Knowledge,motivations, expectations,and traits of an African,African-American,and Afro-Caribbean sequencing cohort and comparisons to the original ClinSeq® cohort

PurposeRacial minority populations are underrepresented in genomics research. This study enrolled African-descended individuals in a sequencing study and reported their characteristics.MethodsWe purposively recruited 467 individuals self-identified as African, African American, or Afro-Caribbean to the ClinSeq® study and surveyed them about knowledge, motivations, expectations, and traits. Summary statistics were calculated and compared with data from the study’s original cohort, which was primarily White and self-referred.ResultsRecruitment took five years and 83% of enrollees completed the survey. Participants had modest knowledge about benefits and limitations of sequencing (x̅s = 5.1, ranges: 0–10), and less than the original cohort (x̅= 7.5 and 7.7, respectively). Common motivations to enroll were learning information relevant to personal health (49%) or family members’ health (33%), and most had realistic expectations of sequencing. Like the original cohort, they had high levels of optimism, openness, and resilience.ConclusionEarly adopters may have relatively consistent personality traits irrespective of majority/minority status and recruitment methods, but high levels of genomics knowledge are not universal. Research should determine whether recruitment and consent procedures provide adequate education to promote informed choices and realistic expectations, which are vital to ethical research and increasing genomics research participation in underrepresented communities.     

Sensory coding, decoding, and representations. Unnecessary and troublesome constructs?

Reception of certain environmental energy patterns can allow organisms to successfully respond to present or future environmental conditions. Sensory systems are the means by which this reception occurs. The bioelectric components of this process are typically characterized as "sensory coding." "Coding" logically requires subsequent "decoding," and implies that the decoder has a special, commanding role. In contrast, the term "transformation," which is sometimes applied to the prebioelectric components of sensory systems, can connote a series of changes in the medium, form, or content of sensory processes. Neither coding nor decoding are implied, no notions of "representation" or "reconstruction" of the world are introduced, and distributed, parallel processing is a natural corollary of transformations. It is proposed that the problematic construct of sensory coding, with its concomitant decoding, be replaced with the more neutral and physical concept of transformations. Elimination of the notions of representation or reconstruction of the world in some special nervous system locus is also suggested.     

Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?

Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases, obesity, or both. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (eg, atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in human subjects. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack of state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway might be important in gut homeostasis and in signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma, obesity, or both.     

Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They are defined here as KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cell or epithelioid neoplasms primary in the GI tract, omentum, and mesentery. GISTs typically present in older individuals and are most common in the stomach (60-70%), followed by small intestine (20-25%), colon and rectum (5%), and esophagus (<5%). Benign tumors outnumber the malignant ones by a wide margin. Approximately 70% of GISTs are positive for CD34, 20-30% are positive for smooth muscle actin (SMA), 10% are positive for S100 protein and <5% are positive for desmin. The expression of CD34 and SMA is often reciprocal. GISTs commonly have activating mutations in exon 11 (or rarely exon 9 and exon 13) of the KIT gene that encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Ligand-independent activation of KIT appears to be a strong candidate for molecular pathogenesis of GISTs, and it may be a target for future treatment for such tumors. Other genetic changes in GISTs discovered using comparative genomic hybridization include losses in 14q and 22q in both benign and malignant GISTs and occurrence in various gains predominantly in malignant GISTs. GISTs have phenotypic similarities with the interstitial cells of Cajal and, therefore, a histogenetic origin from these cells has been suggested. An alternative possibility, origin of pluripotential stem cells, is also possible; this is supported by the same origin of Cajal cells and smooth muscle and by the common SMA expression in GISTs. GISTs differ clinically and pathogenetically from true leiomyosarcomas (very rare in the GI tract) and leiomyomas. The latter occur in the GI tract, predominantly in the esophagus (intramural tumors) and the colon and rectum (muscularis mucosae tumors). They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. Other mesenchymal tumors that have to be separated from GISTs include inflammatory myofibroblastic tumors in children, desmoid, and dedifferentiated liposarcoma. Angiosarcomas and metastatic melanomas, both of which are often KIT-positive, should not be confused with GISTs.     

Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.     

Healing and Normal Fibroblasts Exhibit Differential Proliferation, Collagen Production, α-SMA Expression, and Contraction

This study determines the differences in proliferation, collagen production, α-smooth muscle actin (α-SMA) expression, and contraction between healing and normal fibroblasts. Transected and sham-operated rat medial collateral ligaments (MCL) were used to obtain healing and normal fibroblasts, respectively. It was found that healing fibroblasts in monolayer culture proliferated 1.4-fold faster at 48 h and had 1.7-fold greater protein expression of α-SMA than normal fibroblasts. In addition, it was noted that the proliferation of healing fibroblasts in collagen gels was not significantly different from that of normal fibroblasts at 24 h, but it was at 48 h. Furthermore, in collagen gels, healing fibroblasts produced more type I collagen than normal fibroblasts and generated 1.6- and 1.7-fold larger contractile forces at 15 and 20 h, respectively, than their normal counterparts. Taken together, the results of this study show that healing fibroblasts possess a differential proliferation, α-SMA protein expression, and contraction than normal fibroblasts.     

Spirituality,Religiosity, and Health: a Comparison of Physicians’ Attitudes in Brazil,India, and Indonesia

Background

One of the biggest challenges in the spirituality, religiosity, and health field is to understand how patients and physicians from different cultures deal with spiritual and religious issues in clinical practice.

Purpose

The present study aims to compare physicians’ perspectives on the influence of spirituality and religion (S/R) on health between Brazil, India, and Indonesia.

Method

This is a cross-sectional, cross-cultural, multi-center study carried out from 2010 to 2012, examining physicians’ attitudes from two continents. Participants completed a self-rated questionnaire that collected information on sociodemographic characteristics, S/R involvement, and perspectives concerning religion, spirituality, and health. Differences between physicians’ responses in each country were examined using chi-squared, ANOVA, and MANCOVA.

Results

A total of 611 physicians (194 from Brazil, 295 from India, and 122 from Indonesia) completed the survey. Indonesian physicians were more religious and more likely to address S/R when caring for patients. Brazilian physicians were more likely to believe that S/R influenced patients’ health. Brazilian and Indonesians were as likely as to believe that it is appropriate to talk and discuss S/R with patients, and more likely than Indians. No differences were found concerning attitudes toward spiritual issues.

Conclusion

Physicians from these different three countries had very different attitudes on spirituality, religiosity, and health. Ethnicity and culture can have an important influence on how spirituality is approached in medical practice. S/R curricula that train physicians how to address spirituality in clinical practice must take these differences into account.

     

Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease?

Zinc has several crucial functions in brain development and maintenance: it binds to p53, preventing it from binding to supercoiled DNA and ensuring that p53 cause the expression of several paramount genes, such as the one that encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP), which directs embryonic development of the brain cortex, adrenal glands, etc.; it is required for the production of CuZnSOD and Zn-thionein, which are essential to prevent oxidative damage; it is required for many proteins, some of them with Zn fingers, many of them essential enzymes for growth and homeostasis. For example, the synthesis of serotonin involves Zn enzymes and since serotonin is necessary for melatonin synthesis, a Zn deficiency may result in low levels of both hormones. Unfortunately, Zn levels tend to be low when there is excess Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of Cu and Cd, and smoking and eating food contaminated with Cd result in high levels of the latter. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD).Increased Cu levels may also be found in people with Wilson's disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. Therefore, the developing fetus of a pregnant women who is low in Zn and high in Cu may experience major difficulties in the early development of the brain, which may later manifest themselves as schizophrenia, autism or epilepsy. Similarly, a person who gradually accumulates Cu, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson's disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases.     

Distribution pattern of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors of matrix metalloproteinases 1 and 2, and α2-macroglobulin in cases of generalized AA- and AL amyloidosis

Matrix metalloproteinases (MMPs) degrade basement membranes and connective tissue and play an essential role in the homeostasis of the extracellular matrix which is disrupted by the deposition of amyloid. This immunohistochemical study investigated the distribution pattern of matrix metalloproteinases (MMP-1, -2, -3, and -9) and their inhibitors [alpha 2-macroglobulin (alpha 2-M), tissue inhibitors of MMPs (TIMP)-1, and TIMP-2] in human AA- and AL amyloid deposits. Specimens of liver, kidney, and spleen from 22 autopsy cases were investigated. Nine patients had suffered from generalized AA amyloidosis, eight from generalized AL amyloidosis, and five from rheumatoid arthritis or tuberculosis with no histological evidence of amyloid. In all amyloidotic and non-amyloidotic patients, each protease and protease inhibitor was detected in almost every organ investigated. In the amyloidotic cases, there was no indication that a specific protease or protease inhibitor was absent or expressed, but a difference was observed in their spatial distribution patterns. The most noticeable difference was found in immunostaining of amyloid. Only MMP-1, -2, and -3, and alpha 2-M were present in AA amyloid deposits, and only TIMP-1 and TIMP-2 were found in deposits of AL amyloid. This is the first study to show that MMP-1, -2, and -3 are present in AA amyloid deposits. They may be involved in tissue remodeling or in proteolysis of the precursor and fibril proteins.     

Presence,activities, and molecular forms of cathepsin G,elastase,α 1-antitrypsin,andα 1-antichymotrypsin in bronchiectasis

The presence, activities, and molecular forms of the serine proteinases, elastase, and cathepsin G, and their endogenous inhibitors, ₁-antitrypsin and ₁-antichymotrypsin, were investigated in bronchoalveolar lavage (BAL) fluid of bronchiectasis patients divided into mild, moderate, and severe disease subgroups and compared to BAL fluid from healthy controls. Immunochemical characterization and quantitation were performed by Western immunoblot. The activities of elastase and cathepsin G were recorded spectrophotometrically using synthetic substrates. The results showed a significant difference in elastase and cathepsin G activities in BAL fluid of the three subgroups, revealing the following data—mild subgroup, 0.21±0.09 mU/g and 57.35±20.9 U/g; moderate subgroup, 1.87±1.12 mU/g and 89.24±31.4 U/g; and severe subgroup, 2.64±1.63 mU/g and 139.18±58.3 U/g, respectively—compared to those of the healthy control group, 0.09±0.03 mU/g and 50.96±16.5 U/g. Evidently, the protective shield of plasma-derived antiproteinases was sufficient in healthy subjects and, also, in mild cases of bronchiectasis, but not in cases of severe and moderate forms of bronchiectasis, in which free and catalytically active elastase and cathepsin G were detected. The serine proteinases inhibitors (serpins), ₁-antitrypsin and ₁-antichymotrypsin, have evidently been oxidized and/or proteolytically cleaved in the cases of moderate and severe bronchiectasis. The results indicate that insufficient endogenous downregulation of catalytically active elastase and cathepsin G in BALF leads to tissue injury, resulting in alterative and deformative processes in the bronchiectasis lung.Abbreviations used BAL bronchoalveolar lavage - BALF bronchoalveolar lavage fluid - BE bronchiectasis - ₁-AT ₁-antitrypsin - ₁-ACT ₁-antichymotrypsin - ECM extracellular matrix - CT computerized tomography - PMN polymorphonuclear leukocyte - NCM nitrocellulose membrane - SDS-PAGE sodium dodecyl sulfatepolyacrylamide gel electrophoresis - TBS Tris-buffered saline     

β-Endorphin,adrenocorticotropic hormone,cortisol and catecholamines during aerobic and anaerobic exercise

Summary Twelve non-specifically trained volunteers (aged 26.5 years, SD 3.6) performed exhausting incremental graded exercise (ST) and 1-min anaerobic cycle ergometer exercise (AnT) at 2-h intervals for the purpose of investigating -endorphin (-E) behaviour dependent on exercise intensity and anaerobic metabolism. In order to determine [-E], adrenocorticotropic hormone [ACTH], cortisol [C], adrenaline [A] and noradrenaline [NA] concentrations, venous blood samples were collected prior and subsequent to exercise until the 20th min of the recovery period, as well as in ST before and after exceeding the individual anaerobic threshold (TH_{an, i}). Before, during and after ST, lactate concentration, heart rate and perceived degree of exertion were also determined; after AnT maximum lactate concentration was measured. Both types of exercise led to significant increases in [-E], [ACTH], [A] and [NA], with levels of [-E] and [ACTH] approximately twice as high after ST as after AnT. The [C] increased significantly only after ST. During ST significant changes in [-E] and [ACTH] were measured only after exceeding TH_{an, i}. At all measuring times before and after ST and AnT both hormones correlated positively. In AnT the increases of [-E] and [A] demonstrated a correlation (r= 0.65; P< 0.05). Both in AnT and ST there was a relationship between the maximum concentrations of -E and lactate (r=0.63 and 0.71; each P<0.05). We therefore conclude that physical exercise with increasing or mostly anaerobic components leads to an increase in [-E], the extent correlating with the degree of lactate concentration. The similar behaviour of [-E] and [A] after AnT might suggest mutual influences of endogenous opioids and catecholamines.     

Gene × Environment interaction and resilience: effects of child maltreatment and serotonin, corticotropin releasing hormone, dopamine, and oxytocin genes

In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multicomponent index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes (serotonin transporter linked polymorphic region, corticotropin releasing hormone receptor 1, dopamine receptor D4-521C/T, and oxytocin receptor) were investigated. In a series of analyses of covariance, child maltreatment demonstrated a strong negative main effect on children's resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences.     

Concurrent and Predictive Associations Between Infants’ and Toddlers’ Fearful Temperament,Coparenting, and Parental Anxiety Disorders

This study investigated the bidirectional relations between two dimensions of coparenting (the way parental figures cooperate in parenting), undermining and support, and child fearful temperament longitudinally from infancy to toddlerhood, while inspecting the moderating role of parents’ anxiety disorders. Questionnaire data on coparenting and child fearful temperament were obtained from 135 mothers, fathers, and their firstborns at 4 months, 12 months, and 30 months. Parental anxiety disorder severity was assessed with a semistructured interview before the birth of the child. Multilevel analysis revealed that, across measurement moments, undermining coparenting, but not supportive coparenting, was concurrently related to higher child fearful temperament. Parental anxiety disorder severity was related to more undermining coparenting but not to supportive coparenting. No moderation effects for parental anxiety disorder or for parent gender were found in the relations between coparenting and child fearful temperament. We conclude that more parental anxiety is related to a lower quality of the coparenting relationship, which in turn is associated to more child fearful temperament. More specifically, it appears that undermining coparenting, and not supportive coparenting, is related to child fearful temperament and parental anxiety disorder severity. Our results suggest that undermining coparenting, by both father and mother, is one of the mechanisms that may contribute to the intergenerational transmission of anxiety from parent to child. The coparenting relationship may be a useful target in the prevention and treatment of child anxiety.     

Thymopoiesis, Regulatory T Cells, and TCRVβ Expression in Thymoma With and Without Myasthenia Gravis, and Modulatory Effects of Steroid Therapy

We analyzed thymocyte and thymic regulatory T cell (CD4SPCD25⁺Foxp3⁺cells, Treg) development in thymoma with and without myasthenia gravis (MG, MG-thymoma, non-MG-thymoma) and in MG-associated non-neoplastic thymus (MG-NNT). An increased number of immature CD4⁺CD8⁻CD3⁻ thymocytes through the CD4⁺CD8⁺ to CD4⁺CD8⁻ transition and an abnormal T cell receptor Vβ (TCRVβ) development through the CD4⁺CD8⁺ to CD4⁻CD8⁺ transition were seen both in MG-and non-MG-thymomas. Terminal thymopoiesis, i.e., CD45RA⁺ cells within the CD4⁺CD8⁻CD3⁺ and CD8⁺CD4⁻CD3⁺ subsets, was skewed towards the CD4⁺ compartment in MG-thymoma and CD8⁺ compartment in non-MG-thymoma, but thymic export was increased only in the latter in keeping with the hypothesis that CD8⁺ lymphocytes may play a role in the initial stages of autosensitization and in disagreement with the relevance of an increased output of CD4⁺ T lymphocytes in paraneoplastic MG. Treg level in normal thymus and MG-NNT and both MG- and non-MG-thymoma was similar, and TCRVβ development in Treg cells was slightly altered in thymoma but irrespective of MG presence. Thus, the relevance of a defective Treg development in MG context remains to be established. Most alterations in thymopoiesis were corrected by therapeutic corticosteroid administration, and the effects of steroid administration may be mediated by thymic microenvironment.