Increased number of circulating endothelial cells and plasma markers of endothelial damage in chronic cocaine users

Background

Cocaine use has been related with the development of accelerated atherosclerosis and with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood, although thrombus formation and altered vascular function are prominent findings.

Objectives

Our aim was to evaluate markers of endothelial dysfunction in chronic cocaine consumers before and after drug withdrawal.

Patients/Methods

We determined circulating endothelial cells (CECs) and plasma levels of stromal cell-derived factor-1 (SDF-1), monocyte chemotactic protein-1(MCP-1), soluble intracellular adhesion molecule (sICAM), high-sensitivity C reactive protein (hsCRP) and endothelin-1(ET-1), in DSM-IV cocaine addicts at baseline and after one month of cocaine abstinence.

Results

Cocaine users showed a strikingly higher numbers of CEC (62.35 ± 18.4 vs 8.25 ± 13.8 CEC/mL) and significantly elevated plasma levels for all the markers evaluated as compared to the control group. After cocaine withdrawal, patients improved SDF-1, ET-1, hsCRP and sICAM levels. However, CEC number and MCP-1 plasma levels remained significantly elevated. All the results were adjusted for blood levels of cholesterol and triglycerides and for smoking habit.

Conclusions

Our results demonstrated that chronic cocaine consumption alters several functions of the endothelium towards a pro-thrombotic condition and that some of those functions remain abnormal even after short-term drug withdrawal. These observations support the notion that endothelial dysfunction may play a key role in the pathogenesis of ischemic vascular disease observed in cocaine abusers.     

Bacterial growth kinetics in ACD‐A apheresis platelets: comparison of plasma and PAS III storage

BACKGROUND: Our objective was to determine the growth kinetics of bacteria in leukoreduced apheresis platelets (LR‐AP) in a platelet (PLT) additive solution (PAS; InterSol, Fenwal, Inc.) compared to LR‐AP stored in plasma. STUDY DESIGN AND METHODS: Hyperconcentrated, double‐dose LR‐AP were collected from healthy donors with a separator (AMICUS, Fenwal, Inc.). LR‐AP were evenly divided, InterSol was added to half (65% InterSol:35% plasma [PAS]), and PLTs in autologous plasma were used for a paired control (PL). Bacteria were inoculated into each LR‐AP PAS/PL pair (0.5‐1.6 colony‐forming units [CFUs]/mL), and bacterial growth was followed for up to 7 days. Time to the end of the lag phase, doubling times, maximum concentration (conc‐max), and time to maximum concentration (time‐max) were estimated. RESULTS: Streptococcus viridans did not grow to detectable levels in either PAS or PL units. The other bacteria had no significant overall difference in the conc‐max (p = 0.47) or time‐max (p = 0.7) between PL and PAS LR‐AP; PL had a 0.14 hours faster doubling rate (p = 0.023); and PAS had a 4.7 hours shorter lag time (p = 0.016). CONCLUSION: We observed that five index organisms will grow in LR‐AP stored in a 35%:65% ratio of plasma to InterSol where initial bacterial concentrations are 0.5 to 1.6 CFUs/mL. The more rapid initiation of log‐phase growth for bacteria within a PAS storage environment resulted in a bacterial concentration up to 4 logs higher in the PAS units compared to the plasma units at 24 hours, but with no difference in the conc‐max. This may present an early bacterial detection advantage for PAS‐stored PLTs.     

A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes: a randomized, controlled trial

OBJECTIVE

Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55% IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs.

RESEARCH DESIGN AND METHODS

In this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m²) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0–6.0 mmol/L.

RESULTS

After 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24 mmol/L) than IGlar (1.63 mmol/L), whereas mean FPG was similar (IDegAsp: 6.8 mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events).

CONCLUSIONS

In this proof-of-concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control.Although currently available basal insulin analogs have advantages over NPH insulin, they fail to completely mimic the physiological basal insulin secretion profile; at higher doses in particular, their profile is not completely flat, but shows a gentle rise and fall (1). Furthermore, lower doses do not achieve 24-h insulin coverage in all individuals (2), and there remains some within-subject variability in the metabolic effect impeding optimal insulin titration. These limitations, together with a lack in postprandial insulin coverage, may partly explain why a large proportion of patients with type 2 diabetes fail to reach and maintain recommended A1C targets (3–5) considered to minimize the risk for microvascular complications (6–8).To provide more optimal basal insulin coverage, insulin degludec (IDeg), a new-generation ultra-long-acting basal insulin, was developed. Primarily as a result of the formation of soluble multihexamers at the injection site, IDeg has a smooth and stable pharmacokinetic profile at steady state (9) that gives rise to a considerably longer action profile than current basal insulin formulations (10) as well as lower within-subject variability (11).IDeg can be coformulated with insulin aspart (IAsp) (12) resulting, for the first time, in a soluble preparation comprising two different insulin analogs (IDegAsp: 70% v/v IDeg as basal insulin and 30% v/v IAsp as prandial insulin). By providing both basal and rapid-acting insulin analogs in one injection, IDegAsp could be an attractive alternative to the common strategy of initiating insulin therapy with basal insulin only on top of oral antidiabetic drugs (OADs). Indeed, for many patients, simultaneously targeting fasting and postmeal plasma glucose could be a more suitable approach to achieving and sustaining optimal glycemic control (13).In this exploratory, clinical proof-of-concept trial, we compared the safety and efficacy of IDegAsp with insulin glargine (IGlar), both given once-daily in combination with metformin in insulin-naïve subjects with type 2 diabetes inadequately controlled on OAD therapy. To establish the optimal ratio of IDeg to IAsp, an alternative formulation of IDegAsp (AF) containing a higher percentage of IAsp (45%) was also evaluated.     

Inferior mesenteric artery aneurysm in the setting of chronic colonic vascular ectasia

Colonic vascular ectasia is a condition characterized by dilated submucosal veins, venules, or capillaries found commonly in patients with lower gastrointestinal hemorrhage. We present a case of colorectal ectasia associated with ischemia and an inferior mesenteric artery aneurysm. These pathologic findings may be the result of the vascular ectasia and may add to the natural history of this condition.     

Improving graft survival for patients undergoing liver transplantation

Dickson RC, Pungpapong S, Keaveny AP, Taner BC, Ghabril M, Aranda‐Michel J, Satyanarayana R, Bonatti H, Kramer DJ, Nguyen JH. Improving graft survival for patients undergoing liver transplantation.
Clin Transplant 2011: 25: E345–E355. © 2011 John Wiley & Sons A/S. Abstract: Liver transplant (LT) outcomes are reported to be improving in non‐HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non‐HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998–2002) and Era 2 (2003–2005) with follow‐up through May 31, 2009. Graft survival was compared for HCV, non‐HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non‐HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three‐yr graft survival 58.6 (51.3–65.9) vs. 75.4 (68.9–81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non‐HCV patients up to three yr. The change in management of donor organs into HCV and non‐HCV patients likely contributed to this outcome.     

Does a longer delay in fixation of talus fractures cause osteonecrosis?

This retrospective study investigated active duty soldiers with delayed definitive fixation of combat-related talus fractures. The authors predicted a longer delay to internal fixation and a correlation between the timing of fixation and development of osteonecrosis and posttraumatic arthritis. The Joint Theater Trauma Registry was queried by ICD-9 codes for talus fractures. Soldiers, ages 18 to 40, with talus fracture between 2001 and 2008 were included. Radiographs identified the injury type, Hawkins sign, osteonecrosis, and posttraumatic arthritis. Mean time to fixation was 12.9 days. Hawkins sign was observed in 59% of fractures at a mean of 7 weeks. No correlation was found between osteonecrosis or posttraumatic arthritis and open fractures, comminuted fractures, or timing of fixation. Average follow-up was 16 months. This case series has the longest mean time to fixation by more than threefold. There was no correlation of delayed timing of fixation and development of osteonecrosis or posttraumatic arthritis.