Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

[Hyperinsulinemia as a consequence of systemic venous drainage in patients with pancreas transplantation]

To evaluate the metabolic consequences of pancreatic transplantation with systemic venous drainage on beta cell function, we examined insulin and C-peptide responses to arginine and secretin in type I diabetic recipients of pancreas transplantation (n = 16), and normal controls (n = 28). Basal insulin levels were 24 +/- 3 microU/l in pancreas recipients, and 7 +/- 1 microU/l in controls (p less than 0.001). Stimulated insulin levels following arginine (MANOVA, p less than 0.001), and secretin (MANOVA, p less than 0.001) were 1.5 to 3 fold elevated compared to controls. In contrast, integrated C-peptide responses following stimulation with arginine or secretin did not differ significantly between the two groups. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first pass hepatic insulin clearance although insulin resistance secondary to immunosuppressive therapy (including prednisone) may also play a contributing role. To avoid hyperinsulinemia and its possible long term adverse consequences, transplantation of pancreas allografts in sites with portal rather than systemic venous drainage may be preferable.

Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients

To evaluate the metabolic consequences of pancreas transplantation with systemic venous drainage on beta-cell function, we examined insulin and C-peptide responses to glucose and arginine in type I (insulin-dependent) diabetic pancreas recipients (n = 30), nondiabetic kidney recipients (n = 8), and nondiabetic control subjects (n = 28). Basal insulin levels were 66 +/- 5 pM in control subjects, 204 +/- 18 pM in pancreas recipients (P less than 0.0001 vs. control), and 77 +/- 17 pM in kidney recipients. Acute insulin responses to glucose were 416 +/- 44 pM in control subjects, 763 +/- 91 pM in pancreas recipients (P less than 0.01 vs. control), and 589 +/- 113 pM in kidney recipients (NS vs. control). Basal and stimulated insulin levels in two pancreas recipients with portal venous drainage were normal. Integrated acute C-peptide responses were not statistically different (25.3 +/- 4.3 nM/min in pancreas recipients, 34.2 +/- 5.5 nM/min in kidney recipients, and 23.7 +/- 2.1 nM/min in control subjects). Similar insulin and C-peptide results were obtained with arginine stimulation, and both basal and glucose-stimulated insulin-C-peptide ratios in pancreas recipients were significantly greater than in control subjects. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first-pass hepatic insulin clearance, although insulin resistance secondary to immunosuppressive therapy (including prednisone) probably plays a contributing role. To avoid hyperinsulinemia and its possible long-term adverse consequences, transplantation of pancreas allografts into sites with portal rather than systemic venous drainage should be considered.

Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing

The GH-IGF axis has profound effects on the local and systemic regulation of bone metabolism and may be important for quality of fracture healing. To test the hypothesis that deficiency of the GH/IGF axis may play a role in the pathogenesis of fracture non-union we investigated whether alterations of serum concentrations of the GH-IGF axis could be related to failed fracture healing compared to timely fracture healing in trauma patients. Serum probes were prospectively collected from 186 patients with surgical treatment of long bone fractures up to 6 months after surgery. Samples from 14 patients with atrophic type of non-union have been compared to 14 matched patients with normal bone healing. Postoperative time courses of serum concentrations have been analyzed using commercially available chemiluminescence sandwich assays (GH), fully automated assay systems (IGF-I, IGFBP-3) or sandwich immunometric assays (ALS). Comparison between both collectives revealed significantly lower serum concentrations of GH dependent ALS during early (1st week after surgery) and of both IGFBP-3 and ALS during late stages of fracture healing (6 and 8 weeks after surgery) in non-union patients, coinciding clinically with failed fracture healing. Tendentially lower serum levels of IGF-I in the non-union group over the entire investigation period were statistically not significant. We have been able to show time courses of serum concentrations of the GH/IGF-I axis during normal and failed fracture healing in humans. An impairment of the GH/IGF-I axis might be involved in the biochemical mechanisms determining delayed or failed fracture healing.

[Effects of tobacco use on systemic health: relevant information for dentistry (II)--part 2: cardiovascular diseases and public health issues]

This is the sixth and concluding part of a series of publications from the Swiss task force named "Smoking - Intervention in the private dental office" on the topic "tobacco use and dental medicine". The focus of this review is the effects of smoking for the development of atherosclerosis as pathohistological correlate for acute coronary syndrome (ACS), arterial occlusive disease, and cerebrovascular diseases (stroke). Additionally, a causal relationship between tobacco use and an increased rate for complications during pregnancy and child birth will be discussed. Next to causal therapy of local and systemic diseases in general, an emphasis must be given to tobacco use prevention and cessation. Finally, important public health issues concerning smoking and tobacco use will be demonstrated, and options to improve the current situation will be presented.

Systemic analysis of microarray data sets towards identifying genes regulating root development

Nitrogen and water are essential for plant growth and development. In this study, we designed experiments to produce gene expression data of poplar roots under nitrogen starvation and water deprivation conditions. We found low concentration of nitrogen led first to increased root elongation followed by lateral root proliferation and eventually increased root biomass. To identify genes regulating root growth and development under nitrogen starvation and water deprivation, we designed a series of data analysis procedures, through which, we have successfully identified biologically important genes. Differentially Expressed Genes (DEGs) analysis identified the genes that are differentially expressed under nitrogen starvation or drought. Protein domain enrichment analysis identified enriched themes (in same domains) that are highly interactive during the treatment. Gene Ontology (GO) enrichment analysis allowed us to identify biological process changed during nitrogen starvation. Based on the above analyses, we examined the local Gene Regulatory Network (GRN) and identified a number of transcription factors. After testing, one of them is a high hierarchically ranked transcription factor that affects root growth under nitrogen starvation. It is very tedious and time-consuming to analyze gene expression data. To avoid doing analysis manually, we attempt to automate a computational pipeline that now can be used for identification of DEGs and protein domain analysis in a single run. It is implemented in scripts of Perl and R.

[Unusual pulmonary presentation of systemic Langerhans cell histiocytosis]

An 80-year-old nonsmoking man was referred to our hospital with bilateral perihilar pulmonary opacities. He had a history of epilepsy, sclerosing cholangitis, cutaneous lesions previously diagnosed as localised Langerhans cell histiocytosis. Symptoms included dry cough and dyspnea. Chest CT showed bilateral perihilar alveolar consolidation with bronchiectasis. Histological examination of a lung biopsy showed typical features of Langerhans cell granulomatosis. Investigations revealed anterior and posterior hypopituitarism. An important improvement occurred with corticosteroid and vinblastine treatment.

Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults

BACKGROUND: Postoperative adynamic bowel atony interferes with recovery following abdominal surgery. Prokinetic pharmacologic drugs are widely used to accelerate postoperative recovery. OBJECTIVES: To evaluate the benefits and harms of systemic acting prokinetic drugs to treat postoperative adynamic ileus in patients undergoing abdominal surgery. SEARCH STRATEGY: Trials were identified by computerised searches of the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the Cochrane Colorectal Cancer Group specialised register. The reference lists of included trials and review articles were tracked and authors contacted. SELECTION CRITERIA: Randomised controlled parallel-group trials (RCT) comparing the effect of systemically acting prokinetic drugs against placebo or no intervention. DATA COLLECTION AND ANALYSIS: Four reviewers independently extracted the data and assessed trial quality. Trial authors were contacted for additional information if needed. MAIN RESULTS: Thirty-nine RCTs met the inclusion criteria contributing a total of 4615 participants. Most trials enrolled a small number of patients and showed moderate to poor (reporting of) methodological quality, in particular regarding allocation concealment and intention-to-treat analysis. Fifteen systemic acting prokinetic drugs were investigated and ten comparisons could be summarized. Six RCTs support the effect of Alvimopan, a novel peripheral mu receptor antagonist. However, the trials do not meet reporting guidelines and the drug is still in an investigational stage. Erythromycin showed homogenous and consistent absence of effect across all included trials and outcomes. The evidence is insufficient to recommend the use of cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol or vasopressin. Effects are either inconsistent across outcomes, or trials are too small and often of poor methodological quality. Cisapride has been withdrawn from the market due to adverse cardiac events in many countries. Intravenous lidocaine and neostigmine might show a potential effect, but more evidence on clinically relevant outcomes is needed. Heterogeneity among included trials was seen in 10 comparisons. No major adverse drug effects were evident. AUTHORS' CONCLUSIONS: Alvimopan may prove to be beneficial but proper judgement needs adherence to reporting standards. Further trials are needed on intravenous lidocaine and neostigmine. The remaining drugs can not be recommended due to lack of evidence or absence of effect.

[Systemic ANCA-associated vasculitis--diagnosis and therapy]

ANCA-associated vasculitis represents a group of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis and the Churg-Strauss-syndrome. These diseases affect mainly small arteries, venules and capillaries, showing a lack of immunocomplex formation on immunohistology, the so-called "pauci-immune" vasculitis. Nevertheless, Anti-Neutrophil Cytoplasmatic Autoantibodies (ANCA's) are pathogenic for this type of disease. In spite of important advances in technical diagnostic tools, careful medical history and clinical examinations often give the clues for the correct diagnosis. Recent collaborative therapeutic studies have lead to therapeutic schemas that are much more adapted to the individual disease state. Besides the acute and sometimes life-threatening form of ANCA-vasculitis, chronic disease and relapses become more important in clinical practice. Thus, therapeutic efficacy must be outweighed against long-term toxicity to make the right choice for therapeutic intervention in ANCA-associated vasculitis.

The systemic angiogenic response during bone healing

INTRODUCTION: Angiogenesis is known to be a critical and closely regulated step during bone formation and fracture healing driven by a complex interaction of various cytokines. Delays in bone healing or even nonunion might therefore be associated with altered concentrations of specific angiogenic factors. These alterations might in turn be reflected by changes in serum concentrations. METHOD: To determine physiological time courses of angiogenic cytokines during fracture healing as well as possible changes associated with failed consolidation, we prospectively collected serum samples from patients who had sustained surgical treatment for a long bone fracture. Fifteen patients without fracture healing 4 months after surgery (nonunion group) were matched to a collective of 15 patients with successful healing (union group). Serum concentrations of angiogenin (ANG), angiopoietin 2 (Ang-2), basic fibroblast growth factor (bFGF), platelet derived growth factor AB (PDGF-AB), pleiotrophin (PTN) and vascular endothelial growth factor (VEGF) were measured using enzyme linked immunosorbent assays over a period of 24 weeks. RESULTS: Compared to reference values of healthy uninjured controls serum concentrations of VEGF, bFGF and PDGF were increased in both groups. Peak concentrations of these cytokines were reached during early fracture healing. Serum concentrations of bFGF and PDGF-AB were significantly higher in the union group at 2 and 4 weeks after the injury when compared to the nonunion group. Serum concentrations of ANG and Ang-2 declined steadily from the first measurement in normal healing fractures, while no significant changes over time could be detected for serum concentrations of these factures in nonunion patients. PTN serum levels increased asymptotically over the entire investigation in timely fracture healing while no such increase could be detected during delayed healing. CONCLUSION: We conclude that fracture healing in human subjects is accompanied by distinct changes in systemic levels of specific angiogenic factors. Significant alterations of these physiologic changes in patients developing a fracture nonunion over time could be detected as early as 2 (bFGF) and 4 weeks (PDGF-AB) after initial trauma surgery.

Systemic conditions and treatments as risks for implant therapy

PURPOSE: To evaluate whether systemic diseases with/without systemic medication increase the risk of implant failure and therefore diminish success and survival rates of dental implants. MATERIALS AND METHODS: A MEDLINE search was undertaken to find human studies reporting implant survival in subjects treated with osseointegrated dental implants who were diagnosed with at least one of 12 systemic diseases. RESULTS: For most conditions, no studies comparing patients with and without the condition in a controlled setting were found. For most systemic diseases there are only case reports or case series demonstrating that implant placement, integration, and function are possible in affected patients. For diabetes, heterogeneity of the material and the method of reporting data precluded a formal meta-analysis. No unequivocal tendency for subjects with diabetes to have higher failure rates emerged. The data from papers reporting on osteoporotic patients were also heterogeneous. The evidence for an association between osteoporosis and implant failure was low. Nevertheless, some reports now tend to focus on the medication used in osteoporotic patients, with oral bisphosphonates considered a potential risk factor for osteonecrosis of the jaws, rather than osteoporosis as a risk factor for implant success and survival on its own. CONCLUSIONS: The level of evidence indicative of absolute and relative contraindications for implant therapy due to systemic diseases is low. Studies comparing patients with and without the condition in a controlled setting are sparse. Especially for patients with manifest osteoporosis under an oral regime of bisphosphonates, prospective controlled studies are urgently needed.

Infiltrating Lobular Carcinoma of the Breast: Systemic Treatment

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC). It is characterized by unique clinical, biological and molecular properties. ILC is almost always positive for the estrogen receptor and is typically of a lower grade compared with IDC. We have reviewed selected literature on preoperative (neoadjuvant) and adjuvant systemic therapy of breast cancer focusing on the differential therapy of ILC. Despite the importance of this type of breast cancer, information about its specific treatment is sparse, in particular with regard to adjuvant systemic chemotherapy. ILC has significantly lower rates of response to neoadjuvant chemotherapy compared with IDC; however, the low chemosensitivity seems not to result in a survival disadvantage. Adjuvant hormonal therapy studies do not distinguish between ILC and IDC. Thus, recommendations about endocrine therapies are made using the same criteria as for IDC.

Scleroderma Renal Crisis: A Rare but Severe Complication of Systemic Sclerosis

Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation.