Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype.

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment.

BACKGROUND: Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. METHODS: This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. DISCUSSION: NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.

High prevalence of gallstone disease in rheumatoid arthritis: A new comorbidity related to dyslipidemia?

OBJECTIVE: To assess the prevalence of gallstone disease and identify associated risk factors in rheumatoid arthritis (RA) patients compared to the general population. METHODS: Eighty-four women with rheumatoid arthritis were included in the study. Each patient was assessed via a structured interview, physical examination, abdominal ultrasound and blood test including lipid profile. The prevalence of gallstone disease in rheumatoid arthritis was compared with data from a study of the Spanish population matched by age groups. RESULTS: Twenty-eight of the 84 women had gallstone disease (33.3%). RA women with and without gallstone disease were similar in most of the variables assessed, except for older age and menopausal status in the former. A greater prevalence of gallstone disease was seen in rheumatoid arthritis patients compared to the general population of the same age; however, the differences were significant only in women aged 60 or older (45.5% versus 23.1% respectively, P-value .008). The age-adjusted OR of developing gallstone disease in RA women compared with general population women was 2,3 (95% CI: 1.3-4.1). A significantly higher HDL3-c subfraction and higher apoA-I/HDL and HDL3-c/TC ratios were observed in patients with gallstone disease. CONCLUSION: Women with rheumatoid arthritis may have a predisposition to gallstones that can manifest in middle or older age compared with women in the general population. This situation could be related to chronic inflammation and HDL metabolism.

Clinical relevance of histologic subtypes in locally advanced esophageal carcinoma treated with pre-operative chemoradiotherapy: Experience of a monographic oncologic centre.

BACKGROUND: Locally advanced esophageal carcinoma (LAEC) represents less than 30% of all diagnosed esophageal carcinoma worldwide. The standard of care for resectable tumours consists of preoperative chemoradiotherapy (CRT) followed by surgery. Despite the curative intent, the prognosis is still poor mainly due to relapse. A multidisciplinary approach is required in order to optimize the therapeutic strategy and follow-up. Differences in outcomes between the two main histological subtypes, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), have been reported. Nevertheless, the heterogeneity in trials design and data available have hampered the achievement of clear conclusions. The purpose of this study is to report the outcomes from a cohort of patients with LAEC treated with a multidisciplinary approach and to remark the differences observed between the two main histologic subtypes and their clinical implications. METHODS: We retrospectively reviewed 100 patients diagnosed with LAEC that were treated with preoperative CRT at our institution and integrated centres. Histopathological characteristics and toxicities during treatment were recorded. Patterns of recurrence at the first relapse were analysed. Survival curves were plotted using the Kaplan Meier method and multivariate Cox proportional hazards models were used. RESULTS: Among the patients who received preoperative CRT, 83% underwent surgery. The median overall survival (mOS) was 31.7 months, 26.9 months for ADC and 45.5 for SCC (p-value = 0.33). In the multivariate Cox regression analysis, ypN+ was the only factor that negatively influenced in OS (OR = 4.1, p-value = 0.022). Patterns of recurrence differed according to histologic subtype. Distant relapse was more frequent in ADC (62%), whereas locoregional relapse was higher in SCC (50%) (p-value = 0.027). Second line therapeutic strategies could be offered to 50% of those patients who relapsed. CONCLUSIONS: Differences in outcomes and recurrence pattern could be observed between the two main histologic subtypes of LAEC. A better molecular characterization, adapted therapeutic regimens and follow up strategies should be adopted in order to improve survival of these patients.

Subaxial cervical spine involvement in symptomatic rheumatoid arthritis patients: Comparison with cervical spondylosis.

OBJECTIVE: To investigate the frequency, location, characteristics, and clinical significance of subaxial involvement (below C1-C2) in a series of patients with rheumatoid arthritis (RA) and symptomatic involvement of the cervical spine. METHODS: A total of 41 patients with RA were examined via cervical spine magnetic resonance imaging (MRI). A comparative analysis of the incidence of the different types of subaxial lesions was performed between these patients and 41 age- and sex-matched patients with symptomatic cervical spondylosis. RESULTS: Stenosis of the spinal canal was found at the subaxial level in 85% of RA patients, and at the atlantoaxial level in 44%. Comparative analysis between these patients and the cervical spondylosis patients revealed significant differences in the types and frequencies of subaxial lesions. For both conditions, signs of discopathy and end-plate osteophytosis were the most common abnormalities observed on magnetic resonance imaging (MRI). However, in the RA patients these abnormalities coincided with subchondral bone and ligamentous acute inflammatory changes and with secondary destruction (vertebral instability) or repair (vertebral ankyloses). Only evidence of subaxial myelopathy was significantly associated with an increased risk of neurological dysfunction among the RA patients [Ranawat class II or III; P = 0.01; odds ratio (OR) = 11.43], although subaxial cord compression tended toward a significant association with the risk of neurological dysfunction (P = 0.06; OR = 3.95). CONCLUSION: Subaxial stenosis seems to be the consequence of both the inflammatory process and mechanical-degenerative changes. Despite its frequency, it was not usually related to the occurrence of myelopathy symptoms, not even in cases with MRI evidence of spinal cord compression.

[Efficacy and budget impact of the Focus harmonic scalpel compared to the ACS-14C device in total thyroidectomy due to multinodular goitre. A prospective randomised study]. / Eficacia e impacto económico del bisturí armónico Focus frente al dispositivo ACS-14C en la tiroidectomía total por bocio multinodular. Estudio prospectivo aleatorizado.

OBJECTIVE: To analyse the potential advantages and outcomes of the new Harmonic Focus™ (Focus) device compared to the Harmonic Scalpel™ ACS-14C in benign thyroid surgery. METHODS: A controlled randomised study was conducted in which the Focus was compared to former ACS-14C device in patients undergoing total thyroidectomy for multinodular goitre. The primary endpoint was time of surgery. The secondary endpoints were time of use of the device, number of ligatures, blood loss, hypocalcaemia, laryngeal nerve impairment, postoperative pain and quality of life. RESULTS: Two groups of patients were included, 26 patients in group i (ACS-14C) and 28 in group ii (Focus). There was a 16% reduction in surgical time (78.7 ± 22.01 vs. 66 ± 17.0 min; P<.05) between group i and ii respectively. The Focus was used longer than ACE-14S, both in absolute time (26.0 ± 7.7 vs. 10.0 ± 3.5 minutes; P<.05), as well as in relative time (40.7 ± 11.8% vs. 13.1 ± 4.1%; P<.05), respectively. A significant reduction in number of ligatures in Focus patients was also observed (0,3 ± 0,8 vs. 2.9 ± 3.6; P<.05). Budget impact analysis showed an additional average savings per procedure of 179.74 €. CONCLUSIONS: Focus ergonomics significantly improved the operation time in thyroidectomy causing a positive impact on the budget. Focus also adds further benefits to those previously achieved by Harmonic technology, and it is by itself more cost-effective in total thyroidectomy than ACS-14C.

MR imaging of early rheumatoid arthritis.

Early diagnosis and treatment have been recognized as essential for improving clinical outcomes in patients with early rheumatoid arthritis. However, diagnosis is somewhat difficult in the early stages of the disease because the diagnostic criteria were developed from data obtained in patients with established rheumatoid arthritis and therefore are not readily applicable. Magnetic resonance (MR) imaging is increasingly being used in the assessment of rheumatoid arthritis due to its capacity to help identify the key pathologic features of this disease entity at presentation. MR imaging has demonstrated greater sensitivity for the detection of synovitis and erosions than either clinical examination or conventional radiography and can help establish an early diagnosis of rheumatoid arthritis. It also allows the detection of bone marrow edema, which is thought to be a precursor for the development of erosions in early rheumatoid arthritis as well as a marker of active inflammation. In addition, MR imaging can help differentiate rheumatoid arthritis from some clinical subsets of peripheral spondyloarthropathies by allowing identification of inflammation at the insertions of ligaments and tendons (enthesitis).

Bone marrow edema in the cervical spine of symptomatic rheumatoid arthritis patients.

OBJECTIVE: To investigate the frequency and clinical significance of bone marrow edema (BME) in a series of patients with rheumatoid arthritis (RA) and symptomatic involvement of the cervical spine. METHODS: We studied 19 consecutive RA patients with cervical spine magnetic resonance imaging (MRI) according to a specifically designed protocol that included short inversion time inversion recovery sequences. All cases had neck pain unresponsive to conventional treatment, neurological symptoms, or signs suggestive of cervical myelopathy, or cervical pain with evidence of atlantoaxial subluxation on radiographs. RESULTS: The mean age of the 19 patients (15 women and 4 men) at time of the study was 59 +/- 12 years (range, 23-82) and the median disease duration was 14 +/- 7.4 years (range, 4-30). BME was observed in 74% (14/19) of the patients: at the atlantoaxial level alone in 16% of the patients; subaxially alone in 16%; and at both levels in 42% of the patients. At the atlantoaxial level, BME was usually observed involving the odontoid process, whereas subaxially BME was limited to the vertebral plates and the interapophyseal joints. Patients with BME had higher erythrocyte sedimentation rate (ESR) values at the time of MRI examination (P = 0.014) and more severe atlantoaxial joint MRI synovitis scores (P = 0.05) compared with the remaining patients; the frequency of odontoid erosions was also greater in this group, but the difference did not reach statistical significance. Altogether, these data suggest a more severe inflammatory response in these patients. In this group a significant correlation was found between BME scores at atlantoaxial level and (1) ESR values (r = 0.854; P = 0.001) and (2) atlantoaxial joint MRI synovitis scores (r = 0.691; P = 0.001). CONCLUSION: BME is frequently observed in patients with established RA and symptomatic cervical spine involvement. Both atlantoaxial and subaxial levels are equally affected. The presence of BME seems related to the intensity of the inflammatory response and to the severity of the atlantoaxial joint synovitis.

Spontaneous pyogenic facet joint infection.

OBJECTIVE: To analyze the clinical features, approaches to management, and outcome of spontaneous pyogenic facet joint infection (PFJI) in adults. PATIENTS AND METHODS: Case series of 10 adults with microbiologically proven PFJI diagnosed during a 10-year period in a teaching hospital, plus a review of 32 additional cases previously reported (PubMed 1972 to 2003). Patients with prior spinal instrumentation or surgery and injection drug users were excluded. Only cases that were sufficiently detailed to be individually analyzed were included. These 32 cases, together with our 10 patients, form the basis of the present analysis. RESULTS: PFJI represented nearly 20% of all spontaneous pyogenic spinal infection diagnosed in our hospital during a 10-year period. This data suggest that PFJI is more common than was previously thought. Of the 42 patients with PFJI, 26 (62%) were men and 16 (38%) were women, with ages ranging from 20 to 86 years (mean age, 59+/-15 years); 55% of patients were older than 60 years. The most common location of infections was the lumbosacral region (86%). All patients presented with severe back pain; fever was noted in 83% of the cases and neurological impairment in nearly 48%. In 38% of patients a systemic predisposing factor for infection was present; the most common conditions were diabetes mellitus, malignancies, and alcoholism. In almost 36% of cases, one or more concomitant infectious processes due to the same microorganism was found, mainly arthritis, skin and soft-tissue infections, endocarditis, and urinary tract infections. Staphylococcus aureus was the most common etiologic microorganism (86% of cases). Bacteremia was documented in 81% of the cases. The diagnosis of PFJI was based mainly on imaging study findings. Paraspinal and/or epidural extension was frequent (81% of cases), but its presence did not indicate a worse prognosis. Medical treatment alone was usually successful. The overall prognosis of PFJI was good, with a mortality rate of only 2%. The great majority of patients were cured without functional sequelae. CONCLUSION: Incidence data from our institution reveal that PFJI is not a rare condition, representing approximately 20% of all pyogenic spinal infections. This entity should be considered in the differential diagnosis of patients with low back pain, especially in the presence of fever, whatever the patient's immunological status.