Experimental Disc Herniation in the Rat Causes Downregulation of Serotonin Receptor 2c in a TNF-dependent Manner

Background

During recent decades, the knowledge of the pathophysiology of disc herniation and sciatica has drastically improved. What previously was considered a strict biomechanical process is now considered a more complex interaction between leaked nucleus pulposus and the tissue in the spinal canal. An inflammatory reaction, with tumor necrosis factor (TNF) playing an essential role, has been demonstrated. However, the exact mechanisms of the pathophysiology of disc herniation remain unknown.

Questions/purposes

In this study we use an animal model to investigate (1) if and/or how experimental disc herniation affects gene expression in the early phase (24 hours postsurgery) in the dorsal root ganglion; and (2) if TNF inhibition can reduce any observed changes.

Methods

A rat model of disc herniation was used. Twenty rats were evenly divided into four groups: naïve, sham, disc herniation, and disc herniation with TNF inhibition. The dorsal root ganglion of the affected nerve root was harvested 24 hours after surgery and analyzed with a TaqMan Low Density Array^® quantitative polymerase chain reaction assay. Gene expression levels in sham were compared with disc herniation to assess question 1 and disc herniation to disc herniation with TNF inhibition to assess question 2.

Results

Experimental disc herniation caused a decrease in the expression of the serotonin receptor 2c gene (p = 0.022). TNF inhibition was found to reduce the observed decrease in expression of serotonin receptor 2c (p = 0.037).

Conclusions

Our results suggest that a decrease in the expression of the serotonin receptor 2c gene may contribute to the pathophysiology of disc herniation. Further research on its involvement is warranted.

Clinical Relevance

This pilot study gives a brief insight into cellular changes that may contribute to the pathophysiology of disc herniation. This knowledge may contribute to the development of more and better treatment options for patients with disc herniation and sciatica.     

Pancreatic Follicular Lymphoma Presenting as Acute Pancreatitis: Report of a Case

Pancreatic B-cell lymphoma is rare; it accounts for 0.2% to 2.0% of extranodal non-Hodgkin lymphoma, and constitutes less than 0.5% of all pancreatic malignancies. Most histologic types of the pancreatic lymphoma are diffuse large B-cell lymphoma, and follicular lymphoma is quite rare. We report here a case of pancreatic follicular lymphoma that was initially detected by acute pancreatitis. This is the first reported case of pancreatic follicular lymphoma presenting with acute pancreatitis. A 71-year-old woman had epigastric and left upper quadrant abdominal pain. Computed tomography (CT) revealed features of acute pancreatitis. After standard therapy for pancreatitis, enhanced CT showed a pancreatic tumor (50 × 35 mm) in the body of the pancreas with gradual enhancement. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography showed a complete interruption of the pancreatic duct in the body, with mild dilation of the duct in the tail of the pancreas. Endoscopic ultrasonography revealed hypervascularity of the pancreatic tumor. The patient underwent distal pancreatectomy to remove the cause of pancreatitis and to disclose the diagnosis. Histologic examination revealed follicular lymphoma of pancreas. Despite recent improvement in clinical strategies, differential diagnosis between pancreatic lymphoma and pancreatic cancer is still difficult without histologic information. Pancreatic lymphoma should be considered as a differential diagnosis in a patient who initially presents with acute pancreatitis.Key words: Pancreatic lymphoma, Acute pancreatitis, Follicular lymphomaPancreatic B-cell lymphoma is rare; it accounts for 0.2% to 2.0% of extranodal non-Hodgkin lymphoma¹ and constitutes less than 0.5% of all pancreatic malignancies.^2,3 Most histologic types of pancreatic lymphoma are diffuse large B-cell lymphoma, and follicular lymphoma is quite rare. In addition, acute pancreatitis caused by pancreatic lymphoma is also rare.Despite recent improvements in clinical strategies, differential diagnosis of pancreatic lymphoma with pancreatic cancer or autoimmune pancreatitis (AIP) is still difficult without histologic examination.We report here a rare case of a 71-year-old female with pancreatic follicular lymphoma that initially presented as acute pancreatitis.     

Unmanipulated Reduced-Intensity Stem Cell Transplantation from a Haploidentical Donor Mismatched at 3 HLA Antigens to a Patient with Leukemic Transformation of Myelodysplastic Syndrome: Successful Second Transplantation after Graft Rejection

We present the case of a patient with myelodysplastic syndrome who experienced leukemia transformation and subsequently underwent transplantation of unmanipulated peripheral blood stem cells from a haploidentical sibling mismatched at 3 HLA antigens, along with a reduced-intensity regimen (fludarabine, busulfan, and anti-T-lymphocyte globulin) and tacrolimus-containing graft-versus-host disease (GVHD) prophylaxis. The patient experienced graft rejection but successfully underwent a second transplantation from the same donor with a slightly intensified conditioning regimen. Although the patient developed life-threatening cytomegalovirus (CMV) pneumonia following the second transplantation, he recovered completely from the pneumonia with intensive supportive therapy. He is still in complete remission past day 1000 in the absence of GVHD. As far as we know, this report is the first to describe a successful second transplantation that was performed for graft rejection following HLA-haploidentical nonmyeloablative stem cell transplantation. Furthermore, we emphasize that patients should be carefully monitored for CMV infection when reduced-intensity conditioning is given repeatedly over a short period.     

The renin-angiotensin system is involved in the production of plasminogen activator inhibitor type 1 by cultured endothelial cells in response to chylomicron remnants.

Triglyceride-rich lipoproteins have been suggested to promote atherosclerosis. Plasminogen activator inhibitor type 1 (PAI-1) plays an important role in the events of cardiovascular pathophysiology. The renin-angiotensin system influences various vascular functions, including PAI-1 production. We examined whether or not chylomicron remnants increased PAI-1 mRNA and protein production in endothelial cells and whether or not an inhibition of the renin-angiotensin system interfered with this effect. Chylomicron remnants were isolated from functionally hepatectomized rats injected with chylomicrons. Human umbilical vein endothelial cell cultures (HUVECs) were incubated with chylomicron remnants with or without an angiotensin-converting enzyme inhibitor (temocaprilat), an angiotensin II receptor type 1 antagonist (RNH-6270), or an angiotensin II receptor type 2 antagonist (PD123319). Chylomicron remnants increased PAI-1 secretion in HUVECs (0.5 microg/ml; 128.3 +/- 6.1%, the mean +/- SEM) as well as angiotensin II (10 nmol/l; 130.7 +/- 9.5%) in 18 h, as compared with the controls, as well as stimulated PAI-1 mRNA expression to a maximum level at 4 h. Temocaprilat and RNH-6270, but not PD123319, attenuated all of these effects. Chylomicron remnants enhanced nuclear extract binding to a very low-density lipoprotein response element in the PAI-1 promoter region and activated nuclear factor-kappaB. Extracellular signal-regulated kinase (ERK 1/2) was phosphorylated in response to chylomicron remnants. These effects were inhibited by temocaprilat or RNH-6270. In conclusion, chylomicron remnants increased protein secretion and mRNA expression of PAI-1 in HUVECs. Inhibition of the renin-angiotensin system reduced this stimulation.