The 301 to 314 amino acid residue of beta-tubulin is not a target epitope for serum IgM antibodies in chronic inflammatory demyelinating polyneuropathy

Connolly et al. [Neurology 48 (1997) 243] reported that IgM M-proteins from three patients selectively binds to an epitope on beta-tubulin that consists of amino acids 301 to 314. We therefore investigated whether these 14 amino acid residues beta301-314 are the target epitope for serum IgMs in sera from 67 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 50 with Guillain-Barré syndrome, 50 with motor neuron diseases, and 50 normal controls. IgM anti-beta301-314 antibodies were not restricted to nor were selectively associated with CIDP. We conclude that beta301-314 is not a target epitope for serum IgMs in CIDP.     

22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis

22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis. BACKGROUND: 22-Oxacalcitriol (OCT) is a unique vitamin D analogue with less calcemic activity than calcitriol, and it effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This study was performed to examine the long-term effect of intravenously administered OCT on high-turnover bone disease in model rats of slowly progressive renal failure. METHODS: Slowly progressive renal failure rats were made by a single injection of glycopeptide isolated from rat renal cortical tissues. At 250 days, glycopeptide-induced nephritis (GN) rats were divided into three groups with the same levels of serum creatinine and PTH, and they received either OCT (0.03 or 0.15 microg/kg body wt) or vehicle given intravenously three times per week for 15 weeks. RESULTS: Renal function of GN rats deteriorated very slowly but progressively, as assessed by the increase of serum creatinine concentration. At sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and fibrosis volume were significantly elevated in vehicle-treated GN rats compared with those of sham-operated rats, suggesting the development of high-turnover bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg group, these high PTH levels and high-turnover bone and fibrosis were significantly decreased. Such amelioration of bone abnormalities by OCT was not accompanied by either hypercalcemia or further deterioration of renal function. CONCLUSIONS: These data indicate that OCT may be a useful and safe agent not only for the suppression of PTH, but also for the amelioration of osteitis fibrosa and high-turnover bone without causing hypercalcemia in chronic dialysis patients.     

CTLA4IgG treatment induces long-term acceptance of rat small bowel allografts

BACKGROUND: CTLA4 immunoglobulin (Ig)G that binds to B7 effectively inhibits the signaling of CD28/CTLA4-B7 pathway and induces antigen specific T cell unresponsiveness in vitro and in vivo. Using CTLA4IgG, we examined induction of long-term graft survival and the mechanism of maintenance of tolerance in rat allogeneic small bowel transplantation. METHODS: Small bowels of Brown-Norway rats (RT1n) were heterotopically transplanted into Lewis rats (RT1l). Recipients were treated with an i.p. injection of either CTLA4IgG or control IgG for 7 days. RESULTS: Long-term survival was observed in rats treated with CTLA4IgG, whereas control rats died within 16 days after transplantation. To examine whether a tolerant state was established in long-term survival rats, secondary transplantation was performed using small bowels of Brown-Norway rats or ACI (RT1b) rats. It was demonstrated that small bowels of Brown-Norway rats were accepted; however, those of ACI rats were rejected within 10 days. Serum concentrations of interleukin (IL)-4 were maintained at >50 microg/ml for 7 days after transplantation in rats treated with CTLA4IgG but <15 microg/ml in control rats. IL-2 concentration was reduced to half in CTLA4IgG-treated rats compared with that in control recipients. Serum IFN-gamma in CTLA4IgG-treated recipients increased after transplantation and was not distinguishable from that of control recipients during the first 7 days after transplantation. Conclusion. We demonstrated that CTLA4IgG treatment alone for 7 days induced a long-term donor specific tolerance in rat allogeneic small bowel transplantation. The induction of long-term acceptance of small bowel allografts by CTLA4IgG is not caused by simply the shift of anti-alloimmune responses from Thl to Th2 cytokine production.     

Medial plantar nerve conduction velocities among patients with vibration syndrome due to chain-saw work

Objective: The present study examined the effect of the vibration syndrome (VS) on the peripheral nervous system in the lower extremities. Methods: Thirty-eight patients with VS due to previous exposure to vibration from chain-saw work and 55 age-matched controls were examined for sensory nerve conduction velocities in the medial plantar nerve (SCV-P). The patient group was divided into two subgroups, one with (n=19) and the other without vibration-induced white finger (VWF; n=19). Results: Analysis of variance of SCV-P for the three groups showed significant difference (F _2,89=10.65, P < 0.0001). A significant difference was found between the controls and the VWF⁺ group (P < 0.0001) but not between the controls and the VWF⁻ group (P=0.0508) by multiple comparison using Scheffe's method. Conclusion: These findings suggest that VS affects the peripheral nervous system function in the lower extremities via mediation of circulatory disturbance manifested as VWF. Received: 7 May 1998 / Accepted: 15 June 1999     

Relationship between inositol 1,4,5-trisphosphate receptor isoforms and subcellular Ca2+ signaling patterns in nonpigmented ciliary epithelia.

PURPOSE: Subcellular Ca2+ signaling patterns, such as Ca2+ waves, gradients, and oscillations, are an important aspect of cell regulation, but the molecular basis for these signaling patterns is not understood. Because Ca2+ release patterns differ among isoforms of the inositol 1,4,5-trisphosphate (InsP3) receptor, the relationship between the distribution of these isoforms and subcellular Ca2+ signaling patterns in nonpigmented epithelial (NPE) cells was investigated. METHODS: The distributions of the types I, II, and III InsP3 receptors were determined in NPE cells by immunofluorescence, and subcellular Ca2+ signaling patterns in these cells were examined by confocal line scanning microscopy. RESULTS: The type I InsP3 receptor was concentrated at the basal pole of NPE cells, whereas the type III receptor was localized to the apical pole. The type II InsP3 receptor was not expressed in detectable amounts. Acetylcholine induced increases in Ca2+ that were mediated by InsP3, and these Ca2+ increases began as Ca2+ waves that were initiated at the apical pole, in the region of the type III InsP3 receptor. Acetylcholine occasionally induced sustained or repetitive Ca2+ increases that were prominent at the basal pole, in the region of the type I InsP3 receptor, but only subtle or absent apically. CONCLUSIONS: Because the type I InsP3 receptor is thought to be responsible for repetitive Ca2+ release events, and the type III InsP3 receptor instead is suited to initiate Ca2+ signals, the subcellular distribution of these two isoforms corresponds to the Ca2+ signaling patterns observed in this cell type. Differential subcellular expression of InsP3 receptor isoforms may be an important molecular mechanism by which NPE cells organize their Ca2+ signals in space and time.     

Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery.

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.