Patient experience from a doctor's perspective: A case report concerning treatment, fracture healing and rehabilitation of multiple complex injuries due to a high energy motor vehicle collision.

A 35-year old healthy male trauma surgery chief resident, suffered a high-speed motor vehicle collision. The patient sustained the following injuries: a Gustilo-Anderson grade 2 open comminuted intra-articular fracture of the left distal femur (AO 33C3.3), a Hawkins 1A neck fracture of the right talus (AO 81.2A), an undisplaced Lisfranc injury of the right foot comprising avulsion fractures at the base of the 1st, 2nd and 5th metatarsal as well as the cuboid bone suggesting ligament injury and 2nd to 5th carpometacarpal dislocations of the right (non-dominant) hand with comminuted fractures of the capitate, hamate, trapezoid and the base of the fifth metacarpal bone. A staged-treatment approach ensued. An external fixator (ex-fix) was placed over the left knee, followed by definitive fixation of the distal femoral fracture using a Qwix screw, Non-Contact Bridging (NCB) plate and Locking Compression Plate (LCP). An ex-fix was placed over the right wrist, followed by open reduction and k-wire fixation. The talar fracture of the right foot was treated with a single lag screw and the Lisfranc injury was treated non-operatively with four weeks of non-weight bearing cast immobilization. An intensive clinical rehabilitation program was started, including early use of Continuous Passive Motion (CPM), daily non-weightbearing swimming pool exercises, hand, physical and recreational therapy. One year after the injury the patient was rehabilitated and resumed his surgical residency. Two years after the injury, limited flexion and pain in the left leg remains, possibly related to partial union of the femoral fracture. Range of motion (ROM) of the right ankle and wrist remains limited, not causing significant functional impairment. Lessons learned from a patient experience combined with detailed descriptions of injuries, rehabilitation and long term outcomes can be used as a reference for treating patients with comparable injuries.

Young women's psychological distress after a diagnosis of polycystic ovary syndrome or endometriosis.

STUDY QUESTION: Do young women with polycystic ovary syndrome (PCOS) or endometriosis report more psychological distress than their peers without a history of these conditions? SUMMARY ANSWER: Young women (aged 18-23 years) with PCOS or endometriosis had a greater risk of moderate to severe psychological distress than women without a history of these conditions. WHAT IS KNOWN ALREADY: Psychological distress appears common among women with PCOS and endometriosis. However, population-based studies that examine the psychological outcomes for adolescents and young women are generally absent from the literature. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of data collected from 17 015 young, Australian women participating in a national, longitudinal cohort study. Women were first surveyed in 2012-2013 when they were aged 18-23 years. In 2014, women completed the second survey when they were aged 19-24 years and 11324 (67%) women responded. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed data from 11 238 women who participated in both Surveys 1 and 2 and who responded to questions about PCOS and endometriosis. Using logistic regression, we compared the odds of moderate to severe psychological distress at Surveys 1 and 2 for women reporting a recent diagnosis (within the last 12 months) of PCOS or endometriosis and women with a pre-existing diagnosis, with that for women without a history of these conditions. MAIN RESULTS AND THE ROLE OF CHANCE: At Survey 2, around 60% of women reporting a diagnosis of PCOS or endometriosis had moderate to severe levels of psychological distress. Compared to women without a history of these conditions, the odds of moderate to severe psychological distress at Survey 2 were significantly higher for women recently diagnosed with PCOS [Adjusted Odds Ratio (AOR) = 1.62, 95% CI = 1.21-2.18] or endometriosis (AOR= 1.77; 95% CI = 1.20-2.63) and for women with a pre-existing diagnosis of PCOS (AOR = 1.57, 95% CI = 1.30-1.89) or endometriosis (AOR = 1.61; 95% CI = 1.26-2.06). Women recently diagnosed with PCOS or endometriosis also had a greater likelihood of moderate to severe distress in the year prior to their diagnosis. The association between PCOS and psychological distress was attenuated when adjusting for BMI, but hormonal contraceptive use did not attenuate the risk of distress among the women with PCOS or endometriosis. LIMITATIONS, REASONS FOR CAUTION: All data were self-reported and, therefore, the diagnoses of PCOS or endometriosis were not confirmed by a medical practitioner. WIDER IMPLICATIONS OF THE FINDINGS: Health professionals should be aware of the potential psychosocial and healthcare needs among young women with these conditions, particularly women with PCOS who are obese. While hormonal contraceptives may help to regulate the hormonal aspects of these conditions, they do not appear to reduce women's psychological distress. Because psychological distress among the young women in this study remained elevated even after diagnosis, this supports the need for multidisciplinary health care to help women adjust to their diagnosis and treatment regimens and facilitate positive, long-term mental health outcomes. Future research that examines medical and psychosocial sources of distress for young women with PCOS and endometriosis is needed. STUDY FUNDING/COMPETING INTERESTS: I.J.R. was supported by an Australian National Health and Medical Research Council Centre for Research Excellence (grant number: APP1000986). G.D.M. is funded by the Australian Research Council Future Fellowship (FT120100812). The Australian Longitudinal Study on Women's Health is funded by the Australian Government Department of Health. H.T. is supported by an Australian National Health and Medical Research Council Practitioner Fellowship. The authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Mesenchymal Stromal Cells Prevent Allostimulation In Vivo and Control Checkpoints of Th1 Priming: Migration of Human DC to Lymph Nodes and NK Cell Activation.

Although the immunomodulatory potency of mesenchymal stromal cells (MSC) is well established, the mechanisms behind are still not clear. The crosstalk between myeloid dendritic cells (mDC) and natural killer (NK) cells and especially NK cell-derived interferon-gamma (IFN-γ) play a pivotal role in the development of type 1 helper (Th1) cell immune responses. While many studies explored the isolated impact of MSC on either in vitro generated DC, NK, or T cells, there are only few data available on the complex interplay between these cells. Here, we investigated the impact of MSC on the functionality of human mDC and the consequences for NK cell and Th1 priming in vitro and in vivo. In critical limb ischemia patients, who have been treated with allogeneic placenta-derived mesenchymal-like stromal cells (PLX-PAD), no in vivo priming of Th1 responses toward the major histocompatibility complex (MHC) mismatches could be detected. Further in vitro studies revealed that mDC reprogramming could play a central role for these effects. Following crosstalk with MSC, activated mDC acquired a tolerogenic phenotype characterized by reduced migration toward CCR7 ligand and impaired ability to stimulate NK cell-derived IFN-γ production. These effects, which were strongly related to an altered interleukin (IL)-12/IL-10 production by mDC, were accompanied by an effective prevention of Th1 priming in vivo. Our findings provide novel evidence for the regulation of Th1 priming by MSC via modulation of mDC and NK cell crosstalk and show that off-the-shelf produced MHC-mismatched PLX-PAD can be used in patients without any sign of immunogenicity.

Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study.

BACKGROUND: Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age. METHODS: Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months). RESULTS: In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045). CONCLUSIONS: Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.

A longitudinal study of the bi-directional relationship between tobacco smoking and psychological distress in a community sample of young Australian women.

BACKGROUND: Tobacco smoking and poor mental health are both prevalent and detrimental health problems in young women. The temporal relationship between the two variables is unclear. We investigated the prospective bi-directional relationship between smoking and mental health over 13 years. METHOD: Participants were a randomly selected community sample of 10 012 young women with no experience of pregnancy, aged 18-23 years at baseline (1996) from the Australian Longitudinal Study on Women's Health. Follow-up surveys over 13 years were completed in 2000, 2003, 2006 and 2009, allowing for five waves of data. Measures included self-reported smoking and mental health measured by the Mental Health Index from the 36-item short-form health questionnaire and the 10-item Center for Epidemiologic Studies Depression Scale. Sociodemographic control variables included marital status, education level and employment status. RESULTS: A strong cross-sectional dose-response relationship between smoking and poor mental health was found at each wave [odds ratio (OR) 1.41, 95% confidence intervals (CI) 1.17-1.70 to OR 2.27, 95% CI 1.82-2.81]. Longitudinal results showed that women who smoked had 1.21 (95% CI 1.06-1.39) to 1.62 (95% CI 1.24-2.11) times higher odds of having poor mental health at subsequent waves. Women with poor mental health had 1.12 (95% CI 1.17-1.20) to 2.11 (95% CI 1.68-2.65) times higher odds of smoking at subsequent waves. These results held after adjusting for mental health history and smoking history and sociodemographic factors. Correlation analysis and structural equation modelling results were consistent in showing that both directions of the relationship were statistically significant. CONCLUSIONS: The association between poor mental health and smoking in young women appeared to be bi-directional.

[Autologous bone-marrow stem-cell transplantation for induction of arteriogenesis for limb salvage in critical limb ischaemia]. / Extremitätenerhalt durch autologe Knochenmarksstammzelltransplantation zur Induktion der Arteriogenese bei kritischer, nicht-revaskularisierbarer Extremitätenischämie.

BACKGROUND: Bone marrow cell transplantation has been shown to induce angiogenesis and thus improve ischaemic artery disease. This study evaluates the effects of intramuscular bone marrow cell transplantation in patients with limb-threatening critical limb ischaemia with a very high risk for major amputation. METHODS AND RESULTS: After failed or impossible operative and / or interventional revascularisation and after unsuccessful maximum conservative therapy, 51 patients with impending major amputation due to severe critical limb ischaemia had autologous bone marrow cells (BMC) transplant-ed into the ischaemic leg. Patients 1-12 received Ficoll-isolated bone marrow mononuclear cells (total cell number 1.1 +/- 1.1 x 10(9)), patients 13-51 received point of care isolated bone marrow total nucleated cells (3.0 +/- 1.7 x 10(9)). Limb salvage was 59 % at 6 months and 53 % at last follow-up (mean: 411 +/- 261 days, range: 175-1186 days). Perfusion measured with the ankle-brachial-index (ABI) and transcutaneous oxygen tension (tcpO2) at baseline and after 6 months increased in -patients with consecutive limb salvage (ABI 0.33 +/- 0.18 to 0.46 +/- 0.15, tcpO2 12 +/- 12 to 25 +/- 15 mmHg) and did not change in patients eventually undergoing major amputation. No differences in clinical outcome between the isolation methods were seen. Clinically most important, patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months (p = 0.0001). Analgesics consumption was reduced by 62 %. -Total walking distance improved in non-amputees from zero to 40 metres. Three severe peri-procedural adverse events resolved without sequelae, and no unexpected long-term adverse events occurred. CONCLUSIONS: In no-option patients with end-stage critical limb ischaemia due to peripheral -artery disease, bone marrow cell transplantation is a safe procedure which can improve leg perfusion sufficiently to reduce major amputations and permit durable limb salvage.

Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease.

Bone marrow cell transplantation has been shown to induce angiogenesis and thus improve ischemic artery disease. This study evaluates the effects of intramuscular bone marrow cell transplantation in patients with limb-threatening critical limb ischemia with a very high risk for major amputation. After failed or impossible operative and/or interventional revascularization and after unsuccessful maximum conservative therapy, 51 patients with impending major amputation due to severe critical limb ischemia had autologous bone marrow cells (BMC) transplanted into the ischemic leg. Patients 1-12 received Ficoll-isolated bone marrow mononuclear cells (total cell number 1.1 +/- 1.1 x 10(9)), patients 13-51 received point of care isolated bone marrow total nucleated cells (3.0 +/- 1.7 x 10(9)). Limb salvage was 59% at 6 months and 53% at last follow-up (mean 411 +/- 261 days, range 175-1186). Perfusion measured with ankle-brachial index (ABI) and transcutaneous oxygen tension (tcpO(2)) at baseline and after 6 months increased in patients with consecutive limb salvage (ABI 0.33 +/- 0.18 to 0.46 +/- 0.15, tcpO(2) 12 +/- 12 to 25 +/- 15 mmHg) and did not change in patients eventually undergoing major amputation. No difference in clinical outcome between the isolation methods were seen. Clinically most important, patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months (p = 0.0001). Analgesics consumption was reduced by 62%. Total walking distance improved in nonamputees from zero to 40 m. Three severe periprocedural adverse events resolved without sequelae, and no unexpected long-term adverse events occurred. In no-option patients with end-stage critical limb ischemia due to peripheral artery disease, bone marrow cell transplantation is a safe procedure that can improve leg perfusion sufficiently to reduce major amputations and permit durable limb salvage.

Design and rationale of a randomized, double-blind, placebo-controlled phase III study for autologous bone marrow cell transplantation in critical limb ischemia: the BONe Marrow Outcomes Trial in Critical Limb Ischemia (BONMOT-CLI).

BACKGROUND: Critical limb ischemia (CLI) is the end-stage of peripheral artery disease. Only about two thirds of patients with CLI can be revascularised, one third progresses to leg amputation with high associated morbidity and mortality. Therapeutic angiogenesis with bone marrow cells has shown promising improvement in less severe stages of peripheral ischemia. Our study evaluates the therapeutic value of bone marrow cell induced angiogenesis and arteriogenesis in severe, limb-threatening ischemia. PATIENTS AND METHODS: the BONe Marrow Outcome Trial in Critical Limb Ischemia (BONMOT-CLI) is a investigator-initiated, double-blinded, 1:1 randomized, placebo-controlled multi-centre study at 4 sites in Germany. Only patients with no option for revascularisation or after failed revascularisation will be included. A total of 90 patients is to be included. One arm with 45 subjects will be treated with a concentrate of autologous bone marrow cells which will be injected at 40 sites into the ischemic limb. In the placebo arm, study subjects will undergo a sham bone marrow punction and 40 saline injections. At three months, a combined primary endpoint of major amputation or persisting critical limb ischemia (no clinical or perfusion improvement) will be evaluated. Secondary endpoints are death, changes in perfusion, quality of life, walking distance, minor amputations, wound healing, collateral density and cancer incidence. Post-study follow-up is up to two years. CONCLUSIONS: The results of this first randomized placebo-controlled trial for autologous bone marrow cell therapy in CLI will clarify the value of this new therapeutic modality in a patient population with no other alternatives except major amputation.

Adenoviral infections after transplantation of positive selected stem cells from haploidentical donors in children: an update.

UNLABELLED: We present updated results of stem cell transplantation with highly purified stem cells from haploidentical parental donors and infection with human adenovirus (HAdV) post stem cell transplantation (SCT). Survival post SCT is primarily determined by relapse, infections and far less by GvHD or other transplant related mortality. During the immune reconstitution the host is at significant risk for severe viral infections. HAdV infection is especially in children an important complication post SCT, with significant morbidity and mortality despite new antiviral treatment strategies. Although control of infection seems to require T-cells, the characterization of HAdV-specific T-cells post SCT has not been introduced in surveillance and treatment decisions. METHODS: Therefore we evaluated the impact of HAdV-infections on the survival between 1995 and 2004 (n = 63) and studied the occurrence of adenovirus-specific T-cells in children with (n = 9) and without (n = 9) HAdV-infection post allogeneic SCT and in healthy donors (n = 53). After stimulation ex-vivo with HAdV-antigen IFN-gamma secreting T-cells were analyzed by flowcytometry and defined as HAdV-specific T-cells. RESULTS: Until day 180 post SCT the cumulative incidence of all lethal viral infections (HAdV n = 5, cytomegalovirus n = 3, herpes simplex virus n = 1) was 16 % for the whole cohort of patients. Cumulative incidence of HAdV-associated mortality was 8.5 %. Cumulative incidence of all lethal viral infections could be now reduced from 16 % to 8 % in conjunction with new surveillance- and therapeutic-strategies. Children with HAdV-associated mortality all had no specific T-cells, although reconstitution of absolute lymphocyte counts exceeded 300/microl within 30 days post transplant. Patients who cleared HAdV infection had normal frequencies of HAdV-specific T-cells until day 200 post SCT. CONCLUSION: In summary adenovirus specific T-cell reconstitution should be monitored in patients after SCT to limit the use of anti viral chemotherapy and help to identify those patients that would benefit from new therapeutic strategies like adoptive transfer of virus specific T-cells.

Soluble vascular endothelial growth factor, soluble VEGF receptor Flt-1 and endothelial function in healthy smokers.

OBJECTIVE: To relate levels of vascular endothelial growth factor (VEGF) and its soluble receptor, sFlt-1, with endothelial function in healthy smokers. METHODS: Plasma levels of VEGF and sFlt-1 were measured by ELISA in 22 healthy smokers and 22 matched healthy non-smoking controls, and compared to flow- (FMD) and acetylcholine-mediated (AMD) vasodilatation (endothelial-dependent) (EDV) and nitroglycerine-mediated (NMD) vasodilatation (endothelial-independent) of lower extremities were measured with plethysmography. RESULTS: Smokers and controls had similar plasma VEGF levels, but sFlt-1 levels were lower in smokers than in controls (p<0.01). AMD was lower in smokers compared to controls (p<0.05), but FMD and NMD levels were similar. Smokers and controls with high AMD (>12 ml/100 ml tissue/min) had significantly lower plasma VEGF levels (p<0.001). An inverse correlation was found in both groups, between VEGF and AMD (smokers: r=-0.6, p<0.01; controls: r=-0.71, p<0.005) and with FMD (smokers: r=-0.56, p<0.05; controls: r=-0.58, p<0.005). There were no significant correlations between sFlt-1 with VEGF levels or endothelial-dependent dilatation. CONCLUSION: In conclusion, healthy smokers demonstrate abnormal AMD, and an inverse correlation between plasma VEGF levels (but not sFlt-1) with indices of endothelial dysfunction (FMD and AMD) exists. VEGF, and not sFlt-1, may be related to the pathogenesis of endothelial dysfunction in healthy smoking individuals.

Changes of plasma concentrations of soluble vascular cell adhesion molecule-1 and vascular endothelial growth factor after increased perfusion of lower extremities in humans.

Shear stress modulates vascular structure and function through cytoskeletal remodeling and activation of signaling cascades. Elevated vascular endothelial growth factor (VEGF) concentrations are seen in atherosclerotic disease and after active increase of perfusion. Levels of soluble vascular cell adhesion molecule (sVCAM-1) are increased in atherosclerotic disease without strict correlation to disease progression. In vitro, increased shear stress induces a biphasic response of sVCAM-1. No data are available on in vivo downregulation of VEGF or sVCAM-1 in humans. In 24 healthy individuals, vascular function of lower extremities was assessed by plethysmography measuring flow-mediated dilation and through intra-arterial infusion of acetylcholine and nitroglycerine. Ten healthy individuals were challenged with cycle exercise testing. Cytokines were measured from citrate plasma from cubital and femoral vein blood. Plasma concentrations of VEGF and sVCAM-1 correlated with endothelium-dependent dilation. Two hours after acetylcholine-induced shear stress, plasma concentrations of sVCAM-1 levels were reduced by 31% (p <.001) locally and 18% (p <.05) systemically. Nitroglycerine produced similar local and systemic suppression (36% and 34%; p <.0001). Immediately after exercise, concentrations of sVCAM-1 increased with a significant decrease one hour later (-9%; p <.01). VEGF increased after infusion of nitroglycerine (+35%; p <.05) and dropped after 1 h of 30-min exercising (-31%, p <.05). This is the first study to show changes of sVCAM-1 in vivo. Changes of VEGF and sVCAM-1 in humans seem time, magnitude, and substance specific. Short acting suppression of VEGF and SVCAM-1 under physiological conditions may explain exercise-induced vascular protection and the lack of correlation of these cytokines with activity of atherosclerotic disease.

Low frequency flowmotion/(vasomotion) during patho-physiological conditions.

The role of low frequency flowmotion in physiological or pathophysiological settings is unclear. We performed various series of experiments in young anesthetized New Zealand white (NZW) rabbits. Many animals exhibited flowmotion during control conditions. However, they very often seemed to be in unstable physiological conditions, and our preset inclusion criteria (as to arterial pressure and blood gases) were frequently not met.Therefore, in a first series, we correlated these systematically with the incidence of flowmotion. Eleven of 35 anesthetized rabbits, subjected to extensive surgery, showed flowmotion with a median frequency of 1.5 cpm and a relative "amplitude" of 32%. Arterial pressure was 10 mmHg lower, bicarbonate, base-excess, and PCO(2) values and relative blood flow were also significantly lower compared to animals not exhibiting flowmotion. In a second series, we tested whether flowmotion could be induced by an isolated metabolic acidosis in animals meeting the inclusion criteria and not showing flowmotion at control. Here, flowmotion was induced in 9/10 cases (p < 0.01) 30 min after the start of an HCl-infusion. In a third study, we related the onset of flowmotion to the pressure/flow autoregulation curve. At locally reduced blood pressure all 23 rabbits exhibited flowmotion (p < 0,00001) in the gastrocnemius and the tenuissimus muscles, with maximum flowmotion at a locally reduced blood pressure of 30 mmHg; the LDF-flux level showing 67% of control flow.These results support the concept that low frequency periodic hemodynamics are a characteristic of pathophysiological conditions like hypoperfusion or acidosis rather than indicating a normal physiological state.

Local vascular complications after use of the hemostatic puncture closure device Angio-Seal.

BACKGROUND: As an alternative to manual pressure techniques new systems for achieving arterial hemostasis after cardiac catheterization were developed. Here we report about the diagnosis and therapy of femoral artery complications after use of the closure device Angio-Seal, consisting of an intraarterial anchor and extravascular collagen plug. PATIENTS AND METHODS: Angio-Seal was deployed in 350 patients undergoing cardiac catheterization. Vascular investigations after device application consisted of ankle/brachial-pressure-index measurement, duplex sonography, and angiography. RESULTS: Vascular complications occurred in 10 of 350 patients. In two patients complete occlusions of the superficial femoral artery required immediate vascular surgery. Stenoses of the superficial (five patients) and the common (three patients) femoral arteries were diagnosed in 8 cases. Of these 10 patients eight were obese, in 2 cases there was a further catheterization with Angio-Seal device application via the same femoral approach. Until now six patients underwent successful surgery: in 4 cases the whole Angio-Seal device was located intraarterially, there was 1 case of intima-dissection, and 1 case remained unclear due to a diagnostic delay of 7 months. In three patients with stenoses of the common femoral arteries without hemodynamic relevance no therapy was required. CONCLUSIONS: Occlusions or stenoses of femoral arteries after use of Angio-Seal can be diagnosed easily by duplex sonography. All hemodynamic relevant complications (n = 7 of 350 [2%]) concerned a puncture of superficial femoral arteries. In these patients vascular surgery seems to be an adequate therapy.

Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter, randomized trial. Investigators of the Department of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME).

BACKGROUND: Percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are being applied to high-risk populations, but previous randomized trials comparing revascularization methods have excluded a number of important high-risk groups. OBJECTIVES: This five-year, multicenter, randomized clinical trial was designed to compare long-term survival among patients with medically refractory myocardial ischemia and a high risk of adverse outcomes assigned to either a CABG or a PCI strategy, which could include stents. METHODS: Patients from 16 Veterans Affairs Medical Centers were screened to identify myocardial ischemia refractory to medical management and the presence of one or more risk factors for adverse outcome with CABG, including prior open-heart surgery, age >70 years, left ventricular ejection fraction <0.35, myocardial infarction within seven days or intraaortic balloon pump required. Clinically eligible patients (n = 2,431) underwent coronary angiography; 781 were angiographically acceptable; 454 (58% of eligible) patients consented to random assignment between CABG and PCI. RESULTS: A total of 232 patients was randomized to CABG and 222 to PCI. The 30-day survivals for CABG and PCI were 95% and 97%, respectively. Survival rates for CABG and PCI were 90% versus 94% at six months and 79% versus 80% at 36 months (log-rank test, p = 0.46). CONCLUSIONS: Percutaneous coronary intervention is an alternative to CABG for patients with medically refractory myocardial ischemia and a high risk of adverse outcomes with CABG.

Off-pump coronary artery bypass grafting. Excellent results in a group of selected high-risk patients.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCABG) has assumed an increasing role in many surgical practices. The ideal candidate has not been defined, but high-risk patients seem to benefit most when cardiopulmonary bypass (CPB), aortic cross clamping and cardioplegic arrest are avoided. METHODS: Fourteen high-risk patients (age 52 to 81 years, 1 female, EF 44%+/-8, Parsonnet score 23+/-4) were studied. They presented with acute coronary syndroms on platelet glycoprotein IIb/IIIa antagonists, acute myocardial infarction, worsening renal failure, decompensating ischemic cardiomyopathy, religious beliefs and denial of blood transfusion, and severe peripheral/cerebrovascular disease (total bilateral internal carotid artery occlusion and/or >90% stenosis). These patients underwent OPCABG via sternotomy with the intention of complete coronary revascularization. RESULTS: An average of 2.3 grafts/patient were performed and the posterior descending artery (PDA) and marginal branches of the circumflex artery (LCX) were grafted in 79% of the patients. There were 3 events of intraoperative cardiac arrest precipitated by occlusion of right coronary artery (RCA) or positioning a cardiomegaly heart leading to immediate intravascular shunting (2) and/or conversion to CPB (1). One patient was converted to CPB and graft revision (intraoperative ultrasound and probing). The mortality rate was 0% and one stroke was observed on post-operative day 1. Coronary angiography (n=6) showed no significant stenosis. CONCLUSIONS: OPCABG complete revascularization is feasible in high-risk patients with low morbidity and mortality and excellent early RESULTS: OPCABG may be indicated in patients on platelet receptor antagonists preventing bleeding complications. Cardiomegaly can cause difficult off-pump LCX and PDA exposure and stabilization. RCA grafting off-pump is less tolerated and PDA grafting is preferred. High-risk patients for CPB are the ones who may benefit the most from OPCABG.

Recombinant human GM-CSF in the treatment of poorly healing wounds.

Although most wounds heal rapidly, impaired or delayed tissue repair represents a major clinical challenge. Current therapy is directed at providing a wound with the most favorable environment in which to heal, rather than aiming to increase the rate of healing pharmacologically. Recent studies have suggested that a number of drugs may act specifically to increase healing rates. In vivo studies have demonstrated that recombinant human granulocyte-macrophage colony-stimulating factor facilitates wound contraction, causes local recruitment of inflammatory cells, and induces keratinocyte proliferation. It also activates mononuclear phagocytes, promotes migration of epithelial cells, and further regulates cytokine production. In 2 recent placebo-controlled studies involving venous leg ulceration, subcutaneous perilesional injections of recombinant human granulocyte-macrophage colony-stimulating factor were found to be significantly better than placebo in the time to complete wound healing. In other studies, recombinant human granulocyte-macrophage colony-stimulating factor was administered topically to wounds. Several case reports have also demonstrated the use of recombinant human granulocyte-macrophage colony-stimulating factor for postsurgical wounds, chronic leg ulcers of sickle cell anemia patients, and refractory pyoderma gangrenosum. Despite proper attention to wound care, some wounds fail to heal in an appropriate fashion and may become chronic. Studies of wound physiology as well as experimental and clinical evidence suggest that recombinant human granulocyte-macrophage colony-stimulating factor may promote healing of these lesions.

Anomalous origin of the right coronary artery from the left coronary sinus: case report and review of surgical treatments.

An anomalous right coronary artery arising from the left sinus of Valsalva is a rare but potentially lethal abnormality. We present a case report and literature review of this anomaly as well as its surgical management in the face of unobstructed distal coronary arteries. Furthermore we report the use of intraoperative transesophageal stress echocardiography to evaluate adequacy of graft flow.

A multicenter, randomized trial of percutaneous coronary intervention versus bypass surgery in high-risk unstable angina patients. The AWESOME (Veterans Affairs Cooperative Study #385, angina with extremely serious operative mortality evaluation) investigators from the Cooperative Studies Program of the Department of Veterans Affairs.

This multicenter, prospective randomized trial was designed to test the hypotheses that percutaneous coronary intervention (PCI) is a safe and effective alternative to coronary artery bypass grafting (CABG) for patients with refractory ischemia and high risk of adverse outcomes. As a comparison of revascularization strategies, the trial specifically allows surgeons and interventionists to use new techniques as they become clinically available. After 42 months of this 72-month trial, 17,624 patients have been screened and 2022 met eligibility requirements: 341 have been randomized to either CABG or PCI, and the remaining 1681 are being prospectively followed in a registry. The 3-year overall survival of patients in the registry and randomized trial is comparable. To enhance accrual into the randomized trial, site visits were conducted, a few low-accruing hospitals were put on probation and/or replaced, eligibility criteria were reviewed at annual meetings of investigators, and the accrual period was extended by 1 year. These data demonstrate that a prospective randomized trial and registry of coronary revascularization for medically refractory high-risk patients is feasible.

Mortality and need for reoperation in patients with mild-to-moderate asymptomatic aortic valve disease undergoing coronary artery bypass graft alone.

BACKGROUND: Patients presenting for coronary artery bypass graft (CABG) surgery may have concurrent asymptomatic aortic stenosis (AS) or aortic insufficiency (AI). This retrospective study was performed to evaluate outcomes in patients with aortic valve disease undergoing CABG with or without aortic valve replacement (AVR). METHODS: Study groups included 414 patients undergoing combined AVR and CABG (AVR-CABG group) and 62 patients with asymptomatic mild-to-moderate AS, AI, or both undergoing CABG but not AVR (CABG group). End points included 30-day mortality rate, time to cardiac mortality, time to all-cause mortality, and time to aortic valve reoperation. Reoperation refers to surgery for replacement of the native aortic valve in the CABG group or replacement of the prosthetic aortic valve in the AVR-CABG group. Important patient characteristics affecting outcomes were determined by using Cox proportional-hazard analysis. These variables were then included in multivariable analyses by using logistic regression analysis and Cox proportional-hazard modeling to compare outcomes between each patient group. RESULTS: No difference was seen in any of the mortality end points between the CABG group and the AVR-CABG group after controlling for significant differences between the groups. However, the need for reoperation for AVR was significantly higher for the CABG group than the AVR-CABG group. For patients followed for up to 6 years, the estimated need for aortic valve reoperation was 24.3% in the CABG group versus 3% in the AVR-CABG group. CONCLUSION: On the basis of these results, patients with asymptomatic AS or AI should be considered for AVR at the time of CABG.

Intracellular coexpression of epidermal growth factor receptor, Her-2/neu, and p21ras in human breast cancers: evidence for the existence of distinctive patterns of genetic evolution that are common to tumors from different patients.

Multiparameter flow cytometry studies were performed on cells from the primary tumors of 94 patients with breast cancer. Correlated cellular measurements of cell DNA content, Her-2/neu, epidermal growth factor receptor (EGFR), and p21ras levels were performed on each of 5,000 to 100,000 cells from each tumor. When criteria for positivity were matched with those in common use for immunohistochemical studies, 28 of 94 (30%) breast cancers were classified as positive for Her-2/neu overexpression. When similar criteria were applied to the EGFR measurements, 23 of 94 (24%) cases were classified as positive for EGFR overexpression. Similarly, 23 of 94 (24%) cases were classified as positive for p21ras overexpression. By conventional flow cytometric criteria for DNA ploidy, 24 cases were diploid, 28 were tetraploid, and 42 were aneuploid. When the measurements were treated as separate sets of data, the only statistically significant correlations noted were the high frequency of diploid tumors, which did not overexpress any of the three oncogenes studied (P < 0.05), and an association between Her-2/neu overexpression and aneuploidy (P < 0.03). When the data were treated as correlated intracellular measurements, 90 of the 94 tumors studied contained a population of cells in which the intracellular levels of Her-2/neu expression were directly correlated with the levels of EGFR expression in the same cells. The ratio of Her-2/neu molecules to EGFR molecules in the same cells exceeded 1 in the majority of tetraploid and aneuploid cases and was close to or less than 1 in the majority of diploid cases. In nearly all tumors, p21ras overexpression was observed only in cells that overexpressed Her-2/neu, EGFR, or both, and p21ras levels per cell were more closely correlated with levels of EGFR per cell in the same cells than with Her-2/neu levels per cell. The data are consistent with a model in which heterodimerization of Her-2/neu and EGFR in individual cells is achieved by one of several genetic evolutionary pathways, all of which commonly lead to p21ras overexpression. The two major genetic evolutionary pathways identified in this study are an aneuploid, Her-2/neu overexpression-driven pathway seen in 59 of 94 tumors, and a diploid, EGFR overexpression-driven pathway seen in 19 of 94 tumors. All tumors with Her-2/neu:EGFR ratios greater than 2 contained an infiltrating ductal carcinoma component, whereas all infiltrating pure lobular carcinomas had Her-2/ neu:EGFR ratios that were less than 2. All of the genetic evolutionary pathways identified in this study were represented among the 11 tumors from patients who experienced early tumor recurrences.