Exercise Training Induced Cardioprotection with Moderate Hyperglycemia versus Sedentary Intensive Glycemic Control in Type 1 Diabetic Rats.

Intensive insulin therapy (IIT; 4-7 mmol/L) is the preferred treatment for type 1 diabetes mellitus (T1DM) patients to reduce the risk of cardiovascular disease (CVD). However, this treatment strategy has been questioned as it is accompanied with a sedentary lifestyle leading to weight gain and insulin resistance. T1DM patients who partake in high-intensity aerobic training (AThigh) to reduce CVD often utilize conventional insulin therapy (CIT; 9-15 mmol/L) to offset the risk of hypoglycemia. Moreover, exercise modalities incorporating resistance training (RT) have been shown to further reduce this risk. The purpose of this investigation was twofold: (1) to determine if CIT paired with AThigh results in larger cardioprotection from an ischemia-reperfusion (I-R) injury than IIT and (2) to establish if the integration of RT with AThigh (ART) results in similar cardioprotection as AThigh. Diabetic (D) male Sprague-Dawley rats were divided into D-IIT (n = 12), D-CIT (n = 12), D-AThigh (n = 8), D-RT (n = 8), and D-ART (n = 8). T1DM was induced with streptozotocin, and blood glucose was adjusted with insulin. D-AThigh occurred on a treadmill (27 m/min; 1 hr), D-RT performed weighted ladder climbs, and D-ART alternated daily between AThigh and RT. Exercise occurred 5 days/wk for 12 wks. This investigation demonstrates that cardioprotection following an I-R injury was similar between D-AThigh and D-IIT. This cardioprotection is not exercise-specific, and each provides unique advantages. D-AThigh leads to improved glycemia while insulin sensitivity was enhanced following resistance exercises. Thus, exercise is an effective means to elicit cardioprotection in T1DM. However, in addition to glycemia, other factors should be considered when tailoring an exercise program for T1DM patients.

Effect of Combined Exercise Versus Aerobic-Only Training on Skeletal Muscle Lipid Metabolism in a Rodent Model of Type 1 Diabetes.

OBJECTIVES: Abnormal skeletal muscle lipid metabolism is associated with insulin resistance in people with type 1 diabetes. Although lipid metabolism is restored with aerobic exercise training, the risk for postexercise hypoglycemia is increased with this modality. Integrating resistance and aerobic exercise is associated with reduced hypoglycemic risk; however, the effects of this exercise modality on lipid metabolism and insulin resistance remain unknown. We compared the effects of combined (aerobic + resistance) versus aerobic exercise training on oxidative capacity and muscle lipid metabolism in a rat model of type 1 diabetes. METHODS: Male Sprague-Dawley rats were divided into 4 groups: sedentary control (C), sedentary control + diabetes (CD), diabetes + high-intensity aerobic exercise (DAE) and diabetes + combined aerobic and resistance exercise (DARE). Following diabetes induction (20 mg/kg streptozotocin over five days), DAE rats ran for 12 weeks (5 days/week for 1 hour) on a motorized treadmill (27 m/min at a 6-degree grade), and DARE rats alternated daily between running and incremental weighted ladder climbing. RESULTS: After training, DAE showed reduced muscle CD36 protein content and lipid content compared to CD (p≤0.05). DAE rats also had significantly increased citrate synthase (CS) activity compared to CD (p≤0.05). DARE rats showed reduced CD36 protein content compared to CD and increased CS activity compared to CD and DAE rats (p≤0.05). DARE rats demonstrated increased skeletal muscle lipid staining, elevated lipin-1 protein content and insulin sensitivity (p≤0.05). CONCLUSIONS: Integration of aerobic and resistance exercise may exert a synergistic effect, producing adaptations characteristic of the "athlete's paradox," including increased capacity to store and oxidize lipids.

Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats.

The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9-15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training.

The glucoregulatory response to high-intensity aerobic exercise following training in rats with insulin-treated type 1 diabetes mellitus.

An acute bout of exercise elicits a rapid, potentially deleterious, reduction in blood glucose in patients with type 1 diabetes mellitus (T1DM). In the current study, we examined whether a 10-week aerobic training program could alleviate the rapid exercise-associated reduction in blood glucose through changes in the glucoregulatory hormonal response or increased hepatic glycogen storage in an insulin-treated rat model of T1DM. Thirty-two male Sprague-Dawley rats were divided evenly into 4 groups: non-T1DM sedentary (C) (n = 8), non-T1DM exercised (CX) (n = 8), T1DM sedentary (D) (n = 8), and T1DM exercised (DX) (n = 8). Exercise training consisted of treadmill running for 5 days/week (1 h, 27 m/min, 6% grade) for 10 weeks. T1DM was induced by multiple streptozotocin injections (20 mg/kg) followed by implantation of subcutaneous insulin pellets. At week 1, an acute exercise bout led to a significant reduction in blood glucose in DX (p < 0.05), whereas CX exhibited an increase in blood glucose (p < 0.05). During acute exercise, serum epinephrine was increased in both DX and CX (p < 0.05), whereas serum glucagon was increased during recovery only in CX (p < 0.01). Following aerobic training in DX, the exercise-mediated reduction in blood glucose remained; however, serum glucagon increased to the same extent as in CX (p < 0.05). DX exhibited significantly less hepatic glycogen (p < 0.001) despite elevations in glycogenic proteins in the liver (p < 0.05). Elevated serum epinephrine and decreased hepatic adrenergic receptor expression were also evident in DX (p < 0.05). In summary, despite aerobic training in DX, abrupt blood glucose reductions and hepatic glycogen deficiencies were evident. These data suggest that sympathetic overactivity may contribute to deficiencies in hepatic glycogen storage.

Granulomatous Vertebral Osteomyelitis: An Update.

A granulomatous infection of the spine is characterized by an infectious process within the spinal elements that results in the formation of a granuloma, an organized collection of transformed macrophages (ie, epithelioid cells), matrix, and other inflammatory cells. Causative organisms include various bacteria, fungi, or other parasites; however, the most frequently encountered causative organism is Mycobacterium tuberculosis (ie, Pott disease). The onset of these infections is often insidious, frequently leading to a delay in diagnosis. Left untreated, this disease process may lead to a compromise in the structural integrity of the spine and subsequent spinal deformity that may eventually result in compression of neural elements. Successful treatment of a granulomatous infection requires timely diagnosis, prompt medical management, and potential surgical intervention directed at the decompression of neural elements and the correction of spinal malalignment. Of granulomatous infections, tuberculous infections are the most thoroughly understood and serve as the standard to which other less commonly reported organisms are compared.

Infusion system carrier flow perturbations and dead-volume: large effects on drug delivery in vitro and hemodynamic responses in a swine model.

BACKGROUND: We have previously shown that, at constant carrier flow, drug infusion systems with large dead-volumes (V) slow the time to steady-state drug delivery in vitro and pharmacodynamic effect in vivo compared to those with smaller V. In this study, we tested whether clinically relevant alterations in carrier flow generate perturbations in drug delivery and pharmacodynamic effect, and how these might be magnified when V is large. METHODS: Drug delivery in vitro or mean arterial blood pressure (MAP) and ventricular contractility (max dP/dt) in a swine model were quantified during an infusion of norepinephrine (fixed rate 3 mL/h) with a crystalloid carrier (10 mL/h). The carrier flow was transiently halted for either 10 minutes or 20 minutes and then restarted. In separate experiments, a second drug infusion (50 mL over 10 minutes) was introduced into the same catheter lumen used by a steady-state norepinephrine infusion. The resulting perturbations in drug delivery and biologic effect were compared between drug infusion systems with large and small V. RESULTS: Halting carrier flow immediately decreased drug delivery in vitro, and MAP and max dP/dt. These returned to steady state before restarting carrier flow with the small, but not the large, V. Resuming carrier flow after 10 minutes resulted in a transient increase in drug delivery in vitro and max dP/dt in vivo, which were of longer duration and greater area under the curve (AUC) for larger V. MAP also increased for longer duration for larger V. Resuming the carrier flow after 20 minutes resulted in greater AUCs for drug delivery, MAP, and max dP/dt for the larger V. Adding a second infusion to a steady-state norepinephrine plus carrier flow initially resulted in a drug bolus in vitro and augmented contractility response in vivo, both greater with a larger V. Steady-state drug delivery resumed before the secondary infusion finished. After the end of the secondary infusion drug delivery, MAP and max dP/dt decreased over minutes. Drug delivery and max dP/dt returned to steady state more quickly with the small V. CONCLUSIONS: Stopping and resuming a carrier flow, or introducing a second medication infusion, impacts drug delivery in vitro and biologic response in vivo. Infusion systems with small dead-volumes minimize these perturbations and dampen the resulting hemodynamic instability. Alterations in carrier flow impact drug delivery, resulting in substantial effects on physiologic responses. Therefore, infusion systems for vasoactive drugs should be configured with small V when possible.

Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure.

Clinical right ventricular (RV) impairment can occur with left ventricular assist device (LVAD) use, thereby compromising the therapeutic effectiveness. The underlying mechanism of this RV failure may be related to induced abnormalities of septal wall motion, RV distension and ischemia, decreased LV filling, and aberrations of LVAD flow. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, may reduce RV afterload, and thereby increase LV filling, LVAD flow, and cardiac output (CO). To investigate the mechanisms associated with LVAD-induced RV dysfunction and its treatment, we created a swine model of hypoxia-induced pulmonary hypertension and acute LVAD-induced RV failure and assessed the physiological effects of NO. Increased LVAD speed resulted in linear increases in LVAD flow until pulse pressure narrowed. Higher speeds induced flow instability, LV collapse, a precipitous fall of both LVAD flow and CO. Nitric oxide (20 ppm) treatment significantly increased the maximal achievable LVAD speed, LVAD flow, CO, and LV diameter. Nitric oxide resulted in decreased pulmonary vascular resistance and RV distension, increased RV ejection, promoted LV filling and improved LVAD performance. Inhaled NO may thus have broad utility for the management of biventricular disease managed by LVAD implantation through the effects of NO on LV and RV wall dynamics.

Morphological assessment of pancreatic islet hormone content following aerobic exercise training in rats with poorly controlled Type 1 diabetes mellitus.

Regular exercise has been shown to improve many complications of Type 1 diabetes mellitus (T1DM) including enhanced glucose tolerance and increased cardiac function. While exercise training has been shown to increase insulin content in pancreatic islets of rats with T1DM, experimental models were severely hyperglycemic and not undergoing insulin treatment. Further, research to date has yet to determine how exercise training alters glucagon content in pancreatic islets. The purpose of the present investigation was to determine the impact of a 10-week aerobic training program on pancreatic islet composition in insulin-treated rats with T1DM. Second, it was determined whether the acute, exercise-mediated reduction in blood glucose experienced in rats with T1DM would become larger in magnitude following aerobic exercise training. Diabetes was induced in male Sprague-Dawley rats by multiple low dose injections of streptozotocin (20mg/kg i.p.) and moderate intensity aerobic exercise training was performed on a motorized treadmill for one hour per day for a total of 10 weeks. Rats with T1DM demonstrated significantly less islet insulin, and significantly more islet glucagon hormone content compared with non-T1DM rats, which did not significantly change following aerobic training. The reduction in blood glucose in response to a single exercise bout was similar across 10 weeks of training. Results also support the view that different subpopulations of islets exist, as small islets (<50 µm diameter) had significantly more insulin and glucagon in rats with and without T1DM.

Myocardial drug distribution generated from local epicardial application: potential impact of cardiac capillary perfusion in a swine model using epinephrine.

Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart not only enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively toward the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue.

Case report of an abscess developing at the site of a hematoma following a direct lateral interbody fusion.

BACKGROUND CONTEXT: A direct lateral interbody fusion (DLIF) is relatively new, yet commonly performed procedure in spine surgery. This procedure is associated with risk, including damage to nerve or vascular structures. However, to our knowledge, there has not been a case of an abscess developing at the site of a postoperative hematoma after this procedure. PURPOSE: The objective was to document a case of the delayed presentation of an abscess at the site of a postoperative hematoma after a DLIF. STUDY DESIGN/SETTING: The study was designed to be a case report and literature review. METHODS: We present a case of a 63-year-old patient who developed a large retroperitoneal hematoma after an L2-L5 DLIF. The patient developed a postoperative urinary tract infection with cultures positive for Pseudomonas. The infection was treated with oral antibiotics. Eight months after her procedure, the patient was found to have developed an abscess (measuring 11.6 × 8.4 × 10.0 cm) at the site of the prior hematoma. RESULTS: After radiological-guided aspiration and a 2-week course of oral antibiotics, the abscess resolved and the patient recovered with no sequelae. CONCLUSION: Direct lateral interbody fusion is a minimally invasive procedure that may result in postoperative hematoma formation. We have reported a case of the development of an abscess at the site of a postoperative hematoma.

The 100 most cited spine articles.

PURPOSE: Spine-related research has evolved dramatically during the last century. Significant contributions have been made by thousands of authors. A citation rank list has historically been used within a particular field to measure the importance of an article. The purpose of this article is to report on the 100 most cited articles in the field of spine. METHODS: Science Citation Index Expanded was searched for citations in 27 different journals (as of 30 November 2010) chosen based on the relevance for all cited spine publications. The top 100 most cited articles were identified. Important information such as journal, date, country of origin, author, subspecialty, and level of evidence (for clinical research) were compiled. RESULTS: The top 100 publications ranged from 1,695 to 240 citations. Fifty-three articles were of the lumbar, 17 were of the thoracolumbar, and 15 of the cervical spine. Eighty-one of the articles were clinical and 19 were basic science in nature. Level of evidence varied for the clinical papers, however, was most commonly level IV (34 of 81 articles). Notably, the 1990-1999 decade was the most productive period with 43 of the top 100 articles published during this time. CONCLUSIONS: Identification of the most cited articles within the field of spine recognizes some of the most important contributions in the peer-reviewed literature. Current investigators may utilize the aspects of their work to guide and direct future spine-related research.

Efficacy of preoperative home use of 2% chlorhexidine gluconate cloth before shoulder surgery.

HYPOTHESIS: Deep infection after shoulder surgery is a rare but devastating problem. This study tested the hypothesis that the home application of a 2% chlorhexidine gluconate cloth before shoulder surgery would be more efficacious than a standard shower of soap and water at decreasing the preoperative cutaneous levels of pathogenic bacteria on the shoulder. MATERIALS AND METHODS: This randomized, prospective study evaluated 100 consecutive patients undergoing shoulder surgery. Patients were randomly assigned to use 2% chlorhexidine gluconate-impregnated cloths (treatment group) or to shower with soap and water before surgery (control group). Cutaneous cultures were taken from the patients'shoulders in the preoperative holding area. Patients were monitored for 2 months postoperatively for clinical signs of infection. RESULTS: In the treatment group vs the control group, the overall positive culture rate was 66% vs 94% (P = .0008), and the positive culture rate for coagulase-negative Staphylococcus was 30% vs 70% (P = .0001). The positive culture rate for Propionibacterium acnes was 46% in the treatment group vs 58% in the control group (P = .32). No infections occurred in any patients at a minimum of 2-months after surgery. DISCUSSION: The use of the 2% chlorhexidine cloth was effective at decreasing overall bacterial culture rates before shoulder surgery and was particularly effective at decreasing the quantity of coagulase-negative Staphylococcus, a known causative agent of postoperative shoulder infections. CONCLUSION: Use of chlorhexidine impregnated cloths prior to shoulder surgery may be a useful adjunct to presently used infection prevention strategies.

Identification of quantitative trait loci for chemical/inflammatory nociception in mice.

Sensitivity to pain is widely variable, and much of this variability is genetic in origin. The specific genes responsible have begun to be identified, but only for thermal nociception. In order to facilitate the identification of polymorphic, pain-related genes with more clinical relevance, we performed quantitative trait locus (QTL) mapping studies of the most common assay of inflammatory nociception, the formalin test. QTL mapping is a technique that exploits naturally occurring variability among inbred strains for the identification of genomic locations containing genes contributing to that variability. An F2 intercross was constructed using inbred A/J and C57BL/6J mice as progenitors, strains previously shown to display resistance and sensitivity, respectively, to formalin-induced nociception. Following phenotypic testing (5% formalin, 25 microl intraplantar injection), mice were genotyped at 90 microsatellite markers spanning the genome. We provide evidence for two statistically significant formalin test QTLs - chromosomal regions whose inheritance is associated with trait variability - on distal mouse chromosomes 9 and 10. Identification of the genes underlying these QTLs may illuminate the basis of individual differences in inflammatory pain, and lead to novel analgesic treatment strategies.