Effect of hypoalbuminemia on mortality in cirrhotic patients with spontaneous bacterial peritonitis.

Objectives: The impact of hypoalbuminemia on the short-term and long-term mortality of cirrhotic patients with spontaneous bacterial peritonitis (SBP), both with and without renal function impairment, remains insufficiently elucidated based on population-based data. Materials and Methods: We retrieved data from Taiwan's National Health Insurance Database encompassing 14,583 hospitalized patients diagnosed with both cirrhosis and SBP during the period from January 1, 2010, to December 31, 2013. Prognostic factors influencing 30-day and 3-year survival were computed. Furthermore, the impact of hypoalbuminemia on the mortality rate among SBP patients, with or without concurrent renal function impairment, was also assessed. Results: The 30-day mortality rates for patients with SBP, comparing those with hypoalbuminemia and those without, were 18.3% and 29.4%, respectively (P < 0.001). Similarly, the 3-year mortality rates for SBP patients with hypoalbuminemia and those without were 73.7% and 85.8%, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for patients' gender, age, and comorbid conditions, substantiated that individuals with hypoalbuminemia exhibit an inferior 30-day survival (hazard ratio [HR]: 1.62, 95% confidence interval [CI]: 1.51-1.74, P < 0.001) and reduced 3-year survival (HR: 1.57, 95% CI: 1.50-1.63, P < 0.001) in comparison to those lacking hypoalbuminemia. Among SBP patients with renal function impairment, those presenting hypoalbuminemia also experienced diminished 30-day survival (HR: 1.81, 95% CI 1.57-2.07, P < 0.001) as well as reduced 3-year survival (HR: 1.70, 95% CI 1.54-1.87, P < 0.001). Likewise, in SBP patients without renal function impairment, the presence of hypoalbuminemia was associated with poorer 30-day survival (HR: 1.54, 95% CI 1.42-1.67, P < 0.001) and 3-year survival (HR: 1.53, 95% CI 1.46-1.60, P < 0.001). Conclusion: Among cirrhotic patients with SBP, the presence of hypoalbuminemia predicts inferior short-term and long-term outcomes, regardless of renal function.

Update in diagnosis and management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a lack of structural or biochemical abnormalities. The current diagnosis of IBS is based on the Rome IV criteria, and it is recommended to approach IBS patients using a multidimensional clinical profile (MDCP). The pathophysiology of IBS is multifactorial and involves motility disorders, genetic factors, immune responses, visceral hypersensitivity, brain-gut dysregulation, and altered intestinal microbiota. The management of IBS includes both nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapy options include physical activity, low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol diet, as well as cognitive behavioral therapy. Pharmacologic therapy options include probiotics, antidepressants, antispasmodics, and new agents. In clinical practice, a multidisciplinary strategy, including nonpharmacologic or/and pharmacologic treatment for IBS, is emphasized. Therefore, clinicians should carefully consider the underlying pathophysiology before selecting an appropriate therapeutic option for the treatment of IBS. In other words, individualized treatment plans are necessary for managing IBS.

Prognostic factors of cirrhotic patients with invasive fungal infections.

Fungal infection (FI) is a life-threatening condition in cirrhotic patients. However, a population-based study is required to determine the short-term mortality of these patients. The Taiwan National Health Insurance Database was used to enroll 1214 cirrhotic patients with FIs who were hospitalized between January 1, 2010 and December 31, 2013. Among them, 165 were diagnosed with invasive FIs. The overall 30-day and 90-day mortality rates for patients with invasive FIs were 25.7% and 49.9%, respectively (P < .001). After adjusting for sex, age, and other comorbidities, the following 90-day mortality prognostic factors were statistically different: renal function impairment (hazard ratio = 1.98, 95% confidence interval = 1.05-3.70, P = .034), concurrent with bacterial infections (hazard ratio = 1.75, 95% CI = 1.07-2.88, P = .027). Half of the cirrhotic patients died within 90-daysdue to invasive FIs, highlighting the importance of renal function impairment and concurrent with bacterial infections as an important prognostic factor.

The role of hepatic reserve in the mortality of cirrhotic patients with small hepatocellular carcinoma receiving radiofrequency ablation.

Although radiofrequency ablation (RFA) is considered a curative treatment for early stage small hepatocellular carcinoma (HCC), the long-term prognosis is suboptimal. The major complications in cirrhotic patients are usually related to poor prognosis and include esophageal variceal bleeding, ascites, and hepatic encephalopathy. This study aimed to evaluate the role of liver reserve on mortality after RFA for early stage HCC among cirrhotic patients, according to the presence of the number of complications. The Taiwan National Health Insurance Database was used to identify 2389 cirrhotic patients with treatment-naïve HCC (<3 cm) undergoing RFA hospitalized between January 1, 2010 and December 31, 2013. Of these, 594 patients had concurrent or a history of cirrhotic-related complications. The 1-year and 3-year survival rates in the cirrhotic patients with complications were 78.5% and 39.8%, respectively, and those in the patients without complications were 92.7% and 65.9% (P < .001), respectively. Age (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.02-1.04, P < .001) and cirrhotic-related complications (HR 2.65, 95% CI 2.22-3.16, P < .001) significantly increased 3-year mortality. The HR of mortality in patients with 1, 2, or 3 complications compared to those without complications were 2.35 (95% CI 1.92-2.88), 3.27 (95% CI 2.48-4.30), and 4.63 (95% CI 2.82-7.62), respectively (all P < .001). In cirrhotic patients with early stage HCC undergoing RFA, poor liver reserve correlates with poor outcome. The presence or history of three cirrhotic-related complications increased 3-year mortality 4-fold.

Prognosis of hypoglycemia episode in cirrhotic patients during hospitalization.

BACKGROUND: Studies have shown that hyperglycemia in cirrhotic patients increases mortality. However, no population-based study has evaluated the influence of hypoglycemia upon hospital admission on death in these patients. The aim of this study was to assess the effect of hypoglycemia at admission on the mortality of patients with liver cirrhosis. METHODS: The Taiwan National Health Insurance Database was searched, and 636 cirrhotic patients without baseline diabetes mellitus who presented with hypoglycemia upon hospitalized from 2010 to 2013 were included in the study. A one-to-four propensity score matching was performed to select a comparison group based on age, sex and comorbidities. RESULTS: The overall 30-day mortality rate was 30.2% in the hypoglycemia group and 7.4% in the non-hypoglycemia group (P < 0.001). After Cox regression modeling adjusting for age, sex and comorbid disorders, cirrhotic patients with hypoglycemia had a hazard ratio (HR) of 30-day mortality of 4.96 (95% confidence interval [CI] 4.05-6.08, P < 0.001) as compared to the non-hypoglycemia group. In subgroup analysis, the cirrhotic patients with hypoglycemia and hepatocellular carcinoma (HCC) had a 30-day mortality HR of 6.11 (95% confidence interval [CI] 4.40-8.49, P < 0.001) compared to those with neither hypoglycemia nor HCC. CONCLUSIONS: Hypoglycemia is a very important prognostic factor in the 30-day mortality of cirrhotic patients, especially in those with underlying HCC.

Effects of poor hepatic reserve in cirrhotic patients with bacterial infections: A population-based study.

OBJECTIVE: Ascites, hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, and esophageal variceal bleeding are major complications associated with cirrhosis. The presence of these complications indicates poor hepatic reserve. This study aimed to identify the effects of poor hepatic reserve on mortality in cirrhotic patients with bacterial infections. PATIENTS AND METHODS: The Taiwan National Health Insurance Database was used to identify 43,042 cirrhotic patients with bacterial infections hospitalized between January 1, 2010, and December 31, 2013, after propensity score matching analysis. Of these, 21,521 cirrhotic patients had major cirrhotic-related complications and were considered to have poor hepatic reserve. RESULTS: Mortality rates at 30 and 90 days were 24.2% and 39.5% in the poor hepatic reserve group and 12.8% and 21.7% in the good hepatic reserve group, respectively (P < 0.001 for each group). The cirrhotic patients with poor hepatic reserve (hazard ratio [HR], 2.10; 95% confidence interval [CI] = 2.03-2.18; P < 0.001) had significantly increased mortality at 90 days. The mortality HRs in patients with one, two, and three or more complications compared to patients without complications were 1.92 (95% CI = 1.85-1.99, P < 0.001), 2.61 (95% CI = 2.47-2.77, P < 0.001), and 3.81 (95% CI = 3.18-4.57, P < 0.001), respectively. CONCLUSION: In cirrhotic patients with bacterial infections, poor hepatic reserve is associated with a poor prognosis. The presence of three or more cirrhotic-related complications increases mortality almost four folds.

Effect of proton pump inhibitors on mortality of cirrhotic patients with pneumonia.

OBJECTIVE: Pneumonia is life-threatening in patients with liver cirrhosis. Proton pump inhibitors (PPIs) may increase the risk of these patients developing pneumonia. However, whether PPIs increase mortality in patients with cirrhosis and pneumonia remain unknown. METHODS: We used the Taiwan National Health Insurance Database to enroll 1,201 cirrhotic patients with pneumonia without active gastrointestinal bleeding who were receiving PPIs and were hospitalized between January 1, 2010 and December 31, 2013. A one-to-three propensity score match was performed to select a comparison group based on age, gender, and comorbid disorders. RESULTS: The overall 30-day and 90-day all-cause mortality rates were 13.7% and 26.9% in the PPI group, and 14.3% and 25.1% in the non-PPI group, respectively. After Cox regression model adjusting for age, gender, and comorbid disorders, the hazard ratios of the effect of PPIs on 30-day and 30 to 90-day mortality were 0.94 (95% Confidence Interval [CI], 0.79-1.12, P = 0.468) and 1.26 (95% CI, 1.05-1.52; P = 0.013), respectively. CONCLUSIONS: PPIs were not associated with 30-day mortality among cirrhotic patients with pneumonia but not active gastrointestinal bleeding. However, prolonged PPI therapy may be associated with higher mortality.

Statin use in cirrhotic patients with infectious diseases: A population-based study.

BACKGROUND: Recent studies have shown benefits of statins in patients with liver cirrhosis. However, it is still unknown if statins have a beneficial effect on the mortality of cirrhotic patients with bacterial infections. METHODS: The Taiwan National Health Insurance Database was searched, and 816 cirrhotic patients receiving statins with bacterial infections hospitalized between January 1, 2010 and December 31, 2013 were included in the study. A one-to-four propensity score matching was performed to select a comparison group based on age, sex, and comorbid disorders. RESULTS: The overall 30-day mortalities in statin and non-statin group were 5.3% and 9.8%, respectively (P = 0.001). After Cox regression modeling adjusting for age, sex, and comorbid disorders, the hazard ratio (HR) of statin use on 30-day mortality was 0.52 (95% confidence interval [CI]: 0.38-0.72, P<0.001). In subgroup analysis, the 30-day mortality effect of statin use was more pronounced in patients with pneumonia (HR = 0.34; 95% CI: 0.19-0.59; P<0.001) and bacteremia (HR = 0.55; 95% CI: 0.35-0.85; P = 0.008). Atovastatin (HR = 0.59; 95% CI: 0.37-0.93) and rosuvastatin (HR = 0.59; 95% CI: 0.36-0.98) were associated with a decreased 30-day mortality risk compared to patients not taking statins. CONCLUSIONS: Statin use decreases the 30-day mortality of cirrhotic patients with bacteremia and pneumonia.

Population-based study of Entecavir and long-term mortality in chronic hepatitis B-related decompensated liver cirrhosis.

BACKGROUND AND AIMS: We lack population-based studies that identify the role of entecavir (ETV) in extending long-term survival in chronic hepatitis B (CHB)-related decompensated liver cirrhotic patients. Since 2010, National Health Insurance in Taiwan has covered long-term medical payment for antiviral therapy in CHB-related cirrhotic patients whose HBV DNA is ≥ 2000 IU/mL. We studied the effect of ETV on the mortality of CHB-related decompensated cirrhosis patients compared with patients who did not receive antiviral agents at baseline. METHODS: From the Taiwan National Health Insurance Database, we collected 758 CHB-related decompensated cirrhosis patients with elevated viral loads (HBV DNA ≥ 2000 IU/mL) using ETV and discharged between January 1, 2010, and December 31, 2013. The comparison group consisted of 1516 selected CHB-related decompensated cirrhotic patients without antiviral therapy at baseline using propensity score matching analysis. RESULTS: The 1-, 2-, and 3-year mortality probabilities were 34.7%, 42.5%, and 48.5 % in the ETV group and 21.1%, 37.8% and 51.3 % in the non-ETV group, respectively. Based on a Cox proportional hazards regression model adjusted by patients' sex, age, and comorbid disorders, the hazard ratios (HR) in the ETV group for 1-year, 1-2-year, and 2-3-year mortalities were 1.22 (95% confidence interval [CI] 1.05-1.43, P = .010), 1.02 (0.86-1.20, P = .866), and 0.59 (0.38-0.90, P = .016), compared with the non-ETV group. CONCLUSIONS: Even in CHB-related decompensated cirrhotic patients, higher initial viral loads were correlated with poor outcomes. However, the long-term usage of ETV can decrease long-term mortality in these patients.

Effect of proton pump inhibitors in hospitalization on mortality of patients with hepatic encephalopathy and cirrhosis but no active gastrointestinal bleeding.

BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric complication of decompensated cirrhosis. Proton pump inhibitors (PPIs), used as potent acid suppressants, are associated with HE occurrence in cirrhotic patients. However, it is still unknown if PPIs contribute to mortality in cirrhotic patients with HE and no active gastrointestinal bleeding. METHODS: We used the Taiwan National Health Insurance Database to identify 1004 cirrhotic patients with HE and no active gastric bleeding, who received oral PPIs between January 1, 2010 and December 31, 2013. On the basis of comorbid disorder data, we used propensity score matching at a 1:4 ratio to select 4016 cirrhotic patients with HE and no active gastric bleeding who did not receive PPIs as a comparison group. All patients were followed up for one year from the index time. RESULTS: The overall 30-day, 90-day, and 1-year mortalities were 36.1%, 52.6%, and 70.1% in PPI group, and 27.5%, 41.7%, and 62.4% in non-PPI group. Using Cox regression model analysis with adjustment for age, gender, and other comorbid disorders, we obtained hazard ratios of 1.360 (95% CI: 1.208-1.532, P<0.001), 1.563 (95% CI: 1.314-1.859; P<0.001), and 1.187 (95% CI: 1.008-1.398; P=0.040) for, respectively, 30-day, 30-day to 90-day, and 90-day to 1-year mortality in patients taking PPIs. CONCLUSION: PPIs increase short-term and long-term mortality of cirrhotic patients with HE and no active gastrointestinal bleeding.

Sexual Abuse Is Associated With an Abnormal Psychological Profile and Sleep Difficulty in Patients With Irritable Bowel Syndrome in Taiwan.

BACKGROUND/AIMS: Both sexual and physical abuse history have been reported to be associated with irritable bowel syndrome (IBS) in Western countries. The impact of abuse history in IBS patients in Asia remains unclear. We aim to determine the prevalence of abuse history, its associated psychological profiles, and sleep problems among IBS patients in Taiwan. METHODS: In total, 194 Rome III-defined IBS patients were invited to participate. Age- and sex- matched healthy carriers of chronic hepatitis B or hepatitis C without chronic abdominal symptoms were identified as disease-controls. We administered a validated questionnaire to evaluate bowel symptoms, physical/sexual abuse history, anxiety/depression (Hospital Anxiety and Depression Scale [HADS]), and sleep quality. RESULTS: IBS patients had a significantly higher prevalence of sexual abuse history than the disease-control group both before (16.5% vs 6.7%, P < 0.05) and after (16.0% vs 6.6%, P < 0.05) adolescence. These significant differences were mainly observed in women (13.4% vs 3.4%, P < 0.05). No difference was noted in history of physical abuse between the 2 groups. IBS patients with a history of sexual abuse had significantly higher HADS scores and higher frequencies of sleep difficulty than those without. CONCLUSIONS: In Taiwan, sexual abuse history was more prevalent in female IBS patients than controls. Sexual abuse history may contribute to higher anxiety/depression levels and sleep difficulties, which are commonly experienced in IBS patients. In Asia, abuse history should be obtained when approaching IBS patients to facilitate better management.

Effect of Proton Pump Inhibitors on Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis.

INTRODUCTION AND AIM: Spontaneous bacterial peritonitis (SBP) is a life-threatening infection in patients with cirrhosis. However, it is unknown whether patients with SBP and cirrhosis who do not have active gastrointestinal bleeding have a poorer prognosis if treated with proton pump inhibitors (PPI). MATERIAL AND METHODS: We used the Taiwan National Health Insurance Database to identify 858 patients with SBP and cirrhosis who were administered PPIs and hospitalized between January 1, 2010, and December 31, 2013. One-to-two propensity score matching was performed to select a comparison group based on age, gender, and comorbidities. All patients obtained follow-up for 1 year. RESULTS: The overall 30-day, 90-day, and 1-year mortality was 27.9%, 49.0%, and 73.7%, respectively, in the PPI group and 25.6%, 43.8%, and 67.2%, respectively, in the non-PPI group. After adjusting the Cox regression model for age, gender, and comorbidities, the hazard ratios for PPIs regarding 30-day, 30- to 90-day, and 90-day to 1-year mortality were 1.074 (95% CI 0.917-1.257, P = 0.377), 1.390 (95% CI 1.154-1.673, P = 0.001), and 1.297 (95% CI 1.099- 1.531, P = 0.002), respectively. CONCLUSIONS: PPIs did not increase the short-term mortality of patients with SBP and cirrosis who did not have active gastrointestinal bleeding, but PPIs increased the long-term mortality risk. For these patients, physicians should discontinue PPIs as early as possible.

High Mortality of Cirrhotic Patients With End-Stage Renal Disease.

Ascites, hepatic encephalopathy (HE), and esophageal variceal bleeding (EVB) are 3 major complications in patients with cirrhosis. Limited data exist with which to evaluate the long-term mortality of end-stage renal disease (ESRD) in cirrhotic patients with or without complications.The National Health Insurance Database in Taiwan was used to identify patients with cirrhosis hospitalized between January 1, 2007, and December 31, 2007. The study group consisted of 1068 cirrhotic patients with ESRD, and the control group consisted of 10,680 randomly selected cirrhotic patients without baseline renal function impairment.The overall 1-year and 3-year mortality rates were 48.5% and 73.1% in the ESRD group, and 32.9% and 55.6% in the control group, respectively. After adjusting for other comorbid disorders, the cirrhotic patients with ESRD showed a statistically significant increase in 3-year mortality (hazard ratio [HR], 1.65; P < 0.001). The HR for 3-year mortality of ESRD cirrhotic patients with recurrent complications was 1.98 (P < 0.001), compared to those with no recent or past complications. The HR of ESRD for 3-year mortality was 1.48 (P < 0.001) in cirrhotic patients with ascites, 1.67 (P < 0.001) in patients with EVB, and 1.19 (P = 0.147) in patients with HE.ESRD increases the mortality rate in patients with cirrhosis. Recurrent complications can account for a 2-fold increase in the 3-year mortality of ESRD cirrhotic patients. ESRD has a smaller impact on the 3-year mortality of cirrhotic patients with HE compared to those with ascites or EVB.

High mortality in cirrhotic patients following hemorrhagic stroke.

The impact of hemorrhagic stroke (HS) on the mortality of cirrhotic patients is unknown. To evaluate the morality risk of HS in cirrhotic patients, we used the Taiwan National Health Insurance Database to evaluate cirrhotic patients with HS who were discharged between 1 January and 31 December 2007. In total, there were 321 cirrhotic patients with HS. We randomly selected 3210 cirrhotic patients without HS as a comparison group. The 30 and 90 day mortality rates were 29.6% and 43.0% in the HS group, and 9.1% and 17.7% in the comparison group, respectively (p<0.001). After Cox proportional hazard regression model adjustment of patients' sex, age, and other comorbid disorders, the hazard ratio (HR) for 90 day mortality in the HS group was 3.89 (95% confidence interval [CI] 3.20-4.71, p<0.001), compared to the comparison group. In the subgroup analysis, the HR for 90 day mortality in the subarachnoid hemorrhage and other HS groups were 7.93 (95% CI 5.23-12.0, p<0.001) and 3.51 (95% CI 2.85-4.32, p<0.001), respectively, compared to the comparison group. In conclusion, HS is associated with a very high 90 day mortality risk in cirrhotic patients, in whom subarachnoid hemorrhage can also increase the risk of mortality eight-fold.

Is transarterial chemoembolization beneficial for patients with diffuse infiltrative hepatocellular carcinoma?

PURPOSE: Diffuse infiltrative hepatocellular carcinoma (D-HCC) is an incurable disease with short survival time. Transarterial chemoembolization (TACE) was often used to alleviate patient's symptoms and reduce tumor burden. However, it remains unknown if the TACE benefits the survival of D-HCC patients. METHODS: A hospital-based retrospective study was conducted at a large referral hospital in Taiwan for a 9-year period (2000-2008). RESULTS: Of the 150 D-HCC patients, 106 patients were related to hepatitis B virus (HBV), 17 to hepatitis C virus (HCV), 3 to both HBV and HCV, and 24 not to HBV or HCV. Multivariate Cox regression analysis showed treatment strategy, serum alpha-fetoprotein level, model for end-stage liver disease (MELD) score, serum gamma glutamyl transferase, and serum lactic acid dehydrogenase were associated with survival time. Compared to supportive treatment, the adjusted hazard ratios of transarterial chemoembolization (TACE) and chemotherapy including oral or systemic chemotherapy were 0.383 (p < 0.001) and 0.711 (p = 0.289), respectively. CONCLUSION: TACE is a preferred therapy for D-HCC patients.

Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients.

Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients.

Spinal microglia initiate and maintain hyperalgesia in a rat model of chronic pancreatitis.

BACKGROUND & AIMS: The chronic, persistent pain associated with chronic pancreatitis (CP) has many characteristics of neuropathic pain, initiated and maintained by the activation of spinal microglia. We investigated whether activated microglia in the thoracic spinal cord contribute to chronic pain in a rat model of CP. METHODS: CP was induced in Sprague-Dawley rats by an intraductal injection of 2% trinitrobenzene sulfonic acid. Hyperalgesia was assessed by the measurement of mechanical sensitivity of the abdomen and nocifensive behavior to electrical stimulation of the pancreas. Three weeks after induction of CP, spinal samples were analyzed by immunostaining and immunoblot analyses for levels of CD11 (a marker of microglia, determined with the antibody OX42) and phosphorylated p38 (P-p38, a marker of activation of p38 mitogen-activated protein kinase signaling). We examined the effects of minocycline (inhibitor of microglia) and fractalkine (microglia-activating factor) on visceral hyperalgesia in rats with CP. RESULTS: Rats with CP had increased sensitivity and nociceptive behaviors to mechanical probing of the abdomen and electrical stimulation of the pancreas. The dorsal horn of the thoracic spinal cords of rats with CP contained activated microglia (based on increased staining with OX42), with an ameboid appearance. Levels of P-p38 increased in rats with CP and colocalized with OX42-positive cells. Intrathecal injection of minocycline reversed and prevented the increase of nocifensive behaviors and levels of P-p38 in rats with CP. Fractalkine induced hyperalgesia in rats without CP, which was blocked by minocycline. CONCLUSIONS: Activated spinal microglia have important roles in maintaining and initiating chronic pain in a rat model of CP. Microglia might be a target for treatment of hyperalgesia caused by pancreatic inflammation.