) level and mitochondrial membrane potential were analysed by fluorescence signals. Protein expression was measured by western blotting and NF-κB activity was determined by ELISA assay. In addition, the antitumour effect of combination treatment with Icariin and ATO on HCC was evaluated using a murine HCC cancer xenograft model. Icariin inhibited proliferation and induced apoptosis in both of the tested HCC cell lines in a dose-dependent fashion. Icariin enhanced the antitumour activity of ATO both in vitro and in vivo. The antitumour activity of Icariin and its enhancement of the antitumour activity of ATO correlated with the generation of intracellular ROS and inhibition of NF-κB activity. Our results showed that Icariin potentiated the antitumour activity of ATO in HCC. Therefore, we propose that the combination treatment with Icariin and ATO might facilitate the optimization of ATO therapy for patients with HCC.


Individualized drug dosing using RBF-Galerkin method: Case of anemia management in chronic kidney disease.
Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and is frequently associated with decreased physical component of quality of life, as well as adverse cardiovascular events. Current treatment methods for renal anemia are mostly population-based approaches treating individual patients with a one-size-fits-all model. However, FDA recommendations stipulate individualized anemia treatment with precise control of the hemoglobin concentration and minimal drug utilization. In accordance with these recommendations, this work presents an individualized drug dosing approach to anemia management by leveraging the theory of optimal control. A Multiple Receding Horizon Control (MRHC) approach based on the RBF-Galerkin optimization method is proposed for individualized anemia management in CKD patients. Recently developed by the authors, the RBF-Galerkin method uses the radial basis function approximation along with the Galerkin error projection to solve constrained optimal control problems numerically. The proposed approach is applied to generate optimal dosing recommendations for individual patients. Performance of the proposed approach (MRHC) is compared in silico to that of a population-based anemia management protocol and an individualized multiple model predictive control method for two case scenarios: hemoglobin measurement with and without observational errors. In silico comparison indicates that hemoglobin concentration with MRHC method has less variation among the methods, especially in presence of measurement errors. In addition, the average achieved hemoglobin level from the MRHC is significantly closer to the target hemoglobin than that of the other two methods, according to the analysis of variance (ANOVA) statistical test. Furthermore, drug dosages recommended by the MRHC are more stable and accurate and reach the steady-state value notably faster than those generated by the other two methods. The proposed method is highly efficient for the control of hemoglobin level, yet provides accurate dosage adjustments in the treatment of CKD anemia.


Psychological antecedents of COVID-19 information sharing within strong-tie and weak-tie networks.
This study investigates the psychological mechanisms underlying people's sharing of COVID-19 information within their strong-tie networks and weak-tie networks. A cross-sectional online survey was conducted between March and April 2020 (N = 609 Chinese adults). Measures included emotions and behavioral beliefs about COVID-19 information sharing, risk perceptions, and COVID-19 information acquisition and sharing behaviors. Multiple linear regression was performed to examine the psychological predictors of COVID-19 information sharing. People were more likely to share COVID-19 information within their strong-tie networks when they experienced more negative emotions (β = .09, p = .01) and had stronger beliefs that information sharing would promote disease prevention (β = .12, p = .004). By comparison, negative emotions were the only significant predictor of COVID-19 information sharing (β = .12, p = .002) within weak-tie networks (β = .04, p = .31 for beliefs about sharing). People may share COVID-19 information within weak-tie networks to cope with negative emotions regardless of whether they perceive information sharing as beneficial to disease prevention. Health educators should raise people's awareness of the psychological motivators of COVID-19 information sharing to create a healthy information environment for disease prevention.


Conformational change on calcium binding by the lipopeptide antibiotic amphomycin. A C.D. and monolayer study.
The acidic linear lipopeptide amphomycin is a calcium dependent antibiotic which is thought to bind to carrier lipids such as dolichol monophosphate. The actual role of Ca++ is not definitely established and in this article we have examined the peptides interactions with a range of divalent cations. By CD we have shown that a conformational change is induced by Ca++, Sr++ and Ba++ but not by Mg++, Zn++, Cd++ or Gd+++. Monolayer studies show a decrease in molecular area and an increase in film stability when the subphase contains Ca++. The ensemble of results provides preliminary evidence for the formation of a beta hairpin structure on ion binding (Ka (Ca++) = 2.4 x 10(3)M-1) which could enhance amphomycin's bilayer solubility.


Invasive oral aspergillosis in immunocompromised patients with leukemia.
The clinicopathologic characteristics of invasive oral aspergillosis in 16 immunocompromised patients who developed this infection during antileukemic chemotherapy are described. The primary site of the infection was the marginal gingiva, there was severe spontaneous pain, and the patients developed spiking fever and granulocytopenia. Necrotic ulceration of the gingiva rapidly extended to the contiguous mucosa, muscle, and bone. Microscopically, the necrotic tissue contained thrombotic vascular infarcts and there were hyphae that showed frequent transverse septa and dichotomous branching. The invasive organisms were not responsive to amphotericin B in the absence of remission of the leukemia and restoration of the depressed host defenses. In 15 patients who showed improvement of hematologic status, oral aspergillosis was controlled by the combination of antifungal chemotherapy and debridement of necrotic tissues.


Developing a national database of police-reported fatal road traffic crashes for road safety research and management in India.
Strengthening crash surveillance is an urgent priority for road safety in low- and middle-income countries. We reviewed the online availability and completeness of First Information Reports (FIRs; police reports) of road traffic crashes in India. We developed a relational database to record information extracted from FIRs, and implemented it for one state (Chhattisgarh, 2017-2019). We found that FIRs can be downloaded in bulk from government websites of 15 states and union territories. Another 14 provide access online but restrict bulk downloading, and 7 do not provide online access. For Chhattisgarh, 87% of registered FIRs could be downloaded. Most FIRs reported the date, time, collision-type, and vehicle-types, but important crash characteristics (e.g. infrastructure attributes) were missing. India needs to invest in building the crash surveillance capacity for research and safety management. However, in the interim, maintaining a national database of a sample of FIRs can provide useful policy guidance.


Caffeine administration prevents retinal neuroinflammation and loss of retinal ganglion cells in an animal model of glaucoma.
Glaucoma is the second leading cause of blindness worldwide, being characterized by progressive optic nerve damage and loss of retinal ganglion cells (RGCs), accompanied by increased inflammatory response involving retinal microglial cells. The etiology of glaucoma is still unknown, and despite elevated intraocular pressure (IOP) being a major risk factor, the exact mechanisms responsible for RGC degeneration remain unknown. Caffeine, which is an antagonist of adenosine receptors, is the most widely consumed psychoactive drug in the world. Several evidences suggest that caffeine can attenuate the neuroinflammatory responses and afford protection upon central nervous system (CNS) injury. We took advantage of a well characterized animal model of glaucoma to investigate whether caffeine administration controls neuroinflammation and elicits neuroprotection. Caffeine or water were administered ad libitum and ocular hypertension (OHT) was induced by laser photocoagulation of the limbal veins in Sprague Dawley rats. Herein, we show that caffeine is able to partially decrease the IOP in ocular hypertensive animals. More importantly, we found that drinking caffeine prevented retinal microglia-mediated neuroinflammatory response and attenuated the loss of RGCs in animals with ocular hypertension (OHT). This study opens the possibility that caffeine or adenosine receptor antagonists might be a therapeutic option to manage RGC loss in glaucoma.


Silhouette photography of polyacrylamide slab gels.
A silhouette photography technique for making same-size negative films and positive contact prints of Coomassie blue-stained polyacrylamide slab gels is described. This technique does not require expensive photographic equipment and provides the resolution obtained with conventional camera systems.


Crystal structure and Hirshfeld surface analysis of N-[2-(5-methyl-furan-2-yl)phen-yl]-3-nitro-N-[(3-nitro-phen-yl)sulfon-yl]benzene-sulfonamide.
In the title compound, C23H17N3O9S2, C-H⋯O hydrogen bonds link adjacent mol-ecules in a three-dimensional network, while π-π stacking inter-actions, with centroid-centroid distances of 3.8745 (9) Å, between the furan and an arene ring of one of the two (3-nitro-phen-yl)sulfonyl groups, result in chains parallel to the a axis. The Hirshfeld surface analysis indicates that O⋯H/H⋯O (40.1%), H⋯H (27.5%) and C⋯H/H⋯C (12.4%) inter-actions are the most significant contributors to the crystal packing.


Experimental and theoretical interpretation of the magnetic behavior of two Dy(iii) single-ion magnets constructed through β-diketonate ligands with different substituent groups (-Cl/-OCH3).
Two Dy(iii) single-ion magnets, formulated as [Dy(Phen)(Cl-tcpb)3] (Cl-1) and [Dy(Phen)(CH3O-tmpd)3] (CH3O-2) were obtained through β-diketonate ligands (Cl-tcpb = 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione and CH3O-tmpd = 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione) with different substituent groups (-Cl/-OCH3) and auxiliary ligand, 1,10-phenanthroline (Phen). The Dy(iii) ions in Cl-1 and CH3O-2 are eight-coordinate, with an approximately square antiprismatic (SAP, D 4d) and trigonal dodecahedron (D 2d) N2O6 coordination environment, respectively, in the first coordination sphere. Under zero direct-current (dc) field, magnetic investigations demonstrate that both Cl-1 and CH3O-2 display dynamic magnetic relaxation of single-molecule magnet (SMM) behavior with different effective barriers (U eff) of 105.4 cm-1 (151.1 K) for Cl-1 and 132.5 cm-1 (190.7 K) for CH3O-2, respectively. As noted, compound CH3O-2 possesses a higher effective barrier than Cl-1. From ab initio calculations, the energies of the first excited state (KD1) are indeed close to the experimental U eff as 126.7 cm-1 vs. 105.4 cm-1 for Cl-1 and 152.8 cm-1 vs. 132.5 cm-1 for CH3O-2. The order of the calculated energies of KD1 is same as that of the experimental U eff. The superior SIM properties of CH3O-2 could have originated from the larger axial electrostatic potential (ESP(ax)) felt by the central Dy(iii) ion when compared with Cl-1. The larger ESP(ax) of CH3O-2 arises from synergic effects of the more negative charge and shorter Dy-O distances of the axial O atoms of the first sphere. These charges and distances could be influenced by functional groups outside the first sphere, e.g., -Cl and -OCH3.


A macrophage-monocyte cell line from a dog with malignant histiocytosis.
The DH82 cell line was established from the neoplastic progenitor cells of canine MH and was characterized as histiocytic in origin based on light microscopic and ultrastructural morphology, positive staining reactions for alpha naphthyl acetate esterase and acid phosphatase, presence of Fc receptors, phagocytosis of latex beads, and plastic adherence in culture.


Distinctive quality control method for solid-state fermented Isaria cicadae from strain Ic-17-7 and application in a rat model of type 2 diabetes.
This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7 (Ic-17-7fb) using a rat model of type 2 diabetes (T2DM). Random amplified polymorphic DNA, sequence-characterized amplified region, and high-performance liquid chromatography (HPLC) were used for the quality control of Ic-17-7fb. The pharmacological effects on streptozocin (STZ)-induced high fat diet (HFD)-fed Albino Wistar rats were evaluated. The rats underwent the following treatments: control, metformin, Ic-17-7fb (0.166 and 0.5 g·kg-1) or without treatment. The fasting blood glucose (FBG), blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-c), and low-density lipoprotein (LDL-c) were measured. Ic-17-7fb amplified a single specific band by S11-2-F3 and S11-2-R3 primers. An HPLC-based quality and quantity method was established for industrial application. The contents of adenosine and N6-(2-hydroxyethyl) adenosine (HEA) of the cultivated Ic-17-7fb were analyzed. All of the validation lots of cultured Ic-17-7fb passed the quantity control of the training set (0.90 mg·g-1 of adenosine and 0.89 mg·g-1 of HEA). After two weeks of administration, the average FBG was 4.89 ± 0.42 (control), 26.10 ± 5.77 (model), 23.63 ± 6.15 (metformin), 17.96 ± 9.36 (Ic-17-7fb for 0.166 g·kg-1), and 19.69 ± 8.71 mmol·L-1 (Ic-17-7fb for 0.5 g·kg-1). The FBG of Ic-17-7fb (0.166 g·kg-1) treatment significantly reduced by 31.19%, compared with the model after two weeks of administration (P < 0.01). Metformin, Ic-17-7fb (0.166 g·kg -1), and Ic-17-7fb (0.5 g·kg-1) reduced TC, TG, HDL-c, and LDL-c compared with the T2DM model treatment at the 6th week of treatment (P < 0.05). This study established the first quality standard for Ic-17-7fb, which can be effectively applied in the treatment of T2DM. The reliable quality control method and pharmacological effect will broaden its application space.


Cytotoxicity and apoptotic cell death induced by Vitis vinifera peel and seed extracts in A431 skin cancer cells.
Vitis vinifera. L is one of the most widely consumed fruits in the world and are rich in antioxidant abundant polyphenols. The present study was carried out to assess the antiproliferative and apoptotic effects of Vitis vinifera peel and seed extracts in an in vitro model using human epidermoid carcinoma A431 cell lines. Vitis vinifera peel and seed extracts were incubated with A431 cells to evaluate the antiproliferative, apoptotic effects and the morphological apoptotic changes induced by the extracts. Mitochondrial membrane potential was also measured after incubating the cells with extracts. At the inhibitory concentration (IC50), grape seed extract (111.11 µg/mL) and grape peel extract (319.14 µg/mL) were incubated for 24 h with A431 cells. Vitis vinifera peel and seed extracts were able to impart cytotoxic effects, induced apoptosis and apoptotic morphological changes in A431 cells significantly (p < 0.01) and this effect is associated with the interference with mitochondrial membrane potential. This reduction in mitochondrial membrane potential probably initiated the apoptotic cascade in the extracts treated cells. Vitis vinifera peel and seed phytochemicals can selectively target cancer cells and the phytochemicals that are occluded can serve as potential anticancer agents providing better efficacy in killing cancer cells.


Metabolic rate depression in a marine pulmonate snail: pre-adaptation for a terrestrial existence?
Terrestrial and freshwater pulmonate snails exhibit a marked depression of aerobic metabolism during estivation. This is an adaptation for existence in periodically harsh environments and, though marine gastropods may undergo anaerobic metabolism, they have not been shown to adaptively depress aerobic metabolic rate. We compared the metabolic response to progressive aerial exposure of two intertidal gastropod limpets, a prosobranch and a pulmonate. The prosobranch Patella granularis maintained a constant heart rate until shortly before death. In contrast, the pulmonate Siphonaria oculus underwent facultative depression of heart rate, accompanied by a decline in oxygen consumption. Both heart rate and oxygen consumption returned to normal levels on reimmersion in water. Metabolic rate depression is energy conserving, and may account for the ability of S. oculus to extend higher up the shore than P. granularis, into areas where food availability is low. S. oculus is a primitive, marine pulmonate, periodically subject to harsh conditions, and its capacity for metabolic rate depression may represent a pre-adaptation for life on land.


Can Australia Reach the World Health Organization Hepatitis C Elimination Goal by 2025 Among Human Immunodeficiency Virus-positive Gay and Bisexual Men?
Human immunodeficiency virus (HIV)-positive gay and bisexual men (GBM) in Australia are well engaged in care. The World Health Organization's (WHO) hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030 may be reachable ahead of time in this population. We predicted the effect of treatment and behavioral changes on HCV incidence among HIV-positive GBM up to 2025 using a HCV transmission model parameterized with Australian data. We assessed the impact of changes in behavior that facilitate HCV transmission in the context of different rates of direct-acting antiviral (DAA) use. HCV incidence in our model increased from 0.7 per 100 person-years in 2000 to 2.5 per 100 person-years in 2016 and had the same trajectory as previously reported clinical data. If the proportion of eligible (HCV RNA positive) patients using DAAs stays at 65% per year between 2016 and 2025, with high-risk sexual behavior and injecting drug use remaining at current levels, HCV incidence would drop to 0.4 per 100 person-years (85% decline from 2016). In the same treatment scenario but with substantial increases in risk behavior, HCV incidence would drop to 0.6 per 100 person-years (76% decline). If the proportion of eligible patients using DAAs dropped from 65% per year in 2016 to 20% per year in 2025 and risk behavior did not change, HCV incidence would drop to 0.7 per 100 person-years (70% reduction). Reaching the WHO HCV elimination target by 2025 among HIV-positive GBM in Australia is achievable.


Synthesis and self-assembled ring structures of Ni nanocrystals.
Narrow size distribution Ni nanocrystals with average diameters from 5 to 13 nm ( approximately 20% standard deviation) and a face-centered cubic (fcc) structure were synthesized via rapid thermo-decomposition in the presence of surfactants in solution. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were used to characterize these nanocrystals. It was found that the solvent determined the rate of the decomposition of Ni precursors, while the surfactants controlled the size and shape of Ni nanocrystals. A three-step process was proposed to explain the synthesis. The purified Ni nanocrystals readily formed micrometer-sized ring structures on TEM grids after solvent evaporation (hexanes), and the magnetic field was found to increase the density of the rings.


Observations on the gastric mucosa of rheumatic patients before and after ibuprofen administration as studied by the pentagastrin test, endoscopy, and light and electron microscopy.
The initial results of a study set up to investigate the gastric mucosa in rheumatic patients receiving ibuprofen are described. The study involved seven male patients, aged between 17 to 70 years, suffering from various rheumatic diseases. All patients received a daily dose of 1200 mg of ibuprofen per os divided into three fractions and taken over periods of treatment ranging from one to six weeks. On the data obtained by the gastric secretion test, endoscopy, and specific histological and ultrastructure studies it is concluded that, in the cases investigated, ibuprofen could not be shown to be responsible for any significant modification of the gastric mucosa.


What do patients think about HIV mass screening in France? A qualitative study.
Since 2009, HIV mass screening of the 15-70-year-old general population in low-risk situations has been recommended in France. This, not yet implemented, untargeted screening would be cost-effective with a positive impact on public health. No previous studies had interrogated primary care patients about it. This study aimed at exploring perceptions of patients attending general practitioner's on HIV mass screening and at identifying barriers to its implementation. We conducted a qualitative study through semi-structured individual interviews. Participants were recruited according to age, gender and location of their physician's practice. Data analysis was based on triangulation by two researchers. Twenty-four interviews were necessary to obtain data saturation. HIV transmission was mostly associated with sexual intercourse; main barriers stemming from the screening were related to sexuality, often seen as questioning spouse's faithfulness. It could interfere with religiosity, implying an upsetting perception of sexuality among the elderly. Patients' beliefs and perceptions regarding HIV/AIDS, the fear to be screened and difficulties to talk about sexuality were other barriers. To our knowledge, no studies had previously interrogated primary care patients about barriers to HIV mass screening in France. Although relevance of this untargeted screening is debated in France, our results could be helpful to a better understanding of patients' attitudes toward this and to an outstanding contribution to reduce the number of new cases of HIV contamination.


The novel HLA-A*11:443 allele characterised by two different sequencing-based typing techniques.
The novel allele HLA-A*11:443 differs from HLA-A*11:01:01:01 by one non-synonymous nucleotide substitution in exon 2.


Effects of morphine on hippocampal cells recorded in vitro.
Intracellular recordings from CA1 pyramidal cells were obtained in the in vitro hippocampal slice preparation before and after the application of morphine sulfate. Two distinct effects were observed following addition of morphine (1.0 mM) to the bathing media, or application to individual slices through pressure ejection via large tipped pipettes. Within 3-10 min following morphine application CA1 cell membrane potentials began to depolarize (5-10 mV) toward firing threshold. Spontaneous discharge rates were increased and nonactive cells became active. Rhythmic firing at a rate of 5-8 Hz was observed for 30-40 min following drug application. The spontaneous rhythmic firing could be partially reversed by the addition of naloxone (0.1 mM) to the bathing media. The second effect of morphine was to potentiate the development of epileptiform discharges in CA1 cells in response to low frequency orthodromic synaptic stimulation. The findings indicate that morphine alters the excitability of hippocampal pyramidal cells and such changes are likely to be mediated by opiate specific alterations in membrane conductance and/or tonic inhibitory synaptic inputs.


2-Chloro-N-{3-cyano-1-[2,6-dichloro-4-(trifluoro-meth-yl)phen-yl]-1H-pyrazol-5-yl}acetamide.
The title compound, C(13)H(6)Cl(3)F(3)N(4)O, was synthesized by the reaction of 5-amino-1-[2,6-dichloro-4-(trifluoro-meth-yl)phen-yl]-1H-pyrazole-3-carbonitrile and 2-chloro-acetyl chloride. The five-membered pyrazole ring makes a dihedral angle of 71.5 (3)° with the benzene ring. The -CF(3) group is disordered by rotation, and the F atoms are split over two sets of sites with occupancies of 0.59 (2) and 0.41 (2). The crystal structure features weak C-H⋯O and N-H⋯N inter-actions involving the carbonyl and cyano groups as acceptors.


Use of the Impella 2.5 Microaxial pump for right ventricular support after insertion of Heartmate II left ventricular assist device.
The Impella microaxial pump is a catheter-based device that has been used for left ventricular support. The catheter can be inserted through a peripheral artery or directly into the ascending aorta. The pump is positioned across the aortic valve with the inflow directly in the left ventricle and the outflow in the ascending aorta. We describe the use of the Impella as a right ventricular support device during the placement of a Heartmate II left ventricular assist device. To our knowledge, this is the first report in the literature of the use of the Impella in this manner.


Biochemical Markers of Physical Exercise on Mild Cognitive Impairment and Dementia: Systematic Review and Perspectives.
The cognitive effects of physical exercise in patients with dementia disorders or mild cognitive impairment have been examined in various studies; however the biochemical effects of exercise from intervention studies are largely unknown. The objective of this systematic review is to investigate the published results on biomarkers in physical exercise intervention studies in patients with MCI or dementia. The PubMed database was searched for studies from 1976 to February 2015. We included intervention studies investigating the effect of physical exercise activity on biomarkers in patients with MCI or dementia. A total of eight studies were identified (n = 447 patients) evaluating exercise regimes with variable duration (single session-three sessions/week for 26 weeks) and intensity (light-resistance training-high-intensity aerobic exercise). Various biomarkers were measured before and after intervention. Seven of the eight studies found a significant effect on their selected biomarkers with a positive effect of exercise on brain-derived neurotrophic factor, cholesterol, testosterone, estradiol, dehydroepiadrosterone, and insulin in the intervention groups compared with controls. Although few studies suggest a beneficial effect on selected biomarkers, we need more knowledge of the biochemical effect of physical exercise in dementia or MCI.


Dysregulation of emotional response in current and abstinent heroin users: negative heightening and positive blunting.
Evidence suggests that abstinent opioid users have abnormal emotional response to natural reinforcing stimuli, but little is known about the emotional response of subjects currently using heroin. Abnormal emotional experience could underlie poor sensitivity to negative events related to heroin use and reduced ability to consider alternative reinforcers to help overcome addiction. In this paper, we will assess the subjective response of current and abstinent heroin users exposed to emotionally competent positive and negative stimuli. We administered the "Clinical Instrument for Emotional Response Evaluation" (including neutral, pleasant, and unpleasant images from the International Affective Picture System) to 22 current opioid users enrolled in a clinical trial using controlled prescribed heroin and 41 abstinent opioid users enrolled in residential treatment. The dependent variable was their subjective response to the images measured with the Self-Assessment Manikin, a scale designed to rate the International Affective Picture System (IAPS) images in the three dimensions of emotion: valence, arousal, and dominance. We compared these ratings with IAPS normative values for healthy participants. Significant group x emotional condition interactions were found in the arousal dimension. Post-hoc tests showed that compared to healthy participants, both current and abstinent heroin users had greater emotional response to neutral images and lower response to pleasant images. Furthermore, current opioid users had higher emotional response to unpleasant images when compared to healthy participants and lower response to pleasant images when compared to abstinent users. Current opioid users have abnormal emotional experience, characterized by heightened response to unpleasant stimuli and blunted response to pleasant stimuli.


Ca2+ transients of cardiomyocytes from senescent mice peak late and decay slowly.
Ventricular myocytes were isolated from either young (2 months, "young myocytes") or senescent (20-26 months, "senescent myocytes") mice. Ca2+ transients were evoked by 40ms voltage-clamp pulses depolarising at 0.4, 1, 2, 4 or 8Hz. At 8Hz, Ca2+ transients from senescent cells peaked later (39ms versus 23ms) to smaller systolic [Ca2+](c) (667nM versus 1110nM) and decayed at slower rate (16s(-1) versus 33s(-1)) to higher end-diastolic [Ca2+](c) (411nM versus 220nM) than those from young myocytes. These differences were less pronounced at lower frequencies of pulsing and could not be explained by differences of the time integral of Ca2+ inward current. Since concentrations of SERCA2a and SERCA2b proteins were similar in young and senescent cells, slow rate of Ca2+ decay and high diastolic [Ca2+]c are explained on the assumption that the usual Ca2+ stimulation of SERCA2 activity is attenuated in senescent cells. The prolonged time-to-peak [Ca2+]c is discussed to result from insufficient SR Ca2+ filling by SERCA2 and, in context with confocal images, from a shift of the SERCA2b distribution to the subsarcolemmal space. The age-related changes of the Ca2+ transients are discussed to cause systolic and diastolic failure if senescent mouse hearts beat at high frequencies.


[Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].
In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.


Persistent venous leg ulcers complicated by linear morphea: a case report.
Soft tissue ulceration resulting from chronic venous insufficiency is a common condition that requires standardised long-term therapy, which has been thoroughly established. We report a patient with a five-year history of persistent venous stasis ulcers despite treatment consistent with traditional wound care. Resolution of the ulcers began only upon deviation from conventional therapy. This report considers non-standard treatments in patients with venous ulcers that do not progress.


Differential regulation of TNF receptor 1 and receptor 2 in adiponectin expression following myocardial ischemia.
In vitro experiments demonstrate that adiponectin, a cardioprotective cytokine, is inhibited by tumor necrosis factor-alpha (TNFα). However, the role of TNFα in post-myocardial infarction (post-MI) adiponectin reduction remains unclear. More importantly, the TNF receptor type (TNFR1 or TNFR2) responsible for TNFα-mediated suppression of adiponectin production is unknown. The current study determined the role of TNFα in post-myocardial infarction (post-MI) adiponectin reduction, and identified the receptor type responsible for TNFα-mediated suppression of adiponectin production. Adult male wild type (WT) and three knockout variety (TNFα(-/-), TNFR1(-/-), and TNFR2(-/-)) mice were subjected to MI via coronary artery occlusion. Histological and biochemical analyses were performed 3 and 7days post-MI. In WT mice, MI significantly increased plasma TNFα, reduced adipocyte adiponectin mRNA, and decreased plasma adiponectin levels. TNFα deletion had no significant effect upon basal adiponectin level, and partially restored adiponectin expression/production post-MI (P<0.01 vs. WT). Basal adiponectin levels were significantly increased in TNFR1(-/-) (P<0.05 vs. WT), and unchanged in TNFR2(-/-) mice. Importantly, suppressed adiponectin expression/production by MI or TNFα administration was markedly decreased by TNFR1 deletion (P<0.01 vs. WT), but exacerbated by TNFR2 deletion (P<0.05 vs. WT). Mechanistically, TNFR1 knockout significantly inhibited, whereas TNFR2 knockout further enhanced TNFα-induced mRNA and protein expression of ATF3, a transcriptional factor known to significantly inhibit adiponectin expression. Our study demonstrates that TNFα overproduction is responsible for reduced adiponectin expression/production following MI. Furthermore, we show that TNFR1/TNFR2 exerts opposite effects upon adiponectin expression/production via differential regulation of ATF3.


Concomitant repair of a chronic traumatic aortic aneurysm with tracheal erosion.
Tracheal erosion from a chronic false aneurysm secondary to trauma is unusual. Resection with graft interposition is the treatment of choice. This case report describes the additional use of an intrathoracic muscle flap necessitated by tracheal erosion and contamination.


Network-Guided Sparse Learning for Predicting Cognitive Outcomes from MRI Measures.
Alzheimer's disease (AD) is characterized by gradual neurodegeneration and loss of brain function, especially for memory during early stages. Regression analysis has been widely applied to AD research to relate clinical and biomarker data such as predicting cognitive outcomes from MRI measures. In particular, sparse models have been proposed to identify the optimal imaging markers with high prediction power. However, the complex relationship among imaging markers are often overlooked or simplified in the existing methods. To address this issue, we present a new sparse learning method by introducing a novel network term to more flexibly model the relationship among imaging markers. The proposed algorithm is applied to the ADNI study for predicting cognitive outcomes using MRI scans. The effectiveness of our method is demonstrated by its improved prediction performance over several state-of-the-art competing methods and accurate identification of cognition-relevant imaging markers that are biologically meaningful.


Natural alpha-interferon in combination with hyperfractionated radiotherapy in the treatment of non-small cell lung cancer.
Our previous study in patients with small-cell lung cancer indicated that natural alpha interferon might be a radiosensitiser. In this study we considered 20 patients with inoperable non-small cell lung cancer, who were randomly assigned to receive either hyperfractionation radiotherapy alone, 1.25 Gy twice a day (6 hr interval), 60 Gy/48F/32d; or the same radiotherapy concurrently with alpha interferon. Patients in the radiotherapy+alpha interferon arm received 3 x 10(6) IU natural alpha interferon intramuscularly and 1.5 x 10(6) IU inhaled via a dosimeter-equipped jet nebulizer 30 min before each radiotherapy session. Tumor response and radiation-induced lung injury were assessed by serial chest radiographs, computerized tomography scans and lung function studies, during a 1 year follow-up period. No patient in either arm achieved complete response. On the other hand, five patients in the radiotherapy arm and six in the radiotherapy+interferon arm experienced partial response, and the corresponding figures for stable disease were three and one. Combined treatment with radiotherapy and inhaled and intramuscular interferon proved feasible but laborious, for both patients and staff. Pneumonitis and/or oesophagitis in the radiotherapy+interferon arm were moderate to severe, and only two patients tolerated the treatment without any modifications. No treatment modifications were necessary in the radiotherapy arm. The early deaths in the radiotherapy+interferon arm may have been treatment-related. The optimal way to combine interferon and radiotherapy to further evaluate its role as a radiosensitiser needs further studies in larger series.


The cell cultures and the use of haemocytes from marine molluscs for ecotoxicology assessment.
Among aquatic organisms suitable for biological monitoring, molluscs occupy a prominent place due to their wide geographic distribution, their abundance and accessibility in the field as well as in aquaculture. Molluscs reflect the degree of environmental contamination and are the most useful bioindicator tools. The study of modulation of immune system or immunomodulation in marine molluscs has become one of the privileged ways for evaluating the physiological effects of environmental factors. Physiological responses of molluscs to environmental stresses could be mediated by haemocytes. These cells are continually exposed to the external environment due to the open circulatory system of molluscs and are affected by pollutants. In fact, several studies showed the effects of different environmental contaminants on haemocyte functions (viability, phagocytosis, ROS production) as well as on proteins involved in cytoskeletal structure maintenance using the in vitro approaches. In ecotoxicology, in vitro approach is an alternative to animal testing due to the reduced use of experimental animals, low cost and rapid performance. Although several studies showed the importance of using in vitro cell models to determine the effects of different environmental contaminants on haemocyte parameters in marine molluscs, a few reviews highlight these effects. The main purpose of this paper is to summarize the recent data on the effect of some xenobiotics on haemocyte parameters in some mollusc species and then suggest future research prospects.


Intraventricular self-administration of heroin in the rat: reward seems dissociated from analgesia and physical dependence.
Experimentally naive rats were implanted with a cannula in the lateral ventricle of the brain and were allowed to self-administer heroin in doses of 0.125, 0.25, 0.5, 1 or 2 micrograms/infusion or placebo for five daily sessions of 3 h. The number of self-injections was related to the unit dose in an inverted U-shaped manner: the 0.5 microgram/infusion dose induced the highest infusion rate. The total heroin intake was proportionally related to the unit dose. A hot-plate test performed immediately after the fourth session revealed no analgesic effects in any of the groups that self-administered heroin. A naloxone (10 mg/kg) challenge given immediately after the fifth session induced very mild withdrawal signs only in the group that administered the highest dose of heroin. The results indicate that rats readily acquire intraventricular heroin self-administration behaviour and suggest that the rewarding effects of heroin can be dissociated from its analgesic and physical dependence-inducing effects.


Metabolism of [11-3H]retinyl acetate in liver tissues of vitamin A-sufficient, -deficient and retinoic acid-supplemented rats.
A study was conducted on the incorporation of [11-3H]retinyl acetate into various retinyl esters in liver tissues of rats either vitamin A-sufficient, vitamin A-deficient or vitamin A-deficient and maintained on retinoic acid. Further, the metabolism of [11-3H]retinyl acetate to polar metabolites in liver tissues of these three groups of animals was investigated. Retinol metabolites were analyzed by high-performance liquid chromatography. In vitamin A-sufficient rat liver, the incorporation of radioactivity into retinyl palmitate and stearate was observed at 0.25 h after the injection of the label. The label was further detected in retinyl laurate, myristate, palmitoleate, linoleate, pentadecanoate and heptadecanoate 3 h after the injection. The specific radioactivities (dpm/nmol) of all retinyl esters increased with time. However, the rate of increase in the specific radioactivity of retinyl laurate was found to be significantly higher (66-fold) than that of retinyl palmitate 24 h after the injection of the label. 7 days after the injection of the label, the specific radioactivity between different retinyl esters were found to be similar, indicating that newly dosed labelled vitamin A had now mixed uniformly with the endogenous pool of vitamin A in the liver. The esterification of labelled retinol was not detected in liver tissues of vitamin A-deficient or retinoic acid-supplemented rats at any of the time point studied. Among the polar metabolites analyzed, the formation of [3H]retinoic acid from [3H]retinyl acetate was found only in vitamin A-deficient rat liver 24 h after the injection of the label. A new polar metabolite of retinol (RM) was detected in liver of the three groups of animals. The formation of 3H-labelled metabolite RM from [3H]retinyl acetate was not detected until 7 days after the injection of the label in the vitamin A-sufficient rat liver, suggesting that metabolite RM could be derived from a more stable pool of vitamin A.


Ideal food pyramid for patients with rheumatoid arthritis: A narrative review.
Emerging literature suggests that diet plays an important modulatory role in rheumatoid arthritis (RA) because diet is an environmental factor that affects inflammation, antigen presentation, antioxidant defense mechanisms and gut microbiota. Patients with RA frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions. Given this background, the aim of this review is to evaluate the evidence to date regarding the ideal dietary approach for management of RA in order to reduce the counteracting inflammation, and to construct a food pyramid for patients with RA. The pyramid shows that carbohydrates should be consumed every day (3 portions of whole grains, preferably gluten free), together with fruits and vegetables (5 portions; among which fruit, berries and citrus fruit are to be preferred, and among the vegetables, green leafy ones.), light yogurt (125 ml), skim milk (200 ml), 1 glass (125 ml) of wine and extra virgin olive oil; weekly, fish (3 portions), white meat (3 portions), legumes (2 portions) eggs (2 portions), seasoned cheeses (2 portions), and red or processed meats (once a week). At the top of the pyramid, there are two pennants: one green means that subjects with RA need some personalized supplementation (vitamin D and omega 3) and one red means that there are some foods that are banned (salt and sugar). The food pyramid allows patients to easily figure out what to eat.


Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins.
The bitter taste of drugs, food components, and any other substances which get in the mouth as dissolved in an aqueous solution, or in the saliva, can be strongly reduced or fully eliminated, if the bitter component forms an inclusion complex with an appropriate cyclodextrin (CD). The value of the complex association constant (determined by the structure of the bitter 'guest' molecule and the size and eventual substitution of the 'host' CD molecule), the temperature and the host/guest ratio determine the extent of complexation of the guest molecule (percentage of complexation) at the equilibrium. The K(ass) for most drug/CD complexes at 36 degrees C buccal cavity temperature is between 10(2) and 10(4) mol-1. If the unit dose (of a sublingual or chewing tablet, chewing gum) with a bitter drug (molecular weight of about 150, forming a 1:1 complex with betaCD) is approximately 10mg then the betaCD can be taken in a 5- or even 10-fold molar excess. Under such conditions more than 99% of the bitter drug is complexed, and because complexed molecules cannot react with the taste buds in the buccal cavity no bitter taste is perceived. Frequently, preparation of the drug/CD complex is not necessary, because the betaCD is present in a large excess, dissolved very quickly in the saliva and results in a saturated CD solution. Therefore, the complexation of the bitter drug is completed very rapidly. Only dissolved substances have taste and only CD complexable drug molecules can become debittered by CDs. Bitter, astringent components of foods (e.g. soya), beverages (e.g. naringin in citrus fruit juice, or chlorogenic acid and polyphenols in coffee) cigarette smoke (nicotine) also can be complexed and their taste reduced or fully eliminated.


Single-Cell Profiling Reveals Sex, Lineage, and Regional Diversity in the Mouse Kidney.
Chronic kidney disease affects 10% of the population with notable differences in ethnic and sex-related susceptibility to kidney injury and disease. Kidney dysfunction leads to significant morbidity and mortality and chronic disease in other organ systems. A mouse-organ-centered understanding underlies rapid progress in human disease modeling and cellular approaches to repair damaged systems. To enhance an understanding of the mammalian kidney, we combined anatomy-guided single-cell RNA sequencing of the adult male and female mouse kidney with in situ expression studies and cell lineage tracing. These studies reveal cell diversity and marked sex differences, distinct organization and cell composition of nephrons dependent on the time of nephron specification, and lineage convergence, in which contiguous functionally related cell types are specified from nephron and collecting system progenitor populations. A searchable database, Kidney Cell Explorer (https://cello.shinyapps.io/kidneycellexplorer/), enables gene-cell relationships to be viewed in the anatomical framework of the kidney.


Enhancement of ultraweak photon emission with 3 MHz ultrasonic irradiation on transplanted tumor tissues of mice.
We investigated photon emissions of various bio-samples which were induced by ultrasonic stimulation. It has been reported that ultrasonic stimulations induced the thermal excitation of the bio-tissues. After ultrasonic stimulation, any measurement of photon radiation in the visible spectral range has not been carried out yet. The instruments consisted of electronic devices for an ultrasonic generator of the frequency 3 MHz and a photomultiplier tube (PMT) system counting photons from bio-tissues. The transplanted tumor tissues of mice were prepared for the experiments and their liver and spleen tissues were also used for the controls. It was found that the continuous ultrasonic stimulations with the electrical power 2300 mW induced ultraweak photon emissions from the tumor tissues. The number of induced photon was dependent of the type of the tissues and the stimulation time intervals. The level of photon emission was increased from the mouse tumor exposed to the ultrasonic stimulations, and the changes were discriminated from those of the spleens and livers.


A comparison of the performance of commercially available chromogenic agars for the isolation and presumptive identification of organisms from urine.
To compare four media-UTI medium, BBL CHROMagar, CPS ID2, and Harlequin CLED-using a collection of fully characterised organisms and subsequent "field trial". Seven hundred and eighty seven fully characterised isolates (730 Gram negative bacteria, 47 Gram positive bacteria, and 10 yeasts) were used to test for accuracy of organism identification. To assess isolation rates and ability to detect mixed cultures, 1435 urine samples were cultured in the three best performing chromogenic media (UTI medium, BBL CHROMagar, and CPS ID2) and CLED. The chromogenic agars differed in their accuracy of identification, with BBL CHROMagar performing best and Harlequin CLED performing least well. Similarly, BBL CHROMagar achieved a higher overall isolation rate than UTI medium and CPS ID2. When mixed growth was defined as greater than two organism types, BBL CHROMagar detected more mixed cultures than did UTI medium and CPS ID2, although the differences were not significant. When mixed growth was defined as greater than one organism type the increased number of mixed growths detected by BBL CHROMagar became significant, largely because of differences in enterococcal isolation rates. The use of BBL CHROMagar, UTI medium, or CPS ID2 chromogenic agar as a replacement for CLED agar would improve the detection rate of contaminated urine samples. Enhanced identification helps to distinguish different species, facilitating the monitoring of bacterial resistance in support of the national antibiotic strategy. BBL CHROMagar gave the highest overall organism recovery rates, greatest ability to detect mixed cultures, and the most accurate identification of organisms.


Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer.
Vinorelbine (Navelbine, NVB) is a new semi-synthetic vinca alkaloid that is currently used in the treatment of advanced breast cancer and advanced non-small-cell lung cancer (NSCLC). In this study we investigated the tumoral and healthy pulmonary tissue concentrations of NVB in previously untreated NSCLC patients undergoing surgery. A total of 13 patients (mean age, 60 years; range, 42-70 years) were included and received NVB (20 mg/m2) at 1 h (mean, 1.1 h; SD, 0.2 h; n = 6 patients) and 3 h (mean, 3.0 h; SD, 0.6 h; n = 7 patients) before tumor resection. A tumoral and adjacent healthy lung-tissue specimen as well as simultaneously sampled serum were analyzed for NVB by high-performance liquid chromatography (HPLC). NVB levels were much higher in tissue than in serum (up to 300-fold). The tissue/serum ratio increased between the 1-h sampling time (range, 0.1-100) and the 3-h time point (range, 10-300). In all patients but two, NVB concentrations were lower in tumors than in healthy lung tissue. The tumor/healthy tissue ratio ranged from 0.06 to 1.3 (median, 0.09) at 1 h and from 0.18 to 1.1 (median, 0.55) at 3 h. This ratio increased between the 1-h sampling time and the 3-h time point as a consequence of increasing tumor levels (median, 50.4 ng/g at 1 h and 278 ng/g at 3 h). In four patients, concentrations could be measured in necrotic and peripheral tumor zones, showing lower values in necrotic areas. Thus, these data indicate that NVB is highly distributed in lung tissue, with the disposition rate being slower in tumor tissue than in healthy parenchyma during the first 3 h.


Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy.
Brachytherapy-based APBI (bAPBI) shortens treatment duration and limits dose to normal tissue. While studies have demonstrated similar local control when comparing bAPBI and whole breast irradiation using intensity modulated radiotherapy (WBI-IMRT), comparison of late side effects is limited. Here, we report chronic toxicity profiles associated with these two treatment modalities. 1034 patients with early stage breast cancer were treated at a single institution; 489 received standard-fractionation WBI-IMRT between 2000 and 2013 and 545 received bAPBI (interstitial 40%, applicator-based 60%) between 1993 and 2013. Chronic toxicity was evaluated ≥6 months utilizing CTCAE version 3.0; cosmesis was evaluated using the Harvard scale. Median follow-up was 4.6 years (range 0.1-13.4) for WBI-IMRT versus 6.7 years (range 0.1-20.1) for bAPBI (p < 0.001). Compared to WBI-IMRT, bAPBI was associated with higher rates of ≥grade 2 seroma formation (14.4% vs 2.9%, p < 0.001), telangiectasia (12.3% vs 2.1%, p = 0.002) and symptomatic fat necrosis (10.2% vs 3.6%, p < 0.001). Lower rates of hyperpigmentation were observed (5.8% vs 14.5%; p = 0.001). Infection rates were similar (3.3% vs 1.3%, p = 0.07). There was no difference between rates of fair (6.1% vs. 4.1%, p = 0.30) or poor (0.2% vs. 0.5%, p = NS) cosmesis. Mastectomy rates for local recurrence (3.1% for WBI-IMRT and 1.2% for bAPBI, p = 0.06), or for other reasons (0.8% and 0.6%, p = 0.60) were similar between groups. With 5-year follow-up, WBI-IMRT and bAPBI are associated with similar, acceptable rates of toxicity. These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in a safe and efficacious manner.


Analysis and characterization of phosphinic pseudopeptides by capillary zone electrophoresis.
Capillary zone electrophoresis (CZE) was applied to analysis and characterization of phosphinic pseudopeptides with the general structure N-Ac-Val-Ala(psi)(PO2(-)-CH(2)) Leu-Xaa-NH(2), where Xaa represents one of 20 proteinogenic amino acid residues. Pseudopeptides containing neutral or acidic amino acid residues in position Xaa were analyzed as anions in weakly alkaline (pH 8.1) Tris-Tricine background electrolyte (BGE), pseudopeptides with basic amino acid residues in position Xaa were analyzed as cations in acid BGEs (Tris-phosphate buffers). Acidity of phosphinic acid moiety in peptides with basic amino acid residues was determined from the dependence of effective mobility of these peptides on pH in the acid pH region (pH 1.4-2.8). Additionally, separation of diastereomers of some peptides was achieved.


Two-year clinical outcome in patients with small coronary artery disease treated with everolimus- versus paclitaxel-eluting stenting.
Percutaneous coronary interventions involving small coronary vessels represent a true challenge because of the increased risk of restenosis and adverse outcomes. We evaluated the 2-year clinical outcomes between single everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in small coronary artery disease. From the data of SACRA (SmAll CoronaRy Artery treated by TAXUS Liberté) and PLUM (PROMUS/Xience V Everolimus-ELUting Coronary Stent for sMall coronary artery disease) registries, 245 patients with 258 lesions and 264 patients with 279 lesions, respectively, were enrolled in this study. The 2-year clinical driven target lesion revascularization (4.5% vs. 10.6%, p=0.01) and target vessel revascularization (8.0% vs. 13.9%, p=0.03) rates were significantly lower in the EES group compared with the PES group. Major adverse cardiac events in the EES group tended to be lower than those in the PES group (8.7% vs. 14.3%, p=0.05). On the other hand, all new lesions for remote target vessel revascularization were observed at the proximal site of target lesions in both groups and those rates were not different between the two groups (3.4% vs. 3.3%, p>0.99). EES showed better clinical results at 2-year follow-up compared with PES in small coronary artery diseases, however, new lesions at the proximal remote site of the target lesion remain problematic.


Assessing the significance of health information seeking in chronic condition management.
To examine the relationship between health information seeking and confidence in performing self-management activities, and to assess the influence of predisposing, enabling, and perceive need factors on confidence to perform self-management activities among adults with chronic conditions. The sample included 6724 adults from the 2007 Health Tracking Household Survey who were ≥18 years with a chronic condition. Binary logistic regression examined the relationship between health information seeking, predisposing, enabling, and perceive need factors and confidence in performing three self-management activities; prevent symptoms, tell doctor concerns, and know when to get medical care. Analyses indicated that 63.7% of adults sought health information. Rural residents who sought health information had 50% (95% CI: 0.28-0.89) lower odds of being confident to tell doctor concerns compared to urban residents who did not seek health information. The relationship between health information seeking and confidence to perform self-management varies by self-management activity. Rurality, education level, having a usual source of care, and perceived health status strongly predict confidence to perform self-management activities. Self-management strategies should incorporate health information seeking behavior that will enhance confidence to perform specific self-management activities, and should incorporate predisposing, enabling, and perceive need factors.


Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients.
Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2, and one novel deep intronic splice variant in PXDN. An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants.


Spontaneous Coronary Artery Dissection in a Transplanted Heart.
We report the case of a 37-year-old man who presented with shortness of breath 1 year post heart transplantation. He was receiving tacrolimus, methylprednisolone, and mycophenolate. An angiogram showed spontaneous coronary artery dissection involving the left anterior descending artery. Percutaneous coronary intervention was performed successfully, with stent placement and return of flow. (Level of Difficulty: Advanced.).


Dendrimer type bio-reducible polymer for efficient gene delivery.
Arginine-grafted bio-reducible poly(disulfide amine) (ABP) was incorporated into the poly(amido amine) (PAMAM) dendrimer, creating a high molecular weight bio-reducible polymer, PAM-ABP, to overcome the limitations of the low molecular weight ABP. The newly synthesized PAM-ABP was studied to determine its efficacy as a gene delivery carrier. The PAM-ABP demonstrated superior condensing ability for plasmid DNA through the formation of compact nanosized polyplexes. These compact polyplexes enhanced cellular uptake and were less susceptible to reducing agents, resulting in greater transfection efficiency compared to ABP alone. Based on these results, this newly developed PAM-ABP polyplex is a promising delivery system for clinical gene therapy.


Application of response surface methodology for optimization of decolorization and mineralization of triazo dye Direct Blue 71 by Pseudomonas aeruginosa.
The decolorization and degradation of Direct Blue 71 were investigated using a mono culture of Pseudomonas aeruginosa. The bacterium was able to decolorize the dye medium to 70.43 % within 48 h under microaerophilic conditions. The medium was then aerated for 24 h to promote the biodegradation of the aromatic amines generated from azo bond cleavage. Reduction in total organic carbon in dye medium was 42.58 % in the microaerophilic stage and 78.39 % in the aerobic stage. The degradation metabolites formed were studied using UV-vis techniques, high performance liquid chromatography, Fourier transform infra red spectroscopy and nuclear magnetic resonance spectroscopy analysis. Data obtained provide evidence for the formation of aromatic amines and their subsequent oxidative biodegradation by a single strain of P. aeruginosa during successive microaerophilic/aerobic stages in the same flask. The influence of incubation temperature (20-45 °C), medium pH (5-10) and initial dye concentration (25-150 mg/L) on decolorization was evaluated to greatly influence decolorization extent. The optimal decolorization conditions were determined by response surface methodology based on three-variable central composite design to obtain maximum decolorization and to determine the significance and interaction effect of the variables on decolorization. The optimal conditions of response were found to be 35.15 °C, pH 8.01 and 49.95 mg/L dye concentration giving an experimental decolorization value of 84.80 %. Very high regression coefficient between the variables and the response (R2 = 0.9624) indicated a good evaluation of experimental data by polynomial regression model.


Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.
Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.


Sleep, psychological distress, and clinical pregnancy outcome in women and their partners undergoing in vitro or intracytoplasmic sperm injection fertility treatment.
To explore the prevalence of poor sleep quality in couples undergoing fertility treatment and study possible associations. 163 women and 132 partners receiving in vitro (IVF) or intracytoplasmic sperm injection (ICSI) fertility treatment. Three public Danish fertility clinics. Participants completed the Pittsburgh Sleep Quality Index (PSQI) at three time-points as part of a larger RCT. Additional data from patient records and questionnaires were included to evaluate possible associations with treatment protocol type, psychological distress, and pregnancy outcome. Mean PSQI global scores before treatment were 8.1 (standard deviation = 2.3), with 91% of participants having PSQI scores > 5, indicating poor sleep quality. Scores did not differ between women and their partners and did not change during treatment. Statistically significant associations were found between sleep quality and depressive symptoms and state anxiety (p < .001). No difference in PSQI scores was found between protocol types. While there was a trend towards higher clinical pregnancy rates among women with good sleep quality (PSQI ≤ 5 = 72.7%, PSQI 6-10 = 52.6% and PSQI ≥ 11 = 42.3%), the differences did not reach statistical significance (p = .10-.21). Poor sleep quality is a prevalent problem among couples undergoing fertility treatment and is associated with psychological distress and possibly with pregnancy outcomes. Success rates after fertility treatment remain moderate, and poor sleep quality, a potentially modifiable factor, could be relevant to screen for and treat among couples undergoing fertility treatment. The high prevalence of poor sleep quality calls for further investigation.


A New Species of the Genus Adela (Lepidoptera: Adelidae) from South America.
Adela boliviella n. sp., described from central Bolivia, is the first representative of the subfamily Adelinae found in South America. This species is closely related to Adela astrella Walsingham, from which it differs by larger compound eyes in males (interocular index, i.e. the ratio of vertical eye diameter to interocular distance, equals 1.5 compared to 0.75 in A. astrella), smaller extent of pale yellow scales in the forewing (0.25× forewing length compared to 0.40 in A. astrella), absence of a silver band outside the fascia and presence of three glossy silver spots near the apex of the forewing (six in A. astrella).


Colour Stabilization of Oak, Spruce, Larch and Douglas Fir Heartwood Treated with Mixtures of Nanoparticle Dispersions and UV-Stabilizers after Exposure to UV and VIS-Radiation.
Colour changes and associated wood degradation in exterior and interior applications influenced by ultraviolet (UV) and visible radiation (VIS) decreases the aesthetic value of the products and shortens the overall life of transparent coatings. The aim of the paper is to achieve colour stabilization of oak, larch, Douglas fir and spruce heartwood via surface treatment with UV stabilizers, hindered amine light stabilizers (HALS), nanoparticles TiO₂, ZnO, and mixtures thereof, during exposure to UV and VIS radiation. Colour changes were evaluated during accelerated artificial ageing testing in Xenotest. The distinctly individual character of colour changes in surface treatments due to the underlying wood species was confirmed. A synergistic effect was found when using a combination of active substances compared to substances used individually. The mixture of benzotriazoles with HALS (Tinuvin 5151) in combination with TiO₂ and ZnO nanoparticles was confirmed as one of the most effective treatments for colour stabilization of wood due to UV and VIS spectrums.


[Remarks on ethanol oxidation by an "Acetobacter xylinum" microbial electrode (author's transl)].
A "microbial electrode" for ethanol assay has been designed using combination of an oxygen probe and cellulosic pellicle of Acetobacter xylinum. Assay is feasible with an ethanol concentration below 0.4 mM on a pH range of 2,5-7. The formation of acetic acid leds to a competitive inhibition of ethanol oxidation as observed with free cells. Pellicle stability at room temperature is good over a ten hours period. At 4 degrees C, film preservation is quite satisfactory over a ten days storage period. The author compares the ethanol oxidation kinetics observed, using both cellulosic pellicles and free cells of A. xylinum.


Outcomes After Cryoablation Versus Partial Nephrectomy for Sporadic Renal Tumors in a Solitary Kidney: A Propensity Score Analysis.
While partial nephrectomy (PN) is considered the standard approach for a tumor in a solitary kidney, percutaneous cryoablation (PCA) is emerging as an alternative nephron-sparing option. To compare outcomes between PCA and PN for tumors in a solitary kidney. Patients who underwent PCA or PN between 2005 and 2015 for a single primary renal tumor in a solitary kidney were identified using Mayo Clinic Registries. Exclusion criteria were inherited tumor syndromes and salvage procedures. PCA and PN. To achieve balance in baseline characteristics, we used inverse probability of treatment weighting (IPTW) based on propensity to receive treatment. The risk of having a post-treatment complication and percent drop in estimated glomerular filtration rate (eGFR), as well as the risks of local/ipsilateral recurrence, distant metastasis, and cancer-specific mortality, were compared between groups using logistic, linear, and Fine-and-Gray competing risk regression models. The cohort included 118 patients (PCA: 54; PN: 64) with a median follow-up of 47 mo (interquartile range 18, 74). In unadjusted analyses, PCA was associated with a lower risk of complications (15% vs 31%; odds ratio [OR]=0.38; 95% confidence interval [CI] 0.15, 0.96; p=0.04). However, upon accounting for baseline differences with IPTW adjustment, there was no longer a significant difference in the risk of complications (28% vs 29%; OR=0.95; 95% CI 0.53, 1.69; p=0.9). There were no significant differences between PCA and PN in percentage drop in eGFR at discharge (mean: 11% vs 16%; β=-5%; 95% CI -13, 3; p=0.2) or at 3 mo (12% vs 9%; β=3%; 95% CI -3, 10; p=0.3). Likewise, no significant differences were noted in local recurrence (HR=0.87; 95% CI 0.38, 1.98; p=0.7), distant metastases (HR=0.60; 95% CI 0.30, 1.20; p=0.2), or cancer-specific mortality (HR=1.13; 95% CI 0.32, 3.98; p=0.8). Limitations include the sample size, given the relative rarity of renal masses in solitary kidneys. Our study found no significant difference in complications, renal function outcomes, and oncologic outcomes between PN and PCA for patients with a tumor in a solitary kidney. Validation in a larger multi-institutional analysis may be warranted. Partial nephrectomy (surgery) and percutaneous cryoablation are both options for treating a kidney tumor while preserving the normal portion of the kidney. In patients with a tumor in their only kidney, we found no difference in the risk of complications, kidney function outcomes, or cancer control outcomes between these two approaches.


Histopathological and histochemical changes in honeybee larvae (Apis mellifera L.) after infection with Bacillus larvae, the causative agent of American foulbrood disease.
Morphological, histochemical and cytochemical changes were examined in honeybee larvae after infection with the bacterium Bacillus larvae. The results indicate cell necrosis in the midgut epithelium accompanied by increasing cell vacuolization and nuclear pyknosis following per os inoculation with B. larvae. Many autolysosomes were positive for acid phosphatase. Non-vacuolar acid phosphatase activity was also found in lysed cell compartments. No such activity was found in regenerative epithelial cells. Degradation of haemocytes, salivary glands and other tissues was also observed. Histochemical analyses after per cutaneous inoculation with B. larvae of three- and five-day-old honeybee larvae show intense non-vacuolar acid phosphatase activity followed by disintegration of infected salivary glands, epithelial cell cytoplasm and haemocytes.


Isolation and characterisation of cervine herpesvirus-1 from red deer semen.
This communication describes the isolation of herpesvirus during routine export examination of semen collected from red deer stags in New Zealand. Virus isolation was carried out using bovine embryonic lung (BEL) cells and viruses were characterised by direct immunofluorescense, restriction-fragment-length polymorphism analysis (RFLP), polymerase chain reaction (PCR) analysis and nucleotide sequencing. Herpesvirus was isolated from red deer semen on 2 different occasions from different animals. In both cases the virus was identified as cervine herpesvirus-1 (CvHV-1), based on RFLP, PCR and sequence analysis. Nucleotide sequence analysis of the glycoprotein-D gene showed 99.7% homology to the Banffshire strain of CvHV-1 and 89.5%, 89.2%, 85.3% and 79.6% homology to bovine herpesvirus 1.2 (BoHV-1.2), bovine herpesvirus 1.1 (BoHV-1.1), cervine herpesvirus-2 (CvHV-2) and caprine herpesvirus-1 (CpHV-1), respectively. This is the first time that CvHV-1 has been isolated in New Zealand. Its inclusion in serological surveys will allow the prevalence of CvHV-1 in the red deer population to be assessed in this country. The clinical significance of CvHV1 infection in New Zealand red deer herds has yet to be determined.


Novel glycineB antagonists show neuroprotective activity in vivo.
The degeneration or dysfunction of cholinergic neurons within the basal forebrain of patients with Alzheimer's disease (AD) may be related to the vulnerability of these cells to endogenous glutamate (Beal, 1995; Greenamyre and Young, 1989). The administration of drugs that attenuate the toxic actions of glutamate in the early stages of the disease might significantly delay its rate of progression. Two approaches to neuroprotection from endogenous glutamatergic function were investigated and found to be effective: blockade of voltage-dependent, NMDA-type glutamate receptor channels and antagonism of an NMDA-receptor related glycineB modulatory site.


[Varicocele: spermiogram, testicular biopsy, plasma testosterone. Results of therapy (author's transl)].
In 73 patients with unilateral (70 patients) and bilateral (3 patients) varicocele and subfertility as a clinical finding, spermiograms, testicular biopsies, and plasma testosterone levels were examined for their prognostic evaluation, and therapeutic conclusions were drawn. The high ligature of the internal spermatic vein in the presence of a normal plasma testosterone level resulted, without accompanying therapy, in an improvement of normalization of the spermiogram in 23.3% of cases, and only in 7% did a pregnancy occur. A significant improvement of these results could be achieved through additional combined therapy with Mesterolone and Clomiphene. In primary testosterone deficiency, a combination of surgical correction and chemotheraphy (Mesterolone and Clomiphene) gave relatively satisfactory results. Primary sperm counts below 10(6)/ml, a motility index under 30%, and histologically proven desquamation of the germ epithelium in the testicular biopsy are to be regarded as extremely grave prognostic criteria.


[Purulent lymphadenitis after peritonsillar abscess under immunosuppression. An often forgotten differential diagnosis].
In the present case study, a 75-year-old, immunosuppressed man presented with recurrent cervical abscesses after a peritonsillar abscess. In the cervical region, an ulcer developed with persistent wound healing deficit. Subsequently, the patient's general condition deteriorated, showing symptoms of a Landouzy sepsis. In the course of the examination, Mycobacteria tuberculosis was detected in the cervical ulcer. He suffered from latent tuberculosis, which was reactivated by a combination of his disease, immunosuppressive therapy and the preceding peritonsillar abscess. Upon treatment with tuberculostatics, the patient fully recovered.


Cellulose microcrystalline: A promising ecofriendly approach to control Culex quinquefasciatus larvae.
The growing use of synthetic chemical compounds/substances in vector control of mosquitoes, associated with their adverse effects on the environment and non-target organisms, has demanded the development of eco-friendly alternatives. In this context, this study aimed to evaluate the larvicidal action of different cellulose microcrystalline (CMs) concentrations and investigate their toxicity mechanisms in Culex quinquefasciatus fourth instar larvae as a model species. Probit analysis revealed that the median lethal concentrations (LC50) for 24 h and 36 h exposure were 100 and 58.29 mg/L, respectively. We also showed that such concentrations induced a redox imbalance in the larvae, marked by an increase in the production of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), as well as a reduction in the activity of superoxide dismutase (SOD) and catalase (CAT). Furthermore, different alterations in the external morphology of the larvae were associated with the ingestion of CMs. On the other hand, exposure of adult zebrafish (Danio rerio) to LC5024h and LC5036h for seven days did not induce any behavioral changes or alterations mutagenic, genotoxic, biochemical, or in the production of cytokines IFN-γ and IL-10. Thus, taken together, our study demonstrates for the first time that the use of CMs can constitute a promising strategy in the control of C. quinquefasciatus larvae, combining insecticidal efficiency with an "eco-friendly" approach in the fight against an important mosquito vector of several human diseases.


Clinical and dermatologic aspects of the hereditary intestinal polyposes.
Distinctive cutaneous lesions frequently accompany and occasionally precede the intestinal lesions in Gardner's syndrome, Peutz-Jeghers syndrome, and Muir's syndrome. Awareness of the dermatologic manifestations of these entities may facilitate early diagnosis in these potentially life-threatening hereditary disorders.


Clustering Accelerometer Activity Patterns from the UK Biobank Cohort.
Many researchers are beginning to adopt the use of wrist-worn accelerometers to objectively measure personal activity levels. Data from these devices are often used to summarise such activity in terms of averages, variances, exceedances, and patterns within a profile. In this study, we report the development of a clustering utilising the whole activity profile. This was achieved using the robust clustering technique of k-medoids applied to an extensive data set of over 90,000 activity profiles, collected as part of the UK Biobank study. We identified nine distinct activity profiles in these data, which captured both the pattern of activity throughout a week and the intensity of the activity: "Active 9 to 5", "Active", "Morning Movers", "Get up and Active", "Live for the Weekend", "Moderates", "Leisurely 9 to 5", "Sedate" and "Inactive". These patterns are differentiated by sociodemographic, socioeconomic, and health and circadian rhythm data collected by UK Biobank. The utility of these findings are that they sit alongside existing summary measures of physical activity to provide a way to typify distinct activity patterns that may help to explain other health and morbidity outcomes, e.g., BMI or COVID-19. This research will be returned to the UK Biobank for other researchers to use.


Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling.
Exostosin-1 (EXT1) and EXT2 are the major genetic etiologies of multiple hereditary exostoses and are essential for heparan sulfate (HS) biosynthesis. Previous studies investigating HS in several mouse models of multiple hereditary exostoses have reported that aberrant bone morphogenetic protein (BMP) signaling promotes osteochondroma formation in Ext1-deficient mice. This study examined the mechanism underlying the effects of HS deficiency on BMP/Smad signaling in articular cartilage in a cartilage-specific Ext-/- mouse model. We generated mice with a conditional Ext1 knockout in cartilage tissue (Ext1-cKO mice) using Prg4-Cre transgenic mice. Structural cartilage alterations were histologically evaluated and phospho-Smad1/5/9 (pSmad1/5/9) expression in mouse chondrocytes was analyzed. The effect of pharmacological intervention of BMP signaling using a specific inhibitor was assessed in the articular cartilage of Ext1-cKO mice. Hypertrophic chondrocytes were significantly more abundant (P = 0.021) and cartilage thickness was greater in Ext1-cKO mice at 3 months postnatal than in control littermates (P = 0.036 for femur; and P < 0.001 for tibia). However, osteoarthritis did not spontaneously occur before the 1-year follow-up. matrix metalloproteinase (MMP)-13 and adamalysin-like metalloproteinases with thrombospondin motifs(ADAMTS)-5 were upregulated in hypertrophic chondrocytes of transgenic mice. Immunostaining and western blotting revealed that pSmad1/5/9-positive chondrocytes were more abundant in the articular cartilage of Ext1-cKO mice than in control littermates. Furthermore, the BMP inhibitor significantly decreased the number of hypertrophic chondrocytes in Ext1-cKO mice (P = 0.007). HS deficiency in articular chondrocytes causes chondrocyte hypertrophy, wherein upregulated BMP/Smad signaling partially contributes to this phenotype. HS might play an important role in maintaining the cartilaginous matrix by regulating BMP signaling.


Role of palliative endoscopic drainage in patients with malignant biliary obstruction.
Endoscopic biliary drainage for malignant obstructive jaundice is a viable palliative alternative, but its role and cost-effectiveness compared to percutaneous drainage or surgical bypass are subject to debate. To review the evidence in the literature with regard to the settings in which endoscopic drainage favorably compares with and affords palliation and quality of life comparable to percutaneous drainage or surgical bypass in malignant obstructive jaundice patients. Using PubMed, Embase, Current Contents, and Medline, a literature search was performed for papers published from 1979 to April 2004. All retrieved papers comparing endoscopic drainage with percutaneous or surgical drainage, with special reference to the level of obstruction, were rated according to the strength of evidence and carefully analyzed. Palliative drainage affords improved quality of life. The outcome of endoscopic and percutaneous drainage was similar, but data were few and inconsistent. Due to fewer late complications, surgical bypass is an alternative to metal stents (Wallstenttrade mark) which remain patent longer than plastic stents (large-bore polyethylene), with an overall median of 180 and 109 days, respectively, in patients who survive longer than about 6 months, which cannot be accurately predicted though. Overall early and late morbidity, stent patency, and survival were similar in patients treated for hilar compared to distal obstruction.


Delivering esophago-gastric cancer care during the COVID-19 pandemic in the United Kingdom: a surgical perspective.
The COVID-19 pandemic continues to have a significant impact on the provision of medical care. Planning to ensure there is capability to treat those that become ill with the virus has led to an almost complete moratorium on elective work. This study evaluates the impact of COVID-19 on cancer, in particular surgical intervention, in patients with esophago-gastric cancer at a high-volume tertiary center. All patients undergoing potential management for esophago-gastric cancer from 12 March to 22 May 2020 had their outcomes reviewed. Multi-disciplinary team (MDT) decisions, volume of cases, and outcomes following resection were evaluated. Overall 191 patients were discussed by the MDT, with a 12% fall from the same period in 2019, including a fall in new referrals from 120 to 83 (P = 0.0322). The majority of patients (80%) had no deviation from the pre-COVID-19 pathway. Sixteen patients had reduced staging investigations, 4 had potential changes to their treatment only, and 10 had a deviation from both investigation and potential treatment. Only one patient had palliation rather than potentially curative treatment. Overall 19 patients underwent surgical resection. Eight patients (41%) developed complications with two (11%) graded Clavien-Dindo 3 or greater. Two patients developed COVID-19 within a month of surgery, one spending 4 weeks in critical care due to respiratory complications; both recovered. Twelve patients underwent endoscopic resections with no complications. Care must be taken not to compromise cancer treatment and outcomes during the COVID-19 pandemic. Excellent results can be achieved through meticulous logistical planning, good communication, and maintaining high-level clinical care.


Blue LED-pumped intense short-wave infrared luminescence based on Cr3+-Yb3+-co-doped phosphors.
The growing demand for spectroscopy applications in the areas of agriculture, retail and healthcare has led to extensive research on infrared light sources. The ability of phosphors to absorb blue light from commercial LED and convert the excitation energy into long-wavelength infrared luminescence is crucial for the design of cost-effective and high-performance phosphor-converted infrared LEDs. However, the lack of ideal blue-pumped short-wave infrared (SWIR) phosphors with an emission peak longer than 900 nm greatly limits the development of SWIR LEDs using light converter technology. Here we have developed a series of SWIR-emitting materials with high luminescence efficiency and excellent thermal stability by co-doping Cr3+-Yb3+ ion pairs into Lu0.2Sc0.8BO3 host materials. Benefitting from strong light absorption of Cr3+ in the blue waveband and very efficient Cr3+→Yb3+ energy transfer, the as-synthesized Lu0.2Sc0.8BO3:Cr3+,Yb3+ phosphor emits intense SWIR light in the 900-1200 nm from Yb3+ under excitation with blue light at ~460 nm. The optimized phosphor presents an internal quantum yield of 73.6% and the SWIR luminescence intensity at 100 °C can still keep 88.4% of the starting value at 25 °C. SWIR LED prototype device based on Lu0.2Sc0.8BO3:Cr3+,Yb3+ phosphor exhibits exceptional luminescence performance, delivering SWIR radiant power of 18.4 mW with 9.3% of blue-to-SWIR power conversion efficiency and 5.0% of electricity-to-SWIR light energy conversion efficiency at 120 mA driving current. Moreover, under the illumination of high-power SWIR LED, covert information identification and night vision lighting have been realized, demonstrating a very bright prospect for practical applications.


Efficient rational modification of non-ribosomal peptides by adenylation domain substitution.
Non-ribosomal peptide synthetase (NRPS) enzymes form modular assembly-lines, wherein each module governs the incorporation of a specific monomer into a short peptide product. Modules are comprised of one or more key domains, including adenylation (A) domains, which recognise and activate the monomer substrate; condensation (C) domains, which catalyse amide bond formation; and thiolation (T) domains, which shuttle reaction intermediates between catalytic domains. This arrangement offers prospects for rational peptide modification via substitution of substrate-specifying domains. For over 20 years, it has been considered that C domains play key roles in proof-reading the substrate; a presumption that has greatly complicated rational NRPS redesign. Here we present evidence from both directed and natural evolution studies that any substrate-specifying role for C domains is likely to be the exception rather than the rule, and that novel non-ribosomal peptides can be generated by substitution of A domains alone. We identify permissive A domain recombination boundaries and show that these allow us to efficiently generate modified pyoverdine peptides at high yields. We further demonstrate the transferability of our approach in the PheATE-ProCAT model system originally used to infer C domain substrate specificity, generating modified dipeptide products at yields that are inconsistent with the prevailing dogma.


A 5-year surveillance study of 44,691 isolates of Haemophilus influenzae project Beta-Alert 1993-1997.
Beta-Alert is a surveillance program developed in 1993 to monitor the percentage of beta-lactamase-producing Haemophilus influenzae isolates obtained from specimens submitted to regional commercial laboratories. The results of this study demonstrate that levels of beta-lactamase producers have remained between 31 and 38% in the United States over the past 5 years.


Micro ribonucleic acid-93 promotes oncogenesis of cervical cancer by targeting RAB11 family interacting protein 1.
Micro ribonucleic acid (RNA)-93 (miR-93) is a novel oncogenic miRNA dysregulated in many types of tumors. We aimed to further study the expression pattern and clinical significance of miR-93 and its target, the RAB11 family interacting protein 1 (RAB11FIP1) gene, in cervical cancer. Mir-93 and RAB11FIP1 expression in cervical cancer (n = 168), cervical intraepithelial neoplasia (CIN) 2 or 3 (n = 60) and normal cervical tissues (n = 48) was examined by real-time reverse transcription polymerase chain reaction and immunohistochemical staining. Methyl thiazolyl tetrazolium assay, flow cytometry, and Transwell chamber invasion assay were performed to investigate the function of miR-93 in the proliferation, apoptosis and invasion of cervical cancer cell lines SiHa and CaSki. Luciferase activity assay was conducted to identify the target gene of miR-93. Mir-93 expression levels in cervical cancer and CIN tissues were significantly increased (P = 0.032), but the RAB11FIP1 protein was significantly decreased (P = 0.006) compared with normal tissues. Neither was associated with clinicopathological variables. Enforced miR-93 knockdown or RAB11FIP1 overexpression suppressed proliferation and promoted apoptosis, but did not influence invasion in cervical cancer cells. Luciferase activity indicated that RAB11FIP1 was a direct target for miR-93. Our findings suggest that overexpression of miR-93 via targeting RAB11FIP1 as an early event plays an important role in oncogenesis of cervical cancer. MiR-93 and its target protein RAB11FIP1 may be potential therapeutic targets for cervical cancer and its precursors.