Biomedical subjects

Richard Sievers

Publications and source records attributed to Richard Sievers.

6 recordsLinked to original sources

PubMed2006

Left ventricular pressure-volume relationship in conscious mice.

With the availability of transgenic models, the mouse has become an increasingly important subject for genetic-hemodynamic studies. Recently, we developed a technique to measure left ventricular (LV) pressure in conscious mice with an implanted LV polyethylene tube. We extended our new method by evaluating the LV pressure-volume relationship and examined the feasibility of this method in this study. We studied 17 male mice (age, 11-20 wk) with a conductance catheter inserted into the LV through the polyethylene tube. Load-independent parameters of contractility derived from pressure-volume relationship [slope of the end-systolic pressure-volume relationship (E(es)), slope of the maximum first derivative of LV pressure (dP/dt(max))-end-diastolic volume (EDV) relation, and preload-recruitable stroke work (PRSW)] were evaluated by inferior vena caval occlusion with an implanted snare. LV function assessed by this technique on two different days showed that the parameters were very similar, indicating reproducibility. Both linear and nonlinear regression analyses were performed for E(es). Contractility was enhanced by isoproterenol (E(es), 13.1 +/- 6.6 to 20.8 +/- 8.7 mmHg/microl; dP/dt(max)-EDV, 496 +/- 139 to 825 +/- 178 mmHg.s(-1).microl(-1); and PRSW, 110 +/- 23 to 127 +/- 21 mmHg), depressed by atenolol (E(es), 14.5 +/- 6.1 to 4.6 +/- 2.0 mmHg/microl; dP/dt(max)-EDV, 543 +/- 188 to 185 +/- 94 mmHg.s(-1).microl(-1); and PRSW, 117 +/- 20 to 70 +/- 15 mmHg) and isoflurane (E(es), 12.3 +/- 6.0 to 5.7 +/- 2.1 mmHg/microl; dP/dt(max)-EDV, 528 +/- 172 to 164 +/- 68 mmHg/s.microl; and PRSW, 124 +/- 19 to 48 +/- 10 mmHg), significantly. In conclusion, this is the first description of the LV pressure-volume relationship in conscious mice. These findings suggest that this method is feasible to detect changes of contractility in the conscious state, allowing serial assessment of pressure-volume-derived cardiac function indexes over time without anesthesia or repeated surgery.

Animals↗

PubMed2004

A multicenter, open-label, randomized, two-period crossover trial comparing glycemic control, satisfaction, and preference achieved with a 31 gauge x 6 mm needle versus a 29 gauge x 12.7 mm needle in obese patients with diabetes mellitus.

BACKGROUND: Optimal needle length for subcutaneous insulin injection may differ for obese and nonobese patients, which could affect management of diabetes mellitus (DM). OBJECTIVE: The aim of this study was to determine whether 31 gauge (G) x 6 mm (shorter) needles are appropriate alternatives to 29 G x 12.7 mm (longer) needles in obese patients with DM. METHODS: A multicenter, open-label, randomized, 2-period crossover trial was conducted in insulin-treated patients with type 1 or 2 DM with body mass index >or=30 kg/m(2) and glycosylated hemoglobin A(1c) (HbA(1c)) concentration <or=10%. All patients used the same injection device and were randomized to receive 12 weeks of therapy with 1 injection site (thigh or abdomen) and 1 of the 2 needle lengths. Patients used the same injection site but the alternate needle during the second 12-week period. RESULTS: Sixty-two patients (31 men, 31 women; mean [SD] age, 50.5 [10.6] years; age range, 20-73 years) received treatment. Fifty-six patients completed all 24 weeks of treatment. No differences in glycemic control were found. Double-blind assessments of pain scores and leakage measurements, and results from the World Health Organization Diabetes Treatment Satisfaction Questionnaire and most sections of the Insulin Treatment Satisfaction Questionnaire (ITSQ), indicated no differences. However, patients indicated greater satisfaction with the shorter needle on the ITSQ (P < 0.001). The most common adverse event was injection-site bruising (51% [30/59] for the longer needle vs 34% [21/61] for the shorter needle; P = NS). Eighty-nine percent of patients (49/55) preferred the shorter needle (P < 0.001), and 76% (42/55) had a strong, very strong, or extremely strong preference for it. CONCLUSIONS: In obese patients, use of 31 G x 6 mm and 29 G x 12.7 mm needles produced comparable HbA(1c) values, double-blind pain and leakage scores, convenience, and ease of use. However, patients preferred the shorter needle.

Adult↗

PubMed2003

Exploring heart lymphatics in local drug delivery.

BACKGROUND: Local intramyocardial delivery (IMD) is under active clinical investigation for cell therapies to treat congestive heart failure, and gene therapies to induce revascularization of ischemic myocardium in coronary artery disease. Locally delivered agents can migrate away from the site of delivery through pathways that include lymphatics. Postdelivery redistribution can be observed using fluorescent tracers of different physical geometries. This approach provides a means to characterize these pathways and to delineate their importance in local cardiovascular drug delivery. METHODS AND RESULTS: The left ventricular wall of rats (N = 83) received injections of fluorescent microspheres with mean diameters ranging from 20 nm to 15,000 nm. Fluorescent microscopy was used to observe and image the patterns of migration from the epicardial surface. The animals were sacrificed after delivery. The microspheres with diameters smaller than 200 nm were widely distributed within the lymphatic network on the epicardial surface of the rat heart and through the ventricular wall at the injection site. Cardiac lymph nodes were identified with 20 nm and 100 nm deliveries, but could not be identified in any deliveries 200 nm or larger. The 15000 nm microspheres did not migrate. CONCLUSIONS: Tortuous lymphatic pathways are apparent in the images of fluorescent sphere migration from the intramyocardial site of delivery. These images suggest a lymphatic role in the formation of native collaterals that may implicate potential advantages to IMD in therapeutic angiogenesis. Distribution postdelivery also suggests that IMD may provide a means to administer hydrophilic agents to the periadventitial zone of the arterial wall to limit restenosis. The lack of redistribution of the 15,000 nm microspheres supports the potential for cell therapies to remain localized over an extended time frame.

Animals↗

PubMed2003

Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis.

OBJECTIVE: Subjects (n = 188) with type 2 diabetes and inadequate response to two oral medications (A1C >8.0%) were randomly assigned to treatment with either a third oral medication or an insulin 70/30 mix b.i.d. plus metformin for a comparison of efficacy, safety, and cost. RESEARCH DESIGN AND METHODS: The protocol called for aggressive dose titration to achieve target values of fasting blood glucose (80-120 mg/dl), postprandial glucose (<160 mg/dl), and A1C (<7%). These efficacy parameters were evaluated at weeks 2, 6, 12, and 24 of therapy. If dose adjustments failed to achieve targeted glycemic control, subjects were switched to an alternate therapy. RESULTS: At the end of study (week 24 of therapy), A1C and fasting plasma glucose (FPG) values showed comparable decreases in the two treatment groups. Only 31% (oral therapy) and 32% (insulin plus metformin) of subjects achieved target values of A1C (<7%). A total of 10 of the 98 subjects randomized to triple oral therapy (10.2%) who failed to improve sufficiently were switched to insulin therapy. An additional four subjects dropped out of the oral treatment group due to adverse events felt to be potentially drug related. Only two of the subjects randomized to insulin plus metformin had to be switched to basal-bolus regimens (regular insulin and NPH insulin). Cost analysis determined that insulin plus metformin (mean cost 3.20 dollars/day) provided efficacy equal to that of a triple oral drug regimen (10.40 dollars/day). CONCLUSIONS: Insulin 70/30 mix plus metformin was as effective as triple oral therapy in lowering A1C and FPG values. The triple oral regimen was not as cost effective, and a high percentage of subjects (total of 16.3%) did not complete this regimen due to lack of efficacy or side effects.

Administration, Oral↗

PubMedDate not supplied

Targeting of Lin-Sca+ hematopoietic stem cells with bispecific antibodies to injured myocardium.

Bispecific antibodies (BiAbs) are being used to target T cells or other immune cells to antigen-specific tumor targets. Anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-HER2 BiAb (HER2Bi) have been used to target Her2/neu + breast and prostate carcinoma cells. We adapted BiAb technology to target stem cells to injured myocardium. Since myocardial infarctions can lead to cardiac death and disability, rapid repair and rejuvenation of damaged myocardium is critically needed. Effective homing of stem cells and transdifferentiation of the stem cells into functional elements of the myocardium is needed for repair of damaged myocardium. We use a BiAb that binds c-kit on murine stem cells and VCAM-1 adhesion molecules up-regulated on injured myocardial cells. To test for specific binding and homing in a mouse, we produced anti-c-kit x anti-VCAM-1 to target purified Lin-Sca+ murine stem cells to the injured myocardium. Mice with infarcts created by ligation of the left anterior descending artery (LAD) were directly injected with armed stem cells or injected via the internal jugular vein (IJ) with FACS sorted Lin-Sca+ stem cells from bone marrow after fluorescent dye labeling. There were increased numbers of armed Lin-Sca+ cells retained in infracted myocardium after direct injection of armed Lin-Sca+ cells and increased numbers of Lin-Sca+ cells that were found in injured myocardium after IJ injection. These results suggest that stem cells retargeted with BiAb can be directly injected and retained by injured myocardium or targeted to injured myocardial tissues for tissue regeneration.

Animals↗

PubMedDate not supplied

Injectable biopolymers enhance angiogenesis after myocardial infarction.

Novel strategies by which to repair ischemic myocardium after myocardial infarction include the use of three-dimensional polymer scaffolds. A comparative study was carried out to assess the therapeutic potential of fibrin, collagen I, and Matrigel as injectable biopolymers for repair after myocardial infarction. Using a rat model of left coronary artery occlusion followed by reperfusion, local injection of the biopolymers into the infarct zone yielded significantly higher levels of capillary formation, when compared with the saline control group, at 5 weeks posttreatment. However, the degree of angiogenesis was not significantly different among the biopolymers. In addition, the collagen biopolymer significantly enhanced infiltration of myofibroblasts into the infarct area when compared with the control group. The results of this study highlight the potential clinical benefit of these biopolymers as injectable scaffolds or cell delivery vehicles to the infarct zone after infarction.

Animals↗