Modulation of the inflammatory response and apoptosis using epidermal growth factor and hepatocyte growth factor in a liver injury model: a potential approach to the management and treatment of cholestatic liver disease

Background/Purpose

The major side effect of total parenteral nutrition is liver injury leading to liver failure. This study was designed to assess specific growth factors in modulating the hepatic response in an ANIT-induced liver-injury model.

Methods

Sprague-Dawley rats were divided into four groups: control (n = 5), liver-injury control (α-naphtylisocyocyanate [ANIT], 100 mg/kg, n = 8), ANIT + epidermal growth factor (EGF, 150 μg/kg per day, n = 10), and ANIT + hepatocyte growth factor (HGF, 250 μg/kg per day, n = 9). Rats were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic mini-pump for 7 days of continuous intravenous saline (liver injury control), EGF, or HGF. Seven and 14 days later, liver biopsies were obtained and evaluated for interleukin (IL)-6 and tumor necrosis factor α expression by immunofluorescent staining, and for apoptosis, by the terminal transferase dUTP nick end labeling (TUNEL) technique. All animals were euthanized at 14 days.

Results

Epidermal growth factor (P < .025) and HGF (P < .001) groups induced less IL-6 expression at day 14 compared to liver-injury controls. In addition, the interval decrease in IL-6 expression between days 7 and 14 was greater in EGF (P < .001) and HGF (P < .001) groups compared to liver-injury controls. At day 14, HGF also demonstrated decreased tumor necrosis factor α expression (P < .005). Apoptotic activity was significantly less for the EGF (P < .011) and HGF (P < .0012) groups.

Conclusion

Epidermal growth factor and HGF modulated the hepatic inflammatory response and apoptotic index in this established liver-injury model and may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury.     

Glucocorticoid receptor alpha expression in the intrahepatic biliary epithelium and adjuvant steroid therapy in infants with biliary atresia

Background/Purpose

In patients with cirrhosis, proinflammatory cytokines increase progressively in relation to the severity of liver dysfunction. Proinflammatory cytokines regulate the expression of glucocorticoid receptors (GcRs). On the other hand, GcRs mediate the effects of glucocorticoid steroids on bile excretion in the biliary epithelium. Glucocorticoid receptors have 2 isoforms: a cytoplasmic glucocorticoid receptor α (GcRα) mediates thier physiological effects, whereas a nuclear localized glucocorticoid receptor β (GcRβ) acts as a dominant negative inhibitor of GcRα activity. We examined the histology features of liver biopsy and the expression of GcRα in the intrahepatic biliary epithelium in infants with biliary atresia.

Patients/Methods

The patients were divided into 2 groups: patients in group 1 (n = 17) had a total bilirubin level below 1.0 mg/dL at least once after surgery, whereas patients in group 2 (n = 14) has never had bilirubin level below 1.0 mg/dL postoperatively. Liver biopsies taken from 31 infants with biliary atresia at the time of hepatic portoenterostomy between 1988 and 2002 were examined for immunohistochemistry and histology with H&E staining. The degree of GcRα expression in the biliary epithelium was semiquantitatively analyzed using staining scores. The histology features of the liver biopsy were also semiquantitatively analyzed by using the same scores to evaluate the liver injury. Intravenous prednisolone dosage was started with 4 mg/kg per day and tapered by a half dose every 2 days. The protocol was orally repeated during admission until the stool became constantly cholic. Statistical analysis was performed using Mann-Whitney U test and Spearman correlation coefficient by rank. Significance is set at a 95% confidence interval (P < .05).

Results

There was a significant positive correlation between the liver histology and the GcRα scores in all patients with biliary atresia (P = .0128; r = 0.429). In group 1, there was a significant positive correlation between the GcRα expression scores and the total dose of prednisolone administered (P = .0063; r = 0.767).

Conclusions

The increase and degree of GcRα expression were associated with the severity of liver injury and may correlate with the dose of prednisolone required to sustain bile flow after successful hepatic portoenterostomy.     

Direct measurement of hepatic blood flow during living donor liver transplantation in children

Background

The changes in liver blood flow associated with living donor liver transplantation (LDLT) in children have not yet been studied. The aim of the present study was to investigate changes in hepatic hemodynamics before and after pediatric partial liver transplantation.

Methods

In 7 pediatric recipients with congenital cholestasis and native liver Child-Pugh classes B and C, portal vein flow (PVF) and hepatic arterial flow (HAF) were measured using an ultrasonic transit time flow meter before removal of the native liver and after transplantation and compared with donor left PVF and donor left HAF.

Results

The mean portal contribution to total hepatic blood flow was markedly decreased in the recipient native liver compared with that in the donor (69% ± 15% vs 32% ± 15%; P = .0003) and after reperfusion changed to almost the same ratio as that in the donor liver (73% ± 18%; P < .0001).

Conclusion

The extreme imbalance between PVF and HAF that is common in implanted partial liver in adult LDLT recipients was not observed in pediatric LDLT. After transplantation of an appropriately sized liver graft, the portal contribution to total liver blood flow normalized to the value for normal liver.     

Protective effect of methylprednisolone on warm ischemia-reperfusion injury in a cholestatic rat liver

Background

Cholestasis has been identified as a risk factor for oxidative stress, and it potentially enhances after ischemic-reperfusion injury. The aim of this study was to evaluate the role of methylprednisolone on warm ischemia-reperfusion injury in the presence of cholestasis.

Methods

A reversible cholestatic rat model was created. After 7 days, rats received 30 mg/kg of intravenous methylprednisolone 2 hours before ischemia, followed by 30 minutes of ischemia. Rats were euthanized 24 hours after ischemia. Serum aspartate aminotransferase and interleukin-6 were measured, and the liver was harvested for histology and myeloperoxidase estimation.

Results

Methylprednisolone had a protective effect, with a statistically significant decrease in aspartate aminotransferase (P = .01) and a trend toward decreased levels of interleukin-6 (P = .07). Histology showed a significant difference in architectural distortion (P = .01), cytoplasmic vacuolation (P = .01), and nodular hepatocellular necrosis (P = .04).

Conclusions

Methylprednisolone attenuated the ischemic-reperfusion injury in the presence of cholestasis and can be considered for clinical use in the presence of cholestasis.     

Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease

Background/purpose

Transfection of the HLA-B27 gene into normal Fischer rats induces phenotypic changes similar to inflammatory bowel disease (IBD). This study investigated the benefits of 2 doses of hepatocyte growth factor (HGF) on the manifestations of IBD in this rat model.

Methods

Fischer rats and HLA-B27 rats were divided into 4 groups: Fischer rats treated with saline, HLA-B27 rats treated with saline, HGF at 150 μg/kg/d, and HGF at 300 μg/kg/d. HGF or saline was infused for 14 days via an osmotic pump attached to a catheter in the internal jugular vein. After treatment, rats were evaluated for diarrhea and reduction in gross and microscopic bowel inflammation. Statistics were determined using analysis of variance (ANOVA). A P value ≤ .05 was considered significant.

Results

Administration of HGF at 150 μg/kg/d decreased diarrhea by 40%, gross inflammation by 41%, and microscopic inflammation by 72% (P ≤ .05). At 300 μg/kg/d HGF decreased diarrhea by 46%, gross inflammation by 45%, and microscopic inflammation by 54% (P ≤ .05).

Conclusions

HGF administration reduces the clinical manifestations of IBD in this rat model. Similar effects were seen at both doses of HGF administration, implying that there is a plateau above which further increases in HGF levels provides no added benefit. HGF administration may be clinically useful in the management of IBD.     

The significance of serum hepatocyte growth factor levels in planning follow-up of postoperative jaundice-free patients with biliary atresia

Purpose

The aim of this study was to clarify the significance of serum hepatocyte growth factor (HGF), interleukin (IL)-6, and IL-1 receptor antagonist (ra) levels in the evaluation of disease status in jaundice-free survivors with biliary atresia after Kasai operation.

Patients and Methods

Serum concentrations of HGF, IL-6, and IL-ra were measured in 31 long-term jaundice-free patients with biliary atresia after Kasai operation and 29 controls. Patients were divided into 4 groups: group A (n = 8), normal liver function; group B (n = 9), mild liver dysfunction without portal hypertension; group C (n = 9), moderate liver dysfunction with controllable portal hypertension; and group D (n = 5), receiving liver transplantation.

Results

Serum IL-6 levels were significantly higher in patients than in controls. There was no difference in serum IL-6 levels among groups B, C, and D. Serum IL-1ra levels were elevated according to liver dysfunction. Serum HGF levels in group D were significantly higher than in controls and the other groups. Serum hyarulonic acid levels were positively correlated with serum levels of IL-1ra and HGF.

Conclusions

Elevation of serum IL-1ra and HGF levels correlated with the progression of liver fibrosis and dysfunction. In particular, serum HGF levels could be used as a predictor for requiring liver transplantation.     

Intestinal involvement during 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced chronic liver injury in a mouse model

Purpose

Although a physiologic relationship between intestinal mucosal integrity and hepatic function has been previously described, the effect of primary liver disease on intestinal mucosal homeostasis has not been previously well documented. In the current study, we studied the effects of chronic liver injury as a primary injury on enterocyte turnover (proliferation and apoptosis) in a mouse model.

Methods

The liver toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to induce chronic cholestatic liver injury in mice. Livers and intestine were harvested after 3 weeks of dietary treatment of histologic analysis and a determination of cell proliferation (immunohistochemistry for Ki67), or apoptosis (immunohistochemistry for caspase-3), as well as a determination of Wnt/β-catenin signaling activity.

Results

All DDC-fed animals exhibited histologic evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas and increased oxidative stress. In the intestine, DDC-induced liver damage was associated with decreased villus height, decreased enterocyte proliferation, and increased cell apoptosis compared with control animals. There was also evidence for decreased β-catenin expression by immunostaining in crypt and villus cells of DDC-fed mice compared with control animals.

Conclusion

Primary liver injury and cholestasis is associated with intestinal mucosal hypoplasia. Decreased cell proliferation and increased cell apoptosis may be responsible for decreased intestinal epithelial cell mass. The observed decrease in cell turnover is accompanied by an alteration in Wnt/β-catenin signaling.     

Use of a modified chitosan dressing in a hypothermic Coagulopathic grade V liver injury model

Background

Exsanguination from hepatic trauma is exacerbated by the lethal triad of acidosis, coagulopathy, and hypothermia. We evaluated the application of a modified chitosan dressing in a hypothermic coagulopathic model of grade V liver injury.

Methods

Subject swine underwent induced hypothermic coagulopathy followed by standardized grade V liver injuries. A modified chitosan dressing was applied and compared with standard packing.

Results

Pretreatment temperature, activated clotting time, and blood loss were similar between groups. Post treatment blood loss was significantly less and resuscitation mean arterial pressure were significantly greater in the modified chitosan group (P < .0001 and P < .018, respectively). Mean fluid resuscitative volume was significantly less in the modified chitosan group (P < .0056). Hemostasis was achieved on average 5.2 minutes following modified chitosan and never achieved with standard packing. At 1 hour post injury, all treatment animals survived compared with half of controls.

Conclusions

Modified chitosan dressings provide simple rapid treatment of life-threatening liver injuries.     

Mitochondria-initiated apoptosis triggered by oxidative injury play a role in total parenteral nutrition-associated liver dysfunction in infant rabbit model

Purpose

The aim of the study was to investigate oxidative injury and apoptosis as the mechanisms underlying total parenteral nutrition (TPN)-associated liver dysfunction.

Methods

Twenty New Zealand rabbits (2 weeks old) were divided into 2 groups as follows: 10 in the control group (maternal feed) and 10 in the TPN group. The rabbits in the TPN group received continuous PN infusion through a silastic catheter inserted in the right jugular vein.

Results

After 10 days of treatment, the serum levels of total bilirubin and bile acid were significantly higher in the TPN group than in the control group (P < .01, respectively). The light microscopic findings in the TPN rabbits included inflammatory cell infiltration and hepatic steatosis. Electron microscopy showed change in the cytosolic vacuoles and rare microvilli in the microbile duct. Moreover, 10 days of treatment resulted in an inhibition of the superoxide dismutase (SOD) activity in hepatocytes, an increase of the malondialdehyde level, a significant increase in cytochrome c release from the mitochondria, a significant increase in caspase 3 activity, and increased apoptosis (P < .01, individually).

Conclusions

Oxidative damage may be one of the essential mechanisms of TPN-associated liver dysfunction. Moreover, mitochondria-initiated apoptosis triggered by oxidative damage may play an important role in this process.     

Non-operative management of right side thoracoabdominal penetrating injuries—The value of testing chest tube effluent for bile

Introduction

While mandatory surgery for all thoracoabdominal penetrating injuries is advocated by some, the high rate of unnecessary operations challenges this approach. However, the consequences of intrathoracic bile remains poorly investigated. We sought to evaluate the outcome of patients who underwent non-operative management of right side thoracoabdominal (RST) penetrating trauma, and the levels of bilirubin obtained from those patients’ chest tube effluent.

Patients and methods

We managed non-operatively all stable patients with a single RST penetrating injury. Chest tube effluent samples were obtained six times within (4-8 h; 12-16 h; 20-24 h; 28-32 h; 36-40 h; 48 h and 72 h) of admission for bilirubin measurement and blood for complete blood count, bilirubin, alanine (ALT) and aspartate aminotransferases (AST) assays. For comparison we studied patients with single left thoracic penetrating injury.

Results

Forty-two patients with RST injuries were included. All had liver and lung injuries confirmed by CT scans. Only one patient failed non-operative management. Chest tube bilirubin peaked at 48 h post-trauma (mean 3.3 ± 4.1 mg/dL) and was always higher than both serum bilirubin (p < 0.05) and chest tube effluent from control group (27 patients with left side thoracic trauma). Serum ALT and AST were higher in RST injury patients (p < 0.05). One RST injury patient died of line sepsis.

Conclusion

Non-operative management of RST penetrating trauma appears to be safe. Bile originating from the liver injury reaches the right thoracic cavity but does not reflect the severity of that injury. The highest concentration was found in the patient failing non-operative management. The presence of intrathoracic bile in selected patients who sustain RST penetrating trauma, with liver injury, does not preclude non-operative management. Our study suggests that monitoring chest tube effluent bilirubin may provide helpful information when managing a patient non-operatively.     

Throwing out the "grade" book: management of isolated spleen and liver injury based on hemodynamic status

Purpose

Current organizational guidelines for the management of isolated spleen and liver injuries are based on injury grade. We propose that management based on hemodynamic status is safe in children and results in decreased length of stay (LOS) and resource use compared to current grade-based guidelines.

Methods

Patients with spleen or liver injuries for a 5-year period were identified using our institutional trauma registry. All patients were managed using a pathway based on hemodynamic status. Charts were reviewed for demographics, mechanism, hematrocrit values, transfusion requirement, imaging, injury grade, LOS, and outcome. Exclusion criteria included penetrating mechanism, associated injuries altering LOS or ambulation status, combined spleen/liver injury, initial operative management or death. Statistical comparison was performed using Student's t test; P < .05 is significant.

Results

One hundred one patients (50 spleen, 51 liver) meeting inclusion criteria were identified. Average actual LOS for all patients was 1.9 days vs 3.2 projected days based on American Pediatric Surgical Association guidelines (P < .0001). Actual vs projected LOS for grades III to V was 2.5 vs 4.3 days (P < .0001). All patients returned to full activity without complication.

Conclusions

Isolated blunt spleen and liver injuries, regardless of grade, can be safely managed using a pathway based on hemodynamic status, resulting in decreased LOS and resource use compared to current guidelines.     

Childhood undifferentiated embryonal liver sarcoma: clinical features and immunohistochemistry analysis

Purpose

The aim of the study was to report on 3 cases of childhood undifferentiated embryonal liver sarcoma (UELS) and to highlight the clinical features, laboratory findings, diagnosis, and management of this rare disease.

Methods

The patients' age, sex, clinical features, laboratory findings, pathologic results, and therapy were reviewed. Immunohistochemistry analysis was performed on the resected mass sections.

Results

In this study, 2 cases were female (aged 8 and 12 years) and 1 was male (aged 9 years). The causes of hospitalization were mainly abdominal pain, mass, or fever. An elevated erythrocyte sedimentation rate was noted in 2 available cases, and α fetoprotein (AFP) was within the normal range. Imaging findings indicated a well-defined heterogeneous large mass in the right lobe. Histopathologic evaluation of the mass confirmed the diagnosis of UELS. Immunohistochemical staining showed that vimentin and CD68 antigen were positive in all samples, whereas desmin was positive in one sample. Surgery with chemotherapy was performed in 2 cases.

Conclusion

The diagnosis of UELS depends mainly on the pathologic findings. Undifferentiated embryonal liver sarcoma should be included in the differential diagnosis of mass in the liver, especially with well-defined heterogeneous imaging findings and normal AFP. Diagnosis and management should be made early as UELS is a potentially treatable tumor.     

Serum hepatocyte growth factor and clinical outcome in biliary atresia

Purpose

Biliary atresia (BA) remains one of the most intractable liver diseases leading to liver fibrosis. Serum hepatocyte growth factor (HGF) has been shown to increase in cirrhotic patients. The aim of this study was to investigate the possible role of HGF in BA.

Methods

Serum levels of HGF were determined using an enzyme-linked immunosorbent assay from 28 BA patients and 25 healthy children. The patients were categorized into 3 groups according to their clinical outcomes (good, fair, and poor): group A (good), jaundice-free patients (total bilirubin [TB] < 2.0 mg%); group B (fair), patients with mild to moderate jaundice (TB, 2 to 10 mg%); and group C (poor), patients with marked jaundice (TB > 10 mg%). Unpaired t test and analysis of variance (ANOVA) with post-hoc tests were used. Data were expressed as mean and SEM.

Results

Serum HGF levels in BA patients were higher than the controls (P = .02). Subgroup analysis found that there were 12 patients in group A, 8 patients in group B, and 8 patients in group C. The mean age of patients in groups A, B, and C were 5.34 ± 0.52, 7.45 ± 1.98, and 5.49 ± 1.57 years (P > .05). Serum HGF in controls and groups A, B, and C were 0.24 ± 0.03, 0.28 ± 0.04, 0.36 ± 0.09, and 0.56 ± 0.07 ng/mL, respectively. Serum HGF levels in BA patients with poor outcome were higher than patients with good outcome (P = .02). There was no difference in serum HGF of BA patients with fair outcome compared with other groups.

Conclusions

Serum HGF is elevated in BA. Furthermore, BA patients with poor outcome have significantly elevated HGF compared with patients with good outcome. Serum HGF levels may be predictive of prognosis with respect to the progression of liver dysfunction. However, the results of HGF in patients with fair outcome are inconclusive, probably because of the small sample size. Further studies are needed to elucidate the detailed mechanisms.     

Effect of Immunosuppressant Blood Levels on Serum Concentration of Interleukin-17 and -23 in Stable Liver Transplant Recipients

Introduction

T_H17 cells have been recently described to be involved in inflammatory and immune-mediated diseases, but there is no evidence of their role in human liver transplantation. Interleukin (IL)-23 is considered an inducer cytokine, whereas IL-17 is the main cytokine released by T_H17 cells. The aim of our study was to measure the serum levels of IL-17 and IL-23 in stable liver transplant recipients and examine the influence of immunosuppressant concentrations.

Materials and Methods

Serum levels of IL-23 and IL-17 were determined in 38 healthy subjects and 35 stable hepatic transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the simultaneous blood levels of cyclosporine (n = 20) or tacrolimus (n = 15).

Results

No significant differences were observed in the serum levels of IL-17 and IL-23 between healthy subjects and transplanted patients. In addition, patients with low blood levels of tacrolimus (<6 ng/mL), but not cyclosporine, showed significantly lower serum levels of the 2 cytokines.

Conclusion

These preliminary results suggested a lack of activation of the T_H17 pathway, which was more pronounced among the patient subgroup treated with tacrolimus.     

Pediatric pancreatic trauma: predictors of nonoperative management failure and associated outcomes

Background

Nonoperative management (NOM) is an accepted treatment of pediatric solid organ injuries and is typically successful. Blunt pancreatic trauma tends to require operative intervention more frequently. We sought to identify predictors of failure of NOM and compare the outcome of operative management against NOM.

Methods

A retrospective analysis was performed from January 1993 to December 2002 of all children with blunt pancreatic injuries from the trauma registries of 7 designated level 1 pediatric trauma centers. Failure of NOM was defined as the need for intraabdominal operative intervention. Injuries were graded I to V, and ductal injury was defined as grades III to V. Parameters included mechanism of injury, injury severity score (ISS), organ grade, Glasgow Coma Scale score, and outcome. Data were analyzed by Fisher exact test and Mann-Whitney U test, with mean values ± SD and significance of P < .05.

Results

Pancreatic injuries were present in 173 (9.2%) of 1823 patients. Of these, 43 (26.0% [43/173]) required an operation. Valid morbidity data was obtained in 118 of 173 patients. ISS was significantly higher in all patients treated operatively. Patients with an injury of grade III to V failed NOM more frequently than all patients with pancreatic injury (P =.0169). Length of stay was longer, and the incidence of pseudocysts, drainage procedures, and pancreatitis was higher in NOM patients, although not significant.

Conclusions

Patients with pancreatic injuries had a NOM failure rate of 26.0%. ISS and injury grades III to V were predictors of NOM failure. Patients with pancreatic ductal injury require more aggressive management.     

Chronic Allograft Dysfunction—Is There a Treatment?

Background

The major causes of renal transplant loss are death and chronic allograft dysfunction (CAD). The aims of this study were to determine the incidence of CAD in our population and the relation between allograft survival and immunosuppressive regimens.

Methods

We studied retrospectively 473 patients who received deceased donor kidney transplants with at least 1 allograft biopsy between January 1990 and May 2007. Clinical data included age, gender, biopsy data, and immunosuppression before and after kidney biopsy. Mean age was 45.4 ± 12.7 years including 65% males with a mean follow-up of 6.7 ± 4.5 years. CAD was observed in 177 of 473 biopsies: 48 patients showed interstitial fibrosis (IF); 101 chronic rejection (CR); 16 transplant glomerulopathy (TG); and 12, CR and TG. Mean follow-up since the discovery of the histologic feature was 60.5 ± 50.5 months for IF; 38.3 ± 40.8 for CR, and 18.2 ± 19.2 for TG.

Results

CAD, which was more common in younger patients (P = .03), correlated upon univariate and multivariate analysis with CKD stage 5d development (P < .001). Deposition of C4d in peritubular capillaries was more frequent among CAD patients (P = .004), an association with particular relevance to recipients with CR (P = .02) and TG (P < .001). When we analyzed CAD subpopulation, we observed a positive correlation between allograft survival and immunosuppression modification after biopsy. Substitution of sirolimus (40/177) was shown in univariate, multivariate and Cox regression analyses to be a renal protector (P < .002). Allograft survival was also correlated with initial mycophenolate mofetil versus azathioprine, (62/177) immunosuppression (P < .001).

Conclusion

CAD, a frequent histologic feature, may benefit from sirolimus conversion.     

Platelet-derived growth factor expression correlates with tumor grade and proliferative activity in human oligodendrogliomas

Background

For the last one and a half decade, it has been found that platelet-derived growth factor (PDGF) promotes glial tumor growth through autocrine and paracrine loops, by expression of PDGFα receptor (PDGFRα) on glioma cells and PDGFβ receptor (PDGFRβ) on proliferating endothelial cells. However, studies on oligodendrogliomas, correlating expression of PDGF and its receptor with tumor grade and proliferative activity, through MIB-1 labeling index (LI) are relatively few as compared to astroglial counterpart.

Methods

Formalin-fixed paraffin-embedded tissues from 55 cases of oligodendrogliomas (34 World Health Organization [WHO] grade II and 21 WHO grade III tumors) were subjected to immunohistochemistry. MIB-1 LI was calculated, and a semiquantitative scoring system for expression of PDGF and PDGFRα was used.

Results

MIB-1 LI and PDGF expression increased with histologic grades of malignancy (“t” test, P < .001 and Mann Whitney test, U = 109, P < .001 respectively). The PDGF expression scores had a positive correlation with MIB-1 LI, irrespective of tumor grade (Pearson's correlation coefficient, r = 0.566; P < .001). However, there was no significant difference of PDGFRα expression between 2 grades of tumors.

Conclusions

The results of this study showed that MIB-1 LI is a rapid and cost-effective modality for predicting tumor grade in oligodendrogliomas. Immunohistochemistry for PDGF was found to be useful in differentiating various grades of oligodendroglioma, and therefore, it may be involved in tumor cell proliferation and malignant transformation. Platelet-derived growth factor receptor α, although expressed in oligodendroglial neoplasms, was not found to be useful in predicting tumor grade.     

Protective effect of tumor necrosis factor alpha antibody on experimental necrotizing enterocolitis in the rat

Background

Necrotizing enterocolitis (NEC) is a common and devastating disorder of premature infants. Elevated proinflammatory cytokines, especially tumor necrosis factor α (TNF-α), have been implicated in the pathogenesis of NEC. The aim of this study was to evaluate the effects of TNF-α on the inflammatory response in NEC by immunoneutralizing TNF-α with a selective antibody.

Methods

Neonatal Sprague-Dawley rats were divided in 3 groups: group 1 (n = 20), a NEC-like enterocolitis was induced by formula feeding, asphyxia, and cold exposure; group 2 (n = 9), animals were treated like in group 1 and additionally received TNF-α antibody intraperitoneally; and group 3 (n = 17), animals were dam-fed (controls). Animals were killed in case of imminent death or after 96 hours. Specimens from small bowel were processed for blinded histologic (H&E) and immunhistologic (myeloperoxidase [MPO]) analysis.

Results

In group 1, animals developed severe NEC (mean NEC score, 3.28 ± 0.32; mean MPO, 65.85 ± 9.46). In group 2, animals developed mild NEC (mean NEC score, 1.72 ± 0.41; mean MPO, 34.33 ± 9.69; P < .05). In group 3, no NEC was induced (mean NEC score, 0.0 ± 0; mean MPO, 6 ± 1.32; P < .05).

Conclusion

Tumor necrosis factor α antibody may have an attenuating effect on experimental NEC in rats.     

The effect of vitamin A deficiency in maternal rats on tumor formation in filial rats

Purpose

We established a vitamin A-deficient (VAD) model of pregnant rats to evaluate the effect of vitamin A deficiency in maternal rats on tumor formation in filial rats.

Methods

Ten pregnant Wistar rats were divided into 2 groups: (1) VAD group, 6 rats were given nonvitamin A diet from 2 weeks before mating till delivery and (2) normal diet (ND) group, 4 rats were given normal diet. Twenty random neonatal rats from each group were killed on the next day of delivery. The rest neonates were given normal diet for 1 year until killed. Serum levels of vitamin A, morphology of the kidney, incidence of tumor formation, and retinoid X receptor (RXR) α messenger RNA (mRNA) expression in renal tissue were assessed for the filial rats.

Results

Fifty-six and 49 neonatal rats were born for VAD group and ND group, respectively. The detection rate of nephrogenic rests (NRs) from neonates in VAD group (50%) was significantly higher than that in ND group (20%; P < .05). The incidence of nephroblastoma was 13.9% in filial rats of VAD group and 0% for ND group. The detection rate of NRs for filial rats of VAD group (30.6%) was significantly higher than that of ND group (6.9%; P < .01). The expression of RXRα mRNA in tumor tissue of the filial rats of VAD group (3.17 ± 0.15) was significantly lower than that in kidney tissue of ND group (3.58 ± 0.20; P < .01).

Conclusion

Deficiency in vitamin A for pregnant rats resulted in renal dysplasia, increased NRs, and higher incidence of nephroblastoma.