Molecular and genetic characterisation of the SARS coronavirus auxiliary protein X1 in Drosophila.
1. We have generated monoclonal antibodies against the SARS coronavirus (SARS-CoV) X1/3a protein (3a), which are suitable for western blotting, immunocytochemistry, and immunohistochemistry. 2. We have established and characterised an in-vivo 3a transgenic Drosophila model, and demonstrated its usefulness in studying SARS-CoV 3a gene function. 3. We validated our in-vivo findings on 3a gene function in mammalian Vero E6 cells. 4. Our findings raise the possibility of using ion channel blockers as a novel approach to suppress SARS-CoV-induced cell death.


Changes in alpha-foetoprotein and Gc-globulin in relation to outcomes in non-acetaminophen acute liver failure.
Changes in Gc-globulin (Gc) and in alpha-foetoprotein (AFP) have been shown to be related to outcome in patients with acute liver failure (ALF). Gc is a serum protein that complexes with intravascular actin released during cellular necrosis. AFP, also made by hepatocytes, is associated with hepatocellular growth and regeneration. Previously, low absolute levels or decreases over time in either AFP or Gc portended to be a poor outcome. In a retrospective analysis of the double-blind trial of intravenous N-acetylcysteine (NAC) for ALF not because of acetaminophen, sera on days 1 and 3 or days 2 and 4 following admission were available to measure AFP in 70 patients and Gc in 66 patients. Mann-Whitney U tests were performed on the admission values, the absolute change and the fractional change of AFP and Gc to compare TFS (transplant-free survival) and non-TFS (death or transplantation). Logistic regression and receiver operating characteristic (ROC) analyses were performed to evaluate the markers in comparison and in addition to King's College Criteria (KCC). Transplant-free survival patients were characterized by increases in AFP, whereas non-TFS had significantly different (negative) absolute and fractional changes (P < .01). The addition of declining AFP levels to KCC improved the area under the curve in predicting non-TFS (AUC >70%). Gc globulin values did not differ between TFS and non-TFS in the 2-day intervals studied (P> .2). In this comparison of two prognostic markers in patients with non-acetaminophen-induced ALF, rising AFP but not rising Gc levels was associated with TFS. ClinicalTrials.gov number NCT00004467.


Thrombomodulin changes the molecular surface of interaction and the rate of complex formation between thrombin and protein C.
The interaction of thrombin with protein C triggers a key down-regulatory process of the coagulation cascade. Using a panel of 77 Ala mutants, we have mapped the epitope of thrombin recognizing protein C in the absence or presence of the cofactor thrombomodulin. Residues around the Na(+) site (Thr-172, Lys-224, Tyr-225, and Gly-226), the aryl binding site (Tyr-60a), the primary specificity pocket (Asp-189), and the oxyanion hole (Gly-193) hold most of the favorable contributions to protein C recognition by thrombin, whereas a patch of residues in the 30-loop (Arg-35 and Pro-37) and 60-loop (Phe-60h) regions produces unfavorable contributions to binding. The shape of the epitope changes drastically in the presence of thrombomodulin. The unfavorable contributions to binding disappear and the number of residues promoting the thrombin-protein C interaction is reduced to Tyr-60a and Asp-189. Kinetic studies of protein C activation as a function of temperature reveal that thrombomodulin increases >1,000-fold the rate of diffusion of protein C into the thrombin active site and lowers the activation barrier for this process by 4 kcal/mol. We propose that the mechanism of thrombomodulin action is to kinetically facilitate the productive encounter of thrombin and protein C and to allosterically change the conformation of the activation peptide of protein C for optimal presentation to the thrombin active site.


Etiology and management of bovine graft aneurysms.
From April 1975 to September 1980, 16 symptomatic bovine graft aneurysms were identified in 200 grafts used for long-term hemodialysis. Aneurysms occurred in five (3.6%) straight forearm grafts, two (33%) reversed forearm grafts, two (33%) straight thigh grafts, and seven (18.9%) upper arm grafts. Mean blood pressures were similar in the aneurysm and non-aneurysm groups (142/81 vs 153/83 mm Hg). At operation, the aneurysms were determined to be true in three patients and false in 13. Five patients were treated by graft ligation and aneurysm excision and 11 by aneurysm excision and graft revision, with additional graft survivals of one to 25 months. In conclusion, bovine graft aneurysms are usually false and are more frequent in proximal grafts. In the absence of infection, resection is indicated and will result in considerable prolongation of graft survival.


[Clinico-morphological comparisons in different types of dysentery].
Clinical evidence and morphological picture of rectal biopsy specimens were analysed for 125 dysentery patients. As compared to a light course, moderately severe and severe dysentery presented enhanced microbial adherence and an elevated level of large lymphocytes in the external epithelium of the rectum, deeper penetration of Shigella into crypts. On day 9-15 of the disease in attenuation of the clinical symptoms in severe and moderately dysentery morphological shifts persisted whereas the light run was associated with a marked decline of microbial invasion and cellular infiltration of the epithelium. In the protracted condition elimination of the microbes with desquamative colonocytes appeared inhibited permitting prognosis of the protraction as early as day 2-4 of the disease.


[Acute inflammation of greater omentum].
Results of treatment of 9 patients (3 male, 6 female) with acute omentitis are analyzed. Omentitis was primary in 8 patients, and secondary -- in 1 patient. Right-sided abdominal localization of pains was the cause of incorrect entrance diagnosis (acute appendicitis and acute cholecystitis). All the patients were operated, the resection of affected parts of great omentum was performed; in 3 cases it was supplemented with appendectomy. Problems of pre-operative diagnosis of acute omentitis and the choice of optimal variant of surgery are discussed.


TP53 mutation and haplotype analysis of two large African American families.
Two large apparently unrelated African American families with a high incidence of breast cancer and other tumors characteristic of Li-Fraumeni breast sarcoma cancer family syndrome were studied. Mutation screening revealed that in both families the affected members carried a germline mutation of the TP53 gene at codon 133 (ATG--> ACG, M133T). In order to determine whether an ancestral haplotype was shared by these two families, polymorphic markers within and flanking the TP53 gene were studied. Haplotype analysis using five markers revealed an identical haplotype shared by the two families. Loss of heterozygosity at the TP53 locus in the probands' tumor tissues from each family was observed; in each case, the retained allele carried the common haplotype. The frequency of this haplotype in the general African American population is <0.003. This unique haplotype, combined with the rare TP53 mutation, suggests that these African American families share a common ancestry. This finding suggests that other African Americans may be carriers of this mutation and thus may be at risk of early-onset breast cancer or other cancers characteristic of the Li-Fraumeni breast sarcoma cancer family syndrome. The finding of recurring mutations in African Americans may facilitate carrier screening and identification in this population.


Accelerating HIV-1 VLP production using stable High Five insect cell pools.
Stable cell pools are receiving a renewed interest as a potential alternative system to clonal cell lines. The shorter development timelines and the capacity to achieve high product yields make them an interesting approach for recombinant protein production. In this study, stable High Five cell pools are assessed for the production of a simple protein, mCherry, and the more complex HIV-1 Gag-eGFP virus-like particles (VLPs). Random integration coupled to fluorescence-activated cell sorting (FACS) in suspension conditions is applied to accelerate the stable cell pool generation process and enrich it with high producer cells. This methodology is successfully transferred to a bioreactor for VLP production, resulting in a 2-fold increase in VLP yields with respect to shake flask cultures. In these conditions, maximum viable cell concentration improves by 1.5-fold, and by-product formation is significantly reduced. Remarkably, a global increase in the uptake of amino acids in the Gag-eGFP stable cell pool is observed when compared with parental High Five cells, reflecting the additional metabolic burden associated with VLP production. These results suggest that stable High Five cell pools are a robust and powerful approach to produce VLPs and other recombinant proteins, and put the basis for future studies aiming to scale up this system.


Clinical assessment of collagen cross-linked N-telopeptides as a marker of bone metabolism in patients with primary hyperparathyroidism.
This study assesses the clinical usefulness of collagen cross-linked N-telopeptides (NTx), a new marker for bone resorption, as a marker for primary hyperparathyroidism. The study was conducted on 114 patients who had undergone parathyroidectomy for primary hyperparathyroidism. Urine NTx levels were longitudinally determined by ELISA. Longitudinal serum bone Gla protein (BGP) determinations and dual energy X-ray absorptiometry (DEXA) examinations were also performed before and after parathyroidectomy. Before parathyroidectomy, the mean urine NTx level in primary hyperparathyroidism was 149.0 +/- 116.8 pmol BCE/mumol Cr (normal: < 55 pmol BCE/mumol Cr), and the positive rate was 88.5%. The mean BGP level was 33.5 +/- 59.1 ng/mL (normal: 12.7 ng/mL), and the positive rate was 77.7%. The NTx positive rate was higher than the BGP positive rate. NTx values were significantly correlated with bone mineral density (P < 0.002) and BGP values (P < 0.005). Two weeks after parathyroidectomy the NTx levels had already decreased significantly to 65.1 pmol BCE/mumol Cr (P < 0.001), and by one month postoperatively they had fallen to 55.9 pmol BCE/mumol Cr, reaching the normal range much sooner than BGP. The NTx normalization rate two weeks postoperatively was 37%, and by 12 months postoperatively it was normal in 83% of patients. BGP levels decreased more gradually than the NTx levels, and only became normal in 9% of cases two weeks postoperatively, as opposed to 74% by 12 months. It is concluded that NTx reflects bone turnover in primary hyperthyroidism, and that it is an excellent marker for bony lesions before and after parathyroidectomy.


Comparing in vivo, in vitro and in silico methods and integrated strategies for chemical assessment: problems and prospects.
The RAINBOW workshop addressed the background for the integration of in vivo, in vitro and computer-based (in silico) methods, to facilitate the study of the toxic properties of chemicals. On the basis of these discussions, we prepared the present paper, outlining the strengths, weaknesses, opportunities and threats of each approach, both alone and integrated into a single testing strategy. The current scheme for evaluation of chemicals needs to be reshaped, in the face of the much larger numbers of chemicals which need to be examined and the availability of a diversified set of tools.


An Assessment of Phylogenetic Tools for Analyzing the Interplay Between Interspecific Interactions and Phenotypic Evolution.
Much ecological and evolutionary theory predicts that interspecific interactions often drive phenotypic diversification and that species phenotypes in turn influence species interactions. Several phylogenetic comparative methods have been developed to assess the importance of such processes in nature; however, the statistical properties of these methods have gone largely untested. Focusing mainly on scenarios of competition between closely-related species, we assess the performance of available comparative approaches for analyzing the interplay between interspecific interactions and species phenotypes. We find that many currently used statistical methods often fail to detect the impact of interspecific interactions on trait evolution, that sister-taxa analyses are particularly unreliable in general, and that recently developed process-based models have more satisfactory statistical properties. Methods for detecting predictors of species interactions are generally more reliable than methods for detecting character displacement. In weighing the strengths and weaknesses of different approaches, we hope to provide a clear guide for empiricists testing hypotheses about the reciprocal effect of interspecific interactions and species phenotypes and to inspire further development of process-based models.


Investigation of SIRT1 gene variants in HIV-associated lipodystrophy and metabolic syndrome.
HIV-infected individuals on chronic use of highly active antiretroviral therapy (HAART) are more likely to develop adipose tissue and metabolic disorders, such as lipodystrophy (LD) and metabolic syndrome (MetS). The development of these phenotypes is known to be multifactorial. Thus, variants in genes implicated in adipogenesis and lipid metabolism may increase susceptibility to LD and MetS. Sirtuin 1 (SIRT1) may influence the outcome of these disturbances due to its role in the regulation of transcription factors involved in energy regulation. Therefore, we genotyped four polymorphisms located in SIRT1 (rs2273773 T>C, rs12413112 G>A, rs7895833 A>G, rs12049646 T>C) in 832 HIV-infected patients receiving HAART by real-time polymerase chain reaction. The prevalence of LD was 55.8% and MetS was 35.3%. Lipoatrophy was the most prevalent subtype in all samples (38.0%) and showed significant difference between white and non-white individuals (P = 0.002). None of the genetic variants investigated in SIRT1 was associated with LD and MetS. White individuals and those in longer time of HAART use were more likely to develop LD. We concluded that these SIRT1 polymorphisms are not predictive factors to the development of lipodystrophy and metabolic syndrome in HIV-infected individuals from Brazil.


Spin transition of iron in magnesiowüstite in the Earth's lower mantle.
Iron is the most abundant transition-metal element in the mantle and therefore plays an important role in the geochemistry and geodynamics of the Earth's interior. Pressure-induced electronic spin transitions of iron occur in magnesiowüstite, silicate perovskite and post-perovskite. Here we have studied the spin states of iron in magnesiowüstite and the isolated effects of the electronic transitions on the elasticity of magnesiowüstite with in situ X-ray emission spectroscopy and X-ray diffraction to pressures of the lowermost mantle. An observed high-spin to low-spin transition of iron in magnesiowüstite results in an abnormal compressional behaviour between the high-spin and the low-spin states. The high-pressure, low-spin state exhibits a much higher bulk modulus and bulk sound velocity than the low-pressure, high-spin state; the bulk modulus jumps by approximately 35 percent and bulk sound velocity increases by approximately 15 percent across the transition in (Mg0.83,Fe0.17)O. Although no significant density change is observed across the electronic transition, the jump in the sound velocities and the bulk modulus across the transition provides an additional explanation for the seismic wave heterogeneity in the lowermost mantle. The transition also affects current interpretations of the geophysical and geochemical models using extrapolated or calculated thermal equation-of-state data without considering the effects of the electronic transition.


Implementation of clinical practice changes in the PICU: a qualitative study using and refining the iPARIHS framework.
Like in many settings, implementation of evidence-based practices often fall short in pediatric intensive care units (PICU). Very few prior studies have applied implementation science frameworks to understand how best to improve practices in this unique environment. We used the relatively new integrated Promoting Action on Research Implementation in Health Services (iPARIHS) framework to assess practice improvement in the PICU and to explore the utility of the framework itself for that purpose. We used the iPARIHS framework to guide development of a semi-structured interview tool to examine barriers, facilitators, and the process of change in the PICU. A framework approach to qualitative analysis, developed around iPARIHS constructs and subconstructs, helped identify patterns and themes in provider interviews. We assessed the utility of iPARIHS to inform PICU practice change. Fifty multi-professional providers working in 8 U.S. PICUs completed interviews. iPARIHS constructs shaped the development of a process model for change that consisted of phases that include planning, a decision to adopt change, implementation and facilitation, and sustainability; the PICU environment shaped each phase. Large, complex multi-professional teams, and high-stakes work at near-capacity impaired receptivity to change. While the unit leaders made decisions to pursue change, providers' willingness to accept change was based on the evidence for the change, and provider's experiences, beliefs, and capacity to integrate change into a demanding workflow. Limited analytic structures and resources frustrated attempts to monitor changes' impacts. Variable provider engagement, time allocated to work on changes, and limited collaboration impacted facilitation. iPARIHS constructs were useful in exploring implementation; however, we identified inter-relation of subconstructs, unique concepts not captured by the framework, and a need for subconstructs to further describe facilitation. The PICU environment significantly shaped the implementation. The described process model for implementation may be useful to guide efforts to integrate changes and select implementation strategies. iPARIHS was adequate to identify barriers and facilitators of change; however, further elaboration of subconstructs for facilitation would be helpful to operationalize the framework. Not applicable, as no health care intervention was performed.


Rapid characterization of anti-CRISPR proteins and optogenetically engineered variants using a versatile plasmid interference system.
Anti-CRISPR (Acr) proteins are encoded by mobile genetic elements to overcome the CRISPR immunity of prokaryotes, displaying promises as controllable tools for modulating CRISPR-based applications. However, characterizing novel anti-CRISPR proteins and exploiting Acr-related technologies is a rather long and tedious process. Here, we established a versatile plasmid interference with CRISPR interference (PICI) system in Escherichia coli for rapidly characterizing Acrs and developing Acr-based technologies. Utilizing the PICI system, we discovered two novel type II-A Acrs (AcrIIA33 and AcrIIA34), which can inhibit the activity of SpyCas9 by affecting DNA recognition of Cas9. We further constructed a circularly permuted AcrIIA4 (cpA4) protein and developed optogenetically engineered, robust AcrIIA4 (OPERA4) variants by combining cpA4 with the light-oxygen-voltage 2 (LOV2) blue light sensory domain. OPERA4 variants are robust light-dependent tools for controlling the activity of SpyCas9 by approximately 1000-fold change under switching dark-light conditions in prokaryotes. OPERA4 variants can achieve potent light-controllable genome editing in human cells as well. Together, our work provides a versatile screening system for characterizing Acrs and developing the Acr-based controllable tools.


[Molecular biological aspects of the pathogenesis of diabetes mellitus].
The discovery of the key role played by the immune system in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) opens up new possibilities for its early diagnosis, at the stages preceding its clinical manifestation. Analysed are the markers of genetic susceptibility to IDDM associated with some major histocompatibility complex antigens (specifically with HLA-DR 3, HLA-DR4, and HLA-DQ), of the cellular and humoral anti-islet autoimmunity, as well as the origin of the islet-cell autoantigens. The markers' significance for the diagnosis and prognosis is discussed.


Biased expression, under the control of single promoter, of human interferon α-2b and Escherichia coli methionine amino peptidase genes in E. coli, irrespective of their distance from the promoter.
Human interferon α-2b and Escherichia coli methionine amino peptidase genes were cloned independently as well as bicistronically in expression plasmid pET-21a (+). Production of human interferon α-2b was comparable to that of E. coli methionine amino peptidase when these genes were expressed independently in E. coli BL21-CodonPlus (DE3)-RIL. However, human interferon α-2b was produced in a much less amount whereas there was no difference in the production of methionine amino peptidase when the encoding genes were expressed bicistronically. It is important to note that human interferon α-2b was the first gene in order, after the promoter and E. coli methionine amino peptidase was the next with a linker sequence of 27 nucleotides between them.


[Immunomodulating activity of RNA mononucleotides].
The immunological action of RNA mononucleotides was studied in animal experiments. The most pronounced activation of macrophagal glycolysis urea cycle, oxidative phosphorylation, lysosomal hydrolases was induced by uridine 5'-monophosphate (5'-UMP) and guanosine 5'-monophosphate (5'-GMP); 5'-GMP also induced the maximum increase of the expression of FC gamma receptors. 5'-UMP ensured cell activation comparable with the total action of all mononucleotides. 5'-UMP and 5'-GMP, used in combination, produced the highest stimulating effect on macrophages, and the addition of low-active adenosine 5'-monophosphate (5'-AMP) to active 5'-UMP did not decrease the stimulating potency of the latter. The stimulating activity of sodium nucleinate exceeded that of all mononucleotides and their combinations. 5'-GMP and 5'-AMP induced the maximum activation of oxygen metabolism, evaluated by chemiluminescence, while 5'-UMP and cytidine 5'-monophosphate (5'CMP) proved to be inactive. The shift of the phosphate group to the third carbon atom or the production of the oligonucleotide 5'-UMP consisting of 5-15 nucleotides resulted in the appearance of the capacity for stimulating oxygen metabolism in macrophages. Their in vitro cultivation with 5'-GMP and 5'-AMP induced the maximum increase of cell spreading in comparison with other mononucleotides, while the maximum increase of phagocytosis was ensured only by 5'-UMP and 5'-GMP.2+ 5'-UMP and 5'-GMP enhanced nonospecific resistance to Salmonella typhi infection, and sodium nucleinate, to Pseudomonas pseudomallei and Pseudomonas mallei infections.


Evaluation of two line probe assays for rapid detection of Mycobacterium tuberculosis, tuberculosis (TB) drug resistance, and non-TB Mycobacteria in HIV-infected individuals with suspected TB.
Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV(+)) individuals with suspected TB from southern Africa and South America with <7 days of TB treatment had 1 sputum specimen tested with Direct LPA, MTBDR-Plus LPA, smear microscopy, MGIT, biochemical identification of mycobacterial species, and culture-based drug-susceptibility testing (DST). Of 639 participants, 59.3% were MGIT M. tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities.


[Rheologic properties of the erythrocytes and hemostatic system in patients with polycythemia vera].
Rheologic properties of red blood cells and hemostasis were investigated in 25 patients with polycythemia vera (PV). Manifest hemorheologic and hemocoagulation disorders attended by thrombohemorrhagic complications were revealed in this group of patients. It has been shown that hemorheologic disorders play an important role in the mechanisms of thrombohemorrhagic complications in PV, therefore they should be corrected with antiaggregation agents. In some cases disorders in the rheologic phenomena of red blood cells are a triggering mechanism in the development of disseminated intravascular coagulation (DIC) syndrome. A correlation has been revealed between the parameters of red blood cell rheologic properties and hemostasis and the disease severity. It is suggested that rheologic properties of red blood cells should be studied for the diagnosis of DIC syndrome.


Rapid isolation and purification of phorbol esters from Jatropha curcas by high-speed countercurrent chromatography.
In this work, a high-speed countercurrent chromatography (HSCCC) method was established for the preparation of phorbol esters (PEs) from Jatropha curcas. n-Hexane-ethyl acetate-methanol-water (1.5:1.5:1.2:0.5, v/v) was selected as the optimum two-phase solvent system to separate and purify jatropha factor C1 (JC1) with a purity of 85.2%, as determined by HPLC, and to obtain a mixture containing four or five PEs. Subsequently, continuous semipreparative HPLC was applied to further purify JC1 (99.8% as determined by HPLC). In addition, UPLC-PDA and UPLC-MS were established and successfully used to evaluate the isolated JC1 and PE-rich crude extract. The purity of JC1 was only 87.8% by UPLC-UV. A peak (a compound highly similar to JC1) was indentified as the isomer of JC1 by comparing the characteristic UV absorption and MS spectra. Meanwhile, this strategy was also applied to analyze the PE-rich crude extract from J. curcas. It is interesting that there may be more than 15 PEs according to the same quasi-molecular ion peaks, highly similar sequence-specific fragment ions, and similar UV absorption spectrum.


Reference values for cardiometabolic risk scores in children and adolescents: Suggesting a common standard.
International reference values for cardiometabolic risk variables, to allow for standardization of continuous risk scores in children, are not currently available. The aim of this study was to provide international age- and gender-specific reference values for cardiometabolic risk factors in children and adolescents. Cohorts of children sampled from different parts of Europe (North, South, Mid and Eastern) and from the United States were pooled. In total, 22,479 observations (48.7% European vs. 51.3% American), 11,234 from girls and 11,245 from boys, aged 6-18 years were included in the study. Linear mixed-model regression analysis was used to analyze the associations between age and each cardiometabolic risk factor. Reference values for 14 of the most commonly used cardiometabolic risk variables in clustered risk scores were calculated and presented by age and gender: systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), body mass index (BMI), sum of 4 skinfolds (sum4skin), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), TC:HDL-C ratio, glucose, insulin, homeostatic model assessment-score (HOMA-score), and cardiorespiratory fitness (CRF). This study suggests a common standard to define cardiometabolic risk in children. Adapting this approach makes single risk factors and clustered cardiometabolic disease risk scores comparable to the reference material itself and comparable to cardiometabolic risk values in studies using the same strategy. This unified approach therefore increases the prospect to estimate and compare prevalence and trends of cardiometabolic risk in children when using continuous cardiometabolic risk scores.


Comparison of DRD2 rs1800497 (TaqIA) polymorphism between schizophrenic patients and healthy controls: Lack of association in a Turkish sample.
Abstract Objective. The association of DRD2 rs1800497 (TaqIA) polymorphisms and schizophrenia has been studied in a number of populations, but the results are contradictory. We aimed to define Taq IA allelic differences between schizophrenic and healthy subjects. Methods. The schizophrenic group consisted of 99 schizophrenic inpatients, diagnosed and treated at Gazi University Hospital Psychiatry Service, the healthy group was composed of 109 subjects who did not suffer from any psychiatric or organic diseases. High molecular weight genomic DNAs were prepared from peripheral venous blood cells by using proteinase K digestion followed by salt extraction method. Target DNA amplification of DRD2 gene (Taq1A, 310-bp region) was performed by polymerase chain reaction (PCR) with the primers 5014 and 971. Results. Of the 208 subjects involved in the study, 98.6% had A1 allele (hetero- or homo-zygote) and 1.4% had A2 allele (homozygote). While all schizophrenia patients had A1 allele, 97.2%, of the healthy subjects (n=106) had A1 allele and there was no significant difference between the groups. Conclusion. This study was the first study related to DRD2 polymorphism conducted in a Turkish schizophrenic patient sample. A great percentage of our sample has A1 allele. Our study could not find a significant association between schizophrenia and DRD2 rs1800497 polymorphism.


Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection.
3beta-Hydroxy-lup-20(29)-en-28-oic acid (betulinic acid) is a pentacyclic lupane-type triterpene that is widely distributed throughout the plant kingdom. A variety of biological activities have been ascribed to betulinic acid including anti-inflammatory and in vitro antimalarial effects. However, betulinic acid is most highly regarded for its anti-HIV-1 activity and specific cytotoxicity against a variety of tumor cell lines. Interest in developing even more potent anti-HIV agents based on betulinic acid has led to the discovery of a host of highly active derivatives exhibiting greater potencies and better therapeutic indices than some current clinical anti-HIV agents. While its mechanism of action has not been fully determined, it has been shown that some betulinic acid analogs disrupt viral fusion to the cell in a post-binding step through interaction with the viral glycoprotein gp41 whereas others disrupt assembly and budding of the HIV-1 virus. With regard to its anticancer properties, betulinic acid was previously reported to exhibit selective cytotoxicity against several melanoma-derived cell lines. However, more recent work has demonstrated that betulinic acid is cytotoxic against other non-melanoma (neuroectodermal and malignant brain tumor) human tumor varieties. Betulinic acid appears to function by means of inducing apoptosis in cells irrespective of their p53 status. Because of its selective cytotoxicity against tumor cells and favorable therapeutic index, even at doses up to 500 mg/kg body weight, betulinic acid is a very promising new chemotherapeutic agent for the treatment of HIV infection and cancer.


Altered Metabolomic Profile in Patients with Peripheral Artery Disease.
Peripheral artery disease (PAD) is a common atherosclerotic disease characterized by narrowed or blocked arteries in the lower extremities. Circulating serum biomarkers can provide significant insight regarding the disease progression. Here, we explore the metabolomics signatures associated with different stages of PAD and investigate potential mechanisms of the disease. We compared the serum metabolites of a cohort of 26 PAD patients presenting with claudication and 26 PAD patients presenting with critical limb ischemia (CLI) to those of 26 non-PAD controls. A difference between the metabolite profiles of PAD patients from non-PAD controls was observed for several amino acids, acylcarnitines, ceramides, and cholesteryl esters. Furthermore, our data demonstrate that patients with CLI possess an altered metabolomic signature different from that of both claudicants and non-PAD controls. These findings provide new insight into the pathophysiology of PAD and may help develop future diagnostic procedures and therapies for PAD patients.


Hydrogen Sulfide Reverses Aging-Associated Amygdalar Synaptic Plasticity and Fear Memory Deficits in Rats.
As an endogenous neuromodulator, hydrogen sulfide (H2S) exerts multiple biological effects in the brain. Previous studies have shown that H2S is involved in the regulation of neural synaptic plasticity and cognition in healthy rodents. It is well known that there is a progressive decline of cognitive function that occurs with increased age. The purpose of this study was to investigate the role of H2S in aging-associated amygdalar synaptic plasticity and cued fear memory deficits as well as to explore the underlying mechanisms. We found that H2S levels in the amygdala were significantly lower in aged rats when compared with healthy adult rates, which displayed significant deficits in long-term potentiation (LTP) in the thalamo-lateral amygdala (LA) pathway and amygdala-dependent cued fear memory. Bath application of an H2S donor, sodium hydrogen sulfide (NaHS), significantly reversed the impaired LTP in brain slices from aged rats, and intra-LA infusion of NaHS restored the cued fear memory in aged rats. Mechanismly, we found that H2S treatment significantly enhanced NMDAR-mediated synaptic responses in the thalamo-LA pathway of aged rats. Notably, GluN2B-containing NMDARs, but not GluN2A-containing NMDARs, contributed to the effects of H2S on aging-associated impairments of amygdalar LTP and fear memory, because applying GluN2B antagonist could abolish the beneficial effects of NaHS treatment on amygdalar LTP and cognitive performance in aged rats. Collectively, these results show that H2S can reverse aging-associated amygdalar synaptic plasticity and fear memory deficits by restoring the function of GluN2B-containing NMDARs, suggesting that supplement of H2S might be a therapeutic approach for aging-related cognitive disorders.


Religiosity, spirituality, and HIV risk behaviors among African American women from four rural counties in the southeastern U.S.
In a cross-sectional survey of 1,013 African American women from rural Alabama and North Carolina, we examined the relationship of (1) organizational religiosity (i.e., religious service attendance), (2) non-organizational religiosity (e.g., reading religious materials), and (3) spirituality with these outcomes: women's reports of their sexual behaviors and perceptions of their partners' risk characteristics. Women with high non-organizational religiosity, compared with low, had fewer sex partners in the past 12 months (adjusted prevalence ratio (aPR): 0.58, 95% confidence interval (CI): 0.42, 0.80) and were less likely to have concurrent partnerships (aPR: 0.47, 95% CI: 0.30, 0.73). Similar results were observed for spirituality, and protective but weaker associations were observed for organizational religiosity. Weak associations were observed between organizational religiosity, non-organizational religiosity, and spirituality with partners' risk characteristics. Further exploration of how religiosity and spirituality are associated with protective sexual behaviors is needed to promote safe sex for African American women.


Quality of Life and Mental Satisfaction Improve Slowly in Preemptive Kidney Transplantation Compared With Nonpreemptive Kidney Transplantation.
Preemptive kidney transplantation (PEKT) is recognized as the best therapy to avoid dialysis. However, it is not clear whether PEKT recipients experience an improvement in quality of life (QoL) after kidney transplantation (KT) that exceeds that of non-PEKT recipients, since PEKT recipients have not experienced the heavy burden of dialysis. The aim of this study was to compare the changes in QoL for PEKT and non-PEKT recipients following transplantation. Patients included in this study underwent living donor KT in our hospital. We excluded patients with incomplete SF-36 scores and with factors that could affect QoL, such as complications or rejection. QoL was assessed by the Short Form 36-Item Health Survey version 2.0 preoperatively and 3 and 12 months postoperatively. Eighty-eight patients underwent living donor KT in our hospital. Twelve PEKT and 20 non-PEKT recipients were enrolled in this retrospective study. In the non-PEKT group, both the physical and mental domain scores dramatically improved from baseline at 3 months, and remained at a similar level at 12 months. In contrast, in the PEKT group, only 1 domain of the physical and mental score improved at 3 months, and the social functioning score gradually improved at 12 months. Although the mental component score showed significant improvement in the non-PEKT group, it did not change in the PEKT group. The improvement of QoL after transplantation is more evident in the non-PEKT group. PEKT recipients have less mental satisfaction than non-PEKT recipients.


Canadian Cardiovascular Society/Canadian Heart Rhythm Society position paper on implantable cardioverter defibrillator use in Canada.
The Canadian Heart Rhythm Society in conjunction with the Canadian Cardiovascular Society is committed to the promotion of evidence-based practice in Canada. Since the last Canadian guidelines on the management of sudden cardiac death were published in 2000, several well-conducted clinical trials evaluating the implantable cardioverter defibrillator have been completed and published. The Canadian Cardiovascular Society Council has granted permission to review and update guidelines for the indications for implantable cardioverter defibrillators. Furthermore, data are emerging on the potential benefits of biventricular pacing therapy (cardiac resynchronization) for heart failure; recommendations for the use of this therapy have been included in the present paper. Ethical considerations and the economic implications of these recommendations are also included. Canada's heart rhythm specialists, represented by the Canadian Heart Rhythm Society, have been joined by two heart failure specialists, a medical ethicist and an economist, to develop the present position paper. Members of the Canadian Heart Rhythm Society participated in the discussion of these recommendations in open forum meetings and by electronic communication.


Selenium suppresses leukemia through the action of endogenous eicosanoids.
Eradicating cancer stem-like cells (CSC) may be essential to fully eradicate cancer. Metabolic changes in CSC could hold a key to their targeting. Here, we report that the dietary micronutrient selenium can trigger apoptosis of CSC derived from chronic or acute myelogenous leukemias when administered at supraphysiologic but nontoxic doses. In leukemia CSC, selenium treatment activated ATM-p53-dependent apoptosis accompanied by increased intracellular levels of reactive oxygen species. Importantly, the same treatment did not trigger apoptosis in hematopoietic stem cells. Serial transplantation studies with BCR-ABL-expressing CSC revealed that the selenium status in mice was a key determinant of CSC survival. Selenium action relied upon the endogenous production of the cyclooxygenase-derived prostaglandins Δ(12)-PGJ2 and 15d-PGJ2. Accordingly, nonsteroidal anti-inflammatory drugs and NADPH oxidase inhibitors abrogated the ability of selenium to trigger apoptosis in leukemia CSC. Our results reveal how selenium-dependent modulation of arachidonic acid metabolism can be directed to trigger apoptosis of primary human and murine CSC in leukemia.


Effects of a virtual group cycling experience on people living with dementia: A mixed method pilot study.
Social isolation and sedentary behaviour are common in residential aged care facilities (also known as nursing homes or long-term care). Use of new technologies such as virtual and augmented reality are currently under investigation for their potential to provide exciting and engaging activities for older people in residential aged care facilities. However, there is limited evidence on whether these technologies can promote physical activity in a small group setting for people with cognitive impairment. Using mixed methods, we examined the use of a virtual cycling experience in a sample of 10 participants with cognitive impairment living in residential aged care facilities. In a randomised crossover design, participants engaged in a 25-minute, self-paced, facilitated seated virtual cycling experience and a time-matched seated physical activity session in groups of five. All participants completed a brief pre- and post-intervention mood questionnaire. Video analysis was used for both conditions to compare levels of environmental stimulation, apathy and engagement using both the Person-Environment Apathy Rating Scale and the Engagement of a Person with Dementia Scale. A thematic analysis of semi-structured interviews following the virtual cycling experience was also performed. No differences were observed between conditions for all outcomes except for environmental stimulation, where there was a lower response in the intervention than the control condition (p = 0.032). This was primarily driven by lower scores for the virtual cycling experience than control in physical accessibility (p = 0.012). Participants reported the virtual cycling experience to be immersive and challenging and reminisced about cycling earlier in life. The activity manager observed that the virtual cycling experience was an overall positive experience and emphasised benefits of safety screening and preparation prior to the activities. The findings of this study support the use of the virtual cycling experience as an immersive and engaging alternative to usual activities, which might encourage higher levels of physical activity in residential aged care facilities.


Prefrontal-enriched SLIT1 expression in Old World monkey cortex established during the postnatal development.
To elucidate the molecular basis of the specialization of cortical architectures, we searched for genes differentially expressed among neocortical areas of Old World monkeys by restriction landmark cDNA scanning . We found that mRNA of SLIT1, an axon guidance molecule, was enriched in the prefrontal cortex but with developmentally related changes. In situ hybridization analysis revealed that SLIT1 mRNA was mainly distributed in the middle layers of most cortical areas, robustly in the prefrontal cortex and faintly in primary sensory areas. The lowest expression was in the primary visual area. Analyses of other SLIT (SLIT2 and SLIT3) mRNAs showed preferential expression in the prefrontal cortex with a distinct laminar pattern. By contrast, the receptor Roundabout (ROBO1 and ROBO2) mRNAs were widely distributed throughout the cortex. Perinatally, SLIT1 mRNA was abundantly expressed in the cortex with modest area specificity. Downregulation of expression initially occurred in early sensory areas around postnatal day 60 and followed in the association areas. The prefrontal area-enriched SLIT1 mRNA expression results from a relatively greater attenuation of this expression in the other areas. These results suggest that its role is altered postnatally and that this is particularly important for prefrontal connectivity in the Old World monkey cortex.


Tissue-air ratios and scatter-air ratios for diagnostic radiology (1-4 mm Al HVL).
Tissue-air and scatter-air ratios for use in diagnostic radiology (1-4 mm Al HVL) have been calculated from previously reported measurements of percentage depth doses (PDD) and backscatter factors (BSF) for the same quality range. Tabulations of TAR are presented. The calculated TARs are compared with direct measurements of TAR which have been carried out by other workers. TARs and SARs are shown to be functions of peak tube potential for a given first HVL as a consequence of a similar dependence of PDD. This emphasises once again the inadequacy of the first HVL alone as a specifier of beam quality.


Anti-inflammatory preconditioning by agonists of adenosine A1 receptor.
Adenosine levels rise during inflammation and modulate inflammatory responses by engaging with four different G protein-coupled receptors. It is suggested that adenosine exhibits pro-inflammatory effects through its A(1) receptor (A(1)R), and anti-inflammatory effects through A(2A) receptor (A(2A)R). Therefore, understanding of the mechanisms that govern adenosine receptor regulation may advance treatment of various inflammatory disorders. We previously reported that peak A(1)R expression during leukocyte recruitment, is followed by a peak in A(2A)R during inflammation resolution. Here, we examined whether A(1)R activation sequentially induces A(2A)R expression and by this reverses inflammation. The effect of adenosine on A(1)R mediated A(2A)R expression was examined in peritoneal macrophages (PMPhi) and primary peritoneal mesothelial cells (PMC) in vitro. Induction of A(2A)R was inhibited by pertussis toxin (PTX) and partly dependent on A(2A)R stimulation. Administration of A(1)R agonists to healthy mice reduced A(1)R expression and induced A(2A)R production in PMC. Mice that were preconditioned with A(1)R agonists 24 hours before E. coli inoculation exhibited decreased TNFalpha and IL-6 sera levels and reduced leukocytes recruitment. Preconditioning was blocked by pretreatment with A(1)R antagonist, as well as, or by late treatment with A(2A)R antagonist, and was absent in A(2A)R(-/-) mice. Our data suggest that preconditioning by an A(1)R-agonist promotes the resolution of inflammation by inducing the production of A(2A)R. Future implications may include early treatment during inflammatory disorders or pretreatment before anticipated high risk inflammatory events, such as invasive surgery and organ transplantation.


Bioaccessibility and cellular uptake of β-carotene in emulsion-based delivery systems using scallop (Patinopecten yessoensis) gonad protein isolates: effects of carrier oil.
Emulsion-based delivery systems were structured by using scallop gonad protein isolates (SGPIs) as novel food-grade emulsifiers. The effects of carrier oil, including the long chain triglycerides (LCT) and medium chain triglycerides (MCT), on the bioaccessibility and cellular uptake of β-carotene (BC) were investigated. Both LCT and MCT delivery systems remained stable at pH 7-8 but aggregated at lower pH values (3-6) according to the results of light scattering and microscopy measurements. LCT droplets fabricated within SGPIs were digested and released more slowly than MCT droplets during the simulated gastrointestinal tract digestion. The LCT emulsion showed higher BC bioaccessibility (65.5%) than the MCT emulsion (23.1%) as a result of the greater solubilization of BC in mixed micelles fabricated from long-chain fatty acids. Moreover, the LCT emulsion produced higher cellular uptake of BC as compared with the MCT emulsion in intestinal epithelial cells. These results demonstrated that SGPIs could be used as novel food-grade emulsifiers to protect lipophilic bioactive compounds in emulsion-based delivery systems, in which LCT is more suitable to encapsulate and deliver BC than MCT.


Effects of cisapride on abnormally prolonged endogastric alkalinity time and delayed gastric emptying in cirrhotic patients.
An abnormally prolonged alkalinity time in endogastric long-term pH monitoring has been previously demonstrated in cirrhotic patients. Recently a growing body of evidence suggest the existence of severe abnormalities of gastric emptying in the same patients and more generally of gastrointestinal motility changes in many portal hypertensive animal models. Assuming that there was a good correlation between endogastric alkalinity and a delayed emptying of gastric bile reflux, the aim of this study was to evaluated the effect of a gastrokinetic drug, Cisapride, both on circadian gastric pH and on gastric emptying in cirrhotic patients compared with controls. Ten in patients with chronic liver disease and portal hypertension (six males, four females, median age 49.5, range 28-59) were enrolled. The control group included twelve inpatients without cirrhosis (seven females and five males, average age 45 years, range 31-54) free from endoscopic esophagogastro-duodenal lesions. The subjects were submitted to a 24h endogastric pH monitoring and gastric emptying study before and after administration of Cisapride (10 mg tid for three days). To gastric emptying study we used an ultrasonographic method evaluating the ratio between the antropyloric region volume before and at a fixed time after a solid/liquid standard meal. Basal 24 h gastric pH monitoring in cirrhotic patients showed a significant prolonged time of alkalinity (pH conventionally over 4) during the entire registration and mainly in postprandial period vs controls. The same patients group showed also a delayed gastric emptying when compared to controls. Cisapride administration significantly reduced both the abnormally prolonged alkalinity time and delayed gastric emptying in cirrhotic group without affecting the same parameters in the control group. Cisapride significantly reduces both the delayed gastric emptying time and the abnormally prolonged alkalinity time in cirrhotic group. Taken together, the results offered an indirect evidence that abnormally prolonged alkalinity in cirrhotic patients may be due, at least in part, to changes in gastroduodenal motility leading to a reduced gastric clearance of potentially noxious duodeno-gastric alkaline reflux.


Iron and infection in hemodialysis patients.
Intravenous iron is an important component of the treatment of anemia of end-stage renal disease (ESRD), but it is biologically plausible that iron could increase the risk of infection through impairment of neutrophil and T-cell function and promotion of microbial growth. Any such increase in risk would be particularly important because infection is a significant cause of mortality and morbidity in dialysis patients. The overall evidence favors an association between iron and infection in hemodialysis patients, but the optimal iron management strategy to minimize infection risk has yet to be identified. There is a need for further research on this topic, particularly in light of increased utilization of intravenous iron following implementation of the bundled ESRD reimbursement system.


Dietary changes in Vietnamese marriage immigrant women: The KoGES follow-up study.
The immigrant population has grown considerably in South Korea since the early 1990s due to international marriages. Dietary changes in immigrants are an important issue, because they are related to health and disease patterns. This study was conducted to compare changes in dietary intake between baseline and follow-up periods. Two hundreds thirty three Vietnamese female married immigrants. Baseline data were collected during 2006-2009, and the follow-up data were collected during 2008 and 2010. Food consumption was assessed using a 1-day 24-hour recall. The amount of the total food consumed (P < 0.001) including that of cereals (P = 0.004), vegetables (P = 0.003), and fruits (P = 0.002) decreased at follow-up compared to that at baseline, whereas consumption of milk and dairy products increased (P = 0.004). Accordingly, the overall energy and nutrient intake decreased at follow-up, including carbohydrates (P = 0.012), protein (P = 0.021), fiber (P = 0.008), iron (P = 0.009), zinc (P = 0.006), and folate (P = 0.002). Among various anthropometric and biochemical variables, mean skeletal muscle mass decreased (P = 0.012), plasma high density lipoprotein-cholesterol increased, (P = 0.020) and high sensitivity C-reactive protein decreased at follow-up (P < 0.001). A long-term follow-up study is needed to investigate the association between changes in food and nutrient intake and anthropometric and biochemical variables in these Vietnamese female marriage immigrants.


Effect of Pseudomonas aeruginosa exotoxin A on inner ear function.
Electrophysiological changes were studied in the albino rat following instillation of Pseudomonas aeruginosa exotoxin A into the middle ear cavity through the tympanic membrane. Hearing threshold was measured by a burst-elicited, frequency-specific auditory brainstem response (ABR) technique prior to exposure, then 24 and 48 h, 5 days, 2 and 4 weeks after the toxin instillation. A single dose (1 microgram/20 microliters) of Pseudomonas aeruginosa exotoxin A raised the ABR threshold over the whole frequency range, by 5-25 dB, particularly in the high tones. All threshold shifts were of combined conductive and cochlear type, reversible, with deterioration starting at 24-48 h and recovery at 2-4 weeks. Effusion of serous fluid occurred at 24 or 48 h, resulting in conductive hearing loss. Latency/intensity curves revealed a cochlear component in addition to conductive hearing loss. Morphological examination by SEM showed slight and inconsistent derangement of OHCs. It is concluded that Pseudomonas aeruginosa exotoxin A causes middle ear inflammation, facilitating penetration to the inner ear and that this toxin also reversibly affects cochlear function.


Dermatitis artefacta in a vulnerable adult with a dissociative state.
Dermatitis artefacta (DA), a factitious skin disorder, often occurs as a response to traumatic life events or as a factitious behaviour, which may result in secondary gain. It can be difficult to get patients to engage with health services, and they seldom admit to causing the lesions themselves. The possibility of DA lesions occurring in dissociative states is less well known. We present a case of DA diagnosed in a vulnerable adult, who we believe caused the lesions during periods of dissociation. We discuss the way in which the concept of dissociation can provide an acceptable way of discussing the behaviour with patients and initiating psychological therapy.


Pilates for women with breast cancer: A systematic review and meta-analysis.
To identify and evaluate the characteristics and methodological quality of the studies that have proposed Pilates as a rehabilitation strategy for women with breast cancer and to determine its benefits on health outcomes in this population. A systematic review and meta-analysis were conducted. Medline/PubMed, Pedro, SPORTDiscuss, Scopus and Web of Science were systematically searched up to January 2017. The methodological quality was evaluated by means of the Jadad Scale and the Quality Assessment Tool for Before-After Studies with No Control Group. Risk of bias was assessed by means of the Cochrane Collaboration's tool. Five randomized controlled trials and two un-controlled studies were selected. Four of the randomized controlled trials were pooled in the meta-analysis for effects of Pilates on shoulder range of motion, quality of life, pain, and self-reported upper extremity function. According to the findings reported in the studies analysed in the review, Pilates had a positive and significant effect on the aforementioned variables, as well as on functional status, mood, fitness and upper extremity circumference. The meta-analysis carried out showed that the effects that Pilates had on shoulder range of motion and quality of life, was not significantly greater than those resulting from other exercise programs. Pilates relieves the impact of breast cancer-related symptoms. These effects are not significantly greater than those derived from the performance of other therapies, with the exception of pain and self-reported upper extremity function. Systematic review registration number: PROSPERO CRD42018076852.


The gas phase structure of ethynylferrocene using microwave spectroscopy.
Gas phase structural parameters for ethynylferrocene have been determined using microwave spectroscopy. Rotational transitions due to a- and b-type dipole moments were measured. Twenty four rotational constants have been determined by fitting the measured transitions of various isotopomers using a rigid rotor Hamiltonian with centrifugal distortion constants. Least-squares fits to determine structural parameters and Kraitchman analyses have been used to determine the gas phase structural parameters and the atomic coordinates from the rotational constants. The distance between the Fe atom and the C atoms of the cyclopentadienyl rings is r(Fe-C1) = 2.049(5) A, and the distance between the carbon atoms of the cyclopentadienyl ring is r(C-C) = 1.432(2) A. The ethynyl group is bent away from the Fe atom and out of the plane of the carbon atoms in the adjacent cyclopentadienyl ring by 2.75(6) degrees. Structural parameters were also obtained from DFT calculations and Kraitchman analyses, and the results are compared. Analysis of fit results for 13C isotopic substitution data indicates that the carbon atoms of the two cyclopentadienyl rings are in an eclipsed conformation in the ground vibrational state. Trends in microwave experimental values for the distance from the Fe atom to the center of the cyclopentadienyl ring for a series of substituted ferrocenes have been analyzed. This analysis provides an estimate of the gas phase distance from the Fe atom to the centers of the cyclopentadienyl rings for ferrocene of 1.65(1) A.


Cellular Proliferation by Multiplex Immunohistochemistry Identifies High-Risk Multiple Myeloma in Newly Diagnosed, Treatment-Naive Patients.
Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell-specific marker, and Ki-67. Myeloma cells (CD138+) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.


Antibiotic prophylaxis in the prevention of rebleeding in acute variceal hemorrhage: A randomized trial.
To assess the role of antibiotic prophylaxis in the prevention of rebleeding in acute variceal hemorrhage. A total of 60 patients who underwent endoscopic therapy for bleeding esophageal varices were randomized into the prophylaxis group and the on-demand group. Patients in the prophylaxis group received antibiotic prophylaxis using intravenous ofloxacin till the patient resumed oral fluids, followed by oral ofloxacin tablet for a total of 7 days. In the on-demand group, antibiotics were used only when infection was evident. Patients were monitored for rebleeding and infection during the hospital stay. A total of 30 patients in the prophylaxis group and 26 patients in the on-demand group were analyzed. The clinical characteristics in both the groups were similar. The Child-Pugh score was around 7 in both the groups. The incidence of infection was 5/30 (16.7%) in the prophylaxis group and 7/26 (26.9%) in the on-demand group (P = 0.52). The incidence of early rebleeding in the prophylaxis vs. the on-demand group was 3 vs. 5 (P = 0.69), and the incidence of late rebleeding was 6 vs. 8 (P = 0.48). The differences were not significant. The present study shows a trend toward lower rate of early and late rebleeding, infection rate and mortality in the prophylaxis group; hence, routine use of antibiotics in all such patients may not be necessary. Further studies with a larger sample size and a longer follow-up period are required to validate the usefulness of antibiotics in these patients.


Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy.
Hepatitis C virus (HCV) is believed to exert a suppressive effect on hepatitis B virus (HBV) in most HBV/HCV-coinfected patients; once HCV is cured by interferon-based therapy, these patients may show HBV reactivation. However, recent evidence revealed that the virological status in HBV/HCV-untreated individuals may vary over time and may show fluctuating profiles. To evaluate the behaviour of apparently inactive HBV infection in patients under treatment for a concurrent HCV infection, we performed a prospective study that evaluated nine consecutive patients (eight males with a median age of 45.9 years, and one female aged 62 years) longitudinally followed-up with bi-monthly evaluation of HBV/HCV viraemia levels and liver biochemistry during a 1-year treatment with interferon plus ribavirin. In seven cases the HBV infection maintained its inactive status independently of the HCV response to therapy. By contrast, two non-responder cases with persistently high HCV RNA levels showed HBV DNA flairs during the follow-up, indicating a status of active HBV infection with fluctuating virological profiles. This study suggests that the HBV behaviour may be independent of the HCV activity during anti-HCV therapy in HBV/HCV-coinfected patients, and that the HBV virological profile should be monitored to recognize possible reactivations that might lead to more proper therapeutic choices or adjustments.


Oesophageal intramural pseudodiverticulosis.
Twelve cases of oesophageal intramural pseudodiverticulosis are described and the findings in 85 previously reported cases are reviewed. The condition occurs in all age groups, predominantly in the sixth and seventh decades, with a slight predilection for males. The characteristic radiographic appearance is of multiple flask shaped outpouchings of 1-4 mm with narrow necks communicating with the oesophageal lumen. The source of the pseudodiverticula has been shown to be pathologically dilated excretory ducts of the submucous glands due to chronic submucosal inflammation. The distribution was segmental in 57 cases (59%) and diffuse in 40 (41%). Dysphagia is the main symptom and was found in 85 cases (88%); 88 cases out of 97 had radiological narrowing of the oesophagus; of these, 39 (44%) were in the upper oesophagus, 20 (23%) in the middle oesophagus, and 29 (33%) in the lower oesophagus. Treatment is directed towards management of the associated disorder, as the diverticula themselves rarely cause problems.


Never ending stories: visual diarizing to recreate autobiographical memory of intensive care unit survivors.
The aim of this study was to explore the potential use of visual diarizing to enable intensive care unit (ICU) survivors to create their story of recovery. An ICU experience can have deleterious psychological and physical effects on survivors leading to reductions in quality of life which for some may be of significant duration. Although there has been exploration of many interventions to support recovery in this group, service provision for survivors remains inconsistent and inadequate. A qualitative interpretive biographical exploration of the ICU experience and recovery phase of ICU survivors using visual diarizing as method. This paper is a component of a larger study and presents an analyses of one participant's visual diary in detail. Data collection was twofold. The participant was supplied with visual diary materials at 2 months post-hospital discharge and depicted his story in words and pictures for a 3-month period, after which he was interviewed. The interview enabled the participant and researcher to interpret the visual diary and create a biographical account of his ICU stay and recovery journey. The analysis of one participant's visual diary yielded a wealth of information about his recovery trajectory articulated through the images he chose to symbolize his story. The participant confirmed feelings of persecution whilst in ICU and was unprepared for the physical and psychological disability which ensued following his discharge from hospital. However, his story was one of hope for the future and a determination that good would come out of his experience. He considered using the visual diary enhanced his recovery. The participant perceived that visual diarizing enhanced his recovery trajectory by enabling him to recreate his story using visual imagery in a prospective diary. Prospective visual diarizing with ICU survivors may have potential as an aid to recovery.


Two-dimensional Co-Ln networks bridged by phenyl pyrimidyl substituted nitronyl nitroxides: structural and magnetic properties.
Two-dimensional hetero-tri-spin 2p-3d-4f coordination polymers involving Co(ii) and Ln(iii) ions assembled with a polydentate paramagnetic nitronyl nitroxide ligand are reported. [Ln(hfac)3{Co(hfac)2}2(NITPhPyrim)2] (LnIII = Gd 1, Tb 2; hfac = hexafluoroacetylacetonate, NITPhPyrim = 2-[4-(5-pyrimidyl)phenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) consists of a two-dimensional network in which the NITPhPyrim ligand is coordinated to the metal ions by means of its pyrimidine and aminoxyl (NO) groups. In the layer, the Tb center interacts with two NO groups from two different radical ligands, and each pyrimidine connects two Co(hfac)2 units through its two nitrogen atoms to form one-dimensional Co(ii) arrays. The magnetic behavior of the two compounds results from concomitant ferro- and antiferromagnetic interactions between the spin carriers and the spin-orbit effect from Co(ii) as revealed by modeling performed for the Gd(iii) derivative.


Resonance versus linear responses to alternating electric fields induce mechanistically distinct mammalian cell death.
Alternating electric (AC) fields are known to activate tumor cell death, but the underlying cellular mechanisms are poorly understood. We thus combined live-cell imaging with computational modeling to investigate the dynamic interactions between AC fields and cultured mammalian cells. Our results showed extensive cell death activated via two distinct mechanisms. At frequency range of 100-300 kHz and 800-1000 kHz, AC fields triggered prolonged mitotic arrest followed by apoptosis, and the cell death kinetics showed linear dependence on both field frequency and intensity. However, at intermediate frequencies, from 300 kHz to 800 kHz, cells died as a result of field-induced surface detachment, and the process exhibited a resonance frequency. Based on models of induced dielectric polarization and charge oscillation, we simulated the functional dependence of cell death kinetics on field frequency and intensity for both the linear and resonance response regimes. By comparing the simulated and experimental results, we not only determined the crucial electrical properties of mammalian cells that govern their interaction with AC fields but also acquired novel mechanistic understanding of the resulting cell death processes, which provides important new insight for potentially utilizing AC fields as an alternative anti-tumor remedy.


Determinants of age-appropriate breastfeeding, dietary diversity, and consumption of animal source foods among Indonesian children.
Global child feeding practices remain suboptimal. In this study, we assess the determinants of age-inappropriate breastfeeding, dietary diversity, and consumption of 3+ types of animal source foods (ASFs) using 11,687 observations from combined data from the Indonesian Demographic Health Survey of 2012 and 2017. We used linear and logistic regression after adjusting for the complex sampling design. Child's age and quality of antenatal care (ANC) were associated with all outcomes. Socio-economic status and labour force participation were positively associated with higher dietary diversity score, ASF consumption, and age-inappropriate breastfeeding. More ANC visits and having consultation at ANC were associated with more dietary diversity. Higher women's knowledge level was associated with more dietary diversity and consuming more ASF. Compared with western Indonesia, more children in eastern Indonesia were age-inappropriately breastfed and had lower dietary diversity. The Indonesian government needs to develop programmes to improve child feeding particularly in eastern Indonesia, focusing on improving dietary diversity and ASF consumption in poorer households and on prolonging breastfeeding in richer households. Women's labour force participation should be encouraged, but programmes for working mothers are also needed to support continued breastfeeding and to express breast milk. ANC and postnatal programmes need improved consultation sessions for child feeding.


Novel cross-reactive anti-idiotype antibodies with properties close to the human intravenous immunoglobulin (IVIg).
The most important link between the immune network theory and clinically useful therapies so far is the use of human intravenous immunoglobulin (IVIg) in the treatment of autoimmune diseases. Although still controversial, one of the main mechanisms that has been postulated for the in vivo effects of IVIg, is the selection of immune repertoires through idiotypic interactions. We describe here anti-idiotype IgG monoclonal antibodies (MAbs), which were obtained by immunization of syngeneic mice (Balb/c) with an anti-ganglioside antibody. These anti-idiotype MAbs show multiple idiotypic connections and share some of the properties of the IVIg pool. The antiidiotype (Ab2) MAbs B7 and 34B7 showed heterogeneous binding with the idiotypes of several anti-ganglioside antibodies, MAbs obtained from splenocytes of nonimmunized newborn mice, F(ab')2 fragments of IgG human myeloma proteins, and nonimmunoglobulin antigens. The recognition pattern of the B7 MAb to the idiotypes of human immunoglobulins was also studied using a phage display library obtained from the variable region genes of an asymptomatic AIDS patient and also F(ab')2 fragments obtained from an IVIg pool of healthy human donors. We also demonstrated that these MAbs produced some of the in vitro effects reported for the human IVIg pool, such as the inhibition of cell proliferation of human B and T cell lines and of normal human lymphocytes activated with different mitogens. Another striking property of the MAb B7 was its ability to induce a dose-dependent specific antibody T-cell response in vivo in syngeneic mice. Both anti-idiotype MAbs showed anti-metastatic effect in vivo when injected intravenously to mice inoculated with MB16-F10 melanoma cells. The antimetastatic effect of the antiidiotype MAbs was not observed in athymic mice inoculated with the same tumor. This kind of antibody can become an interesting tool for further exploration of the role of idiotypic network connections in the regulation of the immune system and to study the effects of interventions on network connectivity in experimental autoimmune disease, using a reagent better chemically defined than the IVIg pool.


New web-based applications for mechanistic case diagramming.
The goal of mechanistic case diagraming (MCD) is to provide students with more in-depth understanding of cause and effect relationships and basic mechanistic pathways in medicine. This will enable them to better explain how observed clinical findings develop from preceding pathogenic and pathophysiological events. The pedagogic function of MCD is in relating risk factors, disease entities and morphology, signs and symptoms, and test and procedure findings in a specific case scenario with etiologic pathogenic and pathophysiological sequences within a flow diagram. In this paper, we describe the addition of automation and predetermined lists to further develop the original concept of MCD as described by Engelberg in 1992 and Guerrero in 2001. We demonstrate that with these modifications, MCD is effective and efficient in small group case-based teaching for second-year medical students (ratings of ~3.4 on a 4.0 scale). There was also a significant correlation with other measures of competency, with a 'true' score correlation of 0.54. A traditional calculation of reliability showed promising results (α =0.47) within a low stakes, ungraded environment. Further, we have demonstrated MCD's potential for use in independent learning and TBL. Future studies are needed to evaluate MCD's potential for use in medium stakes assessment or self-paced independent learning and assessment. MCD may be especially relevant in returning students to the application of basic medical science mechanisms in the clinical years.


A convenient synthetic route towards H-bisphosphinates.
A practical generalisable procedure to synthesize hydroxymethylene H-bisphosphinates has been optimised. Unlike previous reports, numerous alkyl (including an alendronate bisphosphinate analogue) or (hetero)aryl compounds were rapidly obtained in satisfactory to excellent yields. A side product could have been identified as a phosphino-phosphonate isomer and plausible mechanistic pathways are proposed here. Moreover to check the literature data, a pKa value study was also performed.


Macrolides for chronic asthma.
Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobic and antiinflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function. To determine whether macrolides are effective in the management of patients with chronic asthma. We searched the Cochrane Airways Group Specialised Register of trials up to May 2004. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search. Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo. Two reviewers independently examined all identified articles. The full text of any potentially relevant article was reviewed independently by two reviewers. Seven studies recruiting a total of 416 participants met the inclusion criteria. The quality of reporting of study methodology was generally low. We assembled findings from studies comparing macrolide treatment for at least 4 weeks in adult and pediatric patients treated for chronic asthma. Four studies showed a positive effect on symptoms of macrolides in different types of asthmatic patients. There were limited data available for meta-analysis. There was no significant difference in FEV1 for either parallel or crossover trials. However, there were significant differences in eosinophilic inflammation and symptoms. One large parallel group trial reported significant differences in peak flow but these differences abated within six months of treatment. Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.


Hypertension: an optometric problem for the 80s.
As primary health care providers, optometrists can make a significant contribution to the overall health of our patients by routinely measuring blood pressure, referring those individuals with elevated blood pressures for evaluation and/or treatment, and supporting previously diagnosed hypertensives to maintain their treatment regimen. The 1984 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure gives optometrists an up-to-date synopsis of blood pressure management. It includes referral procedures, blood pressure classifications, the revised stepped-care treatment approach and patient-professional interaction suggestions for improving long-term treatment compliance. It is imperative that optometrists reinforce the importance of regular hypertension evaluation to our patients and answer questions concerning blood pressure and its related follow-up care.


[The response to normobaric hypoxia and its duration in arterial hypertension patients as shown by a prospective study].
A placebo-controlled parallel trial studied an antihypertensive action of interrupted normobaric hypoxia (INH) in 63 male patients with arterial hypertension (AH) of the first degree and low and moderate risk of vascular complications. The placebo group consisted of 18 patients with AH of the first degree matched by age, the disease duration, initial level of systolic and diastolic pressure. An INH course consisted of 15 daily procedures. INH monotherapy implied oxygen content lowering to 10%. A 6-month follow-up was made with the use of 24-h AP monitoring. The INH course resulted in a significant decrease in systolic and diastolic AP, total peripheral vascular resistance. A morning rise of systolic pressure became slower. A favourable effect of normobaric hypoxia on AP 24-h rhythm was observed. A good hypotensive effect was achieved in 85.7% patients. A 6-month follow-up confirmed a long-term hypotensive effect of INH.


Clinical lung transplantation--current status.
Since 1983, lung transplantation has enjoyed increasing success and has become the mainstay of therapy for most end-stage lung diseases. While the first decade of clinical lung transplantation focused on technical details of the transplant procedure, the second decade was characterized by improvements in techniques of lung preservation and in the postoperative management. This review will focus on the recent improvements made in lung preservation and postoperative management.


[Mortality of acute pancreatitis in a 20 years period].
Mortality for acute pancreatitis (AP) in Chile has fluctuated between 7 ana 10% in last years. To evaluate AP mortality over a period of 20 years in a clinical hospital in Santiago, Chile. Review of the database of hospital discharges with the diagnosis of acute pancreatitis, between 1990 and 2010 and the medical records of those patients. Age, gender, length of hospital stay, surgeries, percutaneous interventions and mortality were registered. To compare the evolution of the disease over time, patients were divided in two groups: those hospitalized between 1990 and 1999 and those hospitalized between 2000 and 2010. We reviewed the records of 1367 patients with a median age of 48 years (48% men). In the first period, 93 of 637 (14.6%) patients died, whereas in the second period, 22 of 730 patients died (3.0%). In the first and second period, 41.9 and 25.3% of patients were subjected to surgical procedures. The hospital stay was shorter in the second group, compared with the first (14.2 and 25.9 days respectively). There was a decrease in mortality caused by AP in the last 10 years, probably associated with a better interdisciplinary management of these patients.


Tracheostomy in ancient Egypt.
It has often been reported that the ancient Egyptians performed tracheostomies. An analysis of this claim demonstrates it to be founded on only two depictions from the Protodynastic period (thirty-first century bc). These depictions are difficult to reconcile with tracheostomy from an anatomical point of view and can more easily be explained as human sacrifices. Considering that Egyptian surgery included only minor procedures even at its zenith during later dynastic periods, it is difficult to imagine that they would have developed such an advanced procedure at such an early date.


Ovomucoid (Gal d 1) specific IgE detected by microarray system predict tolerability to boiled hen's egg and an increased risk to progress to multiple environmental allergen sensitisation.
Egg allergy is a very common finding in early childhood. Detecting hen's egg (HE) allergy outgrowing and reintroduction of food containing egg is a task for the allergist. We sought to evaluate the suitability of boiled egg food challenge compared with IgE to allergenic molecules from HE white using a microarray system. Sixty-eight children referring to our centre by the family paediatricians for a suspected egg allergy were enrolled. Patients underwent double-blind, placebo-controlled food challenge with boiled and raw eggs. Challenge outcomes were compared with skin tests performed using egg white and yolk commercial extracts, to prick-prick test with boiled and raw egg white and yolk, total IgE, egg white specific IgE detected using ImmunoCAP and IgE to egg allergens available on the immunosolid phase allergen chip (ISAC) 103 microarray. Nineteen subjects (28%) were reactive to both raw and boiled egg, 14 (20.5%) to raw egg only and 35 (51.4%) tolerated both boiled and raw egg. Efficiency analysis was carried out using both raw and boiled egg challenges as gold standard. Forty four of 47 Gal d 1 negative patients tolerated boiled egg (94%). Conversely, 20 of 21 Gal d 1 positive patients reacted to raw egg (95%). None of the other tests was able to discriminate patients' response to HE challenge. Furthermore, Gal d 1 positivity seems to lead to broader environmental allergen IgE sensitization. The Gal d 1 IgE reactivity appears to be a very good predictor of HE clinical allergy. Gal d 1 positive children have a high frequency of HE allergy, whereas Gal d 1 negative children have a high frequency of tolerance to boiled egg. Multiple specific IgE detection by means of ISAC improves the diagnostic approach in HE allergic children, disclosing other food and inhalant allergic sensitizations, anyhow requiring a comprehensive clinical evaluation.


High-speed varifocal imaging with a tunable acoustic gradient index of refraction lens.
Fluidic lenses allow for varifocal optical elements, but current approaches are limited by the speed at which focal length can be changed. Here we demonstrate the use of a tunable acoustic gradient (TAG) index of refraction lens as a fast varifocal element. The optical power of the TAG lens varies continuously, allowing for rapid selection and modification of the effective focal length at time scales of 1 mus and shorter. The wavefront curvature applied to the incident light is experimentally quantified as a function of time, and single-frame imaging is demonstrated. Results indicate that the TAG lens can successfully be employed to perform high-rate imaging at multiple locations.


Mapping memories: pulse-chase labeling reveals AMPA receptor dynamics during memory formation.
A tool to map changes in synaptic strength during a defined time window could provide powerful insights into the mechanisms governing learning and memory. We developed a technique, Extracellular Protein Surface Labeling in Neurons (EPSILON), to map α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) insertion in vivo by pulse-chase labeling of surface AMPARs with membrane-impermeable dyes. This approach allows for single-synapse resolution maps of plasticity in genetically targeted neurons during memory formation. We investigated the relationship between synapse-level and cell-level memory encodings by mapping synaptic plasticity and cFos expression in hippocampal CA1 pyramidal cells upon contextual fear conditioning (CFC). We observed a strong correlation between synaptic plasticity and cFos expression, suggesting a synaptic mechanism for the association of cFos expression with memory engrams. The EPSILON technique is a useful tool for mapping synaptic plasticity and may be extended to investigate trafficking of other transmembrane proteins.


An Evidence-Based Theory of Psychological Adjustment to Long-Term Physical Health Conditions: Applications in Clinical Practice.
Around 30% of people with long-term physical health conditions (LTCs) experience comorbid anxiety and depression. For many, comorbid distress is linked to difficulties adjusting to the challenges of the LTC. The aims of this article are to present a transdiagnostic theoretical model of adjustment to LTCs (TMA-LTC), demonstrate the application of this model in clinical practice, and highlight the distinguishing features of treating LTC-related distress compared with treating primary anxiety and/or depression. A systematic review (k = 21) was conducted to collate preexisting evidence-based models of adjustment across LTCs. Models of adjustment for a range of LTCs were extracted and synthesized into a new preliminary TMA-LTC. Two expert consensus meetings were held, where experts rated the relevance and importance of all concepts within the models. The TMA-LTC proposes that acute critical events or ongoing illness stressors can disrupt emotional equilibrium, and that whether a person returns to equilibrium and achieves good psychological adjustment depends on a number of cognitive and behavioral factors, as well as their interpersonal, intrapersonal, environmental, and illness-specific contexts. A case study is presented to demonstrate the clinical application of this model in treating illness-related distress, highlighting how it overcomes roadblocks that may be encountered when working primarily within traditional mental health paradigms. As an empirically and clinically informed model, TMA-LTC provides a useful guide for assessment, formulation, and treatment in the context of psychological adjustment to LTCs. Future studies are needed to test treatments that have been developed based on TMA-LTC.


Consensus workshop on the toxic effects of long-term PUVA therapy.
The possibility that there is an increased risk of melanoma in patients with psoriasis treated with psoralen-UV-A (PUVA) therapy has raised concern on the part of physicians and patients about the long-term safety of this treatment. In response to this concern, the National Psoriasis Foundation sponsored a workshop at which invited participants with expertise in PUVA therapy, psoriasis treatment, melanoma and nonmelanoma skin cancer, and epidemiological and clinical trials were asked to develop a consensus on the following 3 issues: the risk of long-term adverse effects of PUVA therapy with emphasis on nonmelanoma and melanoma skin cancer; the guidelines for physicians and patients for selection and use of PUVA therapy with consideration of the risk-benefit ratio of this treatment compared with the risk-benefit ratios of alternative treatments; and the directions for further evaluation of the long-term effects Of PUVA therapy.


The evaluation of breast findings detected through different visualisation techniques in acromegaly patients — a retrospective study
It is known that the increased growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have mitogenic and antiapoptotic properties in breast cells in acromegaly. Our study aims to evaluate breast findings in patients with acromegaly by comparing them to the control group. Sixty-one patients followed with acromegaly diagnosis and 180 healthy controls were included in our study. Demographic data, laboratory results, Breast Imaging-Reporting and Data System (BI-RADS) scores, and breast density evaluated via mammography, malign and benign breast lesions evaluated via mammography, breast ultrasonography (USG), and breast magnetic resonance imaging (MRI) of patients were compared to the control group. While BI-RADS scores were similar in patient and control groups, breast density in acromegaly patients was found out to be higher compared to the control group (p = 0.754, p = 0.001, respectively). In acromegaly patients, the breast calcification rate was higher than controls (p = 0.021). t was observed that mass frequency in USG in acromegaly patients increased when GH level increased as well (p = 0.021). No difference was detected between benign and malign breast lesions diagnosed histopathologically ( p = 0.031, p = 0.573, respectively). There was not any difference in terms of BI-RADS scores, breast types, and breast lesions in acromegaly patients that were in remission and not in remission (p > 0.05). Benign and malign breast lesions were found out to be similar to the control group, although breast density rate was detected to be higher in acromegaly patients. A regular follow-up is required in these patients via suitable breast visualization techniques considering their age and clinical status due to mass formation risk derived from increased GH level and extreme breast density despite the absence of any detected breast lesion frequency in acromegaly patients.


The value of routine outcome measurement for consumers of mental health services: master or servant?
Standardized instruments have been introduced for routine use within Victorian mental health services. The aim of routine outcome measurement (ROM) is to ensure the highest standard of service delivery as demonstrated through quality and accountability processes. The aim is to determine the extent to which ROM measure against the 12 principles of outcome measurement described by Smith et al. (1997). The three ROM currently used in Victoria were critiqued according to the 12 principles, with the support of a review of the literature regarding outcome measurement. Of the 12 principles articulated, nine are not met by ROM currently used in Victoria. Only one is fully met, one partially met and one cannot be conclusively decided either way in light of current knowledge. ROM currently utilized in Victoria do not reflect the areas considered of most relevance and importance to consumers of mental health services. Priority should therefore be given to developing an alternative consumer-derived approach to determining the effectiveness of mental health services according to those most affected by them.


Endosymbioses between bacteria and deep-sea siboglinid tubeworms from an Arctic Cold Seep (Haakon Mosby Mud Volcano, Barents Sea).
Siboglinid tubeworms do not have a mouth or gut and live in obligate associations with bacterial endosymbionts. Little is currently known about the phylogeny of frenulate and moniliferan siboglinids and their symbionts. In this study, we investigated the symbioses of two co-occurring siboglinid species from a methane emitting mud volcano in the Arctic Ocean (Haakon Mosby Mud Volcano, HMMV): Oligobrachia haakonmosbiensis (Frenulata) and Sclerolinum contortum (Monilifera). Comparative sequence analysis of the host-specific 18S and the symbiont-specific 16S rRNA genes of S. contortum showed that the close phylogenetic relationship of this host to vestimentiferan siboglinids was mirrored in the close relationship of its symbionts to the sulfur-oxidizing gammaproteobacterial symbionts of vestimentiferans. A similar congruence between host and symbiont phylogeny was observed in O. haakonmosbiensis: both this host and its symbionts were most closely related to the frenulate siboglinid O. mashikoi and its gammaproteobacterial symbiont. The symbiont sequences from O. haakonmosbiensis and O. mashikoi formed a clade unaffiliated with known methane- or sulfur-oxidizing bacteria. Fluorescence in situ hybridization indicated that the dominant bacterial phylotypes originated from endosymbionts residing inside the host trophosome. In both S. contortum and O. haakonmosbiensis, characteristic genes for autotrophy (cbbLM) and sulfur oxidation (aprA) were present, while genes diagnostic for methanotrophy were not detected. The molecular data suggest that both HMMV tubeworm species harbour chemoautotrophic sulfur-oxidizing symbionts. In S. contortum, average stable carbon isotope values of fatty acids and cholesterol of -43 per thousand were highly negative for a sulfur oxidizing symbiosis, but can be explained by a (13)C-depleted CO(2) source at HMMV. In O. haakonmosbiensis, stable carbon isotope values of fatty acids and cholesterol of -70 per thousand are difficult to reconcile with our current knowledge of isotope signatures for chemoautotrophic processes.


Conditional inactivation of PDCD2 induces p53 activation and cell cycle arrest.
PDCD2 (programmed cell death domain 2) is a highly conserved, zinc finger MYND domain-containing protein essential for normal development in the fly, zebrafish and mouse. The molecular functions and cellular activities of PDCD2 remain unclear. In order to better understand the functions of PDCD2 in mammalian development, we have examined PDCD2 activity in mouse blastocyst embryos, as well as in mouse embryonic stem cells (ESCs) and embryonic fibroblasts (MEFs). We have studied mice bearing a targeted PDCD2 locus functioning as a null allele through a splicing gene trap, or as a conditional knockout, by deletion of exon2 containing the MYND domain. Tamoxifen-induced knockout of PDCD2 in MEFs, as well as in ESCs, leads to defects in progression from the G1 to the S phase of cell cycle, associated with increased levels of p53 protein and p53 target genes. G1 prolongation in ESCs was not associated with induction of differentiation. Loss of entry into S phase of the cell cycle and marked induction of nuclear p53 were also observed in PDCD2 knockout blastocysts. These results demonstrate a unique role for PDCD2 in regulating the cell cycle and p53 activation during early embryonic development of the mouse.


Non-neurogenic mechanism for reserpine-induced release of catecholamines from the adrenal medulla of neonatal rats: possible modulation by opiate receptors.
Neonatal rats do not have functional splanchnic nerve connections to the adrenal medulla until approximately one week of postnatal age, yet they are able to respond to some drugs or stresses by releasing adrenal catecholamines. Reserpine (5 mg/kg s.c.) resulted in significant loss (20-40%) of neonatal catecholamines within 4 h; unlike the acute effects of reserpine in the adult, depletion was not prevented by pretreatment with a nicotinic blocking agent, demonstrating that the effect in the neonate is non-neurogenic. Depletion did not result simply from inhibition of catecholamine storage by reserpine, but rather, the non-neurogenic depletion represented net movement of the amines from the storage granules into the extracellular space, as evaluated by the subcellular distribution of catecholamines. These results suggest that the non-neurogenic mechanism represents release of catecholamines. The immature response mechanism disappeared by 11 days of age and was replaced by a completely neurogenic release, demonstrating that the special mechanism is lost within several days of the onset of functional innervation of the adrenal. Experiments also were carried out to test whether endogenous opioids and/or opiate receptors are involved in the non-neurogenic mechanism. Naloxone (5 mg/kg s.c.) potentiated the depletion of catecholamines by reserpine, while methadone (2.5 mg/kg s.c.) inhibited the non-neurogenic response. In contrast, no potentiation of release by naloxone or inhibition by methadone was seen in adult rats. Thus, opiate receptors may modulate only the immature secretory mechanism.


Asthma and allergic rhinitis at 4 years of age in relation to fish consumption in infancy.
It has been suggested that consumption of fish and polyunsaturated fatty acids could have a protective effect against inflammation in the airways and the development of asthma and other allergic diseases. Our objective was to test the hypothesis that fish consumption during the first year of life decreases the risk of childhood asthma and allergic rhinitis. We assessed the relation between introduction of fish in the diet during the first year of life and risk of asthma and allergic rhinitis in a prospective 4-year cohort study of 2531 Norwegian children. We estimated odds ratios (OR) in logistic regression analysis adjusting for potential confounders. A total of 47.6% children had fish during the first year of life. The adjusted OR for allergic rhinitis was 0.45 (95% confidence interval [CI]=0.28, 0.74) and for asthma 0.84 (95% CI=0.57, 1.22). Fish consumption in the first year of life may reduce the risk of developing asthma and allergic rhinitis in childhood.