In vitro activity of cefepime combined with sulbactam against clinical isolates of carbapenem-resistant Acinetobacter spp.
The aim of this study was to assess the in vitro activity of cefepime combined with sulbactam against carbapenem-resistant clinical isolates of Acinetobacter spp. The checkerboard method was used to determine whether combinations act synergistically against these strains. Twenty-three Acinetobacter baumannii and one Acinetobacter junii found to be carbapenem resistant were included in the study. The susceptibility results for cefepime and sulbactam were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were used as quality control strains. The combination of cefepime and sulbactam demonstrated the following interactions: 33.3% (8/24) synergism; 58.3% (14/24) partial synergism; 4.2% (1/24) additive; 4.2% (1/24) indifference; and no antagonism (minimum and maximum fractional inhibitory concentration index 0.25 and 1.5, respectively). According to our in vitro study results, combinations of cefepime with sulbactam have moderate synergistic activity against some carbapenem-resistant strains of Acinetobacter spp., which could be beneficial for the treatment of infections due to multidrug-resistant strains of Acinetobacter spp.


The generation of successive unmarked mutations and chromosomal insertion of heterologous genes in Actinobacillus pleuropneumoniae using natural transformation.
We have developed a simple method of generating scarless, unmarked mutations in Actinobacillus pleuropneumoniae by exploiting the ability of this bacterium to undergo natural transformation, and with no need to introduce plasmids encoding recombinases or resolvases. This method involves two successive rounds of natural transformation using linear DNA: the first introduces a cassette carrying cat (which allows selection by chloramphenicol) and sacB (which allows counter-selection using sucrose) flanked by sequences to either side of the target gene; the second transformation utilises the flanking sequences ligated directly to each other in order to remove the cat-sacB cassette. In order to ensure efficient uptake of the target DNA during transformation, A. pleuropneumoniae uptake sequences are added into the constructs used in both rounds of transformation. This method can be used to generate multiple successive deletions and can also be used to introduce targeted point mutations or insertions of heterologous genes into the A. pleuropneumoniae chromosome for development of live attenuated vaccine strains. So far, we have applied this method to highly transformable isolates of serovars 8 (MIDG2331), which is the most prevalent in the UK, and 15 (HS143). By screening clinical isolates of other serovars, it should be possible to identify other amenable strains.


Spatial and temporal variability of idiopathic pulmonary fibrosis cases in Silesian Voivodeship in years 2006-2010.
Idiopathic pulmonary fibrosis (IPF) (J84.1 by the International Statistical Classification of Diseases and Related Health Problems, 10th revision - ICD-10) is a rare disease of unknown cause. Among many risk factors, occupational exposure to metal dust is enumerated. Because of metal industry concentration in the Silesian Voivodeship, Poland, an attempt of spatial and temporal variability of the idiopathic pulmonary fibrosis occurrence evaluation in 2006-2010 is made. The research is a descriptive analysis. Data of the number of new treated cases and firsttime hospitalization due to idiopathic pulmonary fibrosis in the years 2006-2010 was obtained from the National Health Found (Narodowy Fundusz Zdrowia - NFZ). We also assessed spatial and temporal variability of both rates. Data concerned adults aged ≥ 19 years old inhabited the Silesian Voivodeship. The standardized incidence rate due to idiopathic pulmonary fibrosis increased in the study period and was in the range of 2.9-3.8/100 000 population. The highest values of incidence were observed in districts localized in the centre of the Silesian Voivodeship. Incidence of idiopathic pulmonary fibrosis is not so high in the Silesian Voivodeship but the number of newly treated cases slightly increased in 2006-2010. Spatial and temporal variability of incidence rates for treated registered cases of idiopathic pulmonary fibrosis in the Silesian Voivodeship was observed. It could be an effect of occupational exposure to metal dust, however, final conclusions need more precise studies to the extent of analytical epidemiology. Int J Occup Med Environ Health 2017;30(4):593-601.


N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors.
Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1 TK)]. The thymine base has been tethered to a distal triphenylmethoxy moiety through a polymethylene chain (n = 3-8) or through a (2-ethoxy)ethyl spacer. Moreover, substitutions at position 4 of one of the phenyl rings of the triphenylmethoxy moiety have been performed. Compounds with a hexamethylene spacer (18, 26b, 31) displayed the highest inhibitory values against TK-2 (IC50 = 0.3-0.5 microM). Compound 26b competitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationale for the biological data was provided by docking some representative inhibitors into a homology-based model of human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1 TK were able to reverse the cytostatic activity of 1-(beta-D-arabinofuranosyl)thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.


The ligament augmentation device in hamstring grafts for reconstruction of the anterior cruciate ligament.
Twenty-eight patients who had reconstructions of the anterior cruciate ligament with a ligament augmentation device in the semitendinosus and gracilis tendons were compared with 32 patients who had reconstructions with semitendinosus and gracilis tendons alone. Preoperatively, there was no significant difference between the 2 groups with respect to age, sex, Tegner activity level, and time from injury to operation. Mean postoperative followup was 31.4 months for the augmentation group and 32.3 months for the nonaugmentation group. At postoperative evaluation, there was no difference in the 2 groups with respect to Lysholm knee scores, return to activity as measured by Tegner levels, KT-1000 arthrometer laxity testing, presence of pivot shift or Lachman sign, range of motion, and the patient's subjective overall rating of the surgery. Twenty-six of the 28 patients (93%) with augmentation rated their results as either "good" or "excellent" compared with 30 of the 32 patients (94%) with no ligament augmentation who rated their results as good or excellent. Four patients with the ligament augmentation devices needed reoperation for recurrent effusions and pain. No patients in the nonaugmentation group had recurrent effusions.


Anisotropic Triangular Lattice Realized in Rhenium Oxychlorides A3ReO5Cl2 (A = Ba, Sr).
We report the synthesis, crystal structure, and magnetic properties of the two new quantum antiferromagnets A3ReO5Cl2 (A = Sr, Ba). The crystal structure is isostructural with the mineral pinalite Pb3WO5Cl2, in which the Re6+ ion is square pyramidally coordinated by five oxide atoms and forms an anisotropic triangular lattice (ATL) made of S = 1/2 spins. The magnetic interactions J and J' in the ATL are estimated from magnetic susceptibilities to be 19.5 (44.9) and 9.2 (19.3) K, respectively, with J'/J = 0.47 (0.43) for A = Ba (Sr). For each compound, the heat capacity at low temperatures shows a large T-linear component with no signature of long-range magnetic order above 2 K, which suggests a gapless spin liquid state of one-dimensional character of the J chains in spite of the significantly large J' couplings. This is a consequence of one-dimensionalization by geometrical frustration in the ATL magnet; a similar phenomenon has been observed in two compounds with slightly smaller J'/J values: Cs2CuCl4 (J'/J = 0.3) and the related compound Ca3ReO5Cl2 (0.32). Our findings demonstrate that 5d mixed-anion compounds provide a unique opportunity to explore novel quantum magnetism.


Dealing with requests for pharmacological cognitive enhancement from healthy students.
The use of drugs to enhance cognitive function and academic performance is clearly a global phenomenon, with the reported prevalence of stimulant use among medical students ranging from 15-20%. A multi-institution study from the USA reported a 6.9% lifetime prevalence of non-prescription use of cognitive enhancers among college students. A comprehensive systematic review indicates a 16-29% use of non-prescribed stimulants among all students for reasons that include increasing concentration and alertness. While mental health professionals and guidance counsellors anecdotally recall requests for pharmacological cognitive enhancement from otherwise healthy students, the exact magnitude of this problem in the Indian context is not clear.


A medical amulet in the archaeological museum in Florence.
In the Archaeological Museum in Florence, there is a medical amulet which is made of haematite and shows the reproduction of the womb, with four divinities and inscriptions, which can be considered a peculiar evidence of anatomical knowledge of the past.


Spatiotemporal dynamics of triglyceride storage in unilocular adipocytes.
The spatiotemporal dynamics of triglyceride (TG) storage in unilocular adipocytes are not well understood. Here we applied ex vivo technology to study trafficking and metabolism of fluorescent fatty acids in adipose tissue explants. Live imaging revealed multiple cytoplasmic nodules surrounding the large central lipid droplet (cLD) of unilocular adipocytes. Each cytoplasmic nodule harbors a series of closely associated cellular organelles, including micro-lipid droplets (mLDs), mitochondria, and the endoplasmic reticulum. Exogenously added free fatty acids are rapidly adsorbed by mLDs and concurrently get esterified to TG. This process is greatly accelerated by insulin. mLDs transfer their content to the cLD, serving as intermediates that mediate packaging of newly synthesized TG in the large interior of a unilocular adipocyte. This study reveals novel cell biological features that may contribute to the mechanism of adipocyte hypertrophy.


The relationships between posttraumatic stress disorder severity, depression severity and physical health.
This study examines the relationship among posttraumatic stress disorder severity, depression severity, and subjective and objective physical health in a sample of 200 adults with posttraumatic stress disorder. Posttraumatic stress disorder severity was correlated with subjective, but not objective, health. Similarly, depression symptoms had an indirect effect on the relationship between posttraumatic stress disorder symptom severity and three measures of subjective physical health. Finally, depression symptoms had an indirect effect on the relationship between both reexperiencing and hyperarousal symptoms and subjective physical health. This research underscores the important role that posttraumatic stress disorder, particularly reexperiencing and hyperarousal symptoms, and depression may have on perceptions of physical health.


Hemodynamic and pulmonary fluid status in the trauma patient: are we slipping?
Recent reports point to problems in the clinical assessment of the cardiopulmonary system in hemodynamically unstable patients, especially with the decreasing usage of pulmonary artery catheters. Our purpose was to evaluate the hypothesis that clinical judgment alone is inadequate for a reliable estimate of cardiopulmonary status in critically ill patients. Physician assessments (high, normal, or low) of cardiac index (CI) and thoracic fluid content (TFC) were made in 68 acute trauma cases and compared to the results obtained with impedance cardiography (ICG). Physician assessment using clinical judgment alone was correct only 42 per cent and 57 per cent, respectively, for CI and TFC. There was very little difference in heart rate (HR), blood pressure (BP), Glasgow Coma Score (GCS), and the number of injured systems between the incorrect and correct assessments of CI. However, the mean Injury Severity Score (ISS) was markedly higher for the incorrect than the correct CI values (18.8 +/- 9.3 vs 14.2 +/- 9.8, P = 0.0589). Thus, there is a need for an objective measurement of CI and TFC especially in the more severely injured patient. The inaccuracy of the clinical exam strongly suggests the need for a supplemental measurement, which the new and improved ICG monitor could provide.


Early activation of inflammation and clotting in the preterm lamb with neonatal RDS: comparison of conventional ventilation and high frequency oscillatory ventilation.
In neonatal respiratory distress syndrome activation of inflammation and clotting is demonstrated. High frequency oscillatory ventilation (HFOV) is considered to be less damaging to the human preterm lung, resulting in less activation of inflammation and clotting compared with conventional ventilation (CV). To assess the sequence of events of activation of inflammation and clotting and to compare the impact of HFOV to CV, we ventilated preterm lambs delivered by cesarean section at 132 d gestational age (term 145 d) for 8 h by CV (n = 10) or HFOV (n = 11). Fifteen minutes after birth and at 2-h intervals thereafter blood samples, from umbilical catheters, were analyzed for AP50 (complement activation), number of polymorphonuclear leukocytes, beta-glucuronidase, platelet function, activated partial thromboplastin time, thrombin time and thrombin inhibition, and bronchoalveolar lavage fluid was analyzed for elastase, thrombin and protein. We found complement activation, low number of polymorphonuclear leukocytes and high levels of beta-glucuronidase already at 15 min after birth. Within 2 to 4 h after birth platelet function deteriorated, activated partial thromboplastin time prolonged, and thrombin inhibition decreased. Activation of inflammation and clotting in the lungs was demonstrated by increased levels of elastase and thrombin in bronchoalveolar lavage fluid. In the HFOV group, AP50 remained significantly higher than in the CV group, reflecting less complement activation, and platelet function analysis remained significantly lower, reflecting better platelet function. We conclude that systemic activation of inflammation can be found in the ventilated preterm lamb with respiratory distress syndrome within 15 min after birth. Afterward, or due to activation of inflammation, clotting is activated. HFOV possibly attenuates activation of inflammation.


Primary pulmonary epithelioid malignant peripheral nerve sheath tumor in a child: a case report.
Primary pulmonary malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas originating from intrapulmonary nerve sheath and have been rarely observed in children. Here, we report a case of a 16-year-old child who presented with a mass located in the upper lobe of right lung. The patient underwent a sleeve lobectomy and the pathological diagnosis of the tumor was primary pulmonary epithelioid MPNST. Despite the radical resection, multiple suspected metastasis occurred in heart, lung and muscles less than 2 years after the operation and the patient died 6 months after the metastasis.


Modeling Closed Equilibrium Systems of H2O-Dissolved CO2-Solid CaCO3.
In many places in the world, including North Estonia, the bedrock is limestone, which consists mainly of CaCO3. Equilibrium processes in water involving dissolved CO2 and solid CaCO3 play a vital role in many biological and technological systems. The solubility of CaCO3 in water is relatively low. Depending on the concentration of dissolved CO2, the solubility of CaCO3 changes, which determines several important ground- and wastewater parameters, for example, Ca2+ concentration and pH. The distribution of ions and molecules in the closed system solid H2O-dissolved CO2-solid CaCO3 is described in terms of a structural scheme. Mathematical models were developed for the calculation of pH and concentrations of ions and molecules (Ca2+, CO32-, HCO3-, H2CO3, CO2, H+, and OH-) in the closed equilibrium system at different initial concentrations of CO2 in the water phase using an iteration method. The developed models were then experimentally validated.


Characterization of a Fibrinolytic Enzyme Secreted by Bacillus velezensis BS2 Isolated from Sea Squirt Jeotgal.
Bacillus sp. BS2 showing strong fibrinolytic activity was isolated from sea squirt (munggae) jeotgal, a traditional Korean fermented seafood. BS2 was identified as B. velezensis by molecular biological methods.B. velezensis BS2 grows well at 15% NaCl and at 10oC. When B. velezensis BS2 was cultivated in TSB broth for 96 h at 37°C, the culture showed the highest fibrinolytic activity (131.15 mU/µl) at 96 h. Three bands of 27, 35 and 60 kDa were observed from culture supernatant by SDS-PAGE, and fibrin zymography showed that the major fibrinolytic protein was the 27 kDa band. The gene (aprEBS2) encoding the major fibrinolytic protein was cloned, and overexpressed in heterologous hosts, B. subtilis WB600 and E. coli BL21 (DE3). B. subtilis transformant showed 1.5-fold higher fibrinolytic activity than B. velezensis BS2. Overproduced AprEBS2 in E. coli was purified by affinity chromatography. The optimum pH and temperature were pH 8.0 and 37°C, respectively. Km and Vmax were 0.15 mM and 39.68 µM/l/min, respectively, when N-succinyl-Ala-Ala-Pro-Phe-pNA was used as the substrate. AprEBS2 has strong α-fibrinogenase and moderate β-fibrinogenase activity. Considering its high fibrinolytic activity, significant salt tolerance, and ability to grow at 10°C, B. velezensis BS2 can be used as a starter for jeotgal.


Representing clinical knowledge in oral medicine using ontologies.
How can information technology be used to model and handle clinical knowledge in everyday work so that clinicians can more systematically learn from collected clinical data? Ontology is a crucial element in answering this question. Based on nearly ten years of clinical experience, fundamental requirements of an ontology for oral medicine are presented. The use of the proposed W3C standards RDF and OWL for the design and implementation of an ontology for oral medicine is then described and discussed. The reported work contributes to knowledge representation in oral medicine by presenting the pioneering work towards an ontology for oral medicine using RDF/OWL, thereby testing the latter on a new domain.


Conformational barrier for fullerene-porphyrin-fullerene triad.
A recent study (J. Phys. Chem. B 2006, 110, 5337) proposed that fullerene-porphyrin-fullerene triad (C60PC60) could be utilized as a photoinduced switch due to the difference in electron transfer directionality for the cis and trans conformer. It is found that the rotational barrier between the SS and AA conformers of C60PC60 is about 3-5 kcal/mol, which can be facilely controllable in experiment. The rotational energy barrier for the anion system is slightly higher than the neutral C60PC60, whereas the total energy of the neutral triad is decreased by about 60 kcal/mol upon electron attachment. The corresponding reorganization energy is very small. These results reveal that the C60PC60 is a potential candidate for electrochemical machinery and energy storage material.


Streptococcal cell wall-induced arthritis: requirements for IL-4, IL-10, IFN-gamma, and monocyte chemoattractant protein-1.
Intra-articular injection of streptococcal cell wall Ag followed by i.v. challenge ("reactivation") results in a destructive lymphocyte-dependent monoarticular arthritis. To further define the role of immune mechanisms in the model, Abs to Th1 and Th2-related cytokines were evaluated. Treatment of rats with antibodies to IL-4 reduced swelling, while treatment with anti-IL-10 or anti-IFN-gamma either had no effect or slightly enhanced the inflammatory response. These results suggest that Th-2 immune mechanisms may be, at least in part, operative in the model. To more precisely define the role of IL-4, the effects of anti-IL-4 on monocyte chemoattractant protein-1 (MCP-1) expression were evaluated. Initial studies demonstrated that mRNA (as determined by in situ hybridization) and protein (as determined by immunofluorescence) for MCP-1 were detectable in inflamed synovial tissue in a time-dependent manner. Anti-IL-4 treatment significantly reduced the expression of mRNA for MCP-1 24 and 72 h after reactivation. In addition, anti-MCP-1 inhibited swelling and reduced influx of (111)In-labeled T cells. These data suggest that the reactivation model of streptococcal cell wall Ag-induced arthritis is Th-2 dependent, and that an inter-relationship exists between IL-4 and the expression of MCP-1.


Cost of non-communicable diseases in people living with HIV in the Central Denmark Region.
To estimate the economic burden of non-communicable diseases (NCDs) in people living with HIV (PLWH) in Denmark. We conducted a cohort study using population-based Danish medical registries including all adult residents of the Central Denmark Region registered with a first-time HIV-diagnosis during the period 2006-2017. For each PLWH, we matched 10 persons without HIV from the background population by birth year, sex and municipality of residence. Information on healthcare utilization and costs for the PLWH and non-HIV cohorts was retrieved from register data. For each cohort, we estimated the annual costs for major disease categories (HIV care, other somatic care, and psychiatric care) in the period from 3 years before to 9 years after diagnosis/matching date. We identified 407 PLWH and 4070 persons from the background population. The total healthcare costs during the study period were approximately three times higher for PLWH compared to the non-HIV cohort (€76 198 vs. €23 692). Average annual cost of hospital care, primary care and selected prescription medicine was estimated to be €6987 per year in the years after the diagnosis compared to €2083 per year in the non-HIV cohort. In PLWH, the cost of NCDs and psychiatric care was approximately two times higher than the cost of HIV care. PLWH have higher healthcare costs stemming from three areas: excess cost due to the HIV infection, the treatment of NCDs, and psychiatric care.


Clinical Spectrum Of Solitary Rectal Ulcer In Children Presenting With Per-Rectal Bleed.
Solitary rectal ulcer syndrome (SRUS) is a benign and chronic disorder well known in young adults and less common in children. The objective of this study was to determine the frequency and clinical spectrum of solitary rectal ulcer in children with bleeding per rectum. This study was conducted in the Department of Paediatric Gastroenterology Hepatology& Nutrition; The Children's Hospital & The Institute of Child Health, Lahore, from January-December 2015. Total 187 children presenting with per-rectal bleeding who underwent colonoscopy were entered in the study. Demographic and presenting clinical features; colonoscopy and histopathology findings were recorded. Data was analysed using SPSS-20. Out of a total of 187 children with bleeding per rectum, 21 (11.23%) were diagnosed with solitary rectal ulcer. Males were 15 (71.43%) and females were 6 (28.57%) with age range 8-12 years. Mucus in stool 14 (66.7%), constipation 12 (57.1%) and tenesmus 10 (47.6%) were the most common clinical presentations. Colonoscopic finding are solitary erythmatous ulcerative lesion was seen in 8 (38.09%) children, multiple ulcerative lesions in colon 6 (28.57%), multiple ulcerative lesions in rectum 5 (23.81%), polypoidal growth in colon and hyperaemic rectal mucosa in 1 (4.76%) each. Histopathological findings were consistent with SRUS in all the cases. The frequency of SRUS was high (19.6%) in patients with per-rectal bleed. Mucus in stool, constipation and tenesmus were the most common clinical presentations. Colonoscopic and histopathological findings were helpful in the confirmation of the underlying aetiology.


The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.


Hereditary Hemorrhagic Telangiectasia Management.
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that can lead to frequent and severe sequelae. Although the condition has no cure, many of its physical symptoms can be managed to improve the quality of life and lower the risk of life-threatening complications. This article discusses HHT presentation, genetic screening, diagnosis, and management. The management of HHT can involve interventional radiology techniques, particularly for patients with pulmonary arteriovenous malformations.


The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on leukemic cells from chronic B cell leukemia.
It is not clear whether cells from various chronic B cell leukemias including B-chronic lymphocytic leukemia (CLL), CLL in prolymphocytoid transformation (CLL-PLT), B-prolymphocytic leukemia (PLL), and hairy cell leukemia (HCL) simply represent different stages of a single B cell differentiation pathway. Furthermore, it is not known whether cells from any given B cell leukemia are characterized by the same population during the differentiation process. Differentiation of various B cell leukemic cells was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), and the resulting changes in their morphology, cytoplasmic immunoglobulin (clg), and cytochemistry were evaluated. With respect to peculiar morphological change, i.e. extending long thin processes (spreading) and the appearance of clg, each sample showed different responses. According to these two indices samples were classified into three groups; spread+ clg- samples (one case of CLL-PLT, all HCL), spread+ clg+ samples (one of CLL, one of CLL-PLT), and spread- clg+ samples (a majority of CLL, one of CLL-PLT, and all PLL). Unexpectedly, both CLL and CLL-PLT consisted of heterogenous populations as to the reactivity to TPA. In the process of TPA-induced differentiation in CLL cells, features similar to those of HCL cells were not found. Since three different TPA-induced response patterns were observed in each chronic B cell leukemia type, it was not possible to sequentially assign each of these leukemias along a single B cell differentiation pathway. In order to explain this result, we introduced the hypothesis that these groups might be divided into different lineages in B cell differentiation. Since TPA-induced spreading cells were present in the B cell fraction of normal peripheral blood mononuclear cells, this morphological change should not be associated with malignant transformation.


Plasma nitrate as an index of immune system activation in animals and man.
The cytotoxic activity of activated macrophages is based upon their formation and release of nitric oxide (NO). In blood NO is rapidly metabolised to nitrate. We analysed plasma nitrate in rats given zymosan, an activator of the immune system, and found 20-fold increases above the basal level. Furthermore, in two human subjects with acute gastro-enteritis plasma nitrate increased from about 30 to 200 microM two days after onset of symptoms. These increased plasma levels of nitrate may reflect macrophage formation of NO. We propose that plasma nitrate may be a useful index for quantitative assessment of cytotoxic activity during immunological challenge.


Endoscopic knot tying: In vitro assessment in a porcine stomach model.
To determine if surgical knotting performed via endoscopy is an effective closure method for natural orifice translumenal endoscopic surgery. The proposed method was tested on an in vitro pig stomach model using standard endoscopy suite materials. A single use laparoscopy trocar (Versaport Plus manufactured by Tyco Healthcare) was fixed onto a plastic rectangular box in a horizontal position. A fresh pig stomach was tightly attached via its esophageal end to the trocar opening on the inner side of the box. The stomach cavity was closed at the duodenal end with Kocher forceps. A standard upper gastrointestinal endoscope fitted at its tip with a transparent plastic cap was introduced into the stomach through the outer trocar opening, so that the passage of the surgical trocar would mimic the passage of an esophagus. The stomach was subsequently inflated, followed by irrigation and washing. A neutral electrode of an electrocautery unit was placed inside the plastic box, underneath the pig stomach. The stomach's outer surface was kept moist using normal saline in order to maintain the natural elasticity and to ensure good contact with the electrode. The submucosal space on the anterior face of the stomach was accessed using the technique of endoscopic submucosal dissection. First, a site on the anterior face of the stomach was chosen, near the angle. Then, saline was injected into the submucosa with a standard endoscopic needle, so as to create a 20 mm diameter elevation. A linear 15 mm vertical incision was created at its center using a Dual Knife (KD650U manufactured by Olympus). This incision was used to access the submucosal space, and about 10 mm was dissected on both sides of the incision. The endoscope was then pushed through to the outside of the stomach after dilating a small puncture made by the Dual Knife in the muscularis propria, which simulated the peritoneoscopy procedure. Then, a 0.025" guidewire (Jagwire/450 cm manufactured by Boston Scientific) was inserted into the puncture, followed by a dilating balloon (Quantum TT manufactured by Cook Medical) that was used to enlarge the aperture orifice. After withdrawing the scope back into the stomach, the procedure continued with guidewires being passed from the submucosal space into the gastric lumen through small orifices on the left and right sides of the mucosal opening. These orifices were made with the Dual Knife, and the guidewires were inserted via a guiding catheter (HGC-6 manufactured by Cook Medical). As the guidewires were pulled outside of the stomach, they were replaced with a single surgical suture that had been initially attached to their tip and was now untied. Finally, one loop of this surgical suture was formed on the exterior. One loop end was fixed while the opposite suture end was pulled by biopsy forceps through the endoscope channel as the scope was inserted into the stomach. The loop was advanced until it approached and fixed the two mucosal incision margins. Three alternating loops were made in this manner to create a genuine tight surgical knot. Endoscopic knotting of the gastric wall is feasible, but an in vitro survival study is necessary to validate clinical significance.


Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia.
Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs), CYP3A5*3 (6986A>G) and CYP3A4*18 (878T>C), on IM treatment response in CML patients (n = 270; 139 IM resistant and 131 IM good responders) was investigated. Genotyping of CYP3A4*18 and CYP3A5*3 was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression. Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype of CYP3A5*3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090-0.324, p < 0.001 and OR 0.257; 95% CI: 0.126-0.525, p < 0.001, respectively. Although CML patients carrying the heterozygous (TC) genotype of CYP3A4*18 showed a lower risk of acquiring resistance toward IM (OR 0.648; 95% CI: 0.277-1.515), the association was not statistically significant (p = 0.316). No homozygous variant (CC) genotype of CYP3A4*18 was detected among the CML patients. It is concluded that polymorphism of CYP3A5*3 is associated with IM treatment response in Malaysian CML patients with carriers of CYP3A5*1/*3 and CYP3A5*3/*3 genotypes posing lower risk for development of resistance to IM.


Luteolin reduces fluid hypersecretion by inhibiting TMEM16A in interleukin-4 treated Calu-3 airway epithelial cells.
Rhinorrhea in allergic rhinitis (AR) is characterized by the secretion of electrolytes in the nasal discharge. The secretion of Cl- and HCO3- is mainly regulated by cystic fibrosis transmembrane conductance regulator (CFTR) or via the calciumactivated Cl- channel anoctamin-1 (ANO1) in nasal gland serous cells. Interleukin-4 (IL-4), which is crucial in the development of allergic inflammation, increases the expression and activity of ANO1 by stimulating histamine receptors. In this study, we investigated ANO1 as a potential therapeutic target for rhinorrhea in AR using an ANO1 inhibitor derived from a natural herb. Ethanolic extracts (30%) of Spirodela polyrhiza (SPEtOH) and its five major flavonoids constituents were prepared. To elucidate whether the activity of human ANO1 (hANO1) was modulated by SPEtOH and its chemical constituents, a patch clamp experiment was performed in hANO1-HEK293T cells. Luteolin, one of the major chemical constituents in SPEtOH, significantly inhibited hANO1 activity in hANO1-HEK293T cells. Further, SPEtOH and luteolin specifically inhibited the calcium-activated chloride current, but not CFTR current in human airway epithelial Calu-3 cells. Calu-3 cells were cultured to confluency on transwell inserts in the presence of IL-4 to measure the electrolyte transport by Ussing chamber. Luteolin also significantly inhibited the ATP-induced increase in electrolyte transport, which was increased in IL-4 sensitized Calu-3 cells. Our findings indicate that SPEtOH- and luteolin may be suitable candidates for the prevention and treatment of allergic rhinitis. SPEtOH- and luteolin-mediated ANO1 regulation provides a basis for the development of novel approaches for the treatment of allergic rhinitis-induced rhinorrhea.


Is accessing dental care becoming more difficult? Evidence from Canada's middle-income population.
To explore trends in access to dental care among middle-income Canadians. A secondary data analysis of six Canadian surveys that collected information on dental insurance coverage, cost-barriers to dental care, and out-of-pocket expenditures for dental care was conducted for select years from 1978 to 2009. Descriptive analyses were used to outline and compare trends among middle-income Canadians with other levels of income as well as national averages. By 2009, middle-income Canadians had the lowest levels of dental insurance coverage (48.7%) compared to all other income groups. They reported the greatest increase in cost-barriers to dental care, from 12.6% in 1996 to 34.1% by 2009. Middle-income Canadians had the largest rise in out-of-pocket expenditures for dental care since 1978. This study suggests that affordability issues in accessing dental care are no longer just a problem for the lowest income groups in Canada, but are now impacting middle-income earners as a consequence of their lack of, or decreased access to, comprehensive dental insurance.


Cardiac plasmacytoma: a rare clinical entity.
Primary malignant cardiac tumors are rare. Among these tumors, cardiac plasmacytoma is extremely rare and is the subject of few case reports. We present the case of a 73-year-old man who had isolated cardiac plasmacytoma 26 years after successful treatment of an axillary plasmacytoma. Multiple imaging methods-including echocardiography, cardiac magnetic resonance, and positron-emission tomography/computed tomography-were valuable and complementary to each other in this patient's diagnosis and optimal management. His case illustrates the use of these techniques in the successful diagnosis and treatment of a rare clinical entity, cardiac plasmacytoma.


HLA haplotypes in recurrent aphthous stomatitis: a mode of inheritance?
The aim of this study was to investigate the genetic association between recurrent aphthous stomatitis (RAS) and human leucocyte antigen (HLA) class I and II alleles and HLA haplotypes. Families selected had at least one child suffering from recurrent aphthous stomatitis in addition to one or both of the parents. HLA-A, -B and -DR alleles were typed in 29 families, 27 nuclear and two extended (121 subjects). HLA haplotypes of all family members with RAS were compared with those who were RAS negative. Although major histocompatibility complex class I and II gene analysis failed to demonstrate any significant association between RAS and HLA antigens, the study of HLA haplotypes revealed a significant association between HLA haplotypes and susceptibility to RAS. The results indicate that susceptibility to RAS segregates in families in association with HLA haplotypes.


Synergistic activation of the rat laminin gamma1 chain promoter by the gut-enriched Kruppel-like factor (GKLF/KLF4) and Sp1.
Laminin is a multifunctional heterotrimeric protein present in extracellular matrix where it regulates processes that compose tissue architecture including cell differentiation. Laminin gamma1 is the most widely expressed laminin chain and its absence causes early lethality in mouse embryos. Laminin gamma1 chain gene (LAMC1) promoter contains several GC/GT-rich motifs including the bcn-1 element. Using the bcn-1 element as a bait in the yeast one-hybrid screen, we cloned the gut-enriched Kruppel-like factor (GKLF or KLF4) from a rat mesangial cell library. We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. The activity of GKLF is dependent on a synergism with another Kruppel-like factor, Sp1. The LAMC1 promoter appears to have multiple GKLF- and Sp1-responsive elements which may account for the synergistic activation. We provide evidence that the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain. GKLF is thought to participate in the switch from cell proliferation to differentiation. Thus, the Sp1-GKLF synergistic activation of the LAMC1 promoter may be one of the avenues for expression of laminin gamma1 chain when laminin is needed to regulate cell differentiation.


Autoimmune hepatitis--sequel of a relapsing hepatitis A in a 75-year-old woman.
Acute hepatitis A virus (HAV) infection is a global cause of acute hepatitis. However, chronic HAV infection is unlikely. Nevertheless, there is some evidence that acute infection with HAV may trigger chronic active hepatitis which fulfils the criteria of autoimmune hepatitis (AIH). Whether AIH following HAV infection is virus specific remains unclear. Despite evidence that inherited factors may play a role in the development of autoimmunity after viral infection, the pathomechanism remains unclear. We describe a 75-year-old woman with a history of pulmonary sarcoidosis who developed AIH after acute HAV infection.


Primary HIV-1 infection--a "window of opportunity" for healthcare providers.
The diagnosis of primary HIV-1 infection (PHI) is often missed and requires a high index of suspicion and a thorough knowledge of laboratory methods. We report the case of a young promiscuous male who presented with fever, rash and neurological symptoms 8 weeks after unprotected sexual exposure. Clinical and laboratory investigations showed the presence of leucopenia and thrombocytopenia with elevated transaminases, and a normal cerebrospinal fluid analysis, while CNS imaging revealed a vasculitis-like involvement of the corpus callosum. Symptoms resolved spontaneously over 3 weeks. Fourth generation ELISA with p24 antigen assay was positive with high HIV-1 RNA load while Western-Blot was negative, thus confirming the diagnosis of PHI. The patient was subsequently started on antiretroviral therapy (ART) and showed undetectable viral load after 8 weeks of therapy. We present the differential diagnoses which need to be entertained as well as the pros and cons of very early ART intervention.


Dihydroxy(4-thiomorpholinomethyl)benzoic acid: from molecular asymmetry to diode characteristics.
One of the challenges in molecular electronics is to design molecules which can be used as functional units in electronic devices. The subject of our investigations is an asymmetrical molecule, dihydroxy(4-thiomorpholinomethyl)benzoic acid (TMBA), whose structural and electronic properties are characterized. The self-assembly behavior of TMBA on Au(111) surfaces resulting in highly ordered monolayers is obtained using scanning tunneling microscopy (STM). Furthermore, investigations on the electronic properties of the combined metal/molecule system reveal an orbital mediated tunneling process and tunneling decay constants for the carboxylic and thiomorpholino group. Thus, a diode-like character of TMBA is shown to be caused by intrinsic electronic properties of different molecular moieties.


Hepatic transcriptomic responses in mice exposed to arsenic and different fat diet.
Chronic exposure to inorganic arsenic (iAs) or a high-fat diet (HFD) can produce liver injury. However, effects of HFD on risk assessment of iAs in drinking water are unclear. In this study, we examined how HFD and iAs interact to alter iAs-induced liver injury in C57BL/6 mice. Mice fed low-fat diet (LFD) or HFD were exposed to 3 mg/L iAs or deionized water for 10 weeks. Results showed that HFD changed intake and excretion of iAs by mice. Then, HFD increased the amount of iAs-induced hepatic DNA damage and amplified changes in pathways related to cell death and growth, signal transduction, lipid metabolism, and insulin signaling. Compared to gene expression profiles caused by iAs alone or HFD alone, insulin signaling pathway might play important roles in the interactive effects of iAs and HFD. Our data suggest that HFD increases sensitivity of mice to iAs in drinking water, resulting in increased hepatotoxicity. This study highlight that HFD might enhance the risk of iAs hepatotoxicity in iAs-polluted regions. The diet should be considered during risk assessment of iAs in drinking water.


A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome.
Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the "molar tooth" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS. We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families. Homozygosity mapping uncovered a shared ∼2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. "Molar tooth" sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients. We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran.


Luminescent quantum dots fluorescence resonance energy transfer-based probes for enzymatic activity and enzyme inhibitors.
The paper describes the development and characterization of analytical properties of quantum dot-based probes for enzymatic activity and for screening enzyme inhibitors. The luminescent probes are based on fluorescence resonance energy transfer (FRET) between luminescent quantum dots that serve as donors and rhodamine acceptors that are immobilized to the surface of the quantum dots through peptide linkers. Peptide-coated CdSe/ZnS quantum dots were prepared using a one-step ligand exchange process in which RGDC peptide molecules replace trioctylphosphine oxide (TOPO) molecules as the capping ligands of the quantum dots. The peptide molecules were bound to the surface of the CdSe/ZnS quantum dots through the thiol group of the peptide cysteine residue. The peptide-coated quantum dots were labeled with rhodamine to form the FRET probes. The emission quantum yield of the quantum dot FRET probes was 4-fold lower than the emission quantum yield of TOPO-capped quantum dots. However, the quantum dot FRET probes were sufficiently bright to enable quantitative enzyme and enzyme inhibition assays. The probes were used first to test the enzymatic activity of trypsin in solution based on FRET signal changes of the quantum dot-based enzymatic probes in the presence of proteolytic enzymes. For example, exposure of the quantum dot FRET probes to 500 microg/mL trypsin for 15 min resulted in 60% increase in the photoluminescence of the quantum dots and a corresponding decrease in the emission of the rhodamine molecules. These changes resulted from the release of rhodamine molecules from the surface of the quantum dots due to enzymatic cleavage of the peptide molecules. The quantum dot FRET-based probes were used to monitor the enzymatic activity of trypsin and to screen trypsin inhibitors for their inhibition efficiency.


Towards a Christian bioethics.
Rather than revealing itself as a single, unified, ecumenical faith, Christianity is sundered with Christians united neither in one communion nor in one baptism. Christian Bioethics seeks to examine the traditional content-full moral commitments which the Christian faiths bring to life, sexuality, suffering, illness and death within the contexts of medicine and health care. Seeking to understand the differences which separate the bioethics of Roman Catholics, Protestants, and the Orthodox, Christian Bioethics explores the manners in which the faiths diverge. The failure of the Enlightenment project to disclose a content-full communality that would bind mankind has left much to be reconsidered by Christians who face new ethical dilemmas in the novel guise of advances in health care technologies.


[Thoracic Endovascular Aortic Aneurysm Repair in a Young Patient with Descending Aortic Injury;Report of a Case].
A 15-year-old boy was referred to our emergency room due to a penetrating injury of the back. Computed tomography( CT) demonstrated a descending aortic injury at the Th9/10 level, bilateral hemothorax, and spinal cord injury. Although surgical treatment was indicated, multiple organ injury complicated open surgical repair, which required cardiopulmonary bypass with full heparinization. Therefore, the patient was scheduled to undergo thoracic endovascular aortic repair (TEVAR). A 23×33-mm Excluder aortic extension cuff was chosen for the small, 15-mm diameter aorta. The aortic extension was delivered and deployed in the descending aorta. Postoperative CT demonstrated neither endoleak nor collapse of the stent-graft. TEVAR for traumatic aortic aneurysm appears to be safe and effective, and an aortic extension for an abdominal aortic aneurysm may be utilized as an alternative device if the patient is young and the aorta is small.


Rubber hand illusion reduces discomfort caused by cold stimulus.
There is a growing interest in body-ownership disruptions and their consequences for subjective experiences such as tactile sensations or pain. Here, we investigated the effect of the rubber hand illusion (RHI) on the perceived discomfort caused by cold stimulus applied to the real hand. The results showed reduced discomfort to cold reflected in behavioural and subjective measures. The stronger the illusion, the later the cold temperature became unpleasant and the less intense the experience was rated. We discuss the link between thermoception and body ownership as well as possible theoretical and methodological implications for studies on pain experience under RHI.


Effects of glycerol addition to diet in weight-reducing clubs.
As a weight-losing adjunct, 7.5 g glycerol in a 25 per cent solution was administered before meals to members of a commercial weight-reducing club. The same amount of glucose served as placebo. Members were randomly given either solution for six weeks. Body weight and hunger ratings were recorded weekly. Thirty-one members completed the study. Initial mean body weight was 77.5 +/- 12.9 (s.d.) kg corresponding to a Broca index of 1.16 +/- 0.18. Members on glycerol lost 4.1 +/- 2.2 kg and those on glucose lost 3.2 +/- 2.4 kg (n.s.). At the onset of the meal, plasma glycerol concentration was about ten times above baseline values. The study extends previous observations made in smaller groups that glycerol does not improve weight loss in subjects on a hypocaloric diet.


[Left heart bypass with the bio-medicus centrifugal pump by the use of an antithrombin agent, argatroban].
Seventeen adult patients who underwent surgery for the thoracic or thoracoabdominal aortic disease by the use of left heart bypass with the Bio-Pump were divided into untreated, low-dose heparin treated and argatroban treated groups so as to evaluate the effects of systemic infusion of a newly synthesized antithrombin agent, argatroban, for the prevention of platelet loss and consumption coagulopathy. ACT reached 150 to 250 seconds at doses 0.5-7.5 micrograms/kg/min of argatroban and maximum ACT prolongation was limited to around 250 seconds. ACT spontaneously recovered below 150 seconds within 60 minutes following the end of bypass during which no excessive blood loss developed. In argartoban group, platelet loss during and immediately after surgery was effectively prevented as compared to other groups with significance. Fibrinogen was also preserved to some extent by argatroban treatment without evidence of systemic embolization. Argatroban, as an antithrombotic agent, is worthy of further trial of clinical use in bypass with a centrifugal pump.


Dovyalicin-type spermidine alkaloids from Dovyalis species.
Phytochemical investigations of Dovyalis abyssinica, D. hebecarpa, and D. macrocalyx revealed two new spermidine-type alkaloids, dovyalicin E (3) and dovyalicin F (4), along with the previously described dovyalicin A (1), dovyalicin B (2), and dovyalicin C (5). In addition, a new phenol glucoside, 4-hydroxytremulacin (7), and the new 1,2-cyclohexanediol glucoside 9, as well as the known compounds methyl 1-hydroxy-6-oxocyclohex-2-enecarboxylate (6) and tremulacin (8), were isolated. The structures were established using homo- and heteronuclear two-dimensional NMR experiments and chiroptical methods. At ambient temperature, the N-disubstituted amide 4 exists as a mixture of cis and trans conformers. Variable-temperature (1)H NMR studies showed that time-averaged spectra are obtainable at 348 K, and the activation parameters determined for the rotation about the amide bond were DeltaH++ = 89 +/- 4.6 kJ/mol, DeltaS++ = 65 +/- 14 kJ/mol.K, and DeltaG++(298K) = 70 +/- 4.5 kJ/mol.


Cardiac resynchronization therapy in a patient with amyloid cardiomyopathy.
Cardiac involvement in systemic light chain amyloidosis carries poor prognosis. Amyloid deposition in the myocardium can alter regional left ventricular contraction and cause dyssynchrony. Cardiac resynchronization therapy (CRT) is an effective treatment strategy for patients with advanced heart failure and echocardiographic dyssynchrony. We report a clinical and echocardiographic response of a patient with amyloid cardiomyopathy, treated with a combination of chemotherapy and CRT.


Excited skin syndrome: study of 39 patients.
Excited skin syndrome (ESS) is an adverse reaction obtained when carrying out epicutaneous patch tests, characterized by multiple positive test results, associated with one or more strongly positive tests, which are not all reproduced when the patient is tested afterward. The aim of this study was (1) to determine the frequency of ESS in patients submitted to patch testing, (2) to confirm the influence of the evolution time of the primary dermatosis with ESS induction, (3) to determine differences among patients according the rate of positive test loss, and (4) to compare the number of positive tests for each substance between the first test, when all allergens in the test battery were applied, and the second test, when only the allergens with positive tests on the first occasion were applied at a greater distance from one another. Epicutaneous tests were carried out in 630 patients with a suspected diagnosis of allergic contact dermatitis. Patients presenting 2 or more positive test results were considered to have ESS and were submitted to a second patch test. ESS developed in 39 of the 630 patients tested, corresponding to a frequency of 6.2%. Analysis of data found a longer duration of the primary dermatitis in patients who in whom ESS developed compared with those who did not. Parabens, fragrance mix, and thimerosal had more positive patch test reactions using standard application techniques relative to the retest procedure, which placed the substances at a greater distance from one another, suggesting that, in addition to the factors previously reported to influence the reduction of ESS, the position of the allergens in the testing procedure also should be considered.


Functional explanation and the problem of functional equivalence.
The legitimacy of functional explanations in biology is threatened by a problem first identified by Hempel: the problem of functional equivalence. In order for the prevalence of a trait to be explained by its function, the function would have to explain why that very trait is prevalent and not some other functionally equivalent trait. But functions alone cannot meet this explanatory demand. I argue that this is a problem not only for Nagelian deductive-nomological models but also for etiological models of functional explanation. I contrast these models with a dual model of adaptive explanation and design explanation. This dual model largely circumvents the problem of functional equivalence, but divests functions of much explanatory power.


Can Nutrition Contribute to a Reduction in Sarcopenia, Frailty, and Comorbidities in a Super-Aged Society?
Many countries are facing the advent of super-aging societies, where sarcopenia and frailty will become pertinent problems. The prevalence of comorbidities is a major problem in countries with aged populations as elderly people suffer from various diseases, such as diabetes, heart failure, chronic kidney disease and dementia. All of these diseases are associated with sarcopenia and frailty, and they frequently cause falls, fractures, and a decline in activities of daily living. Fractures in the elderly people are associated with bone fragility, which is influenced by diabetes and chronic kidney disease. Nutritional support for chronic disease patients and sarcopenic individuals with adequate energy and protein intake, vitamin D supplementation, blood glucose level management for individuals with diabetes, obesity prevention, nutritional education for healthy individuals, and the enlightenment of society could be crucial to solve the health-related problems in super-aging societies.


Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are not well understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting that central hyperalgesic mechanisms may be involved. In the current study, during the wind-up testing session, a series of 6 heat pulses were presented with an interstimulus interval (ISI) of 3 seconds. Following the 1st, 3rd, and 6th thermal stimuli, subjects were asked to rate the late thermal sensation or second pain. IBS patients who demonstrated temporal summation of pain (TSSP) then received dextromethorphan and placebo in a randomized, double-blind, fashion to block wind-up. The results showed: 1) a subset of IBS patients, but not controls, showed TSSP in response to a series of noxious heat pulses; and 2) TSSP was blocked by administration of dextromethorphan, an NMDA receptor antagonist. In summary, these findings further elucidate mechanisms of somatic hypersensitivity in a subset of IBS patients. Our results also support an etiologic basis for abnormal NMDA receptor mechanisms in some IBS patients. Future studies are needed to determine if NMDA receptor antagonists may be used to treat IBS patients. This study evaluates temporal summation of second pain in a subset of IBS patients that is blocked by Dextromethorphan, an NMDA receptor antagonist. Theses results could lead to the use of an NMDA receptor antagonist in the treatment of pain in a subset of IBS patients.


A Volume Measurement Method for Lunar Soil Collection Based on a Single Monitoring Camera.
In the task of lunar soil collection, estimating the volume of the collected soil is an important part of the sampling control of the lander. Due to the design constraints of the lander, there is no additional installation position for volume measurement equipment. To fully use the sensors already installed, a collected soil volume measurement method is designed in this paper based only on a single monitoring camera. This method uses a sequence of images of the collection area captured by the camera mounted on the acquisition arm to accurately reconstruct the terrain of the collection area surface before and after soil acquisition. Additionally, bi-temporal dense point clouds are reconstructed. Based on the area of change associated with soil collection, the constructed dense point clouds are compared according to the topographic characteristics of the area to estimate the volume of soil collected. Experiments show that the method is stable and reliable and can meet the requirements of actual measurement tasks.


Comparison of the effect of sevoflurane and propofol on the optic nerve sheath diameter in patients undergoing middle ear surgery.
During middle ear surgery, the patient's head is turned away from the surgical site, which may increase the intracranial pressure. Anesthetics also affect the intracranial pressure. The optic nerve sheath diameter (ONSD) measured using ultrasonography is a reliable marker for estimating the intracranial pressure. This aim of this study was to investigate the effect of sevoflurane and propofol on the ONSD in patients undergoing middle ear surgery. Fifty-eight adult patients were randomized into sevoflurane group (n = 29) or propofol group (n = 29). The ONSD was measured using ultrasound after anesthesia induction before head rotation (T0), and at the end of surgery (T1). The occurrence and severity of postoperative nausea and vomiting (PONV) were assessed 1 h after the surgery. The ONSD was significantly increased from T0 to T1 in the sevoflurane group [4.3 (0.5) mm vs. 4.9 (0.6) mm, respectively; P < 0.001] and the propofol group [4.2 (0.3) mm vs. 4.8 (0.5) mm, respectively; P < 0.001]. No significant difference was observed in the ONSD at T0 (P = 0.267) and T1 (P = 0.384) between the two groups. The change in the ONSD from T0 to T1 was not significantly different between the sevoflurane and propofol groups [0.6 (0.4) mm vs. 0.6 (0.3) mm, respectively; P = 0.972]. The occurrence and severity of PONV was not significantly different between the sevoflurane and propofol groups (18% vs. 0%, respectively; P = 0.053). The ONSD was significantly increased during middle ear surgery. No significant difference was observed in the amount of ONSD increase between the sevoflurane and propofol groups.


New species and records of terrestrial slugs from East Africa (Gastropoda, Urocyclidae, Veronicellidae, Agriolimacidae).
New and little-known terrestrial slugs are dealt with based on extensive collections made in East Africa (Kenya, Tanzania, and Uganda) 1993-2007. This account deals primarily with larger species from forests in the Eastern Arc Mountains of Tanzania. In Veronicellidae, Pseudoveronicella Germain, 1908 is extended to Tanzania by P. (Hoffmannia) zootoca tanzaniensis subsp. n. in the Udzungwa Mts. In Urocyclidae, Dendrolimax parensissp. n. is described from the Pare Mts. and Leptichnoides avisexcrementissp. n. is described from the Uluguru Mts. In Urocyclinae, Tanzalimax tattersfieldigen. & sp. n. is described from the Usambara Mts., Tanzalimax seddonaegen. & sp. n. from the Uluguru Mts., and Udzungwalimax suminisgen. & sp. n. from the Udzungwa Mts. In addition, the ill-defined genus Atrichotoxon Simroth, 1910 is discussed and the little-known Dendrolimax leprosus Pollonera, 1906 is reported from Uganda. In Agriolimacidae, a species of Deroceras Rafinesque, 1820 is reported for the first time from southern Tanzania. The taxonomic attribution and significance of each discovery is discussed.


Intractable neonatal jaundice due to hereditary spherocytosis and Gilbert's syndrome.
In this article the authors present a case of pathological neonatal jaundice resistant to phototherapy in a baby with a family history of Gilbert's syndrome and hereditary spherocytosis. Her presentation was ultimately explained with a diagnosis of both conditions, and required treatment with phenobarbitone. The authors discuss the mechanism by which Gilbert's syndrome results in hyperbilirubinaemia and its similarities with Crigler-Najjar syndrome. The presentation of hereditary spherocystosis in the neonatal period is also explored, as is the mechanism of exaggerated hyperbilirubinaemia when the two conditions co-exist.


High resolution photoabsorption and photofragment fluorescence spectroscopy of water between 10.9 and 12 eV.
This work presents absorption and photofragment fluorescence spectra of water (H2O and D2O) simultaneously recorded at rotational resolution and at room temperature, by means of a synchrotron radiation source in the range 10.9-12 eV, covering the nd intense series from n=3 to 8. The Rydberg states observed are assigned in the light of the most advanced theoretical work available [M. S. Child, Philos. Trans. R. Soc. London, Ser. A 355, 1623 (1997)], and by reference to the stretching and bending mode progressions. Comparison between absorption and fluorescence spectra is shown to reveal a fast predissociation mechanism involving the linear 3pb2 1B2 state, and permits the identification of its (0,14,0) vibrational level observed in the absorption spectra.


Evidence that an L-arginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin.
1. The aim of this investigation was to study the relationship between contractile responsiveness, activation of the L-arginine pathway and tissue levels of guanosine 3':5'cyclic monophosphate (cylic GMP) in aortic rings removed from rats 4 h after intraperitoneal administration of bacterial endotoxin (E. coli. lipopolysaccharide, LPS, 20 mg kg-1). 2. LPS-treatment resulted in a reduction of the sensitivity and maximal contractile response to noradrenaline (NA). 3. Depression of the maximal contractile response was restored to control by 6-anilo-5,8-quinolinedione (LY 83583, 10 microM), which prevents activation of soluble guanylate cyclase. 4. Cyclic GMP levels in tissue from LPS-treated rats were 2 fold greater than cyclic GMP levels detected in tissue from control (saline-treated) rats. The LPS-induced increase in cyclic GMP content was observed both in the presence and absence of functional endothelium. 5. Addition of L-arginine 1 mM) to maximally contracted aortic rings produced significantly relaxation of rings from LPS-treated rats but not rings from control animals. In the LPS-treated group, addition of L-arginine was also associated with a significant increase in cyclic GMP content. L-Arginine had no effect on the cyclic GMP content of control rings. D-Arginine (1 mM) was without effect. 6. In rings from LPS-treated rats, NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), an inhibitor of nitric oxide (NO) production, increased the contractile response to NA and prevented the LPS-induced increase in cyclic GMP content. In control rings, L-NAME increased the NA sensitivity only when the endothelium remained intact and reduced the cyclic GMP content of these rings to that of control endothelium-denuded rings. 7. These results demonstrate that LPS-induced hyporeactivity to NA occurs secondarily to activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase in vascular tissue. In addition they suggest that LPS induces the production of an NO-like relaxing factor in non-endothelial cells.


Microbes: A Hidden Treasure of Polyunsaturated Fatty Acids.
Microbes have gained a lot of attention for their potential in producing polyunsaturated fatty acids (PUFAs). PUFAs are gaining scientific interest due to their important health-promoting effects on higher organisms including humans. The current sources of PUFAs (animal and plant) have associated limitations that have led to increased interest in microbial PUFAs as most reliable alternative source. The focus is on increasing the product value of existing oleaginous microbes or discovering new microbes by implementing new biotechnological strategies in order to compete with other sources. The multidisciplinary approaches, including metabolic engineering, high-throughput screening, tapping new microbial sources, genome-mining as well as co-culturing and elicitation for the production of PUFAs, have been considered and discussed in this review. The usage of agro-industrial wastes as alternative low-cost substrates in fermentation for high-value single-cell oil production has also been discussed. Multidisciplinary approaches combined with new technologies may help to uncover new microbial PUFA sources that may have nutraceutical and biotechnological importance.


Olefination with Sulfonyl Halides and Esters: Scope, Limitations, and Mechanistic Studies of the Hawkins Reaction.
Carbanions of alkanesulfonyl halides and esters react with nonenolizable carbonyl compounds to give olefins. Mechanistic studies reveal that initial aldol-type addition of the carbanions is followed by cyclization-fragmentation to alkenes, and the leaving group on the sulfonyl moiety (RSO2X) controls carbanion stability and rate of the olefin formation.


Coverage of knee-tumor-resection prostheses with free flaps.
Free latissimus dorsi free flaps were used for the treatment of three patients with malignant tumors localized at the distal end of the femur. In all cases, a knee prosthesis was used after tumor resection. In two patients, the prosthesis was covered with a free latissimus dorsi flap immediately after insertion. In one patient, the exposed prosthesis that was inserted 9 months previously was also covered with a free latissimus dorsi flap. Histopathologic diagnosis of the tumors was osteosarcoma in two cases and fusiform cell sarcoma in one case. Free-tissue transfers were successful in spite of preoperative chemotherapy and/or radiotherapy. Chemotherapy was started 3 weeks postoperatively in all cases. Patients ambulated 6 weeks after surgery and knee functions were satisfactory during a 1 year follow-up.


Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction.
Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.


The effectiveness of intravenous human immunoglobulin treatment after plasmapheresis in restoring serum immunoglobulin levels: a preliminary study.
This study was performed to examine the effects of intravenous human immunoglobulin (IVIG) on the level of serum immunoglobulin G (IgG) and its subclasses after plasmapheresis in patients with autoimmune disorders. Twenty-nine patients with predominantly rheumatoid arthritis were enrolled in this study. The plasmapheresis was performed by the use of double-filtration plasmapheresis (DFPP). Immediately after DFPP, IVIG (2.5 g, 50 ml) was intravenously administered. The treatment with IVIG had almost no effect on subjective and objective symptoms. Immediately after DFPP, the total of serum IgG was decreased by approximately 40%. After 24 h, the total of serum IgG recovered to 16% reduction in IVIG-treated patients whereas it remained at 32% reduction in nontreated patients. The beneficial effect of IVIG was significantly observed in patients who had shown 1,000-1,800 mg/dl IgG in their sera. After DFPP, IgG subclasses were decreased without change in the ratio of subclasses. Twenty percent to 30% of IgG subclasses were supplemented by the treatment with IVIG without change in the ratio of subclasses. These results suggested that the treatment with IVIG at minimal amount was safe and effective to supplement IgG for hypogammaglobulinemia after DFPP.


Electrofusion Stimulation Is an Independent Factor of Chromosome Abnormality in Mice Oocytes Reconstructed via Spindle Transfer.
Oocytes reconstructed by spindle transfer (ST) are prone to chromosome abnormality, which is speculated to be caused by mechanical interference or premature activation, the mechanism is controversial. In this study, C57BL/6N oocytes were used as the model, and electrofusion ST was performed under normal conditions, Ca2+ free, and at room temperature, respectively. The effect of enucleation and electrofusion stimulation on MPF activity, spindle morphology, γ-tubulin localization and chromosome arrangement was compared. We found that electrofusion stimulation could induce premature chromosome separation and abnormal spindle morphology and assembly by decreasing the MPF activity, leading to premature activation, and thus resulting in chromosome abnormality in oocytes reconstructed via ST. Electrofusion stimulation was an independent factor of chromosome abnormality in oocytes reconstructed via ST, and was not related to enucleation, fusion status, temperature, or Ca2+. The electrofusion stimulation number should be minimized, with no more than 2 times being appropriate. As the electrofusion stimulation number increased, several typical abnormalities in chromosome arrangement and spindle assembly occurred. Although blastocyst culture could eliminate embryos with chromosomal abnormalities, it would significantly decrease the number of normal embryos and reduce the availability of embryos. The optimum operating condition for electrofusion ST was the 37°C group without Ca2+.


Assessment of the bearing-down manoeuvre in pregnancy and detection of paradoxical levator ani muscle contraction using 2D transperineal ultrasound and vaginal palpation: a concurrent validity and inter-rater reliability study.
To examine the concurrent validity and inter-rater reliability of vaginal palpation as a measure of the quality of the bearing-down manoeuvre (BDM) and the detection of a paradoxical levator ani muscle contraction (LAM) in pregnant women, compared with 2D transperineal ultrasound (TPUS). Concurrent validity and inter-rater reliability study. Physiotherapy clinic. Twenty pregnant women in their third trimester. The anterior posterior diameter (APD) was measured during the BDM using TPUS by one experienced physiotherapist. An APD that shortened by >2 mm from rest was described as LAM shortening, an APD that moved by 0-2 mm was described as no change and an APD that lengthened by >2 mm was described as LAM lengthening. Vaginal palpation described the LAM during the BDM as no movement, shortening or lengthening. Participants were allowed two attempts and the best attempt was measured. APD using TPUS and the assessor's subjective description of LAM during the BDM using vaginal palpation. TPUS detected more paradoxical LAM contractions during the BDM than palpation. Agreement between vaginal palpation and TPUS assessment for BDM was poor. The Fleiss kappa coefficients were 0.457 (90% CI 0.16-0.71) between TPUS and one assessor and 0.326 (90% CI 0.01-0.6) between TPUS and the other assessor. In addition, inter-rater reliability was poor between observers palpating the BDM, with a Fleiss kappa coefficient of 0.375 (90% CI 0.13-0.64). This study did not find vaginal palpation of the BDM in pregnant women to have concurrent validity or inter-rater reliability. Clinicians should be aware of potential inaccuracies when palpating the BDM, and, where possible, seek an assessment via TPUS.


Structured home visits to older people. Are they only of benefit for women? A randomised controlled trial.
To investigate whether education of primary care professionals improved functional ability in home-dwelling older people, with special focus on gender differences. A prospective controlled three-year follow-up study (1999-2001) with randomisation and intervention at municipality level and outcomes measured at individual level. Intervention municipality visitors received regular education and GPs were introduced to a short assessment programme. Control municipalities received no education but conducted the preventive programme in their own way. Primary care, 34 municipalities. 5788 home-dwelling 75- and 80-year-olds were invited. 4060 (70.1%) participated: 2104 in 17 intervention- and 1956 in 17 matched control-municipalities. The main outcome measure was obtained from 3383 (95.6%) of 3540 surviving participants. Functional ability. Municipality intervention in coordination with GPs was associated with better functional ability in women (OR: 1.26; CI95: 1.08-1.47, p=0.004), but not in men (OR: 1.04; CI95: 1.85-1.27). Accepting and receiving free preventive home visits was associated with better functional ability among women (OR: 1.36; CI95: 1.16-1.60, p=0.0002), but not among men (OR: 0.98; CI95: 0.80-1.21). A brief, feasible educational intervention for primary care professionals and to accept and receive preventive home visits may have effect in older women, but not in older men.


Photoformation of low-molecular-weight organic acids from brown water dissolved organic matter.
This work describes the effects of simulated solar UV light on the bulk properties of dissolved organic matter (DOM) of bog lake water and on the formation of low-molecular-weight organic acids (LMWOAs). By means of size-exclusion chromatography it was shown that the more hydrophilic moieties of the DOM were preferentially photodegraded while the more hydrophobic ones remained relatively unaffected or were even formed. The combined photochemical-biological degradation proved to be more important than the pure photochemical mineralization. Formic, acetic, pyruvic, oxalic, malonic, and succinic acids were identified as important degradation products. Their contribution to the dissolved organic carbon increased from 0.31% before to 6.4% after 24 h irradiation. About 33% of the bioavailable photoproducts of DOM were comprised of these LMWOAs. The influence of nitrate on the formation of carboxylic acids could not be observed in the investigated system. Kinetic experiments indicated that degradation of LMWOAs occurred simultaneously during irradiation experiments, alpha-oxygen-substituted LMWOAs being more amenable to these processes. Dissolved iron acted as a catalyst of DOM photodegradation and LMWOA photoformation. Copper played an antagonistic role in the irradiation experiments, reducing the formation of formic, acetic, and malonic acids while increasing the formation of oxalic acid.


Quantification of cell size distribution as applied to the growth of Corynebacterium glutamicum.
It is known that the cell size is related to the physiological state of a cell. Therefore, cell size distribution directly reflects the average physiological properties of the cell culture. Cell size distribution can be enumerated by image analysis, flow cytometry and coulter counter. In this study, image analysis was used to characterize the cell size distribution during the growth of Corynebacterium glutamicum and was further analyzed by a distribution function. The parameters of the distribution function indicate the mean value and spread of the distribution. Analysis demonstrated that the maximum specific growth rate was higher (0.67h(-1)) for the growth obtained through serial dilution of seed as compared to growth from a normal seed culture (0.53h(-1)). This was due to a greater percentage of the cell population being in the state of division for the growth through serial dilution in the mid-log phase. The measurement of the cell size distribution demonstrated that the average cell size decreased during the course of growth. The distribution function was also used to enumerate the average specific growth rate of both the conditions of the culture. The demonstrated methodology can be used to predict an average growth property of a cell culture.


Effects of regional limb perfusion technique on concentrations of antibiotic achieved at the target site: A meta-analysis.
Intravenous regional limb perfusions (RLP) are widely used in equine medicine to treat distal limb infections, including synovial sepsis. RLPs are generally deemed successful if the peak antibiotic concentration (Cmax) in the sampled synovial structure is at least 8-10 times the minimum inhibitory concentration (MIC) for the bacteria of interest. Despite extensive experimentation and widespread clinical use, the optimal technique for performing a successful perfusion remains unclear. The objective of this meta-analysis was to examine the effect of technique on synovial concentrations of antibiotic and to assess under which conditions Cmax:MIC ≥ 10. A literature search including the terms "horse", "equine", and "regional limb perfusion" between 1990 and 2021 was performed. Cmax (μg/ml) and measures of dispersion were extracted from studies and Cmax:MIC was calculated for sensitive and resistant bacteria. Variables included in the analysis included synovial structure sampled, antibiotic dose, tourniquet location, tourniquet duration, general anesthesia versus standing sedation, perfusate volume, tourniquet type, and the concurrent use of local analgesia. Mixed effects meta-regression was performed, and variables significantly associated with the outcome on univariable analysis were added to a multivariable meta-regression model in a step-wise manner. Sensitivity analyses were performed to assess the robustness of our findings. Thirty-six studies with 123 arms (permutations of dose, route, location and timing) were included. Cmax:MIC ranged from 1 to 348 for sensitive bacteria and 0.25 to 87 for resistant bacteria, with mean (SD) time to peak concentration (Tmax) of 29.0 (8.8) minutes. Meta-analyses generated summary values (θ) of 42.8 x MIC and 10.7 x MIC for susceptible and resistant bacteria, respectively, though because of high heterogeneity among studies (I2 = 98.8), these summary variables were not considered reliable. Meta-regression showed that the only variables for which there were statistically significant differences in outcome were the type of tourniquet and the concurrent use of local analgesia: perfusions performed with a wide rubber tourniquet and perfusions performed with the addition of local analgesia achieved significantly greater concentrations of antibiotic. The majority of arms achieved Cmax:MIC ≥ 10 for sensitive bacteria but not resistant bacteria. Our results suggest that wide rubber tourniquets and concurrent local analgesia should be strongly considered for use in RLP and that adequate therapeutic concentrations (Cmax:MIC ≥ 10) are often achieved across a variety of techniques for susceptible but not resistant pathogens.


Improvement in the Photobiological Hydrogen Production of Aggregated Chlorella by Dimethyl Sulfoxide.
Photobiological hydrogen production plays a vital role in generating clean renewable energy owing to its low energy consumption and environmental friendliness. Although materials-induced Chlorella aggregates have been developed to achieve sustained photobiological hydrogen production under normal aerobic conditions, the yield is relatively low and equals only 0.42 % of the light-to-H2 energy-conversion efficiency. Herein, we report that only 0.5 vol % dimethyl sulfoxide in an aqueous environment significantly enhances the H2 yield produced by aggregated Chlorella, reaching 0.69 % of the light-to-H2 energy-conversion efficiency. This improvement can be attributed to an increase in the cellular respiration rate by dimethyl sulfoxide, which results in a decrease in the oxygen content inside the aggregates and, ultimately, to the activation of more hydrogenases. More generally, this strategy consists of a functional enhancement in organism-material hybrids by using small molecules.


Effects of the application of ankle functional rehabilitation exercise on the ankle joint functional movement screen and isokinetic muscular function in patients with chronic ankle sprain.
[Purpose] This study was conducted to investigate the effects of ankle functional rehabilitation exercise on ankle joint functional movement screen results and isokinetic muscular function in patients with chronic ankle sprain patients. [Subjects and Methods] In this study, 16 patients with chronic ankle sprain were randomized to an ankle functional rehabilitation exercise group (n=8) and a control group (n=8). The ankle functional rehabilitation exercise centered on a proprioceptive sense exercise program, which was applied 12 times for 2 weeks. To verify changes after the application, ankle joint functional movement screen scores and isokinetic muscular function were measured and analyzed. [Results] The ankle functional rehabilitation exercise group showed significant improvements in all items of the ankle joint functional movement screen and in isokinetic muscular function after the exercise, whereas the control group showed no difference after the application. [Conclusion] The ankle functional rehabilitation exercise program can be effectively applied in patients with chronic ankle sprain for the improvement of ankle joint functional movement screen score and isokinetic muscular function.


Formulation and Evaluation of PLGA Nanoparticulate-Based Microneedle System for Potential Treatment of Neurological Diseases.
The tight structure of the blood-brain barrier severely limits the level of drug therapy for central nervous system disorders. In this study, a novel composite delivery system combining nanocarrier and microneedle technology was prepared to explore the possibility of transdermal delivery of drugs to work in the brain. Nanoparticle solutions containing paroxetine and rhodamine-B were prepared using PLGA as a carrier by the emulsification-solvent volatilization method. Then, they were mixed with hyaluronic acid and the PLGA nanoparticulate-based microneedle system (Rh-NPs-DMNs) was prepared by a multi-step decompression-free diffusion method. The particle size, zeta potential, and micromorphology of the nano solution were measured; the appearance, mechanical strength, dissolution properties, and puncture effect of the Rh-NPs-DMNs were evaluated; also, it was evaluated for in vivo live imaging properties and in vitro skin layer transport and distribution properties. The mean particle size of Rh-NPs was 96.25 ± 2.26 nm; zeta potential of 15.89 ± 1.97 mV; PDI of 0.120 ± 0.079. Rh-NPs-DMNs had a high needle content of 96.11 ± 1.27% and a tip height of 651.23 ± 1.28 μm, with excellent mechanical properties (fracture force of 299.78 ± 1.74 N). H&E skin tissue staining showed that Rh-NPs-DMNs produced micron-sized mechanical pores approximately 550 μm deep immediately after drug administration, allowing for efficient circulation of the drug; and the results of in vivo imaging showed that Rh-B NPs DMNs had a faster transport rate than Rh-B DMNs, with strong fluorescent signals in both brain (P<0.01) and hippocampus (P<0.05) 48 h after drug administration. Nanoparticles can prolong blood circulation time and intracerebral retention time and have certain brain-targeting properties due to their excellent physical properties. The use of microneedle technology combined with nanocarriers provides new ideas for delivery systems for the treatment of central neurological diseases.


Efficient degradation of drug ibuprofen through catalytic activation of peroxymonosulfate by Fe3C embedded on carbon.
Ibuprofen (IBU), a nonsteroidal anti-inflammatory drug, is becoming an important member of pharmaceuticals and personal care products (PPCPs) as emerging pollutants. To degrade IBU, magnetic Fe3C nanoparticles embedded on N-doped carbon (Fe3C/NC) were prepared as a catalyst by a sol-gel combustion method. As characterized, the Fe3C/NC nanoparticles were composed of a NC nano-sheet and capsulated Fe3C particles on the sheet. The Fe3C/NC nanoparticles were confirmed an efficient catalyst for peroxymonosulfate (PMS) activation to generate sulfate radicals (SO4•-), single oxygen (1O2) and hydroxyl radicals (•OH) toward the degradation of IBU. The added IBU (10 mg/L) was almost completely removed in 30 min by using 0.1 g/L Fe3C/NC and 2 g/L PMS. The catalyst was confirmed to have good ability and excellent reusability through leaching measurements and cycle experiments. A catalytic mechanism was proposed for the catalytic activation of PMS on Fe3C/NC, which involves both Fe3C reactive sites and N-doped carbon matrix as reactive sites in Fe3C/NC. Moreover, the degradation pathway of IBU in the Fe3C/NC-PMS system was proposed according to the detections of degradation intermediates.


Alphavirus Replicon DNA Vectors Expressing Ebola GP and VP40 Antigens Induce Humoral and Cellular Immune Responses in Mice.
Ebola virus (EBOV) causes severe hemorrhagic fevers in humans, and no approved therapeutics or vaccine is currently available. Glycoprotein (GP) is the major protective antigen of EBOV, and can generate virus-like particles (VLPs) by co-expression with matrix protein (VP40). In this study, we constructed a recombinant Alphavirus Semliki Forest virus (SFV) replicon vector DREP to express EBOV GP and matrix viral protein (VP40). EBOV VLPs were successfully generated and achieved budding from 293 cells after co-transfection with DREP-based GP and VP40 vectors (DREP-GP+DREP-VP40). Vaccination of BALB/c mice with DREP-GP, DREP-VP40, or DREP-GP+DREP-VP40 vectors, followed by immediate electroporation resulted in a mixed IgG subclass production, which recognized EBOV GP and/or VP40 proteins. This vaccination regimen also led to the generation of both Th1 and Th2 cellular immune responses in mice. Notably, vaccination with DREP-GP and DREP-VP40, which produces both GP and VP40 antigens, induced a significantly higher level of anti-GP IgG2a antibody and increased IFN-γ secreting CD8+ T-cell responses relative to vaccination with DREP-GP or DREP-VP40 vector alone. Our study indicates that co-expression of GP and VP40 antigens based on the SFV replicon vector generates EBOV VLPs in vitro, and vaccination with recombinant DREP vectors containing GP and VP40 antigens induces Ebola antigen-specific humoral and cellular immune responses in mice. This novel approach provides a simple and efficient vaccine platform for Ebola disease prevention.


The Minimally-Invasive Oral Glucose Minimal Model: Estimation of Gastric Retention, Glucose Rate of Appearance, and Insulin Sensitivity from Type 1 Diabetes Data Collected in Real-life Conditions.
Modeling the effect of meal composition on glucose excursion would help in designing decision support systems (DSS) for type 1 diabetes (T1D) management. In fact, macronutrients differently affect post-prandial gastric retention (GR), rate of appearance (R a), and insulin sensitivity (S I). Such variables can be estimated, in inpatient settings, from plasma glucose (G) and insulin (I) data using the Oral glucose Minimal Model (OMM) coupled with a physiological model of glucose transit through the gastrointestinal tract (reference OMM, R-OMM). Here, we present a model able to estimate those quantities in daily-life conditions, using minimally-invasive (MI) technologies, and validate it against the R-OMM. Forty-seven individuals with T1D (weight =78±13kg, age =42±10yr) underwent three 23-hour visits, during which G and I were frequently sampled while wearing continuous glucose monitoring (CGM) and insulin pump (IP). Using a Bayesian Maximum A Posteriori estimator, R-OMM was identified from plasma G and I measurements, and MI-OMM was identified from CGM and IP data. The MI-OMM fitted the CGM data well and provided precise parameter estimates. GR and R a model parameters were not significantly different using the MI-OMM and R-OMM (p 0.05) and the correlation between the two S I was satisfactory ( ρ =0.77). The MI-OMM is usable to estimate GR, R a, and S I from data collected in real-life conditions with minimally-invasive technologies. Applying MI-OMM to datasets where meal compositions are available will allow modeling the effect of each macronutrient on GR, R a, and S I. DSS could finally exploit this information to improve diabetes management.


[Use of phototherapy for in newborns with pathologic jaundice].
An analysis was done of 596 newborns with intermediate hyperbilirubinaemia treated with phototherapy. The causes of hyperbilirubinaemia were determined. The effectiveness of phototherapy was compared in three groups of newborns: in 300 newborns irradiated by continuous method, in 178 newborns irradiated by intermittent method, and in 118 newborns treated with exchange transfusion and phototherapy. It was found that the effectiveness of phototherapy depended on the initial bilirubinaemia and was similar both after continuous irradiation and intermittent phototherapy. In one-third of the newborns subjected to phototherapy side effects were observed mainly in the form of loose stools.


Incidence and Risk Factors of Hypoxemia During Interventional Rigid Bronchoscopy Under Spontaneous-assisted Ventilation.
Interventional rigid bronchoscopy for tracheobronchial stenosis can be performed under total intravenous anesthesia and spontaneous-assisted ventilation. Intraoperative hypoxemia can occur during this procedure, but the incidence and risk factors have not yet been determined. Medical records of patients who underwent rigid bronchoscopy for the treatment of tracheobronchial stenosis under total intravenous anesthesia and spontaneous-assisted ventilation during the study period from January 2011 to December 2012 were retrospectively reviewed. There were 126 patients who underwent 263 procedures. The 2 main causes of tracheobronchial stenosis were tuberculosis (41.3%) and malignancy (35.7%). The 2 main locations of stenotic area were the trachea (58.6%) and the left main bronchus (46.4%). Tracheobronchial dilatation and stent insertion were performed in 78.7% and 21.3% of patients, respectively. The incidence of intraoperative hypoxemia was 25.5%. Independent risk factors for intraoperative hypoxemia were a degree of tracheal stenosis ≥75% (odds ratio: 2.48; 95% confidence interval, 1.19-5.17) and tumor removal procedure (odds ratio: 2.9; 95% confidence interval, 1.13-7.41). Incidence of intraoperative hypoxemia during interventional rigid bronchoscopy for tracheobronchial stenosis under spontaneous-assisted ventilation was 25.5%. Risk factors for hypoxemia were a degree of tracheal stenosis ≥75% and tumor removal procedure.


A High-quality Draft Genome Assembly of Sinella curviseta: A Soil Model Organism (Collembola).
Sinella curviseta, among the most widespread springtails (Collembola) in Northern Hemisphere, has often been treated as a model organism in soil ecology and environmental toxicology. However, little information on its genetic knowledge severely hinders our understanding of its adaptations to the soil habitat. We present the largest genome assembly within Collembola using ∼44.86 Gb (118X) of single-molecule real-time Pacific Bioscience Sequel sequencing. The final assembly of 599 scaffolds was ∼381.46 Mb with a N50 length of 3.28 Mb, which captured 95.3% complete and 1.5% partial arthropod Benchmarking Universal Single-Copy Orthologs (n = 1066). Transcripts and circularized mitochondrial genome were also assembled. We predicted 23,943 protein-coding genes, of which 83.88% were supported by transcriptome-based evidence and 82.49% matched protein records in UniProt. In addition, we also identified 222,501 repeats and 881 noncoding RNAs. Phylogenetic reconstructions for Collembola support Tomoceridae sistered to the remaining Entomobryomorpha with the position of Symphypleona not fully resolved. Gene family evolution analyses identified 9,898 gene families, of which 156 experienced significant expansions or contractions. Our high-quality reference genome of S. curviseta provides the genetic basis for future investigations in evolutionary biology, soil ecology, and ecotoxicology.


Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation, Second Thoughts?
Life expectancy of the population is steadily increasing world wide. Consequently, the incidence and ultimately the prevalence of atrial fibrillation (AF) and it's sequelae will be rising proportionately. It is estimated that 3-5% of persons above 65 years of age have chronic AF, 30% of which will suffer at least one stroke. On the other hand, chronic AF is responsible for about 20% of all cerebrovascular accidents. Predictors of stroke in AF have been defined by the CHADS2 score, and in these patients, oral anticoagulation has been the cornerstone of thromboembolic disease prevention. Because elderly patients have an increased risk of bleeding complications even under the newer antagonists of Factor Xa and direct Thrombin inhibitors, percutaneous occlusion of the left atrial appendage (LAA) as the main thrombogenic source offers an attractive alternative to permanent anticoagulation. This promising new therapeutic approach is put into clinical real world perspective.


Trial of strategy for reducing the use of laboratory tests.
Clinical guidelines and a weekly review of medical records were introduced into a medical unit in a teaching hospital to promote a more discriminating use of laboratory tests. This strategy resulted in an immediate reduction in the average number of requests each week from 74 to 27 haematological tests (64%) and 158 to 58 biochemical tests (64%). During a period of 10 weeks after the strategy was introduced (the intervention period) the mean number of haematological tests for each person decreased from 2.0 during the baseline period to 1.1 (45% reduction; p less than 0.01) and the mean number of biochemical tests decreased from 4.4 to 2.7 (39%; p less than 0.0001). The decrease in the number of repeat requests was greater than that for new requests and accounted for half the reduction in use. There was no significant change in the number of tests requested from an adjacent medical unit that was not exposed to the interventions. This strategy is worthy of trial in other specialties and hospitals, but attention will have to be paid to possible difficulties in sustaining reductions in use over long periods of time.