Design and preliminary testing of an active intramedullary nail.

PURPOSE: To enhance bone healing through controlled interfragmentary movements, numerous experiments have been conducted in animal models employing external fixation devices to apply mechanical stimulation to the fracture site. However, the efficacy of these fixators has been questioned. On the other hand, intramedullary nailing is a widely established clinical practice for reducing closed tibial fractures. MATERIAL AND METHODS: In an effort to enhance bone healing, to overcome the disadvantages of external fixators (i.e., non-uniform linear movement), and to enhance the advantages of intramedullary nailing (i.e., reduced risk of infection), an active intramedullary nail has been designed and fabricated. Active nail will provide controlled in-situ stimulation (simultaneously axial and shear) from a selectable acceleration (0.35 to 8.17g - axial and 0.44g to 10.46 g - shear), associated to a discreet set of high-frequency values (29.82 - 172.05 Hz - axial and 29.68 to 172.13 - shear). RESULTS: Five active intramedullary nails were fabricated, capable of producing average acceleration between 0.35 and 10.4 g. Acceleration is applied simultaneously by all three axes (x, y, and z), resulting in axial and shear stimulation. For each acceleration level, there are a limited number of frequencies that can be selected. For each frequency, there are a limited number of acceleration levels that can be delivered. Bone morphology produces different levels of acceleration in each axe. Acceleration levels are controlled externally only by the variable power source (1.5VDC to 6VDC). Accelerated in-vitro testing showed that the life of the device exceeded the required active period. Mechanical test showed that in case of failure of the active component, the active intramedullary nail will act as a standard nail, allowing bone healing to continue its normal course. Ex vivo experiments were conducted inserting one active intramedullary nail in two intact adult sheep tibia. Results indicate that the strain induced by the active intramedullary nail (from 18.62 µÎµ to 38.13 µÎµ) has been reported to be osteogenic. Additional experiments are required in order to statistically validate the strain that can be induced in vivo by the active intramedullary nail. Also, in vivo experiments using simple fractures of the tibial shaft need to be conducted in order to assess if effectively, applying active mechanical stimulation in situ enhances bone healing.

The VYtorin on Carotid intima-media thickness and overall arterial rigidity (VYCTOR) study.

This study assessed the effect of 3 lipid-lowering therapies on the reduction of the carotid intima-media thickness (IMT) in high-risk coronary Mexican patients. The study was a randomized, comparative, and open clinical trial. Ninety high-risk coronary patients were allocated to 3 groups: pravastatin 40 mg, simvastatin 40 mg, and simvastatin 20 mg and ezetimibe 10 mg initially. If the therapeutic goals were not attained (<100 mg/dL of low-density lipoprotein cholesterol [LDL-C] for type C and <70 mg for type D), patients in group 1 received pravastatin 40 mg and ezetimibe 10 mg, group 2 received simvastatin 80 mg, and group 3 received simvastatin 40 mg and ezetimibe 10 mg. The primary endpoint was the change of IMT over the course of 1 year. The secondary endpoints were changes in LDL-C and in high sensitive C-reactive protein (CRPhs). The overall baseline IMTs generated by combining measurements in the internal carotid artery were 1.33+/-0.32 mm, 1.30+/-0.11 mm, and 1.23+/-0.28 mm for groups 1, 2, and 3, respectively. After 1 year, IMT values were 0.93+/-0.13 mm, 0.90+/-0.11 mm, and 0.92+/-0.01 mm for groups 1, 2, and 3, respectively. At the end of the study, LDL-C levels were 48+/-41, 45+/-37, and 48+/-31 in groups 1, 2, and 3, respectively. No significant differences were observed in CRP, high-density lipoprotein cholesterol, triglycerides, blood pressure, and body mass index, among the groups. This study is one of the first providing evidence that dual therapy has a beneficial effect on a surrogate marker of atherosclerosis.

Intraluminal-restricted 17 beta-estradiol exerts the same myocardial protection against ischemia/reperfusion injury in vivo as free 17 beta-estradiol.

Several in vitro studies show that in animals and isolated cells, 17 beta-estradiol induces cardiovascular protective effects and it has also been observed that it reduces coronary heart disease risk. However, the use of estrogens to improve or protect cardiovascular function in humans has been controversial, this might be explained by the wide variety of effects, because estrogen receptors (ER) are expressed ubiquitously. Therefore, a cell-specific targeting therapeutic approach might be necessary. 17 beta-Estradiol was coupled to a large modified dextran through an aminocaproic spacer. For this study we used intact and gonadectomized male Wistar rats, 15 days after surgical procedure. Intravascular administration of 17 beta-estradiol-macromolecular conjugate, prior to coronary reperfusion diminishes the area of damage induced by coronary ischemia reperfusion (I/R) injury on an in vivo model. This effect was observed at 17 beta-estradiol sub-physiological concentrations [0.01 nmol/L], it is mediated by luminal endothelial ER alpha activation. 17 beta-Estradiol-macromolecular conjugate decreases phosphorylation level of PKC alpha and Akt, as part of the process to induce myocardial protection against coronary I/R. We proved that the hormone-macromolecular conjugate labeled with [3H]estradiol remained confined in the intravascular space the conjugate was not internalized into organs like heart, lung or liver. It is noteworthy that the 17 beta-estradiol-macromolecular conjugate has a slow renal elimination, which might increase its pharmacological advantage. We concluded that the stimulus of endothelial estrogen receptors is enough to decrease the myocardial damage induced by coronary reperfusion.

Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study.

1. Metabolic syndrome (MS) is one of the greatest public health problems in Mexico, where more than 75% of adults in urban populations are overweight or obese. Metabolic syndrome has several comorbidities, which result in a high cardiometabolic risk. 2. Some of the vasopathogenic phenomena in MS are caused by nitroxidant stress, secondary to cardiometabolic dysfunction. 3. The action of metformin to diminish or control MS remains a matter of debate. 4. In the present study, 60 patients with at least three diagnostic criteria for MS were divided into two groups. Both groups received similar dietary counselling, but one group was given 850 mg metformin daily. 5. The variables assessed were body mass index, waist circumference, systolic and diastolic blood pressures (SBP and DBP, respectively), total cholesterol (TC), high- and low-density lipoprotein-cholesterol, triglycerides (TG), fasting glucose, nitroxidant metabolites (free carbonyls, malondialdehyde, dityrosines and advanced oxidative protein products (AOPP)), nitric oxide (NO), carotid vascular stiffness, carotid intima-media thickness (IMT) and C-reactive protein (CRP). 6. After 1 year follow up, both groups reported weight loss, as well as decreases in waist circumference, SBP and DBP. 7. Patients on metformin exhibited reductions in TC and IMT and there were marked changes in nitroxidation: levels of carbonyls, dityrosines and AOPP were reduced, whereas those of NO were increased, indicating better endothelial function. In addition, in patients given metformin, CRP levels decreased. 8. In conclusion, metformin has a considerable beneficial effect on nitroxidation, endothelial function and IMT in patients with MS.

Differential expression of alpha1-adrenergic receptor subtypes in coronary microvascular endothelial cells in culture.

It has been postulated that in blood vessels under alpha(1)-related stimulation, the endothelial intracellular calcium concentration ([Ca(2+)](i)) increases, which is necessary to induce nitric oxide synthesis, is the result of an increase in vascular smooth muscle, which subsequently, flows into the endothelial cells through gap junctions and it is not the result of a direct adrenergic stimulation of endothelial receptors. Others, however, postulate that endothelial alpha(1D)-adrenoceptors, have a direct effect on nitric oxide synthesis. In order to clarify this phenomena, in this work we analyzed the presence of alpha(1)receptor subtypes and their functional association with nitric oxide synthesis in rat coronary microvascular endothelial cells in culture, with pharmacological, immunological and reverse transcriptase polymerase chain reaction approaches. Our results show the presence and functional coupling with nitric oxide synthesis of alpha(1A) and alpha(1D)-adrenoceptor subtypes. alpha(1B)-adrenoceptor subtype is not coupled with nitric oxide production.

The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy.

Diabetes has emerged as a major threat to worldwide health. The increasing incidence of diabetes in young individuals is particularly worrisome given that the disease is likely to evolve over a period of years. In 1972, the existence of a diabetic cardiomyopathy was proposed based on the experience with four adult diabetic patients who suffered from congestive heart failure in the absence of discernible coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism. The exact mechanisms underlying the disease are unknown; however, an important component of the pathological alterations observed in these hearts includes the accumulation of extracellular matrix (ECM) proteins, in particular collagens. The excess deposition of ECM in the heart mirrors what occurs in other organs such as the kidney and peritoneum of diabetics. Mechanisms responsible for these alterations may include the excess production, reduced degradation, and/or chemical modification of ECM proteins. These effects may be the result of direct or indirect actions of high glucose concentrations. This article reviews our state of knowledge on the effects that diabetes-like conditions exert on the cells responsible for ECM production as well as relevant experimental and clinical data.

Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E.

Long-standing diabetes can result in the development of cardiomyopathy, which can be accompanied by myocardial fibrosis. Although exposure of cultured kidney and skin fibroblasts to high glucose (HG) concentration is known to increase collagen synthesis, little is known about cardiac fibroblasts (CFs). Therefore, we determined the influence of HG conditions on CF functions and the effects of losartan and vitamin E in these responses. We cultured rat CFs in either normal glucose (NG; 5.5 mM) or HG (25 mM) media and assessed changes in protein and collagen synthesis, matrix metalloproteinase (MMP) activity, and levels of mRNA for ANG II type 1 (AT(1)) receptors. Results indicate that HG-level CFs synthesized more protein and collagen, and these effects were not due to changes in osmotic pressure. The addition of ANG II stimulated protein and collagen synthesis in NG-concentration but not HG-concentration CFs. Interestingly, losartan pretreatment blocked the HG- or ANG II-induced increases in both protein and collagen synthesis. HG or ANG II decreased total MMP activity. Decreases in MMP activity were blocked by losartan. AT(1) mRNA levels were upregulated with HG concentration. Vitamin E pretreatment blocked the effects of HG on total protein synthesis and stimulated MMP activity. Results suggest that HG levels may promote fibrosis by increasing CF protein and collagen synthesis and decreasing MMP activity. HG levels may cause these effects via the upregulation of AT(1) receptors, which can be blocked by losartan. However, vitamin E can alter HG concentration-induced changes in CF functions independently of AT(1) mRNA levels.

Caveolin scaffolding peptide-1 interferes with norepinephrine-induced PLC-beta activation in cultured rat vascular smooth muscle cells.

Caveolins are a family of integral membrane proteins implicated in various cell functions, including the organization and inactivation of signaling molecules of G protein-coupled receptors. We tested the ability of human caveolin scaffolding peptide-1 (CSP-1) to regulate norepinephrine- (NE) or histamine (HIS)-induced increases on intracellular calcium concentrations ([Ca(2+)]i). In cultured rat vascular smooth muscle cells (VSMC), CSP-1 inhibited in a concentration-dependent manner NE- and HIS-induced increases in [Ca(2+)]i. This effect can be explained by the fact that CSP-1 inhibited a common signaling pathway. We tested the ability of this peptide to decrease the activation of PLC-beta3 and MAPK. CSP-1 inhibited the expression of the activated form of both enzymes, suggesting a direct effect of the peptide on the signaling cascade. CSP-1 readily enters VSMC in culture, as observed when FITC-conjugated CPS-1 is added to cell culture media. Taken together, these data suggest that CSP-1 blocks the effects of NE and HIS on [Ca(2+)]i of VSMC by inhibiting the activation of PLC-beta3 and MAPK.