Primary wound closure with a Limberg flap vs. secondary wound healing after excision of a pilonidal sinus: a multicentre randomised controlled study.

PURPOSE: Off-midline procedures seem to be the best method of primary wound closure after excision of a pilonidal sinus. Primary wound closure with a Limberg flap was compared to secondary wound healing. METHODS: From January 2006 to July 2012, 102 patients with given informed consent (mean age 28 years, men 81%) who had excision of a pilonidal sinus in three hospitals in Switzerland were randomised to group L (Limberg flap, n = 51) or to group E (excision only, n = 51). Primary endpoint was duration of incapacity for work. Follow-up was at 3 weeks and at 1 year postoperative (95% follow-up). RESULTS: Both groups were comparable with regard to patient characteristics. The median (range) operation time was 60 (30-80) min in group L vs. 30 (10-75) min in group E (p < 0.001). No significant differences were found in postoperative pain and painkiller intake; pain, percentage of patients at work and overall satisfaction at 3 weeks postoperative; and overall duration of incapacity for work and overall satisfaction at 1-year follow-up. The complication rate was 49% in group L vs. 12% in group E (p < 0.001). Complications in group L were seroma (6%), wound dehiscence (45%), skin necrosis (10%), hematoma (6%), infection (4%) and recurrent disease (13%). Complications in group E were recurrent disease (6%) and wound healing disorder (6%). CONCLUSIONS: After excision of a pilonidal sinus, primary wound closure with a Limberg flap has no advantage over secondary wound healing. The main reason for this conclusion is the relatively high complication rate of primary wound closure with a Limberg flap.

Adenocarcinomas of the upper third of the rectum and the rectosigmoid junction seem to have similar prognosis as colon cancers even without radiotherapy, SAKK 40/87.

PURPOSE: To investigate the prognosis of adenocarcinomas of the upper third of the rectum and the rectosigmoid-junction without radiotherapy. METHODS: Patients from a multicenter randomized controlled trial from 1987-1993 on adjuvant chemotherapy for R0-resected colorectal cancers with stage I-III disease were retrospectively allocated: cancers of the lower two-thirds of the rectum (11 cm or less from anal-verge, Group A, n = 205), of the upper-third of the rectum and rectosigmoid-junction (>11-20 cm from anal-verge, Group B, n = 142), and of the colon (>20 cm from anal-verge, Group C, n = 378). The total mesorectal excision (TME) technique had not been introduced yet. The adjuvant chemotherapy turned out to be ineffective. None of the patients received neoadjuvant or adjuvant radiotherapy. RESULTS: The patients had a regular follow-up (median, 8.0 years). The 5-year disease-free survival (DFS) rate was 0.54 (95%CI, 0.47-0.60) in Group A, 0.68 (95%CI, 0.60-0.75) in Group B, and 0.69 (95%CI, 0.64-0.74) in Group C. The 5-year overall survival (OS) rate was 0.64 (95%CI, 0.57-0.71) in Group A, 0.79 (95%CI, 0.71-0.85) in Group B, and 0.77 (95%CI, 0.73-0.81) in Group C. Compared with Group C, patients in Group A had a significantly worse OS (hazard ratio [HR] for death 2.10) and a worse DFS (HR for relapse/death 1.93), while patients in Group B had a similar OS (HR 1.12) and DFS (HR 1.07). CONCLUSIONS: Adenocarcinomas of the upper third of the rectum and the rectosigmoid-junction seem to have similar prognosis as colon cancers. Even for surgeons not familiar with the TME technique, preoperative radiotherapy may be avoided for most rectosigmoid cancers above 11 cm from anal-verge.

Serum prolactin in advanced chronic liver disease.

Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etio-logies. Eighteen out of 178 patients - 7 females and 11 males - displayed elevated serum pro-lactin levels. When patients were excluded who suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.

Could hyponatremia be a marker of anastomotic leakage after colorectal surgery? A single center analysis of 1,106 patients over 5 years.

PURPOSE: The aim of this study is to define the significance of hyponatremia as a marker of anastomotic leakage after colorectal surgery. METHODS: All anastomoses in colorectal surgery performed at a single institution between July 2007 and July 2012 (n = 1,106) were retrospectively identified. Serum sodium levels and leukocyte values measured when an anastomotic leak was diagnosed by CT scan and/or surgical reintervention (n = 81) were compared to the values preferably on postoperative day 5 in the absence of an anastomotic leak (n = 1,025). RESULTS: The leak rate in anastomoses of the rectum was 9.0 %, while the leak rate of the other anastomoses was 5.4 %. Mean serum sodium level was 138.8 mmol/l in the group with an anastomotic leak and 140.5 mmol/l in the group without. Hyponatremia (<136 mmol/l) was present in 23 % of patients in the group with an anastomotic leak and in 15 % in the group without (p < 0.001). In multivariate analysis, leukocytes and serum sodium level remained as significant markers of an anastomotic leak. As a marker of an anastomotic leak, hyponatremia had a specificity of 93 % and a sensitivity of 23 %, while the presence of either leukocytosis or hyponatremia had a sensitivity of 68 %, a specificity of 75 %, a positive predictive value of 18 %, and a negative predictive value of 97 %. CONCLUSIONS: Hyponatremia could be a specific and relevant marker of anastomotic leakage after colorectal surgery. If hyponatremia and leukocytosis are present after colorectal surgery, anastomotic leakage should be suspected and a CT scan with rectal contrast dye is recommended.

Distinct spin and orbital dynamics in Sr2RuO4.

The unconventional superconductor Sr2RuO4 has long served as a benchmark for theories of correlated-electron materials. The determination of the superconducting pairing mechanism requires detailed experimental information on collective bosonic excitations as potential mediators of Cooper pairing. We have used Ru L3-edge resonant inelastic x-ray scattering to obtain comprehensive maps of the electronic excitations of Sr2RuO4 over the entire Brillouin zone. We observe multiple branches of dispersive spin and orbital excitations associated with distinctly different energy scales. The spin and orbital dynamical response functions calculated within the dynamical mean-field theory are in excellent agreement with the experimental data. Our results highlight the Hund metal nature of Sr2RuO4 and provide key information for the understanding of its unconventional superconductivity.

Timing of rectosigmoid resection for diverticular disease: the patient's view.

AIM: The study aimed to determine the patient's view on the timing of elective resection for sigmoid diverticulitis. METHOD: A questionnaire was answered by 162 (69%) of 236 consecutive patients who had a resection of the rectosigmoid for diverticulitis from July 2002 to August 2005. Patients (n=45) having resection at or after the first inflammatory attack were excluded, leaving 117 eligible for analysis. Questions asked included those concerning symptoms before surgery, improvement of symptoms after surgery and the timing of surgery. RESULTS: Patient assessment of symptoms after surgery was as follows: no improvement (2%; n=2), some improvement (10%; n=12), marked improvement (34%; n=39) and complete resolution (54%; n=63). Forty-five (38%) patients would have preferred an earlier operation. Preference for earlier surgery related to the number of previous inflammatory attacks was expressed as follows: 13 (34%) of 38 patients after two inflammatory attacks, 5 (18%) of 28 patients after three, seven (37%) of 19 patients after four, four (44%) of nine patients after five, and 16 (70%) of 23 patients after six or more inflammatory attacks would have preferred earlier surgery. Statistically significant factors influencing this potential choice were number of episodes of pain (P=0.006, OR=1.23, 95% CI: 1.060-1.430) and number of attacks of inflammation (P=0.048, OR=1.27, 95% CI: 1.002-1.598). CONCLUSION: Surgery for recurrent diverticulitis resulted in a marked improvement or complete relief of symptoms in 88% of patients. A large proportion of patients with recurrent episodes of sigmoid diverticulitis would have preferred earlier resection.

Plasminogen activator inhibitor 1 and visceral obesity during pronounced weight loss after bariatric surgery.

BACKGROUND AND AIMS: Elevated plasminogen activator inhibitor 1 (PAI-1) concentrations are a hallmark of obesity and are considered to contribute to the development of cardiovascular disease. As adipose tissue constitutes a major source for PAI-1 in obesity, we investigated the individual contribution of subcutaneous and intra-abdominal fat on PAI-1 concentrations during pronounced weight loss after bariatric surgery. METHODS AND RESULTS: Thirty-seven obese adults were examined before and 18 months after surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters and plasma PAI-1 levels by standard methods. BMI was reduced by 9.2 ± 4.9 kg/m(2), while total fat mass and visceral fat diameter (VFD) decreased by 20.7 ± 11.9 kg and 4.2 ± 2.3 cm, respectively. Concomitantly, PAI-1 levels diminished by 3.2 ± 5.6 ng/ml (all p ≤ 0.015). Change in PAI-1 levels was correlated with change in VFD (r = 0.441, p = 0.008), but not with subcutaneous fat diameter. In stepwise multiple regression analysis change in VFD was an independent predictor of change in PAI-1 concentrations. When adjusted for age and sex or total fat mass associations between PAI-1 and VFD remained significant. CONCLUSION: We demonstrate that VFD is a major determinant for PAI-1 concentrations during pronounced weight loss after bariatric surgery. Thus, significant reduction of visceral fat mass may contribute to the reduced cardiovascular morbidity and mortality after bariatric surgery by a concomitant decrease in PAI-1 concentrations.

The role of apolipoprotein A5 in non-alcoholic fatty liver disease.

BACKGROUND: Apolipoprotein A5 (apoA5) is a recently described liver-specific protein that has been shown to influence triglyceride (TG) metabolism. ApoA5 transgenic mice display dramatically reduced TG levels, while in contrast apoA5 deficiency in humans was reported to result in marked hypertriglyceridemia. ApoA5 exerts its extracellular effects by increasing lipolysis of TG-rich lipoproteins, while in vitro data suggest additional intrahepatic effects. METHODS: In this study the authors set out to investigate a possible role of apoA5 in non-alcoholic fatty liver disease (NAFLD). We thus determined hepatic apoA5 expression in 15 obese subjects with histologically proven NAFLD undergoing bariatric surgery. In addition, the authors established a hepatic cell culture model of apoA5 knockdown by transfecting human hepatoma cells (HepG2) with apoA5 small interfering (si) RNA, and determined intracellular TG content and expression levels of key enzymes and transcription factors of intrahepatic lipid metabolism in these cells. RESULTS: Pronounced weight loss and associated histologically verified improvement of hepatic steatosis were accompanied by significant reductions of hepatic apoA5 mRNA expression levels. Significant apoA5 knockdown in HepG2 cells resulted in a marked decrease of intracellular TG content. When HepG2 cells were co-transfected with apoA5 and peroxisome proliferator-activated receptor gamma (PPARγ), reductions in hepatic TG accumulation were significantly less pronounced when compared to apoA5 siRNA transfected HepG2 cells. CONCLUSIONS: In obese subjects, hepatic apoA5 mRNA expression decreases after weight loss and improvements in hepatic steatosis. The authors' in vitro data demonstrate that apoA5 influences intrahepatic TG metabolism and that these intracellular effects of apoA5 are accompanied by changes in PPARγ mRNA expression. In summary, the data suggest that as well as several other factors, apoA5 might be involved in the pathogenesis of hepatic steatosis.

Normal width of the linea alba, prevalence, and risk factors for diastasis recti abdominis in adults, a cross-sectional study.

AIM: The prevalence and definition of diastasis recti abdominis (DRA) is under debate. This retrospective cross-sectional study evaluated the interrectal distance and the prevalence of DRA in computed tomography (CT) in an asymptomatic population. MATERIALS AND METHODS: Patients undergoing CT scans for suspected appendicitis or kidney stones from 01/2016 to 12/2018 were screened retrospectively to participate. A study population with equal distribution according to gender and age (18-90 years) was generated (n = 329 patients) and the interrectal distance was measured at six reference points. RESULTS: DRA (defined as > 2 cm at 3 cm above the umbilicus) was present in 57% of the population. The 80th percentile of the interrectal distance was 10 mm at the xiphoid (median 3 mm, 95% confidence interval (CI) 0-19 mm), 27 mm halfway from xiphoid to umbilicus (median 17 mm, 95% CI 0-39 mm), 34 mm at 3 cm above the umbilicus (median 22 mm, 95% CI 0-50 mm), 32 mm at the umbilicus (median 25 mm, 95% CI 0-45 mm), 25 mm at 2 cm below the umbilicus (median 14 mm, 95% CI 0-39 mm), and 4 mm halfway from umbilicus to pubic symphysis (median 0 mm, 95% CI 0-19 mm). In the multivariate analysis, higher age (p = 0.001), increased body mass index (p < 0.001), and parity (p < 0.037) were independent risk factors for DRA, while split xiphoid, tobacco abuse, and umbilical hernia were not. CONCLUSION: The prevalence of DRA is much higher than commonly estimated (57%). The IRD 3 cm above the umbilicus may be considered normal up to 34 mm. To avoid over-treatment, the definition of DRA should be revised.

The impact of the introduction of total mesorectal excision on local recurrence rate and survival in rectal cancer: long-term results.

PURPOSE: To investigate the influence of the introduction of total mesorectal excision (TME) on local recurrence rate and survival in patients with rectal cancer. METHODS: A total of 171 consecutive patients underwent anterior or abdominoperineal resection for primary rectal cancer. When the TME technique was introduced, the clinical setting, including the surgeons, remained the same. Group 1 (1993-95, n =53) underwent conventional surgery and group 2 (1995-2001, n = 118) underwent TME. All patients were followed for 7 years or until death. RESULTS: Between the two groups, no statistically significant differences were present with regards to patient-, treatment-, or tumor-related characteristics apart from the time point of radiotherapy. The total local recurrence rates were 11 of 53 (20.8%) in group 1 and 7 of 118 (5.9%) in group 2, and the rates of isolated local recurrences were 6 of 53 (11.3%) in group 1 and 2 of 118 (1.7%) in group 2. Both differences were highly statistically significant. The disease-free survival in groups 1 and 2 was 60.4 and 65.3% at 5 years, and 58.5 and 65.3% at 7 years, respectively. Excluding patients with synchronous or metachronous distant metastasis from the analysis, both the disease-free survival and the cancer-specific survival were statistically significantly better in group 2 than in group 1. No statistically significant difference between the two groups was detected regarding the overall survival. CONCLUSIONS: The introduction of TME led to an impressive reduction of the local recurrence rate. Survival is mainly determined by the occurrence of distant metastasis, but TME seems to improve survival in patients without systemic disease.

A salvage procedure for an accidentally twisted small bowel in orthotopic duodenal reconstruction after pylorus-preserving partial pancreatoduodenectomy.

A case of pylorus-preserving Whipple procedure with an accidentally clockwise 360° rotated small bowel limb in orthotopic duodenal reconstruction is presented. A simple salvage procedure is proposed.

Effect of bariatric surgery on circulating chemerin levels.

BACKGROUND: Subclinical inflammation in obesity is critical for development of several obesity-associated disorders. We set out to investigate the effect of pronounced weight loss on circulating chemerin levels, a chemoattractant protein that also influences adipose cell function by paracrine and autocrine mechanisms. MATERIAL AND METHODS: Thirty-two obese patients undergoing bariatric surgery were tested before and on an average of 18 months after gastric banding or gastric bypass surgery. RESULTS: Pronounced weight loss after bariatric surgery was accompanied by improvements in parameters of lipid and glucose metabolism and increased adiponectin levels. Chemoattractant chemerin significantly decreased from 175.91 +/- 24.50 to 145.53 +/- 26.44 ng mL(-1) after bariatric surgery (P < or = 0.01). Concomitantly, hs-CRP as a marker of subclinical inflammation was significantly reduced after weight reduction (P < or = 0.01). CONCLUSIONS: We hypothesize that weight-loss induced reduction in circulating chemerin might in conjunction with other factors be associated with diminished recruitment of macrophages in adipose tissue and reduction of subclinical inflammation, which again could partly explain beneficial long-term effects of weight reduction in obese subjects.

Diagnostic value of inflammation markers in predicting perforation in acute sigmoid diverticulitis.

BACKGROUND: The importance of inflammation markers in predicting perforation in acute sigmoid diverticulitis is not well known. Predicting perforation by clinical examination alone may be hazardous. If perforation is suspected, then appropriate diagnostic tools such as computed tomography (CT) are indicated, and surgical intervention might be necessary. METHODS: A cohort of consecutive patients with acute sigmoid diverticulitis diagnosed by CT and with complete laboratory findings (n = 247) were retrospectively divided into two groups, one with perforation (n = 86) and another without (n = 161). The latest values of C-reactive protein (CRP), white blood cell count (WBC), and serum bilirubin, as well as the activity of the alkaline phosphatase (AP) measured during the 48 h period before the CT scan, were assessed. RESULTS: In the Wilcoxon rank sum test CRP and WBC correlate significantly (p < 0.05) with perforation in acute sigmoid diverticulitis, whereas the logistic regression model shows only CRP to correlate significantly (p = 0.001) with perforation. The sensitivities/specificities for perforation are 98%/5% for elevated CRP (>5 mg/l), 86%/27% for a CRP higher than 50 mg/l, 44%/81% for a CRP higher than 150 mg/l, 28%/93% for a CRP higher than 200 mg/l, 88%/44% for elevated WBC (>10 × 10(9)/l), 35%/90% for hyperbilirubinemia (>20 µmol/l), and 35%/91% for elevated AP (>110 U/l). CONCLUSIONS: A CRP below 50 mg/l suggests a perforation to be unlikely in acute sigmoid diverticulitis, whereas a CRP higher than 200 mg/l is a strong indicator of perforation.

Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) comprises a disease spectrum ranging from simple steatosis and steatohepatitis to cirrhosis. Based on its strongest risk factors namely visceral obesity and insulin resistance, NAFLD is thought to be the hepatic manifestation of the metabolic syndrome and is considered to be the most common liver disorder in Western countries. Pathophysiological mechanisms include an enlarged pool of fatty acids, subclinical inflammation, oxidative stress and imbalances of various adipocytokines such as adiponectin. Accordingly, targets for therapeutic interventions are miscellaneous: amelioration of obesity by pharmacological, surgical or lifestyle intervention has been evaluated with success in numerous, but not all studies. Some efficacy was reported for metformin and short-term glitazone treatment. In a large recently reported trial, vitamin E supplementation improved biochemical and histological markers in subjects with non-alcoholic steatohepatitis. Blockade of the endocannabinoid system has been proposed to be a promising target in NAFLD; however, very recently the cannabinoid receptor blocker rimonabant has been withdrawn because of central nervous system toxicity. Cytoprotective therapies and statins have been mainly ineffective in NAFLD. New but so far insufficiently studied therapeutic approaches include inhibitors of the renin-angiotensin system as well as incretin mimetics respectively.

Effect of obesity and insulin sensitivity on adiponectin isoform distribution.

BACKGROUND: Adiponectin is an insulin-sensitizing, antiatherogenic and anti-inflammatory adipocytokine that circulates in three isoforms: a trimer [low-molecular weight (LMW)], a hexamer (trimer-dimer) of medium molecular weight (MMW) and a multimeric high molecular weight (HMW) isoform. Evidence is accumulating that HMW adiponectin is the active isoform of the adipocytokine. We investigated the impact of adipose tissue and insulin sensitivity on adiponectin isoform distribution. MATERIALS AND METHODS: One hundred and eighty-seven normolipidaemic, non-diabetic lean or obese subjects with or without insulin resistance participating in the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR) were included in the study. Insulin sensitivity was determined by the short insulin tolerance test and the homeostasis model assessment (HOMA) index. Serum adiponectin isoform distribution was determined by an enzyme immunoassay. RESULTS: Total adiponectin as well as HMW/total adiponectin ratio was significantly increased in female subjects. Circulating total adiponectin levels were lowest in obese patients due to reduced concentrations of HMW adiponectin. As determined by stepwise regression analysis, besides age and high density lipoprotein (HDL) cholesterol, visceral fat area and waist-to-hip ratio predicted concentrations of HMW adiponectin, while insulin sensitivity had no influence on either total adiponectin or its isoforms. CONCLUSIONS: Our results underline that determination of adiponectin isoforms are more useful than measurement of total adiponectin in clinical settings. Our data suggest that adiponectin concentrations are strongly associated with visceral fat area but not with insulin sensitivity. Thus, we hypothesize that insulin resistance is a consequence rather than the cause of hypoadiponectinaemia in obese subjects.

Effect of pronounced weight loss on visceral fat, liver steatosis and adiponectin isoforms.

BACKGROUND: Weight loss induced by bariatric surgery is an effective method to reverse obesity and comorbidities. The aim of this prospective weight loss study was to investigate changes of body fat distribution in relation to adiponectin and its isoforms and further to investigate the influence of both body fat distribution and adiponectin on the degree of liver steatosis. DESIGN: Fifteen severely obese female patients (body mass index 43.1 +/- 4.1, mean age 34.5 +/- 8.6 years) were examined before and after surgical treatment. Grading of fatty liver disease and the subcutaneous and visceral fat diameters were determined by abdominal ultrasonography. Metabolic parameters were determined using standard methods; serum total adiponectin and its isoforms were detected by enzyme immuno assay (EIA). RESULTS: Mean weight loss was 28.3 kg, which was mostly due to a loss in fat mass, accompanied by an increase in total adiponectin and the high molecular weight (HMW) adiponectin isoform. Visceral adipose tissue (VAT) diameter was highly correlated with liver steatosis, even more strongly than the parameters of liver function. In addition, liver steatosis correlated negatively with HMW adiponectin and binary logistic regression revealed that changes in fat mass, HMW adiponectin and alanine aminotransferase (ALT) were the best predictors for changes in the degree of hepatic steatosis. CONCLUSIONS: Our results suggest that circulating HMW adiponectin is associated with both VAT and liver steatosis. In summary, the major findings were that the VAT diameter is highly correlated with liver steatosis, even stronger than the parameters of liver function and the association of HMW adiponectin with liver steatosis was better than with total adiponectin.

Body mass index and the risk of infection - from underweight to obesity.

BACKGROUND: Nutritional status is a well-known risk factor for metabolic and endocrine disorders. Recent studies suggest that dietary intake also affects immune function and as a consequence infection risk. AIMS: This reviews aims to give an overview on the effect of body weight on infection rate at different periods of life. SOURCES: Clinically relevant prospective, cross-sectional and case-control community-based studies are summarized. CONTENT: In children and adolescents underweight is a significant risk factor for infection especially in developing countries, probably reflecting malnutrition and poor hygienic standards. Data from industrialized countries suggest that infection rate is also increased in obese children and adolescents. Similarly, several studies suggest a U-shaped increased infection rate in both underweight and obese adults. In the latter, infections of the skin and respiratory tract as well as surgical-site infections have consistently been reported to be more common than in normal-weight participants. Paradoxically, mortality of critically ill patients was reduced in obesity in some studies. IMPLICATIONS: Several studies in children or adults suggest that both underweight and obesity are associated with increased infection risk. However, confounding factors such as malnutrition, hygienic status and underlying disease or co-morbidities might aggravate accurate assessment of the impact of body weight on infection risk.

Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice.

Cytokines derived from macrophages (Mø) play a critical role in the development of type 1 diabetes in the nonobese diabetic (NOD) mouse. Based on earlier findings from lupus-prone strains of inherent cytokine defects in Mø , NOD Mø were evaluated for intrinsically dysregulated cytokine production with the potential to initiate or exacerbate disease. Endotoxin-activated peritoneal Mø from young prediseased NOD mice produced interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha levels similar to those of Mø from a panel of control strains but reduced compared with the congenic diabetes-resistant NOR strain. IL-6 and IL-10 production were similar in NOD and NOR Mø, indicating that reduction in NOD IL-1 and TNF-alpha expression was selective. Nevertheless, the ratio of TNF-alpha and IL-10 production, a stringent index of normal Mø function, distinguished NOD from all normal strains. The most striking feature of NOD Mø, however, was their substantially elevated IL-12 production. This response was induced not only by endotoxin but also by bacillus Calmette-Guerin (BCG) and CD40 ligand and was associated with (and likely caused by) the enhanced and prolonged expression of p40 mRNA. Moreover, NOD Mø IL-12 expression appeared to be near maximally induced by lipopolysaccharide (LPS) alone, because it was only slightly enhanced by the addition of gamma-interferon, a stimulus that substantially elevated LPS-induced IL-12 production in Mø from normal strains. Accompanied by a unique profile of TNF-alpha and IL-10, the dramatic elevation of IL-12 expression by NOD Mø reflects intrinsic defects of the innate immune system with the potential to initiate and propagate the pathogenic autoreactive T-helper type 1 response characteristic of type 1 diabetes.