Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA)

OBJECTIVE: To undertake a multicentre epidemiological study reflecting acromegaly in Spain. DESIGN: Voluntary reporting of data on patients with acromegaly to an online database, by the managing physician. METHODS: Data on demographics, diagnosis, estimated date of initial symptoms and diagnosis, pituitary imaging, visual fields, GH and IGF-I concentrations (requested locally), medical, radiotherapy and neurosurgical treatments, morbidity and mortality were collected. RESULTS: Data were included for 1219 patients (60.8% women) with a mean age at diagnosis of 45 years (s.d. 14 years). Reporting was maximal in 1997 (2.1 cases per million inhabitants (c.p.m.) per year); prevalence was globally 36 c.p.m., but varied between 15.7 and 75.8 c.p.m. in different regions. Of 1196 pituitary tumours, most were macroadenomas (73%); 81% of these patients underwent surgery, 45% received radiotherapy and 65% were given medical treatment (somatostatin analogues in 68.3% and dopamine agonists in 31.4%). Cures (GH values (basal or after an oral glucose tolerance test) <2 ng/ml, normal IGF-I, or both) were observed in 40.3% after surgery and 28.2% after radiotherapy. Hypertension (39.1%), diabetes mellitus (37.6%), hypopituitarism (25.7%), goitre (22.4%), carpal tunnel syndrome (18.7%) and sleep apnoea (13.2%) were reported as most frequent morbidities; 6.8% of the patients had cancer (breast in 3.1% of the women and colon in 1.2% of the cohort). Fifty-six patients died at a mean age of 60 years (s.d. 14 years), most commonly of a cardiovascular cause (39.4%); mortality was greater in patients given radiotherapy (hazard ratio 2.29; 95% confidence interval 1.03 to 5.08; P=0.026), and in those in whom GH and IGF-I concentrations were never normal (P<0.001). CONCLUSIONS: This acromegaly registry offers a realistic overview of the epidemiological characteristics, treatment outcome and morbidity of acromegaly in Spain. As active disease and treatment with radiotherapy are associated with an increase in mortality, efforts to control the disease early are desirable.     

Hidratación con Ringer Lactato combinado con diclofenaco rectal en la prevención de pancreatitis poscolangiopancreatografía retrógrada endoscópica

ObjectiveDifferent measures are recommended to reduce pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We conducted a study in patients with ERCP treated with rectal diclofenac or lactated Ringer's solution, or both interventions, to assess whether there is a decrease in the number of cases of post-ERCP pancreatitis.Material and methodsA mixed cohort study involving 1,896 patients from 2009 to 2018. Up to June 2012 without treatment (Group I). Subsequently, 100 mg of rectal diclofenac (Group II). Since 2016, lactated Ringer's solution 200 ml/hour during the procedure and 4 hours after it, in addition to 500 ml over 30 minutes when the pancreas was cannulated (Group III). Since 2017, lactated Ringer's solution plus Diclofenac (Group IV). There were 725 patients in group I, and 530, 227 and 414 patients in groups II, III and IV, respectively. Factors predisposing to post-ERCP pancreatitis and post-ERCP pancreatitis cases that were defined by consensus criteria have been collected.ResultsThere were 65 cases of post-ERCP pancreatitis (3.4%); 2.9%, 3.4%, 3.1% and 4.3% in groups I, II, III and IV, respectively (P = .640). In group I, there was 4.2% of post-ERCP pancreatitis in naïve papillae and 4%, 4.9% and 6.3% in groups II, III and IV, respectively (P = .585). The severity of post-ERCP pancreatitis and adverse effects were similar in all groups. 38.4% were high-risk patients. There were also no differences in post-ERCP pancreatitis in this group (P = .501).ConclusionIn this work, no benefit was obtained with diclofenac plus hydration in reducing the number and severity of cases of post-ERCP pancreatitis nor with the other prophylactic measures.     

Essential role of insulin-like growth factor I receptor in insulin-induced fetal brown adipocyte differentiation

To define the specific role of IGF-I receptor (IGF-IR) in adipogenic and thermogenic differentiation of brown adipocytes during late fetal life, we have established immortalized brown adipocyte cell lines from fetuses of IGF-IR-deficient mice (IGF-IR(-/-)) as well as from wild-type mice (IGF-IR(+/+)). IGF-IR(-/-) cells showed an increased insulin sensitivity regarding insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation despite a substantial reduction in IRS-1 protein content. Furthermore, insulin-induced total and IRS-1-associated phosphatidylinositol 3-kinase activities were augmented in IGF-IR-deficient cells compared with wild-type cells. Downstream phosphatidylinositol 3-kinase activation of Akt, but not p70s6 kinase, were elicited at lower doses of insulin in IGF-IR(-/-) brown adipocytes. Activation of protein kinase Czeta by insulin was similar in both cell types as was insulin-induced glucose uptake. Treatment of wild-type brown adipocytes with insulin for 12 h up-regulated fatty acid synthase (FAS) and adipocyte determination and differentiation (ADD1/SREBP) mRNAs; this effect was impaired in the absence of IGF-IR. At the protein level, insulin increased FAS content and the amount of the mature form of adipocyte determination and differentiation (ADD1/SREBP) in the nucleus in wild-type cells, but not in IGF-IR(-/-) cells. Furthermore, 24 h of insulin stimulation induced the expression of both uncoupling protein-1 and CCAAT/enhancer-binding protein alpha (C/EBPalpha) in wild-type brown adipocytes; these effects were abolished in IGF-I-R(-/-) cells. Retrovirus-mediated reexpression of peroxisomal proliferator-activated receptor gamma (PPARgamma) in IGF-IR(-/-) brown adipocytes could overcome FAS mRNA impairment, bypassing insulin signaling. However, insulin further increased FAS mRNA expression in C/EBPalpha-IGF-IR(-/-) cells, but not in PPARgamma-IGF-IR(-/-) cells. In addition, fetal brown adipocytes lacking IGF-IR up-regulated uncoupling protein-1 expression in the absence of insulin when PPARgamma, but not C/EBPalpha, was overexpressed. These data provide strong evidence for a critical role of IGF-IR in the differentiation of the brown adipocyte phenotype in fetal life; this effect is mimicked by PPARgamma in an insulin-independent manner.     

Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Modeling Chagas Disease at Population Level to Explain Venezuela's Real Data

Objectives

In this paper we present an age-structured epidemiological model for Chagas disease. This model includes the interactions between human and vector populations that transmit Chagas disease.

Methods

The human population is divided into age groups since the proportion of infected individuals in this population changes with age as shown by real prevalence data. Moreover, the age-structured model allows more accurate information regarding the prevalence, which can help to design more specific control programs. We apply this proposed model to data from the country of Venezuela for two periods, 1961–1971, and 1961–1991 taking into account real demographic data for these periods.

Results

Numerical computer simulations are presented to show the suitability of the age-structured model to explain the real data regarding prevalence of Chagas disease in each of the age groups. In addition, a numerical simulation varying the death rate of the vector is done to illustrate prevention and control strategies against Chagas disease.

Conclusion

The proposed model can be used to determine the effect of control strategies in different age groups.     

Syncope in Patients With Severe Aortic Stenosis: More Than Just an Obstruction Issue

BackgroundSevere aortic stenosis (AoS) is considered a primary cause of syncope. However, other mechanisms may be present in these patients and accurate diagnosis can have important clinical implications. The aim of this study is to assess the different etiologies of syncope in patients with severe AoS and the impact on prognosis of attaining a certain or highly probable diagnosis for the syncope.MethodsOut of a cohort of 331 patients with AoS and syncope, 61 had severe AoS and were included in the study. Main cause of syncope and adverse cardiac events were assessed.ResultsIn 40 patients (65.6%), we reached a certain or highly probable diagnosis of the main cause of the syncope. AoS was considered the primary cause of the syncope in only 7 patients (17.5% of the patients with known etiology). Atrioventricular block (14 patients, 35.0%) and vasovagal syncope (6 patients, 15.0%) were the most frequently diagnosed causes. The presence of a known cause for syncope during the admission was not associated with a lower incidence of recurrence during follow-up (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.20-2.40). Syncope of unknown etiology was independently associated with greater mortality during 1-year follow-up (HR 5.4, 95% CI 1.3-21.6) and 3-year follow-up (HR 3.5, 95% CI 1.2-10.3).ConclusionsIn a high proportion of patients with severe AoS admitted for syncope, the valvulopathy was not the main cause of the syncope. Syncope in two-thirds of this population was caused by either bradyarrhythmia or reflex causes. Syncope of unknown cause was associated with increased short- and medium-term mortality, independently from treatment of the valve disease. An exhaustive work-up should be conducted to determine the main cause for syncope.