Healthcare Digitalisation and the Changing Nature of Work and Society.
Digital technologies have profound effects on all areas of modern life, including the workplace. Certain forms of digitalisation entail simply exchanging digital files for paper, while more complex instances involve machines performing a wide variety of tasks on behalf of humans. While some are wary of the displacement of humans that occurs when, for example, robots perform tasks previously performed by humans, others argue that robots only perform the tasks that robots should have carried out in the very first place and never by humans. Understanding the impacts of digitalisation in the workplace requires an understanding of the effects of digital technology on the tasks we perform, and these effects are often not foreseeable. In this article, the changing nature of work in the health care sector is used as a case to analyse such change and its implications on three levels: the societal (macro), organisational (meso), and individual level (micro). Analysing these transformations by using a layered approach is helpful for understanding the actual magnitude of the changes that are occurring and creates the foundation for an informed regulatory and societal response. We argue that, while artificial intelligence, big data, and robotics are revolutionary technologies, most of the changes we see involve technological substitution and not infrastructural change. Even though this undermines the assumption that these new technologies constitute a fourth industrial revolution, their effects on the micro and meso level still require both political awareness and proportional regulatory responses.


Choline and contribution to normal liver function of the foetus and exclusively breastfed infants: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006.
Following an application from Procter & Gamble BV pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of Belgium, the Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to choline and contribution to normal liver function of the foetus and exclusively breastfed infant. The scope of the application was proposed to fall under a health claim referring to children's development and health. The Panel considers that choline is sufficiently characterised. The claimed effect proposed by the applicant is contribution 'to normal foetal and infant development, especially liver'. The proposed target population is 'unborn fetuses and breastfed infants'. Choline is involved in the structure of cell membranes, cell signalling, metabolism and transport of lipids and cholesterol and neurotransmitter synthesis. Although choline can be synthesised de novo by the human body, depletion-repletion studies in humans show that low choline intake leads to liver dysfunction and muscle damage, which are reverted by the administration of dietary choline. For these functions, de novo synthesis of choline by the human body is insufficient and choline must be obtained from dietary sources. No human studies have addressed the effect of low maternal dietary choline intake on liver function in the fetus or exclusively breastfed infants. However, the Panel considers that the biological role of choline in normal liver function and dietary choline being essential for the function applies to all ages, including fetus and infants. The Panel concludes that a cause and effect relationship has been established between the intake of choline by pregnant and lactating women and contribution to normal liver function of the fetus and exclusively breastfed infants.


Carboxyhaemoglobin levels and their determinants in older British men.
Although there has been concern about the levels of carbon monoxide exposure, particularly among older people, little is known about COHb levels and their determinants in the general population. We examined these issues in a study of older British men. Cross-sectional study of 4252 men aged 60-79 years selected from one socially representative general practice in each of 24 British towns and who attended for examination between 1998 and 2000. Blood samples were measured for COHb and information on social, household and individual factors assessed by questionnaire. Analyses were based on 3603 men measured in or close to (< 10 miles) their place of residence. The COHb distribution was positively skewed. Geometric mean COHb level was 0.46% and the median 0.50%; 9.2% of men had a COHb level of 2.5% or more and 0.1% of subjects had a level of 7.5% or more. Factors which were independently related to mean COHb level included season (highest in autumn and winter), region (highest in Northern England), gas cooking (slight increase) and central heating (slight decrease) and active smoking, the strongest determinant. Mean COHb levels were more than ten times greater in men smoking more than 20 cigarettes a day (3.29%) compared with non-smokers (0.32%); almost all subjects with COHb levels of 2.5% and above were smokers (93%). Pipe and cigar smoking was associated with more modest increases in COHb level. Passive cigarette smoking exposure had no independent association with COHb after adjustment for other factors. Active smoking accounted for 41% of variance in COHb level and all factors together for 47%. An appreciable proportion of men have COHb levels of 2.5% or more at which symptomatic effects may occur, though very high levels are uncommon. The results confirm that smoking (particularly cigarette smoking) is the dominant influence on COHb levels.


Two-suture fish-mouth end-to-side microvascular anastomosis with fibrin glue.
The most decisive step during free tissue transfers and replantation surgery may be respected as microvascular anastomosis. The conventional end-to-side anastomosis technique with simple interrupted sutures is well established and proven to be successful. On the other hand, conventional technique can be time consuming and can cause vascular thrombosis, vessel narrowing, and foreign-body reactions. Search for a more rapid and secure alternative to conventional technique is carried on. In this study, we defined a new technique for end-to-side anastomosis with fish-mouth incisions and application of fibrin glue and compared our results with those we obtained with conventional end-to-side anastomosis. We evaluated end-to-side anastomosis of carotid arteries of a total number of 64 Wistar-Albino rats. In control group (n = 32), conventional anastomoses with 8 to 10 sutures were performed. In experimental group (n = 32), fish-mouth incisions were applied first on the recipient artery, followed by performing anastomosis with only 2 corner sutures and applying commercially available fibrin glue. Time taken to perform the anastomosis was significantly shorter with the experimental group (P = 0.001), whereas early and late patency and aneurysm rates were comparable to those achieved with control group. Histological evaluation did not point out any significant differences between the groups. We have defined a rapid and safe alternative technique of end-to-side anastomosis with the use of fibrin glue. This method may be an alternative especially where multiple anastomoses are required or where it is difficult to approach anastomotic line, as it is easily performed, rapid, safe, and not involving any complex equipments.


Immunological relatedness of chicken and human riboflavin carrier protein.
Polyclonal antibodies (pAbs) to riboflavin carrier protein (RCP) purified from human amniotic fluid were raised in two rabbits. These pAbs apart from recognizing the parent antigen, reacted significantly with chicken RCP as well. When all the 212 octapeptides overlapping by one amino acid residue and covering the entire primary amino acid sequence of chicken RCP immobilized on polyethylene rods were probed with rabbit anti-human RCP antibodies, it was found that these antibodies recognize five epitopic sequences (residues 37-42, 73-76, 133-140, 174-176 and 200-207) in chicken RCP primary structure common to both the rabbits. In addition, the antisera from the two individual animals also recognized additional epitopes characteristic to that particular animal. The reactivities of these antigenic determinants have been confirmed with polyclonal anti-human RCP sera by using synthetic peptides harbouring these chicken RCP sequences in inhibition ELISA. This high level of immunological similarities among linear epitopes observed may reflect the degree of conservation of local conformations among linear antigenic determinants shared by the two evolutionarily distant homologous proteins.


A 'second life' agenda. Psychiatric research issues raised by protease inhibitor treatments for people with the human immunodeficiency virus or the acquired immunodeficiency syndrome.
Seldom in the history of medicine has an entire generation of patients with an incurable, progressive, and ultimately fatal disease suddenly been offered the prospect of extended survival and even, perhaps, a "second life." The relatively simultaneous appearance of 2 major treatment developments has created profound changes in therapeutic options and outlook. The first development is an assay of serum levels of human immunodeficiency virus viral copies, providing a critical tool for clinical decision making. The second is the marketing between December 1995 and April 1997 of 4 human immunodeficiency virus protease inhibitors that, combined with previously available antiviral medications, achieve a new level of efficacy. With the advent of these changes come multiple psychiatric research and policy issues. These include the development of strategies to establish and maintain medication adherence. This is a critical task, given the complexity of combination therapy regimens and the rapid onset of viral resistance to protease inhibitors within days to weeks of missed or suboptimal dosing. The psychological issues to be studied include the process of restructuring lives and expectations in the event of clinical benefit or managing the distress associated with clinical failure. Other research questions include the effects of restored health on the appraisal of human immunodeficiency virus risk behaviors, assessment of effect of neurocognitive functioning, and unanswered questions about psychotropic or protease inhibitor drug interactions due to their shared metabolic pathways. Behavioral scientists can inform provision of care to patients who may be considered difficult to treat, such as those with severe and persistent mental illness or active substance abuse or the homeless. This includes the provision of empirical data regarding individual and situational characteristics that are likely to promote or impede adherence, as well as innovative provision systems. Psychiatry can make notable contributions during this turning point in human immunodeficiency virus therapeutics and research.


[Postoperative mortality and means of reducing it in patients with lung cancer].
The report discusses a 20 year-old experience with surgical treatment for lung cancer. In 1961-1980, the following surgical procedures were carried out in 1,100 cases of lung cancer: pneumonectomy--417 (38%), lobe- and bilobectomy--506 (46%), and exploratory thoracotomy--117 (16%). The range of indications for surgical treatment has been extended within the last 10 years; the percentage of surgical cases older than 60 years has grown from 17 to 35%, with patients older than 70 amounting to 12%. Risk of surgery for lung cancer has been reduced thanks to complex and pathogenetically-grounded therapy given before and immediately after operation as well as application of improved surgical and anesthesiologic support procedures. Among the most frequent death-causing post-operative complications were thromboembolism of the pulmonary artery, bronchial fistula, empyema of the chest and cardiopulmonary failure.


Bitemporal Versus High-Dose Unilateral Twice-Weekly Electroconvulsive Therapy for Depression (EFFECT-Dep): A Pragmatic, Randomized, Non-Inferiority Trial.
ECT is the most effective treatment for severe depression. Previous efficacy studies, using thrice-weekly brief-pulse ECT, reported that high-dose (6× seizure threshold) right unilateral ECT is similar to bitemporal ECT but may have fewer cognitive side effects. The authors aimed to assess the effectiveness and cognitive side effects of twice-weekly moderate-dose (1.5× seizure threshold) bitemporal ECT with high-dose unilateral ECT in real-world practice. This was a pragmatic, patient- and rater-blinded, noninferiority trial of patients with major depression (N=138; 63% female; age=56.7 years [SD=14.8]) in a national ECT service with a 6-month follow-up. Participants were independently randomly assigned to bitemporal or high-dose unilateral ECT. The primary outcome was change in the 24-item Hamilton Depression Rating Scale (HAM-D) score after the ECT course; the prespecified noninferiority margin was 4.0 points. Secondary outcomes included response and remission rates, relapse status after 6 months, and cognition. Of the eligible patients, 69 were assigned to bitemporal ECT and 69 to unilateral ECT. High-dose unilateral ECT was noninferior to bitemporal ECT regarding the 24-item HAM-D scores after the ECT course (mean difference=1.08 points in favor of unilateral ECT [95% CI=-1.67 to 3.84]). There were no significant differences for response and remission or 6-month relapse status. Recovery of orientation was quicker following unilateral ECT (median=19.1 minutes versus 26.4 minutes). Bitemporal ECT was associated with a lower percent recall of autobiographical information (odds ratio=0.66) that persisted for 6 months. Twice-weekly high-dose unilateral ECT is not inferior to bitemporal ECT for depression and may be preferable because of its better cognitive side-effect profile.


TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20.
About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28. We aimed to examine the effect of TNFα inhibitors on bone density, bone biomarkers and cytokine production in responder and non-responder patients and assessed mechanisms of action. BMD in the lumbar spine and femur neck of 117 RA patients was measured by DEXA scan. Bone turnover biomarkers CTX, osteoprotegerin (OPG), osteocalcin and RANKL were measured by ELISA. Levels of 16 cytokines in plasma and in tissue culture supernatants of ex vivo T cells were measured by multiplex assays and ELISA. The effect of treatment with TNFα inhibitors on blood mononuclear cell (MNC) differentiation to osteoclast precursors (OCP) was measured flow cytometry and microscopy. TNFα inhibitors improved lumbar spine BMD but had modest effects on blood bone biomarkers, irrespective of patients' clinical response. Blood OCP numbers and the ability of monocytes to differentiate to OCP in vitro declined after treatment. Treatment also reduced RANK expression and IL-20 production. BMD improvement correlated with reduced levels of IL-20 in responder patients. This study reveals that TNFα inhibitors reduce lumbar spine bone loss in RA patients irrespective of changes in DAS28. The reduction in bone loss is associated with reduction in IL-20 levels in responder patients.


Luminescent conjugates between dinuclear rhenium complexes and 17α-ethynylestradiol: synthesis, photophysical characterization, and cell imaging.
Three new luminescent conjugates between dinuclear rhenium complexes and an estradiol, namely E2-Re, are described. The derivatives have the general formula [Re2(μ-Cl)2(CO)6(μ-R-pydz-17α-ethynylestradiol)] (R-pydz = functionalized 1,2-pyridazine), where the estradiol moiety is covalently bound to the β position of the pyridazine ligand. Different synthetic pathways are investigated, including the inverse-type [4 + 2] Diels Alder cycloaddition reaction between the electron poor 1,2,4,5-tetrazine and 17α-ethynylestradiol for the synthesis of E2-Re1. The three E2-Re conjugates are purified on silica gel and isolated in a spectroscopically pure form in moderate to good yields (28-50%). All the E2-Re conjugates are comprehensively characterized from the spectroscopic and photophysical points of view. Cellular internalization experiments on human MCF-7 and 231 cells are also reported, displaying interesting staining differences depending on the nature of the spacer linking the estradiol unit to the organometallic fragment. Furthermore, the suitability of these conjugates to also stain simple multicellular organisms, i.e. Ciona intestinalis embryos and larvae at different stages of development, is reported here for the first time.


Cross-regulatory mechanisms in hormone signaling.
Recent studies suggest that hormones act through a web of interacting responses rather than through isolated linear pathways. This signal integration architecture may be one mechanism for increasing the specificity of outcomes in different cellular contexts. Several common themes for cross-regulation between pathways can be observed. Here, we propose a classification scheme for different levels of signaling pathway cross-regulation. This scheme is based on which parts of the individual pathways are acting as information conduits between pathways. Examples from the recent plant hormone biology literature are used to illustrate the different modes of interaction.


Factors affecting ultrasonic release from eLiposomes.
Liposomes containing emulsion droplets (eLiposomes) were studied as ultrasound-responsive liposomal drug carriers. This paper presents the effects of temperature, eLiposome size, and ultrasound parameters on the ultrasonically actuated release of calcein, to test hypotheses concerning the physics of acoustic droplet vaporization with regard to vapor pressure and Laplace pressure. Small (200 nm) eLiposomes containing 100-nm emulsion droplets were formed and compared with large (800 nm) eLiposomes containing 100- or 450-nm droplets. Calcein release was quantified by spectroscopic methods. Various experiments examined the influence of perfluorocarbon (PFC) droplet size, vesicle size, temperature, PFC composition and vapor pressure, insonation time, and insonation frequency. Results showed that eLiposome samples released significantly more calcein than their conventional liposome counterparts. Surprisingly, temperature (which directly controls vapor pressure) did not have a strong effect on ultrasound-induced calcein release. In general, calcein release decreased with decreasing droplet size, as hypothesized based on Laplace pressure. Release decreased with increased ultrasound frequency if the pressure amplitude and exposure time were maintained constant, indicating that the gas-phase nucleation rate may have an important role in rupture of eLiposomes. Interestingly, when ultrasound of the same mechanical index was applied at two frequencies, the amount of release correlated strongly with the mechanical index.


Determination in vivo viability of a transfused platelet product by corrected count increment and percentage platelet response.
For many years, platelet concentrates have been used for the prevention as well as treatment of bleeding disorders, especially in those patients with haematological problems involving platelet disorders as well as refractoriness, In addition, platelet concentrates (PCs) have been widely used to support patients undergoing bone marrow transplantation or who are receiving myelotoxic treatments. The aim of this study was to determine the quality of platelet concentrates by assessing platelet counts, volume, pH changes, swirling, residue of the red blood cells and white blood cell counts. Assess the in vivo viability of a transfused platelet product using the corrected count increment (CCI) and the percentage platelets response (PPR). This descriptive analysis study was done in Kenyatta National Hospital Blood Transfusion Unit between July 2016 and December 2016. The in vitro Platelets concentrates quality was accurately determined and assessed using certain parameters. Platelet concentrates in ethylene diamine tetra acetic acid (EDTA) was used for analysis using Cell-Dyn 3700 analyser. The volume of PCs used was an average of 2mls of PCs, the pH was measured using digitalised Hanna edge pH kit. Agitation was done using Helmer agitator and centrifugation was done using Roto silenta 630 RS centrifuge. The in vivo viability of a transfused product was determined using corrected count increment (CCI) and percentage recovery (PR) between 1 and 20-hour after transfusion. Pre and post-transfused whole blood in EDTA collected from the recipients was analysed to access the functional platelets in the circulation. Data analysis was done using SPSS. A total of 384 platelet concentrates were analysed and used in transfusion. The majority 96, (40%) were O Rhesus D+ and the least being AB Rhesus D-at (1%).Centrifugation, separation and agitation was done according to standard procedure (n=384). Only (246 (65%) of the concentrates were found fit for use out of a total of (n=384) leaving 138 (35%) which did not meet the KNH/KNBTS criteria. The minimum specifications for platelet count are 5.5 x (109). The duration of 3 days of storage on average, the WBC count (109) was Mean ± SD 4.50 ± 3.50. Using the Hanna edge pH kit the pH Mean was ±SD 7.18 ± 8.82 and the used Volume (Mls) was at 55 ± 15. The concentrate was issued within 3 days of processing. After transfusion, the percentage platelet response (PPR) was 72% in male recipients at 1-hour and 30% at 20-hours while 69% in female recipients at 1-hour and 25% at 20-hours. The invivo viability of platelet product had a corrected count increment (CCI) of 75% ≥ 7500 at 1-hour and CCI of18% ≥ 30% at 20-hours in male recipients. In the same study, the female recipients had a CCI of 80% ≥ 7500 at 1-hour and a CCI of 25% ≥ 30% at 20-hours. The findings on platelets concentrates quality 65% met platelets transfusion criteria while 35% did not. On preparation of platelets concentrates there was high counts of white blood cells 4.5±3.5×109than recommended counts by Kenya National Blood Transfusion Services < 0.83×109. Both percentage platelet response (PPR) and corrected count increment (CCI) were very low at 20 hours compared to British committee for standards haematology criteria for successful increment of platelet products (PPR ≥ 30% and CCI ≥ 7500). Apheresis platelets transfusion can be introduced at KNH and use of leukoreduction performed on the platelet concentrates which are prepared within the Hospital. With such rate of refractoriness, additional tests to confirm the real cause of unviability of platelets in the patients need to be performed. Recipients should be done evaluation of the pattern of refractoriness followed by HLA compatibility testing. In addition, if there is a high, compatible cross-matched, selected apheresis platelet concentrate pint should be transfused. This unviability was due to recipients with either immune-mediated refractoriness or non-immune mediated refractoriness.


Diffuse Large B-Cell Lymphoma Arising in Warthin's Tumor: Case Study and Review of the Literature.
Warthin's tumor is the second most common type of salivary gland tumor. Microscopically, Warthin's tumor displays a proliferative epithelial component and lymphoid stroma. Carcinomas arising from the epithelial component are well known, but malignant transformations of the lymphoid stroma are rare. When they do occur, they are most commonly B-cell type non-Hodgkin lymphomas. A 60-year-old male patient underwent surgical resection of a parotid mass. After superficial parotidectomy, microscopic examination indicated that the tumor was of epithelial components with basaloid and oncocytic columns of cells neighboring lymphoid components. In addition to the lymphoid follicles with distinct germinal centers, there were large, bizarre and extremely atypical neoplastic cells seen in the lymphoid component. Large neoplastic cells were diffusely CD20 and CD30 positive. The patient was diagnosed with "Warthin's tumor and diffuse large B-cell lymphoma with expression of CD30." The histopathologic and clinical features are discussed along with a review of the literature.


Intraosseous hibernoma: a case report and review of the literature.
Intraosseous hibernoma is a rare benign bone tumor, with only 4 cases reported in English literature. In this report, we describe a 42-year-old man with no past medical history and right chest pain. Imaging studies showed an osteolytic lesion with fat attenuation lesion in the right fourth rib. The lesion was completely resected and microscopic study showed mildly thickened bone trabeculae and multivacuolated brown fat cells replacing the normal white fat and hematopoietic elements. The diagnostic of intraosseous hibernoma was made. Although it is rare, hibernoma should be included in the differential diagnosis of lipomatous tumors.


Prevalence of hepatitis B anti-core antibody in the Republic of Ireland.
The aim of this study was to estimate the prevalence of hepatitis B exposure in the population of the Republic of Ireland, by measuring the prevalence of hepatitis B anti-core antibody in oral fluid collected by postal survey. A random multi-stage stratified sample of Irish households was obtained, using the Irish electoral register as the sampling frame. A total of 962 households were selected, and a household response rate of 60.4% was achieved. Oral fluid specimens totalling 1714 were tested for antibody to hepatitis B core antigen (anti-HBc), using an Immune Capture Enzyme Immuno-Assay. Five specimens (0.29%) were found to contain anti-HBc. Adjusting for study design, the estimated anti-HBc prevalence in the Republic of Ireland is 0.51%. This study demonstrates that self-collection of oral fluid samples is acceptable to the public, and based upon the data generated, that the Republic of Ireland has a low prevalence of hepatitis B infection.


GPER-1 and estrogen receptor-β ligands modulate aldosterone synthesis.
Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 β-estradiol (E2) blunts aldosterone secretion, and thereby affects the gender dimorphism of blood pressure, is unknown. We therefore sought for the estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of E2 on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosterone-producing adenoma cells, the most expressed ERs were the ERβ and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ERβ blockade, E2 (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (+5- to 7-fold vs baseline, P < .001). Under the same condition, the GPER-1 receptor agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) (10 nmol/L) mimicked this effect, which was abrogated by cotreatment with either the GPER-1 receptor antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a selective protein kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic mono-phosphorothioate, Rp-isomer. Silencing of the ERβ significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered aldosterone synthase gene and protein expression. Moreover, it blunted the stimulatory effect of E2 on aldosterone synthase that was seen during ERβ blockade. These results support the conclusion that in humans, E2 inhibits aldosterone synthesis by acting via ERβ. Pharmacologic disinhibition of ERβ unmasks a potent secretagogue effect of E2 that involves GPER-1 and protein kinase A signaling.


Chain relaxation in thin polymer films: turning a dielectric type-B polymer into a type-A' one.
A molecular dynamics simulation study of chain relaxation in a thin polymer film is presented, studying the dielectric response of a random copolymer of cis and trans 1,4-polybutadiene, a type B polymer without net chain dipole moment, confined between graphite walls. We stress the orientational effect of the attractive walls, inducing polarization in the vicinity of the walls, while the center of the film stays bulk-like. This polarization leads to a net dipole moment of the adsorbed chains, which is perpendicular to their end-to-end vector, which we termed as type A' behavior. In this situation, the dipole moment relaxes only upon desorption of the chains from the wall, a dynamic process which occurs on timescales much longer than the bulk relaxation time of the polymer.


An electronic network strategy for managed care.
Electronic networks, which allow payors and providers to send and receive clinical and financial information directly from their computers, must be established to gain efficiency in health care reform. Standards are being built for the various types of health care transactions, with large-scale pilot programs testing how feasible and practical these networks actually will be. A great deal of development still needs to take place, but there are immediate benefits that can be realized for managed care companies that are prepared to move data electronically.


[An increase in cardiopulmonary exercise tolerance after the embolization of a pulmonary arteriovenous fistula].
A 21-year-old woman suffering from increasing dyspnoea on intense physical exercise, was found to have a congenital right-sided arteriovenous pulmonary fistula. This was successfully and without complication embolized using a percutaneously introduced Gianturco wire coil. All symptoms disappeared after this procedure. Definite improvement in physical performance, in comparison with pre-embolization values, was documented by spiroergometry as early as two days later (oxygen uptake 1855 vs. 1459 ml/min; anaerobic threshold 920 vs. 790 ml/min; oxygen-pulse 10.6 vs. 8.0 ml/beat; oxygen partial pressure 77.5 vs. 67.6 mmHg; alveolar arterial oxygen difference 33 vs. 44 mm Hg). Further constant subjective and objective improvement in physical performance was demonstrated 3 months after embolization. This case confirms that embolization of a pulmonary arteriovenous fistula can rapidly achieve lasting improvement in exercise performance.


Effects of a Virtual Pointer on Trainees' Cognitive Load and Communication Efficiency in Surgical Training.
We investigated the cognitive load effect of a trainer providing surgical instruction by pointing/drawing over laparoscopic video to a trainee. Results showed that while cognitive load is higher overall with the use of the instructional system, there is a decrease by the second experience of being instructed by the Virtual Pointer. Further analysis showed that trainees were more likely to perform the surgical task and watch/listen to the trainer's instruction at the same time when the instructional system was used. This is thought to be an indication of more efficient communication when using the instructional system. Thus, although there is a small cognitive overload with the instructional system initially, the more efficient communication allows trainees to better integrate the knowledge and instructions being conveyed into the actions they must perform - indicating a better learning environment.


Airway responsiveness following wheezy bronchitis in infants.
The study was undertaken to assess the airway function and its response to carbachol and salbutamol in infants recovering from wheezy bronchitis. In 82 children aged 3-33 mths, free from wheeze at the time of testing, and in 14 healthy infants, airway resistance (Raw) and thoracic gas volume (TGV) were measured using a body plethysmograph. Specific airway resistance (sRaw = Raw x TGV) was calculated. Increasing doses of nebulized carbachol were applied to challenge the airways. After a positive reaction had been achieved, 0.1 mg of nebulized salbutamol was administered. Raw was monitored during the whole procedure. In 23 of the 82 children the study was repeated after nine months on average. Within this period Raw remained elevated, whereas TGV and sRaw fell considerably (TGV from 37.9 to 28.2 ml.kg-1, p less than 0.01; sRaw from 0.78 to 0.63 kPa.s-1, p less than 0.01). Airway responsiveness also dropped during the observation period (mean log provocation dose producing 50% fall (PD50) 0.026 and 0.358, p less than 0.01). In comparison with controls the study infants responded to lower doses of carbachol (mean log PD50 0.610 and 0.031, respectively, p less than 0.01). Airway responsiveness was not related to baseline airway calibre or to signs of atopy. sRaw returned to baseline 2-5 min following salbutamol. The results suggest that airways of children in a symptom-free period following wheezy bronchitis have reduced patency and reveal hyperresponsiveness to carbachol.


Antidiabetic effects of cinnamon oil in diabetic KK-Ay mice.
The hypoglycemic effect of cinnamon oil (CO) in a type 2 diabetic animal model (KK-A(y) mice) was studied. The main component of CO was cinnamaldehyde, and other nineteen components were also determined. CO was administrated at doses of 25, 50 and 100mg/kg for 35 days. It was found that fasting blood glucose concentration was significantly decreased (P<0.05) with the 100mg/kg group (P<0.01) the most efficient compared with the diabetic control group. In addition, there was significant decrease in plasma C-peptide, serum triglyceride, total cholesterol and blood urea nitrogen levels while serum high density lipoprotein (HDL)-cholesterol levels were significantly increased after 35 days. Meanwhile, glucose tolerance was improved, and the immunoreactive of pancreatic islets beta-cells was promoted. These results suggest that CO had a regulative role in blood glucose level and lipids, and improved the function of pancreatic islets. Cinnamon oil may be useful in the treatment of type 2 diabetes mellitus.


Whole-blood thrombin generation monitored with a calibrated automated thrombogram-based assay.
The calibrated automated thrombogram (CAT) assay in plasma is a versatile tool to investigate patients with hypo- or hypercoagulable phenotypes. The objective was to make this method applicable for whole blood measurements. Thin-layer technology and the use of a rhodamine 110-based thrombin substrate appear to be essential for a reliable thrombin generation (TG) assay in whole blood. Using this knowledge we developed a whole blood CAT-based assay. We demonstrated that the whole blood CAT-based assay is a sensitive and rapid screening test to assess function of the hemostatic system under more nearly physiological conditions than the TG assay in plasma. Under conditions of low tissue factor concentration (0.5 pmol/L) and 50% diluted blood, the intraassay CV of the thrombogram parameters, endogenous thrombin potential and thrombin peak height, were 6.7% and 6.5%, respectively. The respective interassay CVs were 12% and 11%. The mean interindividual variation (SD) of 40 healthy volunteers was 633 (146) nmol · min/L for the endogenous thrombin potential and 128 (23) nmol/L for the thrombin peak. Surprisingly, erythrocytes contributed more than platelets to the procoagulant blood cell membranes necessary for optimal TG. Statistically significant (P < 0.001) and potentially clinically significant correlations were observed between circulating factor-VIII concentrations in blood of hemophilia A patients and endogenous thrombin potential (r = 0.62) and thrombin peak height (r = 0.58). We have developed a reliable method to measure TG in whole blood. The assay can be performed with a drop of blood and may provide a useful measurement of TG under more physiological conditions than plasma.


Roseomonas radiodurans sp. nov., a gamma-radiation-resistant bacterium isolated from gamma ray-irradiated soil.
A bacterial strain, designated 17Sr1-1T, was isolated from gamma ray-irradiated soil. Cells of this strain were Gram-stain-negative, strictly aerobic, motile and non-spore-forming rods. Growth occurred at 18-42 ˚C and pH 6.0-8.0, but no growth occurred at 2 % NaCl concentration. The major fatty acids of strain 17Sr1-1T were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), iso-C17 : 1ω5c and C16 : 0. The polar lipid profile contained diphosphatidylglycerol, glycolipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and four unidentified lipids. The G+C content of the genomic DNA of 17Sr1-1T was 71.9 mol%. The 16S rRNA gene sequence analysis showed that strain 17Sr1-1T was phylogenetically related to Roseomonas pecuniae N75T and Roseomonas rosea 173-96T (96.6 and 96.3 % sequence similarity, respectively). The genotypic and phenotypic data showed that strain 17Sr1-1T could be distinguished from its phylogenetically related species, and that this strain represented a novel species within the genus Roseomonas, for which the name Roseomonas radiodurans sp. nov. (type strain 17Sr1-1T=KCTC 52899T=NBRC 112872T) is proposed as the first reported gamma ray-resistant Roseomonas species.


Receptor binding potencies of chlorpromazine, trifluoperazine, fluphenazine and their 10-N-substituted analogues.
Receptor interactions of three pairs of phenothiazine derivatives, namely chlorpromazine, trifluoperazine, fluphenazine and their dialkylaminoacyl analogues were investigated. The data indicate that neuroleptic derivatives are less effective at dopamine (D2), alpha 1-adrenoceptors (AR) and histamine receptors (H1). No differences in affinity to alpha 2-AR were observed. The chlorpromazine analogue was more effective at muscarinic receptors of both types.


Mini-midvastus versus medial parapatellar approach in total knee arthroplasty: difference in patient-reported outcomes measured with the Forgotten Joint Score.
Low knee awareness after minimally invasive total knee arthroplasty (TKA) has become the ultimate target of a natural-feeling knee that meets patient expectations. The objective of this research was to compare the clinical outcomes of TKA via the mini-midvastus (MMV) approach or the medial parapatellar (MPP) approach, and to evaluate which approach can lead to a better quality of life after surgery. From January 2015 to December 2016, a retrospective cohort study was conducted in 330 patients who underwent TKA via a mini-midvastus (MMV) approach. During this period, we also selected 330 patients who underwent TKA via a medial parapatellar (MPP) approach (MPP group) for comparison. Clinical results were assessed with the visual analog scale score for pain, range of motion, and the Knee Society Score. The Forgotten Joint Score was used to analyze the ability to forget the joint. There were significant differences with regard to visual analog scale score, range of motion, and the Knee Society Score until 6 months after surgery between the MMV and MPP groups (p < 0.05), but the differences were not significant at 12 months, 24 months, and 36 months after surgery. However, there were significant differences in the Forgotten Joint Score between the groups during the follow-up period (p < 0.05). When forgetting the artificial joint after TKA is the ultimate target, better quality of life can be acquired by performing TKA via the MMV approach. In addition, compared with the MPP approach, the MMV approach can offer less pain and a faster recovery.


Vesicular stomatitis virus can establish persistent infections in Syrian hamsters.
Persistent infections by vesicular stomatitis virus (VSV) of the Indiana serotype were readily established in adult Syrian hamsters following intraperitoneal injection of the virus. Plaque-forming virus, identified as VSV by serological and physical criteria, was isolated from brain homogenates of five hamsters that were tested 3 to 8 months after infection. Four of these animals had exhibited either transient or permanent paralysis, whereas the fifth appeared healthy, during the period of observation. At the time of sacrifice all hamsters had high titres of anti-VSV-neutralizing antibodies in their sera.


Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure.
Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.


Implications of uninterrupted preoperative transdermal buprenorphine use on postoperative pain management.
Buprenorphine is a partial µ-receptor agonist resistant to displacement from receptors by conventional opioids, which can block the effect of conventional opioids and may interfere with postoperative pain management. We aimed to quantify perioperative opioid use in patients receiving transdermal buprenorphine (TdBUP). We identified patients receiving TdBUP who underwent surgery between 2004 and 2016. To compare opioid requirements (intravenous morphine equivalents (IV-MEq)), we constructed a matched study, matching each TdBUP patient with two opioid-naive patients by sex, age, and type of anesthesia and procedure. Nineteen unique patients underwent 22 procedures while receiving TdBUP. Total (IQR) amounts of IV-MEq (intraoperative, recovery room, and 24 hours after recovery-room discharge) were 98 (63, 145) and 46 (30, 65) mg IV-MEq for TdBUP and opioid-naive patients, respectively (p<0.001). Postoperative IV-MEq requirements were 54 (38, 90) and 15 (3, 35) mg for TdBUP and opioid-naive patients, respectively (p<0.001). Among TdBUP patients, higher preoperative doses of TdBUP were associated with greater postoperative opioid requirements (p=0.02). Specifically, patients with a 20 µg/hour TdBUP patch required 133.8 mg IV-MEq more postoperatively than patients with a 5 µg/hour patch (p=0.002). Following discharge from the recovery room, 17 (77%) TdBUP patients and 15 (34%) opioid-naive patients reported severe pain (OR 6.6 (95% CI 2.0 to 21.3); p<0.001; adjusting for baseline pain score, 5.0 (95% CI, 1.4 to 17.8); p=0.01). Analgesic management for patients receiving TdBUP therapy must account for increased opioid needs, and greater preoperative doses of TdBUP were associated with greater postoperative opioid requirements.


Enhancement of Radiation Effectiveness in Cervical Cancer Cells by Combining Ionizing Radiation with Hyperthermia and Molecular Targeting Agents.
Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1-i; DNA-dependent protein kinase catalytic subunit inhibitor, DNA-PKcs-i and Heat Shock Protein 90 inhibitor, HSP90-i) in cervical cancer cell lines. Survival curves of SiHa and HeLa cells, concerning the combined effects of radiation with hyperthermia and PARP1-i, DNA-PKcs-i or HSP90-i, were analyzed using the linear-quadratic model: S(D)/S(0) = exp - (αD + βD²). The values of the linear-quadratic (LQ) parameters α and β, determine the effectiveness at low and high doses, respectively. The effects of these sensitizing agents on the LQ parameters are compared to evaluate dose-dependent differences in radio enhancement. Combination of radiation with hyperthermia, PARP1-i and DNA-PKcs-i significantly increased the value of the linear parameter α. Both α and β were significantly increased for HSP90-i combined with hyperthermia in HeLa cells, though not in SiHa cells. The Homologous Recombination pathway is inhibited by hyperthermia. When hyperthermia is combined with DNA-PKcs-i and PARP1-i, the Non-Homologous End Joining or Alternative Non-Homologous End Joining pathway is also inhibited, leading to a more potent radio enhancement. The observed increments of the α value imply that significant radio enhancement is obtained at clinically-used radiotherapy doses. Furthermore, the sensitizing effects of hyperthermia can be even further enhanced when combined with other molecular targeting agents.


Azathioprine and 6-Mercaptopurine-induced Liver Injury: Clinical Features and Outcomes.
The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.


Squamous cell carcinoma lung with progressive systemic sclerosis.
Association between progressive systemic sclerosis (PSS) and lung malignancy is rare yet well recognised. In order of frequency bronchioloalveolar carcinoma (BAC) is most common followed by squamous cell carcinoma, oat cell carcinoma, anaplastic carcinoma of lung. We present a 55 year old non-smoker male patient with PSS, who presented to us with progressively increasing shortness of breath and dry cough. Initially clinico-radiologically he was provisionally diagnosed as a case of non-resolving pneumonia. Subsequent investigations revealed it is a case of squamous cell carcinoma of lung with PSS.


The Effect of Race, Sex, and Insurance Status on Time-to-Listing Decisions for Liver Transplantation.
Fair allocation of organs to candidates listed for transplantation is fundamental to organ-donation policies. Processes leading to listing decisions are neither regulated nor understood. We explored whether patient characteristics affected timeliness of listing using population-based data on 144,507 adults hospitalized with liver-related disease in Pennsylvania. We linked hospitalizations to other secondary data and found 3,071 listed for transplants, 1,537 received transplants, and 57,020 died. Among candidates, 61% (n = 1,879) and 85.5% (n = 2,626) were listed within 1 and 3 years of diagnosis; 26.7% (n = 1,130) and 95% (n = 1,468) of recipients were transplanted within 1 and 3 years of listing. Using competing-risks models, we found few overall differences by sex, but both black patients and those insured by Medicare and Medicaid (combined) waited longer before being listed. Patients with combined Medicare and Medicaid insurance, as well as those with Medicaid alone, were also more likely to die without ever being listed. Once listed, the time to transplant was slightly longer for women, but it did not differ by race/ethnicity or insurance. The early time period from diagnosis to listing for liver transplantation reveals unwanted variation related to demographics that jeopardizes overall fairness of organ allocation and needs to be further explored.


Spinal anesthesia does not impact prostate cancer recurrence in a cohort of men undergoing radical prostatectomy: an observational study.
Prior studies suggest a possible association between the use of neuraxial-general anesthesia and a decrease in prostate cancer recurrence after radical prostatectomy. We examine the correlation of a spinal anesthesia-only technique on prostate cancer recurrence. Charts from consecutive radical prostatectomy patients of 3 experienced urologists from January 1999 to December 2005 were reviewed. In addition to the usual clinical and pathologic predictors of disease recurrence, patient records were queried for the type of anesthesia (general vs spinal) performed. A Cox proportional hazards model was used to determine the statistical significance of predictors of biochemical recurrence. A total of 1964 patients-1166 and 798 receiving spinal with sedation or general anesthesia, respectively-had complete preoperative and follow-up data. In univariate proportional hazards analysis, the use of general anesthesia was associated with a trend toward an increased risk of biochemical recurrence when compared with the use of spinal anesthesia (hazard ratio, 1.29; 95% confidence interval, 0.99-1.66; P = 0.053). In multivariable analysis, the effect size (hazard ratio, 1.10; 95% confidence interval, 0.85-1.42; P = 0.458) was diminished by clinical and pathologic variables. This was a retrospective study of patients with prostate cancer who have undergone radical prostatectomy during a time period when the practice of anesthesia for prostatectomy at our institution was transitioned from spinal to general anesthesia. In our study, when controlling for other predictors of advanced prostate cancer, the type of anesthetic given during prostatectomy had no effect on the risk of biochemical recurrence.


Control of 5-aminolaevulinate synthetase activity in Rhodopseudomonas spheroides a role for trisulphides.
1. The aminolaevulinate synthetase activator of fresh extracts of semi-anaerobically grown Rhodopseudomonas spheroids was resolved into two fractions by ion-exchange chromatography. One fraction was identified as cystine trisulphide (CySSSCy). Analysis of the other fraction indicated the presence of about equal amounts of glutathione trisulphide (GSSSG) and the mixed trisulphide of glutathione and cystine (GSSSCy). 2. Four further fractions with activator activity were observed on ion-exchange chromatography of extracts prepared by methods similar to those described earlier [Neuberger et al. (1973)Biochem. J. 136,491-499]. These activators were generated by the extraction procedure. Two of them have been identified as trisulphanedisulphonate (S5O62-) and additional cystine trisulphide. 3. For the series of polysulphanedisulphonates (-O3S-Sn-SO3-, n greater than or equal to 1), activator activity at muM concentrations was exhibited only by compounds with n greater than 3. This, together with the results described above, indicates that for a compound R-Sn-R' (where R and R' are organic or inorganic groups) the only structural requirement for activity is n greater than or equal to 3. 4. Oxygenation of a semipanaerobic culture of R. spheroids for 1.5h before harvesting the cells produced a decrease of more than 90% in the cellular content of cystine trisulphide and glutathione trisulphides. 5. Chromatography on DEAE-Sephadex confirmed the presence of multiple forms of aminolaevulinate synthetase in extracts of R. spheroides [Tuboi et al. (1970) Arch.Biochem. Biophys. 138,147-154]. Oxygenation of a semi-anaerobic culture resulted in the disappearance of high-activity enzyme (a-form) and the accumulation of low-activity enzyme (b-form) in the cell. Spontaneous activation [Marriott et al. (1969) Biochem. J. 111,385-394] And activation by cystine trisulphide both resulted in the almost complete conversion of the b-form into the a-form.


El Niño/Southern Oscillation and tropical Pacific climate during the last millennium.
Any assessment of future climate change requires knowledge of the full range of natural variability in the El Niño/Southern Oscillation (ENSO) phenomenon. Here we splice together fossil-coral oxygen isotopic records from Palmyra Island in the tropical Pacific Ocean to provide 30-150-year windows of tropical Pacific climate variability within the last 1,100 years. The records indicate mean climate conditions in the central tropical Pacific ranging from relatively cool and dry during the tenth century to increasingly warmer and wetter climate in the twentieth century. But the corals also document a broad range of ENSO behaviour that correlates poorly with these estimates of mean climate. The most intense ENSO activity within the reconstruction occurred during the mid-seventeenth century. Taken together, the coral data imply that the majority of ENSO variability over the last millennium may have arisen from dynamics internal to the ENSO system itself.


Association of personality profiles with coping and adjustment to cancer among patients undergoing chemotherapy.
Specific personality traits are associated with differential use of various coping strategies. Few studies have examined the relationship between personality and coping in oncology patients undergoing chemotherapy. We, therefore, examined the relationship between previously identified personality profiles (ie, Distressed [14.3% of total sample], Normative [53.8%], Resilient [31.9%]) and measures of coping and adjustment. Patients (n = 1248) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer completed measures of personality (NEO-Five Factor Inventory), coping (Brief COPE), and psychological adjustment to cancer (Mental Adjustment to Cancer [MAC] scale). Differences in coping and adjustment among the three personality profiles were evaluated using analysis of variance. On the Brief COPE, the Distressed class endorsed lower use of Active Coping, Positive Reframing, Acceptance, Emotional Support (ie, "engagement" coping); and greater use of Denial, Venting, Behavioral Disengagement, Self-Blame (ie, "disengagement" coping) compared to the Normative and Resilient classes. On the MAC scale, the Distressed class scored higher on Anxious Preoccupation, Helplessness/Hopelessness, Fatalism, and Avoidance, and lower on Fighting Spirit, compared to the other two classes. In this sample of oncology patients receiving chemotherapy, patients in the Distressed personality class showed a reduced repertoire of adaptive coping strategies, while those in the Resilient class reported greater use of adaptive or engagement coping strategies. Further work should examine the potential mediating or moderating role of coping and adjustment in the relationships between personality and patient outcomes. Interventions to enhance beneficial and reduce harmful coping strategies in cancer patients should be evaluated.


Crystal structures of human pantothenate kinases. Insights into allosteric regulation and mutations linked to a neurodegeneration disorder.
Pantothenate kinase (PanK) catalyzes the first step in CoA biosynthesis and there are three human genes that express four isoforms with highly conserved catalytic core domains. Here we report the homodimeric structures of the catalytic cores of PanK1alpha and PanK3 in complex with acetyl-CoA, a feedback inhibitor. Each monomer adopts a fold of the actin kinase superfamily and the inhibitor-bound structures explain the basis for the allosteric regulation by CoA thioesters. These structures also provide an opportunity to investigate the structural effects of the PanK2 mutations that have been implicated in neurodegeneration. Biochemical and thermodynamic analyses of the PanK3 mutant proteins corresponding to PanK2 mutations show that mutant proteins with compromised activities and/or stabilities correlate with a higher incidence of the early onset of disease.


[Recent knowledge on the role of diastolic blood pressure in hypertensive patients on treatment].
Numerous epidemiological studies have shown that the lower the blood pressure the lower the cardiovascular risk. On the other hand, intervention studies with antihypertensive agents in patients with systolic-diastolic or isolated systolic hypertension have shown that the antihypertensive treatment decreases the incidence of cardiovascular events: however it is still undefined which is the better blood pressure goal to reach during antihypertensive therapy. Observational studies and secondary analysis of large randomized trials have shown that treated hypertensive patients with diastolic values below some critical levels have a higher incidence of deaths and cardiovascular events. Studies on different populations evaluated with different protocols have given non-uniform results and many hypothesis have been suggested as causes of low diastolic pressure: 1) excessive antihypertensive treatment, 2) decreased compliance of aorta and large arteries and 3) clinical signs of a concomitant disease. Different studies suggest that diastolic blood pressure values lower than 70-80 mmHg, independently from the responsible physiopathological mechanisms, may rise the risk of cardiovascular events. Therefore, from the clinical point of view, extreme caution in the titration of the antihypertensive therapy for elevated systolic values when the range of diastolic blood pressure is below 70-80 mmHg.


Elective surgery scheduling under uncertainty in demand for intensive care unit and inpatient beds during epidemic outbreaks.
Amid the epidemic outbreaks such as COVID-19, a large number of patients occupy inpatient and intensive care unit (ICU) beds, thereby making the availability of beds uncertain and scarce. Thus, elective surgery scheduling not only needs to deal with the uncertainty of the surgery duration and length of stay in the ward, but also the uncertainty in demand for ICU and inpatient beds. We model this surgery scheduling problem with uncertainty and propose an effective algorithm that minimizes the operating room overtime cost, bed shortage cost, and patient waiting cost. Our model is developed using fuzzy sets whereas the proposed algorithm is based on the differential evolution algorithm and heuristic rules. We set up experiments based on data and expert experience respectively. A comparison between the fuzzy model and the crisp (non-fuzzy) model proves the usefulness of the fuzzy model when the data is not sufficient or available. We further compare the proposed model and algorithm with several extant models and algorithms, and demonstrate the computational efficacy, robustness, and adaptability of the proposed framework.


Changes in macular pigment optical density and serum concentrations of lutein and zeaxanthin in response to weight loss.
The objective of the present study was to investigate whether weight loss is associated with changes in serum concentrations of lutein (L) and zeaxanthin (Z), and/or macular pigment optical density (MPOD). We recruited 104 overweight subjects into this randomised controlled weight loss study. For the intervention group (I group), weight was assessed weekly and body composition, including BMI (kg/m2) and body fat (kg and percentage), was assessed at baseline, 6 and 12 months. Weight loss was encouraged using dietary and exercise programmes. MPOD was measured by heterochromatic flicker photometry and serum concentrations of L and Z by HPLC (at baseline, 1, 3, 6 and 12 months). The control (C) group was assessed at baseline and 12 months. Repeated-measures ANOVA (RMA) demonstrated significant weight loss in the I group over the study period (P = 0·000). There was no significant weight change in the C group (P = 0·993). RMA of dietary L and Z, serum L and Z, and MPOD demonstrated no significant time or time × group interaction effect in any of these parameters (P>0·05 for all), with the exception of a significant decrease in the dietary intake of Z seen in both groups, over the study period (P < 0·05). There was a positive and significant relationship between body fat loss (kg) and increase in serum concentrations of L in the I group (r 0·521; P = 0·006). Our finding that a reduction in body composition (e.g. fat mass) is related to increases in serum concentrations of L is consistent with the hypothesis that body fat acts as a reservoir for this carotenoid, and that weight loss can positively influence circulating carotenoid levels.


Current Diagnosis and Management of Primary Chylomicronemia.
Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.


'Role of bone marrow stromal cells in the growth of human multiple myeloma.
We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast-like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.


Hyperthyroidism and familial hypertrophic cardiomyopathy.
A kindred with a high incidence of hypertrophic cardiomyopathy (HC) was studied to identify the presence of clinical hyperthyroidism. Two and possibly three members with HC had associated hyperthyroidism. In the propositus, clinical, ECG, and vectorcardiographic evidence for HC resolved after treatment of the hyperthyroidism. We hypothesize that the disproportionately high correlation of hyperthyroidism and HC and the resolution found in the propositus after treatment may indicate that antithyroid therapy should be considered in this form of cardiomyopathy.


Impact of central, obstructive and mixed apnea on cerebral hemodynamics in preterm infants.
The objective of this study was to evaluate the effect of central, obstructive and mixed apnea on cerebral total hemoglobin concentration (tHb), which is analogous to cerebral blood volume, and to investigate whether tHb alterations correlate with bradycardia and arterial desaturation. Measurements were carried out on 17 preterm infants (gestational age 26-30 weeks) with frequent apneic events. Near infrared spectrophotometry (NIRS) was used to quantify changes in tHb. Respiration was monitored by chest movements using impedance pneumography and by nasal airflow using a thermistor. In addition, heart rate, arterial oxygen saturation, in each infant and esophageal pressure in 3 babies were continuously recorded. 130 apneic episodes of > 10 s duration showed four different patterns of tHb alterations: (1) no change in tHb (28%); (2) isolated decrease (35%); (3) isolated increase (12%), or (4) both combined, an initial decrease followed by an increase over the previous baseline level (25%). Obstructive apneic episodes were associated with a significantly greater maximum fall in tHb (median 11.5; 5th percentile 0 and 95th percentile 30.5 mumol/l) compared to mixed (4.9, 0 and 26.4 mumol/l) and central events (3.0, 0 and 14.0 mumol/l). Changes in tHb correlated with heart rate only in purely central apnea and were not reflected in arterial oxygen saturation in any type of apnea. Obstructive apnea was observed to have the strongest impact on tHb. As these tHb alterations may exacerbate or cause intraventricular hemorrhage, efforts must be made to prevent obstruction of upper airways and to focus monitoring on cerebral perfusion.


Novel High Oxygen Affinity Hemoglobin Variant in a Patient with Polycythemia: Hb Kennisis [β85(F1)Phe→Leu (TTT>TTG); HBB: c.258T>G].
We report the case of a 61-year-old Canadian male of Maltese descent investigated for unexplained polycythemia. Decreased p50 suggested the presence of a high oxygen affinity hemoglobin (Hb) variant. Molecular genetic testing demonstrated that he carries a novel missense mutation (HBB: c.258T>G), resulting in a Phe→Leu substitution at position 85 of the β chain. The novel Hb variant has been designated Hb Kennisis in recognition of where the proband resides. Two other missense mutations have been reported at this position [Hb Bryn Mawr or Hb Buenos Aires, β85(F1)Phe→Ser (HBB: c.257T>C); Hb Grantham, β85(F1)Phe→Cys; (HBB: c.257T>G)], both of which have increased oxygen affinity.


Management of sporadic duodenal adenomas and the association with colorectal neoplasms: a retrospective cohort study.
To evaluate management, outcome, and follow-up of patients with sporadic duodenal adenomas and assess the presence of colorectal neoplasms. With the widespread use of esophagogastroduodenoscopy, an increasing number of sporadic duodenal adenomas are diagnosed. An optimal algorithm for management has not been fully defined. Accumulating data suggest an association with colorectal neoplasms. Patients diagnosed with sporadic duodenal adenomas at our institute from 1986 until 2008 were retrospectively reviewed. Data were collected from medical records. Fifty-four patients (28 men, 52%) were diagnosed with a sporadic duodenal adenoma at a median age of 59 years (range, 27 to 84 y); 33 patients (61%) underwent endoscopic or surgical intervention, 5 (9%) were only followed endoscopically, and 16 (30%) underwent no intervention or follow-up. Complete endoscopic removal was accomplished in at least 81% of cases, and no complications were reported; surgical intervention was complicated in 4 patients, with 1 resulting in death. Adenoma recurrence was 20% at a median follow-up of 18 months (range, 4 to 54 mo), but no carcinoma developed. Colorectal neoplasms were found in 16 of 29 patients (55%) who underwent colonoscopy, including 2 cancers (7%), 7 advanced adenomas (24%), and 7 nonadvanced adenomas (24%). Although no consistent approach to management of sporadic duodenal adenomas was followed, no duodenal carcinoma developed during the follow-up. Endoscopic intervention is preferred over surgical intervention, whenever possible. Once complete removal is ascertained, there is no strict indication for regular follow-up esophagogastroduodenoscopy, especially in elderly patients or patients with relevant comorbidity. Colonoscopic assessment is warranted in all patients diagnosed with sporadic duodenal adenomas.


[Predicting the risk of nicotine dependence in youth].
The paper presents data of the mathematical models for predicting the risk of nicotine dependence development based on a careful study of multilateral smokers by 66 prognostic factors and selection of a minimal set of factors.


Contour interpolation by deep learning approach.
Contour interpolation is an important tool for expediting manual segmentation of anatomical structures. The process allows users to manually contour on discontinuous slices and then automatically fill in the gaps, therefore saving time and efforts. The most used conventional shape-based interpolation (SBI) algorithm, which operates on shape information, often performs suboptimally near the superior and inferior borders of organs and for the gastrointestinal structures. In this study, we present a generic deep learning solution to improve the robustness and accuracy for contour interpolation, especially for these historically difficult cases. A generic deep contour interpolation model was developed and trained using 16,796 publicly available cases from 5 different data libraries, covering 15 organs. The network inputs were a 128 × 128 × 5 image patch and the two-dimensional contour masks for the top and bottom slices of the patch. The outputs were the organ masks for the three middle slices. The performance was evaluated on both dice scores and distance-to-agreement (DTA) values. The deep contour interpolation model achieved a dice score of 0.95 ± 0.05 and a mean DTA value of 1.09 ± 2.30 mm , averaged on 3167 testing cases of all 15 organs. In a comparison, the results by the conventional SBI method were 0.94 ± 0.08 and 1.50 ± 3.63 mm , respectively. For the difficult cases, the dice score and DTA value were 0.91 ± 0.09 and 1.68 ± 2.28 mm by the deep interpolator, compared with 0.86 ± 0.13 and 3.43 ± 5.89 mm by SBI. The t-test results confirmed that the performance improvements were statistically significant ( p < 0.05 ) for all cases in dice scores and for small organs and difficult cases in DTA values. Ablation studies were also performed. A deep learning method was developed to enhance the process of contour interpolation. It could be useful for expediting the tasks of manual segmentation of organs and structures in the medical images.


Loop-mediated isothermal amplification of a single DNA molecule in polyacrylamide gel-based microchamber.
Loop-mediated isothermal amplification (LAMP) is an original nucleic acid amplification method established by Notomi et al. LAMP is performed under isothermal condition, employing only a basic reaction protocol and minimal supporting electronics. These requirements prove to be viable for exploring the avenues to down-scale this biological reaction for Lab-on-a-chip application. Hence here, we developed a novel technique for fluorescent imaging of LAMP at a single molecule level. The experiment was conducted in a polyacrylamide (PAA) gel-based microchamber where a single DNA template, freely suspended in a solution containing primers and polymerase was initially encapsulated. In order to activate the amplification reaction, a microheater regulated by an automatic computerized feedback system was used for localized heating. This microchamber-based approach for LAMP demonstrated the effective exploitation of minute amount of templates and primers, and the overall reduction in LAMP detection time. An average efficiency of 80% was evaluated for conducting DNA amplification after 50 min of incubation at 65 degrees C. As the total time for reaction including detection can be completed in less than 1 h, this one-step, direct observation method displays the potential as a simple alternative to conventional techniques for genetic analysis and diagnosis in the clinical laboratory.


Testing adaptive plasticity to UV: costs and benefits of stem elongation and light-induced phenolics.
On exposure to ultraviolet radiation (UV), many plant species both reduce stem elongation and increase production of phenolic compounds that absorb in the UV region of the spectrum. To demonstrate that such developmental plasticity to UV is adaptive, it is necessary to show that the induced phenotype is both beneficial in inductive environments and maladaptive in non-inductive environments. We measured selection on stem elongation and phenolic content of seedlings of Impatiens capensis transplanted into ambient-UV and UV-removal treatments. We extended the range of phenotypes expressed, and thus the opportunity for selection in each UV treatment, by pretreating seedlings with either a low ratio of red:far-red wavelengths (R:FR), which induced stem elongation and reduced phenolic concentrations, or high R:FR, which had the opposite effect on these two phenotypic traits. Reduced stem length relative to biomass was advantageous for elongated plants under ambient UV, whereas increased elongation was favored in the UV-removal treatment. Selection favored an increase in the level of phenolics induced by UV in the ambient-UV treatment, but a decrease in phenolics in the absence of UV. These results are consistent with the hypotheses that reduced elongation and increased phenolic concentrations serve a UV-protective function and provide the first explicit demonstration in a wild species that plasticity of these traits to UV is adaptive. The observed cost to phenolics in the absence of UV may explain why many species plastically upregulate phenolic production when exposed to UV, rather than evolve constitutively high levels of these compounds. Finally, pretreatment with low R:FR simulating foliar shade did not exacerbate the fitness impact of UV exposure when plants had several weeks to acclimate to UV. This observation suggests that the evolution of adaptive shade avoidance responses to low R:FR in crowded stands will not be constrained by increased sensitivity to UV in elongated plants when they overtop their neighbors.


Skin manifestations of running.
As the United States comes increasingly closer to being the heaviest nation on earth, many people are turning to exercise, especially running, to lose weight. Most runners, whether novice or professional, will have a skin disorder that may prompt them to seek medical attention. Although case reports and sports reviews have discussed, in a cursory fashion, the nature of these skin lesions, to our knowledge there has never been an extensive review of the literature that specifically addresses the skin diseases of runners. In this article, we present the epidemiology, origin, clinical characteristics, treatment, and prevention of skin diseases inherent to runners.


[Diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. Findings of an autopsy].
Diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. Findings of an autopsy. Diffuse plane xanthomatosis is an uncommon subtype of non-Langerhans histiocytosis. We report a case of a 78 year-old woman with a history of monoclonal gammopathy of undetermined significance and diffuse plane xanthomatosis since 1995. She consulted for malaise and died four days after admission. Autopsy was requested. Findings were diffuse plane xanthomatosis with extensive involvement of internal organs, lymphoplasmacytic lymphoma and cecal adenocarcinoma. Final event was acute bronchopneumonia. This entity is a subtype of histiocytosis. It affects skin and involves mucous membranes in 40% of the cases. Extracutaneous extension has been reported. It is usually associated with haematologic disorders. In this case, the patient had a lymphoplasmacytic lymphoma and colonic adenocarcinoma. We highlight the importance of recognition its association with monoclonal gammopathies and solid tumors in order to make a proper follow up of patients.


Perspectives of mental healthcare providers on pathways to improved employment for persons with mental disorders in two lower middle-income countries.
Mental disorders affect employment and the ability to work, and mental healthcare providers are important in the promotion of health and employment for affected individuals. The objective of this study is to explore the perspectives of mental healthcare providers on pathways to improved employment for persons with mental disorders in two lower middle-income countries. Our study participants included mental healthcare providers (psychiatrists, occupational physicians, psychologists, and social care workers) from Kenya and Nigeria. Qualitative interviews and a focus group discussion were conducted with 15 professionals in Kenya and online questionnaires were completed by 80 professionals from Nigeria. The study participants suggested that work is important for the recovery and wellbeing of persons with mental disorders. A complex interplay of factors related to the health of persons with mental disorders and the socioeconomic system in their setting were identified as barriers to their work ability and employment. Participants proposed four pathways to improved employment: including information on reducing stigma, better healthcare, policy advocacy in employment, and government commitment to healthcare and social welfare. Public education to reduce stigma and better healthcare were the highest reported facilitators of employment. Persons with mental disorders require multilevel support and care in obtaining and retaining employment. A better mental healthcare system is essential for the employment of persons with mental disorders.


Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9.
Neutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients. To clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9). Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations. Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.


The gene regulatory network basis of the "community effect," and analysis of a sea urchin embryo example.
The "Community Effect" denotes intra-territorial signaling amongst cells which constitute a particular tissue or embryonic progenitor field. The cells of the territory express the same transcriptional regulatory state, and the intra-territorial signaling is essential to maintenance of this specific regulatory state. The structure of the underlying gene regulatory network (GRN) subcircuitry explains the genomically wired mechanism by which community effect signaling is linked to the continuing transcriptional generation of the territorial regulatory state. A clear example is afforded by the oral ectoderm GRN of the sea urchin embryo where cis-regulatory evidence, experimental embryology, and network analysis combine to provide a complete picture. We review this example and consider less well known but similar cases in other developing systems where the same subcircuit GRN topology is present. To resolve mechanistic issues that arise in considering how community effect signaling could operate to produce its observed effects, we construct and analyze the behavior of a quantitative model of community effect signaling in the sea urchin embryo oral ectoderm. Community effect network topology could constitute part of the genomic regulatory code that defines transcriptional function in multicellular tissues composed of cells in contact, and hence may have arisen as a metazoan developmental strategy.


The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder.
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication in organ transplant recipients and is most often associated with the Epstein Barr virus (EBV). EBV is a common gammaherpes virus with tropism for B lymphocytes and infection in immunocompetent individuals is typically asymptomatic and benign. However, infection in immunocompromised or immunosuppressed individuals can result in malignant B cell lymphoproliferations, such as PTLD. EBV+ PTLD can arise after primary EBV infection, or because of reactivation of a prior infection, and represents a leading malignancy in the transplant population. The incidence of EBV+ PTLD is variable depending on the organ transplanted and whether the recipient has preexisting immunity to EBV but can be as high as 20%. It is generally accepted that impaired immune function due to immunosuppression is a primary cause of EBV+ PTLD. In this overview, we review the EBV life cycle and discuss our current understanding of the immune response to EBV in healthy, immunocompetent individuals, in transplant recipients, and in PTLD patients. We review the strategies that EBV uses to subvert and evade host immunity and discuss the implications for the development of EBV+ PTLD.


Relating economic conditions to vasectomy and vasectomy reversal frequencies: a multi-institutional study.
It was theorized that the use of permanent contraceptive methods may vary with economic conditions. We evaluated the relationship between vasectomy/vasectomy reversal frequencies at several large referral centers and national economic indicators during 2 recessions spanning 2001 to 2011. We performed an institutional review board approved, retrospective chart review to identify the number of vasectomies/vasectomy reversals per month at several large referral centers from January 2001 to July 2011. The rates of these procedures were pooled, correlated with national economic data and analyzed in a multivariate linear regression model. A total of 4,599 vasectomies and 1,549 vasectomy reversals were performed at our institutions during the study period. The number of vasectomies per month positively correlated with the unemployment rate (r=0.556, p<0.001) and personal income per capita (r=0.276, p=0.002). The number of reversals per month negatively correlated with the unemployment rate (r=-0.399, p<0.001) and personal income per capita (r=-0.305, p<0.001). Neither vasectomy nor vasectomy reversal frequency significantly correlated with the inflation rate or the S&P 500®. Regression models confirmed that the unemployment rate explained more of the variance in vasectomy/vasectomy reversal frequencies than other indicators. We noted a correlation between the number of vasectomies/vasectomy reversals performed at our institutions and national economic indicators. The strongest association was with the unemployment rate. This points to the importance of financial pressure on family planning decisions.


An evaluation of a renewal-mitigation procedure for inappropriate mealtime behavior.
Renewal, the increase in behavior during extinction following context changes, may be particularly concerning during intervention for feeding disorders because context changes are often necessary for intervention generality and maintenance (Podlesnik et al., 2017). In the current study, we tested for renewal and evaluated a renewal-mitigation procedure when we transferred intervention from a therapist to a caregiver, from clinic to the home, and changed the foods the feeder presented. We used an ABA arrangement to evaluate the generality of the renewal effect with 7 participants who engaged in inappropriate mealtime behavior. Context A was functional reinforcement. Context B was function-based extinction during the control and mitigation conditions and our renewal-mitigation procedure in the mitigation condition. The renewal test was function-based extinction in Context A. We observed renewal of inappropriate mealtime behavior in 4 of 7 participants, and our renewal-mitigation procedure was effective for 4 of 4 participants.


Synthesis of modified methyl furanosides by intramolecular oxa-Michael reaction followed by Pummerer rearrangement.
A new method is described for the synthesis of ribofuranoses modified at the C3 and C5 positions. The key step is an intramolecular oxa-Michael reaction on a vinyl sulfoxide to install the C2 hydroxy group. The methyl furanosides are obtained by Pummerer rearrangement of the sulfoxide into the corresponding aldehyde, acidic deprotection of the benzylidene acetal, and cyclization.


The effectiveness of personal education plans in continuing professional development: an evaluation.
The aim of this study was to evaluate the use of personal education plans (PEPs) as a method of continuing professional development (CPD), by means of a questionnaire, analysis of completed PEP reports, and in-depth interviews. The setting was the Yorkshire Deanery, and the participants were general practitioners (GPs) who had completed a PEP. The main outcome measures were reported identification of learning needs, educational methods used, and support received. GPs' views were received on their experiences of undertaking PEPs, personal and professional development, and changes in patient care that resulted from their PEPs. Personal impression was the most frequently used method of deciding on learning needs. A variety of educational methods were used, the most frequent being personal reading, practical sessions, and taught courses. The majority of respondents felt that they were well supported by their GP tutors, and that the PEP had helped them to enhance their personal knowledge and skills, as well as to improve service to patients. There were gains in terms of increased confidence and self-awareness. Most were keen to use PEPs in future, and hoped to involve other members of the practice. Our results suggest that PEPs are an effective method of CPD in that they frequently lead to reported changes in patient care, and personal and professional development of the learner.


Value of selective venous catheterization in the diagnosis of hyperandrogenism.
To discuss the clinical utility of ovarian vessel sampling in the context of the evaluation and treatment of ovarian hyperthecosis. Patient presentation in video format, ovarian vessel sampling demonstration, surgical technique explanation, surgical histology discussion and ovarian hyperthecosis review. Academic medical center. A 30-year-old nulligravid female presented with severe hyperandrogenic features, consistent with polycystic ovary syndrome. During the course of her diagnostic evaluation, she underwent selective ovarian and adrenal vein sampling. Assessment of ovarian vessel testosterone levels and review of final histologic findings. Selective ovarian and adrenal vein sampling revealed right ovarian testosterone levels that were 200 times the upper limit of normal. As occult malignancy was a concern, laparoscopy was performed, with nearly complete removal of the right ovarian stroma. Pathology revealed ovarian stromal hyperthecosis without evidence of malignancy. Selective venous sampling is a technically challenging procedure, which may help localize an occult malignancy in limited circumstances. In utilizing selective venous sampling, one must consider the limitations of the test, potential for false positive results, and possibility of unnecessary surgical interventions.


Unique Substrate Recognition and Sodium-Substrate Binding Stoichiometry in a Bacterial Serotonin Transporter, TuriSERT.
All resolved high-resolution structures of the transporters in the neurotransmitter sodium symporter (NSS) family revealed that the NSS members share common structural and mechanistic features for substrate and ion binding and transport. However, a recently reported bacterial orthologue of the human serotonin transporter (hSERT), TuriSERT, possesses a structural characteristic specific for amino acid substrate binding but does transport a biogenic amine. The unique structural feature of TuriSERT requires a novel configuration for coordinating its substrate and ions. In the present study, we characterized TuriSERT expressed in Escherichia coli cells with a fluorescent substrate by biochemical, structural, and pharmacological approaches. Substrate transport by TuriSERT requires Na+ but not Cl-. Replacement of Asp262 by asparagine renders TuriSERT Cl--dependent. Substitutions of the corresponding Na1 residues did not alter Na+ dependence on substrate transport, whereas the mutation of a Na2 site residue led to a loss of transport activity, suggesting that Na+ binds only to the Na2 site in TuriSERT. In addition, substitutions of several residues essential for recognizing 5-hydroxytryptamine (5-HT) in hSERT had little effect on 5-HT displacement potency in transport assay for TuriSERT. In contrast, mutations of the residues that are proposed to coordinate with 5-HT in our docking model dramatically reduced 5-HT displacement. Furthermore, our results indicated that all tested antidepressants showed a weak inhibitory effect on TuriSERT. The present study demonstrated the existence of a unique substrate binding site and 1:1 stoichiometry of sodium-substrate binding in TuriSERT, a novel structural finding for the NSS transporters.


Wnt10b induces chemotaxis of osteosarcoma and correlates with reduced survival.
Osteosarcoma (OS) is a primary malignant tumor of the bone that typically presents in the second decade of life and has a poor prognosis, especially in metastatic cases. Wnt signaling contributes to the pathogenesis of tumors such as colon cancer and malignant melanoma. Wnt signaling controls normal bone formation during embryogenesis and homeostasis in adult organisms, thus we evaluated Wnt signaling in OS. We surveyed the expression of Wnts, their receptors, Frizzleds and LRPs, and soluble Wnt inhibitors (sFRPs) in four OS cell lines by RT-PCR. We also tested biological response of OS cell lines to exogenous Wnts by measuring beta-catenin stabilization, Dvl phosphorylation, TOPFLASH activity and chemotaxis. Human OS tumor microarrays were evaluated for expression of Wnt10b by immunohistochemistry. All cell lines tested showed expression of at least three Wnts and one Frizzled. Exogenous Wnt3a and Wnt10b treatment induced Dvl phosphorylation, beta-catenin stabilization and TCF4 transcriptional activity in both metastatic and non-metastatic murine OS cell lines. Metastatic OS cell lines showed better chemotaxis response to Wnts than the non-metastatic OS cell lines. Immunohistochemistry studies of 44 human OS samples demonstrated that Wnt10b expression correlated with decreased overall survival. These results further supports a possible autocrine or paracrine Wnt pathway in metastatic potential of OS.


Giant Condyloma Acuminate Due to Human Papillomavirus Type 16 in an Infant Successfully Treated with Topical Imiquimod Therapy.
Anogenital warts related to human papillomavirus (HPV) have been observed in children. Definition of the transmission mode, therapy, and follow-up for long term potential complications is important. A 27-month old girl was admitted with multiple pedunculated red-purple colored cauliflower-like lesions of 1.5 years duration. Clinical/histopathological and microbiological diagnosis was condyloma acuminate due to HPV type 16. After 12 weeks of imiquimod 5% cream application (pea-sized) overnight three times per week, the perianal warts had completely disappeared. The mode of transmission of HPV 16 in our case was probably horizontal, related to the sharing of common personal hygiene items in the women's shelter. We report herein the case of an infant living in a women's shelter with giant condyloma acuminata due to HPV 16, which was successfully treated with topical imiquimod therapy. This patient should be followed up for recurrence and potential malignant lesions related to HPV type 16.


Comparative Study of Salivary, Duodenal, and Fecal Microbiota Composition Across Adult Celiac Disease.
Growing evidence suggests that an altered microbiota composition contributes to the pathogenesis and clinical features in celiac disease (CD). We performed a comparative analysis of the gut microbiota in adulthood CD to evaluate whether: (i) dysbiosis anticipates mucosal lesions, (ii) gluten-free diet restores eubiosis, (iii) refractory CD has a peculiar microbial signature, and (iv) salivary and fecal communities overlap the mucosal one. This is a cross-sectional study where a total of 52 CD patients, including 13 active CD, 29 treated CD, 4 refractory CD, and 6 potential CD, were enrolled in a tertiary center together with 31 controls. A 16S rRNA-based amplicon metagenomics approach was applied to determine the microbiota structure and composition of salivary, duodenal mucosa, and stool samples, followed by appropriate bioinformatic analyses. A reduction of both α- and β-diversity in CD, already evident in the potential form and achieving nadir in refractory CD, was evident. Taxonomically, mucosa displayed a significant abundance of Proteobacteria and an expansion of Neisseria, especially in active patients, while treated celiacs showed an intermediate profile between active disease and controls. The saliva community mirrored the mucosal one better than stool. Expansion of pathobiontic species anticipates villous atrophy and achieves the maximal divergence from controls in refractory CD. Gluten-free diet results in incomplete recovery. The overlapping results between mucosal and salivary samples indicate the use of saliva as a diagnostic fluid.


STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells.
Recent studies have highlighted characteristics of T regulatory cells (Tregs) that underlie their suppressive function. However, mechanisms that override their suppressive function in the context of an adaptive immune response are not well understood. In the lungs of mice undergoing allergic inflammation, appreciable numbers of Tregs were identified that possessed suppressive function when assayed ex vivo. We investigated whether the Th2-promoting cytokine IL-4 played a permissive role that superseded Treg function, thereby allowing the development of allergic inflammation. IL-4 signaling via the IL-4Ralpha-STAT6 axis was required to maintain Foxp3 expression in Tregs and promote their proliferation. However, the results of both in vivo experiments involving adoptive transfer of Tregs into Ag-sensitized vs naive animals and in vitro suppression assays performed with or without exogenous IL-4 showed the ability of IL-4 to compromise Treg-mediated suppression. Use of retrovirally expressed, constitutively active STAT6 revealed that the underlying mechanism was not IL-4-mediated dysfunction of Tregs but involved the resistance of Th cells to Treg-mediated suppression that would permit the development of an adaptive immune response. Our data suggest that infectious tolerance, mediated by membrane-bound TGF-beta expressed by Tregs, is compromised by the competing effects of IL4-induced signaling in naive CD4(+) Th cells.