Biomechanical analysis of the FlatWire Figure 8 sternal fixation device

OBJECTIVE:

To determine whether the FlatWire Figure 8 sternal fixation device (Penn United, USA) is mechanically superior to the current standard in sternotomy closure.

DESCRIPTION:

Unstable sternal closure using traditional steel-wire cerclage can increase postoperative pain, bony cut-through and wound dehiscence. The authors present the Figure 8 sternal fixation device to minimize these complications. Biomechanical properties of the device were compared with conventional steel wire sternal repair.

EVALUATION:

Using two constructs of both FlatWire and steel wire, pull-to-failure, Hertzian contact and cut-through were compared. Samples were tested to 500,000 cycles or failure. Cyclic comparisons were performed using log-rank t tests and Student’s t tests for cut-through analysis. FlatWires were found to have superior biomechanical properties in all categories tested.

CONCLUSION:

The FlatWire provides superior biomechanical properties compared with conventional steel wire, which may lead to reduced sternal wound complications.     

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta

Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK α and ζ synergistically promote T cell maturation in the thymus. Absence of both DGKα and ζ (DGKα^−/−ζ^−/−) results in a severe decrease in the number of CD4⁺CD8⁻ and CD4⁻CD8⁺ single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGKα^−/−ζ^−/− mice. The developmental blockage in DGKα^−/−ζ^−/− mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.     

Nerve Growth Factor Expression after Plantar Incision in the Rat

Background: Postoperative pain control remains a significant problem. Advances will proceed if we can further reveal the underlying mechanisms of incisional pain and its mediators. Previous studies have demonstrated that nerve growth factor (NGF) is released in incised tissue and contributes to hyperalgesia in incisional pain. The purpose of this study is to examine the expression of NGF in skin after planter incision.

Methods: Adult Sprague-Dawley rats underwent incision at the plantar aspect of hind paw. The NGF messenger RNA (mRNA) was measured at various times after incision by polymerase chain reaction. NGF protein expression was detected by Western blot and immunohistochemistry in incisions.

Results: NGF mRNA increased from 2 to 4 h after incision and was the same as control by postoperative day 1. A large-molecular-weight form of NGF, approximately 75 kd, was found in normal skin. The large-molecular-weight NGF protein increased 4 h after incision and returned to baseline on postoperative day 7. The skin immediately adjacent to the incision had the greatest NGF expression. Immunohistochemical staining for NGF was present adjacent to the incision and localized in Schwann cells and axons.     

Correlation between synthetic activity and glycosaminoglycan concentration in epiphyseal cartilage raises questions about the regulatory role of interstitial pH

Current data provide compelling evidence that the pH of the interstitial fluid of cartilage is an important determinant of the metabolic activity of chondrocytes, and this has served as the basis for a mechanistic proposal whereby chondrocytes could sense mechanical compression. The objective of the current study was to test this hypothesis further by examining biosynthetic activity in cartilage as a function of glycosaminoglycan content, which is the major determinant of interstitial pH. On the basis of previous data, increased biosynthetic activity would be anticipated to correlate with a decreased glycosaminoglycan content and an elevated interstitial pH. In contrast to our expectations, we found that the biosynthetic activity (monitored by measurement of incorporation of sulfate and proline) was positively correlated with the glycosaminoglycan content of tissue. These results raise doubt as to whether interstitial pH provides a dominant mechanism for controlling the metabolism of chondrocytes.     

A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro

BACKGROUND: Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known. OBJECTIVE: We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6. METHODS: Airway smooth muscle cells from individuals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from individuals without asthma were incubated with TGF-beta with or without the drugs. RESULTS: Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin. CONCLUSION: In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma. CLINICAL IMPLICATIONS: Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.     

Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle

Transforming growth factor (TGF)-beta and connective tissue growth factor may be implicated in extracellular matrix protein deposition in asthma. We have recently reported that TGF-beta increased connective tissue growth factor expression in airway smooth muscle cells isolated from patients with asthma. In this study, we examined fibronectin and collagen production and signal transduction pathways after stimulation with TGF-beta and connective tissue growth factor. In both asthmatic and nonasthmatic airway smooth muscle cells, TGF-beta and connective tissue growth factor led to the production of fibronectin and collagen I. Fibronectin and collagen expression was extracellular regulated kinase-dependent in both cell types but phosphoinositide-3 kinase-dependent only in asthmatic airway smooth muscle cells. p38 was implicated in fibronectin but not collagen expression in both cell types. TGF-beta induction of fibronectin and collagen was in part mediated by an autocrine action of connective tissue growth factor. Phosphorylation of SMAD-2 may represent an additional pathway because this was increased in asthmatic cells. Our results suggest that these two cytokines may be important in the deposition of extracellular matrix proteins and that the signal transduction pathways may be different in asthmatic and nonasthmatic cells.     

Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons

Multiple gene defects cause Batten disease. Accelerated apoptosis accounts for neurodegeneration in the late infantile and juvenile forms that are due to defects in the CLN3 and CLN2 genes. Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina. When neurons in late infantile and juvenile brain survive, they manage to do so by upregulating the neuroprotective molecule Bcl-2. The CLN3 gene has antiapoptotic properties at the molecular level. We show that the CLN2 gene is neuroprotective: it enhances growth of NT2 cells and maintains survival of human postmitotic hNT neurons. Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis. The drug flupirtine is a triaminopyridine derivative that acts as a nonopioid analgesic. Flupirtine upregulates Bcl-2, increases glutathione levels, activates an inwardly rectifying potassium channel, and delays loss of intermitochondrial membrane calcium retention capacity. We show that flupirtine aborts etoposide-induced apoptosis in CLN1-, CLN2-, CLN3-, and CLN6-deficient as well as normal lymphoblasts. Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level. We show that a mechanism of neuroprotection exerted by flupirtine involves complete functional antagonism of N-methyl-D-aspartate or N-methyl-D-aspartate-induced neuronal apoptosis. Flupirtine may be useful as a drug capable of halting the progression of neurodegenerative diseases caused by dysregulated apoptosis.