Contralateral cytokine gene induction after peripheral nerve lesions: dependence on the mode of injury and NMDA receptor signaling.

There is increasing evidence that unilateral nerve injury evokes contralateral responses, but the underlying mechanisms are largely unknown. In the present investigation, we analyzed cytokine and chemokine gene induction in contralateral, non-lesioned nerves after sciatic nerve crush and chronic constriction injury (CCI) by quantitative reverse transcriptase polymerase chain reaction in mice. After sciatic nerve crush, contralateral changes in cytokine gene expression were restricted to interleukin (IL)-1beta, which showed a monophasic peak at the first postoperative day. Following CCI, contralateral transcripts for IL-1beta, IL-10 and monocyte chemoattractant protein-1 (MCP-1) were significantly increased already at day 1 and upregulation persisted over the next 4 weeks. In contrast, tumor necrosis factor alpha (TNF-alpha) levels remained unchanged. Contralateral gene induction was restricted to the homonymous opposite sciatic nerve, but spared the femoral nerve. NMDA receptor blockade completely abolished contralateral cytokine expression after CCI on the mRNA level. In contralateral dorsal root ganglia, only IL-10 mRNA levels were modified after nerve injury. Sham operation significantly increased the cytokine and chemokine gene expression at the ipsilateral side, but could not mediate contralateral effects. Our study confirms that nerve injury evokes contralateral responses and identifies NMDA-mediated signaling as one underlying mechanism.

The extent of cytokine induction in peripheral nerve lesions depends on the mode of injury and NMDA receptor signaling.

We compared cytokine and chemokine induction in mice after sciatic nerve crush and chronic constriction injury (CCI) by quantitative reverse transcriptase polymerase chain reaction. In both nerve lesion paradigms, transcripts for tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and monocyte chemoattractant protein-1 (MCP-1) were significantly increased in degenerating nerve stumps already at day 1, with a greater magnitude and longer duration in CCI. NMDA receptor blockade significantly reduced cytokine expression after CCI on the mRNA and protein level. In dorsal root ganglia, only IL-10 mRNA levels were modified after nerve injury. Our study indicates that the mode of nerve injury influences the extent of cytokine expression, and identifies NMDA-mediated signaling as one mechanism of cytokine induction in peripheral nerves.

Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice.

Monotherapy with antibodies to tumor necrosis factor-alpha (TNF) or interleukin-1 receptor 1 (IL-1R1) reduces hyperalgesia in an animal model of painful neuropathy. Here we investigated whether combined therapy with epineurial anti-TNF and anti-IL-1R1 antibodies produces a further advantage. C57BL/6 mice with a chronic constrictive injury of one sciatic nerve were treated epineurially with neutralizing antibodies to either IL-1R1 or TNF alone or with a combined application of neutralizing antibodies to TNF and IL-1R1. Combined treatment with anti-IL-1R1 and anti-TNF antibodies markedly reduced thermal hyperalgesia and mechanical allodynia more effectively than monotherapy with either antibody. There were no detectable differences in IL-1beta and TNF endoneurial protein expression between animals with monotherapy and combined treatment. We conclude that combined anti-cytokine therapy may be a useful strategy in the treatment of neuropathic pain.

Weight reducing and metabolic effects of topiramate in patients with migraine--an observational study.

Topiramate is an anticonvulsant agent effective in the prophylaxis of migraine, which also induces weight reduction by an unknown mechanism. We investigated the effect of topiramate on metabolic and endocrine parameters in patients with migraine independently of any intention to lose body weight. Six patients (26-61 years old, body mass indices [BMI] 20.9-32.1 kg/m(2)) with migraine were treated with an average dose of 100 mg topiramate/day over a period of 20 weeks. The following parameters were measured every 4-8 weeks: BMI, body fat proportion, waist and hip circumference, HOMA insulin resistance, fasting serum-/plasma concentrations of adiponectin, leptin, ghrelin, vascular endothelial growth factor (VEGF), cortisol, interleukin-6 and tumor necrosis factor (TNF)-alpha. Profound metabolic changes were observed for the whole treatment period. Compared with the baseline value, 20 weeks of treatment reduced the BMI by 7.2+/-1.4%, body fat proportion by 11.6+/-3.6%, waist circumference by 4.2+/-1.2%, leptin by 39.2+/-6.5% and HOMA insulin resistance by 37.3+/-5%, while adiponectin was increased by 69.9+/-17.3% (P<0.05, respectively). VEGF concentrations increased during the week 2-4 by 177.4+/-39.4% (P<0.05) followed by a continuous decrease. There were trends for a reduction in ghrelin concentration, whereas cortisol, interleukin-6 and TNF-alpha values were unchanged. In summary, in this small sample of migraine patients topiramate treatment was associated with increased insulin sensitivity, increased adiponectin concentration and a reduction of body fat in all treated patients. The role of increased VEGF concentrations prior to these metabolic changes is not clear and might, hypothetically, involve a centrally mediated effect of topiramate on body weight regulation.

Whipple's disease presenting as an isolated lesion of the cervical spinal cord.

Chronic myelitis from Whipple's disease of the spinal cord is extremely rare. The differential diagnosis includes chronic inflammatory lesions, viral or bacterial infections, and tumours of the spinal cord. Here we present a 50-year-old man with mild sensory deficits because of a large lesion of the cervical spinal cord who markedly showed improvement during probatory antibiotic therapy. PCR and jejunal biopsy were initially negative and only later confirmed the diagnosis of Whipple's disease. Clinical and neuroradiological criteria are suggested which may be of help in the early diagnosis of spinal Whipple's disease before confirmation by molecular biology or histology.

Infection of synovial fibroblasts in culture by Yersinia enterocolitica and Salmonella enterica serovar Enteritidis: ultrastructural investigation with respect to the pathogenesis of reactive arthritis.

Synovial fibroblasts were infected with Yersinia enterocolitica or Salmonella enterica serovar Enteritidis and analyzed by electron microscopy and fluorescence in situ hybridization. Intracellular bacterial replication was followed by degradation leading to "ghosts" possessing lipopolysaccharides but not DNA. However, single bacteria survived for more than 2 weeks. Therefore, transient intra-articular infection might be the missing link between initial intestinal infection and late synovial inflammation in the pathogenesis of reactive arthritis.