Impact of switching to raltegravir and/or adding losartan in lymphoid tissue fibrosis and inflammation in people living with HIV. A randomized clinical trial.

BACKGROUND: Persistent inflammation and immune activation are associated with lymph node fibrosis and end-organ diseases in treatment-suppressed people living with HIV (PLWH). We investigated the effect of switching to raltegravir and/or adding losartan on lymphoid tissue fibrosis and on the inflammatory/immune-activation mediators in treated HIV patients. METHODS: Chronic HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors (2NRTI) and one non-NRTI (NNRTI) or protease inhibitor (PI) during at least 48 weeks were randomized to four groups (n = 48): 2NRTI + efavirenz (EFV), 2NRTI + EFV + losartan, 2NRTI + raltegravir and 2NRTI + raltegravir + losartan for 48 weeks. Tonsillar biopsy and peripheral blood markers of CD4 and CD8 T-lymphocyte activation and senescence, monocyte activation and soluble markers of inflammation were determined at baseline and at week 48 and compared between groups. RESULTS: No changes in lymphoid tissue architecture were observed. Adding losartan had no impact on lymphocyte subsets. Conversely, patients who switched to raltegravir showed a higher decrease in all activated [CD4+CD38+HLA-DR+, -0.3 vs. 0.48 (P = 0.033); CD8+CD38+ HLA-DR+, -1.6 vs. 1.3 (P = 0.02)] and senescent [CD4+CD28-CD57+, -0.3 vs. 0.26 (P = 0.04); CD8+CD28-CD57+, -6.1 vs. 3.8 (P = 0.002)] T lymphocytes. In addition, the median CD4/CD8 ratio increased by 0.35 in patients in the raltegravir group vs. 0.03 in the other arms (P = 0.002). Differences between groups in monocyte subpopulations or soluble inflammation markers were not observed. CONCLUSIONS: Losartan had no effect on lymphoid fibrosis or immune activation/inflammation. Conversely, switching to a regimen with raltegravir significantly decreased activated and senescent T-lymphocyte subpopulations and increased CD4/CD8 ratio in successfully treated PLWH.

Evolution of retinal changes measured by optical coherence tomography in the assessment of hydroxychloroquine ocular safety in patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this report is to analyse retinal changes over a five-year period, assessed by spectral domain-optical coherence tomography (SD-OCT), in patients from the Lupus-Cruces cohort treated with hydroxychloroquine (HCQ). METHODS: SD-OCT screening was performed annually between 2012 and 2017. Average macular thickness (AMT), ganglion cell layer thickness (GCLT) and qualitative data of retinal pigment epithelium (RPE) and external retina (ExtR) were collected prospectively. We compared data from 2012 (first) and 2017 (second) SD-OCT. RESULTS: We studied 110 patients and 195 eyes. No cases of HCQ toxicity were detected. At the time of the second SD-OCT, 99% patients had taken a daily dose of HCQ ≤5 mg/kg/day. The median time on HCQ was 133 months. The mean AMT and GCLT were significantly lower in both eyes at the second SD-OCT; however, all the differences were clinically insignificant at less than 1%. Qualitative analysis of RPE and ExtR showed no significant changes. Similar results were found among patients with risk factors for retinopathy. The comparison of patients with and without risk factors showed no differences. CONCLUSIONS: This study shows clinically irrelevant retinal changes in an SLE cohort on HCQ treatment over a five-year follow-up. Our findings support the safety of long-term HCQ at doses ≤5 mg/kg/day.

Factors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (APS) in the APS Alliance for Clinical Trials and International Networking Clinical Database and Repository: a retrospective study.

OBJECTIVE: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. DESIGN: Retrospective study. SETTING: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. POPULATION: Women with Ob-APS. METHODS: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). MAIN OUTCOME MEASURES: Risk factors for thrombosis and aGAPSS. RESULTS: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]. CONCLUSION: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. TWEETABLE ABSTRACT: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.

Follicular Development and Secretion of Ovarian Hormones during the Juvenile and Adult Reproductive Lives of the Myelin Mutant taiep Rat: An Animal Model of Demyelinating Diseases.

Infertility and reproductive problems have been reported in women with several neurological disorders, for example, demyelination. However, the physiology of such problems has remained unknown so far. The taiep rats are an animal neurological model that initially shows a hypomyelination followed by a progressive demyelination of the central nervous system. This animal has reproductive problems, and the aim of this work is to characterize the follicular development, secretion of ovarian hormones, and presence of noradrenaline in the ovaries of the female taiep rats in the juvenile and adult stages. The taiep rats have low body weight (approximately 19% less than that of SD rats), a delay of 4 days in the age of vaginal opening, and an irregularity in the estrous cycle by the absence or prolongation of some estral cycle stage. In the juvenile stage, we observed a decrease of approximately 44% in the total number of follicles with a 15% increase of atresia and an 80% decrease in the fluorescence intensity of catecholamines in the ovaries, with a 21% increment in plasma concentrations of testosterone. In the adult stage, we observed follicular cysts and a 50% decrease in fluorescence intensity of catecholamines in the ovaries, with changes in the secretion of ovarian hormones, an increase of 20 times in progesterone, and a decrement of a half in estradiol. The demyelination in taiep rats affects follicular development and steroidogenesis in the early stages of the animal's life, and this is maintained until adulthood.

Combined mepacrine-hydroxychloroquine treatment in patients with systemic lupus erythematosus and refractory cutaneous and articular activity.

Aim The aim of this study was to evaluate the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with systemic lupus erythematosus and refractory joint and/or skin disease. Methods Mepacrine was added to 46 systemic lupus erythematosus patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs ( n = 24), hydroxychloroquine + prednisone ( n = 16), hydroxychloroquine + prednisone + retinoids ( n = 2), hydroxychloroquine alone ( n = 1), hydroxychloroquine + one immunosuppressive drug ( n = 1), hydroxychloroquine + prednisone + one immunosuppressive drug + belimumab ( n = 1) or hydroxychloroquine + prednisone + belimumab ( n = 1). The outcome variable was the clinical response, either complete or partial, based on clinical judgement. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score were additionally used. Results A total of 91% patients showed complete/partial response, with similar rates among those with joint or skin disease. In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen. There also was a statistically significant decrease in the SLEDAI. The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/d ( p = 0.001). Prednisone could be discontinued in 20% of patients. No serious adverse events were seen. Smoking was the only predictor of complete response. Conclusion In the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses. The fact that smokers responded better opens the door to further studying the combination of mepacrine-hydroxychloroquine as a first-line therapy in such patients.

SLE: the changing prognosis.

Throughout the 20th century, a remarkable improvement in the prognosis of systemic lupus erythematosus (SLE) has been seen, mostly due to a better understanding of the disease and the advent of new therapies. However, a plateau seems to have been reached. Whilst outcomes related to active disease have greatly improved, damage accrual tends to be slowly increasing especially damage secondary to high-dose glucocorticoids, which could lead not only to increased morbidity but also to a worse long-term prognosis. Cardiovascular disease and infections still account for the majority of deaths yet both could potentially be improved, again, by the use of high-dose glucocorticoids. In addition, antimalarials have also demonstrated many beneficial effects on patients with lupus. Thus, the universal use of hydroxychloroquine, a more rational prescription of glucocorticoids and preventive strategies for cardiovascular disease can be used as measures with major impacts on the future prognosis of patients with SLE.

Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.

BACKGROUND: Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer's disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs. RESULTS: The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period. CONCLUSIONS: The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.

Central administration of oxytocin differentially increases yawning, penile erections and scratching in high- (HY) and low-yawning (LY) sublines of Sprague-Dawley rats.

Central administration of oxytocin has been shown to induce yawning, penile erection, grooming and scratching. Yawning and penile erections are due to activation of oxytocinergic neurons in the paraventricular nucleus of the hypothalamus. We selectively bred two sublines from Sprague-Dawley rats, one with a high-yawning frequency (HY) of 20yawns/h, and one with a low-yawning (LY) frequency of 2yawns/h. The aim of the current study was to analyze the behavioral effects of centrally-administered oxytocin [15ng-10µg; intracerebroventricularly (i.c.v.)] on yawning, penile erections, grooming and scratching in adult male rats from both sublines. Oxytocin produced a dose-dependent increase in yawning and penile erection frequencies and this effect was significantly higher in the HY, compared to the LY, subline. However, the number of oxytocin-induced scratching bouts was significantly higher in the LY, compared to the HY group. In conclusion, these sublines represent a suitable model for detailed analysis of behavior induced by oxytocin and other neuropeptides in animals with different spontaneous expression of behavioral traits.

Severe multiorganic flare of systemic lupus erythematosus successfully treated with rituximab and cyclophosphamide avoiding high doses of prednisone.

Both acute pancreatitis and diffuse alveolar haemorrhage are rare conditions associated with systemic lupus erythematosus (SLE). In this case report, a 23-year-old female with SLE was diagnosed with lupus-associated pancreatitis and, within a few days and despite initial therapy with pulse methyl-prednisolone, subsequently suffered an acute respiratory failure due to a diffuse alveolar haemorrhage. The patient was admitted to the intensive care unit and treatment was intensified with cyclophosphamide and rituximab, which shortly induced the complete remission of SLE with resolution of both clinical conditions. She completed treatment with six pulses of cyclophosphamide followed by azathioprine, hydroxychloroquine and prednisone at initial doses of 20 mg/d with rapid tapering to 5 mg/d, without relapse of the disease during the following year. This case can illustrate that, even in severe, life-threatening SLE flares, it is possible to avoid high-dose prednisone, which has been associated with severe side effects, including infections. Acute pancreatitis and diffuse alveolar haemorrhage are rare conditions caused by SLE. DAH can be a life-threatening complication, with an early mortality of at least 50%. When facing such severe SLE activity, there is a general tendency to use high doses of prednisone as the initial therapy, maintaining such high doses for long periods of time, even after the clinical situation has subsided. We report a case of a young woman with SLE, suffering from acute pancreatitis and diffuse alveolar haemorrhage, who was successfully treated with pulse methyl-prednisolone, hydroxychloroquine, cyclophosphamide and rituximab, combined with medium doses of prednisone.

One-year psychosocial functioning in patients in the early vs. late stage of bipolar disorder.

OBJECTIVE: The aim of this 1-year follow-up study was to compare functional outcome as well as clinical differences between patients with first- and multiple-episode bipolar disorder. METHOD: Bipolar disorder patients with first (n = 60) and multiple episodes (n = 59) were recruited from two hospitals in Spain. The Functioning Assessment Short Test (FAST) was used to assess functioning. The Hamilton Depression Rating Scale (HAMD) and the Young Mania Rating Scale (YMRS) were administered to assess mood symptoms. RESULTS: As expected, patients with first episode experienced a greater functioning compared to patients with multiple episodes (11.26 ± 10.94 vs. 26.91 ± 13.96; t = 6.436, P < 0.001). There were significant demographic and clinical differences between both groups. Baseline depressive symptoms (F = 9.553, df = 4, 102; P < 0.001) and age (F = 14.145, df = 4, 103; P < 0.001) were significantly associated with poor functional recovery at 6-month and 12-month assessment, respectively, in a group of patients with multiple episodes. CONCLUSION: Our data give support to the model of staging in bipolar disorder, showing that the enduring neurotoxicity of repeated episodes may contribute to sustained impairment in multiple areas of psychosocial functioning.

[Management of pregnancy in patients with systemic lupus erythematosus]. / Manejo del embarazo en pacientes con lupus eritematoso sistémico.

Patients with systemic lupus erythematosus are exposed to a remarkably high number of maternal-fetal complications during pregnancy. Knowledge regarding the reciprocal influence between lupus and pregnancy is the starting point to assure that these patients are correctly monitored. It is also important to carry out comprehensive preconception evaluation to individually evaluate the risk of each patient. The immunological profile, history of nephritis, presence of chronic damage and disease activity are the basic data that will determine the specific individual risk profile. Finally, correct drug management must be assured during this period, based on the safety profile of the different treatments during pregnancy and lactation.

Antimalarials may influence the risk of malignancy in systemic lupus erythematosus.

BACKGROUND: Recent studies suggest that antimalarials have antineoplastic properties. OBJECTIVE: To investigate whether antimalarials decrease the risk of cancer in systemic lupus erythematosus (SLE). METHODS: An observational prospective cohort study was carried out. 235 patients were included in the study at the time of diagnosis (American College of Rheumatology criteria). The end point was the diagnosis of cancer. Kaplan-Meier cancer-free survival curves for patients treated and not treated with antimalarials were compared. A Cox proportional hazards model was fitted, with cancer as the dependent variable. Age at diagnosis, gender, treatment with azathioprine, cyclophosphamide and methotrexate, smoking, Systemic Lupus International Collaborating Clinics (SLICC) Damage Index 6 months after diagnosis, year of diagnosis and treatment with antimalarials were entered as independent variables. RESULTS: 209 (89%) patients were women. 233 (99%) patients were white. Mean (SD) age at diagnosis was 37 (16) years. Median (range) follow-up was 10 (1-31) years. 156 (66%) patients had ever received antimalarials. 2/156 (1.3%) ever-treated patients compared with 11/79 (13%) never-treated patients had cancer (p<0.001). Cumulative cancer-free survival in treated and not treated patients was 0.98 and 0.73, respectively (p<0.001). Adjusted hazard ratio for cancer among malaria drug users compared with non-users was 0.15 (95% CI 0.02 to 0.99). CONCLUSIONS: This study launches the hypothesis of a protective action of antimalarials against cancer in patients with SLE. This effect should be confirmed in larger multicentre studies.

[Mediastinoscopy in the diagnosis of mediastinal disease. An analysis of 181 explorations]. / La mediastinoscopia para el diagnóstico de la enfermedad mediastínica: análisis de 181 exploraciones.

To validate our experience with standard cervical mediastinoscopy (SCM) and extended cervical mediastinoscopy (ECM) to diagnose mediastinal nodes and masses, we studied 181 patients between January 1992 and February 2001. SCM and ECM were indicated for diagnostic staging of nodes related to bronchogenic carcinoma (Group I) or of mediastinal masses (Group II). An SCM was performed in all cases to explore the paratracheal region (2R, 2L, 4R, 4L, 7, 10R and 10L); in 21 additional cases, an ECM was performed to explore the aortopulmonary window or the subaortic region (area 5) and the para-aortic region (area 6). In Group I, the sensitivity of SCM was 93.6% and specificity was 100%; the positive predictive value (PPV) was 100%, the negative predictive value (NPV) was 82.8%, and the diagnostic yield was 95.1%. The sensitivity of ECM was 91% and specificity was 100%; PPV was 100%, NPV 93.3% and yield was 96%. In Group II, the sensitivity was 93.3%, specificity 100%, PPV 100%, NPV 81.2% and diagnostic yield 94.8%. The sensitivity of ECM in this group was 80%, specificity was 100%, PPV 100%, NPV 66.7% and yield 85.7%. A 2.7% complication rate was observed, with one case of bleeding after injury to the superior vena cava, one tracheal lesion, one recurring paralysis and two cases of surgical wound infection. The mean postoperative stay was 36 hours and mortality was zero. We conclude that SCM is highly specific for the evaluation of mediastinal node involvement in bronchogenic carcinoma and it is the approach of choice when a diagnosis of lesions located in the mid-mediastinal region has not been reached. ECM is a valid, safe alternative to anterior mediastinotomy for staging nodes and masses occupying para-aortic zones or the aortopulmonary window, with good diagnostic yield, low morbidity and absence of mortality.

[Mediastinal dumbbell angiolipoma]. / Angiolipoma mediastínico en reloj de arena.

Dumbbell tumors are extremely rare. Most are neurogenic in origin. Growth is both inside and outside the spinal canal, and symptoms debut with medullary or spinal compression. References to non-neurogenic dumbbell tumors are uncommon. This report describes the case of a 56 year-old woman with a dumbbell angiolipoma having mediastinal and spinal cord portions. The tumor was successfully resected using a two-stage procedure. First, the spinal portion was resected using a posterior neurosurgical approach, with improvement of symptoms. Then, the mediastinal portion was removed thoracoscopically.

[Transient Brown-Séquard syndrome due to spontaneous spinal epidural hematoma]. / Síndrome de Brown-Séquard transitorio por hematoma epidural espinal espontáneo.

Spinal epidural hematoma (SEH) is a low incidence injury. When the cause of bleeding is unknown, which occurs in 50% of the cases, we refer to it as spontaneous SEH. The clinical presentation is characterized by acute radicular pain followed by cord compression syndrome. Brown-Séquard syndrome is exceptional as a result of a SEH. Although standard treatment is prompt surgical evacuation of the hematoma, spontaneous resolution has also been reported. We present a case of spontaneous SEH in a 69 year-old man. An MRI revealed an hematoma in the right posterior epidural space extending from C6 to T2. The hematoma was manifested as a paresis of the right limbs and sensory loss of the left side below C7 level. During the first hours the neurological deficit was improved without treatment and consequently a conservative management was continued. After 72 h, the patient was completely recovered. We have reviewed the 14 cases of spinal epidural hematoma and Brown- Séquard syndrome previously reported, only 2 of them were resolved by conservative management. We conclude that when SEH presents as Brown-Séquard syndrome it usually has a more benign course and that in some cases a conservative management can be considered.

[Minimally invasive video thoracoscopic correction of pectus excavatum]. / Corrección videotoracoscópica mínimamente invasiva del pectus excavatum.

Pectus excavatum, the most common congenital deformity of the chest wall, has esthetic, psychological and social repercussions as well as a slight impact on pulmonary function. Treatment is surgical and is carried out for esthetic purposes in most cases. The most commonly applied surgical technique is based on the one originally described by Ravitch: sub-perichondrial, bilateral chondrectomy and sternal osteotomy. In 1997, however. Nuss described a minimally invasive approach to correction by means of a support bar. Our objective was to perform minimally invasive correction of pectus excavatum using a substernal extrapleural approach guided by video-assisted thoracoscopy. We treated three patients over 15 years of age without surgical complications. In all three cases, the minimally invasive technique corrected the pectus excavatum with excellent esthetic results. Both the path of insertion and duration were shorter with the described approach than with traditional surgery. Video images facilitated extrapleural insertion of the bar and minimized complications.

[The Will-Rogers phenomenon. Stage migration in bronchogenic carcinoma after applying certainty criteria]. / El fenómeno Will-Rogers. Migración de estadios en carcinoma broncogénico, tras aplicar criterios de certeza clasificatoria.

OBJECTIVE: To quantify changes in tumor-node-metastasis (TNM) staging (numerical migration) and survival (prognostic migration) that arise when certainty criteria are applied to a patient population with non-small cell lung cancer (NSCLC) treated surgically. METHODS: The population consisted of 1,844 patients with NSCLC who underwent surgery between 1993 and 1996 at hospitals participating in the Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S). For every patient, surgical-pathological TNM staging (p) was based on two classifications: initial staging by each participating GCCB-S center (pTNM-i) and a second classification bearing greater classificatory certainty (pTNM-cc) resulting from the application of stricter criteria. Numerical migration was said to have occurred in cases where the two classifications did not coincide, and the possible prognostic migration under the new staging was then assessed. RESULTS: The results revealed great numerical migration in the pN0 classification (from 1,091 cases to 665). The changes did not result in prognostic migration either for the group as a whole or for pT1-2N0M0 cases. However, for pT3N0M0 cases, median survival increased by 13 months. The difference in three-year survival (S3) for pT3N0M0-i without certainty confirmation [S3 = 0.30 (95%CI 0.18-0.42), n=59] and pT3N0M0-cc [S3=0.54 (95%CI = 0.44-0.64), n = 92] was significant (log-rank, p = 0.035). Such behavior was not observed for pT1-2N0M0. CONCLUSIONS: The numerical migration observed as a result of applying surgical-pathological classificatory certainty criteria is relevant but the prognostic repercussion is scarce, except in cases classified as pT3N0M0, in which a significant positive prognostic migration is observed (the "Will Rogers phenomenon").