Citations

ABSTRACT Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a devastating, degenerative neurological disorder. It is inherited as an autosomal recessive trait caused by loss‐of‐function mutations in the galactocerebrosidase (GALC) gene. Previously, we have shown that peripheral injection of recombinant GALC, administered every other day, results in a substantial improvement in early clinical phenotype in the twitcher mouse model of GLD. While we did detect active enzyme in the brain following peripheral administration, most of the administered enzyme was localized to the periphery. Given the substantial central nervous system (CNS) involvement in this disease, we were interested in determining whether or not a single‐dose administration of the recombinant enzyme directly to the CNS, which could potentially be achieved clinically, would result in any substantial improvement. Following intracerebroventricu‐lar (icv) administration of GALC we noted a significant, 16.5%, reduction in the GALC substrate psychosine, the abnormal accumulation of which is believed to play a pivotal role in the CNS pathology observed in this disease. Moreover, recombinant GALC was found not only in periventricular regions but also at sites distant to the injection such as the cerebral cortex and cerebellum. Most importantly, animals receiving a single icv dose of the enzyme at postnatal day 20 survived up to 51 days, which compares favorably to the control twitcher animals, which normally only live to postnatal day 40/42. These results indicate that even a single icv administration of the recombinant enzyme can have significant clinical impact and suggests that other lysosomal storage disorders with significant CNS involvement may similarly benefit.—Lee, W.C., Tsoi, Y.K., Troendle, F.J., DeLucia, M.W., Ahmed, Z., Dicky, C.A., Dickson, D.W., Eckman, C.B. Single dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy. FASEB J. 21, 2520–2527 (2007)

Purpose To evaluate patient assessment of long-term effect of pelvic radiotherapy on bowel function. Patients and Methods As part of a prospective randomized trial evaluating the impact of sucralfate on bowel function in patients receiving pelvic radiotherapy, patient-assessed bowel function data were collected during radiotherapy and again at 4 weeks and 1 year after completion of radiotherapy. Results The number of bowel movements per day increased up to week 4 and then slowly decreased. At 1 year, the mean number of bowel movements per day had increased from 1.75 to 2.09 and the median from 1 to 2. All measures of adverse bowel function worsened during radiotherapy. Frequency of bowel movements and symptoms of frequency, nocturnal bowel movements, cramping, and bleeding returned close to baseline values by 1 year. Symptoms of urgency, clustering, and measures of incontinence were all persistent at 1 year. The mean increase in bowel function score at 1 year was 0.74 (range, −5 to 7). Conclusion Pelvic radiotherapy is associated with a slight increase in bowel movement frequency and decrease in several patient-reported measures of adverse bowel function. Several measures of adverse function persisted at 1 year.

Erectile dysfunction (ED) is frequently associated with cardiovascular disease. Epidemiological data on the frequency of ED in vascular surgery patients is rarely reported. We evaluated the prevalence of this comorbidity in patients consulting the vascular surgery outpatient clinic. Over a 6-month period, a short version of the International Index of Erectile Function (IIEF) questionnaire consisting of six EDrelevant questions was handed out to 440 vascular surgery outpatients. Clinical data were collected from patients' records. Linear regression models with forward selection were used to investigate associations between erectile function score and possible risk factors. The return rate was 31% (137 patients). Eight patients (6%) were taking phosphodiesterase inhibitors. ED, as defined by an erectile function score of 25 or less and/or use of phosphodiesterase inhibitors, was found in 90% (95% CI: 84% to 95%) of cases. Moderate or severe ED, as defined by an erectile function score of 16 or less and/or use of phosphodiesterase inhibitors, was found in 70% (95% CI: 62% to 78%) of cases. Increased age, abdominal aortic aneurysm, peripheral arterial disease, urologic disease, insulin-dependent diabetes mellitus, and use of beta-blockers were significantly associated with a lower erectile function score. In conclusion, erectile dysfunction is a frequent and often missed comorbidity in vascular surgery patients. While ED may have a profound impact on the patient's quality of life, attention should also be paid to the patient's preoperative sexual function, considering the availability of oral pharmacotherapies and possible consequences concerning liability in postoperative patients in whom pre-existing ED was not identified properly.

Background— Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored. Methods and Results— We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even >1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81; P =0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02; P =0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted P <0.001 for trend) and new diabetes (adjusted P <0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes. Conclusions— In stable coronary artery disease, an elevated hs-CRP level, even >1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition.

AbstractPurpose: Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor that can progress in the presence of an intact host immune system. We previously reported that survivin and B7-H1 are independently associated with disease progression and death when expressed by ccRCC tumors. Herein, we examine the clinical effect of ccRCC combined expression of both survivin and B7-H1.Experimental Design: Specimens from 298 patients who underwent nephrectomy for ccRCC between 1990 and 1994 were immunohistochemically stained for survivin and B7-H1. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of both markers with ccRCC death were assessed using Cox proportional hazards regression models.Results: At last follow-up, 94 patients died from ccRCC. Among the living patients, the median follow-up was 11.2 years (range, 0-15 years). There were 177 (59.4%) survivinLow/B7-H1−, 51 (17.1%) survivinHi/B7-H1−, 29 (9.7%) survivinLow/B7-H1+, and 41 (13.8%) survivinHi/B7-H1+ tumors. The 5-year cancer-specific survival rates for patients within each group were 89.3%, 59.7%, 70.0%, and 16.2%, respectively. Combined survivinHi/B7-H1+ expression was associated with ccRCC death univariately (risk ratio, 12.82; 95% confidence interval, 7.50-21.92; P &lt; 0.001) and in multivariate analysis (risk ratio, 2.81; 95% confidence interval, 1.56-5.04; P &lt; 0.001). SurvivinHi/B7-H1+ tumors exhibited increased levels of infiltrating mononuclear cells and survivin-specific T cells compared with survivinLow/B7-H1− tumors.Conclusion: Patients with survivinHi/B7-H1+ ccRCC tumors are at increased risk of ccRCC death. SurvivinHi/B7-H1+ tumors also harbor increased amounts of infiltrating mononuclear cells and survivin-specific T cells relative to survivinLow/B7-H1− tumors. Taken together, dual expression of survivin and B7-H1 can be used to predict ccRCC tumor aggressiveness.

Abstract Purpose: B7-H1 is expressed by clinically aggressive forms of renal cell carcinoma (RCC) and predicts adverse outcome. B7-H1 is known to impair host immunity via interaction with the Programmed Death-1 (PD-1) receptor, which is expressed by activated T cells. Levels of immune cells expressing PD-1 (PD-1+) in clinical RCC tumors have not been evaluated. Thus, we tested whether immune cell PD-1 expression is observed within aggressive RCC tumors. Experimental Design: Between 2000 and 2003, 267 patients underwent nephrectomy at our institution for clear cell RCC and had fresh-frozen tissue available for review. These RCC specimens were immunostained using anti–PD-1 (clone MIH4) and outcome analyses were conducted. Results: Mononuclear immune cell infiltration was observed in 136 (50.9%) specimens. PD-1+ immune cells were present in 77 of these 136 (56.6%) tumors. In contrast, RCC tumor cells did not express PD-1. Patients with PD-1+ immune cells were significantly more likely to harbor B7-H1+ tumor cells (P &lt; 0.001), larger tumors (P = 0.001), and tumors of higher nuclear grade (P = 0.001). Likewise, intratumoral PD-1+ immune cells were associated with advanced tumor-node-metastasis stage (P = 0.005), coagulative tumor necrosis (P = 0.027), and sarcomatoid differentiation (P = 0.008). With a median follow-up of 2.9 years, 52 patients died from RCC. Univariately, patients with PD-1+ immune cells were at significant risk of cancer-specific death compared with PD-1− patients (risk ratio, 2.24; P = 0.004). Conclusions: Levels of immune cells expressing PD-1 were increased in patients with high-risk RCC tumors. Interactions between immune cell PD-1 and B7-H1 may promote cancer progression by contributing to immune dysfunction in patients with RCC.

Using the Minnesota Multiphasic Personality Inventory (MMPI), this study investigated preoperative and postoperative emotional and personality adjustment of temporal lobectomy patients from two major epilepsy surgery centers. Temporal lobectomy patients were included only if they were without evidence of lesional pathology on magnetic resonance imaging (MRI; other than evidence of mesial temporal sclerosis), were left-hemisphere language-dominant, and had Wide Range Achievement Test-Revised (WRAT-R) reading achievement standard scores of 70 or higher. The MMPI was completed by 175 patients before and after a temporal lobectomy. There were no significant preoperative differences on any MMPI scale between right temporal (n = 79) and left temporal (n = 96) lobectomy patients. Analysis of MMPI data from one of the surgical centers revealed significant effects for postoperative seizure control. Minimal effects of laterality of seizure onset on preoperative or postoperative psychological adjustment were found. Adequacy of preoperative psychological adjustment and postoperative seizure control have a greater impact on preoperative to postoperative psychological adjustment than side of seizure onset.

The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that Gα i signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a Gα i -signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific Gα i2 -mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation.

To determine whether the insulin dose-response curves for suppression of endogenous glucose production (EGP) and stimulation of splanchnic glucose uptake (SGU) differ in nondiabetic humans and are abnormal in type 2 diabetes, 14 nondiabetic and 12 diabetic subjects were studied. Glucose was clamped at ∼9.5 mmol/l and endogenous hormone secretion inhibited by somatostatin, while glucagon and growth hormone were replaced by an exogenous infusion. Insulin was progressively increased from ∼150 to ∼350 and ∼700 pmol/l by means of an exogenous insulin infusion, while EGP, SGU, and leg glucose uptake (LGU) were measured using the splanchnic and leg catheterization methods, combined with a [3-3H]glucose infusion. In nondiabetic subjects, an increase in insulin from ∼150 to ∼350 pmol/l resulted in maximal suppression of EGP, whereas SGU continued to increase (P &lt; 0.001) when insulin was increased to ∼700 pmol/l. In contrast, EGP progressively decreased (P &lt; 0.001) and SGU progressively increased (P &lt; 0.001) in the diabetic subjects as insulin increased from ∼150 to ∼700 pmol/l. Although EGP was higher (P &lt; 0.01) in the diabetic than nondiabetic subjects only at the lowest insulin concentration, SGU was lower (P &lt; 0.01) in the diabetic subjects at all insulin concentrations tested. On the other hand, in contrast to LGU and overall glucose disposal, the increment in SGU in response to both increments in insulin did not differ in the diabetic and nondiabetic subjects, implying a right shifted but parallel dose-response curve. These data indicate that the dose-response curves for suppression of glucose production and stimulation of glucose uptake differ in nondiabetic subjects and are abnormal in people with type 2 diabetes. Taken together, these data also suggest that agents that enhance SGU in diabetic patients (e.g. glucokinase activators) are likely to improve glucose tolerance.