Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility.
No studies correlate manometric measurements with morphological changes during the esophageal peristaltic sequence. The aim of this study was to develop and use a system for sonographically imaging the esophageal wall while simultaneously recording esophageal pressure changes. An ultrasonography transducer attached to a manometric probe was used to evaluate the esophagus. Four sonographic phases of an esophageal peristaltic sequence were identified. The esophageal lumen was not open at rest in phase 1 (resting), increased to a maximum mean circumference of 4.90 +/- 0.57 cm in phase 2 (passive distention), and returned to a closed position in phases 3 (contraction) and 4 (relaxation). The muscle layers of the esophageal wall were baseline resting width in phase 1, decreased in width during phase 2, increased and reached maximum mean widths during phase 3, and returned to baseline widths during phase 4. The measurement of esophageal intraluminal pressure remained at a baseline resting level during phases 1 and 2, increased to a maximum mean peak of 67.95 +/- 9.18 mm Hg during phase 3, and returned to baseline during phase 4. A combined ultrasonography transducer/manometry probe was used to dynamically and simultaneously evaluate esophageal wall motion, muscle thickness, and esophageal pressure changes during peristalsis.


Is Campylobacter to esophageal adenocarcinoma as Helicobacter is to gastric adenocarcinoma?
Esophageal adenocarcinoma develops through a cascade of cellular changes that shares similarities to the etiology of Helicobacter pylori-associated intestinal-type gastric adenocarcinoma. While host genetics and immune response have been implicated in the progression to esophageal adenocarcinoma, studies investigating esophageal microbial communities suggest that bacteria may also play an important role in driving the inflammation that leads to disease. Of these, emerging Campylobacter species have been found to be more prevalent and abundant in patients progressing through the esophageal adenocarcinoma cascade compared to controls. Given that these bacteria possess several virulence mechanisms such as toxin production, cellular invasion, and intracellular survival, emerging Campylobacter species should be investigated as etiological agents of the chronic esophageal inflammation that leads to cancer.


Optimal mesh size for endoscopic inguinal hernia repair: a study in a porcine model.
Although the recurrence rate for endoscopic herniorraphy is low (0-3%), it can still be improved. In addition to using an expert technique that will minimize the risk of recurrence, it is essential that the mesh be large enough to cover the hernial defect adequately. To gain an impression of the optimal mesh size for such repairs, we performed an experimental study in a porcine model. To mimic inguinal hernial defects, circular holes of different diameters were cut in the pigs' abdominal walls after the peritoneum was lifted from the transverse fascia. The abdominal walls were positioned in a hermetically sealed chamber in which air pressure was applied to replicate intraabdominal pressure. Measurements were obtained to relate the protrusion of the mesh to the following three variables: intraabdominal pressure, defect size, and mesh overlap over the defect after positioning of the mesh between the abdominal wall and the peritoneum. Mesh protrusion increased as defect size and intraabdominal pressure increased. Mesh protrusion decreased as overlap of the mesh over the defect increased. Protrusion was found to level off when the mesh overlapped the defect by 3 cm and adequate positioning of the mesh was maintained. Recurrences after endoscopic inguinal hernia repair due to inadequate mesh size and mesh protrusion can be reduced by using a mesh that overlaps the defect by > or = 3 cm.


Differential effects of recombinant human interleukin-13 on the in vitro growth of human haemopoietic progenitor cells.
Effects of recombinant human interleukin (IL)-13 on in vitro haemopoiesis from non-adherent mononuclear cells (NAMC) or highly enriched CD34+ cells of human cord blood (CB) were studied. IL-13 significantly increased megakaryocyte (MK) colony formation from either NAMC or CD34+ cells cultured in a plasma clot system supplemented with aplastic anaemia serum (AAS) and phytohaemagglutinin-stimulated human peripheral blood leucocyte-conditioned medium (PHA-LCM) in a dose-dependent manner. Experiments using a modified plasma clot culture, in which normal AB serum and various cytokines were added to replace AAS and PHA-LCM, demonstrated an increased MK colony number in the presence of IL-13, especially in combination with IL-3. However, IL-13 had no stimulatory effect, but rather a slight inhibitory effect in some cases on granulocyte-macrophage (GM) colony formation in both plasma clot cultures. Furthermore, the growth of GM progenitor cells in a methylcellulose culture system in the presence of IL-3, GM-CSF, Epo, G-CSF or in combination was significantly inhibited by the addition of IL-13. On the other hand, high concentrations (100 ng/ml) of IL-13 were needed to cause a slight inhibition on the growth of BFU-E-derived colonies under the same methylcellulose culture. These results indicate that IL-13, alone and synergistically with the effect of IL-3, promotes MK colony formation, but it inhibits the growth of GM and erythroid progenitor cells in vitro.


Longitudinal and cross-sectional studies of the relationship between 6-keto PGF1 alpha and high density lipoproteins.
Two studies were performed to examine the relationship between Prostacyclin (PGI2) and high density lipoprotein cholesterol (HDL-C). A longitudinal study examined the stable metabolite of PGI2, 6-keto PGF1 alpha, along with HDL-C, and total cholesterol (TC) before (Week 0), during (Week 4), and after (Week 9) an eight week aerobic conditioning program. 6-keto PGF1 alpha was measured by radioimmunoassay using 125I, and HDL-C and TC were spectrophotometrically analysed. Maximal oxygen uptake and resting heart rate data obtained at Week 0 confirmed that the training group (E) was not different from the sedentary group (C). Results obtained at Week 9 indicated that maximal oxygen uptake was higher (p less than 0.05) and resting heart rate lower (p less than 0.05) in the E group, while these variables remained unchanged in group C. Levels of 6-keto PGF1 alpha, HDL-C, and TC did not differ between groups E and C when Week 0 was compared with Week 9. However, within the E group, significantly lower concentrations of 6-keto PGF1 alpha (p less than 0.05) and HDL-C (p less than 0.05) were found at Week 4 compared with Week 0. A cross-sectional study involving 52 subjects examined the relationship between 6-keto PGF1 alpha and several cardiovascular disease risk factors which included HDL-C. The only significant correlation (r = 0.50 p less than 0.05) observed was between 6-keto PGF1 alpha and HDL-C.


Relationship of Location Between Tear Film Center and Corneal Vertex Following Small-Incision Lenticule Extraction.
We aimed to measure the relationship of location between the tear film center (TFC) and corneal vertex (CV) following small incision lenticule extraction (SMILE). A total of 100 consecutive patients (100 eyes) who underwent the SMILE procedure were included. Screen captures of intraoperative videos and pupillary offset were analyzed. Location was compared using a vector plot for the two reference points. The arithmetic values for the distance from the pupil center (PC) were almost identical between the TFC and CV (P = 0.118). The intraclass correlation coefficient (ICC) for the measures of distance from the CV and TFC to the PC was 0.659. The mean vector and standard deviation ellipse showed similar directional tendencies for both reference points. No significant difference was observed in the arithmetic values of decentration from the TFC and from the CV (P = 0.056). The ICC for the measures of decentration from the TFC and from the CV was 0.768. The difference in the distance from the PC was significant for the tear film mark (TFM) decentration group (P = 0.002, ICC = .480), while the difference in decentration was significant for the TFM centration group (P = 0 .000, ICC = 0.230). The location of the CV in each eye could be simulated by the TFC. Furthermore, TFM decentered displacement could indicate optical zone decentered displacement.


Action of the competitive angiotensin II antagonist saralasin during the initial phase of glycerol-induced acute renal failure of the rat.
The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml.kg-1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure. In healthy rats saralasin (6 microgram.kg-1.min-1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng.kg-1.min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.


X-ray diffraction of newly formed bone close to alumina- or hydroxyapatite-coated femoral stem.
The study was focused on the bone tissue response to two types of ceramic coating [alumina and hydroxyapatite (HA)] obtained with a plasma-spray technique. The HA coating was performed on titanium stems, while the alumina coating was on chromium-cobalt-molybdenum stems. The investigation was carried out by means of micro-area X-ray diffractometric analyses and microdiffractometric analyses at the bone-implant interface. Moreover, the coating before and after implantation was analysed by means of the conventional powder X-ray diffractometric technique. This study demonstrated that 1 yr after implantation in animals the newly formed bone adjacent to the HA-coated hip prosthesis stems was mineralized as much as the pre-existing bone, while 24-64 months after surgery in humans the newly formed bone close to the alumina-coated hip prosthesis stems showed a lamellar and Haversian structure strongly demineralized, probably due to the release of aluminum ions from the alumina covering. The authors conclude that the X-ray diffraction allows the evaluation of the structural modifications of the ceramic coating, the bone formation rate close to the coating and the chemical nature of the particles released from the coating.


Tracheal Bronchus: High Resolution Computed Tomography diagnosis in a symptomatic patient.
A 75-year-old female underwent a High Resolution Computed Tomography (HRCT) scan for recurrent bronchitis and cough. HRCT images showed an anomalous supernumerary bronchus to the right upper lobe directly arising from the right side of distal trachea, corresponding to Tracheal Bronchus (TrB). TrB can cause recurrent right upper lobe pneumonia and special care is requiring during endotracheal intubation.


Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses.
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance.


Effect of laser in situ keratomileusis on retinal nerve fiber layer thickness measurements by scanning laser polarimetry.
To determine the effect of laser in situ keratomileusis (LASIK) on retinal nerve fiber layer measurements by scanning laser polarimetry in a large clinical trial. Asan Medical Center, University of Ulsan, Department of Ophthalmology, Seoul, Korea. Scanning laser polarimetry measurements were performed in 59 eyes of 59 consecutive patients who had LASIK. The mean retardation values of the whole measurement ellipse and of the superior, inferior, temporal, and nasal sectors of the ellipse before and after LASIK were compared statistically. The mean spherical equivalent refractive error was -6.10 diopters (D) +/- 2.34 (SD) (range -1.19 to -15.50 D) preoperatively and -0.31 +/- 0.52 D (range +0.68 to -2.13 D) postoperatively. The mean ablation depth was 94.0 +/- 30.49 microm (range 28.0 to 161.1 microm). The mean postoperative retardation values of all the sectors and of the superior, temporal, inferior, and nasal sectors showed reduced nerve fiber layer thickness (P =.000, P =.000, P =.011, P =.000, and P=.002, respectively). Laser in situ keratomileusis affected nerve fiber layer thickness measurements by scanning laser polarimetry. The change in nerve fiber layer thickness was probably due to modification of the corneal architecture. This effect of keratorefractive surgery should be considered when using scanning laser polarimetry as a diagnostic and follow-up tool for glaucoma.


The combined effects of dietary proteins and fish oil on cholesterol metabolism in rats of different ages.
Male Sprague-Dawley rats at the ages of four weeks and nine months were fed purified diets containing 20% proteins either as casein (CAS), milk whey protein (WHY), or soybean protein (SOY) with 5% sardine oil for four weeks. The hypocholesterolemic effect of SOY was not statistically evident as compared to milk proteins at both ages, although serum cholesterol tended to be low in the SOY groups. A significant age-dependent increase in serum cholesterol was observed in all dietary groups. Liver cholesterol concentrations were comparable in young rats, whereas in adults they were significantly lower in the SOY than in the CAS or WHY groups. At both ages, the activity of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase tended to be higher in the SOY than in the other groups. Fecal steroid excretion was significantly higher in rats fed SOY than those fed either CAS or WHY, especially in adult rats. Significant age- and dietary protein-effects were observed in fatty acid profiles of liver microsomal phospholipids. Thus, the effects of dietary proteins on various lipid parameters were essentially maintained even when fish oil served as the source of dietary fat.


Engineering low-salt growth Halomonas Bluephagenesis for cost-effective bioproduction combined with adaptive evolution.
Halophilic Halomonas bluephagenesis has been engineered to produce various added-value bio-compounds with reduced costs. However, the salt-stress regulatory mechanism remained unclear. H. bluephagenesis was randomly mutated to obtain low-salt growing mutants via atmospheric and room temperature plasma (ARTP). The resulted H. bluephagenesis TDH4A1B5 was constructed with the chromosomal integration of polyhydroxyalkanoates (PHA) synthesis operon phaCAB and deletion of phaP1 gene encoding PHA synthesis associated protein phasin, forming H. bluephagenesis TDH4A1B5P, which led to increased production of poly(3-hydroxybutyrate) (PHB) and poly(3-hydroxybutyrate-co-4-hydrobutyrate) (P34HB) by over 1.4-fold. H. bluephagenesis TDH4A1B5P also enhanced production of ectoine and threonine by 50% and 77%, respectively. A total 101 genes related to salinity tolerance was identified and verified via comparative genomic analysis among four ARTP mutated H. bluephagenesis strains. Recombinant H. bluephagenesis TDH4A1B5P was further engineered for PHA production utilizing sodium acetate or gluconate as sole carbon source. Over 33% cost reduction of PHA production could be achieved using recombinant H. bluephagenesis TDH4A1B5P. This study successfully developed a low-salt tolerant chassis H. bluephagenesis TDH4A1B5P and revealed salt-stress related genes of halophilic host strains.


Sugar uptake by the dermal transfer cells of developing cotyledons of Vicia faba L. : Mechanism of energy coupling.
The mechanism of carrier-mediated sucrose uptake by the dermal transfer cells of developing Vicia faba L. cotyledons was studied using excised cotyledons and isolated transfer cell protoplasts. Addition of sucrose resulted in a transitory alkalinization of the bathing solution whereas additions of glucose, fructose or raffinose had no effect. Dissipating the proton motive force by exposing cotyledons and isolated transfer cell protoplasts to an alkaline pH, carbonylcyanide m-chlorophenylhydrazone, weak acids (propionic acid and 5,5'-dimethyl-oxazolidine-2,4-dione) or tetraphenylphos-phonium ion resulted in a significant reduction of sucrose uptake. The ATPase inhibitors, erythrosin B (EB), diethylstilbestrol (DES) and N,N'-dicyclohexylcarbodiimide (DCCD) were found to abolish the sucrose-induced medium alkanization as well as reduce sucrose uptake. Cytochemical localization of the ATPase, based on lead precipitation, demonstrated that the highest activity was present in the plasma membranes located in wall ingrowth regions of the dermal transfer cells. The presence of a transplasma-membrane redox system was detected by the extracellular reduction of the electron acceptor, hexacyanoferrate III. The reduction of the ferric ion was coupled to a release of protons. The redox-induced proton extrusion was abolished by the ATPase inhibitors EB, DES and DCCD suggesting that proton extrusion was solely through the H+-ATPase. Based on these findings, it is postulated that cotyledonary dermal transfer cells take up sucrose by a proton symport mechanism with the proton motive force being generated by a H + -ATPase. Sucrose uptake by the storage parenchyma and inner epidermal cells of the cotyledons did not exhibit characteristics consistent with sucrose-proton symport.


Salt inducible kinases 2 and 3 are required for thymic T cell development.
Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mice. The combined loss of SIK1 and SIK2 activity did not block T cell development. Conditional knockout of SIK3 in haemopoietic cells, driven by a Vav-iCre transgene, resulted in a moderate reduction in the numbers of peripheral T cells, but normal B cell numbers. Constitutive knockout of SIK2 combined with conditional knockout of SIK3 in the haemopoietic cells resulted in a severe reduction in peripheral T cells without reducing B cell number. A similar effect was seen when SIK3 deletion was driven via CD4-Cre transgene to delete at the DP stage of T cell development. Analysis of the SIK2/3 Vav-iCre mice showed that thymocyte number was greatly reduced, but development was not blocked completely as indicated by the presence of low numbers CD4 and CD8 single positive cells. SIK2 and SIK3 were not required for rearrangement of the TCRβ locus, or for low level cell surface expression of the TCR complex on the surface of CD4/CD8 double positive thymocytes. In the absence of both SIK2 and SIK3, progression to mature single positive cells was greatly reduced, suggesting a defect in negative and/or positive selection in the thymus. In agreement with an effect on negative selection, increased apoptosis was seen in thymic TCRbeta high/CD5 positive cells from SIK2/3 knockout mice. Together, these results show an important role for SIK2 and SIK3 in thymic T cell development.


IL-6 modulates sepsis-induced decreases in transcription of hepatic organic anion and bile acid transporters.
Sepsis, a lethal inflammatory syndrome, is characterized by organ system dysfunction. In the liver, we have observed decreased expression of genes encoding proteins modulating key processes. These include organic anion and bile acid transport. We hypothesized that the inflammatory mediator IL-6 modulates altered expression of several key hepatic genes in sepsis via induction of the intracellular transcription factor signal transducer and activator of transcription (Stat) 3. Sepsis was induced in IL-6 +/+ and IL-6 -/- mice, and expression of the liver-restricted genes encoding the sodium-taurocholate cotransporter (Ntcp), the multidrug resistant protein (MRP) 2 and the organic anion transporter protein (OATP), was determined. As demonstrated previously, cecal ligation and puncture decreases expression of Ntcp, MRP-2, and OATP in IL-6 +/+ mice. Transcription elongation analysis demonstrated that altered expression resulted from decreased transcription. These changes were not observed in IL-6 -/- animals. Cecal ligation and puncture increased the DNA binding activity of Stat-3 in IL-6 +/+ but not IL-6 -/- mice. Because the promoters of Ntcp, MRP-2, and OATP do not contain Stat-3 binding sites, we postulated that altered Ntcp, MRP-2, and OATP expression resulted from activation of hepatocyte nuclear factor (HNF) 1alpha, which is IL-6 dependent. Cecal ligation and puncture decreased HNF-1alpha expression and DNA binding activity in IL-6 +/+ but not IL-6 -/- mice. Recombinant human IL-6 restored the sepsis-induced decrease in Ntcp, MRP-2, OATP, and HNF-1alpha expression in IL-6 -/- mice. We conclude that sepsis decreases the expression of three key hepatic genes via a transcriptional mechanism that is IL-6, Stat-3, and HNF-1alpha dependent.


A comprehensive method for causation analysis of ship-ice collision risk in Arctic waters.
The influence of harsh Arctic environmental factors has caused ship-ice collision accidents to become the main threat faced by navigating ships. It is necessary to quantify the causation of ship accidents and perform effective risk management and control measures to ensure ship navigation safety. This study proposes a Bayesian network (BN) model-based risk analysis method for ship-ice collision accidents, which is used to quantitatively analyze the key risk factors and primary risk causation paths of ship accidents. First, the fault tree analysis (FTA) method is proposed to constructing the BN structure model, and the BN parameter solution method is further established. Consequently, a triangular fuzzy and defuzzification method is developed to quantify uncertain expert knowledge. Then, the BN inference method is used to analyze the collision risk causation where the North Atlantic and Arctic waters meet. The results indicate that the main risk factors in Arctic waters come from the environment. There are four primary risk causation paths; the proposed management and control measures of the risk causation paths (A), (B), (C), and (D) can effectively reduce the navigation risk by 29.95%, 9.98%, 25.05%, and 3.99%, respectively; the combination of these four measures can reduce the navigation risk by 54.63%.The proposed method has positive guiding significance for ensuring the safety of ship navigation in Arctic waters.


Intracerebroventricular infusion of neuropeptide Y up-regulates synthesis and accumulation of luteinizing hormone but not follicle stimulating hormone in the pituitary cells of prepubertal female lambs.
Neuropeptide Y (NPY) is a putative neuroregulator of the reproductive axis in the central nervous system. In this study we evaluated the effects of central infusion of exogenous NPY on the secretory activity of pituitary gonadotrophic cells in prepubertal lambs. Immature female Merino sheep (n=12) were infused of Ringer solution (control) or 50 microg of NPY to the third ventricle for 5 min and then slaughtered 3 h later. Immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) cells were localised by immunohistochemistry using antibody raised against LHbeta and FSHbeta. Messenger RNA analyses were performed by in situ hybridisation using sense and antisense riboprobes produced from beta subunits of LH and FSH cDNA clones. The results were generated by computer image analysis to determine the area fraction occupied by immunoreactive and/or hybridising cells and optical density for immunostaining and hybridisation signal. LH in the blood plasma was determined by radioimmunoassay. It was found, that in the lambs infused with NPY the area fraction and optical density for immunoreactive LH cells and mRNA LHbeta-expressing cells increased significantly (P<0.001), compared to the vehicle-infused animals. The concentration of LH in the blood plasma did not differ between control and treated groups. The NPY infusions had no effect on the immunoreactivity of FSH cells or on expression of mRNA for FSHbeta. In conclusion we suggest that NPY may be an important component of mechanisms stimulating the synthesis and storage but not the release of LH in the pituitary gonadotrophs from prepubertal female sheep. In addition, this effect is specific for LH, no such effect was apparent on FSH.


In vivo imaging translocator protein (TSPO) in autism spectrum disorder.
Converging evidence points to the significant involvement of the immune system in autism spectrum disorders (ASD). Positron emission tomography (PET) can quantify translocator protein 18 kDa (TSPO), a marker with increased expression mainly in microglia and, to some extent astroglia during neuropsychiatric diseases with inflammation. This preliminary analysis explored, for the first time, whether TSPO binding was altered in male and female participants with ASD in vivo using full kinetic quantification. Thirteen individuals with ASD (IQ > 70 [n = 12], IQ = 62 [n = 1]), 5 F, 25 ± 5 years) were scanned with [18F]FEPPA PET. Data from 13 typically developing control participants with matching age and TSPO rs6971 polymorphism (9 F, age 24 ± 5 years) were chosen from previous studies for comparison. The two tissue compartment model (2TCM) was used to determine the total volume of distribution ([18F]FEPPA VT) in four previously identified regions of interest (ROI): prefrontal, temporal, cerebellar, and anterior cingulate cortices. We observe no significant difference in [18F]FEPPA VT relative to controls (F(1,26)= 1.74, p = 0.20). However, 2 ASD participants with higher VT had concurrent major depressive episodes (MDE), which has been consistently reported during MDE. After excluding those 2 ASD participants, in a post-hoc analysis, our results show lower [18F]FEPPA VT in ASD participants compared to controls (F(1,24)= 6.62, p = 0.02). This preliminary analysis provides evidence suggesting an atypical neuroimmune state in ASD.


Motivation and goal attainment. The role of compensatory beliefs.
It was recently proposed that one cognitive strategy people might employ to find a balance between fulfilling their immediate desires and adhering to their long-term goals is to activate compensatory beliefs (CBs). CBs are convictions that the negative effects of a behavior can be compensated for by the positive effects of another behavior (e.g., "I can eat this piece of cake now because I will go to the gym tonight".). The purpose of the present research was to examine the motivational determinants and consequences of CBs in weight-loss dieting. It was proposed that autonomous motivation would lessen the activation of CBs. It was further proposed that activating CBs would decrease goal adherence, which, itself, would facilitate the attainment of one's dieting goals. Results of a prospective study using path analysis provided support for the model.


Cellulase activity of a haloalkaliphilic anaerobic bacterium, strain Z-7026.
The cellulolytic activity of an alkaliphilic obligate anaerobic bacterium, Z-7026, which was isolated from the microbial community of soda-lake sediments and belongs to the cluster III of Clostridia with low G+C content, was studied. The bacterium was capable of growing in media with cellulose or cellobiose as the sole energy sources. Its maximal growth rate on cellobiose (0.042-0.046 h(-1)) was observed at an initial pH value of 8.5-9.0, whereas the maximal rate of cellulase synthesis, assayed by using a novel fluorimetric approach, was found to be 0.1 h(-1) at pH 8-8.5. Secreted proteins revealed high affinity for cellulose and were represented by two major forms of molecular masses of 75 and 84 kDa, whereas the general protein composition of the precipitated and cellulose-bound preparations was similar to cellulosome subunits of Clostridium thermocellum. The optimum pH of the partially purified enzyme preparation towards both amorphous and crystalline cellulose was in the range 6-9, with more than 70% and less than 50% of maximal activity being retained at pH 9.2 and 5.0, respectively.


Regulation of immunity by anti-idiotypic antibodies.
The immune system is under control by idiotypic-anti-idiotypic regulation. This control can operate according to dose of antigen, age of the individual, route of administration etc. and function as a specific stimulator or inhibitor of immune reactivity against a defined antigen. Data already exist to justify the statement that our immune system contains within itself all foreign structures against which it can react in the form of anti-idiotypic receptors. These "foreign" structures as displayed at the anti-idiotypic level may be more or less like their true counterparts outside the body and can serve as immunogen, for instance as vaccines. The regulation of immune reactivity via idiotypic interactions may also serve as a potent regulatory of fetal-neonatal immune reactivity causing it to resemble that of the mother. Potential clinical use of auto-anti-idiotypic immunity can thus be foreseen both with regard to elimination of unwanted immune reactivity as well as induction of wanted immunity.


The pattern ERG in Best's disease.
The aim of this study was to assess inner retinal function in patients with Best's disease using the pattern ERG (PERG). Nine patients with Best's disease, who had good visual acuity, were studied. Five of the nine had abnormal PERGs. All five had some reduction in central visual acuity. We believe that the abnormal PERGs in these patients represents photoreceptor cell loss which is occurring at an early stage in Best's disease.


Relative influence of musical and linguistic experience on early cortical processing of pitch contours.
To assess domain specificity of experience-dependent pitch representation we evaluated the mismatch negativity (MMN) and discrimination judgments of English musicians, English nonmusicians, and native Chinese for pitch contours presented in a nonspeech context using a passive oddball paradigm. Stimuli consisted of homologues of Mandarin high rising (T2) and high level (T1) tones, and a linear rising ramp (T2L). One condition involved a between-category contrast (T1/T2), the other, a within-category contrast (T2L/T2). Irrespective of condition, musicians and Chinese showed larger MMN responses than nonmusicians; Chinese larger than musicians. Chinese, however, were less accurate than nonnatives in overt discrimination of T2L and T2. Taken together, these findings suggest that experience-dependent effects to pitch contours are domain-general and not driven by linguistic categories. Yet specific differences in long-term experience in pitch processing between domains (music vs. language) may lead to gradations in cortical plasticity to pitch contours.


Changes of Explicit and Implicit Stigma in Medical Students during Psychiatric Clerkship.
This study examines the differences in explicit and implicit stigma between medical and non-medical undergraduate students at baseline; the changes of explicit and implicit stigma in medical undergraduate and non-medical undergraduate students after a 1-month psychiatric clerkship and 1-month follow-up period; and the differences in the changes of explicit and implicit stigma between medical and non-medical undergraduate students. Seventy-two medical undergraduate students and 64 non-medical undergraduate students were enrolled. All participants were interviewed at intake and after 1 month. The Taiwanese version of the Stigma Assessment Scale and the Implicit Association Test were used to measure the participants' explicit and implicit stigma. Neither explicit nor implicit stigma differed between two groups at baseline. The medical, but not the non-medical, undergraduate students had a significant decrease in explicit stigma during the 1-month period of follow-up. Neither the medical nor the non-medical undergraduate students exhibited a significant change in implicit stigma during the one-month of follow-up, however. There was an interactive effect between group and time on explicit stigma but not on implicit stigma. Explicit but not implicit stigma toward mental illness decreased in the medical undergraduate students after a psychiatric clerkship. Further study is needed to examine how to improve implicit stigma toward mental illness.


Differential co-localization of neurokinin-3 receptor and NMDA/AMPA receptor subunits in neurons of the substantia nigra of C57/BL mice.
By using a double immunofluorescence method we examined co-localization of neurokinin-3 receptor (NK-3R) and N-methyl-D-aspartate (NMDA)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits in neurons of the substantia nigra of adult mice. Overlapping distribution of NMDA receptor subunit 1 (NR1)/AMPA receptor subunits 1-4 (GluR1-4) and NK-3R-immunoreactive neurons were found in the substantia nigra pars compacta. It revealed that all (100%) of NK-3R-positive neurons displayed NR1, GluR2 or GluR3 immunoreactivity, 80% of them showed GluR1 immunoreactivity. In contrast, these neurons exhibiting both NK-3R and GluR4 immunoreactivity were hardly detected although GluR4-positive neurons were still distributed in the substantia nigra. The co-expression of NK-3R and NMDA/AMPA receptor subunits in the nigral neurons has provided a structural basis for functional modulation of neuronal glutamate receptors by neurokinin-3, suggesting that neurokinin peptides may be involved in modulation of neuronal properties and excitotoxicity in the substantia nigra of basal ganglia.


Beyond harm-producing versus harm-reducing: A qualitative meta-synthesis of people who use drugs' perspectives of and experiences with the extramedical use and diversion of buprenorphine.
This review synthesizes the literature on the perspectives and experiences of people who use drugs to better understand motivations and behaviors related to the extramedical use and diversion of buprenorphine. Given the particular social construction of buprenorphine against methadone, and the centrality of concerns around extramedical use in delivering opioid agonist therapies, a focus on extramedical buprenorphine use can provide an important lens through which to analyze treatment for opioid use disorder. This review is framed within persistent tensions between potential harm-producing versus harm-reducing effects of extramedical use that have long been described for opioid agonist therapies. The research team conducted a qualitative meta-synthesis based on a systematic search of eight databases as well as hand searching. The review includes all primary qualitative and mixed-methods studies related to the perspectives and experiences of people who use drugs on extramedical buprenorphine use. The study team carried out three rounds of qualitative coding using NVivo 12, and constructivist grounded theory and the constant comparative method informed the synthesis. The review includes twenty-one studies. Findings are organized into the following three themes: 1) the experiences of people who use drugs (PWUD) with extramedical use of buprenorphine and their motivations to engage in it (including the desire to self-medicate and achieve "stability", to manage ongoing use of other opioids, and to "get high"); 2) the relationship between extramedical use and formal medical opioid agonist therapy programs; and 3) the established drug economy of extramedical buprenorphine. The review identified varied and often divergent perspectives and experiences with extramedical buprenorphine use. An examination of the reported "normalizing" effects of extramedical buprenorphine suggests this practice as extending medicalized discipline beyond the clinical environment. Taken together, these findings identify a need to move beyond the tension of harm-reducing versus harm-producing effects toward forms of health care and promotion that focus on the needs, perspectives, and priorities of people who use drugs.


Differential channelling of liver lipids in relation to susceptibility to hepatic steatosis in two species of ducks.
In the human, hepatic steatosis can be associated with an imbalance between synthesis, secretion and storage of hepatic lipids, and exhibits a genetic susceptibility. The effect of overfeeding on hepatic lipid channelling was investigated in two genotypes of ducks that differ in their susceptibility to fatty liver, i.e. the common duck, Anas platyrhynchos, and the Muscovy duck, Cairina moschata. Before overfeeeding, the Muscovy duck exhibited a lower subcutaneous adiposity and a higher muscular development, whereas hepatic composition was similar in both genotypes (>5% lipids and triglycerides accounting for 6-10% lipids). In the plasma lipoprotein profile, HDL predominated (5.5-7.8 g/l) over VLDL (0.09-0.25 g/l) and LDL (0.65-1.06 g/l). All lipid and lipoprotein concentrations were lower in the Muscovy duck. In response to overfeeding, the Muscovy duck exhibited a higher degree of hepatic steatosis (62 vs. 50% lipids), and a lower increase in adiposity and in the concentration of plasma triglycerides (6-fold vs. 10-fold) and VLDL (23-fold vs. 34-fold). Thus, certain genotypes may be more responsive to the dietary induction of fatty liver because of a less efficient channelling of hepatic lipids towards secretion into plasma and adipose storage, and the duck may represent a suitable model in which to study the development of hepatic steatosis and its pathogenesis.


Evaluation of a rapid gas-chromatographic method for the simultaneous quantitative determination of ethosuximide, phenyletheylmalonediamide, carbamazepine, phenobarbital, primidone and diphenylhydantoin in human serum.
A simple and rapid gas chromatographic method for the simultaneous estimation of the anticonvulsant drugs ethosuximide, carbamazepine, phenobarbital, primidone, diphenylhydantoin and the metabolite PEMA in serum is presented. The method is based on a simple ether extraction of 1 ml serum before and after precipitation of the proteins by ammonium sulfate and injection of the extract dissolved in methanol without derivative formation. Gas chromatographic separation is performed on a highly polar acidic phase (SP 1000, a terephthalic acid modified Carbowax 20 M), for detection the instrument is equipped with a nitrogen selective detector, quantitation is performed by automatic electronic integration of peak areas in relation to the internal standard Mesantoin. The optimal approach to the gas chromatographic analysis of "problem drugs" like carbamazepine and phenobarbital is discussed, various stationary phases and support materials are compared for effectiveness with this method. In the analysis of over 800 routine serum samples as well as internal and external quality control samples this method was found to be reliable and the results reproducible.


The organizing principle of the platelet glycoprotein Ib-IX-V complex.
The glycoprotein (GP)Ib-IX-V complex is the platelet receptor for von Willebrand factor and many other molecules that are critically involved in hemostasis and thrombosis. The lack of functional GPIb-IX-V complexes on the platelet surface is the cause of Bernard-Soulier syndrome, a rare hereditary bleeding disorder that is also associated with macrothrombocytopenia. GPIb-IX-V contains GPIbα, GPIbβ, GPIX and GPV subunits, all of which are type I transmembrane proteins containing leucine-rich repeat domains. Although all of the subunits were identified decades ago, not until recently did the mechanism of complex assembly begin to emerge from a systematic characterization of inter-subunit interactions. This review summarizes the forces driving the assembly of GPIb-IX-V, discusses their implications for the pathogenesis of Bernard-Soulier syndrome, and identifies questions that remain about the structure and organization of GPIb-IX-V.


The use of bio-monitoring to assess exposure in the electroplating industry.
Workers in the electroplating industry are potentially exposed to a range of hazardous substances including nickel and hexavalent chromium (chromium VI) compounds. These can cause serious health effects, including cancer, asthma and dermatitis. This research aimed to investigate whether repeat biological monitoring (BM) over time could drive sustainable improvements in exposure control in the industry. BM was performed on multiple occasions over 3 years, at 53 electroplating companies in Great Britain. Surface and dermal contamination was also measured, and controls were assessed. Air monitoring was undertaken on repeat visits where previous BM results were of concern. There were significant reductions in urinary nickel and chromium levels over the lifetime of this work in the subset of companies where initially, control deficiencies were more significant. Increased risk awareness following provision of direct feedback to individual workers and targeted advice to companies is likely to have contributed to these reductions. This study has shown that exposures to chromium VI and nickel in the electroplating industry occur via a combination of inhalation, dermal and ingestion routes. Surface contamination found in areas such as canteens highlights the potential for transferral from work areas, and the importance of a regular cleaning regime.


Influence of acetylsalicylic acid on plasma glucose, insulin, glucagon, and growth hormone levels following tolbutamide stimulation in man.
The effects of acetylsalicylic acid (ASA), a known inhibitor of prostaglandin (PG) synthesis, on plasma glucose, insulin, glucagon and growth hormone (GH) responses to tolbutamide were examined in ten normal volunteers. Treatment with 3.2 g ASA daily for 3 days caused a significant reduction in basal plasma glucose levels (p less than 0.05); by contrast, basal insulin rose from 23 +/- 2 to 31 +/- 2 microU/ml (p less than 0.01). No significant changes in the basal concentrations of glucagon and GH were found after ASA. Insulin response to tolbutamide was significantly augmented after ASA (p less than 0.01) while GH response to hypoglycemia was reduced (p less than 0.05). The pattern of plasma glucose and glucagon was not significantly modified by the treatment. Since ASA seems to have an action opposite to PGE on insulin and GH secretion, it is possible that the ASA may work through inhibition of PG synthesis.


An STI upsurge requires a nimble approach to care.
Being fluent in new guidelines helps you meet the challenges of changing disease prevalence, rising antibiotic resistance, and evolving social patterns.


Analgesic use at ovulation and implantation and human fertility.
Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability. The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle. We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids. Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability. Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial.


Effects of a purified cecropin D from a Chinese silk moth on growth, function and differentiation of murine hemopoietic cells.
The effects of cecropin D, a small basic peptide isolated from a Chinese oak silk moth, on the functions or differentiation of mammalian hemopoietic cells are described in the present paper. This peptide suppressed lectin-induced DNA synthesis of murine splenocytes in a dose-dependent manner without any significant cytotoxic effects. It also exhibited inhibitory effects on antibody production in lipopolysaccharide-stimulated lymphocytes and on colony formation of hemopoietic progenitor cells in plasma clots culture. These results indicate that cecropin D can regulate growth, function and differentiation of murine hemopoietic cells. The biological significance of this finding is discussed from the comparative immunological point of view.


Cranial Nerve Palsies: A Rare, Long-Term Complication of Radiotherapy for Nasopharyngeal Carcinoma.
Cranial nerves (CN) are believed to be relatively resistant to radiotherapy (RT); however, there have been case reports of cranial nerve palsy (CNP) following RT. We present a case of a gentleman with cranial nerve palsy of CN V and VII after RT for nasopharyngeal carcinoma (NPC). A 54-year-old male presented to our clinic with masticatory difficulty, facial hypoesthesia, and dysphagia. In 1998, he was treated with external beam RT for NPC. He underwent sural nerve grafting, anastomosing his functioning hypoglossal nerve to the buccal branch of the facial nerve in an end-to-side fashion, and direct implantation of a nerve graft from the spinal accessory to the masseter muscle. He unfortunately was unable to regain masticatory function postoperatively. Cranial nerve palsies are severely debilitating to patients and difficult to treat. Radiation-induced CNP is important to consider in the differential diagnosis in patients previously treated for NPC.


Clinical reasoning for the infectious disease specialist: a primer to recognize cognitive biases.
Infectious disease specialists are frequently consulted for diagnostic and therapeutic advice on challenging cases. When evaluating patients, the infectious disease specialist is well positioned to offer an appropriate diagnostic approach but is also at risk of not recognizing the correct diagnosis for a variety of reasons. We believe it is important to provide infectious disease specialists and trainees with a fundamental understanding of diagnostic errors, clinical reasoning, and cognitive biases. We present 2 cases demonstrating common cognitive biases leading to diagnostic errors, and we reflect on strategies that may aid in their prevention. We hope to provide knowledge and tools that may help prevent diagnostic errors in the future.


Body and distal pancreatectomy for metastatic renal cell carcinoma: case report and review of the literature.
Renal cell carcinoma is known for its unpredictable behavior. Spontaneous regression of metastatic disease has been reported; and patients have been known to survive for years with metastatic disease. Reports of long intervals between nephrectomy and metastatic disease are common. We present a case of a solitary metastasis to the pancreas 20 years after nephrectomy for renal cell carcinoma.


Prescription patterns following first-line new generation antidepressants for depression in Japan: a naturalistic cohort study based on a large claims database.
Several studies have described real-world prescription patterns of first-line antidepressants for depression but little is known about their fate in terms of duration, intensity and changes. An inception cohort of new onset non-psychotic depression initiating antidepressant treatment with a new generation antidpressive agent was identified in a large health insurance claims database in Japan between 2009 and 2010. The duration and intensity of first-line antidepressants, the timing and kind of second-line antidepressants and the total duration of antidepressant treatment were examined. We identified 1592 patients. The starting dose and the maximum dose attained with the first-line agent appeared to be largely in line with the guideline recommendations although the latter tended toward the minimum of the recommended range. The continuity of the first-line antidepressant was far below the guideline recommendations, with 28% never returning after the initial prescription and 55% dropping out within 3 months. Of all the first-line antidepressants, 14% were subsequently augmented by another psychotropic agent while 17% were switched to another antidepressant after a median of 3 or 2 months, respectively. The choice of the second-line agents varied extremely widely. The total duration of antidepressant therapy was as short as a median of 4 months, with 68% stopping treatment by 6 months. The diagnosis of non-psychotic unipolar depression in the claims database analyses remains approximate. The current guidelines are grossly out of touch with the clinical realities. On the one hand, guidelines need to reflect the real-world practices; on the other hand clinicians should limit their treatment options and allow evidence-based comparative effectiveness research among them so that patients shall no longer be given less effective and more effective treatments without being able to distinguish among them.


[Side-reactions in peptide synthesis, III. Synthesis and characterization of Nin-tert-butylated tryptophan derivatives (author's transl)].
It was possible to elucidate a side reaction which had long been assumed to occur during the acidolytic cleavage of protecting groups based on a ter-butyl moiety, by synthesizing Nin-tert-butyltryptophan in different ways. It was found to be absolutely identical with a "modified tryptophan" which was isolated after the total synthesis of a gastrin analogue; Nin-tert-butyl-tryptophan peptides are formed as the main products of a tert-butylation reaction, the mechanism of which is not very clear yet. The proof for a Nin-tert-butylation of tryptophan was obtained by spectroscopic methods, in particular mass spectrometry and nuclear magnetic resonance spectroscopy.


Evaluation of some benzenesulphonylhydrazones of aryl aldehydes and ketones as antiepileptic agents.
Benzaldehyde benzenesulphonamide was shown to have comparable anticonvulsant activity to valproic acid in the maximal electroshock seizure test. Molecular modification of this compound was developed principally to explore whether a correlation between planarity and anticonvulsant activity could be discerned. The interplanar angle (theta) between an aryl ring and the adjacent azomethine group of some representative compounds was measured by electronic absorption spectroscopy. However, the structural alterations of benzaldehyde benzenesulphonamide undertaken in this work led to compounds bereft of anticonvulsant activity.


GSTT1 as a Predictive Marker and Enhancer for Osteogenic Potential of Human Adipose-Derived Stromal/Stem Cells.
Adipose-derived stromal/stem cells (ASCs) have been extensively studied as cell sources for regenerative medicine for bone because of their excellent proliferative capacity and the ability to obtain a large number of cells with minimal donor morbidity. On the other hand, the differentiation potential of ASCs is generally lower than that of bone marrow-derived stromal/stem cells and varies greatly depending on donors. In this study, we mined a marker that can predict the osteogenic potential of ASC clones and also investigated the usefulness of the molecule as the enhancer of osteogenic differentiation of ASCs as well as its mechanism of action. Through RNA-seq gene analysis, we discovered that GSTT1 (Glutathione S-transferase theta-1) was the most distinguished gene marker between highly osteogenic and poorly osteogenic ASC clones. Knockdown of GSTT1 in high osteogenic ASCs by siGSTT1 treatment reduced mineralized matrix formation. On the other hand, GSTT1 overexpression by GSTT1 transfection or GSTT1 recombinant protein treatment enhanced osteogenic differentiation of low osteogenic ASCs. Metabolomic analysis confirmed significant changes of metabolites related to bone differentiation in ASCs transfected with GSTT1. A high total antioxidant capacity, low levels of cellular reactive oxygen species, and increased GSH/GSSG ratios were also detected in GSTT1-transfected ASCs. When the in vivo effect of GSTT1-transfected ASCs on bone regeneration was investigated with segmental long-bone defect model in rats, bone regeneration was significantly better after implantation of GSTT1-transfected ASCs compared with that of control vector-transfected ASCs. In conclusion, GSTT1 can be a useful marker to screen the highly osteogenic ASC clones and also a therapeutic factor to enhance the osteogenic differentiation of poorly osteogenic ASC clones. © 2023 American Society for Bone and Mineral Research (ASBMR).


Posttraumatic stress and other health consequences of catastrophic avalanches: A 16-year follow-up of survivors.
To date, no study has investigated the effects of avalanches on survivor's health beyond the first years. The aim of this study was to examine long-term health status 16 years after exposure to avalanches using a matched cohort design. Mental health, sleep quality and somatic symptoms among avalanche survivors (n=286) and non-exposed controls (n=357) were examined. Results showed that 16% of survivors currently experience avalanche-specific PTSD symptoms (PDS score>14). In addition, survivors presented with increased risk of PTSD hyperarousal symptoms (>85th percentile) (aRR=1.83; 98.3% CI [1.23-2.74]); sleep-related problems (PSQI score>5) (aRR=1.34; 95% CI [1.05-1.70]); PTSD-related sleep disturbances (PSQI-A score≥4) (aRR=1.86; 95% CI [1.30-2.67]); musculoskeletal and nervous system problems (aRR 1.43; 99% CI 1.06-1.93) and gastrointestinal problems (aRR 2.16; 99% CI 1.21-3.86) compared to the unexposed group. Results highlight the need for treatment for long-term PTSD symptoms and sleep disruption in disaster communities.


The immunologic constant of rejection.
The complexity underlying a pathologic process does not necessarily require a complex explanation. The biology determining allograft or cancer rejection, autoimmunity or tissue damage during pathogen infections is complex; however, common patterns are emerging that lead to a common final outcome. For instance, tissue destruction occurs with resolution of the pathogenic process (cancer, infection) or tissue damage and organ failure (autoimmunity, allograft rejection). Observations in humans based on transcriptional profiling converge into what we call an 'immunologic constant of rejection' that characterizes such occurrences. This constant includes the coordinate activation of interferon-stimulated genes (ISGs) and immune effector functions (IEFs). Understanding this final effector pathway may suggest novel strategies for the induction or inhibition of tissue-specific destruction with therapeutic intent in cancer and other immune pathologies.


Artificial ubiquitylation is sufficient for sorting of a plasma membrane ATPase to the vacuolar lumen of Arabidopsis cells.
Sorting of transmembrane proteins into the inner vesicles of multivesicular bodies for subsequent delivery to the vacuole/lysosome can be induced by attachment of a single ubiquitin or K63-linked ubiquitin chains to the cytosolic portion of the cargo in yeast and mammals. In plants, large efforts have been undertaken to elucidate the mechanisms of vacuolar trafficking of soluble proteins. Sorting of transmembrane proteins, by contrast, is still largely unexplored. As a proof of principle, that ubiquitin is involved in vacuolar sorting in plants we show that a translational fusion of a single ubiquitin to the Arabidopsis plasma membrane ATPase PMA-EGFP is sufficient to induce its endocytosis and sorting into the vacuolar lumen. Sorting of the artificial reporter is not dependent on ubiquitin chain formation, but involves ubiquitin's hydrophobic patch and can be inhibited by coexpression of a dominant-negative version of the ESCRT (endosomal sorting complex required for transport) related protein AtSKD1 (SUPPRESSOR OF K+ TRANSPORT GROWTH DEFECT1). Our results suggest that ubiquitin can in principle act as vacuolar sorting signal in plants.


Platelet activating factor-stimulated formation of inositol triphosphate in platelets and its regulation by various agents including Ca2+, indomethacin, CV-3988, and forskolin.
When myo-2-[3H]inositol-labeled rabbit platelets were stimulated with 1 X 10(-9)M sn-3-AGEPC (platelet activating factor) for 5 s, the levels of [3H]inositol monophosphate (IP), [3H]inositol diphosphate (IP2), and [3H]inositol triphosphate (IP3) increased about 1.5-, 3-, and 5-fold, respectively. Formation of these inositol polyphosphates was strikingly independent of extracellular Ca2+. Inactive analogs of sn-3-AGEPC, i.e., lysoGEPC and stereoisomer sn-1-AGEPC, did not cause production of any inositol polyphosphate. Pretreatment of platelets with indomethacin (5 microM) had little effect on this phenomenon. On the other hand, a platelet activating factor antagonist, CV-3988, blocked the AGEPC-stimulated production of radioactive IP, IP2, and IP3. Similarly forskolin, an activator of adenylate cyclase, at 5 microM or above completely abolished AGEPC-induced aggregation, [3H]serotonin secretion, and formation of [3H]inositol polyphosphates. In the light of the emerging role of AGEPC in inflammation, hypotension, and other cardiovascular processes, studies with platelets reported here indicate that forskolin could be a useful tool for manipulating AGEPC responses. It is further concluded that AGEPC-induced formation of inositol polyphosphate is an early response "specific" to AGEPC, mediated via extracellular Ca2+-independent phosphoinositide phosphodiesterase, and could play a role in intracellular Ca2+ mobilization and platelet shape change.


Application of an instrumental neutron activation analysis procedure to analysis of food.
The capabilities of a relatively simple instrumental neutron activation analysis procedure were demonstrated by performing multielement analyses of 240 Food and Drug Administration Total Diet Studies food composites. The analytical results provide a comprehensive database for a wide range of food types. The procedure incorporates only two irradiations and counts, polyethylene packaging and no sample transfer after irradiation. Concentrations were determined for 19 elements, 16 of which were found in most composites. Detection limits were calculated for all food groups and are given for the 22 elements included in the quantitative analysis scheme. In a qualitative search for 18 additional elements for which no standards were run, none were detected in any of the composites. Specific factors such as interferences from the blank are discussed in regard to their effects on the uncertainties associated with the experimental data and the detection limits. Modifications to the procedure are also suggested for lowering the detection limits for specific elements.


Problems with parsimony in sequences of biased base composition.
Parsimony is commonly used to infer the direction of substitution and mutation. However, it is known that parsimony is biased when the base composition of the DNA sequence is skewed. Here I quantify this effect for several simple cases. The analysis demonstrates that parsimony can be misleading even when levels of sequence divergence are as low as 10%; parsimony incorrectly infers an excess of common to rare changes. Caution must therefore be excercised in the use of parsimony.


CPEM: Accurate cancer type classification based on somatic alterations using an ensemble of a random forest and a deep neural network.
With recent advances in DNA sequencing technologies, fast acquisition of large-scale genomic data has become commonplace. For cancer studies, in particular, there is an increasing need for the classification of cancer type based on somatic alterations detected from sequencing analyses. However, the ever-increasing size and complexity of the data make the classification task extremely challenging. In this study, we evaluate the contributions of various input features, such as mutation profiles, mutation rates, mutation spectra and signatures, and somatic copy number alterations that can be derived from genomic data, and further utilize them for accurate cancer type classification. We introduce a novel ensemble of machine learning classifiers, called CPEM (Cancer Predictor using an Ensemble Model), which is tested on 7,002 samples representing over 31 different cancer types collected from The Cancer Genome Atlas (TCGA) database. We first systematically examined the impact of the input features. Features known to be associated with specific cancers had relatively high importance in our initial prediction model. We further investigated various machine learning classifiers and feature selection methods to derive the ensemble-based cancer type prediction model achieving up to 84% classification accuracy in the nested 10-fold cross-validation. Finally, we narrowed down the target cancers to the six most common types and achieved up to 94% accuracy.


Assessment of Cardiac Damage in Aortic Stenosis.
Severe aortic stenosis (AS) causes chronic pressure overload of the left ventricle (LV), resulting in the progressive cardiac damage, which extends beyond the LV. Several previous studies have shown a relationship of the cardiac damage to AS, rather than the stenosis severity, with adverse events after aortic valve replacement (AVR) in patients with severe AS. A new staging system for AS patients has important prognostic implications for clinical outcomes after AVR. This review summarizes the importance of assessment of cardiac damage in patients with AS.


Analysis of the subcellular distribution of avian p95-APP2, an ARF-GAP orthologous to mammalian paxillin kinase linker.
We describe here the identification and characterization of avian p95-APP2, a multi-domain protein of a recently identified family of ADP-ribosylation factor (ARF)-GTPase-activating proteins (GAPs) including mammalian G protein-coupled receptor kinases (GRK)-interactor 1 (GIT1), paxillin kinase linker (PKL), and GIT2, as well as avian p95-APP1. The p95-APP2 is eluted from Rac-GTP-gamma-S, but not from Rac-GDP-beta-S columns. As other members of the family, p95-APP2 has binding regions for the focal adhesion protein paxillin, and for the Rac exchanging factor PIX. Sequence comparison indicates that p95-APP2 is the avian orthologue of mammalian PKL. Expression studies showed a largely diffuse distribution of the full length p95-APP2, without evident effects on cell morphology. We observed a dramatic difference between the localization of the amino-terminal portion of the protein, including the ARF-GAP domain and the three ankyrin repeats, and the carboxy-terminal portion including the paxillin-binding site. Moreover, the expression of truncated carboxy-terminal polypeptides including both the PIX- and paxillin-binding regions leads to a marked localization of the protein together with paxillin at large vesicles. Comparison of the expression of corresponding ARF-GAP-deficient constructs from p95-APP2 and p95-APP1 shows their distribution at distinct endocytic compartments. Altogether, these data support a role of distinct members of this family of ARF-GAPs in the regulation of different steps of membrane traffic during cell motility, and suggest that p95-APP2 may shuttle between an intracellular compartment and the cell periphery, although, further work will be needed to address this point.


Anti-diarrhoeal effects of seirogan in the rat small intestine and colon examined in vitro.
Seirogan is a beechwood extract composed of guaiacol, creosol and other related phenolic compounds which is widely used as an anti-diarrhoeal agent in Asia. Abnormalities in water and electrolyte transport are often the cause of diarrhoea, but the mechanism of action of seirogan on small intestinal and colonic mucosal ion transport is unknown. To examine the effect of seirogan on electrogenic ion transport in vitro. Sheets of rat jejunum and colon were mounted in Ussing chambers, and transmural potential difference (PD) was used as an electrical marker of changes in mucosal ion transport. Hypersecretory conditions were induced by acetylcholine (ACh). Serosal or mucosal application of seirogan (0.1-100 microg/mL) decreased basal jejunal transmural PD. Pre-treatment of the tissue with the neurotoxin, tetrodotoxin, did not inhibit the seirogan-induced changes in basal electrical activity. Seirogan had no effect on basal transmural PD in the ileum and colon. Under ACh-induced hypersecretory conditions in the small intestine and colon, addition of serosal or mucosal seirogan produced antisecretory effects determined indirectly by measurement of transmural PD. The ability of seirogan to decrease basal transmural PD in the jejunum, and inhibit the ACh-induced electrical responses, may contribute to its anti-diarrhoeal action.


Synthesis and antibacterial evaluation of novel oxazolidinone derivatives containing a piperidinyl moiety.
In this article, a series of novel oxazolidinone derivatives containing a piperidinyl moiety was designed and synthesized. Their antibacterial activities were measured against S. aureus, MRSA, MSSA, LREF and VRE by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to linezolid. Among them, compound 9h exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9h, which showed remarkable antibacterial activity against S. aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.25-1 μg/mL, was an interesting candidate for further investigation.


X-ray induction of methotrexate resistance due to dhfr gene amplification.
The effect of ionizing radiation on methotrexate (MTX) resistance and gene amplification in cultured mammalian cells was investigated. X-irradiation of mouse EMT-6 cells induced cell killing and MTX resistance due to amplification of dihydrofolate reductase (dhfr) gene in a dose-dependent manner. The highest yields of mutant cells were obtained at approximately D37 (the dose at which 37% of the cells survive), where the frequency of MTX-resistant cells was four- to eightfold over that of the unirradiated population. The proportion of MTX-resistant cells among the survivors increased logarithmically with dose, up to a 1000-fold increase over unirradiated cells at 1000 cGy, the highest dose tested. The induced frequency of MTX resistance after X-irradiation was greater than the induced frequency of 8-azaguanine resistance, which indicates deletion of the hypoxanthine phosphoribosyltransferase gene. Inhibition of poly(ADP-ribose) polymerase by the addition of 3-aminobenzamide before irradiation increased both cell killing and MTX resistance. Metaphase spreads of chromosomes from EMT-6 cells that had been irradiated and subjected to stepwise increases in MTX concentration showed numerous double minutes. Pulsed-field gel electrophoresis of the DNA from cells containing radiation-induced double minutes showed that many copies of the dhfr gene were present on circular DNA molecules of 10(6), 2 x 10(6), and 3 x 10(6) base pairs. These results suggest a relationship between the induction of chromosome aberrations and the induction of gene amplification.


First asymmetric total synthesis of Us-7 and -8, novel D-seco Corynanthe-type oxindole alkaloids from Uncaria attenuata: structure revision of Us-7 and determination of absolute stereochemistry.
[reaction: see text] Starting from (S)-glycidol, the asymmetric total synthesis of novel D-seco Corynanthe-type oxindoles Us-7 and Us-8 was accomplished. The structure of Us-7 was revised from the reported structure 1 with the (3R,7S) form to structure 22 with (3S,7R), and the absolute stereochemistry at C15 of both alkaloids was established.


Pharmacokinetic data on doxycycline and its distribution in different biological fluids in female goats.
A pharmacokinetic study of doxycycline after intravenous administration at 5 mg/kg body weight in goats revealed that a concentration of greater than or equal to 0.5 microgram/ml was maintained for 5 min-2 h, 4-12 h, 2-12 h and 5 min-greater than 48 h in plasma, interstitial fluid, milk and urine respectively. The low t1/2 alpha of 0.73 +/- 0.11 h and high t1/2 beta of 16.63 +/- 1.58 h show that the drug is rapidly distributed but slowly eliminated from the body. The tissue:plasma concentration of 4.86 +/- 1.06 during the elimination phase [K12/(K21-beta)] indicates a high expected tissue concentration, which is supported by similarly increased drug concentration in interstitial fluid and milk. The high Vdarea of 9.78 +/- 0.86 L/kg observed denotes that, apart from its wide distribution, the drug may be stored in fat depots as it is known to be highly lipophilic. As the drug maintained a therapeutic concentration for a shorter time in plasma, and the calculated dose rate for maintaining a minimal plasma concentration of 0.5-1.5 micrograms/ml is relatively high, it may not be of much use in treating septicaemia in this species. Since the observed tissue:plasma concentration was higher and a therapeutic concentration was maintained in interstitial fluid and milk for longer, the drug can be used for other systemic infections at a lower dose rate than that required for treating septicaemia. As the drug maintained a very high concentration in urine, it may be of particular value in treating urinary tract infections caused by sensitive micro-organisms.


Compounds structurally related to tamoxifen as openers of large-conductance calcium-activated K+ channel.
We found that a variety of compounds containing partial structures of tamoxifen showed activity as chemical modulators of large-conductance calcium-activated K+ channels (BK channels).


Difficulties in the differential diagnosis between Takayasu arteritis and rheumatic fever: case report.
In this article, we present the case of a patient with heart failure with biological aortic valve prosthesis and multiple vascular changes consistent with Takayasu arteritis (TA) who was seen in our department receiving corticosteroids and secondary prevention of rheumatic fever (RF); it was not possible to exclude the association between both diseases.


Pruritus as an early sign of abnormal scarring in the re-epithelialising phase of Toxic Epidermal Necrolysis.
We present a 28-year-old remote-living male who presented to our dermatology clinic with increasing pruritus over his torso and limbs in the context of a recent admission for Toxic Epidermal Necrolysis (TEN) secondary to paliperidone depot. Our case demonstrates that pruritus in the re-epithelialising phase of TEN may be a sign of abnormal scarring. Early assessment and measurement for compression garments is recommended.


Arginine is a physiological precursor of endothelium-derived nitric oxide.
ATP dose dependently stimulated the formation and release of nitric oxide (NO) from perfused rabbit aorta. L-Canavanine, an inhibitor of various L-arginine-utilizing enzymes, abolished basal and ATP-induced NO formation and release. ATP increased the accumulation of presumably NO-derived NO2- in the medium of primary cultures of bovine aortic endothelial cells. 15NO, 15NO2- and 15NO3- formation was found when L-[guanido-15N2]arginine was added to the culture medium. We conclude that the terminal guanidino nitrogens of L-arginine are the physiological precursors of endothelium-derived NO.


Association Between Race, Neighborhood, and Medicaid Enrollment and Outcomes in Medicare Home Health Care.
More than 3 million Medicare beneficiaries use home health care annually, yet little is known about how vulnerable beneficiaries fare in the home health setting. This is particularly important given the recent launch of Medicare's Home Health Value-Based Purchasing model. The objective of this study was to determine odds of adverse clinical outcomes associated with dual enrollment in Medicaid and Medicare as a marker of individual poverty, residence in a low-income ZIP code tabulation area (ZCTA), and black race. Retrospective observational study using individuals-level logistic regression. Home health care. Fee-for-service Medicare beneficiaries from 2012 to 2014. Thirty- and 60-day clinical outcomes, including readmissions, admissions, and emergency department (ED) use. Home health agencies serving a high proportion of dually enrolled, low-income ZCTA, or black beneficiaries were less often high-quality. Dually-enrolled, low-income ZCTA, and Black beneficiaries receiving home health care after hospitalization had higher risk-adjusted odds of 30-day readmission (odds ratio [OR] = 1.08, P < 0.001; OR = 1.03, P < 0.001; and OR = 1.02, P = 0.002 respectively) and 30-day ED use (OR = 1.20, 1.07, and 1.15, P < 0.001 for each). Those receiving home health care without preceding hospitalization had higher 60-day admission (OR = 1.06, P < 0.001; OR = 1.01, P = 0.002; and OR = 1.05, P < 0.001), and 60-day ED use (OR = 1.16, 1.03, and 1.19, P < 0.001 for each). Differences were primarily within agencies rather than between the agencies where these beneficiaries sought care. Medicare beneficiaries receiving home health services who are dually enrolled, live in a low-income neighborhood, or are black have higher rates of adverse clinical outcomes. These populations may be an important target for quality improvement under Home Health Value-Based Purchasing.


Chronic effects of labetalol, pindolol, and propranolol on calf blood flow in intermittent claudication.
To evaluate the role of beta-adrenoceptor blockade on lower limb circulation in patients with peripheral arterial disease, heart rate, blood pressure, calf blood flow and vascular resistance were measured at rest and during reactive hyperemia in seven patients with hypertension and intermittent claudication. The study was performed as a placebo-controlled, double-blind, crossover trial of 10 days with doses of propranolol, 80 mg twice a day, pindolol, 5 mg twice a day, labetalol, 200 mg twice a day, and labetalol, 400 mg twice a day as active drug. Heart rate was lowest during propranolol dosing and blood pressure was lowest during labetalol dosing irrespective of the labetalol dose used. The degree of peripheral arterial disease modulated the effect of beta-blockade on limb circulation. In the less symptomatic limbs, reactive hyperemic flow was greater after pindolol than after the other drugs and did not differ from the level recorded after placebo. These differences were inconsistent and small in the more symptomatic limbs. Thus as the peripheral arterial disease became more severe and extensive, beta-blockade, irrespective of its type, lost its hemodynamic effect on lower limb circulation.


Green synthesis of Pd/walnut shell nanocomposite using Equisetum arvense L. leaf extract and its application for the reduction of 4-nitrophenol and organic dyes in a very short time.
Palladium nanoparticles (PdNPs) have been immobilized on the surface of walnut shell powder using Equisetum arvense L. leaf extract as reducing and stabilizing agents in this work. FT-IR spectroscopy, UV-Vis spectroscopy, photoluminescence spectroscopy, X-ray diffraction (XRD) pattern, field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM) have been used in the characterization of the nanocomposites thus prepared. High catalytic activity was shown by these nanocomposites in the reduction of different dyes. The PdNPs' diameter on the walnut shell was predominantly found within the 5-12-nm range. The advantages of these catalysts include facile and clean synthesis, simple preparation procedure, excellent properties, alterable supports, and low cost, which make them applicable in reduction of 4-nitrophenol (4-NP), Congo red (CR), methylene blue (MB), and rhodamine B (RhB) in the presence of aqueous NaBH4 at room temperature. Pd/walnut shell nanocomposites were highly active catalysts for reduction of these dyes. Moreover, Pd/walnut shell nanocomposite can be recovered and recycled seven times without any appreciable loss of catalytic activity. Graphical abstract Waste walnut shell as a natural valuable resource support for green synthesis of Pd/walnut shell nanocomposite using Equisetum arvense L. leaf extract and its application for the reduction of 4-nitrophenol and organic dyes in a very short time.


Study of cardiothoracic wound infection at St. Thomas' Hospital.
Wound infection occurred after 14.3 per cent of 433 open heart operations. In 309, saphenous veins were harvested for coronary artery bypass grafting (CABG) and 8.7 per cent of sternal wounds and 12.9 per cent of leg wounds were infected. Only 1.6 per cent of the remaining 124 patients who had open heart operations without leg surgery suffered sternal wound infections. In the CABG group sternal infection was theatre-related and significantly associated with length of pre-operative stay, diabetes and re-operation. Similar organisms were isolated from both leg and sternal wounds which suggest that organisms were transferred from legs to sternum with the veins. No clinically relevant cross infection was demonstrated. Skin disinfection and surgical technique seem more important than antibiotic prophylaxis in the control of these infections.


Molecular features of interaction involving hen egg white lysozyme immobilized on graphene oxide and the effect on activity.
Nanomaterials, such as graphene oxide (GO) are being studied to decipher their suitability in biomedical applications. This study investigate the effect on structure and function of hen egg white lysozyme (HEWL) adsorbed on GO, using various biophysical techniques. In spite of there being not much change in the structure, the catalytic activity is reduced significantly. Fluorescence quenching indicates complex formation. Fluorescence lifetime measurement suggests that GO binds at or near the active site close to Trp62 and Trp108. Heat change associated with HEWL-GO interaction suggests hydrogen bond along with van der Waals and electrostatic interactions are involved in the HEWL-GO complex. Molecular docking indicates binding of GO at the active site corroborating experimental findings. Molecular dynamics simulations indicate that the blocking of the active site affects the flexibility of the surrounding residues and contribute to the reduction of the activity. Unfolding experiments indicate that HEWL is more prone to thermal instability in presence of GO. Together, the results obtained established molecular details of HEWL-GO interaction and might be useful in eventual biomedical applications of GO.


The impact of a "Residents as Teachers" Workshop at one year follow-up.
"Residents as Teachers" (RaT) Workshops have been implemented in many General Surgery residency programs to improve resident teaching ability. The aim of this project was to assess whether there was significant degradation of teaching skills and knowledge one year after a RaT workshop. A 4-h interactive workshop was delivered at an academic general surgery residency program. Pre- and post-workshop assessments evaluated participants' knowledge and confidence regarding teaching skills and they were re-evaluated one-year later. On a 5-point Likert scale, residents improved confidence and self-perception following the workshop was stable after one year. A decrease was found in the resident's perception of the education-related training received and scores on the knowledge-based questions. The confidence residents obtained from single-day RaT workshop was maintained at one year, but the knowledge was not. Resident perception of their educational training may benefit from more frequent reinforcement.


[Adherence to and satisfaction with oral outpatient thromboembolism prophylaxis compared to parenteral: SALTO study].
Prolongation of drug-based thromboembolism prophylaxis after discharge from hospital is clearly recommended following total hip and knee replacement. The aim of this study was to evaluate and compare adherence to and satisfaction with outpatient thromboembolism prophylaxis (by injection and oral) under routine clinical practice conditions. We analysed two consecutive cohorts of patients (480 and 366, respectively) who had undergone total hip or knee replacement surgery in 120 Spanish hospitals, and were prescribed outpatient thromboembolism prophylaxis, by injection and orally, respectively. Information on adherence to and satisfaction with both treatments, sociodemographic data and treatment compliance was collected using specific questionnaires. The drop-out rate (9.49 vs. 4.14%), general satisfaction (37 vs. 83.38%), and the TSQM satisfaction scale were better in the oral prophylaxis cohort and, although the differences between the two routes of administration were not significant, treatment compliance was also better in the oral cohort (Morisky-Green test: 53.49 vs. 59.05%). Adherence to and satisfaction with the oral thromboembolism prophylaxis were better than for prophylaxis by injection in the context of outpatient prolongation. Nevertheless, suboptimal treatment compliance was found in both cohorts, which could result in lack of efficacy of the prophylaxis. Both patients and doctors have to be made aware of the importance of post-discharge extension of thromboprophylaxis in orthopaedic surgery with high thrombotic risk. Moreover, strategies should be developed to encourage compliance.


Time course of the ventilatory response to adjuvant arthritis in the rat.
The present study determined the time course of the ventilatory response to adjuvant arthritis in the rat. It was found that the minute ventilation of arthritic rats reliably exceeded that of control animals during a period of about 4 weeks. The ventilatory response had its onset during the 2nd week after inoculation of Mycobacterium butyricum in the tail base, peaked on day 21, and was statistically reliable up to the 35th day. A smaller difference persisted throughout the further six weeks of the study, which covered 77 days in all. The changes in minute ventilation appeared to be closely time-locked with the changes in body weight and paw diameter which are characteristic of rats with adjuvant arthritis. The peak minute ventilation of individual animals also correlated in a significant manner with changes in weight and in paw diameter. The data are consistent with an earlier attempt to characterize the time course of the chronic pain which is presumably associated with adjuvant arthritis in the rat; minute ventilation is discussed as a possible measure of this putative pain.


Can body composition be used to optimize the dose of platinum chemotherapy in lung cancer? A feasibility study.
Current methods of dosing platinum-based chemotherapy are suboptimal. Potentially, taking lean body mass into account may help. To inform the design of a future study, we first examined the feasibility and acceptability of such an approach using dual-energy X-ray absorptiometry (DEXA) and explored aspects suggestive of over- and under-dosing. Patients with lung cancer offered platinum-based chemotherapy over 1 year were identified and, if eligible, invited to take part in a prospective feasibility study. Questionnaires examined acceptability of the DEXA scan and of a future study that randomized between traditional dosing and one adjusted according to body composition. Dose-limiting toxicity (DLT) and a lack of neutropenia explored potential over- and under-dosing, respectively. Of the 173 patients offered chemotherapy, 123 (71%) were ineligible, mostly because of failing entry criteria (84, 49%). Of the 50 approached, 18 (36%) participated, most receiving carboplatin, with 17 providing data. All found a DEXA scan acceptable; other assessments were fully completed, except nadir and pre-chemotherapy blood counts. Most (94%) were prepared to take part in a future study, although the additional hospital visits for a nadir blood count were unpopular with some. Five (29%) patients experienced six episodes of DLT which resulted in discontinuation (3), dose reduction (2) or change to a less toxic regimen (1). Nine (60%) patients experienced either no (2) or inconsistent (7) neutropenia. A randomized trial appears acceptable and feasible in patients receiving carboplatin. Adjustment of our entry criteria and avoiding a hospital visit for a nadir blood count should aid recruitment.


Longitudinal study of normal cognition in Parkinson disease.
To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.


Cardiac MRI of the fetal heart using a novel triggering method: initial results in an animal model.
To investigate MRI of the fetal heart by way of a novel triggering method with the use of an MR-compatible cardiotocography (CTG) in an animal model. Fetal cardiac MRI was performed on four pregnant ewes on a 1.5 Tesla (T) MR system. A CTG was rendered MR compatible and its signal was used for the triggering of the fetal heart to perform cardiac cine MRI of the fetal heart with maternal free-breathing with cine steady-state free precession. The left ventricular volume and function were measured from the short-axis (view). The image quality of anatomical structures was assessed. All cardiac valves and the foramen ovale could be visualized. Myocardial contraction was depicted in cine sequences. The average blood volume at the end systole was 1.7 mL (SD ± 0.12). The average volume at the end diastole was 4.6 mL (± 0.4); thus the average stroke volumes of the left ventricle were 2.87 mL (± 0.31) with ejection fractions of 60.53% (± 4.17). The newly developed MR compatible CTG could be used as a tool for cardiac triggering method of the fetal heart. This novel device might help fetal cardiac MRI technology in the future.


ET-B receptors involvement in peripheral opioid analgesia induced by light-emitting diode photobiomodulation in male and female mice.
Currently, photobiomodulation therapy (PBMT) is gaining space in the scientific and clinical environment. To help elucidate the importance of irradiance, this study evaluated the effect of two different PBMT irradiances (3.5 and 90 mW/cm2), given a fixed wavelength of 630 nm and a dose of 2 J/cm2, on mechanical hyperalgesia following Complete Freund's Adjuvant (CFA) intraplantar (i.pl.) injection in mice. Additionally, we investigated the role of peripheral opioid and endothelin-B receptors (ETB-R), as well as sex differences in treatment outcome. Different groups of male or female mice were evaluated 6 and 96 h after CFA. Mechanical hyperalgesia was evaluated 30 min after treatments. Naloxone or Bq-788 administration, fifteen minutes before PBMT or Sarafotoxin S6c, helped determine the involvement of peripheral opioid and ETB-Rs on PBMT. Lastly, ETB-Rs skin immunocontent in both sexes was quantified after PBMT consecutive daily treatments. PBMT at an irradiance of 90 mW/cm2, was more effective than 3.5 mW/cm2. Bq-788 and naloxone administration prevented the effects of PBMT and SRTX S6c; however, PBMT did not influence peripheral ETB-Rs immunocontent. The results suggest that irradiance influences PMBT effect; and that activation of ETB-R play a role in peripheral PBMT opioid induced analgesia. Lastly, PMBT effects do not appear to be sex-dependent.


Identification of the major human sialoglycoprotein from red cells, glycophorin AM, as the receptor for Escherichia coli IH 11165 and characterization of the receptor site.
The pyelonephritogenic Escherichia coli strain 1 H 11165 specifically agglutinates human erythrocytes carrying the M blood group antigen. The polymorphic forms of this antigen, M and N, are located in the NH2-terminal region of the major human red-cell sialoglycoprotein, glycophorin A. Radioactively labeled glycophorin A from M cells specifically bound to the bacteria. Purified glycophorin AM, but not glycophorin AN, efficiently inhibited for binding. Mild periodate treatment oxidized the NH2-terminal serine in glycophorin AM and this resulted in loss of binding to the bacteria. High concentrations of serine and alkali-labile oligosaccharides derived from glycophorin AM inhibited the binding, whereas the synthetic M-specific NH2-terminal pentapeptide Ser-Ser-Thr-Thr-Gly did not. Neuraminidase treatment of glycophorin AM did not destroy the binding. The most efficient inhibition of binding was observed with the N-terminal glyco-octapeptide obtained from glycophorin AM by CNBr cleavage. This peptide contains both the essential serine residue and the alkali-labile oligosaccharides, which both are recognized by the bacterium.


SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: Behavioral profile predictive of an atypical antipsychotic activity.
SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT(1A) blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.


Coordination of the recruitment of the FANCD2 and PALB2 Fanconi anemia proteins by an ubiquitin signaling network.
Fanconi anemia (FA) is a chromosome instability syndrome and the 20 identified FA proteins are organized into two main arms which are thought to function at distinct steps in the repair of DNA interstrand crosslinks (ICLs). These two arms include the upstream FA pathway, which culminates in the monoubiquitination of FANCD2 and FANCI, and downstream breast cancer (BRCA)-associated proteins that interact in protein complexes. How, and whether, these two groups of FA proteins are integrated is unclear. Here, we show that FANCD2 and PALB2, as indicators of the upstream and downstream arms, respectively, colocalize independently of each other in response to DNA damage induced by mitomycin C (MMC). We also show that ubiquitin chains are induced by MMC and colocalize with both FANCD2 and PALB2. Our finding that the RNF8 E3 ligase has a role in recruiting FANCD2 and PALB2 also provides support for the hypothesis that the two branches of the FA-BRCA pathway are coordinated by ubiquitin signaling. Interestingly, we find that the RNF8 partner, MDC1, as well as the ubiquitin-binding protein, RAP80, specifically recruit PALB2, while a different ubiquitin-binding protein, FAAP20, functions only in the recruitment of FANCD2. Thus, FANCD2 and PALB2 are not recruited in a single linear pathway, rather we define how their localization is coordinated and integrated by a network of ubiquitin-related proteins. We propose that such regulation may enable upstream and downstream FA proteins to act at distinct steps in the repair of ICLs.


Effects of FLONLIZER, ultraviolet sterilizer, on Legionella species inhabiting cooling tower water.
Legionella pneumophila in sterile distilled water was not detected after ultraviolet irradiation by FLONLIZER, a new-type sterilizer, at a flow rate of 82.5 to 364.8 liters/hr. When irradiated by FLONLIZER at a flow rate of under 324.0 liters/hr, no viable cells of legionellae, other heterotrophic bacteria and bacterivorous protozoa were detected in the cooling tower water, which was found to contain L. pneumophila. No viable cells of L. pneumophila and L. bozemanii suspended in sterile distilled water were detected after the irradiation with UV-doses of over 6.16 X 10(3) micro W.sec/cm2. At the irradiation of low UV-doses under 1.06 X 10(4) micro W.sec/cm2, the viable count of legionellae recuperated by photoreactivation from UV-damage increased with the exposure time under a white fluorescent lamp. However, in the samples irradiated with UV-doses of over 3.52 X 10(4) micro W.sec/cm2, equal to the FLONLIZER, legionellae did not recuperate even after 18 hr illumination with a white fluorescent lamp. FLONLIZER is thus expected to act as a sterilizer which can control the legionellae inhabiting cooling tower systems placed in outdoor space.