Teiji Sasaki

Hyperalgesia and decreased neuronal nitric oxide synthase in diabetic rats.

TO evaluate the role of nitric oxide synthase (nNOS) in the pathogenesis of diabetic neuropathy, we investigated nociception and nNOS expression in dorsal root ganglion (DRG) of rats with streptozocin-induced diabetes. Paw withdrawal threshold to noxious mechanical stimuli was decreased in both L-NAME-treated and diabetic rats. The number of NADPH-diaphorase positive neurons was significantly decreased in untreated diabetic compared with control rats. Decreased expression of nNOS protein was confirmed by immunoblotting. Insulin treatment completely prevented decreases in withdrawal threshold and nNOS expression. Cyclic GMP content paralleled nNOS expression in experimental animals. These results suggest that decreased nNOS-cGMP system in DRG may play a role in the pathogenesis of diabetic sensory neuropathy.

A case of severe acute pancreatitis treated with CTR-001 direct hemoperfusion for cytokine apheresis.

Abstract:  Severe acute pancreatitis is a clinical entity that can develop into multiple organ failure (MOF), and still has a poor prognosis. It is generally agreed that excessive humoral mediators such as pro‐inflammatory cytokines play important roles in the pathogenesis of organ failure in patients with severe acute pancreatitis (SAP). Furthermore, it has been reported that continuous hemodiafiltration (CHDF) can remove the excess humoral mediators during the hypercytokinemic state of systemic inflammatory response syndrome (SIRS). We experienced a case of severe acute pancreatitis induced by alcohol abuse, on whom we performed cytokine apheresis. The patient was a 46 year‐old male. He received 14 cytokine apheresis procedures, for about 4 hours in each session, using a CTR‐001 direct hemoperfusion (DHP) cartridge. His serum levels  of  pro‐inflammatory  cytokines  such  as  interleukin‐6 (IL‐6; 1649.1 ± 667.1–1257.1 ± 489.4 pg/mL, P = 0.013) decreased significantly after the CTR‐001 procedures. However tumor necrosis factor‐α (TNF‐α) (26.2 ± 1.7–24.3 ± 1.9 pg/mL, P = 0.087), IL‐1β (6.1 ± 2.9–3.49 ± 1.1 pg/mL, P = 0.477), IL‐8 (192.5 ± 33.4–229.5 ± 51.8 pg/mL, P = 0.754) and IL‐10 (14.4 ± 2.7–14.0 ± 1.9 pg/mL, P = 0.726) did not decrease statistically. Therefore, we conclude that in this case, cytokine apheresis using a CTR‐001 cartridge was effective for reducing the pro‐inflammatory cytokines during severe acute pancreatitis.

Impaired regeneration and no amelioration with aldose reductase inhibitor in crushed unmyelinated nerve fibers of diabetic rats

The regenerative ability of unmyelinated nerve fibers (UNFs) in diabetes and the effect of aldose reductase inhibitor (ARI) on it were ultrastructurally evaluated after sciatic nerve crush in control and untreated and tolrestat-treated streptozocin-induced diabetic rats. The density and number of UNFs were significantly increased in all groups at 5 weeks after the injury. The increase returned to the baseline level in control rats, but not in diabetic rats at 24 weeks. Although the axon size showed a marked decrease at 5 weeks and an incomplete recovery at 24 weeks in all groups, the recovery was significantly worse in diabetic than in control groups. Tolrestat did not have any effect on regeneration of UNFs in diabetes. These results suggest impaired regeneration of UNFs after nerve crush injury in diabetes and less therapeutic effect of ARI on it.

Unusual hypersensitivity to warfarin in a critically ill patient

A patient was admitted to the intensive care unit because of respiratory failure, and warfarin therapy was started at 2 mg/day for the treatment of pulmonary embolism, together with other medications. Despite the low dosage of warfarin, international normalized ratio (INR) was markedly elevated from 1·15 to 11·28 for only 4 days, and bleeding symptoms concurrently developed. Vitamin K2 was infused along with discontinuation of warfarin. One day later, the INR was found to have decreased, and bleeding was also improved. An objective causality assessment indicated a probable relationship between clotting abnormality and warfarin administration, although the degree of elevation of the INR was unusual in the light of the daily warfarin dose and duration of its exposure. Based on the clinical status of the patient, it was suspected that several conditions contributed to the abnormal hypersensitivity to warfarin. Contributory factors probably included pharmacokinetic interactions with co‐administrated drugs, vitamin K deficiency caused by decreased dietary intake, reduced gut bacterial production, impaired intestinal absorption and hepatic synthetic capacity, and increased consumption of clotting factors. In view of our experience in the present case, it should be stressed that close monitoring of coagulation capacity is necessary in critically ill patients in order to avoid fatal haemorrhage after initiating warfarin therapy regardless of the dosage.

Paraneoplastic cerebellar degeneration in olfactory neuroepithelioma

Anti-Hu antibody was first discovered in patients with paraneoplastic encephalomyelitis associated with small cell lung cancer (SCLC). This antibody recognises proteins comprised in the Hu family expressed by neuronal cells as well as SCLC. After the first report, anti-Hu antibody was found in other neoplasms including prostate and breast cancer, adrenal carcinoma, chondromyxosarcoma, neuroblastoma, and neuroendocrine neoplasms at other sites.1 Olfactory neuroepithelioma (9523/3)2 is thought to differ from classic neuroblastoma (9500/3) in its expression pattern of tyrosine hydroxylase, MYCN amplification, and fusion of the Ewing sarcoma gene and the Friend leukaemia virus integration 1 gene or the ETS related gene.3 Anti-Hu antibody in association with olfactory neuroepithelioma has not been reported previously. We report a patient with cerebellar ataxia that paralleled the recurrence of the tumour. Serum and cerebrospinal fluid (CSF) from the patient contained anti-Hu antibody, and the olfactory neuroepithelioma resected from the patient expressed Hu antigen. Seven years before admission, a 65 year old man presented with olfactory neuroepithelioma that had invaded the orbit and frontal lobe. The tumour was dissected surgically, and dura mater graft was not used in the surgery. The patient underwent irradiation (total dose of 50 Gy). …