Association of total antioxidants level with glaucoma type and severity

Objectives:

To compare the mean total antioxidant status (TAS) among 3 glaucoma types, namely: pseudoexfoliation glaucoma (PEG), primary open angle glaucoma (POAG), and primary angle closure glaucoma (PACG), and study its potential association with various clinical glaucoma-parameters.

Methods:

In this case-control study, plasma samples were obtained between September 2013 and October 2014 from 340 glaucoma patients (PEG [n=54]; POAG [n=147]; PACG [n=139]), and 351 controls of matching age, gender, ethnicity, and 5 different systemic co-morbidities from King Abdulaziz University Hospital, Riyadh, Saudi Arabia. The TAS in all samples was determined by a colorimetric-based assay.

Results:

The mean±standard deviation of TAS was significantly lower among cases: 0.77±0.32 than controls: 1.1±0.22, p<0.0001. Moreover, the TAS levels were significantly different across the 3 types of glaucoma: 0.86±0.24 in PEG, 0.47±0.32 in POAG, and 0.98±0.41 in PACG (all p<0.0001). In addition, there was a significant correlation between TAS and age at onset (Pearson correlation coefficient [R] 0.17, p<0.0001), cup/disc ratio (R: -0.13, p=0.004), and number of anti-glaucoma medications (R: -0.16, p=0.001).

Conclusion:

Our findings provide evidence that plasma TAS levels are decreased in patients with glaucoma, more so in POAG and PEG than PACG, supporting the hypothesis that decreased antioxidative defense and/or increased oxidative stress may have a critical role in the pathogenesis of glaucoma.Glaucoma is a progressive optic neuropathy associated with optic nerve damage, and is one of the most leading cause of blindness worldwide.1 Elevated intraocular pressure (IOP) as a result of reduction in normal aqueous outflow is a major causal risk factor that is well supported by animal studies.2-4 Although IOP is considered a major risk factor for glaucoma,2,3 other concomitant factors affecting the pathophysiology of glaucomatous retinal ganglion cell (RGC) death include retinal ischemia,5 nutritional status,6 and oxidative stress.7 There is evidence of oxidative damage in ocular diseases, such as cataract and age-related macular degeneration.8 In addition, significant oxidative damage has been demonstrated in human trabecular meshwork (TM) cells of patients with glaucoma,7 causing elevated IOP and visual field damage.9 Furthermore, our previous studies have documented mitochondrial abnormalities10-12 (oxidative stress marker), and glutathione-S-transferase (antioxidant) gene (GST) polymorphisms to be associated with various types of glaucoma.13 It is clearly evident from the literature, and our own studies, that oxidative stress mechanisms play a critical role in the pathogenesis of glaucoma. Previous studies had demonstrated reduced total antioxidant capacity in aqueous humor and blood samples from patients with glaucoma.14-17 To evaluate the role of oxidative stress in different types of glaucoma we had previously investigated total antioxidants status (TAS) in the plasma of pseudoexfoliation glaucoma (PEG) patients,18 primary angle closure glaucoma (PACG) patients,19 and in the plasma of primary open angle glaucoma (POAG) patients.20 As an extension to these studies, here, we compare the mean TAS level among these 3 glaucoma types, and study the potential association between the TAS level and various clinical parameters important to each type of glaucoma.18-20     

Shared clinical decision making: A Saudi Arabian perspective

Objectives:

To determine preferences of patients regarding their involvement in the clinical decision making process and the related factors in Saudi Arabia.

Methods:

This cross-sectional study was conducted in a major family practice center in King Abdulaziz Medical City, Riyadh, Saudi Arabia, between March and May 2012. Multivariate multinomial regression models were fitted to identify factors associated with patients preferences.

Results:

The study included 236 participants. The most preferred decision-making style was shared decision-making (57%), followed by paternalistic (28%), and informed consumerism (14%). The preference for shared clinical decision making was significantly higher among male patients and those with higher level of education, whereas paternalism was significantly higher among older patients and those with chronic health conditions, and consumerism was significantly higher in younger age groups. In multivariate multinomial regression analysis, compared with the shared group, the consumerism group were more likely to be female [adjusted odds ratio (AOR) =2.87, 95% confidence interval [CI] 1.31-6.27, p=0.008] and non-dyslipidemic (AOR=2.90, 95% CI: 1.03-8.09, p=0.04), and the paternalism group were more likely to be older (AOR=1.03, 95% CI: 1.01-1.05, p=0.04), and female (AOR=2.47, 95% CI: 1.32-4.06, p=0.008).

Conclusion:

Preferences of patients for involvement in the clinical decision-making varied considerably. In our setting, underlying factors that influence these preferences identified in this study should be considered and tailored individually to achieve optimal treatment outcomes.Patients and physicians assume different and varying roles in the medical consultation process. This could determine the extent of involvement of the patient and the physicians in the clinical decision making process and patient care management. In one extreme, the physician assumes the responsibility of the clinical decision with no or very little joint deliberation with the patient. This is known as the “paternalistic” approach.1,2 In the other extreme, the informed medical decision approach means that the clinical decision is made by patients and potential others, including family members, after obtaining all needed medical information that could enable the patient to make on appropriate decision. This is known as the “consumerism” approach to clinical decision-making.3,4 Shared decision making is probably at the center of this spectrum, in which patients and physicians exchange information, discuss the details of the medical problems, explore available treatment options, and conclude together an agreed treatment plan.5 The provision of health care that is consistent with the preferences of patients may improve the patients’ satisfaction and health outcomes.6,7 The practice of shared clinical decision-making was encouraged as it respects patients’ autonomy, values, and commitment to the agreed health plan and continuity of care.8 The relevant literature shows that most patients prefer to be offered information on their medical conditions, available options of treatment, and future plan of care.1,3,9 However, the extent of the involvement of patients in the process of decision making is variable and influenced by issues related to the patients status of their illnesses, and types of decisions under consideration.10,11 Patients of younger age, women, and with higher levels of education have been found to prefer an active role and to share this process. In addition, preferences of patients may change with time and different stages of the sickness.11,12 The complexity of this process is further compounded by the fact that patient views and attitudes towards involvement in medical decision making are influenced significantly by certain underlying cultural aspects. This necessitates a sensitive and individual approach for each patient.13 This study aims to explore preferences of patients from Saudi Arabia regarding their involvement in medical decision making, and to explore factors that may affect these preferences.     

Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia

Parkinson’s disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn–antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

Parkinson’s disease (PD) is characterized by accumulation of α-synuclein (αSyn; encoded by the SNCA gene) (1). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal cell death in part via microglial activation (2, 3). Moreover, misfolded proteins in general are thought to interact with brain microglia, triggering microglial activation that contributes to neurodegenerative disorders, although microglial phagocytosis may also initially clear aberrant proteins to afford some degree of protection (2, 4). Additionally, in Alzheimer’s disease (AD), amyloid-β peptide (Aβ) is thought to trigger similar processes in microglia (5–7); however, the mechanism for this trigger is still poorly understood.Microglial cells contribute to neuroinflammation, specifically that mediated by the inflammasome. In particular, the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome has been associated with several neurodegenerative disorders, although other types of inflammation may also be important in this regard (8). The NLRP3 inflammasome is a multiprotein complex that responds to cell stress and pathogenic stimuli to promote activation of caspase-1, which in turn mediates maturation and release of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18 (9–11). NLRP3 inflammasome activation is a two-step process, involving an initial priming step and a secondary trigger. Priming involves a proinflammatory stimulus, such as endotoxin, a ligand for Toll-like receptor 4 (TLR4), that increases the abundance of NLRP3 and promotes de novo synthesis of pro–IL-1β via nuclear factor κB (11). The secondary trigger promotes inflammasome complex assembly and caspase-1 activation that in turn mediates the cleavage of pro–IL-1β and subsequent release of mature IL-1β. There are various secondary triggers, including adenosine triphosphate (ATP), microparticles, and bacterial toxins, all of which somehow lead to mitochondrial damage and release of oxidized mitochondrial DNA (11). Neuroinflammation has been reported in both human PD and AD brains (12–15), and NLRP3 inflammasome activation in particular has been observed in mouse models of PD and AD (7, 16). Importantly, in these PD models, dopaminergic (DA) neurons in the substantia nigra are resistant to damage in NLRP3-deficient mice compared with wild-type (WT) mice (16). Interestingly, a recent report identified an NLRP3 polymorphism that confers decreased risk in PD (17). Several groups have reported that fibrillar αSyn can activate the NLRP3 inflammasome in mice and in human monocytes (18–22), but it remains unknown if human brain microglia can be activated in this manner. Critically, antibodies targeting misfolded proteins are being tested in human clinical trials for several neurodegenerative diseases, including AD and PD; however, it is still unclear how antibodies to αSyn might affect this inflammatory response. In this study, we characterized the response of human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) to oligomeric/fibrillar αSyn in vitro and in vivo, using engraftment of hiMG in humanized mice. We used these immunocompromised mice because they prevent human cell rejection and express three human genes that support human cell engraftment (23). We show that αSyn and, even more so, αSyn–antibody complexes activate the NLRP3 inflammasome. Moreover, this process is further sensitized by the presence of Aβ and its cognate antibodies. These observations are of heightened interest because recent studies have shown that both misfolded Aβ and αSyn are present in several neurodegenerative disorders such as AD and Lewy body dementia (LBD), a form of dementia that can occur in the setting of PD (24–26).     

Mapping and ablation of ventricular fibrillation—how and for whom?

The involvement of the Purkinje system in a subset of patients with idiopathic ventricular fibrillation or polymorphic VT/VF related to structural heart disease was first demonstrated in the pioneering work of Michel Haissaguerre and co-workers (Circulation 106:962–967, 2002 and Lancet 359:677–678, 2002). It is very important to identify these patients with recurrent episodes of ventricular fibrillation and/or ICD shocks with regard to the presence of triggering premature ventricular contractions (PVC), which may be amenable to mapping and catheter ablation by screening Holter and ICD recordings. The practical problem, which is frequently encountered, is the absence of these PVCs when the patients are brought to the EP lab. However, catheter ablation is an important adjunctive tool to antiarrhythmic drug treatment, beta blocker therapy, and general anesthesia in this setting. Local electrogram criteria related to this phenomenon have been identified guiding mapping and ablation (e.g., low amplitude, high-frequency Purkinje potentials preceding a closely coupled ventricular signal (Fig. 1a)). The favorable long-term follow-up after catheter ablation has been demonstrated in the setting of right and left ventricular Purkinje-related PVCs leading to polymorphic VT/VF (Leenhardt et al., Circulation 89:206–215, 1994) and also following myocardial infarction (Baensch et al., Circulation 108:3011–3016, 2003) and right ventricular outflow tract-associated VF (Noda et al., Journal of the American College of Cardiology 46:1288–1294, 2005). Most recently, epicardial ablation strategies leading to suppression of polymorphic VT/VF episodes related to the Brugada syndrome have been described irrespective to the presence of premature ventricular beats (Nademanee et al., Circulation 123:1270–1279, 2011).     

Isolated Roux loop pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: a prospective randomized study

Objectives

The optimal strategy for the reconstruction of the pancreas following pancreaticoduodenectomy (PD) is still debated. The aim of this study was to compare the outcomes of isolated Roux loop pancreaticojejunostomy (IRPJ) with those of pancreaticogastrostomy (PG) after PD.

Methods

Consecutive patients submitted to PD were randomized to either method of reconstruction. The primary outcome measure was the rate of postoperative pancreatic fistula (POPF). Secondary outcomes included operative time, day to resumption of oral feeding, postoperative morbidity and mortality, and exocrine and endocrine pancreatic functions.

Results

Ninety patients treated by PD were included in the study. The median total operative time was significantly longer in the IRPJ group (320 min versus 300 min; P = 0.047). Postoperative pancreatic fistula developed in nine of 45 patients in the IRPJ group and 10 of 45 patients in the PG group (P = 0.796). Seven IRPJ patients and four PG patients had POPF of type B or C (P = 0.710). Time to resumption of oral feeding was shorter in the IRPJ group (P = 0.03). Steatorrhea at 1 year was reported in nine of 42 IRPJ patients and 18 of 41 PG patients (P = 0.029). Albumin levels at 1 year were 3.6 g/dl in the IRPJ group and 3.3 g/dl in the PG group (P = 0.001).

Conclusions

Isolated Roux loop PJ was not associated with a lower rate of POPF, but was associated with a decrease in the incidence of postoperative steatorrhea. The technique allowed for early oral feeding and the maintenance of oral feeding even if POPF developed.     

Pretransplant serum ferritin level may be a predictive marker for outcomes in patients having undergone allogeneic hematopoietic stem cell transplantation

Iron overload increases the risk of infections, veno-occlusive disease and hepatic dysfunction in post-transplant period. Our objective was to investigate the association of pre-transplant ferritin levels with complications and survival after allogeneic hematopoietic stem cell transplantation (alloHSCT).We retrospectively analysed 84 patients' data who had undergone allogeneic HSCT into two groups: patients with a serum ferritin level ≥ 1000 ng/ml, and patients with <1000 ng/ml at the time of HSCT.Cox-regression analysis showed that pre-transplant serum ferritin levels were significantly higher in patients who had at least one infectious event compared with those who had no any infectious event in the post-transplant 100 days (p<0.023). Overall survival (OS) and disease-free survival (DFS) rates were significantly higher in patients with a time-to-tx interval 12 months (p=0.002 and p=0.008 respectively). A higher risk of death was observed in high-ferritin group (hazard ratio=2.27, CI:1.01-5.09, p=0.023 for OS and hazard ratio=2.49, CI:1.12-5.53 p=0.039 for DFS). No significant effect on OS and DFS among groups was observed for variables conditioning regimen, gender and diagnosis. Acute GVHD was more common in patients with a ferritin level ≥ 1000 ng /mL, but this was not statistically significant (p>0.05). There was no statistical significance in both groups (ferritin ≥ 1000 ng /mL and ferritin <1000 ng/mL) for relapse rates (p>0.05). Platelet and neutrophil engaftment day was not found statistically significant compared with both groups (p=0.273 and p=0.882, respectively). Pre-transplant ferritin levels may predict poor outcomes in patients who had undergone allogeneic hematopoietic stem cell transplantation.     

High risk of transfusion-induced alloimmunization of patients with inflammatory bowel disease

BackgroundAnemia is highly prevalent in inflammatory bowel disease patients, and red blood cell transfusion is often indicated already at reproductive age. Both transfusion and pregnancy may induce red cell alloantibodies, potentially complicating further transfusions and pregnancies. As recent evidence suggests that inflammation may promote red cell antibody induction, the alloimmunization risk of these patients after allogenic erythrocyte exposure was investigated.MethodsRed cell alloantibody status and clinical data were analyzed in 193 inflammatory bowel disease patients with a history of transfusion or pregnancy, and compared with transfused controls with noninflammatory diseases (n = 357).ResultsIn transfused patients with inflammatory bowel disease, a 2.5-fold-increased red cell antibody prevalence was found (10/119, 8.4%), compared with transfused sex-matched controls with noninflammatory diseases (12/357, 3.4%; P = .023). Patients with inflammatory bowel disease had fewer transfusions (mean 3.0 vs 4.2, P = .003) but higher C-reactive protein levels during transfusion than controls (mean 8.4 vs 5.4 mg/dL, P <.001). The red cell antibodies of inflammatory bowel disease patients were clinically significant, directed against different Rh, Kell, Duffy, or Lutheran blood group antigens, and associated with higher number of transfusions (odds ratio 1.57; 95% confidence interval, 1.03-2.39). Conversely, immunomodulatory therapy during transfusion showed negative association (odds ratio 0.12; 95% confidence interval, 0.02-0.61). Only 1.4% of inflammatory bowel disease patients with pregnancy alone had antibodies.ConclusionsPatients with inflammatory bowel disease exhibited a very high risk of transfusion-induced red cell alloimmunization, possibly potentiated by inflammation. Aside from a restrictive transfusion strategy, the implementation of prophylactic blood group phenotype matching of red cell concentrates (not only for ABO and RhD but also RhCcEe, Kell, Kidd, Duffy) could prevent antibody induction and associated complications in these patients.