Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment

The specific mechanisms by which nervous system injury becomes a chronic pain state remain undetermined. Historically, it has been believed that injuries proximal or distal to the dorsal root ganglion (DRG) produce distinct pathologies that manifest in different severity of symptoms. This study investigated the role of injury site relative to the DRG in (1) eliciting behavioral responses, (2) inducing spinal neuroimmune activation, and (3) responding to pharmacologic interventions. Rats received either an L5 spinal nerve transection distal to the DRG or an L5 nerve root injury proximal to the DRG. Comparative studies assessed behavioral nociceptive responses, spinal cytokine mRNA and protein expression, and glial activation after injury. In separate studies, intrathecal pharmacologic interventions by using selective cytokine antagonists (interleukin-1 [IL-1] receptor antagonist and soluble tumor necrosis factor [TNF] receptor) and a global immunosuppressant (leflunomide) were performed to determine their relative effectiveness in these injury paradigms. Behavioral responses assessed by mechanical allodynia and thermal hyperalgesia were almost identical in the two models of persistent pain, suggesting that behavioral testing may not be a sensitive measure of injury. Spinal IL-1beta, IL-6, IL-10, and TNF mRNA and IL-6 protein were significantly elevated in both injuries. The overall magnitude of expression and temporal patterns were similar in both models of injury. The degree of microglial and astrocytic activation in the L5 spinal cord was also similar for both injuries. In contrast, the pharmacologic treatments were more effective in alleviating mechanical allodynia for peripheral nerve injury than nerve root injury, suggesting that nerve root injury elicits a more robust, centrally mediated response than peripheral nerve injury. Overall, these data implicate alternate nociceptive mechanisms in these anatomically different injuries that are not distinguished by behavioral testing or the neuroimmune markers used in this study.     

Schwann cell-conditioned medium inhibits angiogenesis in vitro and in vivo

BACKGROUND: Neuroblastomas are biologically heterogeneous tumors that consist of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. The amount of Schwannian stroma strongly impacts prognosis. Low tumor vascularity, localized stage, and favorable outcome are associated with tumors that are Schwannian stroma-rich/stroma-dominant. PROCEDURE: To investigate if Schwann cells play a role in inhibiting angiogenesis in neuroblastoma tumors, we examined the ability of human Schwann cell-conditioned medium to affect bFGF- and VEGF-induced endothelial cell proliferation and migration, and in vivo angiogenesis. RESULTS: Schwann cell-conditioned medium significantly inhibited bFGF- and VEGF-induced endothelial cell proliferation and migration. This effect appears to be specific for endothelial cells as smooth muscle cell and fibroblast proliferation were not inhibited by this medium. Schwann cell-conditioned medium also inhibited in vivo angiogenesis in rat corneal assays. CONCLUSIONS: Schwann cells produce a potent inhibitor(s) of angiogenesis that may be responsible for the low level of vascularity and more benign clinical behavior of Schwannian stroma-rich/stroma-dominant neuroblastoma tumors. Studies to identify the inhibitor(s) are ongoing.     

Hirntumoren bei Kindern und Jugendlichen

Every year in Germany, around 380 children younger than 16 years of age are diagnosed with a brain tumor. Compared with adults, different types of brain tumors are found in children. The diagnosis is often delayed despite presentation with characteristic symptoms. Nonspecific persistent symptoms must be followed with further diagnostics. Since the 1980s, multimodal therapeutic regimens have been developed systematically by the Society for Pediatric Oncology and Hematology (GPOH) in the context of treatment optimization trials. Neurosurgery, chemotherapy, and irradiation are applied according to the histology, stage of metastasis, and age of the child. Currently, 80–90% of the children diagnosed with brain tumors in Germany are treated according to the respective trial in the context of the treatment network HIT. The principle aims are improved survival and quality of life, reduction of therapy-associated toxicity and late effects, and better diagnostic and therapeutic standards. In this article, typical clinical symptoms and diagnostic recommendations are described, and the structure of the HIT treatment network is illustrated.     

Sinus venosus atrial septal defect associated with vein of Galen malformations: Report of two cases

Summary Two unique cases are presented of infants with signs of vein of Galen malformations, whose unsuspected associated sinus venosus atrial septal defects were detected during routine echocardiography. A conservative approach to cardiac treatment is advocated.     

Total parenteral nutrition in cancer patients

One hundred and twenty-one cancer patients received 134 courses of total parenteral nutrition (TPN); almost all were treated with chemotherapy and/or radiotherapy. The average weight loss prior to TPN was 6.7 kg and albumin 3.1 g%/patient; 25% glucose solution with 4.25 g% amino acids was used as a calorie and nitrogen source. The average weight gain was 2.6 kg for those who received TPN less than 2 wk and 4.5 kg if TPN was given for greater than 2 wk. Complications were low; 3% had proven TPN-related septicemia. Mild to moderate reversible metabolic complications were common, although severe complications were rare; no one died because of TPN. Our experience confirms the previous reports that TPN can be given safely to malnourished compromised cancer patients.     

Responses to the purr call in three areas of the guinea pig auditory cortex

Single electrodes were used to record from anaesthetized animals stimulated with a closed sound system. Neural responses to the purr call were very different in the dorsocaudal core field and in two long-latency belt areas, the ventrorostral belt and the dorsocaudal belt. Responses in the dorsocaudal core field were accurately timed to the start of the nine rhythmic pulses within the purr while the ventrorostral belt responses were more sustained and less temporally precise and most dorsocaudal belt units did not respond. These results are consistent with the separate processing of narrow-band tonal stimuli such as the purr by a ventrorostral pathway involving the primary auditory area and the ventrorostral belt but not by a dorsocaudal pathway from the dorsocaudal core field to the dorsocaudal belt area.     

Effect of 12-month therapy with omega-3 polyunsaturated acids on glomerular filtration response to dopamine in IgA nephropathy

BACKGROUND: Omega-3 polyunsaturated acids therapy is efficient in primary IgA nephropathy. It is unknown whether doses of omega-3 smaller than those given previously are still effective. The aim of the study was to examine the effect of omega-3 therapy on renal vascular function in relation to proteinuria and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). METHODS: 20 IgA patients aged 36.5 +/- 10.77 with creatinine clearance (Cr(cl)) 105.71 +/- 27.3 ml/min and proteinuria 3.31 +/- 2.01 g/24 h were given orally 810 mg EPA and 540 mg DHA daily for 12 months. Before and at the end of the study, 24-hour proteinuria, serum homocysteine, and Cr(cl) were measured. At the same time, renal vascular function was estimated as dopamine-induced glomerular filtration response (DIR). DIR was measured as: two 120-min lasting Cr(cl) (before and during 2 microg/kg b.w./min i.v. dopamine). RESULTS: The results obtained during follow-up were as follows (baseline vs. after therapy): DIR 14.9 +/- 16.4 vs. 30.3 +/- 14.3% (p < 0.01); urine protein 2.31 +/- 2.01 vs. 1.31 +/- 1.37 g/24 h (p < 0.01); (Cr(cl)) 105.71 +/- 27.3 vs. 103.9 +/- 20.9 ml/min (n.s.); NAG 8.3 +/- 1.8 vs. 6.0 +/- 1.2 U/g(creat) (p < 0.01), and homocysteine 16.2 +/- 3.15 vs. 13.8 +/- 2.6 micromol/l (p < 0.05). The only correlation found was linear correlation between basal DIR and DIR change (r = -0.570; p < 0.010) and basal NAG (r = -0.460; p < 0.50). CONCLUSIONS: Omega-3 supplementation is associated with the improvement of both renal vascular function and tubule function.     

Disturbances of purine nucleotide metabolism in uremia

The increased concentration of adenosine triphosphate (ATP) in erythrocytes from patients with chronic renal failure (CRF) has been observed in many studies but the mechanism leading to these abnormalities still is controversial. It is believed that hyperphosphatemia and metabolic acidosis triggering enhanced reutilization of purine bases are the factors responsible for changes in erythrocyte nucleotide concentration. During the past decade we have performed several studies. A summary of the obtained results is presented. A high-performance liquid chromatography technique was used for the determination of plasma and intraerythrocyte nucleotide concentrations. Labeled adenine and adenosine were used for measuring adenine incorporation. In CRF patients treated conservatively increased concentrations of ATP levels and other nucleotides such as adenosine diphosphate were found. Adenosine monophosphate and hypoxanthine levels were lower than in controls. In hemodialyzed patients both ATP and adenosine monophosphate intraerythrocyte concentrations were higher than in controls. At the same time, adenosine monophosphate and hypoxantine level were comparable with levels in healthy people. The main pattern of nucleotides during hemodialysis remained unchanged, independent from the mode of therapy. The only exception was a decreased level of hypoxantine. Results of a consecutive study have suggested that the increased rate of adenine incorporation into the adenine nucleotide pool could be partially responsible for the increased ATP concentration in uremic erythrocytes. Last but not least, trying to elucidate the pathomechanism of adenine nucleotide disturbances in uremia, we have found that the concentration of N-methyl-2-pyridone-5-carboxamide (2PY), one of the end products of nicotinamide-adenine dinucleotide degradation, were enhanced in CRF patients to values that are potentially toxic. Our findings suggest that 2PY could be a novel uremic toxin. Disturbances of nucleotide metabolism are one of the important components of uremic syndrome.