Flurbiprofen and HCT1026 protect mice against acute pancreatitis-associated lung injury

Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Flurbiprofen is a powerful nonsteroidal anti-inflammatory drug (NSAID). However, administration of this drug is associated with severe gastrointestinal side effects. The NO-releasing derivative of flubiprofen (nitroflurbiprofen, HCT1026) has recently been developed by the addition of a nitroxybutyl moiety to the flurbiprofen structure. This modification does not interfere with the anti-inflammatory activity of the drug but markedly reduces its ability to induce gastric injury. The effects of treatment with flurbiprofen and HCT1026 on the severity of pancreatitis and the associated lung injury were investigated in a mouse model. Acute pancreatitis was induced in mice by hourly intraperitoneal injections of cerulein. Flurbiprofen and HCT1026 were administered either 30 min before or 1 h after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury were assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung MPO activity) and by histological examination of lung sections. HCT1026 and flurbiprofen, given prophylactically as well as therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of flurbiprofen as well as HCT1026 as potential treatments for pancreatitis-associated lung injury.     

Methylphenidate may treat apathy independent of depression

OBJECTIVE: To report a case of apathy treated with methylphenidate in which improvement in apathy was independent of improvement of depression. CASE SUMMARY: A 47-year-old woman with a 20-year history of recurrent major depression was diagnosed as having significant apathy with lack of initiative and motivation. Over the course of a 4-week treatment regimen with methylphenidate, her apathy, as measured by the Apathy Evaluation Scale, improved, with her score decreasing from 57 to 31. During this period, her depression, as assessed by the 21-item Hamilton Rating Scale for Depression, remained unchanged. DISCUSSION: Our report of improvement of apathy with methylphenidate is consistent with other reports in the literature, although previous studies have not specifically used the rating scales to assess apathy. Even though this patient had experienced apathy for a long time, it had not been detected due to lack of direct questioning. In this case, as noted, the improvement of apathy was independent of improvement in depression. CONCLUSIONS: A high degree of suspicion and specific inquiry is required for identification of apathy. Once detected, methylphenidate may be beneficial in its treatment, a strategy that may work independently of augmentation of antidepressants.     

Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function.

Treatment of chronic myelogenous leukemia (CML) with interferon-alpha frequently results in normalization of peripheral blood counts and, in up to 20% of patients, reestablishment of normal hematopoiesis. We hypothesize that interferon-alpha may restore normal adhesive interactions between CML progenitors and the bone marrow microenvironment and restore normal growth regulatory effects resulting from these progenitor-stroma interactions. We demonstrate that treatment with interferon-alpha induces a significant, dose-dependent increase in the adhesion of primitive long-term culture initiating cells and committed colony-forming cells (CFC) from CML bone marrow to normal stroma. Adhesion of CFC seen after interferon-alpha treatment could be inhibited by blocking antibodies directed at the alpha 4, alpha 5, and beta 1 integrins and vascular cell adhesion molecule, but not CD44 or intracellular adhesion molecule, suggesting that interferon-alpha induces normalization of progenitor-stroma interactions in CML. Because FACS analysis showed that the level of alpha 4, alpha 5, and beta 1 integrin expression after interferon-alpha treatment is unchanged, this suggests that interferon-alpha may restore normal beta 1 integrin function. Normalization of interactions between CML progenitors and the bone marrow microenvironment may then result in the restoration of normal regulation of CML progenitor proliferation, and explain, at least in part, the therapeutic efficacy of interferon-alpha in CML.     

Deciphering the TLR transcriptome and downstream signaling pathway in cerebrospinal fluid in pediatric meningitis

Inflammation Research - Pediatric meningitis is characterized by a colossal inflammatory response to the pathogen in the central nervous system (CNS). This unabated inflammatory response persists...     

Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions in the peritoneal cavity

BACKGROUND: A novel endoscopic peroral transgastric approach to the peritoneal cavity was tested in a porcine model in acute and long-term survival experiments. METHODS: Transgastric peritoneoscopy was evaluated in 50-kg pigs. After upper endoscopy, the peritoneal cavity was accessed by needle-knife puncture of the gastric wall, followed by extension of the incision either with a pull-type sphincterotome or by balloon dilation. The peritoneal cavity was examined, and a liver biopsy specimen was obtained. The gastric wall incision was closed with clips. OBSERVATIONS: Twelve acute and 5 survival experiments were performed. Both techniques of gastric wall incision were without complication. The acute experiments demonstrated the technical feasibility of the approach. In the survival experiments, all pigs recovered and gained weight. CONCLUSIONS: The peroral transgastric approach to peritoneal cavity technically is feasible and has the potential to be an alternative to laparoscopy and laparotomy.     

Arthritis in the highlands of Papua New Guinea.

Acute polyarthritis is an important cause of morbidity in many tropical countries. Classification has often been difficult, with the term tropical polyarthritis used for those in whom a diagnosis could not be made. The implication that this is a distinct entity is probably incorrect, with likely causes being septic arthritis or post-infective reactive arthritis. This study aimed to determine the types of arthritis found in 43 patients (30 men) presenting consecutively to the Goroka Base Hospital in the Eastern Highlands of Papua New Guinea. Gonococcal arthritis was diagnosed in eight patients (six men) on the basis of isolation of Neisseria gonorrhoeae from the joint aspirate. In all cases the N gonorrhoeae was identified by the closed culture system on chocolate agar, but not always by routine plating. There were no specific clinical features that identified patients with a gonococcal septic arthritis. The remaining 34 patients had an undifferentiated oligoarthritis. The pattern of arthritis in men and women was of a lower limb pauciarticular arthritis with a predilection for the knee and ankle joints. A total of 30% of male patients had a history of urethral discharge and 44% of all patients had preceding diarrhoea. Arthritis was the only feature in 59% of patients and in 32% there was an associated enthesitis. In this study most patients had an oligoarthritis consistent with a reactive arthritis or a septic arthritis due to N gonorrhoeae. Broth inoculation of synovial fluid was the best method to isolate N gonorrhoeae, with standard methods for gonococcal isolation failing in some patients. It is recommended that the term 'tropical polyarthritis' is no longer used as it does not refer to a specific entity but consists of several known arthritides.     

Superior sagittal sinus thrombosis and Budd-Chiari syndrome due to paroxysmal nocturnal hemoglobinuria managed with transjugular intrahepatic portosystemic shunt: a case report.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), caused by somatic mutation of hematopoietic cells, is associated with complement-mediated hemolysis and a hypercoagulable state. Thrombotic complications in this disease are associated with reduced survival. We report a patient with PNH complicated by intracranial venous thrombosis and Budd-Chiari syndrome, who was managed with transjugular intrahepatic portosystemic shunt. CASE PRESENTATION: A 26-year-old man presented with thrombosis of the superior sagittal and right sigmoid sinuses. Initial investigations did not reveal any underlying cause. Nine months later, he developed hepatic venous thrombosis. At this time, Ham test was positive. Flow cytometry confirmed the diagnosis of PNH. The patient was treated with transjugular intrahepatic portosystemic shunt; one episode of stent blockage one month later was managed successfully with balloon dilatation and restenting. CONCLUSION: PNH should be considered in patients with unexplained venous thrombosis. Thrombosis in these patients needs to be managed with prolonged anticoagulation. For Budd-Chiari syndrome in patients with underlying PNH, transjugular intrahepatic portosystemic shunt may be a good option but caution is needed to prevent stent occlusion.     

PTP1B antisense oligonucleotide lowers PTP1B protein,normalizes blood glucose,and improves insulin sensitivity in diabetic mice

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.