Prostaglandin E<Subscript>2</Subscript> receptors in bone formation

Prostaglandins, PGE(2) in particular, have diverse actions on various organs, including inflammation, bone healing, bone formation, embryo implantation, induction of labour and vasodilatation, among others. However, systemic side effects have limited their clinical utility. The pharmacological activities of PGE(2) are mediated through four G protein-coupled receptor subtypes, EP1-EP4. Recent studies have shown that EP2 and EP4 receptors play important roles in regulating bone formation and resorption. EP2 and EP4 receptor-selective agonists have been shown to stimulate local or systemic bone formation, augment bone mass and accelerate the healing of fractures or bone defects in animal models upon local or systemic administration, thus, potentially offering new therapeutic options for enhancing bone formation and bone repair in humans. This review will focus on the studies related to bone formation and bone healing in the EP receptor knockout (KO) mice and the EP2 or EP4 receptor-selective agonist treated animal models.     

Sphingosine-1-phosphate attenuates proteoglycan aggrecan expression via production of prostaglandin E<Subscript>2</Subscript> from human articular chondrocytes

Background  

Sphingosine-1-phosphate (S1P), a downstream metabolite of ceramide, induces various bioactivities via two distinct pathways: as an intracellular second messenger or through receptor activation. The receptor for S1P (S1PR) is the family of Endothelial differentiation, sphingolipid G-protein-coupled receptor (EDG). We have here attempted to reveal the expression of EDG/S1PR in human articular chondrocytes (HAC), exploring the implications of S1P in cartilage degradation.     

Behavioral and morphologic studies of the chronically compressed cauda equina. Experimental model of lumbar spinal stenosis in the rat.

STUDY DESIGN: An experimental model in rats of chronically compressed cauda equina was produced, and behavioral and morphologic changes were examined. OBJECTIVES: To provide a useful model for analyzing the pathophysiologic changes of the cauda equina by chronic compression and to examine behavioral and morphologic changes in this model. SUMMARY OF BACKGROUND DATA: Several animal models have been reported in which various materials were used to compress the cauda equina. However, the pathophysiology of the cauda equina by chronic compression is not yet well understood. Studies in which rats were used are scarce. METHODS: A silicone sheet was applied to the spinal canal at L4 in the rat. Walking durations on treadmill tests and paw-withdrawal latencies to thermal stimuli were measured before and after the operation for 24 weeks. Histologic changes also were examined. RESULTS: Walking durations decreased after chronic compression. However, paw-withdrawal latencies were not significantly changed. Histologically, the number of large-diameter myelinated axons decreased after compression, whereas the number of small-diameter myelinated axons increased. Electron microscopic observation indicated that the continuous degeneration and regeneration of axons occurred throughout the chronic compression experiment. CONCLUSIONS: The current model and behavioral assessments may be useful in analyzing the pathophysiology of chronically compressed cauda equina.     

Implantation of cauda equina nerve roots through a biodegradable scaffold at the conus medullaris in rat

Background contextTraumatic injuries occurring at the conus medullaris of the spinal cord cause permanent damage both to the central nervous system and to the cauda equina nerve roots.PurposeThis proof-of-concept study was to determine whether implanting the nerve roots into a biodegradable scaffold would improve regeneration after injury.MethodsAll experimental works involving rats were performed according to the approved guidelines by the Mayo Clinic Institutional Animal Care and Use Committee. Surgical procedures were performed on 32 Sprague-Dawley rats. Four ventral cauda equina nerve roots were reimplanted either directly into the ventral cord stump or through a poly(lactic-co-glycolic acid) (PLGA) scaffold. These experimental groups were compared with a control group in which the nerves were inserted into a muscle fascia barrier that was placed between the spinal cord and the nerve roots. Animals were sacrificed at 4 weeks.ResultsThere was no difference in motor neuron counts in the spinal cord rostral to the injury in all treatment groups, implying equal potential for the regeneration into implanted nerve roots. One-way analysis of variance testing, with Tukey post hoc test, showed a statistically significant improvement in axon regeneration through the injury in the PLGA scaffold treatment group compared with the control (p<.05, scaffold n=11, control n=11).ConclusionsThis pilot study demonstrated that a PLGA scaffold improved regeneration of axons into peripheral nerve roots. However, the number of regenerating axons observed was limited and did not lead to functional recovery. Future experiments will employ a different scaffold material and possible growth factors or enzymes to increase axon populations.     

Adverse effects of saline neurolysis on a chronically compressed rat sciatic nerve.

We have evaluated the effect of saline neurolysis compared with a simple decompression procedure on chronically compressed sciatic nerves in rats. Eight months after the initiation of nerve compression within a silicone tube, rats were divided into three groups of 35. In group I, saline was injected subepineurially at the compressed segment of the nerve after removal of the tube (decompression plus saline neurolysis). The nerves in group II were treated by removal of the tube only (simple decompression). In group III the tubes were left in place. Adding saline neurolysis to decompression provided no histological, morphometric, electrophysiological, or vascular advantages up to four months, and even gave worse results than simple decompression. We conclude that saline neurolysis has no beneficial effect on a chronically compressed nerve and it is not recommended for clinical use.     

髓核对大鼠腰神经根非压迫性损伤的组织形态学研究

目的　观察硬膜外移植自体髓核后 ,大鼠神经根组织形态学的变化。方法　 2 8只Sprague Dawley(SD)雄性大鼠随机分成对照组和实验组 ,分别将自体肌肉混悬液和尾椎髓核混悬液注射到腰椎硬膜外腔 ,对神经根组织进行形态学观察。结果　在无机械压迫情况下 ,大鼠硬膜外移植自体髓核能使马尾神经根组织形态产生明显改变。结论　髓核所致的炎性反应是引起神经根损伤和坐骨神经痛的重要原因之一     

Unusual myelographic pattern in a case with redundant roots of the cauda equina

An unusual myelographic pattern of the redundant nerve roots of the cauda equina is reported. The typical serpentine filling defect of the contrast material moved along the caudocranial axis of the meningeal sac according to the position of the patient. Such a myelographic feature might be diagnostic of this rare condition.     

Prostaglandin E<Subscript>2</Subscript> Suppresses NK Activity In Vivo and Promotes Postoperative Tumor Metastasis in Rats

Background: Prostaglandins (PGs) were shown in vitro to suppress several functions of cellular immunity. It is unclear, however, whether physiological levels of PGs can suppress cellular immunity in vivo and whether such suppression would compromise postoperative host resistance to metastasis.Methods: Fischer 344 rats were administered PGE₂ in doses (18 to 300 g/kg subcutaneously) that increased the serum levels approximately 2- to 4-fold. We then assessed the number and activity of circulating natural killer (NK) cells, as well as rats resistance to experimental metastasis of a syngeneic NK-sensitive tumor (MADB106). To study whether endogenously released PGs after surgery compromise these indices, we tested whether laparotomy adversely affects them and whether a cyclooxygenase-synthesis inhibitor, indomethacin (4 mg/kg), attenuates these effects.Results: PGE₂ dose-dependently suppressed NK activity per NK cell and dose-dependently increased 4- and 24-hour MADB106 lung tumor retention (LTR); 240 g/kg of PGE₂ quadrupled the number of lung metastases counted 3 weeks later. Selective depletion of NK cells abrogated the promotion of LTR by PGE₂. Surgery significantly suppressed NK activity and increased MADB106 LTR, and indomethacin halved these effects without affecting nonoperated rats.Conclusions:PGE₂ is a potent in vivo suppressor of NK activity, and its postoperative release may promote tumor recurrence.     

Effects of beraprost sodium on canine cauda equina function and blood flow using a chronic spinal cord compression model

Changes in blood flow after chronic compression were observed in 19 dogs after 10 mmHg compression for 1 week before and 1 hour after the intravenous administration of one of three doses of beraprost sodium (BPS; 30 ng x kg(-1) x min(-1), n = 7; 100 ng x kg(-1) x min(-1), n = 7; and 300 ng x kg(-1) x min(-1), n = 5). The speed of blood flow was calculated using a specially designed microscope equipped with a video camera. Dogs treated with BPS had lesser degrees of reduction in their nerve conduction velocity compared with controls. A vascular mechanism of injury likely explains why BPS-treated dogs had a lesser degree of reduction in their nerve conduction velocities compared with the control population.     

Effect of Short-term Administration of Prostaglandin E<Subscript>1 </Subscript>on Viability after Ischemia/Reperfusion Injury with Extended Hepatectomy in Cirrhotic Rat Liver

The cytoprotective effect of prostaglandin E₁ (PGE₁) has been demonstrated experimentally and clinically against hepatic ischemia and reperfusion injury and against the effects of partial hepatectomy in both individual and combined models of noncirrhotic livers. Cirrhotic livers are more vulnerable to ischemia/reperfusion injury during hepatectomy than are noncirrhotic livers, and postoperative malfunctioning complicates life with multiple organ failure. Cirrhotic livers with tumors have mostly been treated conservatively because extended hepatectomy with induced ischemia during surgery is impossible. The purpose of our study was to document postoperative surgical adaptation in inoperable cases with improved survival after extended hepatectomy in a rat model of cirrhosis treated by PGE₁. Cirrhosis was induced by intraperitoneal injections of 1% dimethylnitrosamine. The liver was subjected to 15 minutes of total ischemia by occluding the hepatoduodenal ligament. Hepatectomy was performed during ischemia. Pretreatment with PGE₁ (0.4 g/kg/min) (or without it in the controls) was given for 15 minutes by intravenous infusion prior to inducing ischemia and during reperfusion. Portal venous flow (PVF) and liver tissue blood flow (LTBF) were measured during reperfusion. At the end of 60 minutes of reperfusion, venous blood was collected for liver function tests. The animals were followed up regarding survival for 48 hours. The PVF and LTBF were significantly improved in the PGE₁ group. The blood chemical analysis indicated that PGE₁ significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE₁ treatment markedly improved the survival rate, from 42% in the controls to 75% in the test animals at 24 hours after hepatectomy and from 17% in the controls to 58% in the test animals at 48 hours. We concluded that short-term administration of PGE₁ makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.     

Tolerance to acute compression injury and recovery of nerve function in chronically compressed spinal nerve roots: Experimental study

Chronic compression (10 mm Hg for 1 week) of spinal nerve roots in a dog experimental model has been shown to reduce nerve conduction velocity. Although injured, the compressed nerve roots demonstrated increased resistance to acute compression applied in addition to the chronic compression after 1 week. In the present study reduction of nerve conduction velocity induced by chronic compression recovered when the duration of compression was extended to 1 month. However, the tolerance to additionally applied compression was still present. This study provides important base-line data for continued studies of the basic mechanisms of the development of tolerance to changes in compression pressure levels in chronically compressed nerve roots.     

Early effects of mild brain trauma on the cytoskeletal proteins neurofilament<Subscript>160</Subscript> and MAP<Subscript>2</Subscript>, and the preventive effects of mexilitine

Summary Objective. The aims were to investigate the early effects of graded, closed, mild head injury on neurofilament protein (NF₁₆₀) and microtubule-associated protein-2 (MAP₂) and to examine the levels of lipid peroxidation and the impact of mexilitine, inhibitor of lipid peroxidation, pretreatment on tissue damage.Material and method. One hundred and twenty-six rats were divided into groups as follows: Group 1 (n=14) were controls; group 2 (n=56) sustained trauma alone; and group 3 (n=56) were pretreated with mexilitine (50mg/kg). Groups 2 and 3 were subdivided into subgroups (n=14 each), which were subjected to 100g/cm², 125g/cm², 150g/cm², and 175g/cm² trauma forces, respectively. Two hours after trauma, the frontal lobes from all groups were removed and processed for lipid peroxidation H&E staining, immunofluorescent labelling of neurofilaments and microtubules with anti-NF₁₆₀ and anti-MAP₂ antibodies.Results. Compared to control findings, all the trauma-only animals showed increased lipid peroxidation levels and the elevations paralleled the amount of force applied. Administration of mexilitine significantly reduced the level of lipid peroxidation. In NF₁₆₀ stainings, in group 2, the degree of impairment in axonal organization paralleled the different levels of force that were applied. Groups 3C and 3D (mexilitine pretreated) showed well-preserved axons and intact perikarya. In MAP₂ stainings group 2 animals showed remarkably less MAP₂ staining throughout the sections. There were no significant differences in MAP₂ staining intensity or pattern among the group 2 subgroups. In contrast, in the sections from the group 3 animals, the level of MAP₂ positivity was markedly preserved.Conclusion. In conclusion, our results show that the cytoskeletal proteins we investigated have different capacities for resisting injury, and that MAP₂ is more vulnerable to injury than NF₁₆₀. One of the reason for this cytoskeletal disruption may be increased lipid peroxidation. Inhibition of lipid peroxidation by pre-treatment with 50-mg/kg mexilitine significantly reduces the level of lipid peroxidation and may protect MAP₂ and NF₁₆₀ integrity in closed mild head injury. This protection is inversely proportional to the magnitude of the applied force.     

Effects of experimental graded compression on blood flow in spinal nerve roots. A vital microscopic study on the porcine cauda equina

Compression injuries of spinal nerve roots are very common. However, the basic pathophysiology of these conditions is not fully understood. In this study a model is presented for experimental graded compression of the nerve roots of the pig cauda equina, including a technique for vital microscopic studies on the microcirculation flow of the intrinsic vessels of the nerve roots during compression. With this model critical pressure levels for compression-induced occlusion of the arterioles, capillaries, and venules of the intrinsic vasculature of the nerve roots were determined. The study showed that the average minimum pressure in the inflated balloon required to stop the flow in the arterioles was 127 mm Hg (SD = 18, n = 11), in the capillaries 40 mm Hg (SD = 6, n = 12), and in the venules 30 mm Hg (SD = 10, n = 12). The average mean arterial pressure (MAP) was 150 mm Hg (SD = 14, n = 12). There was a statistically significant correlation (p greater than 0.001) between the MAP and the pressure required to stop the flow in the arterioles (r = 0.83, n = 14), but no correlation between MAP and capillary (r = 0.09 NS, n = 20) or venular (r = -0.28 NS, n = 34) occlusion pressure. After the nerve roots had been compressed at 50 or 200 mm Hg for 10 min or 2 h, the recirculation started immediately. There was a hyperemia during the first 10 min, with a dilatation of the vessels, particularly the venules. In nerve roots exposed to compression for 2 h at either 50 or 200 mm Hg, an intraneural edema developed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute phase effects of ATP-MgCl<Subscript>2</Subscript> on experimental spinal cord injury

The purpose of this study was to study the acute phase effects of adenosine triphosphate (ATP)-MgCl₂ on experimental spinal cord clip compression injury. Spinal cord clip compression injury was performed on 36 albino Wistar rats. The rats were divided into five groups. T4–T8 total laminectomy was performed on all rats. Group 1: sham-operated group. Group 2: clip compression group. In group 3, ATP-MgCl₂ (100 μmol/kg) was given 2 min before the "clip compression injury." In group 4, ATP-MgCl₂ (100 μmol/kg) was given 5 min after the clip compression injury. In group 5, ATP MgC1₂ (100 μmol/kg) was administered 8 h after the injury. The spinal cords were excised for a length of 2 cm and deep frozen at –76°C. Tissue malondialdehyde (MDA) levels were used to determine the effects of ATP-MgCl₂ on spinal cord lipid peroxidation. In the groups in which ATP MgCl₂ was administered after the clip compression injury (groups 4 and 5), the decrease in spinal cord MDA levels was statistically significant when compared with those of the injury group (group 2). Although MDA levels of group 4 were lower than those of group 5, this difference was not statistically significant. Administration of the ATP-MgCl₂ before the clip compression injury (in group 3) did not have a statistically significant effect on lipid peroxidation when compared with the injury group (group 2). In this study, we found that ATP-MgCl₂ has decreased lipid peroxidation in spinal cord injury and protected the spinal cord from secondary injury after the trauma. We concluded that ATP-MgCl₂ may be used in the treatment of spinal cord injuries in conjunction with the other treatment modalities, but further investigations are mandatory. Electronic Publication     

Primary malignant peripheral nerve sheath tumor of the cauda equina in a child case report

STUDY DESIGN: A case report of primary malignant peripheral nerve sheath tumor (MPNST) of the cauda equina in a child is presented, and the literature is reviewed. OBJECTIVE: To discuss the problems involved in the treatment of primary intradural MPNSTs. SETTING: A department of orthopaedic surgery in Japan. METHODS: A 4-year-old boy complained of low-back pain radiating to the left calf. MRI revealed an intradural tumor at L3-L5 level. Following laminectomy of L3, L4 and L5, the tumor was removed en bloc. Based on pathological and immunohistological findings, the tumor was diagnosed as an MPNST. RESULTS: Although adjuvant chemotherapy was administered local recurrence and cerebral and spinal metastases of the tumor were found 6 months after the operation. Following additional incomplete removal of the recurrent tumor, radiation therapy was administered. Although recurrent and metastatic tumors disappeared or diminished in size by radiation, tumors increased in size thereafter, despite additional adjuvant chemotherapy. At 21 months after the first operation, he died of pneumonia. CONCLUSIONS: Reported clinical outcomes for patients with primary intradural MPNST are very poor. Although no gold standard for the treatment of tumors has been established yet, surgical removal of tumors combined with postoperative high-dose radiation may be recommended.     

The Prognostic Significance of Total Lymph Node Harvest in Patients with T<Subscript>2–4</Subscript>N<Subscript>0</Subscript>M<Subscript>0</Subscript> Colorectal Cancer

In patients with radically resected colorectal carcinoma, lymph node involvement is particularly important for a good prognosis and adjuvant therapy. The number of such lymph node recoveries is still controversial, with recommendations ranging from 6 to 17 nodes. The aim of this study is to determine if a specified minimum number of lymph nodes examined per surgical specimen can have any effect on the prognosis of patients who have undergone curative resection for T_2–4N₀M₀ colorectal carcinoma. Between September 1999 and January 2005, a total of 366 patients who underwent radical resection for T_2–4N₀M₀ colorectal carcinoma were retrospectively analyzed in a single institution. All specimen segments were fixed, with node identification performed by sight and palpation. We excluded 186 patients who received postoperative adjuvant chemotherapy via oral or intravenous transmission to prevent possible chemotherapeutic effects on patients’ prognosis; therefore, a total of 180 patients with T_2–4N₀M₀ colorectal carcinoma were enrolled into this study. After the pathological examination, a mean of 12 lymph nodes (range 0–66) was harvested per tumor specimen. No postoperative relapse was found in this group, where the number of examined lymph nodes was 18 or more. Univariate analysis identified the size of the tumor, depth of invasion, grade of tumor, and number of examined lymph nodes, which were significantly correlated with postoperative relapse (all P < 0.05). Meanwhile, both the depth of tumor invasion and the number of harvested lymph nodes were independent predictors for postoperative relapse (P < 0.05). The 5-year overall survival rate of T_2–4N₀M₀ colorectal carcinoma patients who had 18 or more lymph nodes examined was significantly higher than those who had less than 18 nodes examined (P = 0.015). Nodal harvest in patients undergoing radical resection for colorectal carcinoma was highly significant in the current investigation. Our results suggest that harvesting and examining a minimum of 18 lymph nodes per surgical specimen might be taken into consideration for more reliable staging of lymph node-negative colorectal carcinoma.