Citations

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease. The disease course can be highly variable and treatment options are limited. To identify new therapeutic targets and prognostic biomarkers of disease, we conducted parallel discovery microarray profiling in normal and diseased human PKD1 cystic kidney cells. A total of 1,515 genes and 5 miRNA were differentially expressed by more than twofold in PKD1 cells. Functional enrichment analysis identified 30 dysregulated signaling pathways including the epidermal growth factor (EGF) receptor pathway. In this paper, we report that the EGF/ErbB family receptor ErbB4 is a major factor driving cyst growth in ADPKD. Expression of ErbB4 in vivo was increased in human ADPKD and Pkd1 cystic kidneys, both transcriptionally and posttranscriptionally by mir-193b-3p. Ligand-induced activation of ErbB4 drives cystic proliferation and expansion suggesting a pathogenic role in cystogenesis. Our results implicate ErbB4 activation as functionally relevant in ADPKD, both as a marker of disease activity and as a new therapeutic target in this major kidney disease.

Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

Purpose Long-term occlusion of coiled aneurysms frequently fails, probably because of poor intrasaccular healing and inadequate endothelialization across the aneurysm neck. The purpose of this study was to determine if attachment of autologous mesenchymal stem cells (MSCs) to platinum coils would improve the healing response in an elastase-induced aneurysm model in rabbits. Materials and methods With approval from the institutional animal care and use committee, aneurysms were created in rabbits and embolized with control platinum coils (Axium; Medtronic) (n=6) or coils seeded ex vivo with autologous adipose-tissue MSCs (n=7). Aneurysmal occlusion after embolization was evaluated at 1 month with angiography. Histological samples were analyzed by gross imaging and graded on the basis of neck and dome healing on H&E staining. Fibrosis was evaluated using a ratio of the total area presenting collagen. Endothelialization of the neck was quantitatively analyzed using CD31 immunohistochemistry. χ2 and Student's t-test were used to compare groups. Results Healing score (11.5 vs 8.0, p=0.019), fibrosis ratio (10.3 vs 0.13, p=0.006) and endothelialization (902 262 μm2 vs 31 810 μm2, p=0.041) were significantly greater in the MSC group. The MSC group showed marked cellular proliferation and thrombus organization, with a continuous membrane bridging the neck of the aneurysm. Angiographic stable or progressive occlusion rate was significantly lower in the MSC group (0.00, 95% CI 0.00 to 0.41) compared with controls (0.67, 95% CI 0.22 to 0.96) (p=0.02). Conclusions Autologous MSCs attached to platinum coils significantly improve histological healing, as they result in improved neck endothelialization and collagen matrix formation within the aneurysm sac.

Diurnal changes in gut microbiota localization and function alter host physiology through circadian epigenetic and transcriptional changes.

In 2002, the Physician Charter on Medical Professionalism was published to provide physicians with guidance for decision making in a rapidly changing environment. Feedback from physicians indicated that they were unable to fully live up to the principles in the 2002 charter partly because of their employing or affiliated health care organizations. A multistakeholder group has developed a Charter on Professionalism for Health Care Organizations, which may provide more guidance than charters for individual disciplines, given the current structure of health care delivery systems. This article contains the Charter on Professionalism for Health Care Organizations, as well as the process and rationale for its development. For hospitals and hospital systems to effectively care for patients, maintain a healthy workforce, and improve the health of populations, they must attend to the four domains addressed by the Charter: patient partnerships, organizational culture, community partnerships, and operations and business practices. Impacting the social determinants of health will require collaboration among health care organizations, government, and communities. Transitioning to the model hospital described by the Charter will challenge historical roles and assumptions of both its leadership and staff. While the Charter is aspirational, it also outlines specific institutional behaviors that will benefit both patients and workers. Lastly, this article considers obstacles to implementing the Charter and explores avenues to facilitate its dissemination.

We studied the use of minor and major recurrence classifications with regard to observer variability, which directly affects validity of these terms as outcome measures. Recurrences at the time of a three to six month follow-up angiogram were assessed independently by two experienced observers in 83 cases. Intra- and interobserver concordance is approximately 90% for assessment of minor and major recurrence.

Electroencephalogram (EEG) reactivity has been increasingly utilized in prognostication after cardiac arrest. Recent studies have demonstrated a false-positive rate of 0% in predicting poor outcome with a nonreactive EEG. The reemergence of reactivity after an initial nonreactive EEG has been noted in cases of drug intoxication, rewarming after hypothermia, and after discontinuing sedation. This is the first case describing the reemergence of EEG reactivity without the confounding factors listed above. We describe a case of resuscitated cardiac arrest with initial EEG demonstrating a lack of reactivity. A repeat EEG completed 3 days later revealed a reemergence of reactivity in the setting of normothermia, a negative drug screen, and the absence of sedation. The delayed recovery of EEG reactivity without previously established confounding factors is novel. Serial EEGs may be beneficial as the available literature on reactivity and prognostication is based on an average of 24 to 48 hours of EEG tracing. Prognostication after cardiac arrest continues to require a multimodal approach.

Chronic administration of oestrogen and/or progesterone does not affect adrenergic neurotransmission or contractions initiated by sympathomimetic amines in the cutaneous venous smooth muscle of the dog. However, contractions initiated by the venotropic Ruscus-extract are enhanced following chronic exposure to progesterone, an affect that can be reversed by oestrogen. The contractions are mediated by an adrenergic and non-adrenergic component. The adrenergic component is enhanced by progesterone and decreased by oestrogen; the non-adrenergic component is most prominent when the serum-levels of the female steroid hormones are low.