Effects of cyclosporin A on the development of osteonecrosis in rabbits

BACKGROUND: Osteonecrosis (ON) of the femoral head is a serious complication in patients who have undergone organ transplantation. Introduction of cyclosporin A has resulted in lower-dosage steroid treatment and a decrease in the occurrence of ON. We examined the effect of cyclosporin A on the development of ON in rabbits. METHODS: In experiment A, rabbits were given cyclosporin A and 20 mg/kg methylprednisolone acetate. The control group was given 20 mg/kg methylprednisolone acetate only. Experiment B was then performed to mimic the clinical situation in which the use of cyclosporin A and lower steroid doses resulted in a decrease in occurrence of ON. In Experiment C, the effects of treatment with cyclosporin A only on development of ON were examined. 4 weeks after injection, bilateral femora and humeri were examined histopathologically for ON. RESULTS: Cyclosporin A increased the incidence of ON in rabbits when given in combination with steroid (p = 0.04). No ON lesions were observed in rabbits treated with cyclosporin A alone. INTERPRETATION: Our findings suggest that the clinically reported reduction in occurrence of ON following the use of cyclosporin A is probably attributable to the lower steroid doses used.     

Long-term follow-up in patients with Pendred syndrome: vestibular,auditory and other phenotypes

Fourteen patients with a Pendred syndrome gene ( Pds) mutation and three patients without the mutation were studied to evaluate long-term vestibular and auditory manifestations among patients with bilateral enlarged vestibular aqueducts (EVA). Charts were reviewed retrospectively for age, gender, otological history, presence or absence of vertigo, results of magnetic resonance imaging, relevant gene mutations and perchlorate discharge test. A missense mutation, His 723 Arg (H723R), was identified in the homozygous state in six patients and in the heterozygous state in seven patients. Another missense mutation, Tyr 410 Met (T410 M), was identified in the heterozygous state in one patient. Patients with vertigo tended to have hearing fluctuation, compared with the patients without vertigo. Patients homozygous for H723R tended to have more episodes of vertigo than the heterozygous individuals. Only one patient who was homozygous for H723R had goiter. The long-term outcome of hearing level in patients with the H723R mutation was significantly better compared with published results for patients with a Pds mutation, but not for those with the H723R mutation. Whether environmental factors or a subtype of the Pds mutation H723R are related to the long-term outcome for these patients must be clarified.Part of this paper was presented at the 61st Conference of the Japanese Society of Equilibrium Research held in Toyama, Japan, 1 November 2002.     

Histogenesis of intralesional fibrous septum in chordoma

Intralesional fibrous septum (IFS), a histologic architecture that is typical of chordoma, consists of proliferating spindle-shaped, fibroblast-like cells with an abundance of collagen fibers. However, the histogenesis of IFS is still controversial. In a series of 122 chordomas, special emphasis was placed on the morphology of host tissues involved in IFS and on a transition between IFS and neighboring tissues. In 23 lesions, IFS was also characterized both histochemically and immunohistochemically. IFS was observed in 79 (64.8%) lesions. Occasionally, IFS contained bone fragments and hyalinized matrix with no lining of osteoblastic cells, suggesting degenerated rather than metaplastic bone tissue. Moreover, IFS occasionally showed a direct transition to host bone trabeculae. Histochemically and immunohistochemically, IFS included calcium deposits positive for Alizarin red S staining and expressed both type I and type III collagen. In extraosseous lesions extending to the adjacent soft tissues, IFS frequently involved muscle fibers or peripheral nerve fibers and displayed a smooth transition to neighboring soft tissues. We believe that IFS is induced by a tumor-host interaction that is based on the host bone trabeculae in intraosseous lesions or on soft tissues in extraosseous lesions.     

Beneficial effect of transfusion with low-affinity red blood cells in endotoxemia

BACKGROUND: Sepsis caused by endotoxins such as lipopolysaccharide (LPS) impairs the microcirculation, diminishing tissue blood supply and aggravates systemic hypoxia. A novel lower-affinity hemoglobin (Hb) variant, Hb Presbyterian, enhances oxygen release to peripheral tissues and may improve tissue oxygen supply during sepsis. STUDY DESIGN AND METHODS: This study investigated the effectiveness of Presbyterian Hb in transfusion therapy with LPS-challenged sepsis mouse model. Septic wild-type mice were transfused with RBCs from Presbyterian Hb-carrying mutant mice and wild-type mice. Their survival rates were assessed, and apoptosis of hepatocytes was evaluated. Survival rates of septic Presbyterian mutant mice and the wild-type littermates were also studied. RESULTS: The Presbyterian mutant RBC-transfused septic group survived longer than the wild-type RBC-transfused group. Apoptosis was reduced in the hepatocytes of the former group. Presbyterian mutant mice themselves, however, did not have stronger resistance to LPS-induced sepsis. CONCLUSION: Transfusion of low-affinity Hb-containing RBCs has beneficial effects in septic mice.     

Clinical course and prognosis of 27 patients with childhood onset multiple sclerosis in Japan

To investigate whether outcomes of childhood onset multiple sclerosis (MS) have changed or not, the clinical courses of childhood onset MS in 27 patients at our hospital and those reported by Fukuyama in 1991 were compared. The ratios of our patients with poor prognosis in walking and vision were decreased. Widespread use of high-dose corticosteroid therapy and interferon therapy may be one cause of the low frequency of severe sequelae in our study.     

Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats

We examined whether fibroblasts, genetically modified to express BDNF and NT-3 (Fb-BDNF/NT3) and transplanted into a thoracic spinal injury site, would enhance recovery of bladder function and whether this treatment would be associated with reorganization of lumbosacral spinal circuits implicated in bladder function. Rats received modified-moderate contusion injuries at T8/9, and 9 days later, Fb-BDNF/NT3 or unmodified fibroblasts (OP-controls) were delivered into the cord. Fb-BDNF/NT3 rats recovered from areflexic bladder earlier, showed decreased micturition pressure and fewer episodes of detrusor hyperreflexia, compared to OP-controls. There were also improvements in hindlimb function in the Fb-BDNF/NT3 group although locomotion on a more challenging substrate (grid) and tail withdrawal latency in response to a thermal stimulus showed persisting deficits, little recovery, and no differences between the groups. Immunocytochemistry at L6-S1 revealed changes in density of afferent and descending projections to L6-S1 cord. The density of small dorsal root axons increased in the superficial layers of the dorsal horn in OP-controls but not in Fb-BDNF/NT3, suggesting sprouting of primary afferents following injury that was inhibited by Fb-BDNF/NT-3. In contrast, the trophic factor secreting transplants stimulated sprouting and/or sparing of descending modulatory pathways projecting to the lumbosacral spinal cord. No differences in synaptophysin immunoreactivity were seen in the dorsal horn which suggested that synaptic density was similar but achieved by sprouting of different systems in the two operated groups. Fb-BDNF/NT3 transplanted into injured spinal cord thus improved both bladder and hindlimb function, and this was associated with reorganization of spinal circuitry.     

The Role of dihydropyrazines in accelerated death of Escherichia coli on addition of copper(II)

Dihydropyrazines (DHPs), which are derived from sugars, inhibit the growth of Escherichia coli. Addition of copper(II) ion (Cu2+) accelerates the effect of DHPs, resulting in cell death. Investigation of the lethal effect in several DNA repair-deficient or detoxifying enzyme-deficient mutant strains and radical scavengers suggested that the cytotoxic and genotoxic damage was caused by radical species (hydroxyl, superoxide anion, and carbon-centered radicals) generated from reaction of DHPs with Cu2+.