Evaluation of vector competence for West Nile virus in Italian Stegomyia albopicta (=Aedes albopictus) mosquitoes.
West Nile virus (WNV) is a zoonotic arboviral pathogen transmitted by mosquitoes in a cycle that involves wild birds as reservoir hosts. The virus is responsible for outbreaks of viral encephalitis in humans and horses. In Europe, Culex pipiens (Diptera: Culicidae) is considered to be the main vector of WNV, but other species such as Stegomyia albopicta (=Aedes albopictus) (Diptera: Culicidae) may also act as competent vectors of this virus. Since 2008 human cases of WNV disease have been reported in northeast Italy. In 2011, new areas of southern Italy became involved and a first outbreak of WNV lineage 1 occurred on the island of Sardinia. On the assumption that a potential involvement of St. albopicta in WNV transmission cannot be excluded, and in order to evaluate the competence of this species for the virus, an experimental infection of an St. albopicta laboratory colony, established from mosquitoes collected in Sardinia, was carried out. The results were compared with those obtained in a colony of the main vector Cx. pipiens. The study showed St. albopicta collected on Sardinia to be susceptible to WNV infection, which suggests this Italian mosquito species is able to act as a possible secondary vector, particularly in urban areas where the species reaches high levels of seasonal abundance.


Chemical composition, mass size distribution and source analysis of long-range transported wildfire smokes in Helsinki.
Special episodes of long-range transported particulate (PM) air pollution were investigated in a one-month field campaign at an urban background site in Helsinki, Finland. A total of nine size-segregated PM samplings of 3- or 4-day duration were made between August 23 and September 23, 2002. During this warm and unusually dry period there were two (labelled P2 and P5) sampling periods when the PM2.5 mass concentration increased remarkably. According to the hourly-measured PM data and backward air mass trajectories, P2 (Aug 23-26) represented a single, 64-h episode of long-range transported aerosol, whereas P5 (Sept 5-9) was a mixture of two 16- and 14-h episodes and usual seasonal air quality. The large chemical data set, based on analyses made by ion chromatography, inductively coupled plasma mass spectrometry, X-ray fluorescence analysis and smoke stain reflectometry, demonstrated that the PM2.5 mass concentrations of biomass signatures (i.e. levoglucosan, oxalate and potassium) and of some other compounds associated with biomass combustion (succinate and malonate) increased remarkably in P2. Crustal elements (Fe, Al, Ca and Si) and unidentified matter, presumably consisting to a large extent of organic material, were also increased in P2. The PM2.5 composition in P5 was different from that in P2, as the inorganic secondary aerosols (NO3-, SO4(2-), NH4+) and many metals reached their highest concentration in this period. The water-soluble fraction of potassium, lead and manganese increased in both P2 and P5. Mass size distributions (0.035-10 microm) showed that a large accumulation mode mainly caused the episodically increased PM2.5 concentrations. An interesting observation was that the episodes had no obvious impact on the Aitken mode. Finally, the strongly increased concentrations of biomass signatures in accumulation mode proved that the episode in P2 was due to long-range transported biomass combustion aerosol.


From continuous flow analysis to programmable Flow Injection techniques. A history and tutorial of emerging methodologies.
Automation of reagent based assays, also known as Flow Analysis, is based on sample processing, in which a sample flows towards and through a detector for monitoring of its components. The Achilles heel of this methodology is that the majority of FA techniques use constant continuous forward flow to transport the sample - an approach which continually consumes reagents and generates chemical waste. Therefore the purpose of this report is to highlight recent developments of flow programming that not only save reagents, but also lead by means of advanced sample processing to selective and sensitive assays based on stop flow measurement. Flow programming combined with a novel approach to data harvesting yields a novel approach to single standard calibration, and avoids interference caused by refractive index. Finally, flow programming is useful for sample preparation, such as rapid, extensive sample dilution. The principles are illustrated by selected references to an available online tutorial http://www.flowinjectiontutorial,com/.


Gender differences in the prediction of problem alcohol use in adulthood: exploring the influence of family factors and childhood maltreatment.
The purpose of this study was to contrast men and women in prospective relationships among family-oriented and alcohol-related variables obtained during adolescence, childhood physical, emotional and sexual abuse collected retrospectively, and later adult problem alcohol use. In structural equation models, early family processes (support/bonding, parent drug-use problems, parental divorce and childhood maltreatment) and prior alcohol use simultaneously predicted adult problem alcohol use at two later time points in a longitudinal community sample of 426 (305 female) adults. Significant relationships were found among family processes, childhood maltreatment, and problem alcohol use within time and longitudinally for both men and women. Greater family support/bonding during adolescence predicted less problem alcohol use in adulthood. Men and women who experienced sexual abuse as a child reported more problem alcohol use in adulthood. Problem alcohol use was stable across time. Men reported more problem alcohol use in adolescence and adulthood, and women reported more early sexual abuse. These results contradict those that find no significant relationships between childhood abuse and subsequent alcohol-related problems. Parental drug use problems during the participant's adolescence did not directly predict problem alcohol use in adulthood. The relationship was more indirect in that parental drug use was associated with family-related concomitants that in turn were significant predictors of more problem alcohol use in adulthood. The strong stability for problem alcohol use across the three time periods is a signal that alcohol use in adolescence should not be ignored; furthermore, family dynamics need attention in addressing problem alcohol use.


[Evaluation of the effects of experimental hypertension on monocyte-endothelial cell interactions].
Adhesion of monocytes to endothelial cells is considered as one of the initial factors leading on the long term to the development of atherosclerosis. We evaluated whether hypertension affects adhesion of monocytes on rat carotid endothelium, and whether this adhesion may be modified by a chronic treatment with L-arginine, the physiological precursor of nitric oxide (NO). Hypertension was induced in Dahl rats using a sodium-rich diet (8%), in the absence or the presence of L-arginine (1.25 mg/kg/day). After 1 month, the carotid arteries were isolated, opened longitudinally, and incubated in the presence of monocytes previously rendered fluorescent by incubation with tetramethyl rhodamine isothiocyanate (TRITC), and adherent cells were counted under fluorescence microscopy. Monocyte adhesion was minimal in carotid arteries isolated from normotensive rats (13 +/- 5, n = 8). Hypertension induced a marked, significant increase in monocyte adhesion (97 +/- 17; n = 10; p < 0.01 vs normotensive). This increased adhesion was significantly reduced by chronic treatment with L-arginine (37 +/- 13; n = 12, p < 0.05 vs untreated hypertensive). Thus, hypertension was associated with an increased adhesion of monocytes, which is probably due to a decrease production of NO. The increased adhesion was partly prevented by L-arginine, possibly secondary to an increased production of NO. Such an increased adhesion of monocytes may contribute to the increased cardiovascular risk in hypertension.


Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: a stereocontrolled diversity oriented route to oxindole derivatives.
An efficient and highly enantioselective Michael addition of nitroalkanes to 3-ylidene oxindoles is described, mediated by thiourea-based bifunctional organocatalysts. The stereochemistry at C(α) and C(β) centers is perfectly controlled, and the intermediate C-3 enolate is trapped with a second Michael acceptor. The developed one-pot three-component consecutive reactions generate up to four contiguous stereocenters, including the C-3 all-carbon quaternary center, in a perfectly defined configuration. The conversion of the β-nitro oxindole into the corresponding β-amino derivative discloses synthetically useful transformations, exploitable to generate pharmaceutically attractive molecular targets.


Using the atomic force microscope to observe and study the ultrastructure of the living BIU-87 cells of the human bladder cancer.
In this study, the ultrastructure of living BIU-87 cells of human bladder cancer was mapped using atomic force microscopy to reveal the dynamic change of single cancerous cell division. Simultaneously, the feasibility and functional reliability of the atomic force microscope (AFM) were established and a laboratory model using AFM to study living cancerous cells was created. In this experiment, BIU-87 cells of human bladder cancer were cultured by conventional methods and grown in gelatin-treated dishes. A thermostat was used for preserving the cell's living temperature. Scanning of these cells using AFM was carried out in physiologic condition. The AFM images of the ultrastructure of living BIU-87 cells as well as those of the cell's membrane and cytoskeleton were very clear. The dynamic phenomenon of single cell division was observed. It was concluded that the AFM was able to observe and depict the ultrastructure of living cells of human bladder cancer directly and in real time. This experimental model is expected to play an important role in elucidating the cancerous mechanism of bladder normal cells at the atomic or nanometer level.


Suicidal risk from TADS study was higher than it first appeared.
Completed suicides are a major cause of death in adolescents in Sweden. Forensic analysis of completed suicides in children and adolescents shows there is one completed suicide per 1000 children taking a selective serotonin re-uptake inhibitor (SSRI). In order to elucidate these events we undertook a study of the results and reporting of suicidal events in the Treatment of Adolescents with Depression Study (TADS). We conclude that a major, albeit underreported, finding in the TADS was the significant increase of suicidal events in the adolescents on antidepressant medication in comparison to the group on placebo medication. The proportions of suicidal events were 11% and 2.7% respectively. This increased risk of suicidal events might be related to the high incidence of medication with an SSRI in the group of completed suicides among Swedish adolescents.


The risk of volvulus in abdominal wall defects.
Congenital abdominal wall defects are associated with abnormal intestinal rotation and fixation. A Ladd's procedure is not routinely performed in these patients; it is believed intestinal fixation is provided by adhesions that develop post-repair of the defects. However, patients with omphalocele may not have adequately protective postoperative adhesions because of difference in the inflammatory state of the bowel wall and in repair strategy. The aim of this study is to describe the occurrence of midgut volvulus in patients with gastroschisis or omphalocele. A retrospective chart review was performed for all patients managed in a single institution born between 1/1/2000 and 12/31/2008 with a diagnosis of gastroschisis or omphalocele. Patient charts were reviewed through 12/31/2012 for occurrence of midgut volvulus or need for second laparotomy. Of the 206 patients identified with abdominal wall defects, 142 patients (69%) had gastroschisis and 64 patients (31%) had omphalocele. Patients' follow up ranged from 4 years to 13 years. The median gestational age was 36 weeks (26-41 weeks) and the median birth weight was 2.42 kg (0.8-4.87 kg). None of the patients with gastroschisis developed midgut volvulus, however two patients (3%) with omphalocele developed midgut volvulus. No patients with gastroschisis developed midgut volvulus. Therefore, the current practice of not routinely performing a Ladd's procedure is a safe approach during surgical repair of gastroschisis. The two cases of volvulus in patients with omphalocele may be related to less bowel fixation. It is necessary to examine current practice in regards to the need for assessing the risk of volvulus during omphalocele closure and counseling of these patients. This assessment may be achieved via routine examination of the width of the small bowel mesenteric base, whenever feasible; however, the sample size is relatively small to draw any definitive conclusions.


MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.
In order to characterize, at the clinical, molecular and imaging level, myopathies due to MYH7 gene mutations, MYH7 gene analysis was conducted by RT-PCR/SSCP/sequencing in two patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapulo-peroneal myopathy of unknown etiology. MYH7 gene studies revealed the 5533C>T mutation (Arg1845Trp) in both myosin storage myopathy and in 2 of the 17 scapulo-peroneal patients studied. 5533C>T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in our cohort of patients included asymptomatic hyperCKemia, scapulo-peroneal myopathy and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies in only half of biopsied patients (2/4). In conclusion, phenotypic and histopathological variability may underlie MYH7 gene mutation and the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations.


Infectious Hepatitis A and Enteric Hepatitis E.
Infectious hepatitis A and enteric hepatitis E have a peak incidence in late adolescence or young adulthood. Using a 14-year-old boy as an example, the authors trace the course of hepatitis A through the preicteric and icteric phases, the development of persistent jaundice, relapse, and liver failure. The discussion of hepatitis E addresses microbiology and clinical course of the condition.


A quest to find good primers for gene expression analysis of Candida albicans from clinical samples.
Biofilm production contributes to several human diseases, including oral candidiasis. Among the Candida species, Candida albicans is the most prevalent. The expression of virulence genes is implicated in the pathogenic potential of Candida biofilms. However, the evaluation of microbial gene expression from in vivo biofilm samples is not trivial, specifically, assessment via quantitative PCR (qPCR) can be a challenge because of several species present in clinical samples. Hence, the necessity of primers specificity. The aim of this study was to evaluate through in silico and in vitro analyses the specificity of published primers and newly designed primers for C. albicans virulence genes: ALS1, CAP1, CAT1, EFG1, HWP1, LIP3, PLB1, SAP1, SAP4, SOD1, SOD5 and ACT1 (normalizing gene). In silico analysis was performed through a PubMed search of articles with primer sequences that evaluated gene expression of C. albicans. Then, the sequence similarity of twenty-eight primers was checked through BLASTn and ClustalW2. The analysis of secondary structures was performed using mfold. When the primers did not present satisfactory characteristics (absence of secondary structures, not discrepant Tm of forward and reverse sequences and specificity) following in vitro analysis (i.e., end point PCR), new primers were designed using Beacon Designer™ and sequences obtained from the "Candida Genome Database". The selected primers were tested in vitro by end point PCR using a panel of genomic DNA from five different Candida species (C. albicans, Candida glabrata, Candida dubliniensis, Candida krusei, and Candida tropicalis). The resulting PCR products were visualized on agarose gel. qPCR reactions were performed to determine primers' optimal concentration and PCR efficiency. End point PCR demonstrated that published primers for the SAP1 and HWP1 were specific for C. albicans and the one for SOD1 reacted with C. albicans and C. dubliniensis. The sequence of primers designed for ACT1, ALS1 and HWP1 genes were specific for C. albicans, while the ones for CAP1, CAT1, EFG1, LIP3, and PLB1 were detected in C. albicans and C. dubliniensis. After optimization, all primers presented a single peak on melt curves, correlation coefficient of ≅1 and qPCR reaction efficiency of 90-110%, with slope of ≅-3.3. Therefore, these primers should be suitable for future gene expression analyses from clinical samples.


Controlled release of insulin from self-assembling nanofiber hydrogel, PuraMatrix™: application for the subcutaneous injection in rats.
The concept of this research is, using the acetyl-(Arg-Ala-Asp-Ala)₄-CONH₂ peptide hydrosol (PuraMatrix™, PM), to develop an new injectable formula of controlled insulin delivery for subcutaneous injection. PM has sol-gel phase transition behavior, and was developed as a scaffold in the field of tissue engineering. The aqueous media of the PM including insulin changed from a sol to a gel phase with increasing ion strength of phosphate ion and pH in working environments in vitro and in vivo. In this study, we examined the in vitro insulin dissolution behavior and the in vivo pharmacokinetics and pharmacodynamics after subcutaneous administration of PM-insulin sol (PM-Isol). In the in vitro release study, after PM-Isol was converted to a gel phase (PM-Igel), PM concentration-dependent and controlled release of insulin were observed at the final concentrations of PM between 0.1% and 2.0% (w/v). The PM-Isol is changed to gel form in vivo, and exhibited a sustained-release pharmacokinetics of insulin, where PM concentration-dependent prolongation of efficacy was found. The plasma glucose level markedly decreased, and the lowest plasma glucose level was maintained up to 24h when 2.0% (w/v) PM-Isol was administered subcutaneously to rats. The PM-Isol, we developed here, is applicable for the wild-type of insulin, and increased the bioavailability and hypoglycemic efficacy of insulin after subcutaneous injection. Hence, the PM is a useful inactive ingredient to produce various types of control-released system of insulin by making just a few changes in PM content of the formulation.


Endogenous protein C is essential for the functional integrity of human endothelial cells.
Circulating protein C (PC) plays a vital role as an anti-coagulant and anti-inflammatory mediator. We show here that human endothelial cells produce PC that acts through novel mediators to enhance their own functional integrity. When endogenous PC or its receptor, endothelial protein C receptor (EPCR), was suppressed by small interfering (si) RNA, human umbilical cord endothelial cell (HUVEC) proliferation was decreased and apoptosis elevated. Interestingly, PC or EPCR siRNA significantly increased HUVEC permeability, which is likely via reduction of the angiopoietin (Ang)1/Ang2 ratio and inhibition of the peripheral localization of the tight junction protein, zona occludins-1. In addition, PC or EPCR siRNA inhibited type IV collagen and matrix metalloproteinase-2, providing the first evidence that PC contributes to vascular basement membrane formation. These newly described actions of endogenous PC act to stabilize endothelial cells and enhance barrier function, to potentially promote the functional integrity of blood vessels.


Quantitative interactions between Pb2+ and Ca2+ homeostasis in cultured osteoclastic bone cells.
Cellular calcium homeostasis and calcium-mediated cell functions are conceptually attractive processes to be involved in the manifestation(s) of lead toxicity including impaired skeletal growth and cardiovascular and neurological dysfunction. Knowledge of Ca:Pb and Pb:Ca ratios in different structural and functional compartments of cells is essential for identifying, characterizing, and understanding the significance of Pb2+-Ca2+ interactions. Experiments were conducted to characterize the steady-state kinetic distribution and behavior of 45Ca in primary cultures of murine osteoclastic bone cells. Bone cells, derived from mouse calvaria, were enriched for osteoclasts by a sequential collagenase digestion and maintained in primary culture for 1 week. Cultures were labeled with 45Ca for two or 24 hr and the kinetic parameters were obtained by analysis of 45Ca washout curves. Cellular metabolism was based upon a model with three kinetic pools of intracellular Ca2+ containing approximately 45, 25, and 30% of the total cell calcium. In addition, we describe quantitative measurements of Ca:Pb and Pb:Ca ratios at important functional cell sites of Ca2+ transport and storage in intact cells. The intracellular relationships of Ca2+ and Pb2+ were calculated concurrently in individual cultures, using kinetic analysis of dual-label 45Ca and 203Pb washout curves. The Ca:Pb ratios of the rate constants and half-times were approximately 1:1, supporting the concept of similar cellular metabolism of the two elements. The Ca:Pb ratios for the kinetic pools and fluxes were considerably higher than 1:1. These in situ Ca:Pb relationships should be useful for designing and evaluating Ca-Pb studies with calmodulin, isolated mitochondria, and other individual components of the calcium messenger system. Moreover, these data demonstrate both similarities and differences in the kinetic distribution and behavior of Ca2+ and Pb2+ in osteoclastic bone cells.


Isolating Pediatric Mesenchymal Stem Cells with Enhanced Expansion and Differentiation Capabilities.
Mesenchymal stem cells/marrow stromal cells (MSCs) are attractive for applications ranging from research and development to use in clinical therapeutics. However, the most commonly studied MSCs, adult bone marrow MSCs (A-MSCs), are limited by significant donor variation resulting in inconsistent expansion rates and multilineage differentiation capabilities. We have recently obtained permission to isolate pediatric MSCs (P-MSCs) from surplus iliac crest bone chips. Here, we developed a simple and easily replicable isolation protocol yielding P-MSCs, which adhere to MSC defining guidelines. After confirming immunophenotypic marker expression, we compared expansion rates, senescence, morphology, and trilineage differentiation of P-MSCs to A-MSCs for multiple donors. We found P-MSCs have faster in vitro replication, consistently show significantly lower senescence, and are capable of more reproducible multilineage differentiation than A-MSCs. We, therefore, believe P-MSCs are a promising candidate for use in research applications and potentially as part of an allogeneic therapeutic treatment.


Harry M. Vars Research Award. Increase in lumbar spine bone mineral content in patients on long-term parenteral nutrition without vitamin D supplementation.
We had previously shown that short-term withdrawal of vitamin D in patients with metabolic bone disease complicating home parenteral nutrition (HPN) corrected osteomalacia. We therefore conducted a prospective study of the effect of long term withdrawal of vitamin D in patients on home parenteral nutrition. Baseline measurements of bone mineral content, serum levels of calcium, phosphorus, parathormone, 25-OH and 1,25 (OH)2D; urinary calcium; and bone mineral density were measured. Then all parenteral vitamin D was withdrawn and the above parameters were followed for a mean of 4.5 years. Lumbar spine bone mineral content (LSBMC) was 0.79 +/- 0.06 g/cm2 at the start of the study, well below the reference value, 1.16 +/- 0.13 g/cm2. Parathyroid hormone (PTH) (0.48 +/- 0.24 pmol/L) and 1,25-(OH)2D levels (22.8 +/- 7.9 pmol/L) were low and 25-hydroxyvitaniin D levels were normal (33.3 +/- 5.5 nmol/L) before removing vitandn D from the HPN solutions. After withdrawal of vitamin D for 4.5 +/- 0.2 years LSBMC increased from 0.79 +/- 0.06 to 0.93 0.07 g/cm2 (p < 0.005). Calcium phosphorus, magnesium and 25-hydroxyvitamin D did not change significantly, 1,25(OH)2D, and PTH levels became normal after withdrawal of vitamin D. In selected patients with depressed PTH levels, long-term withdrawal of vitamin D during HPN increases LSBMC and levels of PTH and 1,25(OH)2D. There is no reduction of the mean level of 25-hydroxyvitamin D.


Phylogenetic position of a renal coccidium of the European green frogs, 'Isospora' lieberkuehni Labbé, 1894 (Apicomplexa: Sarcocystidae) and its taxonomic implications.
'Isospora' lieberkuehni, an unusual isosporoid renal coccidium that parasitizes the European water frog was isolated from the edible frog, Rana kl. esculenta, in the Czech Republic. Sequencing of the small-subunit (SSU) rRNA gene showed that it belongs to the family Sarcocystidae, being closely related to a clade comprising members of the subfamily Toxoplasmatinae. The position within Sarcocystidae correlates with the mode of excystation via collapsible plates as postulated by previous authors. Phylogenetic, morphological and biological differences between 'Isospora' lieberkuehni and the other Stiedabody-lacking members of the genus Isospora justify separation of this coccidium on a generic level. Hyaloklossia Labbé, 1896 is the oldest available synonym and is herein re-erected. The original definition of the genus Hyaloklossia is emended based on recent observations.


Paediatric functional abdominal pain: significance of child and maternal health. A prospective study.
First, to what extent do general paediatric outpatients with functional abdominal pain experience other somatic and mental health symptoms compared with children in a population-based sample? Second, to what extent are such symptoms in both patients and their mothers associated with persistent child abdominal pain and functional disability? Ninety-four referred patients [mean age (SD) 11.1 (1.9) years, 62% girls] were assessed by questionnaires and a paediatric consultation at baseline and at follow-up after 6-9 months (94% follow-up participation). At baseline, somatic and mental health symptoms in the patients were compared with a population-based sample of 14,000 school children. Outcome at follow-up was patient self-reported abdominal pain and disability. Prognostic factors explored included patient and maternal somatic and mental health symptoms. The patients experienced significantly more somatic [e.g. headache (OR: 9.2; 95% CI: 5.9-14.6)] and emotional symptoms than the school children. Patient's older age and peer problems at baseline were significantly associated with more abdominal pain at follow-up, whereas patient's older age, emotional symptoms, prosocial behaviour and maternal somatic symptoms were associated with disability. Our results highlight the importance of focusing wider than just the patient's symptoms of abdominal pain in clinical practice and research.


Three-dimensional in vivo dynamic motion analysis of anterior cruciate ligament-deficient knees during squatting using geometric center axis of the femur.
Anterior cruciate ligament (ACL) injury often leads to symptoms of instability, which may cause meniscus injury, osteochondral lesions, and degenerative changes. For thorough evaluation of the effects of abnormal motion of ACL-deficient (ACLD) knees on the meniscus and articular cartilage, it is necessary to assess tibiofemoral motion in the medial and lateral compartments separately. Our aim was to determine if in vivo three-dimensional (3D) dynamic motion of ACLD knees differs from that of contralateral uninjured knees by assessing knee motion in the medial and lateral compartments respectively. A total of 22 patients with an isolated ACL-injured knee were examined. 3D to two-dimensional registration was used to determine 3D knee motion during squatting from full knee extension to full flexion for both ACLD and contralateral uninjured knees. The knee motion was evaluated by the movement of the geometric center axis of the femur projected onto the tibial axial plane. In ACLD knees the lateral femoral condyle was located significantly more posteriorly during nearly full extension than in contralateral uninjured knees. The range of anteroposterior translation of the medial femoral condyle was significantly greater than those of contralateral uninjured knees. Almost all of the contralateral uninjured knees demonstrated medial pivot motion, while the ACLD knees showed higher variance. The ACLD knees exhibited a motion pattern different from those of contralateral uninjured knees with higher variance. During nearly full extension of the ACLD knees, the lateral femoral condyle translated posteriorly and the screw-home movement seemed to be impaired. The ACL might have an important role in maintaining normal knee function, especially during the early flexion phase. The larger range of anteroposterior translation of the medial femoral condyle in ACLD knees may be associated with a risk of secondary meniscal injury and degenerative change in the articular cartilage. Level IV.


European patients' views on the responsiveness of health systems and healthcare providers.
Responsiveness to patients is now seen as a key characteristic of effective health systems. This study aimed to learn more about European people's views on the responsiveness of their country's health systems and healthcare providers. Telephone survey with random samples of the populations in Germany, Italy, Poland, Slovenia, Spain, Sweden, Switzerland and the UK using random digit dialling. Responses were obtained from 8119 people aged 16 and over. Just over half the respondents said that doctors always listened carefully to them, gave them time for questions and provided clear explanations. Respondents from Switzerland and the UK reported consistently high rates of satisfaction with doctors' communication skills, while respondents from Poland were significantly less satisfied. Younger people were more critical than older people. Expectations of patient involvement in treatment decisions were high, particularly among younger people, with 74% indicating a desire to be actively involved. Most respondents felt they should have a choice of primary care doctor, specialist doctor and hospital, but less than half felt they had sufficient information to make an informed choice. There were significant variations between the countries in reported levels of involvement and in satisfaction with opportunities for choice. The results suggest that many European patients want a more autonomous role in health care decision-making. Policy-makers and clinicians should consider how to narrow the gap between public expectations and patients' experience.


Midaortic syndrome and subarachnoid hemorrhage associated with ruptured middle cerebral artery aneurysm: case report and review of the literature.
We describe the presentation, screening, management, and clinical outcome of a 21-year-old man who sought care for a ruptured middle cerebral artery (MCA) aneurysm and midaortic syndrome (MAS). Only three cases of MAS and intracranial aneurysm rupture have previously been described in the literature. Cranial computed tomographic (CT) scanning, cerebral and abdominal angiography, and multislice three-dimensional CT angiography were used to evaluate intracerebral hemorrhage and to assess medically intractable hypertension in the patient. Digital subtraction angiography revealed a right MCA aneurysm, and multislice three-dimensional CT angiography revealed narrowing of the abdominal aorta. The patient's right MCA aneurysm was successfully clipped via a right pterional craniotomy. A narrowed abdominal aorta was confirmed by an abdominal aortic angiogram (performed at Day 5 after surgery) and then dilated by using percutaneous transcatheter angioplasty during the same session. The patient was normotensive even without antihypertensive medications. Neurological examination and postoperative cranial CT findings were within normal limits at the last follow-up examination, performed 4 months after the operation. Our patient is the first reported case of ruptured MCA aneurysm with MAS in an adult. The most important problem in the management of MAS associated with ruptured intracranial aneurysm is medically intractable hypertension, which may markedly increase the incidence of rebleeding. It is hard to achieve normotension unless the narrowed aorta and its branches are dilated. For these reasons, MAS should be considered in patients with medically intractable hypertension associated with ruptured intracranial aneurysm.


Executive functioning: developmental consequences on adolescents with histories of maltreatment.
Research suggests that children exposed to maltreatment have deficits in executive functioning (EF) but few studies have focused on the adolescent age group. We investigated whether maltreated adolescents had lower EF abilities compared to a group of non-maltreated adolescents. Forty adolescents with histories of child maltreatment, together with a comparison group of 40 non-maltreated adolescents matched for age, completed a comprehensive battery of EF tasks. Hierarchical multiple regression analyses, controlling for IQ, were carried out using each of the EF measures as dependent variables to examine group differences. Maltreated adolescents had significantly lower performance than non-maltreated adolescents on tasks assessing executive loaded working memory, fluency, and inhibition, although switching was not impaired. Emotional and behavioural difficulties (EBD) were included in additional regression analyses to examine whether these variables would explain the group differences. The inclusion of EBD variables had some effect on group differences, as expected, but did not eliminate them. These findings support the theory that impairments in EF may be one underlying reason why adolescents with histories of maltreatment struggle to cope both inside and outside the classroom.


Propranolol in yawning prophylaxis: a case report.
Yawning is a frequent behavior with circadian effects. Sometimes, its frequency is very high and it is disturbing. However, there is no evidence-based treatment for yawning. This is a case report of a man with severe yawning from about 2 years ago. Yawning reduced after taking propranolol. Current evidence suggests that propranolol may decrease yawning through its thermoregulation effect. It is worthwhile conducting controlled clinical trials to study whether propranolol is an effective treatment for yawning.


Carotid intima-media thickness and ACE-gene polymorphism in hemodialysis patients.
Carotid artery intima-media thickness (CIMT) has been used as a marker of atherosclerosis. An insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with various cardiovascular diseases. This study is aimed at evaluating early atherosclerotic involvement of carotid vessels and the relation to known risk factors and ACE gene I/D in hemodialysis (HD) patients. We measured CIMT using high-resolution B-mode ultrasonography in 51 non-diabetic HD patients and in 70 age- and sex-matched healthy controls, and evaluated the factors influencing CIMT. An I/D polymorphism in intron 16 of the gene coding for ACE was analysed by polymerase chain reaction. The mean CIMT was significantly higher in HD patients than in healthy subjects (p<0.0001). In multiple regression analysis, independent risk factors for increased CIMT in HD patients were predialysis systolic blood pressure (p<0.001) and ACE D allele (p<0.01). The present data suggest that CIMT is enlarged in HD patients. The ACE gene seems to be a candidate for influencing the CIMT and might therefore be involved in an HD patient's predisposition to the development of atherosclerosis.


Polyphenol rich botanicals used as food supplements interfere with EphA2-ephrinA1 system.
The Eph tyrosine kinase receptors and their ephrin ligands play a central role in several human cancers and their deregulated expression or function promotes tumorigenesis, inducing aggressive tumor phenotypes. Green tea extracts (GTE) have been recently found to inhibit Eph-kinase phosphorylation. In order to evaluate the potential contribution of edible and medicinal plants on EphA2-ephrinA1 modulation, 133 commercially available plant extracts used as food supplements, essential and fixed oils were screened with an ELISA-based binding assay. Nine plant extracts, rich of polyphenols, reversibly inhibited binding in a dose-dependent manner (IC₅₀ 0.83-24 μg/ml). Functional studies on PC3 prostate adenocarcinoma cells revealed that active extracts antagonized ephrinA1-Fc-induced EphA2-phosphorylation at non-cytotoxic concentrations (IC₅₀ 0.31-11.3 μg/ml) without interfering with EGF-induced EGFR activation, suggesting a specific effect. These findings could furnish an interesting starting point regarding the potential relationship between diet, edible plant secondary metabolites and Eph-ephrin system, suggesting their possible involvement in cancer development modulation.


The evidence of production or activation of a natriuretic factor in the liver.
The natriuretic activity was measured with the aid of bioassay in blood flowing out from the brain, kidney and liver before and after the expansion of extracellular space in dogs. In another experiments in rats the volume natriuresis and the natriuretic activity in blood were measured in controls and in animals with carbon tetrachloride liver dystrophy and pharmacological stimulation (dehydrocholic acid, Ca pantothenate, cyanocobalamin) of liver functions. In dogs, the level of natriuretic activity in blood flowing out of the liver before and after the expansion of extracellular fluid volume was significantly higher than that in arterial blood. In contrast, the natriuretic activity was not found in the blood flowing out of the brain and the kidney. In rats the experimental dystrophy of the liver decreased the content of a natriuretic factor in blood plasma and the expansion of extracellular space did not produce any natriuretic effect as compared to control rats. After pharmacological stimulation of the liver by dehydrocholic acid, Ca pantothenate and cyanocobalamine the volume expansion led to a significant increase of the excretion of sodium by the kidney and to the increase of the content of a natriuretic factor in blood plasma as compared to control rats. These facts are considered to support the view that a natriuretic factor is either synthesized or activated by the liver.


Diagnostic Performance of Retinopathy in the Detection of Diabetic Nephropathy in Type 2 Diabetes: A Systematic Review and Meta-Analysis of 45 Studies.
To conduct an evidence-based evaluation of diabetic retinopathy (DR) for the diagnosis of diabetic nephropathy (DN) in type 2 diabetics with kidney disease. We systematically searched PubMed, EMBASE, and the Cochrane Library from inception to June 27, 2018, including the reference lists of identified primary studies. A study was included if it (1) used DR as a diagnostic test for DN; and (2) used histological evaluation of renal tissues as the reference standard. The analysis included 45 studies (4,561 patients). A bivariate analysis yielded a sensitivity of 0.67 (95% CI 0.61-0.74) and a specificity of 0.78 (95% CI 0.73-0.82). The summary receiver operating characteristic curve analysis provided an area under the curve (AUC) of 0.79 (95% CI 0.76-0.83). In a setting of 41% prevalence of DN, the probability of DN would be 68% if the test of DR was positive, and the probability of DN would be 23% if it was negative. In addition, although the mean specificity of proliferative DR for the detection of DN was 0.99 (95% CI 0.45-1.00), the mean sensitivity was 0.34 (95% CI 0.24-0.44), and the AUC was 0.58 (95% CI 0.53-0.62). DR is helpful in diagnosing DN in persons with type 2 diabetes and kidney disease, but the severity of DR may not parallel the presence of DN.


High vulnerability to household food insecurity in a sample of Canadian renter households in government-subsidized housing.
To determine the prevalence and severity of household food insecurity and examine household material circumstances related to food insecurity in a sample of renter households in government-subsidized housing. Cross-sectional data from the 2010 Survey of Household Spending were used to determine the food insecurity status of 455 renter households living in the 10 provinces and receiving a government housing subsidy. Multivariable logistic regressions were conducted to examine the relationship between household characteristics describing material circumstances and food insecurity. One in two households was food insecure. Marginal, moderate and severe food insecurity affected 9.0%, 23.3% and 18.5% of households respectively. Household economic resources, as captured with after-tax income, after-rent income, or total expenditure, had an independent, inverse relationship with food insecurity. Among the other characteristics examined, more adults or children in the household, presence of a member with disability, and receipt of social assistance increased the odds of food insecurity, but receipt of social assistance lost statistical significance when controlling for total expenditure. Presence of a senior in the household was independently associated with lower odds of food insecurity. Our findings suggest that more effective income-based interventions are needed to address food insecurity among low-income households receiving government housing subsidies. A better integration of housing and income-based policies is necessary to support household food security among government-subsidized renter households.


Silicene beyond mono-layers--different stacking configurations and their properties.
We carry out a computational study on the geometric and electronic properties of multi-layers of silicene in different stacking configurations using state-of-the-art ab initio density functional theory based calculations. In this work we investigate the evolution of these properties with increasing number of layers (n) ranging from 1 to 10. Although a mono-layer of silicene possesses properties similar to those of graphene, our results show that the geometric and electronic properties of multi-layers of silicene are strikingly different from those of multi-layers of graphene. We observe that strong inter-layer covalent bonding exists between the layers in multi-layers of silicene as opposed to weak van der Waals bonding which exists between the graphene layers. The inter-layer bonding strongly influences the geometric and electronic structures of these multi-layers. Like bi-layers of graphene, silicene with two different stacking configurations AA and AB exhibits linear and parabolic dispersions around the Fermi level, respectively. However, unlike graphene, for bi-layers of silicene, these dispersion curves are shifted in the band diagram; this is due to the strong inter-layer bonding present in the latter. For n > 3, we study the geometric and electronic properties of multi-layers with four different stacking configurations, namely AAAA, AABB, ABAB and ABC. Our results on cohesive energy show that all the multi-layers considered are energetically stable. Furthermore, we find that the three stacking configurations (AAAA, AABB and ABC) containing tetrahedral coordination have much higher cohesive energy than the Bernal (ABAB) stacking configuration. This is in contrast to the case of multi-layers of graphene, where ABAB is reported to be the lowest energy configuration. We also observe that bands near the Fermi level in lower energy stacking configurations AAAA, AABB and ABC correspond to the surface atoms and these surface states are responsible for the semi-metallic character of these multi-layers.


Comparative effect of lymph node metastasis classified by the anatomical site or by the number of nodes involved on prognosis of patients with gastric cancer.
Lymph node metastasis (pN) is one of the most significant prognostic factors in patients with gastric cancer. The pN classification of the Japanese Gastric Cancer Association (JGCA) is based on the anatomical site of metastatic nodes from the primary tumor, whereas that of the International Union Against Cancer (UICC) is based on the number of nodes involved. The purpose of this study was to determine which system is more useful for predicting patient outcomes. From 1992 to 2002, a total of 318 patients at our hospital underwent surgical resection with lymph node dissection for primary gastric cancer. Their medical records were examined, and the overall survival rates were compared between the two pN classification systems. Under the JGCA system, there was a significant difference in patient survival between pN0 and pN1 and between pN1 and pN2 but not between pN2 and pN3. Under the UICC-TNM system, there was a significant difference in patient survival between all pN classes. When the JGCA-pN1 and JGCA-pN2 classes were regrouped as UICC-pN1 and UICC-pN2-3, respectively, the survival rate was still better for the UICC-pN1 class than for the UICC-pN2-3 class. The better differentiation of outcomes by the UICC-pN system suggests that the number of metastatic lymph nodes is more important than the anatomical site in predicting outcomes.


Medical Aid service overuse assessed by case managers in Korea.
This paper is a report of a study conducted to describe characteristics of overusers of the Medical Aid service, assess appropriateness of overusers' medical service use, and determine contributing factors to medical aid overuse in Korea. Medical Aid use in Korea has increased in recent years, but no systematic studies reported the characteristics of overusers and appropriateness of their medical service use. In a cross-sectional study, case managers conducted interviews, evaluated participants' insurance claim data, and determined overusers by the case managers' determination of the appropriateness of their medical service use and their expenditures during the year of 2006. Descriptive statistics, chi-square analysis, analysis of variance, and multiple logistic regression were used for data analysis. Most heavy users were elderly, female, less educated, and had stress, lower perceived health status and multiple clinic visits. Twenty-five per cent of inpatients and 63.9% of outpatients were classified as overusers. The average total cost per capita of an overuser was 43.3% higher than that of an optimal user. Age, education, stress, arthritis, multiple clinic visits and frequent clinic visit recommendations by providers were statistically significant contributing factors to the overuse. Preventive measures are needed to decrease the overuse of Medical Aid in Korea; such measures should focus on characteristics contributing to overuse, including the provider-induced demand for more clinic visits. Case managers could play an important role as gatekeepers, managers, and educators for optimal use of Medical Aid in Korea and elsewhere in the world that faces similar problems.


Ventilatory responses during varied stride and pedal frequencies.
The effects of limb movement frequency during walking and running and cycling at 60 and 90 rpm on the ventilatory responses were studied in 19 male subjects. Ten of the subjects were trained runners whereas nine of the subjects were trained cyclists. The runners completed walk and run exercise trials at equal levels of CO2 excretion (VCO2) and low (approximately 60) rpm and high (approximately 90) rpm cycling trials at equal VCO2 levels. The cyclists completed low and high rpm cycling trials at equal VCO2 levels. The cyclists were not tested on the walk/run trials as they had been tested previously and had been shown to have similar ventilatory responses when walking and running at equal VCO2 levels. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), end-tidal CO2 (PETCO2) and O2 (PETO2) tensions, and inspiratory (TI) and expiratory (TE) times were not found to differ significantly between the low and high pedal frequency trials for either the cyclists or the runners. No significant differences were found in estimated arterial CO2 tensions (PaCO2) or estimated alveolar ventilation (VA) between the cycling trials for either the runners or the cyclists. When comparing running to walking, the runners were found to have a greater VE and estimated VA. This was mediated by an increase in f as VT was found to decrease. The increased f was associated with a shortened TI as TE was not significantly different between the walk and run trials. End-tidal CO2 tension and estimated PaCO2 was significantly lower during the run trial as compared to the walk trial. These results suggest some form of neurogenic stimuli influencing ventilation in the runners while running. This same neurogenic influence is not present when cyclists run and when either cyclists or runners exercise on the bicycle. A possible source for the neurogenic stimuli is discussed.


Lung transplantation for cystic fibrosis.
Significant progress has been made since the first successful human heart-lung transplantation (HLT) for pulmonary vascular disease performed in 1981. The refinement of surgical techniques, use of cyclosporin as the main immunosuppressant, technique of distant organ procurement to expand the donor organ pool, and improved diagnosis and management of pulmonary infection and rejection have all contributed to this accomplishment. This has inevitably coincided with the extension of this procedure to other groups of patients with end stage heart and lung disease. Initially, HLT was offered to patients with cardiac disease associated with pulmonary hypertension. Because of the success, consideration was given to transplantation for parenchymal pulmonary diseases, initially pulmonary fibrosis and emphysema, and then suppurative lung disease such as in cystic fibrosis (CF). However, the application of HLT to patients with CF lagged behind because of concern related to the risk of sepsis, the systemic nature of the disease, malnourishment, and fear of recurrence of the epithelial CF defect in the transplanted lungs.


Tea and Brexit in the Commons.
Helena Cotton, BVA Public Affairs Manager, describes how BVA engaged a roomful of parliamentarians at our annual Afternoon Tea lobbying event held in the House of Commons on October 9.


Dexmedetomidine Improves Cerebral Ischemia-Reperfusion Injury in Rats via Extracellular Signal-Regulated Kinase/Cyclic Adenosine Monophosphate Response Element Binding Protein Signaling Pathway.
To investigate the mechanism of dexmedetomidine (Dex) in improving brain damage induced by cerebral ischemia-reperfusion injury in rats. Rats were randomly divided into a sham operation group, ischemia-reperfusion group, Dex group, piracetam group, and yohimbine + Dex group, with 12 rats per group. 2,3,5-Triphenyltetrazolium chloride staining was used to analyze cerebral infarct size. Hematoxylin-eosin staining and immunohistochemistry were used to observe brain damage caused by ischemia-reperfusion. Cognitive and memory functions was detected by Morris water maze test, and the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylated cyclic adenosine monophosphate response element binding protein (CREB) were measured by Western blot. Cognitive dysfunction was improved in the Dex group and the piracetam group compared with the ischemia-reperfusion group. Compared with the ischemia-reperfusion group, infarct size and neuronal cell death rates were decreased in the Dex group and the piracetam group. The expression of phosphorylated ERK1/2 and phosphorylated CREB in the Dex group was increased, whereas the expression of phosphorylated ERK1/2 and phosphorylated CREB in the yohimbine + Dex group was lower than in the Dex group (P < 0.05). Dex improved ischemic brain damage by promoting signal transduction of the ERK/CREB pathway, which may provide new ways for clinical treatment of cerebral ischemia-reperfusion injury.


Anomalous left coronary artery from pulmonary artery: autogenous arterial tube for aortic implantation.
Many surgical procedures for the implantation of anomalous left coronary artery from pulmonary artery have been described. A dual coronary system offers most benefit and is most advantageous for the patient. Two autogenous flaps of the pulmonary trunk and ascending aorta, without mobilizing the coronary artery, were created for use in this procedure. This technique was successfully used in an 8 month-old patient with severe myocardial dysfunction and moderate mitral regurgitation. This procedure allows 2 coronary systems to be repaired for any anatomic change of the left coronary artery without the use of prosthetic material. There were no technical complications. During the postoperative course minimal inotropic support was used. The magnetic resonance study, 11 months postoperative, showed wood flow of the left coronary artery and mild mitral regurgitation. The operative technique was simple and its execution easy. The follow-up in the intermediate and late period showed the growth of this endothelized tube.


Effects of water temperature and substrate type on spore production and release in eastern Tubifex tubifex worms infected with Myxobolus cerebralis.
Eastern Tubifex tubifex worms were exposed to Myxobolus cerebralis spores at 9, 13, 17, and 20 C in 1-L jars that contained sand, mud, or leaf litter as substrata. Beginning 60 days after exposure, water from each jar was filtered daily and examined for the presence of waterborne triactinomyxon spores (TAMs). On discovering a single TAM from an experimental jar, 48 T. tubifex worms from that jar were placed individually into 24-well plates. Spores released from individual infected T. tubifex worms were quantified to determine the first day of TAM release from infected worms, the infection rate, the total number of TAMs released per worm, and the duration of release. No TAMs were found in any of the jars incubated at 20 C or in uninfected, control worms at any temperature. The total number of TAMs released by infected worms in mud and sand was highest at 13 C compared with other temperatures. Infection rates among individual worms increased with temperature between 9 and 17 C. Higher temperatures (up to 17 C) induced earlier TAM releases among infected worms, and substratum did not influence this production parameter. The average duration of TAM release decreased as the temperature increased from 9 to 17 C, and there was a significant effect of substratum in the groups maintained at 13 and 17 C. In all temperature treatments between 9 and 17 C, the duration of release was least in the worms maintained in leaf litter, as was the total number of TAMs released during the experimental period and the median number of TAMs per production day.


Cellular immunity in pediatric uveitis.
To evaluate cellular immunity in children with uveitis, we used the flow cytometry method to study the T lymphocyte subpopulation in peripheral blood. Cytometric analysis of peripheral blood lymphocytes using fluorochrome-marked monoclonal antibodies was carried out in 29 children aged 6-18 years with parasitic uveitis (group A) and with uveitis of another etiology (group B). The control group consisted of 28 healthy children aged 6-15 years. A substantially higher percentage of B lymphocytes (19.0 +/- 6.03) was observed in the children with parasitic uveitis than was observed in the healthy children. Moreover, the absolute values were higher in groups A (1.60 +/- 0.53) and B (1.81 +/- 0.40) than in controls (1.50 +/- 0.38). The lowest percentage of CD4+ lymphocytes (34.25 +/- 6.06) and the highest percentage of CD8+ lymphocytes (31.14 +/- 6.50) was found in children with parasitic uveitis. The lowest index CD4+/CD8+ (1.29 +/- 0.53) in the group of children with parasitic uveitis reflected severe disorders in response regulation. However, the percentage values of natural killer cells was lower in the two groups of patients than in controls. These results suggest that quantitative changes in the subpopulation of peripheral blood lymphocytes are more pronounced in parasitic uveitis.


How to interpret randomised trials of test-treatment combinations: a critical evaluation of research on uterine Doppler test to predict, and aspirin to prevent, pre-eclampsia.
The methodology to evaluate either a test or treatment is well developed and understood. However, the design, conduct and interpretation of a combination of a test and a treatment in a single study are fraught with complexities. There are two distinct study designs to evaluate test-treatment combinations, with randomisation occurring either before or after the test. We present critical issues that need to be considered when evaluating and appraising test-treatment combinations, using the example of research on the uterine artery Doppler test to predict, and aspirin to prevent, pre-eclampsia.


Toward an integrative understanding of narrative and emotion processes in Emotion-focused therapy of depression: implications for theory, research and practice.
This paper addresses the fundamental contributions of client narrative disclosure in psychotherapy and its importance for the elaboration of new emotional meanings and self understanding in the context of Emotion-focused therapy (EFT) of depression. An overview of the multi-methodological steps undertaken to empirically investigate the contributions of client story telling, emotional differentiation and meaning-making processes (Narrative Processes Coding System; Angus et al., 1999) in EFT treatments of depression is provided, followed by a summary of key research findings that informed the development of a narrative-informed approach to Emotion-focused therapy of depression (Angus & Greenberg, 2011). Finally, the clinical practice and training implications of adopting a research-informed approach to working with narrative and emotion processes in EFT are described, and future research directions discussed.


Rh(III)-catalyzed relay carbenoid functionalization of aromatic C-H bonds: access to π-conjugated fused heteroarenes.
A novel Rh(III)-catalyzed relay cross-coupling/cyclization cascade between arylketoimines and diazoesters is described. This transformation provides a concise access to unique π-conjugated 1-azaphenalenes (1-APLEs) via a double aryl Csp(2)-H bond carbenoid functionalization process. As illustrative examples, the 1-APLE-based π-conjugated molecules which possess low-lying HOMO levels could be converted to promising organic optoelectronic materials.


Current management of Cushing's disease.
Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission. Transsphenoidal pituitary surgery (TSS) remains the mainstay of treatment for CD but requires considerable neurosurgical expertise and experience in order to optimize patient outcomes. Up to 90% of patients with microadenomas (tumour below 1 cm in largest diameter) and 65% of patients with macroadenomas (tumour at or above 1 cm in greatest diameter) achieve endocrine remission after TSS by an experienced surgeon. Patients who are not in remission postoperatively or those who relapse may benefit from undergoing a second pituitary operation. Alternatively, radiation therapy to the sella with interim medical therapy, or bilateral adrenalectomy, can be effective as definitive treatments of CD. Medical therapy is currently adjunctive in most patients with CD and is generally prescribed to patients who are about to receive radiation therapy and will be awaiting its salutary effects to occur. Available treatment options include steroidogenesis inhibitors, centrally acting agents and glucocorticoid receptor antagonists. Several novel agents are in clinical trials and may eventually constitute additional treatment options for this serious condition.


Caries prevention through the fluoridation of milk. A review.
The aim of this review is to give an overview of 50 years experience of milk fluoridation and draw conclusions about the applicability of the method. Fluoridated milk was first investigated in the early 1950s, almost simultaneously in Switzerland, the USA and Japan. Stimulated by the favourable results obtained from these early studies, the establishment of The Borrow Dental Milk Foundation (subsequently The Borrow Foundation) in England gave an excellent opportunity for further research, both clinical and non-clinical, and a productive collaboration with the World Health Organization from the early 1980s onwards. Numerous peer-reviewed publications in international journals showed clearly the bioavailability of fluoride in milk, and increased concentrations of fluoride in saliva, dental plaque, dental enamel and dentine, and urine, after consumption of fluoridated milk. Clinical trials were initiated in the 1980s--some of these can be classed as randomised controlled trials, while most of the clinical studies were community preventive programs. These evaluations showed clearly that the optimal daily intake of fluoride in milk is effective in preventing dental caries. At present, milk fluoridation programs are running continuously in about ten countries of the world. Fluoridation of milk can be recommended as a caries preventive measure where the fluoride concentration in drinking water is suboptimal, caries experience in children is significant, and there is an existing school milk program. The program should aim to provide fluoridated milk for at least 200 days per year and should commence before the children are 4 years of age.


A follow-up of the career preferences of Manchester and Sheffield graduates of 1972 and 1973.
Pre-registration house officers who answered enquiries in 1973 and 1974 about career preferences were written to again in 1976. This yielded 205 comparisons, in which 134 (65.5%) doctors retained their original first choice of career, thirty-five (17%) opted for their previous second or third choice and thirty-six (17.5%) gave a completely new choice. The most common reasons for a change in career choice were reappraisal of aptitudes and abilities, altered domestic circumstances, additional knowledge of promotion and career prospects and additional experience of the new choice of career.


[NONINVASIVE VENTILATION IN THE POSTOPERATIVE PERIOD].
Acute respiratory failure is relatively common postoperative complication, occurs frequently in patients with preexisting compromised respiratory function and/or undergoing major thoracoabdominal procedures. Although endotracheal intubation and mechanical ventilation is still considered the cornerstone for the treatment of patients with acute respiratory failure, literature data have shown that mortality of these patients is closely associated to complications of intubation and mechanical ventilation. Therefore, the goal is to prevent complications and if possible to avoid endotracheal intubation. Noninvasive ventilation (NIV) is a form of mechanical support that does not require endotracheal intubation and is nowadays often used in prophylactic and therapeutic purposes in surgical patients with acute respiratory failure. In this article we give a brief overview of the indications and limitations of non-invasive ventilation in perioperative period.


Quadriceps Strength and Functional Performance After Anterior Cruciate Ligament Reconstruction in Professional Soccer players at Time of Return to Sport.
Herrington, L, Ghulam, H, and Comfort, P. Quadriceps strength and functional performance after anterior cruciate ligament reconstruction in professional soccer players, at time of return to sport. J Strength Cond Res XX(X): 000-000, 2018-Poor quadriceps strength has been associated with poor outcome after anterior cruciate ligament (ACL) reconstruction (ACLR). This study aims to assess quadriceps strength, muscle inhibition, and hop test performance in professional soccer players after ACLR. Fifteen professional soccer players (age 22.3 ± 3.1 years, body mass 81.0 ± 11.5 kg, and height 1.75 ± 0.1 m) who had undergone ACLR participated. Isometric, eccentric, and concentric quadriceps strength was assessed, along with quadriceps inhibition and single and cross-over hop performance, at the time of return to full-time unrestricted play. In comparison with the uninjured leg, the ACLR leg demonstrated large significant (d ≥ 0.84, p < 0.01) deficits in isometric, eccentric, and concentric quadriceps strength, quadriceps inhibition, and hop distance. Over 80% of the players failed to exceed the limb symmetry criteria of ≥90% for strength tests, although 75% of the cohort passed the ≥90% criteria for hop tests. The outcome from ACLR in professional soccer players who received full-time intensive rehabilitation has not previously been reported in detail. There were significant deficits in quadriceps strength at the time of return to sport, whereas hop testing, a commonly used outcome measure, failed to show the same levels of deficit. These deficits in quadriceps function may have implications for the development of ongoing knee symptoms and risk of future ACL injury. If this proves to be the case, then it would seem that greater attention should be paid to re-establishing full quadriceps strength before returning to unrestricted sporting activity.


Oxybutynin extended-release: a review of its use in the management of overactive bladder.
The OROS-based oxybutynin extended-release (ER) formulation (Lyrinel XL; Ditropan XL) represents a new form of oral delivery for oxybutynin, a muscarinic receptor antagonist used in the treatment of overactive bladder (OAB). The release of oxybutynin from oxybutynin ER occurs in a sustained manner, resulting in a smoother plasma concentration-time profile and a lower maximum plasma concentration than those seen with oxybutynin immediate-release (IR). The ER formulation has been developed with the aim of improving the tolerability of oxybutynin therapy and facilitating once-daily administration. Moreover, oxybutynin ER offers greater flexibility in dosage (5-30 mg/day) than the other available treatment options. At dosages of 5-30 mg once daily, oxybutynin ER produced significant decreases from baseline in weekly urinary urge incontinence in patients with OAB. In addition, there were significant decreases in weekly total incontinence episodes and micturition frequency. In two randomised, double-blind studies in patients with OAB, the improvement in all the symptoms with once-daily oxybutynin ER 5-30 mg/day was similar to that produced by oxybutynin IR 5-20 mg/day given one to four times daily. Once-daily oxybutynin ER 10 mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations. Oxybutynin ER was well tolerated in all the trials, with adverse events usually being mild to moderate and transient. In direct comparisons, the overall tolerability profile of oxybutynin ER was better than that of oxybutynin IR. Oxybutynin ER was similar to tolterodine (IR and ER) with respect to the incidence of clinically important dry mouth. A large 12-month tolerability study demonstrated no significant risks associated with the long-term use of oxybutynin ER. A few noncomparative studies have shown promising results with oxybutynin ER in the treatment of adult and paediatric patients with neurogenic bladder dysfunction secondary to neuronal injury. Long- and short-term studies have reported significant improvements in health-related quality of life with oxybutynin ER therapy. In addition, pharmacoeconomic studies have suggested that oxybutynin ER is more cost effective than oxybutynin IR and at least as cost effective as tolterodine IR. In conclusion, oxybutynin ER shows excellent efficacy in the treatment of symptoms associated with OAB in adults and the elderly with a good tolerability profile over a prolonged period of use (12 months). The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability profile and dosage flexibility, oxybutynin ER provides an excellent treatment option in the first-line pharmacotherapy of OAB.


Policy, organisation and practice of specialist old age psychiatry in England.
To describe and compare service arrangements in old age psychiatry across England according to three broad domains: (i) levels of professional autonomy; (ii) degree of community orientation (delivery of and links with community services) and (iii) degree of integration between health and social care provision. Cross sectional survey of consultants in old age psychiatry in England. Potential respondents were sourced from the Royal College of Psychiatrists and Regional Advisers in Old Age Psychiatry. A self-administered postal questionnaire was piloted and refined. The questionnaire domains listed above reflect core policy issues for older people's services, covering the domains above. There is marked variation in the deployment and use of professional staff in old age psychiatry, ranging from open access to multidisciplinary assessment to services only accessible by clinician referral. Patterns of linkage with primary care are likewise variable with only half of services providing the types of support recommended by the Audit Commission (2000). Community orientation was evident to a considerable extent in support to care homes and assessment practices. Links between health and social care appeared strongest in terms of liaison and training. There was less evidence of more formal integration through shared management of staff or for links with intensive home support for those with dementia. The data provide a unique picture and benchmark of the configuration of old age psychiatry, a core element of mental health care in old age, after some 25 years of development in the UK. There appears to be substantial variation on all three domains of comparison.


Alleviation of mandibular anterior crowding with copper-nickel-titanium vs nickel-titanium wires: a double-blind randomized control trial.
The purpose of this study was to investigate the efficiency of copper-nickel-titanium (CuNiTi) vs nickel-titanium (NiTi) archwires in resolving crowding of the anterior mandibular dentition. Sixty patients were included in this single-center, single-operator, double-blind randomized trial. All patients were bonded with the In Ovation-R self-ligating bracket (GAC, Central Islip, NY) with a 0.022-in slot, and the amount of crowding of the mandibular anterior dentition was assessed by using the irregularity index. The patients were randomly allocated into 2 groups of 30 patients, each receiving a 0.016-in CuNiTi 35 degrees C (Ormco, Glendora, Calif) or a 0.016-in NiTi (ModernArch, Wyomissing, Pa) wire. The type of wire selected for each patient was not disclosed to the provider or the patient. The date that each patient received a wire was recorded, and all patients were followed monthly for a maximum of 6 months. Demographic and clinical characteristics between the 2 wire groups were compared with the t test or the chi-square test and the Fisher exact test. Time to resolve crowding was explored with statistical methods for survival analysis, and alignment rate ratios for wire type and crowding level were calculated with Cox proportional hazards multivariate modeling. The type of wire (CuNiTi vs NiTi) had no significant effect on crowding alleviation (129.4 vs 121.4 days; hazard ratio, 1.3; P >0.05). Severe crowding (>5 on the irregularity index) showed a significantly higher probability of crowding alleviation duration relative to dental arches with a score of <5 (138.5 vs 113.1 days; hazard ratio, 2.2; P=0.02). The difference of the loading pattern of wires in laboratory and clinical conditions might effectively eliminate the laboratory-derived advantage of CuNiTi wires.


Double Vision: Eye Findings in Twins Reared Apart/Twin Research: Perinatology and Conjoined Twins; Thoracopagus Twin Cattle; MZ Twins Discordant for Musical Training/In the News: College Benefits for Twin Parents; Octomom Revisited; Genetic Editing of Infant Twins; Quarternary Marriages; Unusual Twin Pregnancy.
Findings related to visual functioning, drawn from early reared-apart twin studies, are summarized. These data are supplemented by more recent research from similar investigations. This section is followed by a survey of findings and conclusions from a special issue of the journal Seminars in Perinatology concerning the challenges and management of conjoined twins. An early case report on thoracopagus-conjoined twin cattle is also presented, as are neuroanatomical findings from a study of monozygotic twins discordant for musical training. Items noted in the news include college benefits for twin parents, an update on octomom, claims of gene editing of infant twins, the nature of quarternary marriages and an unusual planned twin pregnancy.


Early prediction of spontaneous twin very preterm birth: a population based study 2002-2012.
The aim of this study was to establish early pregnancy risk indicators for spontaneous twin very preterm birth. We conducted a retrospective observational population-based study. Twenty-one potential early pregnancy risk factors were analyzed using multivariable logistic regression to determine which of them was independently associated with spontaneous twin very preterm birth. Of 1815 spontaneous twin births 15.3% (277) occurred before 32 weeks. Previous preterm delivery (aOR 3.73; 95% CI, 2.52-5.52), nulliparity (aOR 2.94; 95% CI, 2.09-4.14), body mass index <18.5 (aOR 1.86; 95% CI, 1.12-3.10), body mass index ≥30 (aOR 1.87; 95% CI, 1.21-2.89), hysteroscopic metroplasty (aOR 1.63; 1.07-2.49), conization (aOR 2.05; 95% CI, 1.07-3.94) and monochorionicity (aOR 1.83; 95% CI, 1.28-2.63) were significantly associated with twin very preterm birth. Pending verification in other populations, twin pregnancies at significant risk for spontaneous very preterm birth can be identified in early pregnancy using several risk indicators.


Cyclodextrin Nanoparticles Bearing 8-Hydroxyquinoline Ligands as Multifunctional Biomaterials.
Cyclodextrins are used as building blocks for the development of a host of polymeric biomaterials. The cyclodextrin polymers have found numerous applications as they exhibit unique features such as mechanical properties, stimuli responsiveness and drug loading ability. Notwithstanding the abundance of cyclodextrin polymers studied, metal-chelating polymers based on cyclodextrins have been poorly explored. Herein we report the synthesis and the characterization of the first metal-chelating β-cyclodextrin polymer bearing 8-hydroxyquinoline ligands. The metal ions (Cu2+ or Zn2+ ) can modulate the assembly of the polymer nanoparticles. Moreover, the protective activity of the new chelating polymer against self- and metal-induced Aβ aggregation and free radical species are significantly higher than those of the parent compounds. These synergistic effects suggest that the incorporation of hydroxyquinoline moieties into a soluble β-cyclodextrin polymer could represent a promising strategy to design multifunctional biomaterials.


Pathogenetic significance of p53 and c-Ki-ras gene mutations and human papillomavirus DNA integration in adenocarcinoma of the uterine cervix and uterine isthmus.
The pathogenetic significance of p53 and c-Ki-ras gene mutations and genomic integration of human papillomavirus (HPV) DNA was examined in surgically resected specimens of adenocarcinomas of the uterine cervix and isthmus using polymerase chain reaction (PCR), single-strand-conformation polymorphism and Southern blotting analysis. Among 25 cervical adenocarcinomas, p53 gene mutations between exons 5 and 8 were detected in 32%, and the incidence of these mutations was higher in cases at advanced clinical stages and with high grades of nuclear and structural atypia both in endocervical and in endometrioid types. HPV DNA type 16 or 18 in cervical adenocarcinomas was detected in 35% of cases by PCR and in 29% by Southern blotting, and, in contrast to the p53 mutations, the majority of cases with the HPV DNA were at a relatively early clinical stage with low-grade histological atypia. c-Ki-ras gene mutation was detected in only 4% of cervical adenocarcinomas. Among 8 isthmus adenocarcinomas, the incidence of p53 and c-Ki-ras gene mutations, and the presence and integration of HPV DNA type 16 or 18 were 38%, 50%, 57% and 25% respectively. The pattern of p53 mutations differed between isthmus and cervical adenocarcinomas: all of the mutations in the former were one-base substitutions of the transition type, whereas in the latter nearly half of the mutations were of the transversion type. Among cervical adenocarcinomas, p53 mutations between exons 5 and 8 were indicated as being mostly involved in the pathogenesis and development of biologically aggressive tumors, whereas HPV type 16 or 18 infection appeared to be involved in less aggressive cases. In isthmus adenocarcinoma, c-Ki-ras gene mutation, apart from p53 mutation and HPV-type-16 or -18 infection, appeared to be involved frequently in cancer development.


Recognition of the beta-2 microglobulin-B molecule by a CTL clone.
In this report we offer evidence that the beta-2 microglobulin-B (beta 2M-B) molecule is recognized by a cytotoxic T lymphocyte (CTL). Production of GA5, a CTL clone reactive against a membrane antigen with the same strain distribution pattern as beta 2M-B, is described. This clone lysed syngeneic target cells in which native beta 2M-A molecules had been exchanged with beta 2M-B molecules by incubating the cells in serum from beta 2M-B-positive mouse strains. Conversely, the CTL clone GA5 failed to lyse its specific target when beta 2M-B molecules had been exchanged with beta 2M-A molecules by incubating the cells in serum from beta 2M-A-positive, beta 2M-B-negative mouse strains. Strain combinations were chosen so as to limit reactivity to beta 2M and to preclude reactivity to H-3 antigens, thus indicating CTL clone GA5 to be reacting specifically with beta 2M-B.


The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats.
We determined the effect of a short-term angiotensin II signaling blockade on vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO), and malondialdehyde (MDA) (index of lipid peroxidation) levels in the systemic circulation and on peroxynitrite generation and insulitis development in the streptozotocin (STZ) diabetic rats' pancreas. Diabetes was induced in Wistar rats by intraperitoneal STZ injection. Diabetic rats were treated for 1 week with losartan (20 mg/kg/body weight/day in the drinking water), and pancreas and blood were collected for histochemical, immunohistochemical, and biochemical studies. Diabetic rats showed greater VEGF, sICAM-1, NO, and MDA levels, a high score of insulitis, increased nitrotyrosine staining, and markedly reduced pancreatic insulin content when compared with controls. Losartan treatment suppressed the excessive NO and lipid peroxidation production systemically without restoring them to that of healthy subjects and reduced VEGF levels while leaving sICAM-1 levels unchanged. The insulitis score and nitrotyrosine staining were reduced, whereas the pancreatic islets and the beta-cell area were increased significantly in the treated group, indicating the reduction of inflammation and nitrosative stress and an early regeneration of beta-cell mass in the pancreas. Conclusively, in the STZ diabetic rat model, even a short-term losartan treatment improves oxidative and nitrosative stress systemically and locally, improving the islets' environment and accelerating beta-cell regeneration.


Current concepts in surgical management of pediatric lung and chest wall diseases.
The management of pediatric lung and chest wall diseases has changed dramatically in the last decade because of the application of minimally invasive surgical techniques. This review will try to highlight some of the more significant recent contributions. Most of the papers quoted will show that the application of minimally invasive surgery to the treatment of common problems such as empyema, pneumothorax, and lung biopsy has significantly altered our treatment algorithms, because of decreased morbidity and improved outcomes compared to standard surgical or medical treatment plans. This has also been true for pediatric chest wall deformities, which previously were treated in only the most severe cases and thought to be mostly cosmetic in nature. More recent reports now show statistically significant improvements in cardio-pulmonary physiology as well as quality of life. The application of less invasive surgical procedures for lung and chest wall diseases has warranted earlier intervention, with better outcomes, and less morbidity than previously used techniques. A clear understanding of these techniques and their benefits is important for the referring and treating physician as previously used treatment protocols may no longer provide the best patient care.


Low-Power Vs High-Power Holmium Laser Enucleation of the Prostate: Critical Assessment through Randomized Trial.
To assess the non-inferiority of Low-power Holmium laser enucleation of the prostate (LP-HoLEP) to high-power (HP-HoLEP) for enucleation efficiency pertaining to the advantages of lower cost and minimal postoperative dysuria, storage symptoms, and negative sexual impact. HoLEP was performed using 100W Versapulse, Luminis Inc., with 2J/25Hz for LP-HoLEP (61 patients) and 2J/50Hz for HP-HoLEP (60 patients). Two surgeons with different experience performed equal number of both procedures. Non-inferiority of enucleation efficiency (enucleated weight/min) was evaluated. All perioperative parameters were recorded and compared. Dysuria was assessed at 2 weeks by dysuria visual analog scale, urinary (Q.max and IPSS) and sexual (sexual health inventory for men score) outcome measures were evaluated at 1, 4, and 12 months. Baseline and perioperative parameters were comparable between the two groups. Mean enucleation efficiency was 1.42±0.6 vs 1.47±0.6 gm/min, P = .6 following LP-HoLEP and HP-HoLEP, respectively. Patients reported postoperative dysuria similarly in both groups as per dysuria visual analog scale. There was significant comparable improvement in IPSS (international prostate symptom score) and Q.max in both groups at different follow-up points. At one year, median IPSS and Q.max were comparable in both groups (P = .4 and .7 following LP-HoLEP and HP-HoLEP, respectively). Median postoperative reduction in prostate specific antigen was 89% (42:99) following LP-HoLEP vs 81% (62:94) after HP-HoLEP, P = .92. Both groups showed comparable perioperative and late postoperative complications. There were no statistically significant changes in the last follow-up sexual health inventory for men score in comparison to baseline score. LP-HoLEP is non-inferior to HP-HoLEP in terms of all efficiency parameters regardless level of surgeon experience.


Effect of phentolamine on wakefulness and sleep during recovery from REM sleep deprivation in cats.
Adult cats with permanent EEG, EMG, EOG, and PGO electrodes were recorded for 24 hours started at the end of a 72-hour REMS deprivation induced by a platform-water-tank procedure and after receiving IP injections of phentolamine (20 mg/kg) or saline. Exposure of the cats to the platform-REMS deprivation procedure increased the percentage of REMS during the subsequent 24 hours. Phentolamine interacted with the platform REMS deprivation causing the peak of REMS percentage to occur during recovery hours 5-12. These findings indicate that blockade of alpha-receptors has an additive effect on platform-REMS deprivation induced REMS rebound in cats.


[Ultrastructure of blood capillaries in vascular plexuses of the lateral ventricles of the human brain].
Ultrastructure of the wall of the microcirculatory bed links in the lateral ventricles of the human brain has been studied, as well as their interrelations with neural elements and ependyma. Together with typical morphological structural signs, certain peculiarities are revealed, characterizing organic specificity. Elements, performing function of the blood-brain barrier are determined: epithelium (ependyma), basal membranes, interstitium. A well developed afferent and efferent nervous apparatus of the vascular plexus, evidently, actively participates in regulation of the microcirculatory blood bed and in formation of liquor.


Energy cost of walking with hip joint impairment.
The energy cost of walking was measured in 12 patients (age 39-73 years) with hip joint impairment and 10 healthy controls during unassisted walking (2-6 km.h-1) on a level treadmill surface and on a 5% incline. The energy cost of locomotion in most patients increased up to 50% and 70% during level-surface and uphill walking, respectively. This difference between patients and controls was probably due to the increased external mechanical work. The energy cost of walking, although related to pain experienced during walking but not to hip joint range of motion or to joint status evaluated radiographically, provides an additional variable when defining the conditions of disability and functional impairment in individuals with this pathological condition. [Gussoni M, Margonato V, Ventura R, et al: Energy cost of walking with hip joint impairment.


[Effect of Paeonia lactiflora on platelet cytosolic free calcium and erythrocyte membrane Ca(2+)-Mg(2+)-ATPase activity in hyperlipid rabbits].
The effect of Paeonia lactiflora (PL) on platelet cytosolic free calcium and erythrocyte membrane Ca(2+)-Mg(2+)-ATPase activity in hyperlipid rabbits were observed. Results showed the level of platelet cytosolic free calcium in the PL group (276.25 +/- 27.00 nmol/L) was significantly lower than that in the cholesterol group (390.88 +/- 70.00 nmol/L), P < 0.01, the basal and calmodulin-stimulated activities of erythocyte membrane Ca(2+)-Mg(2+)-ATP ase in PL group (0.79 +/- 0.05 mumol.pi-1.mg-1.h-1 and 1.34 +/- 0.10 mumol.pi-1.mg-1.h-1) were higher than that in the cholesterol group (0.65 +/- 0.09 mumol.pi-1.mg-1.h-1 and 1.04 +/- 0.13 mumol.pi-1.mg-1.h-1).


Endovascular Treatment of Post Type A Chronic Aortic Arch Dissection With a Branched Endograft: Early Results From a Retrospective International Multicenter Study.
MINI: The objective of this study was to evaluate the outcome of endovascular repair of chronic aortic arch dissecting aneurysms with a custom-made branched endograft during follow-up after acute type A aortic dissection open repair. Unmatched outcomes are reported in a population at high risk for a redo sternotomy. The objective of this study was to evaluate the outcome of endovascular aortic arch repair for chronic dissection with a custom-made branched endograft. Acute type A aortic dissections are often treated with prosthetic replacement of the ascending aorta. During follow-up, repair of an aneurysmal evolution of the false lumen distal to the ascending prosthesis can be a challenge both for the surgeon and the patient. We conducted a multicenter, retrospective study of consecutive patients from 14 vascular units treated with a custom-made, inner-branched device (Cook Medical, Bloomington, IN) for chronic aortic arch dissection. Rates of in-hospital mortality and stroke, technical success, early and late complications, reinterventions, and mortality during follow-up were evaluated. Seventy consecutive patients were treated between 2011 and 2018. All patients were considered unfit for conventional surgery. In-hospital combined mortality and stroke rate was 4% (n = 3), including 1 minor stroke, 1 major stroke causing death, and 1 death following multiorgan failure. Technical success rate was 94.3%. Twelve (17.1%) patients required early reinterventions: 8 for vascular access complication, 2 for endoleak correction, and 2 for pericardial effusion drainage. Median follow-up was 301 (138-642) days. During follow-up, 20 (29%) patients underwent secondary interventions: 9 endoleak corrections, 1 open repair for prosthetic kink, and 10 distal extensions of the graft to the thoracic or thoracoabdominal aorta. Eight patients (11%) died during follow-up because of nonaortic-related cause in 7 cases. Endovascular treatment of aortic arch chronic dissections with a branched endograft is associated with low mortality and stroke rates but has a high reintervention rate. Further follow-up is required to confirm the benefits of this novel approach.


Akt is a neutral amplifier for Th cell differentiation.
Both CD28 and its relative, inducible costimulator (ICOS), have a binding motif for phosphatidylinositol 3-kinase (PI3K) in their cytoplasmic tail, and the binding of PI3K leads to activation of a serine/threonine kinase, Akt. The role of Akt in cytokine production and helper T (Th) cell differentiation remains obscure. In this study, we found that enforced expression of the constitutively active form (E40K) of Akt rendered CD4(+) T cells activated. Wild-type of Akt and E40K promoted Th1 cell differentiation in C57BL/6-derived and Th1-polarized BALB/c-derived CD4(+) T cells, while both promoted Th2 cell differentiation in BALB/c-derived and Th2-polarized C57BL/6 CD4(+) T cells. E40K also facilitated Th1 differentiation in CD4(+) T cells from IL-4-deficient mice with the BALB/c background. E40K up-regulated expression of NF-AT and c-Myb, which may be related to the augmentation of cytokine production by E40K. These findings indicate that the mechanism by which Akt augments cytokine production via CD28 and ICOS is Th cell type-specific and reflects the intracellular status affected by the cytokine milieu. We conclude that Akt is a neutral amplifier of T cell activation and Th differentiation.


Intracellular pH regulation in guinea-pig caecal and colonic enterocytes during and after loading with short-chain fatty acids and ammonia.
Absorption of short-chain fatty acids (SCFA) and ammonia implies considerable fluxes of protons across the epithelium of the large intestine. Efficient regulation of intracellular pH (pH(i)) is therefore essential in these cells. The aim of the present study was to examine the effects of SCFA and of ammonia on pH(i), on pH(i) regulation and to characterize the mechanisms involved in pH(i) regulation in surface enterocytes of the guinea-pig caecal and colonic mucosa. Intact epithelia from the caecum and the distal colon were mounted in a microperfusion chamber. pH(i) was measured by fluorescence microscopy using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Addition of SCFA or ammonia to the serosal side changed the enterocyte pH(i) markedly, whereby ammonia caused larger changes in pH(i) than SCFA. In contrast, addition of SCFA to the mucosal solution had no effect on pH(i) and ammonia increased pH(i) only slightly. Basolaterally located pH(i) regulation mechanisms, Na(+)-H(+) exchange and Cl(-)-HCO(3)(-) exchange, are involved mainly in returning pH(i) to normal values. It is concluded that, due to apparently lower permeability of the apical membranes, the caecal and colonic epithelium is protected against pH(i) disturbances caused by the naturally high luminal SCFA and NH(3) concentrations. The major regulation mechanisms of pH(i) are located in the basolateral membrane of the enterocytes.


Toxicity and pharmacokinetics of 2-(2-dimethylaminoethoxy)ethanol following cutaneous dosing.
A 9-day repeated cutaneous toxicity study in the New Zealand White rabbit was conducted using 6-h occluded contact with 0 (water control), 50, 250 and 500 mg dimethylaminoethoxyethanol (DMEE)/kg. There were no clinical signs, and no effects on body weight, food consumption or serum chemistry. Hematological effects were limted to increased leukocyte count due to heterophil leukocytosis, increased platelet count, and decreased hemoglobin and hematocrit at the high dose. These findings are typical of the response of cutaneous inflammation. Histopathological findings were limited to the DMEE-treated skin, and consisted of acanthosis and ulcerative/necrotizing dermatitis. Thus, there was no evidence for cumulative percutaneous systemic toxicity for DMEE. The pharmacokinetics of DMEE was investigated in the Fischer 344 rats. Rats were given an intravenous dose of 15 or 150 mg/kg, or an occluded cutaneous dose of 150 mg/kg [14C]DMEE, and its fate was followed for 48-72 h. DMEE was readily absorbed through the skin (bioavailability=72-80%). Concentration in plasma rose steadily to a maximum at about 3.5 h after dosing, and then declined in a biphasic manner. 14C-DMEE-derived radioactivity was distributed throughout the body, with no apparent sequestration in any particular organ. The highest concentrations were observed in the kidney, liver and lung, and the lowest concentrations were found in the brain and fat. Urine was the major route of excretion, with minor amounts eliminated in the feces and as expired CO(2). The rate of excretion was moderate, with about 30% of the applied dose eliminated in the first 12 h, and by 72 h after dosing, less than 4% of the dose remained in the carcass. Unchanged DMEE was the principal component detected in the urine. This observation, together with the less than 1% of the dose excreted as CO(2), showed that metabolism was not an important process in the elimination of DMEE in the rat.


Expression of rat liver fructose-1,6-bisphosphatase in Escherichia coli.
Rat liver fructose-1,6-bisphosphatase was expressed in Escherichia coli using a T7 RNA polymerase-transcribed expression system. Maximum yields of soluble active enzyme were obtained when the bacterial host cell, BL21(DE3), carrying the expression plasmid was grown and transcription induced in LB medium at 37 degrees C. Approximately 20mg of fructose-1,6-bisphosphatase are synthesized per liter of culture after 4hr, of which about 10mg are soluble and enzymatically active. Expressed fructose-1,6-bisphosphatase, purified to homogeneity by substrate elution from a carboxymethyl Sephadex column, was indistinguishable from that purified from rat liver in terms of subunit size and kinetic properties. The in vitro expression of fructose-1,6-bisphosphatase in an heterologous system is a necessary preliminary step for future studies on site-directed mutant enzyme forms.


Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma.
In asthma T cells are characterized by an increased activation state and by reduced apoptosis. Because the clinical efficacy of inhaled corticosteroids combined with long-acting beta 2 -agonists has been widely demonstrated in asthma, we studied, in vitro, the effect of fluticasone propionate (FP) and salmeterol alone and in combination on the activation and apoptosis of peripheral blood T cells (PBTs), on the expression of phosphorylated nuclear factor kappaB inhibitor (IkappaBalpha), and on the nuclear translocation of glucocorticoid receptor (GR) in PBTs from asthmatic subjects. Apoptosis was evaluated on the basis of annexin V binding, whereas the expression of caspases 8 and 3 and phosphorylated IkappaBalpha, as well as the nuclear translocation of the GR, were evaluated by means of Western blot analysis. FP alone increases and salmeterol alone does not affect T-cell apoptosis. The combination of FP and salmeterol significantly increases PBT apoptosis in comparison with FP alone. FP at the lower concentration, when combined with salmeterol, is equivalent to FP at the higher concentration in inducing PBT apoptosis. The synergy in the induction of cell apoptosis is associated with more efficient activation of caspases 8 and 3. FP plus salmeterol is also able to synergistically reduce the expression of phosphorylated IkappaBalpha, thus limiting nuclear factor kappaB activation. The synergy was related to an increased nuclear translocation of the GR. This study shows that the combination of FP and salmeterol is able to control PBT activation in asthmatic patients more efficiently than FP alone and with a lower concentration of steroids.


[Sucralfate: the agent of choice in the treatment of peptic ulcer?].
As many as 72 patients with erosive and ulcerous injuries to the stomach and duodenum were examined for the clinical efficacy of antepsin (sucralfate). Of these patients, 42 were with duodenal ulcer, 10 with gastric ulcer and 20 with erosive gastroduodenitis). Antepsin exerted a beneficial effect on the painful syndrome and on ulcer and erosion healing. The coefficient of the therapeutic efficacy of antepsin in duodenal ulcer patients turned out to be equal to 2.67 that of gastric ulcer to 2.1 and that in patients with gastroduodenitis was 2.6. The drug did not produce any well-defined side effects. In some cases (8.3%), it caused the appearance or enhancement of constipation. Antepsin is indicated not only in ulcer disease but also in duodenogastric reflux, reflux gastritis and reflux esophagitis.


Duration of the effect of intravitreal triamcinolone acetonide as treatment for diffuse diabetic macular edema.
To evaluate the duration of the effect of intravitreal triamcinolone acetonide on visual acuity in patients with diffuse diabetic macular edema. Clinical interventional case series. Subjects were 31 patients (38 eyes) with diffuse diabetic macular edema who received an intravitreal injection of 20- to 25-mg triamcinolone acetonide. Mean follow-up time was 13.2 +/- 6.0 months (6.03-25.2 months). Visual acuity and intraocular pressure began to increase significantly (P =.003) within the first week, reaching a plateaulike maximum at 1 to 7 months postinjection, returning to baseline values 8 to 9 months postinjection. The effect of an intravitreal injection of approximately 20- to 25-mg triamcinolone acetonide in patients with diffuse diabetic macular edema lasts approximately 7 to 8 months. This information may be helpful in determining the optimal dosage of intravitreal triamcinolone acetonide for the treatment of diffuse diabetic macular edema.