Peptide YY: Food for thought

Obtaining a fuller understanding of gut hormones as mediators of appetite regulation and energy homeostasis has never been so important with obesity rates increasing at pandemic proportions. The role of the gut hormone peptide YY 3-36 (PYY3-36) in particular has sparked interest since the discovery of its anorectic effect in obese rodents and humans.Fasting circulating PYY concentrations correlate negatively with BMI and waist circumference in humans, whilst postprandial PYY levels predict subsequent changes in weight over a period of at least 6 months. Furthermore, Pyy null mice demonstrate increased adiposity and hyperphagia, which is reversed by exogenous PYY3-36. Chronic administration of PYY3-36 to diet-induced obese rodents has shown a dose-dependent reduction in adiposity.Taken in concert, these findings suggest that the PYY system may hold significant potential in the treatment and prevention of obesity.     

Relationship of creative projects in anatomy to medical student professionalism, test performance and stress: an exploratory study

Background  

The anatomy course offers important opportunities to develop professionalism at an early stage in medical education. It is an academically significant course that also engenders stress in some students.     

Co-delivery of FGF-2 and G-CSF from gelatin-based hydrogels as angiogenic therapy in a murine critical limb ischemic model

Peripheral artery disease and critical limb ischemia have become prevalent health risks in the United States due to an increasing elderly population and the prevalence of obesity and diabetes mellitus. Although highly invasive endarterectomy is the most popular method for treatment, angiogenic therapies based on growth factor administration are quickly becoming a popular alternative. Enzymatic degradation of these factors in vivo may be avoided by their incorporation in a delivery vehicle where the growth factor's release rate can be controlled by altering the vehicle's properties (i.e. cross-linking density, material selection, biodegradation, etc.). Herein, we report on the immobilization and controlled release of human recombinant basic fibroblast growth factor (FGF-2) and human recombinant granulocyte colony-stimulating factor (G-CSF) from ionic, gelatin-based hydrogel scaffolds to re-establish perfusion and induce capillary outgrowth in a murine hindlimb ischemic model. In vitro studies showed that endothelial cell proliferation was highly depended on FGF-2, whereas G-CSF stimulated migration and formation of a tubular network. When FGF-2 and G-CSF were used in combination there was an 82% increase in endothelial branch point formation compared to control groups. Leg reperfusion was assessed with laser Doppler perfusion imaging, while capillary outgrowth in the ischemic leg was evaluated using CD31(+) and alpha-SMA immunostaining. The co-delivery of G-CSF (1000 ngml(-1)) and FGF-2 (1000 ng ml(-1)) from the gelatin hydrogels resulted in a 3-fold increase in the perfusion levels and a 2-fold increase in capillary density and positive alpha-SMA vessels compared to the empty vehicle group. In conclusion, the co-delivery of FGF-2 and G-CSF was superior to bolus administration or the delivery of either factor alone in promoting reperfusion and mature vessel formation.     

Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: Array CGH study of 47 unrelated cases

Investigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, revealed a proportion of unsuspected imbalances. It was estimated recently that 40% of apparently balanced de novo translocations with abnormal phenotype were associated with cryptic deletion.We explored 47 unrelated mental retardation patients carrying an apparently balanced chromosomal rearrangement with high-resolution oligonucleotides arrays. We included 33 de novo cases (21 translocations, 7 inversions and 5 complex chromosomal rearrangements (CCR)) and 14 inherited cases (7 translocations, 5 inversions and 2 CCR).Twenty of the 47 cases (42.6%) carried a cryptic deletion ranging from 60 kb to 15.37 Mb. It concerned 16/33 de novo rearrangements (8/21 translocations, 4/7 inversions and 4/5 CCR) and 4/14 inherited rearrangements (1/7 translocations, 2/5 inversions and 1/2 CCR). The proportion of imbalances was not statistically different between de novo and inherited cases.Our results support that about 40% apparently balanced chromosomal rearrangements with abnormal phenotype are in fact imbalanced and that these rearrangements should be systematically investigated by array CGH independently of their de novo or inherited character.     

Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity

Complete lack of function of the tyrosine kinase ZAP70 in humans results in a severe immunodeficiency, characterized by a lack of mature CD8⁺ T cells and non‐functional CD4⁺ T cells. We report herein an immunodeficiency with an inherited hypomorphic mutation of ZAP70 due to a single G‐to‐A substitution in a non‐coding intron. This mutation introduces a new acceptor splice site and allows low levels of normal alternative splicing and of WT ZAP70 expression. This partial deficiency results in a compromised TCR signaling that was totally restored by increased expression of ZAP70, demonstrating that defective activation of the patient T cells was indeed caused by the low level of ZAP70 expression. This partial ZAP70 deficiency was associated with an attenuated clinical and immunological phenotype as compared with complete ZAP70 deficiency. CD4⁺ helper T‐cell populations including, follicular helper T cells, Th1, Th17 and Treg were detected in the blood. Finally, the patient had no manifestation of autoimmunity suggesting that the T‐cell tolerogenic functions were not compromised, in contrast to what has been observed in mice carrying hypomorphic mutations of Zap70. This report extends the phenotype spectrum of ZAP70 deficiency with a residual function of ZAP70.     

Endosomal processing for antigen presentation mediated by CD1 and Class I major histocompatibility complex: roads to display or destruction

The presentation of antigen in a form that can be recognized by T lymphocytes of the immune system requires antigen processing and association of antigen-derived fragments with molecules encoded by the major histocompatibility complex (MHC) locus or by the CD1 locus. Much emphasis on antigen processing and presentation in the last decades has focused on what we consider ‘conventional routes’ of antigen processing and presentation, whereby extracellular antigens are processed for presentation via Class II MHC complexes and cytosolic antigens are presented as peptide–Class I MHC complexes. We here highlight two other pathways in myeloid dendritic cells, those of lipid antigen presentation in association with CD1 and of peptide cross-presentation via Class I MHC complexes. Some pathogens evade immune recognition through inhibition of antigen presentation of phagosomal origin. Deviations in endosomal antigen processing and presentation are also seen in individuals suffering from glycosphingolipid lysosomal lipid storage diseases. We summarize recent developments in the endosomal antigen processing and presentation pathway, for display as lipid–CD1 complexes to natural killer T cells and as peptide–Class I MHC complexes to CD8 T cells.     

Associations of cigarette smoking with rheumatoid arthritis in African Americans

Objective

To examine the associations of cigarette smoking with rheumatoid arthritis (RA) in African Americans, and to determine whether this association is impacted by the HLA–DRB1 shared epitope (SE).

Methods

Smoking status, cumulative smoking exposure, and SE status were determined in African American patients with RA and African American healthy controls. Associations of smoking with RA were examined using age‐ and sex‐adjusted logistic regression analyses. Additive and multiplicative SE–smoking interactions were examined.

Results

After adjustment for age and sex, ever smoking (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.07, 1.97) and current smoking (OR 1.56, 95% CI 1.07, 2.26), relative to never smoking, were more common in African American patients with RA (n = 605) than in controls (n = 255). The association of smoking with RA was limited to those with a cumulative exposure exceeding 10 pack‐years, associations that were evident both in autoantibody‐positive and in autoantibody‐negative disease. There was evidence of a significant additive interaction between SE status and heavy smoking (≥10 pack‐years) in relation to RA risk (attributable proportion [AP] due to interaction 0.58, P = 0.007), with similar results for the additive interaction between SE status and ever smoking (AP 0.47, P = 0.006). There was no evidence of multiplicative interactions.

Conclusion

Among African Americans, cigarette smoking is associated not only with the risk of autoantibody‐positive RA but also with the risk of autoantibody‐negative disease. The risk of RA attributable to smoking is limited to African Americans with more than 10 pack‐years of exposure and is more pronounced among individuals positive for the HLA–DRB1 SE.

     

Socioeconomic inequalities in prognostic markers of non-Hodgkin lymphoma: analysis of a national clinical database

The survival of non-Hodgkin lymphoma patients strongly depends on a range of prognostic factors. This registry-based clinical cohort study investigates the relation between socioeconomic position and prognostic markers in 6234 persons included in a national clinical database in 2000-2008, Denmark. Several measures of individual socioeconomic position were achieved from Statistics Denmark. The risk of being diagnosed with advanced disease, as expressed by the six prognostic markers (Ann Arbor stage III or IV, more than one extranodal lesion, elevated serum lactate dehydrogenase (LDH), performance status of two or more, presence of B symptoms and International Prognostic Index (IPI) of two or more), increased with decreasing level of education, in patients living alone, and in men. For instance, a significant decrease in the odds of being diagnosed with elevated LDH (p = 0.02), high performance status (p = 0.004), high IPI score (p = 0.004) and B symptoms (p = 0.02) was seen with higher level of education, whereas high stage of disease was significantly less likely in the higher educated (odds ratio [OR] = 0.85 (0.74-0.99)). The difference in risk seemed not to be mediated by differences in histological subgroups reflecting aggressiveness of disease among the social groups. One of the most likely mechanisms of the social difference is longer delay in those with low socioeconomic position. The findings of social inequality in prognostic markers in non-Hodgkin lymphoma (NHL) patients could already be implemented in the clinical practice if general practitioners (GP’s) and physicians on hospitals paid special attention to patients with low educational level and unspecific symptoms.