Citations

Background and Purpose— Development of stroke networks is critical to bringing guideline-driven stroke care to rural, underserved areas. Methods— A Web-based telestroke tool, REACH, was developed to provide a foundation for a rural stroke network that delivered acute stroke consults 24 hours per day 7 days per week to 8 rural community hospitals in Georgia. Results— There were 194 acute stroke consults delivered. Thirty patients were treated with tissue plasminogen activator (tPA). The mean National Institutes of Health Stroke Score (NIHSS) was 15.4, and the median NIHSS was 12.5. The mean onset to treatment time (OTT) was 122 minutes. The OTT dropped from 143 minutes in the first 10 patients treated to 111 minutes in last 20 patients. Of the 30 patients treated with tPA, 23% (7) were treated in ≤90 minutes and 60% (18) were treated within 2 hours. There were no symptomatic intracerebral hemorrhages. Conclusions— The REACH telestroke system permits the rapid and safe use of tPA in rural community hospitals. Over time, the system became more efficient and OTT decreased.

ABSTRACT Vascular endothelial growth factor receptor‐2 (VEGFR‐2, also known as KDR) is a receptor tyrosine kinase (RTK) regulating mitogenic, chemotactic, permeability, and survival signals in vascular endothelial cells (EC) in response to its ligand, vascular permeability factor/VEGF (VPF/VEGF), arguably the most important angiogenic cytokine. However, the compartmentalization of KDR in EC and the mechanisms regulating this process have not been well defined. Here, we demonstrate that KDR is present on the plasma membrane, on endosomes, and in the perinuclear region of EC and colocalizes with early endosomal antigen (EEA1), caveolin‐1, and dynamin‐2, a signal transducing GTPase involved in receptor endocytosis. Furthermore, we also observed that dynamin‐2 coimmunoprecipitates with KDR and is required for EC signaling/survival. Interestingly, EC overexpressing a mutant form of dynamin deficient in GTP binding (K44A) caused a selective inhibition in KDR protein level and endosomal vesicle formation and induced cell cycle arrest by inducing p21. Taken together, our findings suggest that dynamin‐2 regulates KDR expression and function and hence plays an important role in VPF/VEGF mediated angiogenesis.

ABSTRACT Nystatin is an antifungal compound with potent proinflammatory properties. Herein, we demonstrate that nystatin induces interleukin (IL)-1β, IL-8, and tumor necrosis factor alpha secretion through its activation of toll-like receptor 1 (TLR1) and TLR2. Hence, a TLR-dependent mechanism could serve as the molecular basis for the proinflammatory properties of nystatin.

ABSTRACT Due to increasing mupirocin resistance, alternatives for Staphylococcus aureus nasal decolonization are needed. Lauric acid monoesters combined with lactic, mandelic, malic, or benzoic acid are being evaluated as possible alternatives. We determined the in vitro activity of 13 lauric acid monoester (LAM) formulations and mupirocin against 30 methicillin-susceptible S. aureus (MSSA) isolates and 30 methicillin-resistant S. aureus (MRSA) isolates. We then used a murine model of MRSA nasopharyngeal colonization to compare the in vivo activity of mupirocin with three LAM formulations. MSSA and MRSA MIC 90 values were 0.25 μg/ml for mupirocin and ≤4 μl/ml for all LAM formulations tested. Hsd:ICR mice were challenged with 10 8 CFU/naris MRSA. Five days later, S. aureus colonization was documented by culture. Treatment with bland, mupirocin, or one of three LAM ointments was then administered unblinded thrice daily for 2 days. Three days after treatment, both anterior nares were cultured for S. aureus . Administration of 128774-49E or 128774-53A was associated with greater eradication of MRSA carriage (24/34 [71%] or 33/40 [83%]) of animals, respectively) than bland ointment (12/38 [32%]) ( P < 0.005). 128774-53A administration resulted in greater MRSA carriage eradication than mupirocin (19/38 [50%]) ( P < 0.005) in this model. LAM formulations warrant evaluation for S. aureus nasal decolonization in humans.

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

AbstractHigh-dose melphalan followed by stem cell transplantation (HDM-SCT) has become the treatment of choice for patients with immunoglobulin light chain amyloidosis (AL). Unfortunately, treatment mortality can be excessive in certain subpopulations. We have noted that patients who gained more than 2% body weight during mobilization had a poorer outcome following HDM-SCT. Excluding 2 patients for lack of weight record and denial of consent, 126 patients between July 1997 and June 2003 were retrospectively studied. Weight increased more than 2.0% during mobilization in 51.6% of the patients. Patients who accumulated more than 2.0% tended to have more proteinuria, more organs involved, lower serum albumin, more diuretic use, and dosage adjustment during mobilization. First-year mortality was significantly higher in those with more than 2% weight gain (33.9% versus 9.8%, P = .002). Multivariate analysis showed weight gain, glomerular filtration rate, and septal thickness to be independent predictors of first-year mortality. The increase in mortality was noted even after the excess weight was diuresed prior to conditioning. The impact on mortality dissipated after the first year. Weight gain during mobilization appears to be a new marker of adverse outcome following HDM-SCT. Better prognostication may improve the treatment mortality rate of these patients.

ABSTRACT Although electrical coupling along the arteriolar endothelium is central in arteriolar conducted response and in control of vascular resistance, little is known about the pathophysiological effect of hypoxia and reoxygenation (H/R) on this coupling. We examined this effect in a monolayer of cultured microvascular endothelial cells (ECs) derived from wild‐type (WT) or connexin (Cx)40 −/− mice (Cx40 is a key gap junction protein in ECs). To assess electrical coupling, we used a current injection technique and Bessel function model to compute the monolayer intercellular resistance. Hypoxia (0.1% O 2 , 1 h) followed by abrupt reoxygenation (5–90 min) reduced coupling (i.e., increased resistance) in WT but not in Cx40 −/− monolayer. H/R increased superoxide production and reduced protein kinase A (PKA) activity in both monolayers. Activation of PKA by 8‐bromo‐cAMP prevented the reduction in coupling. Preloading of the WT monolayer with the antioxidant ascorbate prevented reductions in both PKA activity and cell coupling. Inhibition of PKA with 6–22 amide during normoxia mimicked the reduction in coupling. Finally, hypoxia followed by slow reoxygenation caused no change in superoxide level, PKA activity, or coupling. Using intravital microscopy, we assessed the physiological relevance of these findings in terms of KCl‐induced conducted vasoconstriction in arterioles of WT mouse cremaster muscle in vivo. Ischemia (1 h) followed by abrupt reperfusion (15–30 min) reduced conduction. 8‐bromo‐cAMP prevented this reduction, while 6–22 amide mimicked this reduction in control nonischemic arterioles. We propose that abrupt reoxygenation reduces interendothelial electrical coupling via oxidant‐ and PKA‐dependent signaling that targets Cx40. We suggest that this mechanism contributes to compromised arteriolar function after H/R.