Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: Part 2

The transient receptor potential (TRP) vanilloid subtype 4 (V4) is a nonselective cation channel that exhibits polymodal activation and is expressed in the endothelium, where it contributes to intracellular Ca2+ homeostasis and regulation of cell volume. The purpose of the present study was to evaluate the systemic cardiovascular effects of GSK1016790A, a novel TRPV4 activator, and to examine its mechanism of action. In three species (mouse, rat, and dog), the i.v. administration of GSK1016790A induced a dose-dependent reduction in blood pressure, followed by profound circulatory collapse. In contrast, GSK1016790A had no acute cardiovascular effects in the TRPV4-/- null mouse. Hemodynamic analyses in the dog and rat demonstrate a profound reduction in cardiac output. However, GSK1016790A had no effect on rate or contractility in the isolated, buffer-perfused rat heart, and it produced potent endothelial-dependent relaxation of rodent-isolated vascular ring segments that were abolished by nitric-oxide synthase (NOS) inhibition (N-nitro-L-arginine methyl ester; L-NAME), ruthenium red, and endothelial NOS (eNOS) gene deletion. However, the in vivo circulatory collapse was not altered by NOS inhibition (L-NAME) or eNOS gene deletion but was associated with (concentration and time appropriate) profound vascular leakage and tissue hemorrhage in the lung, intestine, and kidney. TRPV4 immunoreactivity was localized in the endothelium and epithelium in the affected organs. GSK1016790A potently induced rapid electrophysiological and morphological changes (retraction/condensation) in cultured endothelial cells. In summary, inappropriate activation of TRPV4 produces acute circulatory collapse associated with endothelial activation/injury and failure of the pulmonary microvascular permeability barrier. It will be important to determine the role of TRPV4 in disorders associated with edema and microvascular congestion.     

Catheter-less robotic radical prostatectomy using a custom-made synchronous anastomotic splint and vesical urinary diversion device: report of the initial series and perioperative outcomes

OBJECTIVE

To study the feasibility of avoiding a urethral catheter after robotic radical prostatectomy by using suprapubic diversion with a urethral splint, as urethral catheterization is often a source of major discomfort and pain to the patient, and can cause more concern to the patient than the procedure; we present the outcomes of a pilot study.

PATIENTS AND METHODS

This pilot study involved 30 patients; in group 1 (the study group of 10 patients) we used a custom‐made suprapubic catheter which provided a small anastomotic splint, multiple holes for drainage and the ability to retract the splint to give a voiding trial before removing the drainage device. Group 2 was a control group of 20 patients who had standard urethral catheterization with an 18 F Silastic Foley catheter. Demographic, intraoperative and outcome data were measured and analysed. Urethral symptoms were recorded using a specially developed questionnaire.

RESULTS

The two groups were comparable in terms of age, serum prostate specific antigen level, body mass index, Gleason scores, tumour stage, operative duration, amount of bleeding, console times, anastomotic leakage and postoperative retention rates. The study group had significantly less penile shaft or tip pain and discomfort during walking or sleeping. No patient in either group had haematuria or clot retention requiring irrigation.

CONCLUSION

Urethral catheter‐less robotic radical prostatectomy is feasible. The advantages are decreased penile shaft and tip pain, and decreased patient discomfort and an earlier return of continence.     

Successful use of subcutaneous anakinra in hemophagocytic lymphohistiocytosis precipitated by candidiasis in a patient with systemic lupus erythematosus: A case report and description of a novel therapeutic regimen

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal condition characterized by inappropriate immune system activation leading to a “cytokine storm”, and ultimately resulting in end-organ damage. Causes include primary defects in genes involved in immune-mediated cytolytic pathways, or secondary triggers such as infection or malignancy. We describe a case of HLH precipitated by fungal infection which occurred as a consequence of immunosuppression for management of systemic lupus erythematosus (SLE) and necrotizing myopathy. The patient presented with immune-mediated disease of the muscles and lung which was treated with high-dose corticosteroids and aggressive immunosuppression. HLH emerged in the context of confirmed candidiasis and features of severe sepsis. The patient responded rapidly to antifungal therapy and high-dose anakinra, which was administered subcutaneously and progressively weaned over 4 weeks. She completed HLH treatment as an outpatient and remains well at 12 months with controlled SLE and no recurrence of HLH.     

Toward assessing traumatic events and stress symptoms in preschool children from low-income families

Traumatic events can seriously disrupt the development of preschool children. Yet few studies capture developmentally specific examples of traumas and the expression of distress for this age group. Mothers and teachers of 138 preschoolers from low-income families were interviewed about traumatic events and completed a new measure assessing their child's traumatic stress symptoms. They reported traumatic events as the death of a person, death of a pet, family violence, high conflict divorce, sudden family loss, accident or injury, and viewing the World Trade Center attack. Factor analysis of 17 trauma symptoms revealed three internally consistent and valid scales: Intrusions, Emotional Reactivity, and Fears, plus a Total omnibus score. Traumatic stress symptoms varied by the type of event. Scores were higher for traumatic events involving close family members than for distal events.     

Cancer resistance in transgenic mice expressing the SAC module of Par-4

Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-kappaB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance.     

Tissue-associated self-antigens containing exosomes: Role in allograft rejection

Exosomes are extracellular vesicles that express self-antigens (SAgs) and donor human leukocyte antigens. Tissue-specific exosomes can be detected in the circulation following lung, heart, kidney and islet cell transplantations. We collected serum samples from patients who had undergone lung (n?=?30), heart (n?=?8), or kidney (n?=?15) transplantations to isolate circulating exosomes. Exosome purity was analyzed by Western blot, using CD9 exosome-specific markers. Tissue-associated lung SAgs, collagen V (Col-V) and K-alpha 1 tubulin (Kα1T), heart SAgs, myosin and vimentin, and kidney SAgs, fibronectin and collagen IV (Col-IV), were identified using western blot. Lung transplant recipients diagnosed with bronchiolitis obliterans syndrome had exosomes with higher expression of Col-V (4.2-fold) and Kα1T (37.1-fold) than stable. Exosomes isolated from heart transplant recipients diagnosed with coronary artery vasculopathy had a 3.9-fold increase in myosin and a 4.7-fold increase in vimentin compared with stable. Further, Kidney transplant recipients diagnosed with transplant glomerulopathy had circulating exosomes with a 2-fold increased expression of fibronectin and 2.5-fold increase in Col-IV compared with stable. We conclude that circulating exosomes with tissue associated SAgs have the potential to be a noninvasive biomarker for allograft rejection.     

Long noncoding RNAs could be potential key players in the pathophysiology of Sjögren's syndrome

Long noncoding RNAs (lncRNAs) are a recently discovered class of noncoding functional RNAs encoded by metazoan genomes. Recent studies suggest a larger regulatory role for lncRNAs in critical biological and disease processes. Mounting evidence on the role of lncRNAs in regulating key processes of the immune system prompted us to hypothesize the role of lncRNAs as key regulators of the pathophysiology of Sjögren's syndrome (SS). We used two similar approaches based on reanalysis of microarray expression datasets and curation of lncRNA‐protein coding gene interactions from literature to derive support for our hypothesis. We also discuss potential caveats to our approach and suggest approaches to validate the hypothesis. Our analysis suggests the potential larger and hitherto unknown role of lncRNA regulatory networks in modulating the expression of key genes involved in the pathogenesis of SS and thereby modulating the pathophysiology of SS.