Primary Thrombosis Prophylaxis in Antiphospholipid Antibody–Positive Patients: Where Do We Stand?

Persistently positive antiphospholipid antibodies (aPLs) with thrombosis and/or pregnancy morbidity are the hallmark of the antiphospholipid syndrome. However, aPL-positive patients with no prior history of thrombosis exist. On the basis of a limited number of studies that predominantly included systemic lupus erythematosus patients, aPL-positive patients without previous thrombosis have a 0% to 3.8% annual incident thrombosis risk. Given that every positive aPL test is not clinically significant and every aPL-positive patient does not have the same thrombosis risk, risk stratification (based on aPL profile, age, systemic autoimmune diseases, and traditional cardiovascular disease or venous thrombosis risk factors) is crucial to determine the first thrombosis risk in aPL-positive patients. The optimal primary thrombosis prevention strategy in patients with clinically significant aPL profiles should include 1) regular monitoring and elimination of non-aPL thrombosis risk factors, 2) aggressive management of clinical and subclinical systemic autoimmune disease activity, and 3) patient counseling and education. The protective effect of low-dose aspirin against incident thrombosis in patients with clinically significant aPL profiles is not supported by randomized controlled data; general population cardiovascular disease risk prediction tools and prevention guidelines formulated based on risk–benefit calculations should play a role in the decision whether to recommend low-dose aspirin. The effectiveness of hydroxychloroquine, statins, or their combination remains to be determined by well-designed randomized controlled trials.     

Targeting Parkinson's - tyrosine hydroxylase and oxidative stress as points of interventions

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons leading to decrease in striatal dopamine (DA) levels. In the present review, our focus was on recent advances in the treatment procedures of PD to achieve an increase in deficient tyrosine hydroxylase (TH) activity and/or expression. Stimulation of residual TH activity by the cofactors, 6R-L-erythro-tetrahydrobiopterin (BPH4) or NADH, or by brain transplant of natural TH-containing cells (fetal substantia nigra) or genetically engineered TH-containing cells, has been tried experimentally and clinically lately. As a promising approach to the gene therapy, intrastriatal expression of DAsynthesizing enzymes through transduction with separate adeno-associated virus (AAV) vectors/ marrow stromal cells (MSCs) or nonviral intravenous administration of rat transferrin receptor monoclonal antibody (TfRmAb)-targeted PEGylated immunoliposomes (PILs) has been found to be effective in animal models. Oxidative stress has been identified as one of the intermediary risk factors that could initiate and/or promote degeneration of DA neurons. TH itself is a prime target of oxidative/nitrosative injury. Certain superoxide dismutase and catalase mimetic prevented nitration of TH in cultured dopaminergic neurons. Therefore, development of therapeutic agents that can prevent formation of or specifically remove nitrating agents without interfering with normal neuronal function may protect protein from inactivation and provide means of limiting neuronal injury in PD. Non-pharmacological approaches such as diet therapy or use of active constituents of plants and phytomedicines have also emerged as a new - area of high interest. New treatment strategies for TH dysfunction rectification, a provision for neuroprotection in PD, seem to be on the horizon with many therapies under investigation.     

A brief overview of tyrosine hydroxylase and α-synuclein in the Parkinsonian brain

Parkinson's disease (PD) is associated with neurodegeneration of the nigrostriatal tract and is accompanied with loss of tyrosine hydroxylase (TH) and dopamine (DA). Development of neuroprotective strategies targeting PD is often undermined by lack of proper understanding of processes contributing to the pathology. In this mini review we have tried to briefly outline the involvement of TH and α-synuclein in PD. Aberrant expression of α-synuclein is toxic to dopaminergic neurons. It interacts with ubiquitin-proteasomal processing system, implicated in oxidative injury and mitochondrial dysfunction which ultimately induce neurodegenration and cell death. The contributions of DJ-1 in TH regulation have also been discussed. Brain specific TH expression with the combined use of the pegylated immunoliposome (PILs) gene transfer technology and brain specific promoters as a new approach to treat PD has also been included.     

Accuracy of Dexcom G6 Continuous Glucose Monitoring in Non–Critically Ill Hospitalized Patients With Diabetes

OBJECTIVEAdvances in continuous glucose monitoring (CGM) have transformed ambulatory diabetes management. Until recently, inpatient use of CGM has remained investigational, with limited data on its accuracy in the hospital setting.RESEARCH DESIGN AND METHODSTo analyze the accuracy of Dexcom G6, we compared retrospective matched-pair CGM and capillary point-of-care (POC) glucose data from three inpatient CGM studies (two interventional and one observational) in general medicine and surgery patients with diabetes treated with insulin. Analysis of accuracy metrics included mean absolute relative difference (MARD), median absolute relative difference (ARD), and proportion of CGM values within 15, 20, and 30% or 15, 20, and 30 mg/dL of POC reference values for blood glucose >100 mg/dL or ≤100 mg/dL, respectively (% 15/15, % 20/20, % 30/30). Clinical reliability was assessed with Clarke error grid (CEG) analyses.RESULTSA total of 218 patients were included (96% with type 2 diabetes) with a mean age of 60.6 ± 12 years. The overall MARD (n = 4,067 matched glucose pairs) was 12.8%, and median ARD was 10.1% (interquartile range 4.6, 17.6]. The proportions of readings meeting % 15/15, % 20/20, and % 30/30 criteria were 68.7, 81.7, and 93.8%, respectively. CEG analysis showed 98.7% of all values in zones A and B. MARD and median ARD were higher in the case of hypoglycemia (<70 mg/dL) and severe anemia (hemoglobin <7 g/dL).CONCLUSIONSOur results indicate that CGM technology is a reliable tool for hospital use and may help improve glucose monitoring in non–critically ill hospitalized patients with diabetes.