Biomedical subjects

Yukio Ando

Publications and source records attributed to Yukio Ando.

At least 55 records · Page 3Linked to original sources

PubMed2004

Applications of gene therapy for familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP), caused by mutated transthyretin (TTR), is the common form of hereditary generalised amyloidosis. As TTR is predominantly synthesised in the liver, liver transplantation is now considered an effective treatment for FAP to halt the production of variant TTR. However, this invasive therapy has several problems, leading to a requirement for a non-invasive treatment to be developed. At present, gene therapy for FAP has focused on two therapeutic strategies for suppressing variant TTR gene expression. The first is inhibition of variant TTR mRNA expression by antisense or ribozymes, and the other is the repair of mutated TTR gene by chimaeraplasts or single-stranded oligonucleotides. In particular, targeted gene repair is considered to be a promising tool for gene therapy because the effect can last permanently and the method is more suitable for proteins with a short plasma half-life. This article summarises the general concept of gene therapy and reviews the recent data on gene therapy for FAP.

Amyloid Neuropathies, Familial↗

PubMed2004

[New molecular marker in dialysis setting--misfolded beta 2-microglobulin].

More than 25 clinical settings in amyloidosis have been acknowledged in which a peculiar criminal protein, a precursor protein, has been identified. As of now, however, the mechanism of amyloidogenesis, by which a precursor protein is transformed irreversibly into an amyloid protein, remains to be clarified. We speculated that a study of the molecular conformation of beta 2-microglobulin (beta 2 m), a precursor protein in dialysis-related amyloidosis (DRA), might provide a typic model of amyloidogenesis in other precursor proteins. Therefore, we investigated the misfolding of beta 2 m in DRA using a specific monoclonal antibody against C-terminal peptide 92-99 of beta 2 m. Our study indicated the possibility that the monoclonal antibody specific for C-terminal 92-99 of beta 2 m can detect a pre-amyloid state in amyloidogenesis in vivo, which might take place in the extravascular space.

Amyloidosis↗

PubMed2004

[Evaluation of autonomic dysfunction by novel methods].

The autonomic nervous system innervates every organ in the body. Since autonomic disturbances affect patient survival, an understanding and recognition of these disturbances are important. We adopted several new methods to evaluate autonomic function accurately. 123I-metaiodobenzylguanidine scintigraphy can assess the cardiac autonomic function even in the presence of cardiac arrhythmia. Laser-Doppler flowmetry, ultrasonographic study in the vessels and near-infrared spectrophotoscopy techniques serve as useful markers for screening the dysfunction of vasomotor neurons and blood circulation. Electrogastrography and the circadian rhythms of protein C secretion could be markers of the visceromotor nerves in the abdomen. Electrogastrography is a particularly useful tool for reflecting on functional changes in gastrointestinal motility. The evaluation of anemia could be a marker of autonomic dysfunction in the kidney and bone marrow in patients with familial amyloidotic polyneuropathy, pandysautonomia, and multiple system atrophy. Normocytic and normochromic anemia correlated with the severity of autonomic dysfunction were shown in these patients. We also evaluated the dysfunction of the neuroendocrine system and sudomotor neuron using our new autonomic function tests. The glucose-tolerance test could become one of the most useful clinical tools for detecting autonomic dysfunction in the endocrine system. Microhydrography and thermography could be useful tools for diagnosing the lesion site of dyshidrosis. Moreover, it is clinically important to check the systemic circulation and autonomic function in patients treated with sildenafil citrate and organ transplantation to save their lives. Our new autonomic function tests, such as laser-Doppler flowmetry and 123I-metaiodobenzylguanidine scintigraphy, are crucial tools in supplying the best symptomatic treatment for such patients.

3-Iodobenzylguanidine↗

PubMed2004

Familial amyloid polyneuropathy: hypertrophy of ligaments supporting the spinal cord.

We describe characteristic spinal MR findings of two cases of familial amyloid polyneuropathy (FAP). Both cases showed leptomeningeal enhancement on contrast-enhanced T1-weighted image. In addition, three-dimensional constructive interference in steady-state imaging demonstrated thickening of the ligaments, other connective tissues within the spinal canal, dura matter, and dorsal nerve roots. These findings in FAP are felt to represent amyloid deposition.

Adult↗

PubMed2004

[Gene therapy in familial amyloidotic polyneuropathy by single-stranded oligonucleotides (SSOs)].

Transthyretin (TTR) related familial amyloidotic polyneuropathy (FAP) is the common form of hereditary generalized amyloidosis and is characterized by the accumulation of amyloid deposits in the peripheral nerves and other organs. Liver transplantation has been utilized as therapy for FAP, because the variant TTR is predominantly synthesized by the liver, but this therapy is associated with several problems. Since we need to develop a new treatment, we examined the feasibility of gene therapy in FAP to prevent the production of variant TTR in the liver by using single-stranded oligonucleotides (SSOs). To examine in vitro and in vivo conversion of the TTR gene by SSOs embedded in atelocollagen, we used HepG2 cells and liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the mouse TTR V30M gene. The level of gene conversion was determined by real-time RCR combined with mutant-allele-specific amplification. The level of gene conversion was approximately 11% and 9% of the total TTR gene in HepG2 cells and liver from transgenic mice, respectively. Therefore, gene therapy via this method may be a promising alternative to liver transplantation for treatment of FAP.

Amyloid Neuropathies, Familial↗

PubMed2003

Role of VLDL/chylomicron in amyloid formation in familial amyloidotic polyneuropathy.

We examined the affinity of transthyretin (TTR) for lipoproteins and the effect of lipoproteins on TTR-related amyloidogenesis using serum samples from healthy volunteers and patients with familial amyloidotic polyneuropathy (FAP) ATTRVal30Met. In both volunteers and patients, TTR levels were highest in the VLDL fraction containing chylomicrons (VLDL/CM) and next highest in the HDL fraction. Levels were lowest in the LDL fraction. Mass spectrometric analyses of TTR spectra revealed significant TTR association with VLDL/CM and the levels of variant TTR were decreased in the FAP patients. Examination of the affinity of wild-type and variant TTRs for lipoprotein via a quartz crystal microbalance (QCM) revealed the highest affinity of both proteins for VLDL/CM. In in vitro amyloid formation test measured with thioflavin T and electron microscopy, in the presence of VLDL/CM, amyloid formation of TTR was enhanced more than in the presence LDL or in the absence of lipoprotein species. These results suggest that TTR should be highly associated especially with VLDL/CM and amyloidogenicity of TTR should be enhanced around the adipocytes.

Adult↗

PubMed2003

Secondary glaucoma in patients with familial amyloidotic polyneuropathy.

OBJECTIVE: To elucidate the clinical features and surgical outcomes of the treatment of secondary glaucoma associated with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). DESIGN: Retrospective case study. PARTICIPANTS: Forty-nine Japanese patients with FAP. METHODS: For all patients, measurement of best-corrected visual acuity, intraocular pressure, and visual fields as well as slitlamp and ocular fundus examinations were conducted and compared. In addition, the exact mutation of the amyloidogenic TTR variants was analyzed for all 49 patients with FAP. The TTR mutations included amyloidogenic TTR (ATTR) Val30Met in 41 patients, ATTR Tyr114Cys in 6, ATTR Ser50Ile in 1, and a compound heterozygous mutation of ATTR Val30Met + Arg104His in 1. RESULTS: The onset of secondary glaucoma was defined as elevation of intraocular pressure and glaucomatous changes in visual field defects. Secondary glaucoma was detected in 12 (24%) of the 49 patients. The incidence of secondary glaucoma in patients with the Val30Met mutation (17%) was lower than for the other FAP genotypes (P =.02 using the chi(2) test). Of 20 glaucomatous eyes, amyloid deposition on the pupil and anterior surface of the lens was found in 18 eyes. Amyloid deposition was found prior to glaucoma in 11 eyes and at the first visit to our clinic in another 7 eyes. In the 11 eyes in which the onset of glaucoma occurred following amyloid deposition along the pupil, the mean +/- SD period between the onsets of pupillary amyloid deposition and glaucoma was 2.55 +/- 1.43 years (range, 0.2-4.0 years). Further statistical analyses revealed significant relationships between the onset of secondary glaucoma and both amyloid deposition (P<.001) and vitreous opacity (P<.001). Surgical treatment was required in 15 (75%) of the 20 glaucomatous eyes. In 9 (81%) of the 11 eyes that underwent trabeculectomy, the intraocular pressure was well controlled at or lower than 20 mm Hg during the follow-up period. In the eyes that underwent combined trabeculotomy and sinusotomy (2 eyes), nonpenetrating trabeculectomy (1 eye), or a cyclodestructive procedure (1 eye), the intraocular pressure was poorly controlled. CONCLUSIONS: Glaucoma is not a rare condition in patients with FAP, especially because liver transplantation now enables patients with FAP to live longer. Careful observation of amyloid deposition along the pupil allows the prediction of glaucoma onset.

Adult↗

PubMed2003

Hereditary dysautonomias: current knowledge and collaborations for the future.

The hereditary dysautonomias (H-Dys) are a large group of disorders that affect the autonomic nervous system. Research in the field of H-Dys is very challenging, because the disorders involve interdisciplinary, integrative, and "mind-body" connections. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for the first time in order to discuss recent findings and future directions in the H-Dys field. The H-Dys workshop was instrumental in promoting interactions between basic science and clinical investigators. It also allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families. Future advances in H-Dys research will depend on a novel multi-system approach by investigators from different medical disciplines, and it is hoped that towards a common goal, novel "bench-to-bedside" therapeutics will be developed to improve the lives of, or even cure, patients suffering from dysautonomic syndromes.

Animals↗

PubMed2003

Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy.

PURPOSE: To report the prevalence of vitreous opacities and the outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy (FAP). DESIGN: Observational case series. METHODS: In 37 patients with FAP and the ATTR Val30 Met mutation, vitreous opacities were present in 14 eyes of 9 patients and vitrectomy combined with phacoemulsification and intraocular lens implantation was performed in five eyes of three patients. In six patients with the ATTR Tyr114Cys mutation, vitreous opacities were present in both eyes of all six patients and vitrectomy combined with phacoemulsification and intraocular lens implantation was performed in nine eyes of six patients. The mean follow-up period after vitreous surgery was 20.9 +/- 16.8 months (range, 3 to 52 months). RESULTS: The prevalence of vitreous opacities is much higher in patients with ATTR Tyr114Cys (100%) than in those with ATTR Val30 Met (24%). The mean age at the onset of vitreous opacities was significantly lower in the patients with ATTR Tyr114Cys (37.0 +/- 5.3 years) than in the nine patients with ATTR Val30 Met (52.8 +/- 9.1 years; P <.005). Visual acuity improved in all 14 eyes after vitreous surgery; however, final visual acuity decreased in one eye owing to the occurrence of a central retinal vein occlusion. Vitreous opacities mildly increased in two eyes. CONCLUSIONS: Our data suggest that the ATTR Val30 Met and ATTR Tyr114Cys mutations induce different clinical features of vitreous opacities. Vitreous surgery combined with phacoemulsification and implantation of an intraocular lens is a safe and useful treatment. Careful long-term follow-up should be performed.

Adult↗

PubMed2003

Circulating level of alpha2-macroglobulin-beta2-microglobulin complex in hemodialysis patients.

BACKGROUND: The presence of alpha2-macroglobulin (alpha2M) in amyloid tissue from patients with dialysis-related amyloidosis (DRA) was demonstrated by Argilés et al in 1989. Thereafter, the formation of the complex of beta2-microglobulin (beta2m) with alpha2m was confirmed directly by in vitro study. In Alzheimer's disease, complex formation of amyloid beta-peptide and alpha2M is considered to play an important role in the pathogenesis by modifying the degradation processes of amyloid protein. Thus, we hypothesized that the alpha2M-beta2m complex is an important factor in the pathogenesis of DRA as well. Here, we measured the circulating levels of alpha2M-beta2m complex in the maintenance hemodialysis patients and discussed about its clinical significance in DRA. METHODS: One hundred and thirty-seven hemodialysis patients and 11 prehemodialysis chronic renal failure (CRF) patients were included in this study. The affinity of purified alpha2M for beta2m was confirmed by a highly sensitive 27 MHz quartz crystal microbalance (QCM). The presence of circulating alpha2M-beta2m complex was analyzed by immunoblotting analysis. Furthermore, the serum levels of alpha2M-beta2m complex were measured by sandwich enzyme immunoassay. RESULTS: QCM analysis revealed the high affinity of alpha2M for beta2m. The presence of circulating alpha2M-beta2m complex was detected in two out of a total 11 prehemodialysis CRF patients and in 95 out of the total of 137 hemodialysis patients. None of the healthy subjects, however, were observed to present with any alpha2M-beta2m complex. Serum levels of the alpha2M-beta2m complex were correlated to the duration of hemodialysis (P= 0.043). Serum levels of the alpha2M-beta2m complex were significantly higher in patients with high DRA score than in patients with negative DRA score (P= 0.018). Moreover, serum levels of the alpha2M-beta2m complex showed significantly lower in the hemodiafiltration patients compared to the hemodialysis patients (P= 0.002) and showed a strong correlation with DRA score in hemodialysis patients excluding 11 hemodiafiltration patients (P= 0.0004). CONCLUSION: This study is the first to demonstrate the presence of circulating alpha2M-beta2m complex in hemodialysis patients. Furthermore, we observed the correlation between serum levels of alpha2M-beta2m complex and clinical characteristics of DRA. Thus we concluded that a formation of an alpha2M-beta2m complex may be implicated in DRA.

Amyloidosis↗

PubMed2003

A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo.

We synthesized (trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) and used this compound to detect amyloid fibrils in autopsy and biopsy samples from patients with localized amyloidosis, such as familial prion disease, and systemic amyloidosis, such as familial amyloidotic polyneuropathy, amyloid A (AA) amyloidosis, light chain (AL) amyloidosis, and dialysis-related amyloidosis. BSB showed reactions in all Congo red-positive and immunoreactive regions of the samples examined in the study, and some amyloid fibrils in the tissues could be detected more precisely with BSB than with the other methods. In the mouse model of AA amyloidosis, injected BSB reacted with amyloid in all regions in the serial sections in which Congo red staining was positive. A highly sensitive 27-MHz quartz crystal microbalance analysis revealed that BSB showed a significant affinity for amyloid fibrils purified from familial amyloidotic polyneuropathy and dialysis-related amyloidosis samples and suppressed formation of transthyretin amyloid in vitro. These results suggest that BSB may become a valuable tool for detection of amyloid deposits in amyloidosis and of the mechanism of amyloid formation.

Adult↗

PubMed2003

[A case of corneal lactoferrin amyloidosis secondary to trichiasis].

PURPOSE: A case of corneal lactoferrin amyloidosis secondary to trichiasis is reported. CASE: A 30-year-old male suffered from trichiasis with an elevated gray whitish lesion just under the center of the cornea in his right eye. The lesion had an irregular surface. METHOD: We excised the corneal lesion, and studied the excised corneal lesion morphologically. RESULT: The deposit observed just under the corneal epithelial layer was positive for Congo red staining, and showed dichroism under polarizing microscopy. The deposit also showed a immunoreactivity against anti-human lactoferrin antibody. CONCLUSION: The morphological study proved that the deposits under the corneal lesion were derived from lactoferrin. Long term injury of the corneal surface by trichiasis may lead to the deposition and structural changes of lactoferrin originating from tears.

Adult↗

PubMed2003

[Amyloidosis and oxidative stress].

Recent studies on oxidative stress have revealed that free radical injury appears to be involved in either the amyloid formation process or in post-fibrillar modification in several types of amyloidosis. Here, we report the role of oxidative stress in the pathogenesis of dialysis-related amyloidosis(DRA) and familial amyloidotic polyneuropathy(FAP), and propose radical scavenger treatment for such amyloidosis. For patients under maintenance hemodialysis, EC-SOD Arg213Gly was a risk factor for the progression of DRA, atherosclerosis, and renal failure causing hemodialysis. In FAP patients who had EC-SOD Arg213Gly, massive amyloid deposition which may be related to increased oxidative stress in loco was found especially prominently around blood vessels in the interstitial tissues. Histological and biochemical examinations revealed that oxidative stress is deeply connected with amyloid formation mechanisms in FAP. We started radical scavenger therapy, such as N-acetyl cysteine, vitamin E and vitamin C in 20 Swedish FAP patients for 6 months. Although no improvement was found in the amount of amyloid deposition in biopsy specimens, modified body mass index(mBMI), an index of nutritional status, tended to be increased, suggesting the therapeutic possibility of radical scavenger treatment for amyloidosis.

Amyloidosis↗

PubMed2003

[Analyses of pathogenesis and therapeutic approaches for hereditary amyloidosis].

Amyloidosis is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils, causing structural and functional disruptions. We have recently identified the novel localized amyloidosis accompanied by trichiasis. The precursor protein of amyloid deposits was mutated lactoferrin and all the patients had lactoferrin Glu561Asp. The disease was classified hereditary amyloidosis whose risk factor is trichiasis. We examined the therapeutic possibilities for mutated transthyretin(ATTR) related familial amyloidotic polyneurpathy(FAP), one of the systemic amyloidoses. Cr3+ suppressed amyloid formation by stabilizing ATTR structure in vitro. BSB is a useful new diagnostic tool to detect amyloid deposits both in in vitro and in vivo and may have therapeutic potential for preventing amyloid deposition. Gene therapy using single-stranded oligonuclotides(SSOs) may become a promising tool for therapy instead of liver transplantation. SSOs with athrocollagen effectively replaced the TTR gene both in vitro and in vivo.

Amyloidosis↗

PubMed2003

Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan.

Type I (transthyretin Val30Met) familial amyloid polyneuropathy (FAP ATTR Val30Met) has been reported in relation to two endemic foci in Japan. These cases are characterized by a relatively young age at onset, between the second and third decade, high penetrance rate, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. In contrast to these endemic cases, because of advances in DNA diagnosis, late-onset cases of FAP ATTR Val30Met with symptoms appearing at or over 50 years of age are now recognized to occur widely throughout Japan. These cases have a male preponderance, low penetrance rate, no relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. This type of FAP ATTR Val30Met has been overlooked because its clinical and genetic features differ from those of "typical" early-onset cases. Anticipation of age at onset is known to occur in pedigrees from the two endemic foci in Japan, with age at onset becoming younger in patients of successive generations. On the other hand, age at onset of patients in late-onset families seems to be uniformly late among the patient siblings when family history is present. Pathologic findings of the peripheral nervous system also differ in accordance with differences of clinical features. Loss of dorsal root and sympathetic ganglion neurons was severe in the early-onset cases, whereas it was only mild to moderate in the late-onset cases. Unmyelinated fibers in the biopsied sural nerve specimens of late-onset cases seemed to be relatively well preserved compared to those of previously reported early-onset cases.

Age of Onset↗

PubMed2003

Clinical and pathological findings of non-Val30Met TTR type familial amyloid polyneuropathy in Japan.

Non-Val30Met TTR type FAP is being increasingly recognized; a total of 21 TTR gene mutations related to the development of non-Val30Met type FAP have been identified among Japanese. The clinical phenotypes of these FAP kindreds varied considerably corresponding to the different mutations of TTR gene. In the nervous system, peripheral nerve involvement sometimes started as a carpal tunnel syndrome in addition to peripheral somatic and autonomic neuropathy. Brain and spinal cord dysfunctions due to leptomeningeal amyloidosis infrequently appeared. Severe involvement of the heart was a common finding in the visceral organs, which might causally lead to a poor prognosis for the patients with this form of FAP. Several patients with ATTR non-Val30Met have recently undergone living-related partial liver transplantation, and their postoperative courses have been under careful investigation.

Amyloid Neuropathies, Familial↗

PubMed2003

New therapeutic approaches for familial amyloidotic polyneuropathy (FAP).

Because the use of liver transplantation as therapy for familial amyloidotic polyneuropathy (FAP) has given rise to several problems, an alternative treatment is needed. We have tried several other approaches. To suppress production of variant transthyretin (TTR) in the liver, we injected purified normal human TTR into patients with FAP. Production of variant TTR decreased significantly for 48 h. However, 1 week after the injection, production returned to levels that were almost the same as those before injection. TTR has a rapid turnover, so this method cannot be used to suppress production of the harmful protein for an extended time. Recent studies suggested that certain metal ions affect amyloidogenesis. Among metal ions tested in an in vitro amyloid formation study, Cr3+ increased stability of both normal and mutant TTR tetramers and suppressed TTR amyloidogenesis induced by low pH. Our findings indicate that Cr3+ acts to suppress TTR amyloidogenesis. (Trans, trans)-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), a Congo red derivative that binds to amyloid fibrils in FAP, as well as to those in senile plaques in Alzheimer's disease, effectively suppressed TTR amyloid formation in vitro. BSB may thus be useful for preventing amyloid formation. Free radical scavenger therapy was also tried with FAP patients but yielded no conclusive results. Finally, an RNA/DNA chimera and single-stranded oligonucleotides (SSOs) were tested in vitro and in vivo in an attempt to repair the amyloidogenic TTR gene in the liver and retina. On the basis of results achieved so far, SSOs are a promising tool for gene therapy.

Amyloid Neuropathies, Familial↗

PubMed2002

Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid fibril formation in vivo and in vitro.

The Y114C mutation in human transthyretin (TTR) is associated with a particular form of familial amyloidotic polyneuropathy. We show that vitreous aggregates ex vivo consist of either regular amyloid fibrils or disordered disulfide-linked precipitates that maintain the ability to bind Congo red. Furthermore, we demonstrate in vitro that the ATTR Y114C mutant exists in three forms: one unstable but nativelike tetrameric form, one highly aggregated form in which a network of disulfide bonds is formed, and one fibrillar form. The disulfide-linked aggregates and the fibrillar form of the mutant can be induced by heat induction under nonreduced and reduced conditions, respectively. Both forms are recognized by the amyloid specific antibody MAB(39-44). In a previous study, we have linked exposure of this epitope in TTR to a three-residue shift in beta-strand D. The X-ray crystallographic structure of reduced tetrameric ATTR Y114C shows a structure similar to that of the wild type but with a more buried position of Cys10 and with beta-mercaptoethanol associated with Cys114, verifying the strong tendency for this residue to form disulfide bonds. Combined with the ex vivo data, our in vitro findings suggest that ATTR Y114C can lead to disease either by forming regular unbranched amyloid fibrils or by forming disulfide-linked aggregates that maintain amyloid-like properties but are unable to form regular amyloid fibrils.

Adult↗