Expression of decorin and collagens I and III in different layers of human skin in vivo: a laser capture microdissection study

Extracellular matrix (ECM) organization is a complex process that requires the coordinated efforts of many molecules. For the regulation of collagen fiber diameter, the proteoglycan decorin appears to be of major relevance. To investigate the role of decorin in the process of (photo-)aging in more detail, full-thickness punch biopsies were isolated from human buttock skin. Single exposure with two minimal erythemal doses of solar simulated irradiation caused down-regulation of decorin mRNA in young (n = 5) and old subjects (n = 5) after 24 h. Interestingly, decorin mRNA was elevated with age. To test the hypothesis that a decreased collagen-to-decorin-ratio impairs collagen structure we also investigated collagens I and III gene expression. Both were down-regulated with increasing age and after single UV-irradiation. As determined by laser capture microdissection-quantitative real time-Polymerase chain reaction (n = 11), decorin is mostly present in the reticular dermis while being absent from the papillary dermis. Minor expression was also observed in the epidermis. However, in contrast to full-thickness skin biopsies age-dependent changes in collagens I, III, and decorin expression could not be observed with this methodology indicating technical limitations. Together with our finding that collagens I and III mRNA are similarly expressed in the reticular and papillary dermis and are down-regulated by UV, our studies support the idea of a major role of decorin in ECM organization. Altered expression of decorin mRNA in the different dermal strata and a decrease in the collagen-to-decorin ratio inflicted by both age and ultraviolet irradiation possibly affect collagen bundle diameter and subsequently the mechanical properties of human skin.     

Advanced heart failure: prognosis, uncertainty, and decision making

Heart failure is a serious clinical management challenge for both patients and primary care physicians. The authors studied the perceptions and practices of internal medicine residents and faculty at an academic medical center in the Southeast to guide design of strategies to improve heart failure care. Data were collected via a self-administered survey. Eighty-nine faculty and resident physicians in general internal medicine and geriatrics participated (74% response rate). Items measured perceived skills and barriers, adherence to guidelines, and physician understanding of patient prognosis. Case studies explored practice approaches. Clinical knowledge and related scales were generally good and comparable between physician groups. Palliative care and prognostic skills were self-rated with wide variance. Physicians rated patient noncompliance and low lifestyle change motivation as major barriers. Given the complexities of caring for elderly persons with heart failure and comorbid conditions, there are significant opportunities for improving physician skills in decision making, patient-centered counseling, and palliative care.     

The Hong Kong Society of Rheumatology consensus recommendations for the management of gout

Clinical Rheumatology - Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains...     

Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress

A variety of early life stressors have consistently been implicated in the development of psychopathology in adulthood. The current study investigates a rarely considered form of early life stress, bacterial infection, for its ability to induce psychopathology-like symptoms in adult rat. Specifically, neonatal rats were exposed to a simulated bacterial infection. In adulthood the acoustic startle response of these animals was evaluated both prior to and following exposure to restraint stress. Our results indicate that animals neonatally exposed to infection exhibit a significantly exaggerated acoustic startle response but only following exposure to stress. Additionally, we observed that adult animals neonatally exposed to infection, exhibited increased production of circulating corticosterone following stress, indicating potentiated hypothalamic pituitary adrenal axis activity as well as altered novelty seeking behaviour and locomotor activity. These results extend upon existing pre-clinical findings that indicate certain stressful early life events can predispose the adult animal to exhibit abnormal behaviour in adulthood.     

Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM)

Background Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.Methods KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.Results Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.Conclusions The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.Subject terms: Mesothelioma, Biochemistry, Cell biology     

Diagnosis of acute myocardial infarct with ventricular paced rhythm

Management of acute myocardial ischaemia is dependent upon interpretation of the 12‐lead electrocardiogram. The presence of ventricular pacing and acute myocardial infarction makes electrocardiogram interpretation difficult. This may impact upon patient management if treating staff are unaware of the expected electrocardiogram morphology or do not have a rapidly available means to make the diagnosis. This case highlights the difficulty with diagnosis of acute myocardial infarction in the presence of ventricular paced rhythm and demonstrates the electrocardiogram changes that occur with myocardial infarction.