Increased clinical symptoms of acromegalic arthropathy in patients with long-term disease control: a prospective follow-up study

Arthropathy is an invalidating complication of acromegaly. This arthropathy deteriorates radiographically despite long-term disease control. However, the clinical course and its relationship to the radiographic course are currently unknown. We aimed to investigate the clinical course of arthropathy during follow-up and its relationship to radiographic progression in long-term controlled acromegaly patients. Prospective follow-up study. We studied 58 patients (mean age 62 years, women 41 %) with controlled acromegaly for a mean of 17.6 years. Clinical progression of joint disease was defined at baseline and after 2.6 years, by the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Australian/Canadian Osteoarthritis Index (AUSCAN) questionnaires for lower limb and hand OA, respectively, and performance tests. Potential risk factors for progression were assessed. The clinical course of arthropathy was related to the radiographic course. On average, hand and lower limb function deteriorated during follow-up, despite large interindividual variations. Joint pain was stable over time. High levels of pain and functional impairment at baseline were related to clinical progression of hand pain and functional limitations. High baseline BMI was a risk factor for functional deterioration in the lower limb. The changes in symptoms and radiographic progression during follow-up were not related. In treated acromegaly patients, joint function deteriorates during prolonged follow-up, despite biochemical disease control, although there was interindividual variation. Clinical and radiographic course of arthropathy were not related. Therefore, in clinical practice, a combination of clinical and radiographic assessment is necessary to evaluate the course of acromegalic arthropathy.     

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

Ischemia/reperfusion injury is a major cause of acute kidney injury. Improving renal repair would represent a therapeutic strategy to prevent renal dysfunction. The innate immune receptor Nlrp3 is involved in tissue injury, inflammation, and fibrosis; however, its role in repair after ischemia/reperfusion is unknown. We address the role of Nlrp3 in the repair phase of renal ischemia/reperfusion and investigate the relative contribution of leukocyte- versus renal-associated Nlrp3 by studying bone marrow chimeric mice. We found that Nlrp3 expression was most profound during the repair phase. Although Nlrp3 expression was primarily expressed by leukocytes, both leukocyte- and renal-associated Nlrp3 was detrimental to renal function after ischemia/reperfusion. The Nlrp3-dependent cytokine IL-1β remained unchanged in kidneys of all mice. Leukocyte-associated Nlrp3 negatively affected tubular apoptosis in mice that lacked Nlrp3 expression on leukocytes, which correlated with reduced macrophage influx. Nlrp3-deficient (Nlrp3KO) mice with wild-type bone marrow showed an improved repair response, as seen by a profound increase in proliferating tubular epithelium, which coincided with increased hepatocyte growth factor expression. In addition, Nlrp3KO tubular epithelial cells had an increased repair response in vitro, as seen by an increased ability of an epithelial monolayer to restore its structural integrity. In conclusion, Nlrp3 shows a tissue-specific role in which leukocyte-associated Nlrp3 is associated with tubular apoptosis, whereas renal-associated Nlrp3 impaired wound healing.Ischemia/reperfusion (IR) injury is a major cause of acute kidney injury¹ and increases the risk of developing chronic kidney disease (CKD).² After injury, wounded tissue organizes an efficient response that aims to combat infections, clear cell debris, re-establish cell number, and reorganize tissue architecture. First, necrotic tissue releases danger-associated molecular patterns, such as high-mobility group box-1³ or mitochondrial DNA,⁴ which leads to chemokine secretion⁵ and a subsequent influx of leukocytes. Second, neutrophils and macrophages clear cellular debris but also increase renal damage because depletion of neutrophils⁶ or macrophages within 48 hours of IR will reduce renal damage.⁷ At approximately 72 hours of reperfusion, the inflammatory phase transforms into the repair phase and is characterized by surviving tubular epithelial cells (TECs) that dedifferentiate, migrate, and proliferate to restore renal function.⁸Previously, we have shown that Toll-like receptor (TLR) 2 and TLR4 play a detrimental role after acute renal IR injury.^{9, 10, 11} In addition, TLR2 appeared also pivotal in mediating tubular repair in vitro after cisplatin-induced injury,¹² indicating a dual role for TLR2. The cytosolic innate immune receptor Nlrp3 is able to sense cellular damage¹³ and mediates renal inflammation and pathological characteristics after IR^{14, 15, 16} or nephrocalcinosis.¹⁷ Next to the detrimental role of Nlrp3 in different renal disease models and consistent with the dual role of TLR2, Nlrp3 was shown to protect against loss of colonic epithelial integrity.¹⁸ We, therefore, speculate that Nlrp3, which contributes to sterile renal inflammation during acute renal IR injury, might also drive subsequent tubular repair.To test this hypothesis, we investigated the role of leukocyte- versus renal-associated Nlrp3 with respect to tissue repair after renal IR. We observed that both renal- and leukocyte-associated Nlrp3s are detrimental to renal function after renal IR injury; however, this is through different mechanisms. Leukocyte-associated Nlrp3 is related to increased tubular epithelial apoptosis, whereas renal-associated Nlrp3 impairs the tubular epithelial repair response. Our data suggest Nlrp3 as a negative regulator of resident tubular cell proliferation in addition to its detrimental role in renal fibrosis and inflammation.^{14, 19}     

Incidence of stroke in the diabetic compared with the non‐diabetic population: A systematic review protocol

People with diabetes have a largely increased risk of stroke compared with people without diabetes. Exact data on incidence of stroke in people with and without diabetes are important for improvements in preventive diabetes care, avoidance of fatal outcomes and as a solid basis for health policy and the economy. However, published data are conflicting, underlining the necessity for this systematic review of population‐based studies on incidence, relative risks (RRs) and changes in stroke rates over time. The purpose of our review is to evaluate the incidence of stroke in the diabetic population and its differences with regard to sex, ethnicity, age and regions; to compare the incidence rate (IR) in the diabetic and non‐diabetic populations and to investigate time trends. We will perform a systematic literature search in MEDLINE, Embase and LILACS designed by an experienced information scientist. Two review authors will independently screen the abstracts and full texts of all references on the basis of inclusion criteria regarding types of study, types of population and the main outcome. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess IR or cumulative incidence (CumI) and RR of stroke comparing the diabetic and non‐diabetic populations. The attributable risk (AR = proportion of stroke among persons with diabetes that is attributable to diabetes) and the population attributable risk (PAR = proportion of stroke in the whole population that is attributable to diabetes) will be considered where available. In conclusion, this review will help to summarize the available evidence for incidence of stroke in the diabetic and nondiabetic population. The publication of this protocol will contribute to making the search strategy, methods, and assessment of reviews transparent and accessible for all involved professional groups.     

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea

BackgroundIron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.Methods and ResultsConsecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO₂), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO₂ (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV–pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm² vs 2.58 ± 1.14 mm Hg/cm²; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO₂/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.ConclusionsIn patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.