Neighborhood location, rurality, geography, and outcomes of peritoneal dialysis patients in the United States

♦ Background: The adjusted 5-year survival for dialysis patients in the United States is 33%–35%, and patients treated with peritoneal dialysis (PD) have a high risk of transfer to hemodialysis (HD). No data are available on the effect of neighborhood characteristics or regional differences on the outcomes of PD patients in the United States.♦ Methods: We analyzed the relationships of selected patient demographics, socio-economic characteristics of the dialysis unit’s neighborhood, “rurality,” and geographic location with transfer to HD and with a composite outcome of transfer to HD or death, for all PD patients in the United States who, between 2004 and 2009, used supplies manufactured by Baxter Healthcare (n = 58 700).♦ Results: Over a median follow-up of 18.7 months, 29% of patients transferred to HD (median time to HD transfer: 49 months), and 54% reached the composite outcome. More than 20% of the events occurred within the first 90 days of PD start. The risk for each of the study outcomes was higher for patients who had received any previous treatment with HD, for those treated in units located in areas with a higher proportion of black residents, and for those living in remote rural areas. Furthermore, the risk for reaching either of the study outcomes was consistently lower for patients treated in units located in California, Alaska, Hawaii, Guam, the Mariana Islands, and American Samoa.♦ Conclusions: We observed significant regional differences in the outcomes of PD patients in the United States that have not previously been reported. Understanding the differences in clinical practice that underlie these regional differences might help to further improve PD outcomes.     

Improving immunogenicity of HIV-1 envelope gp120 by glycan removal and immune complex formation

HIV-1 envelope (Env) gp120 is an important target for neutralizing antibody (Ab) responses against the virus; however, developing gp120 vaccines that elicit potent and broad neutralizing Abs has proven to be a formidable challenge. Previously, removal of an N-linked glycan at residue 448 by an N to Q mutation (N448Q) has been found to enhance the in vitro antigenicity of neutralizing epitopes in the V3 loop. In this study the mutated gp120 was first compared with wild type gp120 for immunogenicity in mice using a DNA prime and protein boost immunization regimen. The N448Q mutant did not elicit higher titers of anti-gp120 serum Abs and failed to generate anti-V3 Abs. The sera also had no virus-neutralizing activity, even though the mutant induced higher levels of lymphoproliferation and cytokine production. Subsequently, the N448Q mutant was used to construct an immune complex vaccine with the anti-CD4 binding site monoclonal antibody (mAb) 654. The N448Q/654 complex stimulated comparably high levels of serum Abs to gp120 and V3 as the wild type complex. However, Abs against the C1 and C2 regions in the gp120 core were more elevated. Importantly, the mutant complex also elicited higher titers of neutralizing Abs activity than the wild type counterpart. Similar results were achieved with a complex made with gp120 bearing an N448E mutation, confirming the importance of the N448-linked glycan in modulating gp120 immunogenicity. Neutralizing activity was directed to V3 and other undefined neutralizing epitopes. Improved immunogenicity of the immune complexes correlated with alterations in exposure of V3 and other Ab epitopes and their stability against proteases. These data demonstrate the advantage of combining site-specific N-glycan removal and immune complex formation as a novel vaccine strategy to improve immunogenicity of targeted Ab epitopes on critical regions of HIV-1 gp120.     

Correction to: Development of a conceptual model and patient-reported outcome measures for assessing symptoms and functioning in patients with heart failure

Quality of Life Research - The article Development of a conceptual model and patient-reported outcome measures for assessing symptoms and functioning in patients with heart failure.     

Radionuclide scintigraphy in Caroli's disease

Congenital cystic dilatation of the intrahepatic bile ducts involving the major intrahepatic radicles was first described by Caroli and hence named as Caroli's disease. We present here a case in which the only symptom was intermittent pain in the abdomen for last one-and-a-half-year and a radionuclide scan done effectively, not only diagnosed the disease but also the associated cholangitis.     

Cardiovascular implications of chronic kidney disease in older adults

Because serum creatinine is an imprecise indicator of glomerular filtration rate (GFR), estimating equations derived from the Modification of Diet in Renal Diseases study are increasingly being used to estimate GFR. The notion that GFR declines with aging is based largely on the results of cross-sectional studies that have generally not differentiated the effects of senescence from those of co-existing conditions such as hypertension. Nevertheless, GFR probably declines in many, if not all, aging individuals. The introduction of automated reporting of estimated GFR may result in an over-diagnosis of chronic kidney disease (CKD). There is a large body of evidence to suggest that a decrease in GFR and/or albuminuria is associated with an increased risk of death, particularly from cardiovascular causes, and that this risk extends to the elderly. Although the data are not consistent with regard to the level of GFR at which the increase in cardiovascular risk becomes apparent, small amounts of urine albumin excretion (levels that do not meet the definition of microalbuminuria) are associated with a higher risk of death, even among the elderly. There is currently no evidence that aggressive control of blood pressure and/or use of medications that reduce proteinuria, such as those that block the renin-angiotensin-aldosterone system, reduce the risk of cardiovascular events or death among individuals with CKD. On the other hand, secondary analyses of at least two studies have documented the benefit of lipid lowering in CKD patients. Paradoxically, a recent study has raised concern that normalizing haemoglobin may enhance the cardiovascular risk associated with CKD. To conclude, the available evidence indicates that early identification of CKD may allow physicians to aggressively modify cardiovascular risk, which, in turn, has the potential to improve patient outcomes.     

Autonomic Denervation Dermatitis: A Relatively Undocumented ‘ADD’itional Complication of Total Knee Replacements and Other Surgeries Around the Knee

BackgroundInfrapatellar branch of the saphenous nerve lies subcutaneously and supplies the anterolateral aspect of knee below the patella. It is extremely susceptible to iatrogenic injuries during the surgeries around the knee, mainly total knee replacements (TKRs). Post operatively the patients present with localised area of numbness and in some instances a traumatic eczematous reaction termed autonomous denervation dermatitis (ADD) is witnessed, leading to skin manifestations that range from a simple rash to extensive lesions.MethodologyA review of literature was conducted with search of relevant articles from Medline (PubMed), Embase, and Scopus which discussed eczematous skin lesions secondary to total knee replacements. Additionally, we noted studies which described these lesions in other surgeries around the knee like arthroscopies and fracture fixations.ResultsEight studies including atleast one case after TKR were reviewed. There was only one cohort study while the remaining included case reports and small case series. There were 69 cases of ADD appearing after TKR. The appearance of the skin lesions was lateral to the incision in 30/34 operated knees and on both sides of the incision in four knees after TKRs. Bilateral lesions were seen in only six patients of TKRs. There was no functional limitation caused by these lesions and they resolved either spontaneously or after using topical steroids.ConclusionADD is a relatively uncommonly reported complication of TKRs, which can reduce patient satisfaction and increase surgeon apprehension. Although all cases of nerve damage do not manifest as cutaneous lesions, steps to minimise the damage to the nerve intra operatively should be taken. The diagnosis requires a high index of suspicion, and should not be dispelled as a simple allergic reaction without adequate investigations. Patients should be counselled to alleviate unnecessary fear and apprehensions.     

Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (−)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (−)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(R)-PQ may have a better safety margin than the racemate in human.     

Tumor necrosis factor-α -308 polymorphism in North Indian rheumatoid arthritis patients and association with mRNA and serum TNF-α

Rheumatoid arthritis (RA) is a severely disabling chronic autoimmune disorder that leads to progressive inflammation of the joints and surrounding tissues. TNF-α, a potent proinflammatory cytokine, plays a pivotal role in the pathogenesis of RA. The endogenous formation of TNF-α may be influenced by TNF-α promoter polymorphisms. Hence, the present study was designed to explore any possible association between genetic polymorphism of TNF-α -308 G/A, messenger RNA (mRNA) expression, serum levels of TNF-α, and inflammatory markers in North Indian RA patients. A total of 214 controls and 187 RA patients were recruited according to the revised American College of Rheumatology 2010 criteria. TNF-α -308 G/A genetic polymorphism within promoter region was analyzed by using PCR-RFLP. Levels of inflammatory markers and serum TNF-α were estimated by ELISA. The mRNA expression of TNF-α gene was measured by quantitative real-time PCR. Higher levels of autoantibodies (RF and anti-CCP) were present in RA patients as compared to controls. We found a positive and significant correlation of circulating TNF-α levels with RF (r = 0.18), anti-CCP (r = 0.16), and mRNA expression of TNF-α gene (r = 0.57) in RA patients. The mRNA expression levels of TNF-α was 4.5-fold higher in patients with RA as compared to controls. The heterozygous mutant variants (G/A) and homozygous mutant variants (A/A) were found to be significantly associated with RA as compared to control (OR = 1.52 and 3.02, respectively). Our observations illustrated a significant association of allele -308 A TNF-α with progression of RA. Significant and positive correlation of TNF-α levels with mRNA expression and inflammatory marker levels suggests that serum TNF-α may be a susceptibility marker for RA.     

Pharmacological screening for anti-inflammatory, analgesic activity of pyrazolyl derivatives along with molecular docking studies

The pyrazole derivatives were synthesized and pharmacologically evaluated for analgesic (tail flick) and anti-inflammatory (based on carrageenan-induced paw edema) activities. Compound 4k showed high potency as an anti-inflammatory agent after 3 and 4-h time intervals (P?<?0.001) equipotent to indomethacin. They were devoid of ulcerogenic potential when administered at a dose of 30?mg/kg. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde content (MDA), which is one of the byproduct of lipid peroxidation. Further docking studies of titled compounds was done to understand key interactions responsible for observed inhibition of COX enzyme. The most active compound 4k was found to have ?11.192?kcal/mol, as the free energy of binding. Various other key interactions between the synthesized molecules and active site of COX-2 enzyme, responsible for the obtained pharmacological results were also reported. Most of the active compounds were docked well into the active sites of the receptor.     

Mid-term outcomes of patients undergoing adjustable pulmonary artery banding

ObjectiveThe adjustable pulmonary artery band (APAB) has been demonstrated by us earlier to be superior to the conventional pulmonary artery banding (CPAB), in terms of reduced early morbidity and mortality. In this study, we assessed the adequacy of the band and its complications over the mid-term.MethodsBetween 2002 and 2012, 73 patients underwent adjustable PAB, and their operative and follow-up data were collected and analyzed.ResultsThere was one early death following the APAB. Follow-up data were available for 57 patients of which 44 patients (61.7%) underwent definitive repair, 10 were awaiting definitive repair, and 3 patients were kept on medical follow-up because of inadequate fall in pulmonary artery (PA) pressures. 14 patients (19%) were lost to follow-up. Major PA distortion or stenosis was absent in the majority. 1 patient had pseudoaneurysm of the main pulmonary artery (MPA) with sternal sinus infection and required surgical reconstruction. 1 patient had infective endocarditis of the pulmonary valve managed medically. Band migration was not encountered. There were two deaths after definitive repair and one after APAB.ConclusionsPatients undergoing APAB fulfilled the desired objectives of the pulmonary artery banding (PAB) with minimum PA complications in the mid-term. This added to the early postoperative benefits, makes the APAB an attractive alternative to the CPAB.