Matthias Turina

Acute hyperglycemia and the innate immune system: Clinical, cellular, and molecular aspects

Objective:To extract from the biomedical literature the reported effects of acute hyperglycemia on the major components of the innate immune system and to describe the clinical benefits of strict blood glucose control in certain patients. Data Source and Selection:A Medline/PubMed search (1966 to July 2004) with manual cross-referencing was conducted, including all relevant articles investigating the effects of acutely elevated glucose levels on innate immunity. All publication types, languages, or subsets were searched. Data Extraction and Synthesis:Original and selected review articles, short communications, letters to the editor, and chapters of selected textbooks were extracted. Most recent and relevant clinical trials were reviewed for the introductory section to provide the clinical background to this topic. The selected bench laboratory articles were then divided into three main categories based on the timing of events: a) the early phase of the innate immune reaction; b) the cytokine network; and c) the phagocytic phase. The most obvious findings related to hyperglycemia included reduced neutrophil activity (e.g., chemotaxis, formation of reactive oxygen species, phagocytosis of bacteria), despite accelerated diapedesis of leukocytes into peripheral tissue, as well as specific alterations of cytokine patterns with increased concentrations of the early proinflammatory cytokines tumor necrosis factor-α and interleukin-6. Furthermore, a reduction of endothelial nitric oxide formation takes place, thus decreasing microvascular reactivity to dilating agents such as bradykinin, and complement function (e.g., opsonization, chemotaxis) is impaired, despite elevations of certain complement factors. Conclusions:Acute, short-term hyperglycemia affects all major components of innate immunity and impairs the ability of the host to combat infection, even though certain distinctive proinflammatory alterations of the immune response can be observed under these conditions.

Frequency and surgical management of chronic complications related to pelvic radiation.

HYPOTHESIS Refractory complications from pelvic radiotherapy often require surgical treatment. Their management may be dictated by the primary tumor, radiation dose, and type and combination of radiation injuries, and may require transient diversion in most cases to guarantee good outcomes. DESIGN Retrospective 10-year cohort analysis compared with statewide epidemiologic data. PATIENTS During a 10-year period, 14 791 patients in Kentucky were treated with pelvic radiotherapy. Forty-eight were referred to a university colorectal surgical unit for evaluation of refractory radiotherapy complications that had failed conservative medical management. MAIN OUTCOME MEASURES Epidemiologic statewide data were compared with hospital data regarding the treatment and outcome of patients with refractory pelvic radiotherapy complications. RESULTS Twenty-five patients had received radiotherapy for colorectal carcinoma, 10 for prostate cancer, 7 for carcinoma of the cervix, and 6 for other tumors. Patients presented with 1 or more complications, including radiation enteritis (60%), strictures (53%), fistulae (17%), nonhealing wounds (15%), and de novo cancers in radiated fields (10%). Low anastomotic strictures (10%) were initially treated by dilation under sedation. Six patients (12%) ultimately required permanent diversion. All radiation-induced fistulae required an operation. CONCLUSIONS Determining the proper treatment requires careful judgment and assessment of the degree and type of injury, patient anatomy, and sphincter function. Patients presenting with colorectal anastomotic and primary bowel strictures as their main complication had the best results, while most patients with severe radiation enteritis and very distal strictures required permanent diversion.

Diabetes and hyperglycemia : Strict glycemic control

Objective:To critically review recent evidence on pathophysiology, diagnosis, and control of acute and chronic hyperglycemia in medical and surgical intensive care unit (ICU) patients. Data Source and Study Selection:A MEDLINE/PubMed search (1966 through February 2006) with manual cross-referencing was conducted, including all relevant articles published on blood glucose control in intensive care patients. An emphasis was placed on more recent clinical trials investigating the effects of tight glycemic control in ICU patients and on basic science studies investigating the pathophysiology and systemic effects of transient hyperglycemia in nondiabetic patients. Data Extraction and Synthesis:Original articles, selected reviews, letters to the editor, and chapters of selected textbooks were extracted. The reviewed information was then analyzed with respect to the prevalence of hyperglycemia in ICU patients, the pathophysiology of hyperglycemia in nondiabetics, and evidence on glycemic control in various subgroups of ICU patients. The risk of iatrogenic hypoglycemia in the ICU and potential future research directions are discussed at the end of the review. Conclusions:Recent evidence shows direct improvements in patient mortality and in-hospital morbidity with strict control of even short-term elevations of glucose levels in certain subgroups of ICU patients. However, precisely defined target glucose levels, subgroup analyses of different patient populations and treatment interventions, and the avoidance of hypoglycemic episodes during insulin therapy remain incompletely resolved and warrant future investigation.

Opportunities for Improved Performance in Surgical Specialty Practice

Objective:To identify opportunities for improvement in quality performance profile while maintaining better clinical outcomes. Methods:A prospective study of 5285 surgical specialty procedures including hip and knee replacement, cholecystectomy, hysterectomy, nonaccess vascular and cardiac procedures, and colorectal resections in 16 Kentucky hospitals was undertaken. The following observations were made after univariate and stepwise logistic regression analysis, from the Surgical Care Improvement Project. Results:(1) Impaired functional status, age ≥65, and ASA class 4 or 5 status were significant predictors for both morbidity and mortality. (2) β blockade medication was maintained in only 70% of patients already receiving such medications; interestingly, vascular surgery and patients with known cardiac history did not have β blockade initiated 52% of the time. (3) Appropriate blood glucose control was not achieved in 31% of patients with diabetes and in 20% of nondiabetics. (4) deep vein thrombosis (DVT) prophylaxis was independent of high-risk status, with wide variation in practice. Patients undergoing total hip or knee replacement or colorectal resections had highest rates (0.7%) of pulmonary emboli. (5) A poor choice of antibiotic prophylaxis agent occurred in 8% of patients and was associated with a 3-fold increase in mortality (P < 0.01). (6) Hypothermia on arrival in PACU was present in 7% of patients after major colorectal resections and was ominously associated with an over 4-fold increase in mortality (P < 0.01). (7) Preoperative WBC >11,000/mm3 in elective operations was associated with nearly 3-fold increase in mortality (P < 0.05). Conclusion:Now more than ever, surgeons must verify performance measures and outcomes. This study of clinical outcomes permits identification of underappreciated contemporary risk factors and some obvious measures by which surgical practices can more objectively be evaluated.

Chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: effect on quality of life.

Chronic pouchitis can be observed in up to 30% of patients after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). It remains a poorly understood complication and often requires chronic antibiotic and antidiarrheal treatment. We hypothesized that its occurrence can be predicted by distinct clinical parameters and that it adversely affects quality of life. Sixty-eight of 129 consecutive UC patients who underwent IPAA over a 10-Year period were evaluated by Cleveland Clinic Global Quality of Life questionnaires, telephone interviews, and by chart review. Using bivariate comparison, clinical predictors for the occurrence of chronic pouchitis were sought, and postoperative data analyzed with regard to functional results and quality of life. Nineteen of 68 patients (28%) experienced chronic pouchitis, but its occurrence could not be predicted by any variable assessed. Patients with chronic pouchitis complained of more frequent fecal incontinence (32% vs. 4% in controls; P < 0.01), of more frequent bowel movements (7.7/day vs. 6.2/day; P < 0.05), and experienced severe abdominal pain more often (P < 0.05). Overall quality of life and satisfaction with surgery, as well as subjective health and energy levels were lower in patients with chronic pouchitis (P < 0.01); however, greater than 80% of these patients would consider undergoing the same procedure again.

Endotoxin Inhibits Apoptosis but Induces Primary Necrosis in Neutrophils

Lipopolysaccharide (LPS) is known to prolong the functional lifespan of neutrophils at a site of infection by preventing apoptosis through inhibitor of apoptosis proteins (IAPs). We hypothesized that the increased neutrophil lifespan ultimately leads to a larger fraction of cells undergoing uncontrolled, primary necrosis. Diluted venous whole blood was incubated with increasing concentrations of LPS for up to 36 hr. The percentages of apoptotic, necrotic and viable neutrophils were assessed using the Annexin V/propidium iodide flow cytometric assay. LPS led to a reduction of neutrophil apoptosis and increased the number of viable cells at 12, 24, and 36 hr of incubation. At the same time intervals, there was a significant increase in the percentage of cells undergoing primary necrosis for all concentrations of LPS (e.g., 10 ng/ml LPS at 24 h produced a mean increase from 9.6% in controls to 30.6%, p < 0.001). This increase in direct neutrophil necrosis following LPS activation may amplify local proinflammatory effects through less well controlled release of neutrophil contents into surrounding tissue.

Slow transit colon constipation is not related to the number of interstitial cells of Cajal

Background and aimsRecent studies have demonstrated decreased numbers of interstitial cells of Cajal in patients suffering from severe chronic constipation as measured by c-Kit (CD117) and CD34 immunohistology. In this study, we wished to determine whether there were abnormalities in the number of neurons of the Auerbachs plexus, their CD117 and CD34 immunoreactivity, or the thickness of colon wall sections in patients with refractory slow transit colonic constipation as compared with control subjects.Patients and methodsSpecimens from 13 patients who had undergone subtotal colectomy for severe chronic constipation refractory to medical treatment were compared with normal controls. Enteric neurons of Auerbachs plexus were counted, and thickness of the circular and longitudinal layer of the muscularis externa as well as total muscularis externa was measured. Quantitative assessment of anti-CD117 and anti-CD34 immunoreactivity was performed using an Automated Cellular Imaging System and expressed as fractional scores.ResultsExcept for a decreased circular muscle layer thickness in the constipated patients, no statistically significant differences were observed between the two groups. In particular, there was no relationship between CD117/CD34 fractional staining score and the duration or severity of disease, despite the selection of highly symptomatic individuals requiring colonic resection.ConclusionUsing quantitative immunohistochemistry for CD117/CD34, we could not detect a relationship between fractional CD117/CD34 staining score and chronic constipation as compared to controls.

Microbial tolerance in secondary peritonitis is dose dependent.

Local microbial tolerance was investigated in a murine model of peritonitis. Peritoneal bacterial burden and inflammatory cytokine concentrations were determined at different times, within 48h after infection. Peritoneal macrophages were harvested from naïve mice or from mice 48h after infection and underwent ex vivo stimulation with different concentrations of Klebsiella. Cytokine secretion was determined in the supernatants. Peritoneal bacteria concentrations, remained relatively steady between 24h (median: 5.04 log CFU) and 48h (median: 5.19 log CFU) after infection. Peritoneal cytokine concentrations peaked early but were already diminished at 48h after infection, despite persistent high bacteria levels. Macrophages, harvested from naïve mice responded vigorously to ex vivo stimulation with 10(5) CFU and 2 x 10(8) CFU Klebsiella. Cells harvested from animals 48h after infection, were unresponsive to an ex vivo stimulation with 10(5) CFU Klebsiella, but fully responded to 10(8) CFU. Persistent intraabdominal bacterial infection induced dose dependent microbial tolerance in peritoneal macrophages.