BackgroundMacrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system.MethodsCIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay.ResultsIntraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin.ConclusionsOur data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.

A model of intracerebral hematoma that closely resembles the state in humans after spontaneous intracerebral hematoma was developed. Sequential changes in experimental intracerebral hematomas were compared with the in vivo findings in spontaneous intracerebral hemorrhage. The clinical series consisted of 28 patients with spontaneous intracerebral hemorrhage observed by CT during their natural course from 1976 through 1978. The experimental series consisted of 26 adult mongrel dogs with intracerebral hematoma near the basal ganglia studied by CT and histological examinations. In neither the clinical nor the experimental series was the time of decrease in density beginning in the periphery of the hematoma or the first appearance of ring enhancement and its concentric concentration toward the center of the hematoma affected by the size of the hematoma. In the experimental series, the tissue reaction near the periphery of the intracerebral hematoma showed constant processes: First, a necrotic layer appeared; this was then replaced by immature connective tissue with newly formed vessels and argentophilic fibers, and finally the immature layer was gradually transformed into mature connective tissue with collagenous fibers. Ring enhancement was accompanied by the appearance of immature connective tissue and capillaries. This process of change was also unrelated to the size of the hematoma. The following correlations were suggested from the chronological observation of CT images and the histological appearance: 1) acute stage - homogeneous high density extending to the periphery, appearance of the necrotic layer; 2) subacute stage - decreased density spreading from the periphery and formation of ring enhancement, appearance of immature connective tissue with argentophilic fibers; 3) chronic stage - concentric concentration of ring enhancement and development of mature connective tissue with collagenous fibers.

We conclude that aspiration lumpectomy is a useful and safe technique for the treatment of small rectal carcinoid tumors contained within the submucosa.

Sarcomas and related proliferative lesions of the specialized stroma of the prostate are very rare and have been classified into prostate stromal sarcoma (PSS) and prostatic stromal tumor of uncertain malignant potential based on histology. We herein describe a case of PSS. A 40-year-old male presented at a hospital with urinary distention. Magnetic resonance imaging revealed a large prostate mass, and the diagnosis was prostate sarcoma of uncertain differentiation by ultrasound-guided needle biopsy. Total pelvic exenteration was performed and a pathological diagnosis of PSS was ultimately reached. Ten months later, there have been no signs of metastasis or recurrence.

SUMMARY An unusual case of peripheral hypoglossal nerve palsy, caused by lateral position of the external carotid artery and an abnormally high carotid bifurcation is reported. Improvement followed ligation and cutting of the external carotid artery at its origin. Stroke Vol 15, No 4, 1984 VARIATIONS AND ANOMALIES are common at the bifurcation of the external and internal carotid arteries.1 Lateral position of the external carotid artery 2 " 6 formerly considered extremely rare, has recently been found to be more common.7 8 However, there are few reports, that this condition causes neurological signs.1 In this paper, a case of peripheral hypoglossal nerve palsy caused by lateral position of the external carotid artery and a carotid high bifurcation is presented.Case Report A 49-year-old man was admitted because of tongue deviation and dysarthria on December 8, 1980. At age 42, his blood pressure was found to be high and antihypertensive drugs were presented. He had felt throbbing pains in the occipital region beginning November 10, 1980, but these pains became intense from midday of November 21. At that time he visited a neurosurgical clinic, but no abnormalities could be found. On the morning of November 22, eating became difficult, and movement of the tongue was impeded, making speech inarticulate.Tongue deviation to the right and atrophy and fasciculation of the right lingual muscle were observed ( fig. 1). Tactile sensibility and taste sensation of the tongue were normal, and no abnormality of other cranial nerves was observed. There were no other abnormalities on neurological examination. Homer's sign was not presented and no bruit was heard in the neck. A diagnosis of peripheral hypoglossal nerve palsy with suspected hypoglossal neurinoma was made.A CT scan demonstrated no abnormality related to the right hypoglossal palsy. Right jugular venography revealed good filling by contrast medium and no abnormal findings. Tomography of the hypoglossal ca- nals, was normal. Bilateral carotid angiography and bilateral vertebral angiography were performed. No abnormalities were observed in the vertebral angiogram, except conspicuous elongation of the basilar artery. In the right carotid angiogram, marked lateral displacement of the right external carotid artery was noticed and the bifurcation of the external and internal carotid arteries was abnormally high (upper margin of the C 2 vertebra); there was conspicuous kinking and elongation of the external and internal carotid arteries and, in particular, prominent dilatation of the proximal portions of both arteries. In the lateral view of the angiogram, a loop-like elongation was observed 3.5 cm distal to the bifurcation ( fig. 2). In the left carotid angiogram, as in that of right side, the bifurcation was at a high level (center of C 2 vertebra) and elongation was conspicuous, but a lateral position of the external carotid artery was not seen.From this examination, the possibility of hypoglossal neurinoma was excluded and the following two mechanical processes wer...