Minimizing risk of bias in clinical implant research study design.
The field of clinical implant research has been flourishing in recent years. The number of related publications has been on the rise, as has the number of dental journals. However, the information gathered from surveillance studies on the quality of reporting and methodologic quality of published studies is unsettling. An important challenge faced by researchers endeavoring to conduct implant studies is how to factor the differences between implant surfaces and dental surfaces in the study design. Given the considerable experience that has been gained in the research methodology of the study of teeth and periodontal tissues, clinical implant research studies have often been conducted without giving much consideration to the fundamental differences between implants and teeth. This article discusses study design related to implant research in view of these differences. Observational and interventional study design methodology is discussed, and guidelines are provided to inform researchers on how to minimize bias in the design and implementation of these clinical studies when implant-related outcomes are studied.


Number of options in a movement sequence affects learners' behavior in a self-controlled practice condition.
Self-controlling practice implies a process of decision making, which suggests that the options in a self-controlled practice condition could affect learners. The number of task components with no fixed position in a movement sequence may affect the way learners self-control their practice. A 200-cm coincident timing track with 90 light-emitting diodes (LEDs)--the first and the last LEDs being the warning and the target lights, respectively--was set so that the apparent speed of the light along the track was 1.33 m/sec. Participants were required to touch six sensors sequentially, the last one coincidently with the lighting of the target light (timing task). Group 1 (n = 55) had only one constraint, and were instructed to touch the sensors in any order, except for the last sensor which had to be the one positioned close to the target light. Group 2 (n = 53) had three constraints: the first two and the last sensor to be touched. Both groups practiced the task until timing error was less than 30 msec. on three consecutive trials. There were no statistically significant differences between groups in the number of trials needed to reach the performance criterion, but (a) participants in Group 2 created fewer sequences compared to Group 1, and (b) were more likely to use the same sequence throughout the learning process. The number of options for a movement sequence affected the way learners self-controlled their practice, but had no effect on the amount of practice to reach criterion performance.


[Selection vector and ontogenetic development of behavior under domestication of wild Norway rats].
Hereditary variation in rates of ontogenetic formation of exploratory behavior, glucocorticoid functions, and neurotransmitter systems in wild Norway rats during selection for absence of defensive response towards humans (domestication) is demonstrated. Interrelated shifts in the development of behavior and neurohormonal systems are shown. A comparison of the data obtained with the results of domestication of another species-silver fox-suggests that equally vectorized selection of animals belonging to different taxa produces equally directed changes of their regulatory systems.


Molecular Phylogenetics and Biological Potential of Fungal Endophytes From Plants of the Sundarbans Mangrove.
The Sundarbans forest in Bangladesh is the world's largest mangrove. It is a unique ecosystem where living organisms face extreme challenges to compete for survival. Such competition results in the production of bioactive molecules which are useful for agriculture and human health. In this study, eighty fungal endophytes from nine mangrove plants growing in a region, as yet unexplored, of the Sundarbans were isolated by surface sterilisation and pure culture techniques. Among the eighty isolates subjected to a preliminary antimicrobial screening using an agar plug diffusion assay, only fifteen showed some promising activity. These were subsequently identified by polymerase chain reaction of their ITS gene. Extracts prepared from the identified isolates were screened for antimicrobial, antioxidant, cytotoxic and α-glucosidase inhibitory activities. Their total polyphenol and flavonoid content and their FRAP value were also determined. All endophytes are reported for the first time in the plants under investigation.


Improved method for simultaneous determination of thermal properties.
An improved method to simultaneously determine the heat capacity, thermal diffusivity, and thermal conductivity of a small-sized material is described. In this method, the heat of a square wave with a superimposed constant component is applied to one side of a plate-shaped sample using a thin-film heater, which is thermally linked to a heat reservoir. The response temperature is measured by a thermometer attached to the heater. In contrast to a previously reported method, the amplitude of the temperature oscillation detected by the thermometer is enhanced by the internal thermal relaxation in the improved method. This feature is advantageous for determining thermal properties with low-heat modulation. We theoretically analyzed the proposed method using a one-dimensional model and demonstrated the method on synthetic quartz (SiO2) and poly(methyl methacrylate) plates in the temperature range of 80-300 K. The thermal properties obtained for both samples using the proposed method were consistent with values reported in the literature. The deviations from the data for the specific heat capacity, thermal diffusivity, and thermal conductivity were estimated to be ∼1%, 2%, and 2%, respectively.


Human polymorphisms at long non-coding RNAs (lncRNAs) and association with prostate cancer risk.
Long non-coding RNAs (lncRNAs), representing a large proportion of non-coding transcripts across the human genome, are evolutionally conserved and biologically functional. At least one-third of the phenotype-related loci identified by genome-wide association studies (GWAS) are mapped to non-coding intervals. However, the relationships between phenotype-related loci and lncRNAs are largely unknown. Utilizing the 1000 Genomes data, we compared single-nucleotide polymorphisms (SNPs) within the sequences of lncRNA and protein-coding genes as defined in the Ensembl database. We further annotated the phenotype-related SNPs reported by GWAS at lncRNA intervals. Because prostate cancer (PCa) risk-related loci were enriched in lncRNAs, we then performed meta-analysis of two existing GWAS for discovery and an additional sample set for replication, revealing PCa risk-related loci at lncRNA regions. The SNP density in regions of lncRNA was similar to that in protein-coding regions, but they were less polymorphic than surrounding regions. Among the 1998 phenotype-related SNPs identified by GWAS, 52 loci were located directly in lncRNA intervals with a 1.5-fold enrichment compared with the entire genome. More than a 5-fold enrichment was observed for eight PCa risk-related loci in lncRNA genes. We also identified a new PCa risk-related SNP rs3787016 in an lncRNA region at 19q13 (per allele odds ratio = 1.19; 95% confidence interval: 1.11-1.27) with P value of 7.22 × 10(-7). lncRNAs may be important for interpreting and mining GWAS data. However, the catalog of lncRNAs needs to be better characterized in order to fully evaluate the relationship of phenotype-related loci with lncRNAs.


Factors associated with suicidal risk among a French cohort of problem gamblers seeking treatment.
Compared to general population, pathological gamblers are 3.4 times more likely to attempt suicide. Our objective was to identify specific profiles of problem gamblers (PGs) with suicidal risk according to sociodemographic, clinical and gambling characteristics. The PGs cohort, called "EVALJEU" , consists in the inclusion of any new PG seeking treatment in our Department. Patients underwent a semi-structured clinical interview and completed self-report questionnaires. The "suicidal risk module" of the Mini International Psychiatric interview (MINI) allowed to constitute two groups of patients that were compared, according to the presence of a suicidal risk. A logistic regression was performed to identify factors related to suicidal risk in PGs. In our sample (N=194), 40.21% presented a suicidal risk. A history of major depression and anxiety disorders were predictors of suicidal risk as well as the perceived inability to stop gambling. Suicidality is a significant clinical concern in PGs. Therefore, three specific predictors, identified by our study, must be assessed.


In Chagas disease, transforming growth factor beta neutralization reduces Trypanosoma cruzi infection and improves cardiac performance.
Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, a neglected tropical disease caused by Trypanosoma cruzi infection. During CCC, the parasite remains inside the cardiac cells, leading to tissue damage, involving extensive inflammatory response and irregular fibrosis. Among the fibrogenic factors is transforming growth factor-β (TGF-β), a key cytokine controlling extracellular matrix synthesis and degradation. TGF-β is involved in CCC onset and progression, with increased serum levels and activation of its signaling pathways in the cardiac tissue, which crucially contributes to fibrosis. Inhibition of the TGF-β signaling pathway attenuates T. cruzi infection and prevents cardiac damage in an experimental model of acute Chagas disease. The aim of this study was to investigate the effect of TGF-β neutralization on T. cruzi infection in both in vitro and in vivo pre-clinical models, using the 1D11 monoclonal antibody. To this end, primary cultures of cardiac cells were infected with T. cruzi trypomastigote forms and treated with 1D11. For in vivo studies, 1D11 was administered in different schemes for acute and chronic phase models (Swiss mice infected with 104 parasites from the Y strain and C57BL/6 mice infected with 102 parasites from the Colombian strain, respectively). Here we show that the addition of 1D11 to cardiac cells greatly reduces cardiomyocyte invasion by T. cruzi and the number of parasites per infected cell. In both acute and chronic experimental models, T. cruzi infection altered the electrical conduction, decreasing the heart rate, increasing the PR interval and the P wave duration. The treatment with 1D11 reduced cardiac fibrosis and reversed electrical abnormalities improving cardiac performance. Taken together, these data further support the major role of the TGF-β signaling pathways in T. cruzi-infection and their biological consequences on parasite/host interactions. The therapeutic effects of the 1D11 antibody are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-β neutralization.


Prevalence of clinical manifestations and orthopedic alterations in patients with lipedema: A prospective cohort study.
Lipedema is a chronic disease seen frequently in women that causes abnormal fat deposition in the lower limbs and associated bruising and pain. Despite increasing knowledge concerning lipedema, there are still aspects of diagnosis that need further investigation. We performed a prospective, observational cohort study to describe prevalence of clinical characteristics present in patients with lipedema in an attempt to establish diagnostic criteria. Participants were consecutive patients with lipedema presenting at a public hospital in Spain from September 2012 to December 2019. Patients were examined for the following signs and symptoms of lipedema: symmetrical involvement; disproportion between the upper and lower part of the body; sparing of the feet; pain; bruising; Stemmer' sign; pitting test; fibrosis; venous insufficiency; upper limbs involvement; vascular spiders; skin coldness; and lymphangitis attacks. In addition, orthopedic alterations were examined in all patients. We recruited 138 patients (median age=47.6 years; mean BMI=29.9 Kg/m2). Using waist-to-height-ratio, 41.3% of the patients were slim or healthy. The most frequent type of lipedema was Type III (71%), and most were in stage 1 and 2. The features of lipedema with a prevalence >80% were symmetrical involvement, unaffected feet, pain, bruising, vascular spiders, and disproportion. Pain was nociceptive in 60.2% and neuropathic in 33.1%, and there was a reduced social or working activities in 37.9%. Orthopedic alterations including cavusfeet or valgus-knees were observed in 1/3 of the patients. X-ray of the knees was performed in 63 patients and knee osteoarthritis diagnosed in 37. We found that the most frequent manifestations of lipedema were bilateral involvement, unaffected feet, pain, easy bruising, vascular spiders, and disproportion between the upper and lower parts of the body. These should be considered as major criteria for diagnosis. In addition, our findings on the prevalence of orthopedic alterations in patients with lipedema highlights the need for a multidisciplinary and integrated approach.


Higher Concentration of Hypertonic Saline Shows Better Recovery Effects on Rabbits with Uncontrolled Hemorrhagic Shock.
BACKGROUND Our previous study found a novel fluid combination with better resuscitation effects under hypotensive condition at the early stage of uncontrolled hemorrhagic shock (UHS). However, the optimal recovery concentration of hypertonic saline in this fluid combination remains unknown. This experiment aimed to explore the optimal concentration. MATERIAL AND METHODS New Zealand white rabbits (n=40) were randomly divided into 5 groups, including a sham-operated group (SO), a shock non-treated group (SNT), a normal saline group (NS), and hypertonic saline groups (4.5% and 7.5%). We established an UHS model and administered various fluid combinations (dose-related sodium chloride solution+crystal-colloidal solution) to the groups followed by monitoring indexes of hemodynamic and renal function, measuring infusion volume and blood loss, and analyzing pathological morphology by hematoxylin and eosin staining. RESULTS The hypertonic saline groups showed more stable hemodynamic indexes, reduced blood loss, fewer required infusions, and milder decreases in renal function than those of control groups (SNT and NS groups), and exhibited fewer pathological changes in the heart, lung, kidney, and liver. All indexes in the 4.5% and 7.5% groups were better than those of the NS group, and the hemodynamic indexes in the 7.5% group were more stable than those of the 4.5% group (P<0.05), with reduced blood loss and infusion volume and a milder decrease in renal function. CONCLUSIONS The novel fluid combination with 7.5% hypertonic saline group had a better recovery effect at the early stage of UHS before hemostasis compared to that of the 4.5% hypertonic saline group. This result may provide guidance for clinical fluid resuscitation.


Identification of recurring protein structure microenvironments and discovery of novel functional sites around CYS residues.
The emergence of structural genomics presents significant challenges in the annotation of biologically uncharacterized proteins. Unfortunately, our ability to analyze these proteins is restricted by the limited catalog of known molecular functions and their associated 3D motifs. In order to identify novel 3D motifs that may be associated with molecular functions, we employ an unsupervised, two-phase clustering approach that combines k-means and hierarchical clustering with knowledge-informed cluster selection and annotation methods. We applied the approach to approximately 20,000 cysteine-based protein microenvironments (3D regions 7.5 A in radius) and identified 70 interesting clusters, some of which represent known motifs (e.g. metal binding and phosphatase activity), and some of which are novel, including several zinc binding sites. Detailed annotation results are available online for all 70 clusters at http://feature.stanford.edu/clustering/cys. The use of microenvironments instead of backbone geometric criteria enables flexible exploration of protein function space, and detection of recurring motifs that are discontinuous in sequence and diverse in structure. Clustering microenvironments may thus help to functionally characterize novel proteins and better understand the protein structure-function relationship.


Validation of pre-procedural aortic aneurysm volume calculations to estimate procedural fill volume of endobags in endovascular aortic sealing.
Endovascular aortic sealing (EVAS) with a sac anchoring endoprosthesis excludes abdominal aortic aneurysms based on polymer filling of endobags. Primary objective was to assess the reliability of pre-procedural computed tomography (CT) scans based calculations of required endobag volume in relation to intraoperative volume of the endobags. Forty elective EVAS patients were included. Pre-procedural estimations of endobag volume were based on CT segmentations of aortic flow lumen volume, including both automated and manually-adjusted segmentations, performed by two experienced users. Additionally, changes in maximum AAA diameter, thrombus volume and total AAA volume were calculated from pre- and post-procedural CT scans. Automatically determined volumes were comparable to manually-adjusted calculations (75.3 vs. 75.7 mL) and inter-observer agreement regarding pre-EVAS calculations of prefill volume appeared almost perfect with an intra-class correlation coefficient of 0.98 (95% CI: 0.96-0.99). The mean pressure of the endobags was 185 mmHg. Manually-adjusted pre-procedural volume calculations underestimated procedural volume of the endobags (-11.3±9.9 mL). Differences between pre-EVAS and procedural volume measurements were independent from endobag pressure (r=-0.06, P=0.72), prepocedural thrombus volume (r=-0.303, P=0.057) and changes in total AAA volume (r=0.02, P=0.91). A significant association was determined between differences in pre-EVAS and endobag volume versus changes in thrombus volume pre- and post-procedural (r=0.39, P=0.01). In this validation study, pre-procedural volume measurements underestimate the actual fill volume of the endobags. It should be advised to perform a prefill of the endobags during the EVAS procedure.


The Repurposing Drugs in Oncology (ReDO) Project.
The Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well-characterised non-cancer drugs for new uses in oncology. The rationale for this project is presented, examining current issues in oncological drug development, challenges for health systems, and existing and future patient needs. In addition to discussing the advantages of repurposing, the paper also outlines some of the characteristics used in the selection of drug candidates by this project. Challenges in moving candidate drugs into clinical trial and subsequent practice are also discussed.


Body shape ideals across gender, sexual orientation, socioeconomic status, race, and age in personal advertisements.
To assess body shape ideals across gender, sexual orientation, race, socio-economic status, and age, An analysis of personal advertisements was conducted across seven different publications which targeted the groups of interest. Women advertised body weight much less often than men, and lesbians reported body shape descriptors significantly less often than heterosexual women. Gay men and African-American men described their body shape significantly more often than did other groups. However, their reported body mass indices (BMI) were significantly different-African-American men reported a higher BMI, and gay men a lower BMI, than Euro-American heterosexual men. Race and sexual orientation may influence the importance of size of body shape ideals for men. For women, however, their advertised weights conformed to the thin ideal across all groups surveyed. Gender roles affecting body shape ideals and mate attraction are discussed.


Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.
Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA expression analysis was conducted on ECFCs from control and GDM pregnancies. Candidate genes were validated by quantitative RT-PCR and Western blotting. Bisulfite sequencing evaluated DNA methylation of placenta-specific 8 (PLAC8). Proliferation and senescence assays of ECFCs transfected with siRNA to knockdown PLAC8 were performed to determine functional impact. Thirty-eight genes were differentially expressed between control and GDM-exposed ECFCs. PLAC8 was highly expressed in GDM-exposed ECFCs, and PLAC8 expression correlated with maternal hyperglycemia. Methylation status of 17 CpG sites in PLAC8 negatively correlated with mRNA expression. Knockdown of PLAC8 in GDM-exposed ECFCs improved proliferation and senescence defects. This study provides strong evidence in neonatal endothelial progenitor cells that GDM exposure in utero leads to altered gene expression and DNA methylation, suggesting the possibility of altered epigenetic regulation.


Neuroanatomy in Rett syndrome: cerebral cortex and posterior fossa.
Rett syndrome (RS), a neurodevelopmental disorder of unknown etiology occurring almost exclusively in females, is characterized by autistic-like behavior, motor dysfunction, loss of language skills, dementia, and microcephaly. This study is a follow-up and extension of a previously reported neuroimaging study of patients with RS. We replicated previously reported findings with a larger patient population, and the volumetric MRI analysis was extended to include an analysis of neuroanatomy of the posterior fossa. Twenty girls with RS were compared with individually age- and gender-matched normal controls. Patients with RS showed global reduction in gray- and white-matter volumes. The prefrontal, posterior-frontal, and anterior-temporal regions showed the largest bilateral decrease in gray-matter volume, whereas white-matter volume was uniformly reduced throughout the brain. We found confirmation for the preferential reduction in caudate nucleus volume. However, we observed no preferential reduction in midbrain volume despite a preferential reduction in the midsagittal area of this region. We also present an individual case comparison between monozygotic twins discordant for RS.


The critical role of technologies in neonatal care.
Neonatal care has made significant advances in the last few decades. As a result, mortality and morbidity in high-risk infants, such as extremely preterm infants or those infants with birth-related brain injury, has reduced significantly. Many of these advances have been facilitated or delivered through development of medical technologies allowing clinical teams to be better supported with the care they deliver or provide new therapies and diagnostics to improve management. The delivery of neonatal intensive care requires the provision of medical technologies that are easy to use, reliable, accurate and ideally developed for the unique needs of the newborn population. Many technologies have been developed and commercialised following adult trials without ever being studied in neonatal patients despite the unique characteristics of this population. Increasingly, funders and industry are recognising this major challenge which has resulted in initiatives to develop new ideas from concept through to clinical care. This review explores some of the key medical technologies used in neonatal care and the evidence to support their adoption to improve outcomes. A number of devices have yet to realise their full potential and will require further development to optimise and find their ideal target population and clinical benefit. Examples of emerging technologies, which may soon become more widely used, are also discussed. As neonatal care relies more on medical technologies, we need to be aware of the impact on care pathways, especially from a human factors approach, the associated costs and subsequent benefits to patients alongside the supporting evidence.


Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein.
Plasminogen has been implicated in extracellular matrix degradation by invading cells, but few high affinity cell surface receptors for the molecule have been identified. Previous studies have reported that the plasma protein, histidine-rich glycoprotein (HRG), interacts with plasminogen and cell surfaces, raising the possibility that HRG may immobilize plasminogen/plasmin to cell surfaces. Here we show, based on optical biosensor analyses, that immobilized HRG interacts with soluble plasminogen with high affinity and with an extremely slow dissociation rate. Furthermore, the HRG-plasminogen interaction is lysine-dissociable and involves predominately the amino-terminal domain of HRG, and the fifth kringle domain of plasminogen, but not the carboxyl-terminal lysine of HRG. HRG was also shown to tether plasminogen to cell surfaces, with this interaction being potentiated by elevated Zn(2+) levels and low pH, conditions that prevail at sites of tissue injury, tumor growth, and angiogenesis. Based on these data we propose that HRG acts as a soluble adaptor molecule that binds to cells at sites of tissue injury, tumor growth, and angiogenesis, providing a high affinity receptor for tethering plasminogen to the cell surface and thereby enhancing the migratory potential of cells.


Developing facilitation skills--a narrative.
Effective facilitation has been identified in the literature as one of three elements, along with context and evidence, that have a dynamic and coexisting relationship to enable the successful uptake of evidence into practice. This paper presents an overview of the concept of facilitation within the context of practice development, ahead of a personal and professional reflective account of a 'developing facilitator'. In the summer of 2001, the author was instrumental in organising the first Practice Development School in Melbourne. Thrown in at the deep end, she found herself co-facilitating with an experienced practice developer from the United Kingdom. Having never facilitated in the arena of an action learning group, nor worked in the field of practice development, there was initially a sense of impending overload and drowning in the new knowledge and skills that needed to be acquired. Drawing upon the work of narrative inquiry the author shares her experiences in the anticipation that in telling her story it will assist others in their journey of becoming a facilitator.


[Roentgenologic diagnosis of cerebral concussion].
The article presents the findings of computer-aided tomography in 6 patients with brain concussion. In 27% of the cases the symptom-complex was accompanied by the development of brain plethora or hydrocephalus which was reflected in changes in the cerebral and densitometry characteristics. The objective nature of such changes was confirmed by the factorial analysis of the computer-aided tomographic and clinical symptoms as well as the presence of correlation between them. The authors has devised a linear regression model of the expected mean roentgen density of the white matter with regard to the degree of its atrophy. It has been shown that computer-aided tomography provides the possibility of identifying the pathological changes that develop following a mild craniocerebral injury and of predicting the outcome of their pathogenetic therapy.


Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's disease (MSPD).
Although improved cognition has been reported in patients with mild Parkinson's disease (PD) following the administration of levodopa, mixed results have been found in moderately-to-severely affected PD patients (MSPD), particularly in studies conducted since 1980. In the present study, 16 MSPD patients were tested on separate days, once following overnight levodopa withdrawal and once while optimally treated. A battery of neuropsychological tests that assess a range of cognitive functions (i.e., attention, language, visuospatial, memory, and executive), as well as a measure of depression, were used. Although patients performed better on a measure of confrontation naming in the untreated than in the treated condition, there were no significant differences for any of the other cognitive variables or for the depression scale variable. Thus, these data suggest that there are generally no adverse or beneficial effects of levodopa therapy on cognition in MSPD patients.


Stem Cell Therapies for the Treatment of Diabetic Neuropathies: Future Perspectives.
Diabetic neuropathies (DN) are the most common complications in diabetic patients, affecting about 70% of them. Patients with DN may lose sensation in certain areas of the body, facilitating the onset of foot ulcers, as well as chronic pain. This is due to the progressive degeneration of nerve fibers, demyelination, and axonopathy. Recent studies about stem cell therapies for the treatment of DN show promising potential for tissue regeneration. Results with mesenchymal stem cells derived from various organs/tissues demonstrate great therapeutic potential considering their easy obtainment, as well as their immunomodulatory and pro-regenerative effects. However, problems such as cell transplant rejection, tumor formation, transplantation safety, and effectiveness still need to be solved. Developmental biology lacks detailed insights into some aspects of cell mechanisms, like the genetic components of cell growth or differentiation. These gaps can limit a rapid advance in stem cell therapy research and put it in the future a little bit farther from the expectations that have emerged in recent media. In the present review, we attempt to discuss the potential of most studied types of stem cells, their application for the treatment of experimental diabetic neuropathies and associated clinical manifestations including future perspectives around these themes.


Formulation strategies for the development of high drug-loaded amorphous solid dispersions.
Amorphous solid dispersions (ASD) have gained tremendous attention over the past two decades as one of the most promising techniques for enhancing the solubility of poorly water-soluble drugs. However, low drug loading is one of the major challenges of ASD technology that limits its commercialization to only a few drug candidates. Increasing the drug loading increases the risk of recrystallization during storage (solid state) and/or during dissolution (solution state). Various formulation and process-related strategies have been explored that open the possibility of formulating high drug-loaded ASDs without the risk of recrystallization. Here, we review various formulation approaches, such as the use of surfactants, mesoporous silicas, polymer combinations, in situ thermal crosslinking, structural modification of polymeric carriers, and surface nanocoating using minerals. We also discuss the mechanisms by which these approaches inhibit solid state and/or solution state recrystallization.


Rattus norvegicus: not a model for Aeromonas-associated gastroenteritis in man.
The lack of a suitable animal model of Aeromonas-associated diarrhoea has hampered investigations into Aeromonas pathogenic mechanisms. Hence, a published report that clindamycin-pretreated rats developed signs and symptoms of enteritis following intragastric inoculation of an Aeromonas strain required further investigation. Although we could demonstrate long-term colonisation (>12 days) and histological damage in this animal model with Pseudomonas aeruginosa isolated from patients with chronic diarrhoea, this was not seen with Aeromonas spp. Six Aeromonas strains, selected for their potential virulence and colonising abilities and including the strain from the original report, were either not recovered from stools or were recovered for no longer than 2 days post inoculation. Intestinal histology remained normal. Destruction of bacteria in vivo appeared to be due to immune mechanisms as inoculum strains were not 'suicidal' or unduly sensitive to low pH or clindamycin. This study was, therefore, unable to validate the clindamycin-treated rat model as a useful one for investigating the enteropathogenicity of Aeromonas species. Possible reasons for the discrepancy between our study and the original report are discussed.


Primary Hyperaldosteronism Induced by Aldosterone-Producing Adenoma Co-Existing with A Left Suprarenal Accessory Spleen: Two Case Reports and A Review of The Literature.
We encountered 2 patients (a 33-year-old woman and a 66-year-old man) with an aldosterone-producing adenoma (APA) and a left accessory spleen. The patients' primary symptoms were hypertension and hypokalemia, and both had elevated serum aldosterone levels. Preoperative computed tomography a left suprarenal retroperitoneal mass and laparoscopic left adrenalectomy was performed in both cases. The postoperative microscopic examination revealed splenic tissue. Both patients experienced relief of their hypertension and hypokalemia, with an uneventful recovery.


Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial.
The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency. To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk. Post hoc analysis. The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers. 980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration < 124 micromol/L [<1.4 mg/dL]) Patients with a baseline serum creatinine concentration greater than 200 micromol/L (2.3 mg/dL) were excluded. The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke. Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs. 15.1%; P < 0.001) and increased with serum creatinine concentration. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs. 6.6%) and total mortality (17.8% vs. 10.6%) (P < 0.001 for both comparisons). The effect of renal insufficiency on the primary outcome (adjusted hazard ratio, 1.40 [95% CI, 1.16 to 1.69]) was independent of known cardiovascular risks and treatment. Ramipril reduced the incidence of the primary outcome in patients with and those without renal insufficiency (hazard ratio, 0.80 vs. 0.79; P > 0.2 for the difference). In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.


GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells.
The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+ release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+ entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+ by the GPR40 agonist, fasiglifam. Furthermore, β-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but also in vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic β-cells.


Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli.
The 5'-AMP-activated protein kinase (AMPK) plays a critical role in the regulation of cellular energy homeostasis. AMPK is a heterotrimer composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma). To date, purified AMPK has only been obtained in small, microgram quantities from tissues. Here, we describe an expression and purification system for production of functional AMPK in Escherichia coli. A plasmid carrying all three subunits of AMPK (alpha1, beta1, and gamma1) for T7 RNA polymerase-driven transcription of a single tricistronic messenger was constructed, allowing spontaneous formation of the heterotrimeric complex in the bacterial cytosol. AMPK was purified from the bacterial lysates by single-step nickel-ion chromatography, utilizing a poly-histidine tag fused to the N-terminus of the alpha-subunit. The recombinant AMPK complex was monodisperse, as shown by gel filtration chromatography with elution of a single peak at a Stokes radius of 52A. Bacterially expressed AMPK was entirely inactive, yet it could be activated by upstream kinase in the presence of AMP. Sufficient quantities of purified functional AMPK should prove to be an invaluable tool to solve many of the pertinent questions about its molecular structure and function, in particular facilitating protein crystallization for X-ray structure analysis.


Physical mapping of adeno-associated virus serotype 4 DNA.
The organization of adeno-associated virus serotype 4 (AAV 4) DNA was probed by using restriction enzymes. The cleavage sites of the following enzymes were mapped: BglII, BamI, HincII, KpnI, PstI, SalI, SstI, and XhoI. The orientation of transcription on the physical cleavage map was determined by locating the fragments which contain the 3' end of the mRNA. Strand separation gels were run for HinII fragments of AAV 4 DNA. By hybridizing AAV 4 mRNA to the resolved strands, the polarity of the DNA strands was identified. Restriction digestion of AAV 4 DNA sometimes produced terminal fragments which migrated in agarose gels as doublets. However, when AAV 4 DNA was prepared devoid of any single-stranded nicks, these terminal doublet bands were not observed upon subsequent restriction analysis. During these studies, the molecular weights of both AAV 4 and AAV 2 duplex DNA were measured and were found to be somewhat larger than previously reported (3.18 x 10(6) and 3.10 x 10(6), respectively).


Oxygen-18 of O2 records the impact of abrupt climate change on the terrestrial biosphere.
Photosynthesis and respiration occur widely on Earth's surface, and the 18O/16O ratio of the oxygen produced and consumed varies with climatic conditions. As a consequence, the history of climate is reflected in the deviation of the 18O/16O of air (delta18Oatm) from seawater delta18O (known as the Dole effect). We report variations in delta18Oatm over the past 60,000 years related to Heinrich and Dansgaard-Oeschger events, two modes of abrupt climate change observed during the last ice age. Correlations with cave records support the hypothesis that the Dole effect is primarily governed by the strength of the Asian and North African monsoons and confirm that widespread changes in low-latitude terrestrial rainfall accompanied abrupt climate change. The rapid delta18Oatm changes can also be used to synchronize ice records by providing global time markers.


Tumor risk in disorders of sex development.
Certain patients with disorders of sex development (DSD), who bear Y chromosome material in their karyotype, are at increased risk for the development of type II germ cell tumors (GCT), which arise from early fetal germ cells. DSD gonads frequently harbor immature germ cells which express early fetal germ cell markers. Some of them (e.g. OCT3/4 and NANOG) seem to be of pathogenetic relevance in GCT development providing cells with the ability of pluripotency, proliferation and apoptosis suppression. Also TSPY (testis-specific protein Y-encoded), the main candidate for the so-called gonadoblastoma locus on Y chromosome, is overexpressed in germ cells of DSD patients and possibly contributes to their survival and proliferation. Nowadays, the use of immunohistochemical methods is highly relevant in identifying DSD gonads at risk. The risk for GCT development varies. While the prevalence of GCT is 15% in patients with partial androgen insensitivity, it may reach more than 30% in patients with gonadal dysgenesis. Patients with complete androgen insensitivity and ovotesticular DSD develop malignancies in 0.8% and 2.6% of cases, respectively. However, these data may be biased for various reasons. To better estimate the risk in individual groups of DSD, further investigations on large patient series are needed.


Pulmonary arterial hypertension associated with neurofibromatosis type 1.
The authors report a case of severe pulmonary arterial hypertension (PAH) in a 75-year-old woman who had received a diagnosis of neurofibromatosis type 1 (NF1) 23 years before. She presented with progressive dyspnoea and recurrent syncope. Even though the patient initially improved after starting supportive and specific treatment for PAH, she then deteriorated and died from respiratory failure 11 months after the diagnosis of PAH. Prompt recognition of such an unusual association between PAH and NF1 and appropriate therapeutic intervention could ameliorate quality of life and prolong survival in this patient population.


Rupture of thin liquid films on structured surfaces.
We investigate stability and breakup of a thin liquid film on a solid surface under the action of disjoining pressure. The solid surface is structured by parallel grooves. Air is trapped in the grooves under the liquid film. Our mathematical model takes into account the effect of slip due to the presence of menisci separating the liquid film from the air inside the grooves, the deformation of these menisci due to local variations of pressure in the liquid film, and nonuniformities of the Hamaker constant which measures the strength of disjoining pressure. Both linear stability and strongly nonlinear evolution of the film are analyzed. Surface structuring results in decrease of the fastest growing instability wavelength and the rupture time. It is shown that a simplified description of film dynamics based on the standard formula for effective slip leads to significant deviations from the behavior seen in our simulations. Self-similar decay over several orders of magnitude of the film thickness near the rupture point is observed. We also show that the presence of the grooves can lead to instability in otherwise stable films if the relative groove width is above a critical value, found as a function of disjoining pressure parameters.


Asymmetric distribution of anionic phospholipids in supported lipid bilayers.
Lipid bilayers with a controlled content of anionic lipids are a prerequisite for the quantitative study of hydrophobic-electrostatic interactions of proteins with lipid bilayers. Here, the asymmetric distribution of zwitterionic and anionic lipids in supported lipid bilayers is studied by neutron reflectometry. We prepare POPC/POPS (3:1) unilamellar vesicles in a high-salt-concentration buffer. Initially, no fusion of the vesicles to a SiO(2) surface is observed over hours and days. Once the isotonic buffer is exchanged with hypotonic buffer, vesicle fusion and bilayer formation occur by osmotic shock. Neutron reflectivity on the bilayers formed this way reveals the presence of anionic lipids (d(31)-POPS) in the outer bilayer leaflet only, and no POPS is observed in the leaflet facing the SiO(2) substrate. We argue that this asymmetric distribution of POPS is induced by the electrostatic repulsion of the phosphatidylserines from the negatively charged hydroxy surface groups of the silicon block. Such bilayers with controlled and high contents of anionic lipids in the outer leaflet are versatile platforms for studying anionic lipid protein interactions that are key elements in signal transduction pathways in the cytoplasmic leaflet of eukaryotic cells.


Metabolism of four novel structural analogs of ketamine, 2-FXE [2-(ethylamino)-2-(2-fluorophenyl) cyclohexan-1-one], 2-MDCK [2-(methylamino)-2-(o-tolyl) cyclohexan-1-one], 3-DMXE [2-(ethylamino)-2-(m-tolyl) cyclohexan-1-one], and 2-DMXE [2-(ethylamino)-2-(o-tolyl) cyclohexan-1-one], in human liver microsomes based on ultra-performance liquid chromatography-high-resolution tandem mass spectrometry.
New psychoactive substances are constantly emerging, among which ketamine analogs with the core structure of 2-amino-2-phenylcyclohexanone have attracted global attention due to their continued involvement in acute intoxications. The monitoring of these substances largely relies on the acquisition of metabolic data. However, the lack of in vitro human metabolism information for these emerging structural analogs presents significant challenges to drug control efforts. To address this challenge, we investigated the first-phase metabolism patterns of four novel ketamine structural analogs of 2-FXE [2-(ethylamino)-2-(2-fluorophenyl) cyclohexan-1-one], 2-MDCK [2-(methylamino)-2-(o-tolyl) cyclohexan-1-one], 3-DMXE [2-(ethylamino)-2-(m-tolyl) cyclohexan-1-one], and 2-DMXE [2-(ethylamino)-2-(o-tolyl) cyclohexan-1-one] utilizing human liver microsomes for the first time. Metabolites were identified using ultra-performance liquid chromatography coupled with high-resolution tandem mass spectrometry. Our findings reveal that N-dealkylation and hydroxylation are the primary metabolic reactions, alongside other notable reactions, including oxidation, reduction, and dehydration. Based on our extensive research, we propose N-dealkylation and hydroxylation metabolites as appropriate analytical markers for monitoring the consumption of these substances.


Lentil lectin binding properties of the leucocyte common antigen from rat dividing and non-dividing thymocytes.
The surface glycoproteins of rat large, mainly dividing, thymocytes and their small, non-dividing, progeny have been examined by labelling with 3H-sodium borohydride. A prominent glycoprotein component of apparent mol. wt. 150 K was labelled on both the cell types and by immunoprecipitation with a specific monoclonal antibody, was demonstrated to contain the leucocyte common antigen (LCA). The binding of this glycoprotein to Lens culinaris lectin (LcH) has been studied. Preliminary results obtained by different binding of ratiolabelled LcH to sodium dodecyl sulphate (SDS) solubilised crude plasma membrane from large and small thymocytes, fractionated by polyacrylamide gel electrophoresis (PAGE) indicated that a 150 K apparent molecular weight glycoprotein in the small cells bound radiolabelled LcH whereas virtually no binding of the lectin was observed in the 150 K region for large cells. However, by utilizing a different approach of lectin affinity chromatography on LcH-Sepharose 4B of solubilized NaB3H4 labelled membrane, followed by immunoprecipitation, we unequivocally showed that the 150 K labelled glycoprotein of both large and small cells was bound to LcH lectin and only eluted with the specific sugar alpha-methyl pyranoside (alpha-MP). The implications of these results is discussed.


Differentiating enteric Escherichia coli from environmental bacteria through the putative glucosyltransferase gene (ycjM).
This study is to tackle the challenge posed by the "naturalized" Escherichia coli population against the worldwide practice of E. coli-based water quality monitoring. In the literature, the putative glucosyltransferase gene (ycjM) of E. coli has been identified in silico to be one of the 114 genes specific to enteric E. coli. Based on the sequence of E. coli K-12 MG1655, a PCR assay (ycjPCR) targeting ycjM was developed in this study. As demonstrated by the ycjPCR assay using 367 E. coli strains isolated from animal feces, 97.2% of the isolates carried the ycjM with variations from 93.9% to 100% among nine different host sources, but none of the 17 strains of non-E. coli bacteria and only 23.0% of the environment-isolated cryptic Escherichia strains contained the ycjM. These data experimentally confirmed ycjM to be enteric specific. Our study also showed that the ycjPCR assay was superior to the commonly used tuf- or uidA-based PCR methods in differentiating enteric E. coli from ß-D-glucuronidase-positive environmental bacteria. Furthermore, study on 190 E. coli isolates from water samples, using EPA Method 1603 followed by bacterial identification with Biolog MicroStation™ and ycjPCR assay, indicated that the prevalence of ycjM in the E. coli water isolates had a significant (p < 0.05, odds ratio ) spatial variation from 69.6% to 93.8%. These data suggest that E. coli profile using EPA Method 1603 or other ß-D-glucuronidase-activity-based methods may need further analysis using the ycjM profile to accurately determinate fecal pollution in water.


Recovirus NS1-2 Has Viroporin Activity That Induces Aberrant Cellular Calcium Signaling To Facilitate Virus Replication.
Enteric viruses in the Caliciviridae family cause acute gastroenteritis in humans and animals, but the cellular processes needed for virus replication and disease remain unknown. A common strategy among enteric viruses, including rotaviruses and enteroviruses, is to encode a viral ion channel (i.e., viroporin) that is targeted to the endoplasmic reticulum (ER) and disrupts host calcium (Ca2+) homeostasis. Previous reports have demonstrated genetic and functional similarities between the nonstructural proteins of caliciviruses and enteroviruses, including the calicivirus NS1-2 protein and the 2B viroporin of enteroviruses. However, it is unknown whether caliciviruses alter Ca2+ homeostasis for virus replication or whether the NS1-2 protein has viroporin activity like its enterovirus counterpart. To address these questions, we used Tulane virus (TV), a rhesus enteric calicivirus, to examine Ca2+ signaling during infection and determine whether NS1-2 has viroporin activity that disrupts Ca2+ homeostasis. We found that TV increases Ca2+ signaling during infection and that increased cytoplasmic Ca2+ levels are important for efficient replication. Further, TV NS1-2 localizes to the endoplasmic reticulum, the predominant intracellular Ca2+ store, and the NS2 region has characteristics of a viroporin domain (VPD). NS1-2 had viroporin activity in a classic bacterial functional assay and caused aberrant Ca2+ signaling when expressed in mammalian cells, but truncation of the VPD abrogated these activities. Together, our data provide new mechanistic insights into the function of the NS2 region of NS1-2 and support the premise that enteric viruses, including those within Caliciviridae, exploit host Ca2+ signaling to facilitate their replication.IMPORTANCE Tulane virus is one of many enteric caliciviruses that cause acute gastroenteritis and diarrheal disease. Globally, enteric caliciviruses affect both humans and animals and amass >65 billion dollars per year in treatment and health care-associated costs, thus imposing an enormous economic burden. Recent progress has resulted in several cultivation systems (B cells, enteroids, and zebrafish larvae) to study human noroviruses, but mechanistic insights into the viral factors and host pathways important for enteric calicivirus replication and infection are still largely lacking. Here, we used Tulane virus, a calicivirus that is biologically similar to human noroviruses and can be cultivated by conventional cell culture, to identify and functionally validate NS1-2 as an enteric calicivirus viroporin. Viroporin-mediated calcium signaling may be a broadly utilized pathway for enteric virus replication, and its existence within caliciviruses provides a novel approach to developing antivirals and comprehensive therapeutics for enteric calicivirus diarrheal disease outbreaks.


Comprehensive comparison of social cognitive performance in autism spectrum disorder and schizophrenia.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are separate neurodevelopmental disorders that are both characterized by difficulties in social cognition and social functioning. Due to methodological confounds, the degree of similarity in social cognitive impairments across these two disorders is currently unknown. This study therefore conducted a comprehensive comparison of social cognitive ability in ASD and SCZ to aid efforts to develop optimized treatment programs. In total, 101 individuals with ASD, 92 individuals with SCZ or schizoaffective disorder, and 101 typically developing (TD) controls, all with measured intelligence in the normal range and a mean age of 25.47 years, completed a large battery of psychometrically validated social cognitive assessments spanning the domains of emotion recognition, social perception, mental state attribution, and attributional style. Both ASD and SCZ performed worse than TD controls, and very few differences were evident between the two clinical groups, with effect sizes (Cohen's d) ranging from 0.01 to 0.34. For those effects that did reach statistical significance, such as greater hostility in the SCZ group, controlling for symptom severity rendered them non-significant, suggesting that clinical distinctions may underlie these social cognitive differences. Additionally, the strength of the relationship between neurocognitive and social cognitive performance was of similar, moderate size for ASD and SCZ. Findings largely suggest comparable levels of social cognitive impairment in ASD and SCZ, which may support the use of existing social cognitive interventions across disorders. However, future work is needed to determine whether the mechanisms underlying these shared impairments are also similar or if these common behavioral profiles may emerge via different pathways.


Molecular model of the A subunit of protein phosphatase 2A: interaction with other subunits and tumor antigens.
Protein phosphatase 2A consists of three subunits, the catalytic subunit (C) and two regulatory subunits (A and B). The A subunit has a rod-like shape and consists of 15 nonidentical repeats. It binds the catalytic subunit through repeats 11 to 15 at the C terminus and the tumor antigens encoded by small DNA tumor viruses through overlapping but distinct regions at N-terminal repeats 2 to 8. A model of the A subunit was developed on the basis of the fact that uncharged or hydrophobic amino acids are conserved at eight defined positions within each repeat. Helical wheel projections suggested that each repeat can be arranged as two interacting amphipathic helixes connected by a short loop. Mutational analysis of the A subunit revealed that the proposed loops are important for binding of tumor antigens, the B subunit, and the C subunit. Native gel analysis of mutant A subunits synthesized in vitro demonstrated that the binding region for the B subunit, previously thought to include repeats 2 to 8, covers repeats 1 to 10 and that the B and C subunits cooperate in binding to the A subunit.


Metformin-associated lactic acidosis reported to the United Kingdom National Poisons Information Service (NPIS) between 2010 and 2019: a ten-year retrospective analysis.
Metformin toxicity following therapeutic use or overdose may result in metabolic acidosis with hyperlactatemia. This study aims to assess the relationship between serum lactate concentration, arterial pH, and ingested dose with severity of poisoning, and to identify if serum lactate concentration is a useful marker of severity in metformin toxicity. A retrospective study of telephone enquiries relating to metformin exposures to the National Poisons Information Service between 2010 and 2019 from hospitals in the United Kingdom. Six-hundred and thirty-seven cases were identified; 117 involved metformin only and 520 involved metformin with other drugs. The majority of cases involved acute (87%) and intentional (69%) exposures. There was a statistically significant difference in doses between the Poisoning Severity Scores, as well as between intentional and unintentional or therapeutic error doses (P < 0.0001). The distribution of cases for each Poisoning Severity Score differed between the metformin only and metformin with other drugs cases (P < 0.0001). Lactic acidosis was reported in 232 cases. Serum lactate concentration and arterial pH differed across Poisoning Severity Scores. Arterial pH inversely correlated with ingested dose (r=-0.3, P = 0.003), and serum lactate concentration positively correlated with ingested dose (r = 0.37, P < 0.0001). Serum lactate concentration and arterial pH did not correlate with each other. Twenty-five deaths were recorded, all following intentional overdoses. The dataset focuses mostly on acute, intentional overdoses. Increasing ingested metformin dose, a higher serum lactate concentration and worsening arterial pH were all associated with an unfavourable Poisoning Severity Score in patients in both metformin only and metformin with other drugs groups. As serum lactate concentration did not correlate with arterial pH, it represents an independent marker of poisoning severity. Data from the present study suggest that serum lactate concentration can be used to assess severity of poisoning in patients who have reportedly ingested metformin.


Effect of low-dose ketamine versus fentanyl on attenuating the haemodynamic response to laryngoscopy and endotracheal intubation in patients undergoing general anaesthesia: a prospective, double-blinded, randomised controlled trial.
The use of drugs to attenuate the haemodynamic response to laryngoscopy and endotracheal intubation is the standard of care during elective surgery. Current evidence is conflicting concerning the best agent and optimal dose for this purpose. In the majority of cases, fentanyl is widely utilized to attenuate haemodynamic responses. Ketamine, an established available drug, has been scarcely studied in this regard at low doses and against varying doses of other common agents. To compare the overall occurrence of hypertension and tachycardia immediately pre-intubation (post-induction) until 10 minutes post intubation between the study group receiving fentanyl at 1.0 µg/kg and the other receiving ketamine at 0.5 mg/kg, to compare the occurrence of post-induction hypotension and the occurrence of neuropsychiatric phenomena during emergence between the two groups. One hundred and eight ASA I and II patients aged 18-65 years scheduled for elective surgery under general anaesthesia were randomized into two groups: Control group: received fentanyl 1.0 µg/kg intravenously. Intervention group: received ketamine 0.5 mg/kg intravenously. General anaesthesia was standardized in both groups. The patients and physicians administering anaesthesia were blinded to the study. Haemodynamic responses were evaluated by determining heart rate and blood pressure immediately before laryngoscopy and at 2.5, 5, 7.5 and 10 minutes. Neuropsychiatric phenomena were assessed upon recovery from anaesthesia. One hundred and eight ASA I and II patients scheduled to undergo elective surgery were included in this study, 54 participants (50%) in the fentanyl arm and 54 (50%) in the ketamine arm. Baseline demographic characteristics were similar between the groups. There were more hypertensive episodes in the ketamine arm (11%) compared to the fentanyl arm (1.85%), but not achieving statistical significance: Fisher's exact test, p=0.06. There was no significant difference in the number of episodes of tachycardia between the Ketamine group 7/54 (13%) and the fentanyl group, 6/54 (11%); x2=0.05, p=0.82. Hypotensive episodes were more common in those who received Fentanyl, 41/54 (76%), compared to ketamine recipients, 21/54 (39%), X2=16.9, p<0.001. The use of Ketamine was associated with less episodes of hypotension, adjusted odds ratio = 0.18 (95% confidence interval 0.07, 0.45). We conclude, based upon findings in this study group, that there is no difference in the occurrence of hypertension with the use ketamine at 0.5 mg/kg in combination with Propofol at 2.0 mg/kg. In this regard, ketamine provides a viable alternative to fentanyl at 1.0 µg/kg for attenuating the pressor response to laryngoscopy and endotracheal intubation. Additionally, our results suggest that ketamine may protect against post-induction (pre-laryngoscopy) hypotension.


rac-Methyl (3aR*,4S*,5R*,7aR*)-5,7a-bis-(acet-yloxy)-3-oxo-2-phenyl-octa-hydro-1H-iso-indole-4-carboxyl-ate.
The title molecule, C20H23NO7, the product of nucleophilic cleavage of the 3a,6-ep-oxy bridge in 1-oxo-2-phenyl-octa-hydro-3a,6-ep-oxy-iso-indole-7-carboxyl-ate, comprises a cis-fused bicyclic system containing a 2-pyrrolidinone ring in an envelope conformation (with the C atom bearing the carboxyl-ate substituent as the flap) and a cyclo-hexane ring in a chair conformation. The carboxyl-ate substituent occupies the equatorial position, whereas the two acet-yloxy substituents are in axial positions. The N atom has a trigonal-planar geometry, the sum of the bond angles being 359.3 (3)°. The dihedral angle between the mean plane of the four planar atoms of the pyrrolidinone ring and the phenyl ring is 25.98 (6)°. In the crystal, mol-ecules are linked into zigzag chains along the c-axis direction by C-H⋯O hydrogen bonds.


Close relationship between non-viral retroposons in Drosophila melanogaster.
G elements constitute one of the several moderately repeated DNA families of the Drosophila melanogaster genome. G elements lack terminal repetitions and structurally resemble mammalian processed pseudogenes because they terminate at one end in oligo-A tracts of variable length. G elements are mostly interspersed in the chromocentric heterochromatin with other repeated DNA sequences. Nucleotide sequence analysis of G3A, a family member inserted in a non-nucleolar rDNA unit, shows that functional G elements might have coding capacity for two polypeptides; one has homology to reverse transcriptases, the other is reminiscent of RNA binding proteins derived from the cleavage of retroviral gag polyproteins. Functionally related polypeptides are similarly encoded by members of two other Drosophila repeated DNA families, the F elements and the I factors. The similarity in structural organization and the relatedness of their potential gene products favors the hypothesis that G, F, and I sequences derive from a common ancestor and result from processes based on the reverse transcription of RNA intermediates that probably differ markedly from those ensuring the maintenance and dispersion of copia-like elements.


[Academy of medical sciences during the Great Patriotic War and first years after war].
In the article presented the history of foundation of the Academy of Medical Sciences of the USSR and its activities during the World War Two and the early postwar years. According to the authors, the scientific development of many fundamental problems from domestic medicine experience during the war has retained its relevance in solving of the contemporary issues in health and medical science in modern Russia.


Micro-level mechanisms of identity development: The role of emotional experiences in commitment development.
Based on Marcia's theory, many researchers consider exploration and commitment as the main processes in identity development. Although some identity theorists have hypothesized that emotional experience may also be an important part of the mechanisms of identity development, empirical research to investigate this claim has been lagging behind. In this study, we shed light on the role of emotional experiences in micro-level commitment dynamics, and compare this to the role of exploration. We take a within-individual approach, and particularly focus on educational commitment. We collected weekly measurements among 103 first year university students over several months, resulting in 22 to 30 measurements for each individual. Every week, the students reported an important experience and accompanying positive and negative emotions, their level of educational exploration and commitment. We generated linear growth models for each individual separately, using Dynamic Linear Modeling. These individual models generate regression weights that indicate how strong the impact is of exploration, positive and negative emotional experiences on changes in micro-level commitment for each individual. Our main finding is that both positive and negative emotional experiences are indeed related to changes in educational commitment. Positive experiences, but surprisingly, also negative experiences, are related to increases in educational commitment for the majority of individuals. Moreover, for the large majority of individuals, the impact of emotional experiences is larger than the impact of exploration. Therefore, we conclude that it is highly likely that emotional experiences are an essential part of the micro-level mechanisms of identity development. (PsycINFO Database Record


Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates.
The use of drug-eluting stents (DES) in patients at high risk of bleeding or thrombosis has not been prospectively studied; limited data are available in patients who have a low restenosis risk. This study sought to compare a hydrophilic polymer-based, second-generation zotarolimus-eluting stent (ZES) with a unique drug fast-release profile versus bare-metal stents (BMS) under similar durations of dual-antiplatelet therapy (DAPT). We randomly assigned 1,606 patients with stable or unstable symptoms, and who on the basis of thrombotic bleeding or restenosis risk criteria, qualified as uncertain candidates for DES, to receive ZES or BMS. DAPT duration was on the basis of patient characteristics, rather than stent characteristics, and allowed for a personalized 1-month dual antiplatelet regimen. The primary endpoint was the risk of 1-year major adverse cardiovascular events (MACE), which included death, myocardial infarction (MI), or target vessel revascularization (TVR). Median DAPT duration was 32 days (interquartile range [IQR]: 30 to 180 days) and did not differ between the groups. In the ZES group, 140 patients (17.5%) reached the primary endpoint, compared with 178 patients (22.1%) in the BMS group (hazard ratio: 0.76; 95% confidence interval: 0.61 to 0.95; p = 0.011) as a result of lower MI (2.9% vs. 8.1%; p < 0.001) and TVR rates (5.9% vs.10.7%; p = 0.001) in the ZES group. Definite or probable stent thrombosis was also significantly reduced in ZES recipients (2.0% vs. 4.1%; p = 0.019). Compared with BMS, DES implantation using a stent with a biocompatible polymer and fast drug-eluting characteristics, combined with an abbreviated, tailored DAPT regimen, resulted in a lower risk of 1-year MACE in uncertain candidates for DES implantation. (Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS] Study; NCT01385319).


Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus.
Oxidative stress, resulting in a marked increase in the level of oxygen free radicals (OFR), has been implicated in the etiology of diabetic neuropathy (DN). Antioxidant enzymes may protect against the rapid onset and progression of DN, by reducing the excess of OFR and peroxide. Mutations and polymorphisms in the genes encoding such enzymes may therefore result in predisposition to DN. We investigated the role of genes encoding two antioxidant enzymes, mitochondrial (Mn-SOD) and extracellular (EC-SOD) superoxide dismutase, in DN pathogenesis in a Russian population. We studied Ala(-9)Val and Ile58Thr polymorphisms of the Mn-SOD gene and Arg213Gly dimorphism of the EC-SOD gene in type 1 diabetic patients with (n = 82) and without DN (n = 84). We developed and used a new polymerase chain reaction (PCR) assays for rapid detection of polymorphisms. These assays involved the use of mismatch PCR primers to create restriction sites in the amplified product only in presence of the polymorphic base. The PCR product was than digested with BshTI, Eco32I or Eco52I to detect Ala(-9)Val, Ile58Thr or Arg213Gly polymorphic site respectively. The frequencies of the Ala allele (50.6% vs. 68.5%, p < 0.002) and the Ala/Ala genotype (17.1% vs. 39.3%, p < 0.005) of the Mn-SOD gene were significantly lower in DN patients than in diabetic subjects without DN. In contrast, the Val allele (49.4% vs. 31.5%, p < 0.002) and the Val/Val genotype (15.9% vs. 2.4%, p < 0.01) were significantly more frequent in the DN patients than in the control group. Ala(-9)Val substitution in the Mn-SOD gene was associated with DN in a Russian population


Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication.
Bicyclic pyrimidine nucleoside analogues (BCNAs) represent highly potent and selective inhibitors of varicella-zoster virus (VZV) replication in cell culture. The compounds inhibit a variety of clinical VZV strains, in the higher picomolar range, whilst being non-toxic at micromolar concentrations. The compounds do not inhibit the closely related simian varicella virus or any other viruses, including herpes simplex virus type 1 (HSV-1), HSV-2 and cytomegalovirus. The BCNAs owe at least part of their antiviral selectivity to a specific activation/phosphorylation by the VZV-encoded thymidine kinase (TK) and associated thymidylate kinase (dTMP-K) activity, while being not recognized by the closely related HSV-1-encoded TK/dTMP-K enzyme. In addition, the 5'-monophosphates of BCNAs are neither a substrate nor an inhibitor of the cellular dTMP-K, and are not subject of back-conversion to the corresponding nucleosides by 5'-deoxynucleotidases. In contrast to the anti-HSV-1/VZV drug (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), the BCNAs are not catabolized by human (erythrocyte) or bacterial (Escherichia coli) thymidine phosphorylase to release the free bicyclic pyrimidine base. Also, unlike BVU (the free base of BVDU), the BCNA bases do not inhibit dihydropyrimidine dehydrogenase. Consequently, the catabolism of the anticancer drug 5-fluorouracil (5-FU) is not influenced by the BCNA base in cell-free enzyme assays or in mice that were exposed to combinations of 5-FU with BCNAs or their free base. BCNAs have a good oral bioavailability and, owing to their highly lipophilic nature, are assumed to be able to cross the blood-brain barrier efficiently. Given the above-mentioned favourable properties, BCNAs may represent a promising novel class of highly selective anti-VZV drugs that should be further pursued for clinical application.


Overexpression of BiP in tobacco alleviates endoplasmic reticulum stress.
To study the role of the lumenal binding protein (BiP) in the transport and secretion of proteins, we have produced plants with altered BiP levels. Transgenic plants overexpressing BiP showed dramatically increased BiP mRNA levels but only a modest increase in BiP protein levels. The presence of degradation products in BiP overproducers suggests a regulatory mechanism that increases protein turnover when BiP is abundant. Antisense inhibition of BiP synthesis was not successful, demonstrating that even a minor reduction in the basal BiP level is deleterious to cell viability. Overexpression of BiP leads to downregulation of the basal transcript levels of endogenous BiP genes and greatly reduces the unfolded protein response. The data confirm that BiP transcription is regulated via a feedback mechanism that involves monitoring of BiP protein levels. To test BiP activity in vivo, we designed a functional assay, using the secretory protein alpha-amylase and a cytosolic enzyme as a control for cell viability. During tunicamycin treatment, an overall reduction of alpha-amylase synthesis was observed when compared with the cytosolic marker. We show that the tunicamycin effect is due to the depletion of BiP in the endoplasmic reticulum because coexpressed BiP alone is able to restore efficient alpha-amylase synthesis. This is a novel assay to monitor BiP activity in promoting secretory protein synthesis in vivo.


Investigation of Radiotracer Metabolic Stability In Vitro with CYP-Overexpressing Hepatoma Cell Lines.
The characterization of novel radiotracers toward their metabolic stability is an essential part of their development. While in vitro methods such as liver microsome assays or ex vivo blood or tissue samples provide information on overall stability, little or no information is obtained on cytochrome P450 (CYP) enzyme and isoform-specific contribution to the metabolic fate of individual radiotracers. Herein, we investigated recently established CYP-overexpressing hepatoblastoma cell lines (HepG2) for their suitability to study the metabolic stability of radiotracers in general and to gain insight into CYP isoform specificity. Wildtype HepG2 and CYP1A2-, CYP2C19-, and CYP3A4-overexpressing HepG2 cells were incubated with radiotracers, and metabolic turnover was analyzed. The optimized protocol, covering cell seeding in 96-well plates and analysis of supernatant by radio thin-layer-chromatography for higher throughput, was transferred to the evaluation of three 18F-labeled celecoxib-derived cyclooxygenase-2 inhibitors (coxibs). These investigations revealed time-dependent degradation of the intact radiotracers, as well as CYP isoform- and substrate-specific differences in their metabolic profiles. HepG2 CYP2C19 proved to be the cell line showing the highest metabolic turnover for each radiotracer studied here. Comparison with human and murine liver microsome assays showed good agreement with the human metabolite profile obtained by the HepG2 cell lines. Therefore, CYP-overexpressing HepG2 cells provide a good complement for assessing the metabolic stability of radiotracers and allow the analysis of the CYP isoform-specific contribution to the overall radiotracer metabolism.


Proton pump inhibitors. Compliance with a mandated step-up program.
To assess compliance with a step-up approach to proton pump inhibitor (PPI) therapy before implementation of a new provincial policy to promote histamine-type 2 receptor antagonist (H2RA) use before PPI therapy. Population-based, retrospective, open cohort study using prescribing and medical procedure data from January 1, 1995, to April 30, 1999. Health administration databases for the universal health care system in Ontario. Approximately 1.4 million residents of Ontario older than 65 years. Proportion of patients who received a trial of H2RA therapy or gastrointestinal diagnostic testing 12 months before starting PPI therapy in 1996. Among the 25,870 patients who met study criteria in 1996, about 63% had received H2RAs 12 months before starting PPI therapy and 73% had had a trial of H2RAs or gastrointestinal diagnostic testing. Repeat analysis for January through April 1999, following the new policy implementation, showed that about 72% of patients had had a trial of H2RAs within 12 months of starting PPI therapy. A modest gain (9%) in compliance with using H2RA therapy within 12 months before starting PPI therapy was seen following introduction of the step-up intervention. In future, costs and benefits of potential interventions should be carefully considered before implementing new policies.


Binary classification of Mueller matrix images from an optimization of Poincaré coordinates.
A new binary classification method for Mueller matrix images is presented which optimizes the polarization state analyzer (PSA) and the polarization state generator (PSG) using a statistical divergence between pixel values in two regions of an image. This optimization generalizes to multiple PSA/PSG pairs so that the classification performance as a function of number of polarimetric measurements can be considered. Optimizing PSA/PSG pairs gives insight into which polarimetric measurements are most useful for the binary classification. For example, in scenes with strong diattenuation, retardance, or depolarization certain PSA/PSG pairs would make two regions in an image look very similar and other pairs would make the regions look very different. The method presented in this paper provides a quantitative method for ensuring the images acquired can be classified optimally.


[The complications of retropubic radical prostatectomy].
Between January 1989 and October 1995, 104 prostatectomies were performed in patients with prostate carcinoma in our centre. Mean follow-up 22 months, range 3-84 months. Overall frequency of complications was 33%. No fatal complications were reported. Complications in the early post-operative occurred in 17 patients (16%); late complications in 18 patients (17%), the most frequent one was stenosis of urethrovesical by-pass. No case of total incontinence has been recorded. The rate of stress incontinence at 3 months was 36% and 15% at 9 months.


Biplane ventriculography in the rat.
Biplane ventriculography was performed on nine intact anesthetized rats. Images of the left ventricle large enough for analysis were obtained by placing the rats close to the radiographic tubes (direct enlargement). Sampling rates, adequate for heart rates of 500 beats/min, were obtained by filming at 500 frames/s. From the digitized silhouettes of the left ventricle the following information was obtained (means +/- SE): end-diastolic volume 0.60 +/- 0.03 ml, end-systolic volume 0.22 +/- 0.02 ml, stroke volume 0.38 +/- 0.02 ml, ejection fraction 0.63 +/- 0.02, cardiac output 118 +/- 7 ml/min, diastolic septolateral dimension 0.41 +/- 0.01 mm, diastolic anteroposterior dimension 0.40 +/- 0.01 mm, diastolic base-to-apex dimension 1.58 +/- 0.04 mm. To determine the accuracy with which the volume of the ventricle could be measured, 11 methyl methacrylate casts of the left ventricle were made. The correlation was high (r = 0.99 +/- 0.02 ml E) between the cast volumes determined by water displacement and by use of two monoplane methods (Simpson's rule of integration and the area-length method applied to the analysis of the anteroposterior films) and a biplane method (area-length). These results demonstrate that it is possible to obtain accurate dimensions and volumes of the rat left ventricle by use of high-speed ventriculography.


Obesity, Leptin and Breast Cancer: Epidemiological Evidence and Proposed Mechanisms.
The prevalence of obesity has been steadily increasing over the past few decades in several developed and developing countries, with resultant hazardous health implications. Substantial epidemiological evidence has shown that excessive adiposity strongly influences risk, prognosis, and progression of various malignancies, including breast cancer. Indeed, it is now well recognized that obesity is a complex physiologic state associated with multiple molecular changes capable of modulating the behavior of breast tumor cells as well of the surrounding microenvironment. Particularly, insulin resistance, hyperactivation of insulin-like growth factor pathways, and increased levels of estrogen due to aromatization by the adipose tissue, inflammatory cytokines, and adipokines contribute to breast cancerogenesis. Among adipokines, leptin, whose circulating levels increase proportionally to total adipose tissue mass, has been identified as a key member of the molecular network in obesity. This review summarizes the current knowledge on the epidemiological link existing between obesity and breast cancer and outlines the molecular mechanisms underlying this connection. The multifaceted role of the obesity adipokine leptin in this respect is also discussed.


2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis.
This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.


Lipid peroxidation and depressed mood in community-dwelling older men and women.
It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70-79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF2α was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF2α than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p = 0.03, Cohen's d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences.


Molecular characterization of a microbial consortium involved in methane oxidation coupled to denitrification under micro-aerobic conditions.
Methane can be used as an alternative carbon source in biological denitrification because it is nontoxic, widely available and relatively inexpensive. A microbial consortium involved in methane oxidation coupled to denitrification (MOD) was enriched with nitrite and nitrate as electron acceptors under micro-aerobic conditions. The 16S rRNA gene combined with pmoA phylogeny of methanotrophs and nirK phylogeny of denitrifiers were analysed to reveal the dominant microbial populations and functional microorganisms. Real-time quantitative polymerase chain reaction results showed high numbers of methanotrophs and denitrifiers in the enriched consortium. The 16S rRNA gene clone library revealed that Methylococcaceae and Methylophilaceae were the dominant populations in the MOD ecosystem. Phylogenetic analyses of pmoA gene clone libraries indicated that all methanotrophs belonged to Methylococcaceae, a type I methanotroph employing the ribulose monophosphate pathway for methane oxidation. Methylotrophic denitrifiers of the Methylophilaceae that can utilize organic intermediates (i.e. formaldehyde, citrate and acetate) released from the methanotrophs played a vital role in aerobic denitrification. This study is the first report to confirm micro-aerobic denitrification and to make phylogenetic and functional assignments for some members of the microbial assemblages involved in MOD.


Measurement and clinical applications of C-reactive protein in gastrointestinal diseases of dogs.
C-reactive protein (CRP) is a positive acute-phase protein, serum concentrations of which increase nonspecifically in response to inflammatory processes of the dog. As such, it can aid in the identification of inflammatory disease and, maybe more importantly, the objective monitoring of disease progression. In dogs, CRP is frequently used to evaluate dogs with gastrointestinal diseases, such as chronic inflammatory enteropathies (also termed idiopathic inflammatory bowel disease), acute pancreatitis, canine parvovirus infection, hepatic disease, acute abdomen, and protein-losing enteropathy. The diversity of the assays available to measure CRP in dogs is nearly as numerous as the diseases in which serum concentrations of this protein are increased. Assay methodologies include laser nephelometric immunoassays, enzyme-linked immunosorbent assays, immunoturbidimetric assays, and time-resolved immunofluorometric assays. While many of these assays are acceptable for clinical use in the dog, the same assay and analyzer should be used to measure a patient's CRP concentration longitudinally. By looking at the uses of CRP in human gastroenterology, including reducing the duration of antibiotic therapy, the veterinary profession can gain insight into novel ways in which serum CRP concentration measurements might be applied in veterinary medicine in the future.


In vitro Ploidy Manipulation for Crop Improvement.
In vitro regeneration systems provide a powerful tool for manipulating ploidy to facilitate breeding and development of new crops. Polyploid induction can expand breeding opportunities, assist with the development of seedless triploid cultivars, enhance ornamental characteristics and environmental tolerances, increase biomass and restore fertility in wide hybrids. In vitro ploidy manipulation is commonly induced using antimitotic agents such as colchicine, oryzalin and trifluralin, while many other antimitotic agents have been relatively unexplored. Successful induction requires a synergistic pairing of efficient penetration of the antimitotic agent and may be dependent the length of exposure and concentrations of antimitotic agents, tissue types, and interactions with basal media and plant growth regulators. In vitro conditions vary among taxa and individual genera, species, and cultivars, often requiring unique treatments to maximize polyploid induction. In some taxa, the induction of polyploidy influences in vitro growth, development, and root formation. Here we provide an overview of mitotic inhibitors and their application for in vitro ploidy manipulation for plant breeding and crop improvement.


Foregut duplications: is there an advantage to thoracoscopic resection?
Thoracoscopy has an expanding role in the treatment of FD cysts (bronchogenic cysts and esophageal duplications). We examined this trend in our patients and reviewed our overall experience. All charts of children undergoing surgery for foregut duplications (FDs) in 2 pediatric hospitals between 1992 and 2003 were retrospectively reviewed. Data gathered included age, weight, symptoms, diagnostic tests, operative technique, postoperative course, complications, and outcome. There were 39 children, with FD resected by thoracotomy in 21 patients, thoracoscopy in 11 patients (no conversions to open), cervical incision in 6 patients, and laparotomy in 1 patient for an FD near the gastroesophageal junction. Diagnosis was made by antenatal ultrasound in 7 cases. Four of these neonates had tachypnea or cough, and the rest were asymptomatic. Seventy-five percent of patients diagnosed postnatally presented with respiratory symptoms. Excision of isolated FD (without lung resection) was compared between those who had a thoracotomy (n = 16) vs thoracoscopy (n = 11). The age, weight, operating time, and anesthesia time were not different between the 2 groups. However, the thoracoscopy group had significantly fewer chest tube days (1.6 vs 3.3 days) and a shorter hospital stay (2.6 vs 6.6 days). Intraoperative complications consisted of tracheal injury in 3 patients (2 thoracotomy, 1 thoracoscopy) and esophageal mucosal injury in 2 patients (both thoracotomy), which were all recognized and repaired. Foregut duplications may present in a variety of ways and locations. Thoracoscopy is advantageous for isolated intrathoracic FDs.


Gastric-floating microcapsules provide controlled and sustained release of multiple cardiovascular drugs.
Floating polymeric microcapsules that simultaneously entrap multiple drugs were prepared using a solid/water/oil/water emulsion solvent evaporation method, based on harnessing interfacial phenomena and manipulation of the solvent removal process. The fabricated microcapsules exhibited excellent buoyancy in simulated gastric fluid and provided controlled and sustained release of multiple drugs for up to 24 h, thus revealing their potential as a rate-controlled oral drug delivery system.


Reliability and validity of the habitual activity estimation scale (HAES) in patients with cystic fibrosis.
To understand potential benefits of exercise in the cystic fibrosis (CF) population, there needs to be accurate methods to quantify it. The Habitual Activity Estimation Scale (HAES) questionnaire has been shown to be a feasible tool to measure physical activity however the reliability and validity have yet to be determined in the CF population. Fourteen (seven male, seven female) patients aged 16.2 +/- 4.2 years with CF participated in this study. Participants were clinically stable at the time of the study and participating in their habitual physical activity. To assess reliability, patients completed the HAES and a validated 3-day activity diary, and wore an ActiGraph Accelerometer for two consecutive weeks. Validity was assessed by comparing the activity results of each of the three instruments over a single week time period. ICC estimates of reliability for the HAES, diary, and accelerometer were 0.72 (P < 0.0001), 0.76 (P < 0.0001), 0.63 (P < 0.0001), respectively. Validity analysis indicated that there were significant relationships between the participants' activity results as estimated by the HAES, diary and accelerometer. Further, significant relationships were detected between activity measures when broken into morning, afternoon, or evening periods, and between measures from weekday or weekend days. There were also significant relationships among the three instruments when recording different activity levels (somewhat inactive, somewhat active, and very active). The findings of this study suggest that the HAES questionnaire is a reliable and valid instrument that can be used to assess activities of varying intensity in patients with CF.


Tiara Valve Implantation in a Patient With Previously Implanted Mono-disk Mechanical Aortic Prosthesis.
Transcatheter mitral valve replacement with the Tiara valve can be performed in inoperable patients with severe functional regurgitation. Risk of left ventricular outflow tract obstruction can be prevented using preoperative 3D imaging and 3D-printed models. However, in the case of mono-disk mechanical prostheses previously implanted in aortic position (Bjork-Shiley), there is an additional risk of mechanical interference leading to reduced leaflet motion and aortic valve dysfunction. Hereafter, we describe the case of a patient with a 27-mm mono-disk mechanical aortic valve implanted in 1978, a EuroSCORE II of 18%, and a Society of Thoracic Surgeon score (mortality) of 16% who successfully underwent a transapical Tiara valve implantation.


[Indices of lipid peroxidation in the condensate of exhaled air--a simple and objective method of estimating injuries to the pulmonary surfactant system].
A method for assessing injury to the pulmonary surfactant system is suggested, based on studies of lipid peroxidation parameters in exhaled air condensate. Free-radical processes in pulmonary surfactants were examined in normal subjects and in patients with various forms of chronic nonspecific diseases of the respiratory organs. The findings evidence that a disease essentially intensifies lipid peroxidation in the alveolar lining, this being parallelled by reduced antiradical defense. Such an approach to studies of pulmonary surfactant system injuries is marked for its simplicity and atraumatism, this recommending it for mass clinical check-ups. Use of this method is promising as regards the disease prognosis and assessment of the treatment efficacy, as well as detection of subjects at high risk of developing bronchopulmonary diseases.


DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males.
Essential hypertension is highly prevalent in the elderly population, exceeding 70% in people older than 60 yr of age, and remains a leading risk factor for heart disease, stroke, and chronic renal disease. Elucidation of genetic determinants is critical but remains a challenge due to its complex, multifactorial pathogenesis. We investigated the role DEspR promoter variants, previously associated with male essential hypertension susceptibility, in blood pressure (BP) regulation. We detected a single nucleotide polymorphism within the DEspR 5'-regulatory region associated with increased BP in a male Sardinian cohort accounting for 11.0 mmHg of systolic BP (P<10(-15)) and 9.3 mmHg of diastolic BP (P<10(-15)). Sequence analysis of three normotensive subjects homozygous for the rs6535847 "normotension-associated T-allele" identified a canonical TATAAAA-box in contrast to a CATAAAA-motif in three hypertensive subjects homozygous for the rs6535847 "hypertension-associated C-allele." In vitro analysis detected decreased transcription activity with the CATAAAA-motif promoter-construct compared with the canonical TATAAAA-box promoter-construct. Although BP did not differ between DEspR+/- knockout male mice and wild-type littermates at 6 mo of age, radiotelemetric BP measurements in 18 mo old inbred DEspR+/- knockout male mice known to have decreased DEspR RNA and protein detected higher systolic, mean, and diastolic BPs in DEspR+/- mice compared with littermate wild-type controls (P<0.05). Our results demonstrate that promoter variants in DEspR associated with hypertension susceptibility and increased BP in Sardinian males affect transcription levels, which then affect BP in an age-dependent and male-specific manner. This finding is concordant with the late-onset and sex-specific characteristics of essential hypertension, thus reiterating the mandate for sex-specific analyses and treatment approaches for essential hypertension.


Skin wrinkling: can food make a difference?
This study addressed whether food and nutrient intakes were correlated with skin wrinkling in a sun-exposed site. 177 Greek-born subjects living in Melbourne (GRM), 69 Greek subjects living in rural Greece (GRG), 48 Anglo-Celtic Australian (ACA) elderly living in Melbourne and 159 Swedish subjects living in Sweden (SWE) participating in the International Union of Nutritional Sciences IUNS "Food Habits in Later Life" study had their dietary intakes measured and their skin assessed. Food and nutrient intakes were assessed using a validated semi-quantitative food frequency questionnaire (FFQ). Skin wrinkling was measured using a cutaneous microtopographic method. SWE elderly had the least skin wrinkling in a sun-exposed site, followed by GRM, GRG and ACA. Correlation analyses on the pooled data and using the major food groups suggested that there may be less actinic skin damage with a higher intake of vegetables (r(s)=-0.31, p<0.0001), olive oil (r(s)=-0.29, p<0.0001), fish (r(s)=-0.24, p<0.0001) and legumes (r(s)=-0.16, p<0.0001), and lower intakes of butter (r(s)=0.46, p<0.0001) and margarine (r(s)=0.24, p<0.001), milk products (r(s)=0.16, p<0.01) and sugar products (r(s)=0.12, p<0.01). Similar findings were obtained using regression analyses, except fish was no longer significant; 32% of the variance for actinic skin damage was predicted by six out of the ten major food groups. In particular, a high intake of vegetables, legumes and olive oil appeared to be protective against cutaneous actinic damage (collectively explaining 20% of the variance); a high intake of meat, dairy and butter appeared to be adverse (explaining <5% of the variance). Prunes, apples and tea explained 34% of variance amongst ACA. This study illustrates that skin wrinkling in a sun-exposed site in older people of various ethnic backgrounds may be influenced by the types of foods consumed.


A micro creeping robot for colonoscopy based on the earthworm.
Minimally Invasive Surgery (MIS) has become one of the most important research areas in the field of medical engineering. Robotic colonoscopy is a typical medical procedure that complies with the requirements of MIS. In this paper, a new novel miniature robot for intestinal inspection based on the earthworm is described; its diameter and length are 7.5 mm and 120 mm respectively. The micro robot is driven by a DC motor which has good performance and sufficient power. In this paper the structure and locomotion mechanism of this robot are introduced; the mechanical model is built; and simulation is carried out. The control system and software design are also discussed in detail. Some actuating characteristic experiments have been performed, where the micro robot creeps in declining rubber tubes. The experimental results are in accord with simulation results, and show that this kind of robot can move reliably in horizontal and certain declining tubes. This research has laid a foundation for the application of the miniature robot endoscope.