Citations

Background— We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) –mediated hypertension. Methods and Results— First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure–lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng · kg −1 · min −1 , 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 ( P =0.01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mm Hg at 30 minutes, 124±2 mm Hg at 1 hour, and 130±5 mm Hg at 2 hours after oral hBNP-054; P <0.001). Conclusions— This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure–lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

ABSTRACT The diagnostic gains of repeat testing for Clostridium difficile by enzyme immunoassay and PCR (i.e., initial negative result followed by positive result) within a 7-day period were 1.9 and 1.7%, respectively. There is little value of repeat testing for C. difficile by enzyme immunoassay or PCR.

Background— Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Methods and Results— Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure–volume analysis and aortic pressure–dimension and pressure–flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N ε -(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. Conclusions— In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

Abstract Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Tregs), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (1) TGFβ1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previously found to result from dysregulation of TGFβ signaling and regulatory T cells. Together, these findings indicate that the Notch and TGFβ signaling pathways cooperatively regulate Foxp3 expression and regulatory T-cell maintenance both in vitro and in vivo.

Abstract Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage, including damage from tobacco exposure. Single-nucleotide polymorphisms (SNP) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development. We performed a clinic-based, case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls. Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1, XPD/ERCC2, XPC, XPF/ERCC4, OGG1, and XRCC1 were compared after adjusting for age, sex, and smoking history. Subgroup analysis by sex and smoking history was performed. Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40–0.85]. Heavy smokers (&gt;40 pack-years) had increased risk for cancer if they were carriers of at least one minor allele for XPD/ERCC2 at D312N (OR, 2.78; 95% CI, 1.28–6.04) or D711D (OR, 2.19; 95% CI, 1.01–4.73). No other significant differences in risk were identified. Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer. [Cancer Res 2008;68(12):4928–35]

Background and Purpose Hemipelvectomy is a life-changing treatment for pelvic malignancies. This study compared functional outcomes and quality of life of patients following internal or external hemipelvectomies. Subjects Ninety-seven patients who underwent tumor-related internal (n=39) or external (n=58) hemipelvectomy surgery between January 1, 1988, and December 31, 2004, participated in the study. Methods Using a descriptive retrospective cohort study design, functional status was evaluated with the Barthel Index at 3 time points. Quality-of-life parameters were evaluated at follow-up using the Linear Analog Self-Assessment tool (LASA). Results Data were collected on all 97 patients at rehabilitation consultation and hospital discharge. Follow-up data were obtained via survey on 44% of the original group at a median of 5.8 years (interquartile range [IRQ]=1.7–10.4) after surgery. Median total Barthel Index scores were similar between the internal and external hemipelvectomy groups at the initial physical medicine and rehabilitation assessment (10 [IQR=10–15] versus 10 [IQR=3.75–15]), at discharge (40 [IQR=30–65] versus 50 [IQR=35–66.25]), and at follow-up (92.5 [IQR=76.25–100] versus 92.5 [IQR=78.75–96.25]). Participants with external hemipelvectomies were less independent in bladder function and experienced greater pain severity at follow-up compared with those with internal hemipelvectomies. Overall quality-of-life parameters were similar between the groups. Discussion and Conclusion Despite significant differences in surgical procedures, immediate and long-term functional outcomes and quality-of-life parameters were similar among participants with internal and external hemipelvectomies.

Childhood sexual abuse (CSA) is common and is associated with both mental and physical health problems in adulthood. Using data from an age- and sex-stratified population survey of 600 Olmsted County, Minnesota, residents, a Sexual Abuse Severity Score was developed. The abuse characteristics of 156 CSA respondents were associated with self-reported trauma, somatization, and alcohol use. Characteristics included age of first sexual abuse, more than one perpetrator, degree of coercion, severity of abuse (i.e., attempted intercourse is more severe than fondling), and the number of occurrences. This is one of the few reports to develop a risk summary that quantifies the severity of CSA.

OBJECTIVE—Current criteria for the diagnosis of diabetic ketoacidosis (DKA) are limited by their nonspecificity (serum bicarbonate [HCO3] and pH) and qualitative nature (the presence of ketonemia/ketonuria). The present study was undertaken to determine whether quantitative measurement of a ketone body anion could be used to diagnose DKA. RESEARCH DESIGN AND METHODS—A retrospective review of records from hospitalized diabetic patients was undertaken to determine the concentration of serum β-hydroxybutyrate (βOHB) that corresponds to a HCO3 level of 18 mEq/l, the threshold value for diagnosis in recently published consensus criteria. Simultaneous admission βOHB and HCO3 values were recorded from 466 encounters, 129 in children and 337 in adults. RESULTS—A HCO3 level of 18 mEq/l corresponded with βOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. With the use of these threshold βOHB values to define DKA, there was substantial discordance (∼≥20%) between βOHB and conventional diagnostic criteria using HCO3, pH, and glucose. In patients with DKA, there was no correlation between HCO3 and glucose levels on admission and a significant but weak correlation between βOHB and glucose levels (P &lt; 0.001). CONCLUSIONS—Where available, serum βOHB levels ≥3.0 and ≥3.8 mmol/l in children and adults, respectively, in the presence of uncontrolled diabetes can be used to diagnose DKA and may be superior to the serum HCO3 level for that purpose. The marked variability in the relationship between βOHB and HCO3 is probably due to the presence of other acid-base disturbances, especially hyperchloremic, nonanion gap acidosis.