Search tips
Search criteria

Results 1-7 (7)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats 
Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are a newer class of antidiabetics named as incretin-based therapy. In addition to the homeostatic control of glucose, the incretin-based therapy has shown beneficial effects on the cardiovascular system in preclinical and clinical studies. However, there is limited information on their renal effects. To this end, we assessed the acute hemodynamic and renal effects of a GLP-1 analog, Liraglutide, and a DPP4 inhibitor, MK-0626.
Experiments were performed in anesthetized male Sprague–Dawley rats. Three ascending doses of Liraglutide (3, 9, and 27 nmol/kg/h) or MK-0626 (1 mg/kg) with or without GLP-1 peptide (2.4, 4.8, or 9.6 pmol/kg/min) were administered. Blood pressure (BP) and heart rate (HR) were recorded from an indwelling catheter. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by inulin and para-aminohippurate clearance, respectively. Renal excretory function was assessed in metabolic studies.
Both Liraglutide and MK-0626 plus GLP-1 evoked significant diuretic and natriuretic responses and increased GFR. MK-0626 alone increased RBF. Liraglutide at 27 nmol//kg/h and MK-0626 plus GLP-1 at 9.6 pmol/kg/min also increased HR, whereas BP was not affected.
The results of the present study demonstrated that a GLP-1 analog and a DPP4 inhibitor may have beneficial effects on renal sodium and water handling. Additionally, the DPP4 inhibitor, MK-0626, favorably affects renal hemodynamics by increasing RBF. However, exceedingly high levels of GLP-1 receptor agonists may adversely affect the cardiovascular system in acute setting, as demonstrated by an acute increase in HR.
PMCID: PMC4476171  PMID: 25888997
Glucagon-like peptide 1; Dipeptidyl peptidase-4; Hemodynamics; Renal function
2.  Are the 10 Meter and 6 Minute Walk Tests Redundant in Patients with Spinal Cord Injury? 
PLoS ONE  2014;9(5):e94108.
To evaluate the relationship and redundancy between gait speeds measured by the 10 Meter Walk Test (10MWT) and 6 Minute Walk Test (6MWT) after motor incomplete spinal cord injury (iSCI). To identify gait speed thresholds supporting functional ambulation as measured with the Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI).
Prospective observational cohort.
Seven outpatient rehabilitation centers from the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN).
249 NRN patients with American Spinal Injury Association Impairment Scale (AIS) level C (n = 20), D (n = 179) and (n = 50) iSCI not AIS evaluated, from February 2008 through April 2011.
Locomotor training using body weight support and walking on a treadmill, overground and home/community practice.
Main Outcome Measure(s)
10MWT and 6MWT collected at enrollment, approximately every 20 sessions, and upon discharge.
The 10MWT and 6MWT speeds were highly correlated and the 10MWT speeds were generally faster. However, the predicted 6MWT gait speed from the 10MWT, revealed increasing error with increased gait speed. Regression lines remained significantly different from lines of agreement, when the group was divided into fast (≥0.44 m/s) and slow walkers (<0.44 m/s). Significant differences between 6MWT and 10MWT gait speeds were observed across SCI-FAI walking mobility categories (Wilcoxon sign rank test p<.001), and mean speed thresholds for limited community ambulation differed for each measure. The smallest real difference for the 6MWT and 10MWT, as well as the minimally clinically important difference (MCID) values, were also distinct for the two tests.
While the speeds were correlated between the 6MWT and 10MWT, redundancy in the tests using predictive modeling was not observed. Different speed thresholds and separate MCIDs were defined for community ambulation for each test.
PMCID: PMC4006773  PMID: 24788068
3.  Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms 
PLoS ONE  2012;7(4):e35240.
Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.
PMCID: PMC3323649  PMID: 22506074
4.  Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension 
We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
PMCID: PMC3231850  PMID: 21950654
mineralocorticoid receptor antagonist; hypertension; end organ protection; eplerenone; Dahl salt-sensitive rats
5.  IgG2m4, an engineered antibody isotype with reduced Fc function 
mAbs  2009;1(6):572-579.
The Fc region of an antibody mediates effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and plays a key role in the in vivo half-life of an antibody. In designing antibody therapeutics, it is sometimes desirable that the antibody has altered Fc-mediated properties. In the case of a “benign blocker” antibody, it is often desirable to diminish or abolish the ADCC and CDC functions while retaining its PK profile. Here, we report a novel engineered IgG isotype, IgG2m4, with reduced Fc functionality. IgG2m4 is based on the IgG2 isotype with four key amino acid residue changes derived from IgG4 (H268Q, V309L, A330S and P331S). An IgG2m4 antibody has an overall reduction in complement and Fcγ receptor binding in in vitro binding analyses while maintaining the normal in vivo serum half-life in rhesus.
PMCID: PMC2791314  PMID: 20073128
IgG2m4; IgG; isotype; benign blocker; Fcγ receptors; C1q
6.  Underestimation of Bone Loss of the Spine With Posterior-Anterior Dual-Energy X-Ray Absorptiometry in Patients With Spinal Cord Injury 
Bone mineral density (BMD) of the lumbar spine (L-spine) has been reported to be normal by routine posterior-anterior (PA) bone density imaging in patients with chronic spinal cord injury (SCI).
To determine BMD of the L-spine by PA and lateral (LAT) dual-energy radiographic absorptiometry (DXA) in patients with chronic SCI.
Prospective study.
Veterans Affairs Medical Center and a private rehabilitation facility.
Measurements of the PA and LAT L-spine and hip were performed in 15 patients with SCI: 9 with tetraplegia and 6 with paraplegia. The DXA (GE Lunar Advance DXA) images were obtained using standard software. Results are reported as mean ± SD.
The mean age was 35 ± 15 years (range  =  20–62 years), and the duration of injury was 57 ± 74 months (range  =  3–240 months). T- and Z-scores were lower for the LAT L-spine than those for PA L-spine (T-scores L2: −0.7 ± 1.2 vs 0.0 ± 1.4, P < 0.01; L3: −0.9 ± 1.6 vs 0.3 ± 1.3, P < 0.002; L2-L3: −0.8 ± 1.3 vs 0.2 ± 1.3, P < 0.001; Z-scores L2: −0.3 ± 1.1 vs 0.2 ± 1.2, P < 0.05; L3: −0.6 ± 1.3 vs 0.5 ± 1.3, P < 0.01; L2-L3: −0.4 ± 1.1 vs 0.4 ± 1.2, P < 0.005). The T- and Z-scores for the total hip (−1.1 ± 1.0 and −1.0 ± 1.0, respectively) and L2-L3 LAT L-spine demonstrated remarkable similarity, whereas the L2-L3 PA L-spine scores were not reduced. Bone mineral density of the LAT L-spine, but not the PA L-spine, was significantly reduced with increasing duration of injury.
Individuals with SCI may have bone loss of the L-spine that is evident on LAT DXA that may be misdiagnosed by PA DXA, underestimating the potential risk of fracture.
PMCID: PMC2920114  PMID: 20737794
Spinal cord injuries; Paraplegia; Tetraplegia; Bone mineral density; Vertebral body; Dual-energy X-ray absorptiometry; Osteoporosis
7.  Neuromotor and Musculoskeletal Responses to Locomotor Training for an Individual With Chronic Motor Complete AIS-B Spinal Cord Injury 
To determine the effects of locomotor training (LT) using body weight support (BWS), treadmill, and manual assistance on muscle activation, bone mineral density (BMD), and body composition changes for an individual with motor complete spinal cord injury (AIS B), 1 year after injury.
A man with chronic C6 AIS B (motor complete and sensory incomplete) spinal cord injury (SCI), 1 year after injury, completed 2 blocks of LT over a 9-month training period (35-session block followed by 8.6 weeks of no training and then a 62-session block).
Before training, muscle activation was minimal for any muscle examined, whereas after the 2 blocks of LT (97 sessions), hip and knee muscle activation patterns for the bilateral rectus femoris, biceps femoris, and gastrocnemius were in phase with the kinematics. Mean EMG amplitude increased for all bilateral muscles and burst duration increased for rectus femoris and gastrocnemius muscles, whereas burst duration decreased for the biceps femoris after 62 LT sessions. Before LT, left biceps femoris had a pattern that reflected muscle stretch, whereas after training, muscle stretch of the left biceps femoris could not totally account for mean EMG amplitude or burst duration. After the 62 training sessions, total BMD decreased (1.54%), and regional BMD decreased (legs: 6.72%). Total weight increased, lean mass decreased (6.6%), and fat mass increased (7.4%) in the arms, whereas fat mass decreased (3.5%) and lean mass increased (4%) in the legs.
LT can induce positive neural and body composition changes in a nonambulatory person with chronic SCI, indicating that neuromuscular plasticity can be induced by repetitive locomotor training after a motor complete SCI.
PMCID: PMC2607123  PMID: 19086708
Spinal cord injuries; Tetraplegia; Locomotor training; Kinematic profiles; Electromyography profiles; Neural alterations; Bone and muscle changes; Body composition

Results 1-7 (7)