Citations

Object The cervical foraminotomy was pioneered in the 1940s to address radicular symptoms via a posterior approach, but the long-term outcome has not been adequately studied. Methods The authors retrospectively analyzed data obtained from 303 patients (188 male and 115 female, mean age 49.2 years) who had consecutively undergone a single-level posterior foraminotomy for cervical radiculopathy between 1972 and 1992. The median follow-up duration was 7.1 years. The major end point studied was the development of symptomatic adjacent- or same-segment disease. Incidence rates per 1000 person-years were calculated, and the natural history of the disease was predicted using Kaplan–Meier survivorship analysis. In 15 (4.9%) of 303 patients, symptomatic adjacent-segment disease developed, yielding a rate of 6.4/1000 person-years at risk. This included nine (2.9%) of 303 patients requiring reoperation, yielding a rate of 3.8/1000 person-years. Kaplan–Meier survivorship analysis suggested a relatively stable annual 0.7% rate for developing adjacent-segment disease, with a 10-year rate of 6.7%. Ten patients developed same-segment disease, yielding a risk rate of 3.9/1000 person-years. Kaplan–Meier survivorship analysis demonstrated a 5- and 10-year risk rate of developing same-segment disease of 3.2 and 5.0%, respectively. Conclusions Although additional study is needed, analysis of the present data suggests that posterior foraminotomy is associated with a low rate of same- and adjacent-segment disease.

Background: Ghrelin is a 28-amino acid acylated peptide that potentiates GHRH stimulation and opposes somatostatin inhibition acutely. Whether prolonged ghrelin administration can sustain physiological patterns of GH secretion remains unknown. Hypothesis: Continuous delivery of ghrelin will amplify physiological patterns of GH secretion over 24 h. Subjects: Men and women ages 29–69 yr, body mass indices 23–52 kg/m2, were included in the study. Location: The study was performed at an academic medical center. Methods: Twenty-four hour continuous sc infusion of saline vs. ghrelin (1 μg/kg·h) with frequent sampling was examined. Deconvolution and entropy analyses were performed. Outcomes: IGF-I concentrations were determined. Basal, pulsatile, nycthemeral, and entropic measures of GH secretion were calculated. Results: Ghrelin infusion compared with saline infusion for 24 h elevated (median) acylated ghrelin, GH, and IGF-I concentrations by 8.1-fold (P < 0.001),11-fold (P < 0.001), and 1.4-fold (P = 0.002). GH secretory-burst mass and frequency increased by 6.6-fold (P = 0.004) and 1.7-fold (P < 0.001), respectively, resulting in a 12-fold increase in pulsatile GH secretion (P < 0.001). Interpulse variability decreased significantly (P = 0.046), whereas GH secretory-burst shape and half-life did not change. The amplitude of the nycthemeral GH rhythm increased by 3.4-fold (P < 0.001), and GH patterns became more irregular (higher approximate entropy P < 0.001). Combining GHRH with ghrelin was not an additive in driving GH secretion. Conclusions: Continuous ghrelin infusion for 24 h elevates acylated ghrelin, GH and IGF-I concentrations, and stimulates pulsatile, nycthemeral, and entropic modes of GH secretion. The consistency of outcomes in a heterogeneous cohort of adults suggests potentially broad utility of this physiological secretagogue in hyposomatotropic states.

Abstract Purpose: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival. Experimental Design: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates. Results: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004). Conclusion: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.

AbstractCancer statistics show a disproportionately higher burden of tumors in the old. Most of the studies evaluating vaccination strategies have not taken into consideration the effect that aging has on the immune system. For the first time, we describe an animal tumor model in which self-tolerance and aging are present at the same time. FVB-Her-2/neu mice which are tolerant to neu antigens crossed with HLA-A2/Kb mice (A2xneu) develop spontaneous tumors when they are more than 22 months old. Analysis of CD8+ T-cell–specific responses in A2xneu mice indicated that the priming activity of old A2xneu mice to induce an immune response was diminished compared with young animals. Following intratumoral injections of CpG-ODN, ∼30% of young A2xneu mice rejected the tumor; however, no antitumor effect was observed in old A2xneu mice. Analysis of T regulatory cells (Treg) indicated that there are significantly more Tregs in old animals. After CpG-ODN vaccination plus Treg depletion, 70% of young A2xneu mice rejected the tumor. The same treatment prolonged survival in old A2xneu mice, but none of the animals rejected the tumor. Even though CpG-ODN injections plus Treg depletion could rescue the antitumor responses against self-tumor antigens in young tolerant mice, the same therapy is not as effective in old tolerant hosts. Relevant tumor models such as the A2xneu mice in which self-tolerance and aging are present at the same time are critical to allow the optimization of vaccination strategies to effectively stimulate immune responses against self-tumor antigens in the young and the old. [Cancer Res 2008;68(13):5423–31]

Abstract The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here, we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated exon 3 and two truncated versions lacking the COOH terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel exon 2b at their 3′ end. Functionally, these AR isoforms are constitutively active and promote the expression of endogenous AR-dependent genes, as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, exon 2b–derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR and thus circumvent androgen ablation. [Cancer Res 2008;68(13):5469–77]

We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 “good” responders (diastolic BP response [mean±SD]=−18.3±4.2 mm Hg; age=47.1±6.1 years; 51.5% women) and 97 “poor” responders (diastolic BP response=−0.18±4.3; age=47.4±6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme ( LYZ ), YEATS domain containing 4 ( YEATS4 ), and fibroblast growth receptor substrate 2 ( FRS2 ) were significantly associated with diastolic BP response (nominal P =2.39×10 −7 ; Bonferroni corrected P =0.024; simulated experiment-wise P =0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to “tag” linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.

Background— The clinical efficacy of alcohol septal ablation for drug-refractory hypertrophic cardiomyopathy remains unclear. This study examines the outcome of alcohol septal ablation performed at a tertiary hypertrophic cardiomyopathy referral center. Methods and Results— Among 601 patients with severely symptomatic obstructive hypertrophic cardiomyopathy referred for alcohol septal ablation or myectomy from 1998 to 2006, 138 patients (median age, 64 years; 39% men) chose to undergo ablation. Procedural complications included death in 1.4%, sustained ventricular arrhythmias in 3%, tamponade in 3%, and pacemaker implantation in 20%. This rate was higher than a combined complication rate of 5% in age- and gender-matched patients who had undergone septal myectomy at Mayo Clinic ( P <0.0001). Four-year survival free of all mortality was 88.0% (95% confidence interval, 79.4 to 97.5%), which was similar to that of the age- and gender-matched patients who had undergone myectomy ( P =0.18). Six patients had documented ventricular arrhythmias after ablation, 4 of whom had successful intervention. Four-year survival free of death and severe New York Heart Association class III/IV symptoms after septal ablation was 76.4%, and 71 patients (51%) became asymptomatic. Myectomy patients ≤65 years of age had significantly better survival free of death and severe symptoms ( P =0.01). Conclusions— Alcohol septal ablation is an efficacious procedure if performed in an experienced institution and may resolve symptoms in a subset of patients with obstructive hypertrophic cardiomyopathy. However, the procedural complication rate exceeds that of myectomy. Patients ≤65 years of age have better symptom resolution with myectomy. No impairment in short-term survival was noted in this nonrandomized study, but the long-term outcome remains unknown.

Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for ≈75–80% of cases (LQT1–11). Direct sequencing of SNTA1 , the gene encoding α1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S -nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.