Efficacy and safety of total lymphoid irradiation in different chronic lung allograft dysfunction phenotypes

Total lymphoid irradiation (TLI) is an alternative treatment for chronic lung allograft dysfunction (CLAD). However, data regarding its efficacy and tolerance are scarce. This study included patients with CLAD treated with TLI at our center between 2011 and 2018. Clinical characteristics before and after TLI and related complications were analyzed. Forty patients with CLAD (twenty-nine bronchiolitis obliterans syndrome [BOS], nine restrictive allograft syndrome [RAS], and two mixed) were included. Significant attenuation of the forced expiratory volume in 1-sec (FEV₁) decline slope was observed in all phenotypes, in both the BOS and RAS. The median FEV₁ 12, 6, and 3 months pre-TLI were as follows: 1980 (IQR 1720-2560), 1665 (IQR 1300-2340) and 1300 (IQR 1040-1740) ml (p < .001), while the median FEV₁ at 3, 6, and 12 months post-TLI was 1110 (IQR 810–1440), 1130 (IQR 860–1470), and 1115 (IQR 865–1490) ml (p = .769). No dropouts due to radiation toxicity were observed. The mean survival according to the Karnofsky Performance Status Scale (KPS) >70 or ≤70 at baseline was 1837 (IQR 259–2522) versus 298 (IQR 128–554) days (p < .0001), respectively. In conclusion, TLI may stop FEV₁ decline in both BOS and RAS. Moreover, a good KPS score may be an important prognostic factor.     

Expression of membrane-bound mucins (MUC1 and MUC4) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in mucoepidermoid carcinomas of salivary glands

Mucins are glycoproteins normally synthesized by a variety of secretory epithelial cells. The aim of this study was to investigate the expression of mucins (MUC1, MUC2, MUC4, MUC5AC, MUCB, MUC6, MUC7) in mucoepidermoid carcinomas, the most frequent malignant tumor of salivary glands. Forty mucoepidermoid carcinomas and twenty-two normal salivary glands were studied for these mucins by immunohistochemistry from formalin-fixed and paraffin-embedded material. Normal salivary glands frequently expressed MUC1 and MUC4, mainly in ductal cells; MUC5B and MUC7 stained mucous and serous acini respectively of submandibular and minor salivary glands; and MUC5AC and MUC2 were poorly detected in excretory ducts. All mucoepidermoid carcinomas expressed MUC1, and 38/40 tumors expressed MUC4. Both membrane-bound mucins stained membranes and cytoplasm of all cell types (epidermoid, intermediate, mucous, clear and columnar). MUC5AC and MUC5B stained glandular differentiated cells in most tumors (29/40 and 33/40 cases, respectively). MUC6 was positive in 13/40 tumors, and both MUC2 and MUC7 in only 2/40 tumors. The high expression of MUC1 was related to high histologic grades, high recurrence and metastasis rates and a shorter disease-free interval (P < 0.05). Conversely, MUC4 high expression was mainly related to low-grade tumors, lower recurrence rates and a longer disease-free interval (P < 0.05). In conclusion, mucoepidermoid carcinomas of salivary glands usually express MUC1, MUC4, MUC5AC and MUC5B; less frequently MUC6; and rarely MUC2 and MUC7. This mucin expression pattern can be useful for diagnostic purposes. Therefore, MUC1 expression is related to tumor progression and worse prognosis, whereas MUC4 expression is related to a better prognosis.     

Economic Cost of Treating the Patient With Asthma in Spain: The AsmaCost Study

ObjectiveThis analysis of the cost of asthma in Spain includes both direct health care costs and indirect costs arising from illness.Patients and MethodsProspective, 12-month observational cohort study of adult patients with asthma diagnosed according to the guidelines of the Global Initiative for Asthma (GINA) and the adapted Spanish criteria (GEMA). We recorded information on health care resources utilized (medications, medical visits, emergency care, hospital admissions, and tests) and indirect costs (patient travel or transfer costs and workdays lost).ResultsA total of 627 patients throughout Spain were studied. Of these, 21.2% had intermittent asthma, 24.6% mild asthma, 27.6% moderate asthma, and 26.6% severe asthma. The total societal cost of asthma (including indirect costs) was €1726 (95% confidence interval [CI], €1314-€2154) per patient annually. Indirect costs accounted for 11.2% of the total. The cost to the National Health Service was €1533 (95% CI, €1133-€1946) per patient annually. The cost of asthma was higher for patients older than 65 years (€2079) and for those with more severe disease (€959 for intermittent asthma; €1598, mild asthma; €1553, moderate asthma; and €2635 severe asthma). Based on these findings, the total annual cost of asthma in Spain is estimated to be €1480 million (95% CI, €382-€2565 million) for patients with demonstrated bronchial hyperreactivity and €3022 million (95% CI, €2472-€3535 million) for patients diagnosed based on symptoms alone.ConclusionsThe average annual cost of asthma in adults in Spain comes to €1726 per patient, considering both direct and indirect costs from a societal perspective. The average annual cost per patient to the National Health Service is €1533.     

Sleep disorders and quality of life in renal transplant recipients

Kidney transplantation provides the best outcome for patients with end-stage renal failure both in terms of morbidity and mortality and health-related quality of life (QoL). Health-related QoL has become recognized as an important outcome measure in patients with different chronic medical conditions, including chronic kidney disease (CKD). There are several factors in kidney-transplanted patients which have a negative impact on QoL in these patients. Sleep disorders, such as insomnia, sleep apnea syndrome (SAS), and restless legs syndrome (RLS), are common in kidney-transplanted patients and clearly belong to this group of factors, although there is only limited published data available about the association between sleep problems and QoL in this patient population. The prevalence of both insomnia and RLS is reduced in kidney-transplanted patients compared to dialysis patients, and it is similar to the prevalence observed in the general population. The prevalence of sleep apnea, however, is very high, around 30%. The association between the presence of these sleep disorders and impaired QoL has been relatively well documented in dialysis patients, but there is only scarce published information about this association in the kidney transplant population. In this paper, we will summarize data from the literature describing the impact of sleep problems, which are potentially treatable, on QoL in kidney-transplanted patients. We suggest that the appropriate diagnosis and management of sleep disorders may improve QoL in kidney-transplanted patients.     

Comparison of the Cozart DDS 801 on-site drug test device and gas chromatography/mass spectrometry (GC/MS) confirmation results of cannabis and cocaine in oral fluid specimens

Driving under the influence of drugs (DUID) is a problem around the world. The objective of this study is to assess the reliability of the oral fluid screening device the Cozart DDS 801 by comparing the on-site results with confirmatory gas chromatography/mass spectrometry (GC/MS) oral fluid analysis. The study was carried out in Catalonia (Spain) with a sample of 2180 oral fluid specimens taken from subjects suspected of driving under the influence of drugs of abuse, and collected by police officers during 2009–2010. Statistical parameters of the tests were determined for cannabis and cocaine. The sensitivity, specificity, predictive positive value, predictive negative value, likelihood positive ratio and likelihood negative ratio for cocaine were 92%, 90%, 95%, 85%, 9.44, and 0.09 respectively. Sensitivity, specificity, predictive positive value, predictive negative value, likelihood positive ratio and likelihood negative ratio for cannabis were 87%, 86%, 94%, 73%, 6.15 and 0.6 respectively. Accuracy was 91% for cocaine and 86% for cannabis. The Cozart DDS 801 drug test system is a simple to use screening tool for cocaine and cannabis in oral fluid, at initial screening cut-off established by the manufacturer, confirmed with a GC/MS analysis. The system has demonstrated its acceptable performance.     

Rapid progression of midventricular obstruction in adults with double-chambered right ventricle

OBJECTIVE: The purpose of this study was to determine the rate of progression of midventricular obstruction in adolescents and adults with double-chambered right ventricle. METHODS: Clinical and echocardiographic findings in 45 patients (mean age 26 +/- 6 years, range 15-44) diagnosed with double-chambered right ventricle were retrospectively analyzed. Twenty patients underwent surgical repair before the age of 15 years. The relationship between Doppler midventricular pressure gradient and patient age was analyzed in 25 patients without previous repair. Sequential change in midventricular obstruction was determined for patients with 2 or more Doppler echocardiographic examinations performed within at least a 2-year interval. RESULTS: Right midventricular pressure gradient in nonrepaired patients was 70 +/- 38 mm Hg (range 25-150). A significant relationship between midventricular obstruction and patient age (r = 0.64, P <.001) was found. Midventricular pressure gradient at initial evaluation was 32 +/- 27 mm Hg in 16 patients < 25 years and 73 +/- 45 mm Hg in 9 patients >/= 25 years (P <.03). After the initial study, 5 patients underwent surgical repair and 13 patients without repair were followed up for a period of 6.1 +/- 2.7 years (range 2-9), in which midventricular pressure gradient increased from 32 +/- 26 mm Hg to 67 +/- 35 mm Hg (P <.001). The slope of the change in midventricular pressure gradient was 6.2 +/- 3 mm Hg per year of follow-up. Seven more patients underwent surgical repair during follow-up due to progression of the obstruction. There was no mortality nor residual midventricular obstruction in surgically repaired patients. CONCLUSIONS: Mild right midventricular obstruction shows a fast rate of progression in adolescents and young adults. Thus, close clinical and echocardiographic follow-up is advised, and surgical repair should be considered if significant progression of obstruction is detected.     

Combining lisinopril and l-arginine slows disease progression and reduces endothelin-1 in passive Heymann nephritis

BACKGROUND: Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease. METHODS: Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control. RESULTS: Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy. CONCLUSION: Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.     

Angiotensin II increases parathyroid hormone-related protein (PTHrP) and the type 1 PTH/PTHrP receptor in the kidney

Angiotensin II (AngII) participates in the pathogenesis of kidney damage. Parathyroid hormone (PTH)-related protein (PTHrP), a vasodilator and mitogenic agent, is upregulated during renal injury. The aim of this study was to investigate the potential relation between AngII and PTHrP system in the kidney. Different methods were used to find that both rat mesangial and mouse tubuloepithelial cells express PTHrP and the type 1 PTH/PTHrP receptor (PTH1R). In these cells, AngII increased PTHrP mRNA and protein production. In contrast, PTH1R mRNA was increased in mesangial cells and downregulated in tubular cells, but its protein levels were unmodified in both cells. AT(1) antagonist, but not AT(2), abolished AngII effects on PTHrP/PTH1R. The in vivo effect of AngII was further investigated by systemic infusion (a low dose of 50 ng/kg per min) into normal rats. In controls, PTHrP immunostaining was mainly detected in renal tubules. In AngII-infused rats, PTHrP staining increased in renal tubules and appeared in the glomerulus and the renal vessels. After AngII infusion, PTHR1 staining was markedly increased in all these renal structures at day 3 but remained elevated only in tubules at day 7. The AT(1) antagonist, but not the AT(2), significantly diminished AngII-induced PTHrP and PTHR1 overexpression in the renal tissue, associated with a decrease in tubular damage and fibrosis. The results indicate that AngII regulates renal PTHrP/PTH1R system via AT(1) receptors. These findings demonstrate that PTHrP upregulation occurs in association with the mechanisms of AngII-induced kidney injury.     

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.