Local insulin-zinc injection accelerates skin donor site wound healing

BACKGROUND: Systemically administered insulin has been shown to accelerate wound healing. To minimize the hypoglycemic and hypokalemic effects of insulin, we investigated a new route of insulin administration by local injection into skin wounds. MATERIALS AND METHODS: Partial thickness skin donor site wounds were created on the backs of adult rabbits with a dermatome set at 0.015 inch. The wounds were covered by Aquaphor gauze (Smith and Nephew, Largo, FL), and OpSite membrane (Smith and Nephew, Hull, United Kingdom) and protected by rabbit jackets. Long-acting insulin-zinc suspension was selected for local injection. In study 1, insulin was injected into the wound at different doses, and the concentrations of blood glucose and wound insulin were measured to determine the proper dose and injection frequency. In study 2, wound healing days were compared between two groups (n = 7 each) receiving local injection of either insulin-zinc or zinc alone as control. Based on the results from study 1, a dose of 0.25 units of long-acting insulin-zinc suspension was injected into the wound every other day in the insulin group. RESULTS: After injection, 0.25 units of insulin decreased blood glucose concentration (minimum 60 mg/dL) during the first 3 h, which then returned to the preinjection level (80 mg/dL). One injection maintained wound insulin concentration above 50 muU/mL for more than 24 h. With local injection of 0.25 units insulin-zinc every other day, the wound healing time was 11.2 +/- 2.3 d, which was faster (P = 0.02) than 15.1 +/- 4.1 d in the control group. CONCLUSION: Local injection of long-acting insulin-zinc suspension accelerated skin wound healing without major systemic side effects, demonstrating its potential usefulness in burn treatment.     

Isoniazid-related hepatic failure in children: a survey of liver transplantation centers

BACKGROUND: Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients. METHODS: The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database. RESULTS: Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH. CONCLUSIONS: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.     

Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats

Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.     

Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts.

Osteogenesis is synergistically enhanced by the combined effect of complimentary factors. This study showed that Nell-1 and BMP-2 synergistically enhanced osteogenic differentiation of myoblasts and phosphorylated the JNK MAPK pathway. The findings are important because of the osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of coordinated BMP-2 and Nell-1 delivery. INTRODUCTION: BMPs play an important role in the migration and proliferation of mesenchymal cells and have a unique ability to alter the differentiation of mesenchymal cells toward chondrogenic and osteogenic lineages. Signaling upstream of Cbfa1/Runx2, BMPs effects are not limited to cells of the osteoblast lineage. Thus, additional osteoblast-specific factors that could synergize with BMP-2 would be advantageous for bone regeneration procedures. NELL-1 (NEL-like molecule-1; NEL [a protein strongly expressed in neural tissue encoding epidermal growth factor like domain]) is a novel growth factor believed to preferentially target cells committed to the osteochondral lineage. MATERIALS AND METHODS: C2C12 myoblasts were transduced with AdLacZ, AdNell-1, AdBMP-2, or AdNell-1+AdBMP-2 overexpression viruses. Effects were studied by cell morphology, alkaline phosphatase activity, osteopontin production, and MAPK signaling. Additionally, in a nude mouse model, viruses were injected into leg muscles, and new bone formation was examined after 2 and 8 wk. RESULTS: C2C12 myoblasts co-transduced with AdNell-1+AdBMP-2 showed a synergistic effect on osteogenic differentiation as detected by alkaline phosphatase activity and osteopontin production. Nell-1 stimulation on AdNell-1 + AdBMP-2 preconditioned C2C12 cells revealed significant activation of the non-BMP-2 associated c-Jun N-terminal kinase (JNK) MAPK signaling pathway, but not the p38 or extracellular signal-regulated kinase (ERK1/2) MAPK pathways. Importantly Nell-1 alone did not induce osteogenic differentiation of myoblasts. In a nude mouse model, injection of AdNell-1 alone stimulated no bone formation within muscle; however, injection of AdNell-1+AdBMP-2 stimulated a synergistic increase in bone formation compared with AdBMP-2 alone. CONCLUSIONS: These findings are important because of the confirmed osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of enhanced BMP-2 action with coordinated Nell-1 delivery.     

重症急性胰腺炎死亡的高危因素分析

目的探讨与重症急性胰腺炎（SAP）死亡相关的高危因素。方法回顾性分析2001年1月至2005年10月收治的141例SAP患者的临床资料。将患者分为死亡组和生存组,对可能影响SAP预后的15个因素采用Logistic回归分析。结果141例SAP患者中死亡34例（24．1％）。死亡组患者在年龄、体重指数、住院时间、APACHEⅡ评分和并发多器官功能障碍综合征（MODS）、腹腔室隔综合征（ACS）等方面与生存组相比差异有统计学意义（P〈0．05）。多因素分析显示,MODS（OR=67．358,P〈0．01）、APACHEII评分（OR=9．716,P〈0．01）和ACS（OR=5．775,P〈0．05）是早期影响SAP预后的独立危险因素;胰腺感染（OR=9．652,P〈0．01）、MODS（OR=5．212,P〈0．05）和腹腔出血（OR=4．707,P〈0．05）则是后期影响SAP预后的独立危险因素。结论SAP早期死亡的主要原因是MODS,特别是呼吸功能障碍和肾功能障碍,而后期死亡的主要原因是感染、MODS和腹腔出血。对高危因素进行早期预防和及时处理是降低SAP病死率的关键。     

Influence of acute normovolaemic haemodilution on the dose-response relationship and time course of action of cisatracurium besylate

BACKGROUND: Acute normovolaemic haemodilution (ANH) is an efficacious bloodconservation strategy aiming at avoiding allogeneic blood transfusion.ANH was shown to increase the potency of vecuronium, atracurium,and rocuronium. The aim of our study was to investigate whethercisatracurium potency is altered with ANH. METHODS: Using the Relaxometer mechanomyograph, we compared cisatracuriumdose–response relationship and time course of action in60 patients randomly allocated to the ANH or control groups.Patients in each group were randomly allocated to receive oneof three cisatracurium doses (30, 40, 50 µg kg^–1)followed by a second supplemental dose to reach a total of 100 µg kg^–1. RESULTS: ANH did not result in a significant shift in cisatracurium logdose–probit dose–response curve. There was no significantdifference in mean (95% confidence intervals) ED₅₀, ED₉₀, andED₉₅ (effective doses required for 50, 90, and 95% first twitchdepression) between the ANH group [29.5 (27–32), 50.4(47.4–53.4), 58.7 (55.3–62) µg kg^–1]and the control group [28.2 (25.3–31), 47.6 (44.9–50.3),55.3 (52.5–58.1) µg kg^–1], whereasthere was no difference in mean (SD) Dur₂₅ and Dur_0.8 (timeuntil 25% first twitch and 0.8 train-of-four ratio recoveries)between the ANH group [40.8 (5.9), 64.7 (8.4) min] and the controlgroup [42.2 (7.6), 66.5 (10.7) min]. CONCLUSIONS: Our results demonstrated that unlike other previously reportedneuromuscular blocking drugs, ANH did not alter cisatracuriumpotency. Thus, cisatracurium would be the neuromuscular blockingdrug of choice in patients who undergo surgery with ANH, asno dose adjustments are required.     

Elevation of intact parathyroid hormone level is a risk factor for low bone mineral density in pretransplant patients with liver diseases

The purpose of this study was to investigate the frequency and risk factors for low bone mineral density (BMD) among patients awaiting liver transplantation. BMD of the lumbar spine (LS) and femoral neck (FN), measured by dual-energy X-ray absorptiometery (DEXA), were obtained in 64 pretransplant patients. We measured markers of bone metabolism including serum calcium, phosphorus, serum 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline/creatinine (DPD/Cr) ratio. Osteoporosis and osteopenia (low BMD) were observed in 36 patients (36/64, 56.2%), including 6 cases of osteoporosis (6/64, 9.3%) and 30 cases of osteopenia (30/64, 46.9%). Of all variables, cholestatic liver disease and elevated levels of iPTH were significantly associated with low BMD. Moreover, elevated iPTH level was identified as an independent risk factor for low BMD (P<.05, OR=1.017, 95% CI=1.001-1.032) by multivariate analysis. The median level of iPTH was increased to 55.6 pg/mL (range, 7.8-337 pg/mL) in the low BMD group, while the median level was 33 pg/mL (range, 3-162 pg/mL) in the normal BMD group (P<.05). This study revealed a high incidence of low BMD in the pretransplant patients with liver diseases. The elevated iPTH level was the predominant risk factor for low BMD. We suggest that both BMD and iPTH examinations be considered routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.     

Requirement of MyD88 for macrophage-mediated islet xenograft rejection after adoptive transfer

BACKGROUND: Porcine antigen primed and CD4+ T-cell activated macrophages are able to migrate to and destroy porcine xenografts. However, the specific signaling mechanisms involved remain to be identified. METHODS: In this study macrophages which lack the universal toll-like receptor (TLR) adaptor MyD88 were used to investigate the role of TLR in the recognition and activation of macrophages in islet xenograft rejection. Macrophages were isolated from rejecting MyD88(-/-) and wild-type C57BL/6 mice that were recipients of neonatal porcine pancreatic cell cluster (NPCC) xenografts, and were transferred to NPCC recipient NOD-SCID mice. RESULTS: Both wild-type C57BL/6 and MyD88(-/-) mice rejected NPCC xenografts 8 and 10 days, respectively after transplantation, and the grafts were heavily infiltrated with CD4+ T cells and macrophages. However, graft infiltrating macrophages from rejecting MyD88(-/-) recipients demonstrated impaired up-regulation of TLR expression and impaired activation phenotype, when compared to those from rejecting C57BL/6 recipients. Transfer of NOD-SCID recipients with macrophages from rejecting C57BL/6 mice resulted in NPCC xenograft rejection along with massively infiltrated macrophages 8 days after transfer, whereas NPCC xenografts in NOD-SCID mice transferred with macrophages from rejecting MyD88(-/-) mice remained intact until the end of this study, 90 days after transfer, with insulin-positive islets and no infiltration by macrophages. CONCLUSION: This study demonstrates that deletion of MyD88 causes impaired macrophage activation after pig islet xenotransplantation. However, graft survival is not prolonged and xenografts are rejected rapidly by alternate mechanisms.