Discovery of small-molecule inhibitors of tyrosinase.
To identify novel inhibitors of tyrosinase, a fluorescent assay was developed which is suitable for high-throughput screening. In the assay, oxidation of the substrate by tyrosinase leads to the release of a fluorescent coumarin. Several small molecules were identified that inhibited mushroom tyrosinase in vitro and human tyrosinase in cell culture. These compounds may represent lead structures for therapies targeted at disorders of hyperpigmentation.


Algorithmic sequential decision-making in the frequency domain for life threatening ventricular arrhythmias and imitative artefacts: a diagnostic system.
A preliminary study to approach the problem of reliably detecting life threatening ventricular arrhythmias in real time is described. An algorithm (DIAGNOSIS) has been developed in order to classify ECG signal records on the basis of the computation of four simple parameters calculated from a representation in the frequency domain. This algorithm uses a set of rules constituting an operative classification scheme based on the comparison of the parameters with a set of pre-established thresholds. This allows us to differentiate four general categories: ventricular fibrillation-flutter, ventricular rhythms, imitative artefacts and predominant sinus rhythm.


[A rare metastatic manifestation of vulvar cancer--a case report].
A case of a solitary metastasis of a vulvar carcinoma we describe in the present paper. Anamnestic, a radical laser-vulvectomy with bilateral lymphonodectomy in 1986 (5 years ago) was carried out on account of a well differentiated squamous cell carcinoma (pT2 pN1 MX). The localization of this metastasis and the speed of progression under radiation therapy was very unusual.


Effect of lipopolysaccharide on the production of prostaglandin E2 and inhibition of uterine contractions by nitric oxide in pregnant inducible nitric oxide synthase knockout mice.
The aim of the present study was to evaluate the effect of lipopolysaccharide (LPS) on the production of prostaglandin E2 (PGE2) and inhibition by nitric oxide (NO) of spontaneous contractions of uterine rings from pregnant inducible isoform of nitric oxide synthase knockout (iNOS KO) mice. iNOS KO and wild-type mice were sacrificed 6 h after intraperitoneal (i.p.) administration of LPS on day 14 of gestation. Uterine rings were equilibrated in Krebs-Henseleit solution for isometric tension recording. In part of the uterine rings, placental tissues were left attached. The bathing solution was analyzed for PGE2 by radioimmunoassay. Changes in spontaneous contractions in response to cumulative concentrations of L-arginine, diethylamine/nitric oxide (DEA/NO), and 8-bromo-cyclic guanosine monophosphate (8-br-cGMP) were determined. Treatment with LPS increased PGE2 production by uterine rings from wild-type and iNOS-KO mice. DEA/NO and 8-br-cGMP inhibited spontaneous contractions in uterine rings in the absence or presence of placenta, in both LPS-treated and LPS-untreated animals. LPS treatment attenuated maximal inhibition induced by the agents, both in the absence and presence of placental tissues in iNOS KO and wild-type mice. LPS induces PG production in mice myometrium that is not dependent on the integrity of iNOS, while LPS could induce pathophysiological iNOS obstruct uterine quiescence by physiological iNOS. Infection affects uterine contractile activity through PG production, as well as through placental and genetic factors. NO may be a double-edged sword in pregnant mice myometrium.


Less is more in rural hospital staffing.
The concept of multidisciplinary staff members grew out of the manpower needs and financial limitations of rural hospitals, but the idea is now sparking new interest.


Nickel-catalyzed switchable 1,3-dienylation and enantioselective allenylation of phosphine oxides.
The development of general catalytic methods for the regio- and stereoselective construction of phosphoryl derivatives from identical substrates remains a formidable challenge in organic synthesis. Enabled by the newly developed BDPP-type ligands, we disclosed a nickel-catalyzed allenylation of phosphine oxides rationally and predictably, allowing the construction of versatile chiral allenylphosphoryl derivatives with high enantiopurity (up to 94% e.e.). Alternatively, using an achiral phosphine ligand dcypbz under acidic conditions, we achieved a regiochemical switch of the 1,3-dienylation to afford functionalized phosphinoyl 1,3-butadienes (up to 93% yield). The salient features of this method include switchable reactivity, broad substrate scope, readily available feedstock, single-step preparation, and high asymmetric induction.


School role in improving parenting skills and academic performance of secondary schools students in Pakistan.
This research investigated the association between school role in improving parenting skills and the academic performance of secondary school students. And to examine the role of student gender, literacy status of the parents and parental importance to children education in the association between school role in improving parenting skills and students' academic performance. A multistage stratified random sampling technique was adopted to portray information from 448 students on a Likert scale. Chi-square, Kendall's Tau-c tests were used to determine the direction and strength of association among variables. The results depicted that the association of children's academic performance was found significant (P = 0.000) and positive (Tau-c = 0.215) with school capacitating parents how to monitor and discuss schoolwork at home with children, assisting parents in setting academic goals for children (P = 0.000, Tau-c = 0.225). Moreover, the respondent's gender, parent literacy status and parental importance to children's education explained variation in the association between school role in improving parenting skills and children's academic performance. The school role in improving parenting skills significantly and positively contributed to children's academic performance. Moreover, boys, children of literate parents and children whose parents give more importance to their education with school active role in improving parenting skills were more liable to score higher grades.


Becky's legacy: personal and professional reflections on loss and hope.
The author, a psychologist who has been specializing in end-of-life issues for over a decade, uses the death of his fiancée (Becky), following the withdrawal of a ventilator and the refusal to place her back on the machine, to discuss research and analysis of end-of-life care in the United States. After briefly discussing his own background, Becky's history, and their relationship, he details Becky's last weeks of life and the first weeks of his grieving process. This story provides a background for discussing end-of-life issues including what constitutes a "good death," concerns about aggressive treatment and the cost of care near the end of life, prognosis, advance directives, and demographic issues. There is also a major section on psychosocial issues that arise when a person is dying. The author concludes with a set of "lessons learned" as a result of his relationship with Becky and going through the dying process with her and her family.


Knockdown of rno_circRNA_009194 Improves Outcomes in Traumatic Brain Injury Rats through Inhibiting Voltage-Gated Sodium Channel Nav1.3.
Excessive activation of voltage-gated sodium channel Nav1.3 has been recently reported in secondary traumatic brain injury (TBI). However, the molecular mechanisms underlying regulating voltage-gated sodium channel (Nav1.3) have not been well understood. The present study used a TBI rat model induced by a fluid percussion device and performed a circular RNA (circRNA) microarray (n = 3) to profile the altered circRNAs in the hippocampus after TBI. After polymerase chain reaction (PCR) validation, certain circRNAs were selected to investigate the function and mechanism in regulating Nav1.3 in the TBI rat model by intracerebroventricular injection with lentivirus. The neurological outcome was evaluated by Morris water maze test, modified Neurological Severity Score (mNSS), brain water content measurement, and hematoxylin and eosin staining. The related molecular mechanisms were explored with PCR, Western blotting, luciferase reporter, chromatin immunoprecipitation assay, and electrophoretic mobility shift assay (EMSA). A total of 347 circRNAs were observed to be differentially expressed (fold change [FC] ≥ 1.2 and p < 0.05) after TBI, including 234 up-regulated and 113 down-regulated circRNAs. Among 10 validated circRNAs, we selected circRNA_009194 with the maximized up-regulated fold change (n = 5, FC = 4.45, p < 0.001) for the in vivo functional experiments. Down-regulation of circRNA_009194 resulted in a 27.5% reduced mNSS in rat brain (n = 6, p < 0.01) after TBI and regulated the expression levels of miR-145-3p, Sp1, and Nav1.3, which was reversed by sh-miR-145-3p or Sp1/Nav1.3 overexpression (n = 5, p < 0.05). Mechanistically, circRNA_009194 might act as a sponge for miR-145-3p to regulate Sp1-mediated Nav1.3. This study demonstrated that circRNA_009194 knockdown could improve neurological outcomes in TBI in vivo by inhibiting Nav1.3, directly or indirectly.


Perforated inferior vena cava filters as the cause of unclear abdominal pain.
Inferior vena cava filters are considered a valuable therapeutic option in patients with deep vein thrombosis, subsequent pulmonary emboli, and contraindication for anticoagulation. However, these filters bear the risk of rare but serious complications (e.g., symptomatic caval perforation). We report our experiences with retrievable vena cava filters by means of an actual case and review the recent literature with special regard to filter-dependent delayed symptomatic vena cava perforations. Here, an inferior vena cava filter could be identified as the source of a patient's abdominal pain; after an interventional retrieval approach had failed, open surgical removal became necessary and led to the instant relief of this patient's symptoms. Retrievable vena cava filter removal should be performed in all cases as soon as no longer needed to avoid fatal complications.


The effects of fasting during Ramadan on glycemic excursions detected by continuous glucose monitoring system (CGMS) in patients with type 2 diabetes.
Safety of fasting in Ramadan for diabetic patients is not clearly known. The aim of this study was to determine the effects of fasting on glycemic excursions by continuous glucose monitoring system (CGMS). This pilot, observational study conducted in the Endocrine Research Center, Mashhad University of Medical Sciences, Mashhad, IRAN, in Ramadan 2008. Seventeen well controlled patients with diabetes type 2 who were taking oral agents underwent 72 hour monitoring of glycemic excursions by CGMS one month before Ramadan and during Ramadan. The extent and duration of hyperglycemic and hypoglycemic events were evaluated and compared. A significant reduction in hyperglycemic events was observed during Ramadan. The extent and duration of hypoglycemic events was not significantly different between two states (Ramadan and before). A significant increase in number of hypoglycemic events in Ramadan was found in patients who take sulfonylurea compared with those who take only metformin. Fasting in Ramadan can be safe for well controlled patients with type 2 diabetes.


Rivaroxaban prescribing in a Saudi tertiary care teaching hospital.
This drug utilization review (DUR) aimed to describe the use of rivaroxaban in a tertiary care teaching hospital and to audit the hospital physicians' prescribing practice. This study reviewed rivaroxaban prescriptions for patients admitted to a tertiary care teaching hospital in Riyadh, Saudi Arabia, between October 1, 2016 and January 15, 2017. It included all in-patients who received at least one dose of rivaroxaban, using data from the hospital's health information system (HIS). Appropriateness of prescribing was evaluated based on documented indication, dosing according to the patient's renal function for each approved indication, and restriction policy as per hospital department. During the study period, a total of 343 rivaroxaban prescriptions for 322 patients were identified. Overall, more than 56% of rivaroxaban prescriptions met at least one inappropriate criterion. Inappropriate dosing per patient's creatinine clearance (CrCl) was recognized in 42% of rivaroxaban prescriptions with the majority of these prescriptions issued for lower doses in 82.9% of prescriptions and non-approved indications identified in 14% of rivaroxaban prescriptions. The introduction of oral rivaroxaban represents a paradigm shift in anticoagulation management. Future longer, larger multi-center research is needed to identify the most effective interventions to enhance rivaroxaban knowledge translation and reduce the likelihood of inappropriate rivaroxaban prescribing and associated economic and side effects sequelae.


Identification of proximal left anterior descending artery stenosis with thallium-201 defect patterns in patients with angina pectoris.
We determined the accuracy of perfusion defect patterns in predicting the presence of proximal left anterior descending (LAD) artery stenosis in patients with angina pectoris. The development population consisted of 80 patients with single-vessel LAD stenosis and reversible LAD territory defects on thallium-201 tomography. The types of defect patterns associated with angiographic proximal LAD stenosis in this population were categorized as "proximal LAD patterns." The accuracy of these patterns for identifying proximal LAD stenosis was evaluated in a separate validation population of 152 patients with angina pectoris. The development population demonstrated LAD territory defects of type I (most of the LAD territory; n = 12); type II (apex, apicoanterior, and most of the septum; n = 26), type III (septum; n = 19); type IV (anteroseptum; n = 6); type V (apex; n = 10); and type VI patterns (anterolateral wall; n = 7). Patients with type I, II, and IV patterns were highly associated with proximal LAD stenosis (38 of 44 segments), whereas those with type III, V, and VI patterns were mostly related to distal LAD disease (29 of 36 segments). In the validation population, proximal LAD patterns had a sensitivity, specificity, and accuracy of 72%, 95%, and 91%, respectively, for identifying patients with proximal LAD stenosis. Test sensitivity was 86% when patients without LAD territory defects were excluded from analysis. Results were virtually identical in the subgroup of 84 patients with stable angina. Thus, recognition of LAD territory thallium defect patterns is useful for identifying patients with angina who are likely to have proximal LAD stenosis.


Retrospective study of laparoscopic versus open gastric resection for gastric gastrointestinal stromal tumors based on the propensity score matching method.
Surgical resection with a free margin is considered the gold standard for the treatment of gastric gastrointestinal stromal tumors (GISTs). Previous studies about the advantages of laparoscopic resection versus open surgery have generally been non-randomized and retrospective and have some obvious shortcomings that could influence the veracity and reliability of the results. Therefore, the aim of this study was to evaluate the efficacy of laparoscopic resection in the treatment of gastric GISTs using the propensity score matching (PSM) method. Between 2005 and 2014, 217 consecutive patients undergoing laparoscopic or open resection for gastric GISTs were enrolled in a retrospective, single-center study. Patient and tumor characteristics, intraoperative and postoperative characteristics, and oncologic outcomes were collected from a database. The efficacy of the laparoscopic approach was analyzed using the PSM method by comparing the clinical parameters of patients who underwent laparoscopic (LAP) and open resection (OPEN) procedures. After PSM, 88 patients involved in the analysis (44 LAP vs. 44 OPEN) were randomly matched (1:1) by tumor size, localization, disease course, body mass index, age, and gender. The LAP group was clearly superior to the open group in terms of intraoperative indicators and postoperative short-term efficacy. The incidence of postoperative complications in the LAP group was lower than in the OPEN group (4.5 vs. 18.2 %, P = 0.044). A survival analysis showed that there was no significant difference in the disease-free survival time between the two groups (χ 2 = 0.211, P = 0.646). These data should be processed using the PSM method in a non-randomized controlled trial (non-RCT) study. It is safe and feasible for patients with gastric GISTs up to 5 cm in size or located in the gastroesophageal junction to be treated with laparoscopic surgery.


Analysis of human terminal deoxynucleotidyl transferase cDNA expressible in mammalian cells.
Human Molt3 cDNA library was constructed using pcD vector system which permits the expression of cDNA inserts in mammalian cells. Nearly full-length human terminal deoxynucleotidyltransferase (TdT) cDNA was cloned using a fragment of bovine TdT cDNA as a probe. The human TdT cDNA contains an open reading frame of 1,557 bp coding for 519 amino acids, including 31 bp and 341 bp from 5' and 3' untranslated regions, respectively. The TdT cDNA was transfected into COS7 monkey fibroblasts directed the synthesis of enzymatically active protein of Mr 59,495. The cloned TdT cDNA hybridized with poly A+ RNAs of 2,100 b and 3,300 b from stable T-cell leukemia Molt3 and Molt4 cells.


Pancreatic tissue damage by transcatheter arterial embolization for hepatoma.
We analyzed the serial changes in serum pancreatic enzyme activities by transcatheter arterial embolization (TAE) in 20 hepatoma patients with liver cirrhosis in an attempt to evaluate the incidence of the pancreatic tissue damage by TAE. Serum amylase activities increased in two (10%) cases, elastase 1 levels in six (30%) cases, and trypsin and pancreatic secretory trypsin inhibitor (PSTI) levels in each of five (25%) cases. Consequently, TAE resulted in the elevation of at least more than one serum pancreatic enzyme in eight (40%) of 20 cases, although none had clinical symptoms related to pancreatitis. When the adverse effect on the pancreatic tissue was compared among 6 cases of the superselective TAE and 14 cases of the nonsuperselective TAE, which were performed from the segmental and the nonsegmental hepatic arteries, respectively, the elevation of serum pancreatic enzymes was caused only by nonsuperselective TAE, not by superselective TAE. The volumes of Spongel and Lipiodol used or the injected doses of the anticancer agent mitomycin C were not different between the two groups. These results indicate that TAE for the treatment of hepatoma frequently causes pancreatic tissue damage, and the position of the inserted catheter tip is very important to avoid the pancreatic tissue damage by TAE.


Pacemaker-mediated tachycardias: a new modality of treatment.
Three patients with pacemaker interactive drug resistant tachycardia underwent invasive electrophysiological studies. In the first patient, the retrograde conduction of the artificial reciprocating tachycardia was provided by two right-sided accessory pathways and the antegrade conduction by an atrial synchronous pulse generator. In addition, AV-nodal tachycardia occurred alternately. In the second patient with intermittent atrial flutter, the AV node and, coincidentally, an AV sequential pulse generator provided high-rate antegrade conduction to the ventricles. In the third patient with surgical complete heart block, intermittent AV-nodal tachycardia induced retrograde atrial activation while an atrial synchronous pacemaker provided the antegrade conduction. Electrode catheter exploration of the heart allowed localization and closed-chest ablation of the accessory pathways or AV node by delivering two to seven 200-joule direct-current shocks through the appropriate electrode of the exploring catheter. Thereby, pacemaker-mediated arrhythmias could be controlled in these patients in the follow-up of 6 to 8 months.


Delayed iris prolapse with unsutured 5.1 mm clear corneal incisions.
I describe two cases of iris prolapse after sutureless 5.1 mm clear corneal incision cataract surgery with implantation of a 5 mm poly(methyl methacrylate) lens. Both patients reported having exerted localized digital pressure on the globe peripheral to the temporally located incision. Following resection of the prolapse, the pupil was reconstructed in situ using a translimbal transfixation technique. The prolapse and other observed complications (e.g., transient pupillary capture, delayed endophthalmitis) indicate that 5.1 mm clear corneal incisions do not provide adequate stability if localized pressure is exerted peripheral to the wound. Thus, securing the incisions with a radial 10-0 nylon suture is strongly advocated to provide sufficient wound stability against deformation.


Predictors of mortality in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) has become a major and growing health problem, with a mortality rate that continues to increase. Several factors, have been identified as individual predictors of mortality in COPD. This article reviews individual predictors for mortality. It also discusses the ability of an integrated, multidimensional tool to more broadly characterize COPD severity, assess response to therapeutic interventions and exacerbations, and predict mortality.


Evaluation of gastroesophageal reflux disease following various reconstructive procedures for a distal gastrectomy.
Some patients develop gastroesophageal reflux disease (GERD) after a distal gastrectomy. In these patients, the evaluation of GERD with 24-h pH monitoring could be difficult because they may have an insufficient amount of gastric acid. To evaluate GERD following a distal gastrectomy, we retrospectively evaluated 38 patients postoperatively with an acid reflux test (ART), a barium study, endoscopy, and esophageal manometry. Three reconstructive procedures, Billroth I (B-I group: 14 patients), Billroth II (B-II group: 11 patients), and jejunal interposition (interposition group: 13 patients) were compared with respect to GERD and short- term operation results. Operation time and postoperative hospital stay were longest in the interposition group. Reflux symptoms were present in ten patients (26%). The ART, barium study and endoscopy demonstrated evidence of GERD in 22 (58%), 10 (26%) and 4 (11%) of the 38 patients, respectively. The frequency of a positive ART in the interposition group was significantly lower than in both the B-I and the B-II groups. The abdominal length of the lower esophageal sphincter in the interposition group was higher than that in the B-II group ( P<0.05). Although jejunal interposition required longer operation time and hospital stay, the lower esophageal sphincter function following jejunal interposition appears to be superior to that following a Billroth-I or Billroth-II procedure.


Non C-banding variants in some normal families might be homogeneously staining regions.
Three families are reported showing transmission of a previously described variant, which is not associated with any clinical abnormality. The variant involves additional material at the band 9p12, which shows homogeneous staining of intermediate density with GTL- and RBG-banding, and negative staining with CBG-banding. The region stains positively with Feulgen stain. In situ hybridization with total genomic human DNA, cloned alpha satellite, satellite III, and ribosomal DNA all show no hybridization to the 9p12 variant. Two members of one of the families show the largest 9p12 variant yet reported; two other carriers in this family have inherited a variant of decreased size. It is suggested that the 9p12 variants are homogeneously staining regions. Using the ISCN three-letter convention, this variant could be described as hsr(9)(p12).


Phosphorylation by actin kinase of the pointed end domain on the actin molecule.
Fragmin from plasmodium of Physarum polycephalum binds G-actin and severs F-actin in the presence of Ca2+ over 10(-6) M. The fragmin-actin complex consisting of fragmin and G-actin nucleates actin polymerization and caps the barbed (fast growing) end of F-actin, regardless of the concentrations of Ca2+, and the actin filaments are shortened. Actin kinase purified from plasmodium abolishes the nucleation and capping activities of the complex by phosphorylating actin of the fragmin-actin complex (Furuhashi, K., and Hatano, S. (1990) J. Cell. Biol. 111, 1081-1087). This inactivation of the complex leads to production of long actin filaments. We obtained evidence that Physarum actin is phosphorylated by actin kinase at Thr-201, and probably at Thr-202 and/or Thr-203, with 1 mol of phosphate distributed among them. This finding raises the possibility that the site of phosphorylation, Thr-201 to Thr-203, is positioned on the pointed (slow growing) end domain of the actin molecule, because growth of actin filaments from the fragmin-actin complex occurs only from the pointed end. These observations are consistent with a model of the three-dimensional structure of G-actin. Inactivation of the fragmen-actin complex may follow phosphorylation of the pointed end domain of actin.


Daily administration of the GIP-R antagonist (Pro3)GIP in streptozotocin-induced diabetes suggests that insulin-dependent mechanisms are critical to anti-obesity-diabetes actions of (Pro3)GIP.
Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro3)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in a streptozotocin (STZ)-induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro(3))GIP to STZ-treated mice. Swiss TO mice received once-daily injection of (Pro3)GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. (Pro3)GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro3)GIP. These effects were observed on an STZ-induced background characterized by severe reductions of circulating insulin, beta-cell mass and pancreatic insulin stores. These data indicate that the beneficial actions of the GIP-R antagonist, (Pro3)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation.


TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter.
As a lipid metabolic disorder, non-alcoholic fatty liver disease (NAFLD) is an important cause of cirrhosis and hepatocellular carcinoma, with no effective drug up to date. Previous studies have demonstrated increased methylation levels of key genes in NAFLD, suggesting that hydroxymethylation, a key step in demethylation, may be a possible strategy to reverse NAFLD. TET1 is well known as a key hydroxymethylase, however, its role and mechanism in NAFLD remains unclear. In this study, we utilized TET1 knockout mice, fed with high-fat diet. Furthermore, by ChIP and hMeDIP. TET1 knockdown L02 and HepG2 cell lines. Their degree of liver steatosis was more severe than that of wild-type mice, suggesting that TET1 had a significant protective effect against NAFLD. We further found that PPARα, a key regulator of fatty acid oxidation, and its downstream key enzymes ACOX1 and CPT1A, as well as the fatty acid oxidation product β-HB were significantly decreased in TET1 knockout mice. While the key genes for fatty acid synthesis and uptake were not significantly changed, suggesting that TET1 inhibits NAFLD by promoting fatty acid oxidation via PPARα pathway. TET1 was confirmed to directly bind to the promoter of PPARα and elevate its hydroxymethylation level. This study is the first to show that TET1 can activate PPARα, promote fatty acid oxidation and inhibit NAFLD progression by hydroxymethylation of PPARα promoter, which may be a new strategy to reverse NAFLD.


Appropriate Evaluation of Psychiatric Patients Highlighted by Creutzfeldt-Jakob Disease: A Case Report.
Determination of medical stability for patients presenting with psychiatric complaints is common for emergency clinicians. A thorough history and physical examination is important. A 53-year-old male presented to the emergency department (ED) with depression, suicidal ideation, and decline in activities of daily living over six months. While his initial neurologic examination was non-focal, subsequent re-evaluations demonstrated significant changes, and he was ultimately diagnosed with Creutzfeldt-Jakob disease. This case demonstrates how a detailed history of the present illness could have led to a more accurate and timely medical disposition from the ED.


Intracranial Aneurysms in the Context of Variant Cerebrovascular Anatomy: A Review of the Literature.
The cerebrovascular anatomy varies, with many associated variants and persistent channels. Many such vessels have been reported to carry an increased risk of intracranial aneurysm (IA) formation. We conducted a systematic literature review of IAs associated with variant anatomy. We performed a systematic review without a meta-analysis in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for studies involving IA formation in patients with variant anatomy. Studies were excluded if 1) the IAs were associated with malformations; 2) the variant anatomy discussed was in the form of segment hypoplasia or aplasia; 3) the anatomical variants were discussed secondary to the intervention; 4) insufficient information had been included; or 5) they were literature reviews. A total of 64 studies had met the inclusion and exclusion criteria for the final review. IA rupture was present in 91 of 131 cases (69.5%). Of the 131 IAs, 45 (34.3%) had been associated with an anomalous vessel origin or course, 43 with segmental fenestration (32.8%), 26 with a primitive persistent anastomosis (19.8%), and 17 with multiple or accessory vessels (12.9%). A total of 122 IAs (93.1%) had been treated with endovascular (64 of 122; 52.5%), microsurgical (57 of 122; 43.5%), or combined (1 of 122; 0.8%) methods. Variant, anomalous, and persistent primitive anatomy have often been reported in association with IA formation. These lesions present with a high proportion of rupture and warrant a low threshold for treatment. Preservation of perfusion is critical because such vessels developmentally exist to maintain flow.


Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer.
In a multicenter, prospectively randomized study we evaluated bacillus Calmette-Guérin alone vs bacillus Calmette-Guérin plus interferon α-2b and megadose vitamins vs recommended daily allowance vitamins during induction and maintenance intravesical therapy in the treatment of nonmuscle invasive bladder cancer. Patients who were bacillus Calmette-Guérin naïve with carcinoma in situ, Ta or T1 urothelial cancer were randomized to receive intravesical bacillus Calmette-Guérin or bacillus Calmette-Guérin plus interferon α-2b. Patients were further randomized to receive a recommended daily allowance or megadose vitamin preparation. Induction bacillus Calmette-Guérin treatment was given weekly for 6 weeks, and patients who were recurrence-free received maintenance treatment at 4, 7, 13, 19, 25 and 37 months. Patients were followed with quarterly cystoscopy for 2 years, then semiannually through year 4 and then annually. The primary end point was biopsy confirmed tumor recurrence or positive cytology. A total of 670 patients were accrued and randomized. At 24-month median followup recurrence-free survival was similar in all groups with 63% in the bacillus Calmette-Guérin with recommended daily allowance vitamins group, 59% in bacillus Calmette-Guérin with megadose vitamins, 55% in bacillus Calmette-Guérin/interferon α-2b with recommended daily allowance vitamins and 61% in bacillus Calmette-Guérin/interferon α-2b with megadose vitamins (p >0.05). The addition of interferon α-2b was associated with a more frequent incidence of fever (11% vs 5%) and constitutional symptoms (18% vs 11%) vs bacillus Calmette-Guérin alone (p <0.05). Interferon α-2b added to bacillus Calmette-Guérin induction and maintenance intravesical therapy did not decrease tumor recurrence in bacillus Calmette-Guérin naïve cases, but was associated with increased fever and constitutional symptoms. No difference in time to recurrence was present in patients receiving recommended daily allowance vs high dose vitamins.


Thiol-Stabilized Gold Nanoparticles: New Ways To Displace Thiol Layers Using Yttrium or Lanthanide Chlorides.
We use the aurophilic interactions shown by lanthanides to overcome the sulfur-gold interaction. UV-vis and X-ray photoelectron spectroscopy confirm that yttrium or lanthanide chlorides easily displace sulfur ligands from the surface of thiol-stabilized gold nanoparticles.


The Logical Case for Love as an Ingredient in Policy Formulation After COVID-19.
In the backdrop of the COVID-19 pandemic, which has already had disastrous public health and economic effects, but also resulted in the positive emotion of love as a spontaneous response at many levels, this article asks whether there is a need for the explicit inclusion of the emotion of love in policy formulation. It answers this affirmatively by first proposing, in Part I, what love should mean in policy formulation. However, as rationality remains highly prized in policy formulation, it considers emotion as prejudicial to its cool and level-headed processes and assumes that human behaviour is exclusively negative. To overcome this drawback, love is proposed for inclusion in policy formulation on the rationale that it is a real and positive emotion. Part II takes an eclectic approach and provides six examples of love's relevance drawn from hate studies, medicine, business, psychology, religion, and women's preferences. Together, they constitute a significant pattern and demonstrate love's versatility, making it relevant for those who formulate policy. Suggestions for policy applications are also made. While acknowledging that including love in policy formulation is not a panacea, this positive, universal, and resilient emotion should be incorporated in policy formulation to increase its effectiveness and relevance given the exceptional negativity of our times following COVID-19.


Systematic review of comparing single-incision versus conventional laparoscopic right hemicolectomy for right colon cancer.
Single-incision laparoscopic right hemicolectomy (SILS) has long used in surgery for a long time. However, there is barely a systemic review related to the comparison between the SILS and the conventional laparoscopic right hemicolectomy (CLS) for the right colon cancer in the long term follow-up. Herein, we used the most recent articles to compare these two techniques by meta-analysis. We searched PubMed, Web of Science, Cochrane Library and Wanfang databases to compare SILS with CLS for right colon cancer up to May 2019. The operative, postoperative, pathological and mid-term follow-up outcomes of nine studies were extracted and compared. A total of 1356 patients participated in 9 studies, while 653 patients were assigned to the SILS group and 703 patients were assigned to the CLS group. The patients' baselines in the SILS group were consistent with those in the CLS group. Compared to the CLS group, the SILS group had a shorter operation duration (SMD - 23.49, 95%CI - 36.71 to - 10.27, P < 0.001, chi-square = 24.11), shorter hospital stay (SMD - 0.76, 95% `CI - 1.07 to - 0.45, P < 0.001, chi-square = 9.85), less blood loss (SMD - 8.46, 95% CI - 14.59 to - 2.34; P < 0.05; chi-square = 2.26), smaller incision length (SMD - 1.60, 95% CI - 2.66 to - 0.55, P < 0.001; chi-square = 280.44), more lymph node harvested (SMD - 0.98, 95% CI - 1.79 to - 0.16, P < 0.05; chi-square = 4.61), and a longer proximal surgical edge (SMD - 0.51, 95% CI - 0.93 to - 0.09, P < 0.05; chi-square = 2.42). No significant difference was found in other indexes. After we removed a single large study, we performed another meta-analysis again. The operation duration in the SILS group was still better than that in the CLS group. SILS could be a faster and more reliable approach than CLS for the right colon cancer and could accelerate patient recovery, especially for patients with a low BMI.


First report of heavy metal presence in muscular tissue of loggerhead turtles Caretta caretta (Linnaeus, 1758) from the Balearic Sea (Balearic Islands, Spain).
The concentrations of cadmium (Cd), mercury (Hg) and lead (Pb) were determined in muscular tissue of eleven loggerhead turtles (Caretta caretta) from the Balearic Islands (Spain, Western Mediterranean). The metal levels found in the present study were similar or lower than concentrations detected in Andalusia (mainland Spain), Italy, Canary Islands (Spain) or Japan. As the main source of metals in the loggerhead turtle is the diet, low metal burdens could be explained by its opportunistic feeding way. No significant differences were found in metal concentrations between juveniles and subadults in any of the heavy metals analysed. Furthermore, no significant correlation was detected between heavy metal concentrations and straight carapace length (SCL) of the studied individuals. These results could derive from the homogeneity in age and size of the turtles sampled, so further studies including adults are needed in order to assess the heavy metal accumulation with turtle growth.


Growth rates and size at metamorphosis of high elevation populations of Ambystoma tigrinum.
The role of temperature in determining the alternative life history sequences in high elevation populations of Ambystoma tigrinum is given a physiological base. Growth rates of larval populations increase with increased average pond temperatures whereas sizes of the larvae at metamorphosis decrease with increased average pond temperatures. This results in a negative correlation between growth rate and size at metamorphosis for these populations. Data collected from naturally occurring populations and presented here are compatible with laboratory studies. The impact of temperature on the physiological processes of growth and metamorphosis substantiates the claim that temperature, rather than food abundance, determines the alternative life history sequences followed by high elevation populations of A. tigrinum.


3-Aminophenyl boronic acid-functionalized CuInS2 quantum dots as a near-infrared fluorescence probe for the determination of dopamine.
Water-soluble CuInS2 ternary quantum dots (QDs) capped by mercaptopropionic acid were directly synthesized in aqueous solution. Consequently, the CuInS2 QDs were covalently linked to 3-aminophenyl boronic acid molecules to form the 3-aminophenyl boronic acid-functionalized CuInS2 QDs (F-CuInS2 QDs). The F-CuInS2 QDs had a fairly symmetric fluorescence emission centered at 736nm that was in the near-infrared region (NIR). The F-CuInS2 QDs containing boronic acid functional groups were reactive toward vicinal diols to form five- or six-member cyclic esters in an alkaline aqueous solution. The reaction would cause the fluorescence quenching, which could be used as a fluorescence probe for the determination of dopamine (DA). This assay could also probe other vicinal diols such as catechol, pyrogallol, and gallate, based on the fluorescence quenching of the F-CuInS2 QDs, and this assay was nearly unaffected by other phenol compounds such as phenol, resorcinol, and hydroquinone without the vicinal diol structures. The developed F-CuInS2 QDs were applied to the detection of DA in human serum samples with satisfactory results. Therefore, this experment provided a simple and sensitve NIR fluorescence probe for the detection of DA, catechol, pyrogallol, and gallate.


The history of atrial fibrillation: the last 100 years.
Atrial fibrillation (AF) has had a rich history that has touched the careers of many of the great clinicians and investigators of the 20th century. More recently, there has been an explosion of research into various aspects of the mechanisms and therapy for AF, as evidenced by over 8,000 publications on AF from 2000 to 2007. A century of research and clinical observations, coupled with modern investigative technologies, has enabled modern investigators to have their own "fantastic voyage" as they travel beyond the cell borders into the ionic mechanisms responsible for AF and its many atrial perturbations. One can only imagine the satisfaction of Wenckebach, MacKenzie, and Lewis if they could see how their seeds of wisdom have grown into such sturdy ideas, or how delighted Scherf would be to learn that his ectopic focus theory for AF has been given new life. This paper on 100 years of AF was initially prepared for presentation as the Plenary Lecture at the AFib Summit for Heart Rhythm 2007 in Denver, Colorado. I have tried to provide the reader with some of the most important observations on AF, realizing that it would be impossible to include all or even most of the major research done during this time frame. I apologize to my many colleagues whose research has helped us to understand better the clinical and basic aspects of AF, yet who could not be cited for lack of space.


N-acetyltransferase 10 promotes cutaneous wound repair via the NF-κB-IL-6 axis.
Cutaneous wound healing, an integral part for protection of skin barrier, is a complex biological process and intimately associated with keratinocyte migration. However, mechanisms regulating keratinocyte migration in the process of cutaneous wound repair remain largely unknown. Here, we found that N-acetyltransferase 10 (NAT10) is essential for cutaneous wound repair in an in vivo skin wound healing model-a significant delay of wound repair in Nat10 haploinsufficient mice and a remarkable inhibition of keratinocyte migration by NAT10 knockdown in an in vitro keratinocyte migration model. We further demonstrate that loss of NAT10 expression attenuates the wound-induced IL-6/IL-8 expression through inhibiting NF-κB/p65 activity in keratinocytes. By deeply digging, silencing NAT10 compromises the level of nuclear p65 by facilitating its poly-ubiquitination, thus accelerates its degradation in the nucleus. Notably, we detected a strong positive correlation between the expression of NAT10 and relevant NF-kB/p65-IL6 signaling activity in mouse wound skin tissues. Overall, our study reveals an important role of NAT10 on cutaneous wound repair by potentiating NF-κB/p65-IL-6/8-STAT3 signaling. Targeting NAT10 might be a potential strategy for the treatment of skin wound dysfunctions and related diseases.


Effects of cyanide and uncouplers on chemoreceptor activity and ATP content of the cat carotid body.
In cat carotid bodies (c.b.'s) incubated in vitro with [3H]tyrosine to label the stores of catecholamines, it was found that CN promotes dose- and Ca2+-dependent release of [3H]dopamine (DA) from c.b. tissues in parallel to the increased electrical activity recorded from the carotid sinus nerve (c.s.n.). Two different uncouplers, dinitrophenol (DNP) and carbonyl-cyanide-m-chlorophenyl-hydrazone (CCCP), both activate also in a dose-dependent fashion, release of DA and electrical activity in the c.s.n. However, while cyanide (CN) (10(-4) M) applied during 5 min reduced the adenosine triphosphate (ATP) content of the c.b. by 45%, DNP (2.5 x 10(-4) M) and CCCP (10(-6) M) applied for the same period of time did not modify the ATP levels of the organ. At the above concentrations, the 3 agents increased about 8-fold the electrical activity recorded from the c.s.n. Thus, contrary to the postulates of the metabolic hypotheses, our findings indicate that the decrease in the ATP content in the c.b. is not a prerequisite for the activation of the chemoreceptors. We propose alternative mechanisms to explain the chemostimulant action of the metabolic poisons.


Life cycle assessment of fuel ethanol derived from corn grain via dry milling.
Life cycle analysis enables to investigate environmental performance of fuel ethanol used in an E10 fueled compact passenger vehicle. Ethanol is derived from corn grain via dry milling. This type of analysis is an important component for identifying practices that will help to ensure that a renewable fuel, such as ethanol, may be produced in a sustainable manner. Based on data from eight counties in seven Corn Belt states as corn farming sites, we show ethanol derived from corn grain as E10 fuel would reduce nonrenewable energy and greenhouse gas emissions, but would increase acidification, eutrophication and photochemical smog, compared to using gasoline as liquid fuel. The ethanol fuel systems considered in this study offer economic benefits, namely more money returned to society than the investment for producing ethanol. The environmental performance of ethanol fuel system varies significantly with corn farming sites because of different crop management practices, soil properties, and climatic conditions. The dominant factor determining most environmental impacts considered here (i.e., greenhouse gas emissions, acidification, eutrophication, and photochemical smog formation) is soil related nitrogen losses (e.g., N2O, NOx, and NO3-). The sources of soil nitrogen include nitrogen fertilizer, crop residues, and air deposition. Nitrogen fertilizer is probably the primary source. Simulations using an agro-ecosystem model predict that planting winter cover crops would reduce soil nitrogen losses and increase soil organic carbon levels, thereby greatly improving the environmental performance of the ethanol fuel system.


Evidence for the presence of cholinergic nerves in cerebral arteries: an immunohistochemical demonstration of choline acetyltransferase.
The presence of cholinergic nerves in cerebral arteries of several species was investigated by an immunohistochemical method using antibodies against choline acetyltransferase (ChAT). In cats, pigs, rats, and dogs, ChAT immunoreactivities were found to be associated with large bundles and single fibers in the circle of Willis and anterior cerebral, middle cerebral, and basilar arteries. In the rabbit, the ChAT-immunoreactive (ChAT-I) nerves were also observed in the circle of Willis and anterior and middle cerebral arteries, but only few or none were found in the basilar and vertebral arteries. The ChAT-I nerves were found only in the adventitial layer of vessels examined. Superior cervical ganglionectomy did not appreciably affect the distribution of ChAT-I nerves. These results indicate the presence of cholinergic nerves in cerebral arteries. The distribution pattern of ChAT-I nerves was different from that of vasoactive intestinal polypeptide (VIP)-like-immunoreactive nerves and acetylcholinesterase-positive nerves. The possible coexistence of ChAT and VIP-like substance in the same neuron is discussed.


Surface structure of spermatozoa frozen for artificial insemination.
Samples of human semen frozen in liquid nitrogen ( - 196 degrees C) with no glycerol, 5 and 10% glycerol were compared with samples that were untreated, with 10% glycerol but not frozen, and spermatozoa frozen at -20 degrees C. SEM and TEM of the samples indicates that 10% glycerol caused fewer surface changes of the spermatozoa than other treatments. Motility counts after the various freezing treatments were also highest when 10% glycerol was used as the cryoprotectant. Nonetheless, cryopreservation is detrimental to spermatozoa and often causes considerable damage to the acrosome with a leakage of the acrosomal contents.


Minimally invasive retrocapital osteotomy of the first metatarsal in hallux valgus deformity.
Percutaneous retrocapital distal osteotomy of the first metatarsal for surgical treatment of hallux valgus. Mild to moderate hallux valgus deformity in both juveniles and adults. Recurrent hallux valgus deformity after previous surgery. Severe degenerative changes of the first metatarsophalangeal joint (hallux valgus et rigidus). Previous Keller's procedure. A percutaneous distal linear osteotomy of the first metatarsal is performed and stabilized with a Kirschner wire. The surgical technique follows these steps: distal Kirschner wire insertion; skin incision; sparse periosteal detachment; distal retrocapital osteotomy of the first metatarsal; correction of the first intermetatarsal angle by lateral displacement of the capital fragment; stabilization with Kischner wire insertion into the proximal metatarsal; postoperative taping. The patients were satisfied following 107 (91%) of 118 consecutive percutaneous procedures with a follow-up of 35.9 months (range 24-78 months). According to the American Orthopaedic Foot and Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale for the clinical assessment, a mean score of 88.2 +/- 12.9 was obtained at follow-up. The clinical results can be compared to those obtained with open techniques, with the advantages of a minimally invasive procedure.


Risk factors for postictal generalized EEG suppression in generalized convulsive seizure: A systematic review and meta-analysis.
Postictal generalized EEG suppression (PGES) has been suggested as a pathophysiological hallmark for sudden unexpected death in epilepsy (SUDEP). We aimed to characterize the clinical determinants for PGES occurrence after generalized convulsive seizures (GCS). We systematically searched Pubmed, Embase and Medline databases up to 30 August 2021. Eligibility screening, data extraction, and quality assessment of the retrieved articles were conducted by two independent reviewers. Studies reporting potential risk factors of PGES occurrence in GCS were included for subsequent meta-analysis and PGES was defined as a generalized EEG attenuation of any duration >1s below 10μV, immediately or within 30s after an ictal EEG pattern has terminated. A fixed-effects model was applied when the heterogeneity is low (I2 values < 50%). Otherwise, a random-effects model was used (I2 values ≥ 50%). We assessed the odds ratio (OR) as outcome measure for dichotomous variables and the STD Mean Difference (SMD) for continuous variables. The Begg test and the Egger test was applied in the assessment of publication bias. A total of 15 relevant studies were identified, enrolling 2057 GCSs. The incidence of PGES in GCS from 15 studies varied from 23% to 86%. The longer tonic phase duration (SMD, 0.26; 95%CI, 0.13 to 0.39; p < 0.001), sleep state at GCS onset (OR,1.63; 95%CI, 1.24 to 2.16; p = 0.001), older age of epilepsy onset (SMD, 0.48; 95%CI, 0.21 to 0.75; p = 0.001), the presence of postictal immobility (OR, 78.05; 95%CI, 32.31 to 188.53; p < 0.001) and oxygen desaturation nadir (SMD, -0.54; 95%CI, -0.76 to -0.33; p < 0.001) showed significant association with the likelihood of having PGES in GCS, but not total seizure duration (SMD, -0.06; 95%CI, -0.20 to 0.08; p = 0.385), tonic-clonic duration (SMD, -0.12; 95%CI, -0.26 to 0.01; p = 0.071), clonic phase duration (SMD, -0.09; 95%CI, -0.27 to 0.08; p = 0.293), epilepsy duration of patients (SMD, -0.09; 95%CI, -0.27 to 0.08; p = 0.293) or lack of early O2 administration (OR, 1.59; 95%CI, 0.80 to 3.17; p = 0.184). The current study informed that PGES is common after GCS. Early identification should be considered among individuals with GCS at high risk of PGES through clinical screening. Further studies with larger sample size are required for individualized evaluation of the risk of PGES in GCS and more effort is needed to further evaluate the risk of SUDEP.


Distinguished prognosis after hepatectomy of HBV-related hepatocellular carcinoma with or without cirrhosis: a long-term follow-up analysis.
Conflicting results have often been observed for the prognosis of hepatocellular carcinoma (HCC) patients, but few studies have attempted to explore the reasons for the conflicting results. We aimed to distinguish the prognosis of patients with HCC with cirrhosis (HCC-C) and that of patients with HCC without cirrhosis (HCC-NC). Patients with hepatitis B virus (HBV)-associated HCC treated by curative liver resection at a single institution between 1995 and 2013 were retrospectively evaluated. Kaplan-Meier and multivariate analyses were performed to identify risk factors, including tumor-related factors, hypoxia-inducible factor 1α expression, HBV X protein (HBx) expression, and HBx double mutations for overall survival and recurrence-free survival in these patients. The long-term prognosis of HCC-NC patients is better than that of HCC-C patients. Male sex, poor differentiation, preoperative serum alanine aminotransferase level greater than 80 IU/L, and α-fetoprotein level greater than 400 ng/mL were risk factors for overall survival among HCC-NC patients but not among HCC-C patients, and age greater than 50 years was associated with poor overall survival only in cirrhotic patients. HCC-C patients benefit more from antiviral therapy following curative hepatectomy than do HCC-NC patients. The clinical value of the biomarkers hypoxia-inducible factor 1α, HBx, and HBx double mutations for predicting HCC prognosis was significantly different between these two groups. There were differences in tumor-related prognostic factors, effectiveness of the antiviral therapy after hepatectomy, and biomarkers between HCC-C and HCC-NC patients, indicating that subgroup analysis of the prognostic factors may result in better management of HCC and that HCC patients, especially those with liver cirrhosis, should be given antiviral therapy.


The contribution of exbB gene to pathogenicity of Pseudomonas plecoglossicida and its interactions with Epinephelus coioides.
To study the roles of the exbB gene in Pseudomonas plecoglossicida during interactions with Epinephelus coioides, five short hairpin RNAs (shRNAs) were designed and synthesized to silence the exbB gene in P. plecoglossicida which resulted in significant reductions in exbB mRNA expression. The mutant with the best silencing efficiency (89.3%) was selected for further study. Silencing exbB in the exbB-RNA interference (RNAi) strain resulted in a 70% increase in the survival rate and a 3-day delay in the onset of infection in E. coioides. Silencing of the exbB gene also resulted in a significant decrease in the number of white spots on the spleen surface and in the spleen pathogen load. The results of dual RNA-seq showed that exbB silencing in P. plecoglossicida also resulted in a significant change in both the pathogen and host transcriptomes in the spleens of infected E. coioides. Comparative transcriptome analysis showed that silencing exbB caused significant changes in multiple signaling molecules and interaction- and immune system-related genes in E. coioides. Gene silencing also resulted in the differential expression of flagellar assembly and the bacterial secretion system in P. plecoglossicida during the infection period, and most of the DEGs were down-regulation. These host-pathogen interactions may make it easier for E. coioides to eliminate the exbB-RNAi strain of P. plecoglossicida, suggesting a significant decrease in the pathogenicity of this strain. These results indicated that exbB was a virulence gene of P. plecoglossicida which contributed a lot in the pathogen-host interactions with E. coioides.


Primary chemotherapy in the treatment of rhabdomyosarcoma in children: trial of the International Society of Pediatric Oncology (SIOP) preliminary results.
This therapeutic trial deals with 81 patients with stage III rhabdomyosarcoma (RMS), from different centers of the International Society of Pediatric Oncology. These patients were included between October 1975 and March 1983. The aim of this work is to minimize the sequelae of treatment without jeopardizing the survival rate. After a pretrial course of VAC, two groups of patients are compared: the first treated with systematic extensive surgery or radiotherapy on the initial tumor volume, and the second treated with combined chemotherapy using vincristine, dactinomycin, adriamycin, cyclophosphamide until maximum tumor reduction, followed by radiotherapy or surgery on the residual mass only. Eighty one patients were included in the trail; 15 patients were not randomized due to the failure of the pretrial course of chemotherapy, 3 were excluded after randomization (2 were found not to have RMS, and in one case the protocol was not observed). The preliminary results for the 63 patients show a survival rate of 40% at 3 years. The sequential scheme for patients at 3 years follow-up does not show a superiority in either arm.


An academic perspective of participation in healthcare redesign.
Healthcare redesign, based on building collaborative capacity between academic and clinical partners, should create a method to facilitate flow between the key elements of health service improvement. However, utilising the skills and resources of an organisation outside of the health facility may not always have the desired effect. Accountability and mutually respectful relationships are fundamental for collaborative, sustainable and successful completion of clinical research projects. This paper provides an academic perspective of both the benefits of academic involvement in facilitating healthcare redesign processes as well as the potential pitfalls of involving external partner institutions in internal healthcare redesign projects.


RNA sequencing provides evidence for allelism of determinants of the N-, B- or NB-tropism of murine leukemia viruses.
Previous genetic and biochemical studies identified three large RNAase T1-resistant oligonucleotides, each associated with either the N-, B- or NB-tropism of murine C-type viruses of BALB/c origin. These oligonucleotides were shown to lie in the 5' third of the oligonucleotide maps of their respective viruses. We sequenced the three oligonucleotides and found that they share a 10 base sequence. Together these observations provide good evidence that the determinants of N-, B- or NB-tropism monitored by the three oligonucleotides are allelic. The oligonucleotides associated with N- and B-tropism differ in sequence at four of sixteen nucleotides, while the B- and NB-tropism-associated oligonucleotides differ in sequence by only one base out of sixteen. These results are consistent with the possibilities that B-tropic viruses may arise from N-tropic viruses by recombination, while NB-tropic viruses may arise from B-tropic virus by mutation. An unexplained finding was that a 10 base sequence present in the oligonucleotide associated with N-tropism is also found in the 3' third of the genomes of the N-, B- and NB-tropic viruses studied.


Combination of TREF, high-temperature HPLC, FTIR and HPer DSC for the comprehensive analysis of complex polypropylene copolymers.
A novel, powerful analytical technique, preparative temperature rising elution fractionation (prep TREF)/high-temperature (HT)-HPLC/Fourier transform infrared spectroscopy (FTIR)/high-performance differential scanning calorimetry (HPer DSC)), has been introduced to study the correlation between the polymer chain microstructure and the thermal behaviour of various components in a complex impact polypropylene copolymer (IPC). For the comprehensive analysis of this complex material, in a first step, prep TREF is used to produce less complex but still heterogeneous fractions. These chemically heterogeneous fractions are completely separated by using a highly selective chromatographic separation method--high-temperature solvent gradient HPLC. The detailed structural and thermal analysis of the HPLC fractions was conducted by offline coupling of HT-HPLC with FTIR spectroscopy and a novel DSC method--HPer DSC. Three chemically different components were identified in the mid-elution temperature TREF fractions. For the first component, identified as isotactic polypropylene homopolymer by FTIR, the macromolecular chain length is found to be an important factor affecting the melting and crystallisation behaviour. The second component relates to ethylene-propylene copolymer molecules with varying ethylene monomer distributions and propylene tacticity distributions. For the polyethylene component (last eluting component in all semi-crystalline TREF fractions), it was found that branching produced defects in the long crystallisable ethylene sequences that affected the thermal properties. The different species exhibit distinctively different melting and crystallisation behaviour, as documented by HPer DSC. Using this novel approach of hyphenated techniques, the chain structure and melting and crystallisation behaviour of different components in a complex copolymer were investigated systematically.


Formation of ethyl ferulate by rice koji enzyme in sake and mirin mash conditions.
Formation mechanism of ethyl ferulate (EF) in sake and mirin mash conditions was investigated to understand EF level control in the manufacturing process. Rice koji formed EF from ferulic acid (FA) and ethanol and decomposed EF to FA. This did not occur in sake yeast and chemical esterification was rare. Esterification of FA and hydrolysis of EF by rice koji might be due to feruloyl esterase(s). The rice koji enzyme showed normal Michaelis-Menten kinetics for FA in ethyl esterification and for EF in hydrolysis, but not for ethanol in the esterification reaction. Substrate specificity of the rice koji enzyme for hydroxycinnamic acids suggested that the main enzyme involved might be similar to type A feruloyl esterase. We studied the rice koji enzyme properties, short-term digestion of steamed rice grains with exogenous ethanol and small scale mirin making with pH adjustment. Our results suggested differences in the esterification and hydrolysis properties of the enzyme, in particular, different pH dependencies and different behaviors under high ethanol conditions; these factors might cause the differing EF levels in sake and mirin mashes.


Factors influencing [F-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) uptake in melanoma cells: the role of proliferation rate, viability, glucose transporter expression and hexokinase activity.
Using human (SK-MEL 23, SK-MEL 24 and G361) and murine (B16) melanoma cell lines, the coregulatory potential of the uptake of the positron emission tomography (PET) tracer, [Fluorine-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) has been investigated in relationship to tumor characteristics. Comparative studies among the four melanoma cell lines demonstrated that the lowest FDG uptake in SK-MEL 24 corresponded strongly to the data for DT (population doubling time) and MTT (tetrazolium salt) cell viability as well as hexokinase (HK) activity, but was not related to the glucose transporter 1 (GLUT 1) expression level. Furthermore, the FDG uptake in each melanoma cell line measured by cell cycle kinetics was significantly positively correlated to both the proliferation index (PI=S/G2M phase fractions) and the cell viability, though with one exception relating to the PI of the lowest FDG uptake cell line, SK-MEL 24. No positive correlation was found between the expression of GLUT 1 and FDG uptake in any individual cell line. However, the HK activities in SK-MEL 23 and 24 showed considerable positive relationships with FDG uptake. Our present study suggests that both the proliferation rate and the cell viability of melanoma cells may be key factors for FDG uptake and that HK activity, rather than GLUT 1 expression, seems to be a major factor.


Synthesis of new 1,3,4-benzotriazepin-5-one derivatives and their biological evaluation as antitumor agents.
New derivatives of 1,3,4-benzotriazepin-5-one were designed and synthesized as structural analogues to the antitumor agents devazepide and asperlicin. An efficient and novel approach to the synthesis of 2-amino-1,3,4-benzotriazepin-5-one 2 was developed and its structure was confirmed. The newly synthesized derivatives were evaluated for their in vitro antitumor activity on 60 different cell lines. Compounds 8 and 9 displayed the most potent antitumor activity against several cell lines specifically ovarian cancer, renal cancer and prostate cancer, while compounds 5, 10 and 12 showed significant activities against UO-31 renal cancer cell line.


Protein phosphatase inhibitors induce the sustained expression of the Egr-1 gene and the hyperphosphorylation of its gene product.
The immediate-early gene Egr-1 is strongly and rapidly induced in human and mouse Balb/c fibroblasts by okadaic acid and calyculin A, both specific inhibitors of protein serine/threonine phosphatases 1 and 2A. In contrast to the transient induction of the Egr-1 gene by serum or phorbol 12-myristate 13-acetate, these phosphatase inhibitors stimulated a sustained induction of the Egr-1 gene. The induction is shown to occur transcriptionally and is sustained post-transcriptionally. Okadaic acid-induced Egr-1 mRNA is significantly more stable than serum-induced Egr-1 mRNA. The half-life of serum-induced Egr-1 mRNA is estimated to be 12 min, compared with a half life of 2 h for okadaic acid-induced Egr-1 mRNA. Okadaic acid also induced the expression of the related immediate-early genes Egr-2 and Egr-3 albeit to a lesser extent than Egr-1. Treatment of cells with okadaic acid and calyculin A also induced the synthesis of Egr-1 protein. The Egr-1 protein is weakly or not phosphorylated in quiescent cells, but multiple species of the phosphorylated forms of the Egr-1 protein are detected in cells treated with either of the phosphatase inhibitors. Simultaneous treatment of cells with TPA and okadaic acid synergistically induced Egr-1 gene expression, and H7 strongly inhibits this induction. Taken together, the results indicate that the induction of Egr-1 gene transcription and the phosphorylation of the induced Egr-1 protein are under the control of protein kinase(s) and protein phosphatase(s). The phosphorylation and dephosphorylation of Egr-1 protein may play a role in controlling cell growth.


First-order curvature corrections to the surface tension of multicomponent systems.
The dependence of surface tension on curvature is investigated for the case of an equilibrium phase coexistence in multicomponent systems. Employing Gibbs's method of description of heterogeneous systems, an equation is derived to determine the dependence of surface tension on curvature for widely arbitrary paths of variation of the independent thermodynamic parameters. It is supposed hereby merely that the temperature is kept constant and that the variations of the different molar fractions are such that the radius of the dividing surface varies monotonically in dependence on the change of the state parameters of the ambient phase along any of the chosen paths. In the analysis, an approach developed by Blokhuis and Bedeaux for one-component systems is utilized. It relies on the expansion of the surface free energy on curvature of the dividing surface. An equation is derived that connects the first-order correction term in the expansion with the interaction potential of the particles in the multicomponent solution and with the two-particle distribution functions in the planar interfacial layer between the two phases coexisting in equilibrium at planar interfaces. The connection of the first-order curvature correction to the surface tension and the first moment of the pressure tensor at a planar interface is analyzed as well.


Immunoplasticity--triggers of regulatory function.
Regulatory T cells (Tregs) as key players of the immune system are exposed to numerous triggers including exogenous and endogenous factors. Autonomous nerve activity, melatonin, hormones such as vitamin D and glucocorticoids as well as the exposure to sunlight and microorganisms shape our immunological profile. The complexity of this system is highlighted by the power of each single trigger but more impressive by influencing each others function and potentials directly and indirectly. However, while monocausal correlations of single triggers on Tregs have been studied at length, there is much less known about the impact of numerous coexistent triggers on the dynamics of Treg activity. It can be hypothesized that the dynamics of Treg activity plays a crucial role for the control of our immune system. Therefore it is of the utmost importance that a new translational, multi- and interdisciplinary approach finds its way into future research efforts, which should lead to a more comprehensive and holistic view on the complex immunoregulatory mechanisms and to act in the sense of public health.


Investigation of 2D and 3D electrospun scaffolds intended for tendon repair.
Two-dimensional (2D) electrospun fibre mats have been investigated as fibrous sheets intended as biomaterials scaffolds for tissue repair. It is recognised that tissues are three-dimensional (3D) structures and that optimisation of the fabrication process should include both 2D and 3D scaffolds. Understanding the relative merits of the architecture of 2D and 3D scaffolds for tendon repair is required. This study investigated three different electrospun scaffolds based on poly(ε-caprolactone) fibres intended for repair of injured tendons, referred to as; 2D random sheet, 2D aligned sheet and 3D bundles. 2D aligned fibres and 3D bundles mimicked the parallel arrangement of collagen fibres in natural tendon and 3D bundles further replicated the tertiary layer of a tendon's hierarchical configuration. 3D bundles demonstrated greatest tensile properties, being significantly stronger and stiffer than 2D aligned and 2D random fibres. All scaffolds supported adhesion and proliferation of tendon fibroblasts. Furthermore, 2D aligned sheets and 3D bundles allowed guidance of the cells into a parallel, longitudinal arrangement, which is similar to tendon cells in the native tissue. With their superior physical properties and ability to better replicate tendon tissue, the 3D electrospun scaffolds warrant greater investigation as synthetic grafts in tendon repair.


Fluid and electrolyte balance: the impact of goal directed teaching.
We aimed to determine if a structured workshop on fluid and electrolyte balance for junior surgical trainees led to an improvement in knowledge on the subject and to evaluate the perceived helpfulness of such a workshop. Surgical trainees attended an interactive lecture-based workshop on fluid and electrolyte balance. Participants had online access to the presentation prior to the training event. They completed a multiple choice question (MCQ) test, derived from topics covered in the presentation, prior to the lecture. The MCQ test was repeated after the lecture to assess retention and application of knowledge. Participants were unaware that they would be tested and provided written feedback on their perceptions of the session. Thirty-seven trainees from speciality training years 1 and 2 participated in the workshop. There was a significant improvement in mean test scores after the lecture when compared with pre-lecture scores (24.6/30 vs. 19.7/30, p<0.001). Trainees felt the topic and event were relevant to everyday practice (mean score 4.9/5) and that it would improve their clinical skills (4.5/5). The provision of a dedicated fluid and electrolyte physiology interactive workshop to postgraduate trainees is a successful way of tackling current inadequacies in training.


Tetanus and botulinum neurotoxins: turning bad guys into good by research.
The neuroparalytic syndromes of tetanus and botulism are caused by neurotoxins produced by bacteria of the genus Clostridium. They are 150 kDa proteins consisting of three-domains, endowed with different functions: neurospecific binding, membrane translocation and specific proteolysis of three key components of the neuroexocytosis apparatus. After binding to the presynaptic membrane of motoneurons, tetanus neurotoxin (TeNT) is internalized and transported retroaxonally to the spinal cord, where it blocks neurotransmitter release from spinal inhibitory interneurons. In contrast, the seven botulinum neurotoxins (BoNT) act at the periphery and inhibit acetylcholine release from peripheral cholinergic nerve terminals. TeNT and BoNT-B, -D, -F and -G cleave specifically at single but different peptide bonds, VAMP/synaptobrevin, a membrane protein of small synaptic vesicles. BoNT types -A, -C and -E cleave SNAP-25 at different sites within the COOH-terminus, whereas BoNT-C also cleaves syntaxin. BoNTs are increasingly used in medicine for the treatment of human diseases characterized by hyperfunction of cholinergic terminals.


Synthetic genome recoding: new genetic codes for new features.
Full genome recoding, or rewriting codon meaning, through chemical synthesis of entire bacterial chromosomes has become feasible in the past several years. Recoding an organism can impart new properties including non-natural amino acid incorporation, virus resistance, and biocontainment. The estimated cost of construction that includes DNA synthesis, assembly by recombination, and troubleshooting, is now comparable to costs of early stage development of drugs or other high-tech products. Here, we discuss several recently published assembly methods and provide some thoughts on the future, including how synthetic efforts might benefit from the analysis of natural recoding processes and organisms that use alternative genetic codes.


Properties and regulation of human platelet cation channels.
The stimulation of calcium influx by various human platelet agonists which differ in their activation pathways was investigated. ADP activates a receptor-operated cation channel (ROC) and stimulates a phospholipase C (PLC)/inositol-trisphosphate (IP3)-mediated calcium mobilization associated with a secondary calcium influx. Thrombin only stimulates the PLC/IP3-mediated calcium mobilization and associated calcium influx, perhaps followed by an additional phase of calcium influx. The platelet calcium response after incubation with the thromboxane A2 mimetic U 46619 is similar but more transient compared to that after thrombin stimulation. Tert-butylhydroquinone (an inhibitor of endoplasmatic reticulum Ca(2+)-ATPases and cyclooxygenase) elevates cytosolic calcium levels by emptying intracellular calcium stores and stimulates a biphasic calcium influx. Activation of platelet cAMP- and cGMP-dependent protein kinases inhibits the ADP- and thrombin-evoked, calcium store-associated cation influx, but not the fast receptor operated cation influx induced by ADP. Experiments with various ADP-analogs, ATP and ATP-gamma-S suggest that two different ADP-receptors may mediate the calcium responses in human platelets.


Cerebrovascular disorders in children.
Cerebrovascular disorders are an important cause of mortality and chronic morbidity in children. International incidence rates for childhood stroke (ie, from 30 days to 18 years of age) have ranged from 1.3 to 13 per 100,000 children. Ischemic stroke is probably more common than hemorrhagic stroke in children. The clinical presentation of stroke in children varies according to age and location of the stroke. Over 100 risk factors for stroke in children have been reported, but in up to one third of cases no cause is identified. The management and prevention of stroke in children is not well studied and current recommendations are based on adult studies, nonrandomized trials, or expert opinion. Over half of children with stroke will develop lifelong cognitive or motor disability and up to one third will have a recurrent stroke. This review briefly describes the epidemiology, risk factors, evaluation, treatment, and outcome of stroke in children.


A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1.
Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one. Two patients out of 41 (4.9%) experienced transplant-related mortality. CD34 selection was discontinued after subjects were enrolled due to serious viral illness. From the time of study enrollment, the overall 3-year EFS and OS were 44.8 ± 9.6% and 59.2 ± 9.2% (N=41). These results demonstrate that tandem transplantation in the cooperative group setting is feasible and support a randomized comparison of single vs tandem myeloablative consolidation with PBSC support for high-risk neuroblastoma.


Multiple objects tracking in fluorescence microscopy.
Many processes in cell biology are connected to the movement of compact entities: intracellular vesicles and even single molecules. The tracking of individual objects is important for understanding cellular dynamics. Here we describe the tracking algorithms which have been developed in the non-biological fields and successfully applied to object detection and tracking in biological applications. The characteristics features of the different algorithms are compared.


Toxicity of microcystin-LR, isolated from Microcystis aeruginosa, against various insect species.
Microcystin-LR (MC-LR), isolated from the cyanobacterium Microcystis aeruginosa Kuetzing emend. Elenkin strain CCAP 1450/4 was tested for biological activity against four species of insect and the invertebrate Artemia salina. The efficacy of pesticidal activity was compared with various insecticides. The 24 hr LD50 value for third instar diamond-backed moth, Plutella xylostella, on ingestion from a treated leaf surface was 1.0 micrograms cm2, compared with a 72 hr LD50 value for rotenone of 2.0 micrograms cm-2. The 24 hr LD50 values of MC-LR and malathion on intrathoracic injection into adult house flies (Musca domestica) were 0.5 and 3.7 mg kg-1, respectively. MC-LR had no effect on M. domestica when applied topically at dosages up to 32 mg kg-1. MC-LR and malathion gave 24 hr LD50 values of 4.7 and 13.1 mg kg-1, respectively when injected into third instar cotton leafworm (Spodoptera littoralis). In fourth instar cabbage white butterfly larvae (Pieris brassicae) MC-LR injected gave 24 and 48 hr LD50 values of 3.9 and 1.9 mg kg-1, respectively, whilst the 24 and 48 hr LD50 values for carbofuran were 0.4 and 0.3 mg kg-1, respectively. An immersion bioassay with 1-day-old brine shrimp larvae (Artemia salina) gave 24 hr LD50 values of 3.8 micrograms ml-1 for MC-LR and 1.8 micrograms ml-1 for carbofuran. MC-LR has appreciable insect toxicity, comparable to the three insecticides tested. The toxin look 24-48 hr to exert its full lethal effect in insects, much longer than the 1-3 hr it takes in mammals. The potential use of MC-LR as an insecticide is discussed.


Farnesyltransferase inhibitors.
The farnesyltransferase inhibitors (FTIs) were designed to inhibit the post-translational processing of Ras proteins, which are mutated in 30% of all human cancers. Recent studies suggest, however, that the target of FTIs may be a protein other than Ras, and that these agents may be more appropriately used to treat tumors with activated wild-type ras signaling. Preliminary results from several phase II and phase III studies have been reported. The FTIs fail to show significant single-agent activity in non-small cell lung cancer, small cell lung cancer, pancreatic cancer, refractory colorectal cancer, and bladder cancer. Activity has been shown in hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome), breast cancer, and glioma. Several combination studies of FTIs and standard cytotoxic agents are ongoing.


Limosilactobacillus johnsoni and Limosilactobacillus mucosae and Their Extracellular Vesicles Alleviate Gut Inflammatory Injury by Mediating Macrophage Polarization in a Lipopolysaccharide-Challenged Piglet Model.
Limosilactobacillus johnsoni (L. j) and Limosilactobacillus mucosae (L. m) can alleviate the inflammatory response. This study aimed to elucidate the underlying mechanisms by which L. j- and L. m-derived extracellular vesicles (EVs) mitigate lipopolysaccharide (LPS)-induced intestinal injury. Piglets were assigned to 4 groups: oral phosphate-buffered saline inoculation for 2 wk prior to intraperitoneal injection of physiological saline or LPS, and oral L. j/L. m inoculation for 2 wk prior to intraperitoneal injection of LPS. The intestinal integrity, macrophage markers, cytokine levels, and microbiota were determined. The cytokine levels and macrophage phenotype were detected after L. j/L. m and their EVs were coincubated with macrophages. The levels of cytokines, tight junction proteins, and apoptosis were measured after intestinal epithelial cells were cocultured with macrophages. LPS challenge decreased jejunal villus length; expression levels of zonula occludens-1 (ZO-1), occludin, arginase-1 (Arg1), and interleukin (IL)-10; and number of CD163+ cells and increased the expression levels of inducible nitric oxide synthase (iNOS), IL-1β, IL-6, and tumor necrosis factor (TNF)-α compared with that in the control. L. j and L. m pretreatment rescued the aforementioned indicators compared with LPS challenge. Pretreatment of L. j and L. m and their EVs reversed the levels of IL-1β, IL-6, TNF-α, and IL-10 and the gene expression of iNOS and Arg1 in the LPS group in macrophages. Pretreatment with L. j and L. m-derived EVs increased ZO-1 and occludin mRNA expression and reduced IL-1β, caspase-3, and bax gene expression in intestinal epithelial cells of the coculture system. Enzyme-treated EVs were less effective than native EVs. This study suggests that EVs secreted by L. j and L. m control inflammation by modulating macrophage polarization, thereby improving intestinal barrier function.


Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Macrophages, particularly alternatively activated macrophages (M2), have been recognized to contribute to the pathogenesis of pulmonary fibrosis. Therefore, targeting macrophages might be a viable therapeutic strategy for IPF. Herein, we report a potential nanomedicine-based gene therapy for IPF by modulating macrophage M2 activation. In this study, we illustrated that the levels of pleckstrin homology and FYVE domain containing 1 (Plekhf1) were increased in the lungs originating from IPF patients and PF mice. Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation. Mechanistically, Plekhf1 was upregulated by IL-4/IL-13 stimulation, after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis. Therefore, intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis, concomitant with a significant reduction in M2 macrophage accumulation in the lungs. In conclusion, Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis, and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.


Interplay of Diabetes Mellitus and End-Stage Renal Disease in Open Revascularization for Chronic Limb-Threatening Ischemia.
Chronic limb-threatening ischemia (CLTI) in patients with end-stage renal disease (ESRD) confers a significant survival disadvantage and is associated with a high major amputation rate. Moreover, diabetes mellitus (DM) is an independent risk factor for developing CLTI. However, the interplay between end-stage renal disease (ESRD) and DM on outcomes after peripheral revascularization for CLTI is not well established. Our goal was to assess the effect of DM on outcomes after an infrainguinal bypass for CLTI in patients with ESRD. Using the Vascular Quality Initiative dataset from January 2003 to March 2020, records for all primary infrainguinal bypasses for CLTI in patients with ESRD were included for analysis. One-year and perioperative outcomes of all-cause mortality, reintervention, amputation-free survival (AFS), and major adverse limb event (MALE) were compared for patients with DM versus those without DM. Of a total of 1,058 patients (66% male) with ESRD, 726 (69%) patients had DM, and 332 patients did not have DM. The DM group was younger (median age, 65 years vs. 68 years; P = 0.002), with higher proportions of obesity (body-mass index>30 kg/m2; 34% vs. 19%; P < 0.001) and current smokers (26% vs. 19%; P = 0.013). The DM group presented more frequently with tissue loss (76% vs. 66%; P < 0.001). A distal bypass anastomosis to tibial vessels was more frequently performed in the DM group compared to the non-DM group (57% vs. 45%; P < 0.001). DM was independently associated with higher perioperative MALE (OR 1.34; 95% CI, 1.06-1.68; P = 0.013), without increased risks of loss of primary patency and composite outcomes of amputation or death. On the mean follow-up of 11.4 ± 5.5 months, DM patients had a significantly higher rate of one-year MALEs (43% vs. 32%; P = 0.001). However, the one-year primary patency and AFS did not differ significantly. After adjusting for confounders, the risk-adjusted hazards for MALE (HR 1.34; 95% CI, 1.06-1.68; P = 0.013) were significantly increased in patients with DM. However, DM was not associated with increased risk of AFS (HR 1.16; 95% CI, 0.91-1.47; P = 0.238), or loss of primary patency (HR 1.04; 95% CI, 0.79-1.37; P = 0.767). DM and ESRD each independently predict early and late major adverse limb events after an infrainguinal bypass in patients presenting with CLTI. However, in the presence of ESRD, DM may increase perioperative adverse events but does not influence primary patency and AFS at one year. The risk profile associated with ESRD appears to supersede that of DM, with no additive effect.


Monocytic HLA DR antigens in schizophrenic patients.
A genetic association of specific human leukocyte antigens (HLA) DR genes and schizophrenia has recently been shown. These HLA play a fundamental role in the control of immune responses. Furthermore infectious agents have been proposed to be involved in the pathogenesis of schizophrenia. In this study we investigated the rate of HLA DR positive monocytes in schizophrenic patients compared to controls with a special focus on the adaption to in vitro stimulation with toll-like receptor ligands. Patients with schizophrenia and matched controls were included. For each individual, we evaluated the rate of HLA DR positive monocytes (either incubated at 37 °C or after stimulation with lipopolysaccharide or Poly I:C). We found a significantly higher percentage of schizophrenic patients with elevated HLA DR positive cells (p=0.045) as compared to controls. The adjustment rate from baseline levels of monocytic HLA DR positive cells to stimulation with Poly I:C was significantly lower in schizophrenic patients (p=0.038). The increased monocytic HLA DR in schizophrenic patients and the maladjustment of their monocytic HLA DR levels to an infectious stimulus might be a sign for a disturbed monocytic immune balance in schizophrenic individuals.


Monitoring microcirculation changes in port wine stains during vascular targeted photodynamic therapy by laser speckle imaging.
This study was conducted to test laser speckle perfusion imaging (LSPI) for imaging microcirculation and monitoring microcirculatory changes of port wine stains (PWS) during vascular targeted photodynamic therapy (V-PDT). Before and 5 min after V-PDT, PWS lesions and the corresponding contralateral healthy skins of 24 PWS patients were scanned, whereas seven PWS patients were scanned throughout V-PDT. V-PDT was conducted immediately after intravenous injection of photocarcinorin (4-5 mg kg(-1)). A 532 nm laser was used for irradiation (power density: 80-100 mW cm(-2), exposure time: 20-50 min). Before V-PDT, all 24 PWS patients demonstrated a significant difference in perfusion between the PWS lesion and the contralateral healthy control skin (1132 ± 724 and 619 ± 478 PU, respectively, P < 0.01). Five minutes after V-PDT, the mean perfusion value of the 24 PWS lesions was 1246 ± 754 PU. There was no significant difference compared to the perfusion before V-PDT (P > 0.05). During V-PDT, the perfusion of seven PWS patients increased rapidly after initiation of V-PDT, reached a maximum within 10 min, lasted for several minutes, and slowly returned to a relatively lower level at the end of V-PDT. On the basis of these results, LSPI is capable of imaging PWS microvasculature and monitoring microvascular reactivity to V-PDT.


The -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early-onset Alzheimer's disease.
The -491 polymorphism in the promoter region of the apolipoprotein E gene (APOE) has been suggested to be associated with increased risk for Alzheimer's disease (AD) independent of APOE status. We studied the association between the -491 polymorphism and risk for early-onset Alzheimer's disease in 99 Dutch and 78 Spanish patients. In patients with early-onset AD, we found no consistent relationship with a single allele of the -491 polymorphism. Linkage disequilibrium between the polymorphism and the APOE gene was found which most likely might explain the inconsistent findings.


Prediction of chain turns in globular proteins on a hydrophobic basis.
Peptide chain turns are those parts of a globular protein where the backbone changes its direction. A simple, non-empirical hypothesis is presented to account for both the turns and the hydrophobic core of the protein using only the amino acid sequence.


Teachers' Psychological Needs Satisfaction and Thwarting: Can They Explain Students' Behavioural Engagement in Physical Education? A Multi-Level Analysis.
Students' engagement in Physical Education has been linked to several adaptive consequences. Even though the existing literature suggests that perceived autonomy support can predict engagement, research is scarce on how teachers' antecedents might influence this behavioural outcome. This study sought to compare the influence of teachers' basic psychological needs' satisfaction and basic psychological needs' thwarting on students' behavioural engagement and on the relationship between perceived autonomy-support and the students' behavioural engagement. The sample included 29 Physical Education teachers and 644 students who were taught by the participants teachers. Data were collected using both paper and online surveys and they were analysed using multilevel modelling techniques. The results revealed that, while teachers' autonomy satisfaction might be significant in the explanation of students' engagement (β = 0.33, p < 0.01), it seems that needs thwarting could be a better predictor of this outcome (β autonomy thwarting = -0.17, p < 0.01; β competence thwarting = -0.06, p < 0.05). These findings suggest the impact of certain external pressures on teachers' practices which, in turn, might affect students' behavioural outcomes.


Failure to find a humoral factor which influences the compensatory response after resection of the rat small bowel.
Small bowel resection was performed in one parabiont of a parabiotic rat pair to determine whether there was a "humoral" or other circulating factor present which could influence the compensatory response seen in the remainder of the small bowel. Following intestinal resection in one parabiont, there was an increase in DNA synthesis in the intestine of that member provided at least 40% of the small intestine was removed. The compensatory response seen in a resected animal was not observed in its parabiotic partner, even though an attempt was made to make the potentially responding animal more sensitive to the influence of any circulating "factors" by resecting its intestine as well. The results obtained are in disagreement with the one closely related report in the literature; it is suggested that there is no good evidence for the existence of a resection-induced circulating factor with the capability of crossing a vascular anastomosis and controlling proliferation of small intestinal epithelium.


Involvement of the dopaminergic receptors of the rat basolateral amygdala in anxiolytic-like effects of the cholinergic system.
Cholinergic system stimulation in some parts of the brain may affect anxiety-related behaviors. This system has many interactions with dopaminergic neurotransmission in the brain. We have studied the effect of cholinergic system activation in the basolateral amygdala on anxiety-related behaviors in adult male wistar rats using the acetylcholinesterase inhibitor physostigmine. Furthermore, the possible involvement of dopamine D(1) and D(2) receptors of basolateral amygdala in physostigmine induced effects has been evaluated. The elevated plus-maze task was used to assess anxiety parameters and all drugs were delivered into basolateral amygdala via bilaterally implanted chronic cannulas. Physostigmine (20 μg/rat) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), revealing an anxiolytic-like effect. However, muscarinic receptor antagonist scopolamine (8 μg/rat) decreased %OAT indicating anxiogenic-like effect. A sub-effective dose of scopolamine (2 μg/rat) plus physostigmine decreased %OAT and %OAE in comparison to saline plus physostigmine (20 μg/rat). Muscarinic receptor agonist pilocarpine (5 μg/rat), dopamine D(1) receptor antagonist SCH23390 (1 μg/rat) and dopamine D(2) receptor antagonist sulpiride (5 μg/rat) significantly increased %OAT which may show anxiolytic-like effects of drugs. Sulpiride (5 μg/rat) also increased %OAE parameter. Pre-treatment with SCH23390 (0.5 and 1 μg/rat) or sulpiride (5 μg/rat) blocked anxiolytic-like effect of physostigmine (20 μg/rat). All drugs were devoid of any significant effect on locomotor activity. It is concluded that intra-basolateral amygdala administration of physostigmine has anxiolytic-like effects which may be via muscarinic mechanisms. Furthermore, dopaminergic system activation probably via dopamine D(1) and D(2) receptors is necessary for mediating anxiolytic-like effects of physostigmine.


Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach.
The presence of cardiovascular calcification significantly predicts patients' morbidity and mortality. Calcific mineral deposition within the soft cardiovascular tissues disrupts the normal biomechanical function of these tissues, leading to complications such as heart failure, myocardial infarction, and stroke. The realization that calcification results from active cellular processes offers hope that therapeutic intervention may prevent or reverse the disease. To this point, however, no clinically viable therapies have emerged. This may be due to the lack of certainty that remains in the mechanisms by which mineral is deposited in cardiovascular tissues. Gaining new insight into this process requires a multidisciplinary approach. The pathological changes in cell phenotype that lead to the physicochemical deposition of mineral and the resultant effects on tissue biomechanics must all be considered when designing strategies to treat cardiovascular calcification. In this review, we overview the current cardiovascular calcification paradigm and discuss emerging techniques that are providing new insight into the mechanisms of ectopic calcification.


Do most lymphocytes in humans really reside in the gut?
It is widely believed that the gut, and particularly the lamina propria (LP) of the gut, contains most of the lymphocytes in humans. The strong depletion of CD4(+) T cells from the gut LP of HIV-infected patients was, therefore, suggested to be such a large, irreversible insult that it could explain HIV disease progression. However, reviewing data from different mammalian species, we found that only 5%-20% of all lymphocytes reside in the gut, and that only 1%-9% of the total lymphocyte number is located in the gut LP. Our findings suggest that spleen and lymph nodes, rather than the gut, are the largest immune compartments in mammals.


Fractionation of particulate glycogen and bound enzymes using high-performance liquid chromatography.
During a study aimed at the specificity of binding of phosphorylase and glycogen synthase to glycogen particles we investigated the separation of these particles with the technique of high-performance liquid chromatography using several media. The technique allowed relatively rapid fractionations with little, if any, loss of enzyme activity. The basis of some separations was molecular weight of the particle. Of the molecular exclusion media used, Superose 6 had an exclusion limit large enough to accommodate most glycogens but excluded mouse liver and bovine liver glycogen particles. Toyopearl HW-75 F was a medium that could accommodate liver glycogen and gave us reasonably well-defined separation of the particles that carried phosphorylase and glycogen synthase. Separations on ion-exchange columns, that were obviously based on the overall charge of proteins associated with the glycogen particles, were not very effective in terms of allowing the separation of different types of particle. Of all the media used the hydrophobic interaction column was best in terms of separating what appeared to be distinct populations of particles that had definite preferences in terms of binding phosphorylase and glycogen synthase. As expected, these separations were based on the hydrophobic interaction of the proteins associated with the glycogen particles, since particles that had been deproteinized by a cold water extraction procedure did not bind to the column.