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Zhou Q.,University of South Florida | Whelan G.,University of South Florida | Whelan G.,Genentech | Zhou S.-F.,University of South Florida | And 2 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2014

Vessel dilator, a hormone synthesized in the heart, eliminates 71% of human small-cell lung cancers and 67% of human breast cancers growing in mice when given subcutaneously (s.c.) via osmotic pumps. The pharmacokinetics of s.c. administered vessel dilator have not been evaluated previously. In the present study, the pharmacokinetics of vessel dilator following s.c. bolus (ScB) or 3 h s.c. infusion (ScI) were compared with those following i.v. bolus (IvB) administration in male Fischer 344 rats. The half-life (t1/2) of vessel dilator after ScI, IvB and ScB was 54, 43 and 30 min, respectively. The tmax for vessel dilator after IvB, ScB and ScI administration was 1.5, 23 and 156 min, respectively, whereas the corresponding Cmax values were 3749, 887 and 471 ng/L (normalized against the dose used for ScB and IvB). The area under the curve (AUC0-∞) for vessel dilator was 1166, 880 and 1652 ng h/mL (normalized) following IvB, ScB and ScI administration, respectively. The volume of distribution for vessel dilator was 2.38, 0.92 and 1.08 L following IvB, ScB and SCI administration, respectively; corresponding clearance values were 1.69, 1.50 and 0.78 L/h, respectively. Plasma concentrations of vessel dilator after each of the three methods of administration mirrored their predicted concentration-time profiles. We conclude that vessel dilator administered via ScI has a significantly greater AUC and t1/2 and slowed clearance compared with IvB or ScB administration (P < 0.001), suggesting that s.c. infusion is the preferred method of administration, based on pharmacokinetics, to treat cancers. © 2014.


Sajan M.P.,James ley Veterans Medical Center | Sajan M.P.,University of South Florida | Ivey III R.A.,James ley Veterans Medical Center | Lee M.,James ley Veterans Medical Center | And 8 more authors.
Molecular Endocrinology | Year: 2014

Tissue-specific knockout (KO) of atypical protein kinase C (aPKC), PKC-λ, yields contrasting phenotypes, depending on the tissue. Thus, whereas muscle KO of PKC-λ impairs glucose transport and causes glucose intolerance, insulin resistance, and liver-dependent lipid abnormalities, liver KO and adipocyte KO of PKC-λ increase insulin sensitivity through salutary alterations in hepatic enzymes. Also note that, although total-body (TB) homozygous KO of PKC-λ is embryonic lethal, TB heterozygous (Het) KO (TBHetλKO) is well-tolerated. However, beneath their seemingly normal growth, appetite, and overall appearance, we found in TBHetλKO mice that insulin receptor phosphorylation and signaling through insulin receptor substrates to phosphatidylinositol 3-kinase, Akt and residual aPKC were markedly diminished in liver, muscle, and adipose tissues, and glucose transport was impaired in muscle and adipose tissues. Furthermore, despite these global impairments in insulin signaling, other than mild hyperinsulinemia, glucose tolerance, serum lipids, and glucose disposal and hepatic glucose output in hyperinsulinemic clamp studies were normal. Moreover, TBHetλKO mice were protected from developing glucose intolerance during high-fat feeding. This metabolic protection (in the face of impaired insulin signaling) in HetλKO mice seemed to reflect a deficiency of PKC-λ in liver with resultant 1) increases in FoxO1 phosphorylation and decreases in expression of hepatic gluconeogenic enzymes and 2) diminished expression of hepatic lipogenic enzymes and proinflammatory cytokines. In keeping with this postulate, adenoviral-mediated supplementation of hepatic PKC-λ induced a diabetic state in HetλKO mice. Our findings underscore the importance of hepatic PKC-λ in provoking abnormalities in glucose and lipid metabolism. © 2014 by the Endocrine Society.


Yu H.,Harvard University | Fujii N.L.,Harvard University | Toyoda T.,Harvard University | An D.,Harvard University | And 5 more authors.
Physiological Reports | Year: 2015

Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζWT), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζT410A). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζWT, and PKC-ζT410A tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζT410A tibialis anterior muscles compared to WT or PKC-ζWT tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λζ activity is not necessary for contraction-stimulated glucose uptake. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.


Latlief G.A.,James ley Veterans Medical Center | Highsmith M.J.,University of South Florida
Topics in Geriatric Rehabilitation | Year: 2014

Lower extremity amputation is known to compromise gait, balance, and overall capacity to react to slips and trips. Given an estimated 1.8 million persons in the United States living with limb loss with an expectation for this number to double by the year 2050, the need for rehabilitative care providers to evaluate and develop treatment plans to minimize the potential for falls will surely rise. Objective measurement of fall risk and evaluation of the effect of targeted treatment interventions are essential to enhancing the quality of rehabilitative care. As a means to this end, the development and use of objective outcome measures that are relevant to the amputee population are necessary. The purpose of this article is to identify and describe these tools and critically review their respective clinical strengths and limitations. © 2014 Lippincott Williams and Wilkins.


Addisu A.,University of South Florida | Addisu A.,Cardiac Hormone Center | Gower Jr. W.R.,University of South Florida | Gower Jr. W.R.,Cardiac Hormone Center | And 5 more authors.
Experimental Biology and Medicine | Year: 2011

Our recent study showed that intravenously administered B-type natriuretic peptide (BNP) decreases gastric emptying and intestinal absorption in mice. We aimed to test whether acute myocardial injury and heart failure have similar effects. Wildtype (WT) and natriuretic peptide receptor type A (NPR-A) knockout (KO) mice underwent cryoinfarction (myocardial infarction [MI]) of the left ventricle (LV) versus sham. LV dysfunction was confirmed by echocardiography. Percent gastric emptying and intestinal absorption were measured and analyzed one and two weeks after infarction, by gavage feeding the mice with fluorescein-isothiocyanate-dextran. Ejection fraction was 48±3% versus 64±2% (P<0.05) and fractional shortening was 24±2% versus 35±2% (P<0.01), MI versus sham, respectively. BNP levels (pg/mL) were 4292±276 one week after MI versus 105±11 in sham (n = 5, P<0.05) and 1964±755 two weeks after MI (n = 5, P<0.05). Gastric emptying was significantly decreased, 68±6% in MI versus 89±3% in sham (n = 5, P<0.05) one week after MI and 82±0.5% versus 98±0.4%, MI versus sham (n = 5, P<0.05), two weeks post-MI. Absorption, measured in relative plasma fluorescence units in WT mice, was 350±79 in MI versus 632±121 in sham (n = 6, P<0.05). KO mice did not show a significant difference in emptying or absorption compared with sham. These findings suggest that MI and LV dysfunction decrease gastric emptying and absorption in mice through a mechanism that involves NPR-A. © 2011 by the Society for Experimental Biology and Medicine.


PubMed | University of Oslo, Harvard University and James ley Veterans Medical Center
Type: Journal Article | Journal: Physiological reports | Year: 2015

Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms and (PKC-/) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-/ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC- (PKC-(WT)), or an enzymatically inactive T410A-PKC- mutant (PKC-(T410A)). We also studied skeletal muscle-specific PKC- knockout (MKO) mice. Basal glucose uptake was similar between WT, PKC-(WT), and PKC-(T410A) tibialis anterior muscles. In contrast, insitu contraction-stimulated glucose uptake was increased in PKC-(T410A) tibialis anterior muscles compared to WT or PKC-(WT) tibialis anterior muscles. Furthermore, invitro contraction-stimulated glucose uptake was greater in soleus muscles of MKO mice than WT controls. Thus, loss of PKC-/ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC- activity is not necessary for contraction-stimulated glucose uptake.


Greene J.,University of South Florida | Cohen D.,University of South Florida | Siskowski C.,American Association of Caregiving Youth | Toyinbo P.,James ley Veterans Medical Center
Journal of Behavioral Health Services and Research | Year: 2016

Caring for dependent relatives has become a normative challenge for families in the USA and throughout the world. The study objective was to examine the relationship of family caregiving responsibilities and the mental health and well-being of individuals, ages 18–24 years, referred to as emerging young adults. It was hypothesized that young adult caregivers with past and present responsibilities would report significantly more symptoms of depression and anxiety, have lower self-esteem, and use less adaptive coping styles than non-caregiving peers. The sample consisted of 353 undergraduates (81 past caregivers, 76 current/past caregivers, and 196 non-caregivers). Caregivers were also evaluated in terms of care recipients, duration of caregiving, tasks, and hours of effort. Caregivers had significantly higher levels of symptoms of depression and anxiety than non-caregivers. Research to clarify how caregiving interacts with other stressors in emerging young adults and influences behavioral health should be a priority. © 2016 National Council for Behavioral Health


Mohapatra S.S.,University of South Florida | Mohapatra S.S.,James ley Veterans Medical Center | Qazi M.,University of South Florida | Hellermann G.,University of South Florida | Hellermann G.,James ley Veterans Medical Center
Current Opinion in Pharmacology | Year: 2010

Allergen immunotherapy (IT) is a proven approach for treating allergic rhinitis and allergic asthma that has been practiced since 1911 and has undergone significant development in the past two decades. As currently practiced, IT involves subcutaneous or sublingual administration of allergens, both methods of which have been extensively investigated. In addition to allergen IT, a number of additional nonspecific IT approaches are being used or are in phase II/phase III clinical trials, which may be available in clinics within the next one to three years. Such therapies include anti-IgE antibodies and the soluble IL-4 receptor. Other experimental IT approaches are at the preclinical research stage and may proceed to clinical trials and the clinic within the next five to ten years. This review discusses the pros and cons of recent developments in both currently practiced and experimental IT approaches. © 2010 Elsevier Ltd.


Ostendorf B.N.,University Hospital Freiburg | Oehler R.L.,University of South Florida | Oehler R.L.,James ley Veterans Medical Center | Greene J.N.,University of South Florida
Infectious Diseases in Clinical Practice | Year: 2011

Staphylococcus intermedius is known primarily for its role as a commensal and pathogen in dogs and a variety of other animals. It has also been reported as a cause of human infection in a limited number of cases. Here, we report a case of S. intermedius wound infection in a 47-year-old woman with postradiation skin changes. Transmission occurred most likely through direct skin contact with her pet dog. This case highlights the possibility of pet-transmitted infections in predisposed patients and should raise awareness of possibly drug-resistant pathogens in animal reservoirs. © 2011 by Lippincott Williams & Wilkins.


Maroun E.N.,University of South Florida | Chakrabarti A.,University of South Florida | Baker M.,University of South Florida | Canchi D.,University of South Florida | And 3 more authors.
Infectious Diseases in Clinical Practice | Year: 2012

INTRODUCTION: Pyogenic liver abscess accounts for 80% of hepatic abscess cases in the United States. Increasing rates of anaerobic involvement has been reported since 1974. Fusobacterium species are among the most commonly encountered anaerobes, although it is a rare finding to see Fusobacterium species as a cause of liver abscess. CASE PRESENTATION: A 60-year-old man with a history of 100 pack year of tobacco use and chronic obstructive pulmonary disease, presented with radiological findings for metastatic liver malignancy. This was an incidental finding when the patient had a computed tomographic pulmonary angiogram to rule out pulmonary embolism. The incidental findings were followed up with radiological testing, a colonoscopy, endoscopy, and 2 biopsies. The patient's condition was finally diagnosed as a liver abscess due to Fusobacterium and was successfully treated with a prolonged course of metronidazole. CONCLUSION: Pyogenic liver abscess can mimic metastatic malignancy and should be considered when multiple hepatic lesions are seen on an abdominal computed tomography or other compatible diagnostic imaging. Copyright © 2012 by Lippincott Williams & Wilkins.

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