Incidence, prevalence, and treatment of Moyamoya disease in Japan: A population-based descriptive study.

BACKGROUND: Moyamoya disease (MMD) is characterized by progressive stenosis or occlusion of the terminal portions of the bilateral internal carotid arteries. A Japanese survey in 2003 reported an incidence and prevalence of MMD of 0.54 and 6.03 per 100,000 people, respectively, showing an upward trend over previous surveys. An update to these estimates is therefore warranted. Additionally, evidence is lacking on trends in revascularization and antiplatelet therapy in MMD patients. METHODS: We conducted a population-based descriptive study using a Japanese claims database. From fiscal year (FY) 2015 to 2019, we standardized the incidence and prevalence estimates of MMD to the 2015 Japanese census population by age and sex. We also estimated the 1-year cumulative incidence of revascularization among incident MMD patients and the proportion of prevalent MMD patients receiving antiplatelet therapy in each FY. RESULTS: The age-standardized male-to-female ratio of both incident and prevalent MMD patients was approximately 1:2. Standardized incidence and prevalence of MMD per 100,000 population increased slightly from 1.8 to 2.4 and 14.7 to 17.6, respectively. The 1-year cumulative incidence of revascularization among incident MMD patients varied between 21.9 % and 28.9 %. Among prevalent MMD patients, 36.6 % to 39.0 % received antiplatelet therapy. CONCLUSIONS: The incidence and prevalence of MMD in Japan from FY 2015 to 2019 were higher than those estimated in 2003. The trends in revascularization and antiplatelet therapy identified in this study will be useful in further improving the quality of MMD clinical practice.

Therapeutic Potential of Polyamidoamine Dendrimer for Amyloidogenic Transthyretin Amyloidosis.

Amyloidogenic transthyretin (ATTR) amyloidosis is caused by a formation of ATTR amyloid fibrils. Because ATTR misfolding triggers the formation of aggregates and amyloid fibrils, which are considered to deposit on the tissues, novel clinically effective therapeutic strategies targeted to those processes are urgently needed. In this study, to discover a new drug candidate for ATTR amyloidosis therapy, we focused on polyamidoamine dendrimer (dendrimer), a 3D-structural nanomaterial, which has a branched cationic polymer repeating polyamidoamine units. Dendrimer (G2) not only inhibited ATTR V30M amyloid fibril formation, but also reduced already formed ATTR V30M amyloid fibrils by reducing ß-sheet structure of ATTR V30M protein. Moreover, intravenous administration of dendrimer (G2) reduced TTR deposition in human ATTR V30M transgenic rats. These results indicate that dendrimer (G2) may possess both inhibitory and breaking effects on ATTR V30M amyloid, suggesting that dendrimer has the potential as a dual effective agents against TTR amyloidosis.

Posterior Reversible Encephalopathy Syndrome and Guillain-Barré Syndrome after Head Injury: Case Report.

We report a case of head injury with posterior reversible encephalopathy syndrome (PRES), followed by Guillain-Barré syndrome (GBS). A 74-year-old man was brought to our hospital after a fall. Computed tomography revealed intracranial hemorrhage. Magnetic resonance imaging showed bilateral reversible intensities with features of vasogenic edema in parietooccipital areas, suggesting PRES. After admission, weakness and areflexia of extremities and respiratory muscles developed gradually, which favored a diagnosis of GBS. Common etiologies of PRES were absent. Concurrent occurrence of PRES and GBS is rare. Given that PRES can be an initial manifestation of GBS, GBS must be considered in head trauma patients with PRES.

[Unruptured Arteriosclerotic Aneurysm in the Distal Middle Cerebral Artery:A Case Report].

We report a rare case of an unruptured cerebral aneurysm in the left distal middle cerebral artery(MCA). A 76-year-old woman was referred to our department for unruptured cerebral aneurysms detected incidentally by magnetic resonance angiography. A left carotid angiogram revealed a saccular aneurysm arising in an arterial trunk unrelated to the branching zone of the distal MCA. The patient underwent an operation for trapping and excision of the saccular aneurysm in the distal MCA followed by end-to-end anastomosis. Histological analysis revealed an aneurysmally-dilated artery exhibiting thickened fibrous intima with foci of calcification and fragmented internal elastic lamina. Neither dissection nor infection were observed. The histological findings suggested that the aneurysm in this case was associated with arteriosclerotic change. Considering the medical history of the patient, we conclude that aging and hypertension are factors of the development of the cerebral aneurysm in our case, although the aneurysm is located in the distal MCA in which it is considered to low hemodynamic stress. We report this extremely rare case with a literature review.

Infected subdural hematoma caused by Edwardsiella tarda.

Objective: Both infected subdural hematoma (ISH) and Edwardsiella tarda infections are rare in humans. E. tarda is a motile, facultative anaerobic, gram-negative rod bacterium, which is isolated from fresh or brackish water, but not usually from humans. Extra-intestinal E. tarda infections are rare and might cause severe clinical symptoms. However, ISH caused by E. tarda has not been reported previously. We report the first case of ISH due to E. tarda. Patient: A 76-year-old man was admitted to our hospital with a headache, loss of appetite, and nausea. Computed tomography revealed bilateral subdural hematoma. Results: We performed burr hole drainage. A hematoma with pus was found on the left side and chronic hematoma was found on the right side. Consequently, we diagnosed him with ISH on the left side and chronic subdural hematoma on the right side. E. tarda was detected in a culture from the hematoma with pus on the left side. As postoperative antibiotic therapy, we administered ceftriaxone and metronidazole for 47 days. The patient was discharged with no residual neurological deficit. Conclusion: Our case implied that favorable outcomes can be obtained by drainage and appropriate antibiotic therapy for ISH caused by E. tarda.

[Shunt passer clamp: a new device to prevent rotation of CSF-shunt passer].

Cerebrospinal fluid shunting is a surgical treatment alternative for hydrocephalus. In general, ventriculoperitoneal (VP) and lumboperitoneal (LP) shunts have been widely practiced as standard procedures. However, these procedures are difficult because the shunt passer often rotates unintentionally. Therefore, we developed a simple device that prevents shunt passer rotation and termed it a "shunt passer-clamp"(SP-C). This device consists of two parts: the first part is the body with a hole through which the passer goes and a "female" screw perpendicular to the hole. The second part is a "male" screw set to the body. The surgeon can attach the SP-C to the shunt passer without the requirement for remodeling. We employed a SP-C for 14 consecutive shunt surgeries and received favorable feedback from the surgeons. Handling was considered "easy" in all cases. The surgical duration was significantly shorter than that if the SP-C was not employed. We conclude that our specially designed SP-C is relatively effective.

Potential use of glucuronylglucosyl-ß-cyclodextrin/dendrimer conjugate (G2) as a siRNA carrier for the treatment of familial amyloidotic polyneuropathy.

We previously reported that 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-ß-cyclodextrin (GUG-ß-CyD) conjugate with polyamidoamine dendrimer (dendrimer, generation 2; G2) (GUG-ß-CDE (G2)) is useful as a gene transfer carrier. In the present study, to investigate the potentials of GUG-ß-CDE (G2) as a siRNA carrier, we evaluated the RNAi effect of its complex with siRNA against transthyretin (TTR) mRNA (siTTR) for the treatment of familial amyloidotic polyneuropathy (FAP). Among the various GUG-ß-CDEs (G2) having the different degrees of substitution of GUG-ß-CyD (degree of substation (DS) 1.8, 2.5, 3.0 and 5.0), GUG-ß-CDE (G2, DS 1.8) showed the highest siTTR transfer activity. GUG-ß-CDE (G2, DS 1.8)/siTTR complex showed no cytotoxicity in HepG2 cells. After intravenous administration of GUG-ß-CDE (G2, DS 1.8)/siTTR complex to BALB/c mice, TTR mRNA expression was tended to reduce with negligible change of blood chemistry data. Particle size, ζ-potential and cellular association of the GUG-ß-CDE (G2, DS 1.8) complex were almost the same as those of the other CDEs complexes. Meanwhile, GUG-ß-CDE (G2, DS 1.8)/siTTR complex showed high endosomal escaping ability of siTTR in cytoplasm. These findings suggest the potential of GUG-ß-CDE (G2, DS 1.8) as a siRNA carrier for the FAP treatment.

Potential use of glucuronylglucosyl-ß-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy.

Transthyretin (TTR)-related familial amyloidotic polyneuropathy, which is induced by amyloidogenic transthyretin (ATTR), is characterized by systemic accumulation of amyloid fibrils. Although it is believed that protein misfolding of monomeric form of TTR is a rate-limiting step for TTR amyloid formation, no effective therapy targeting this misfolding step is available. Our recent studies revealed that cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, might interact with TTR and prevent the protein misfolding. In this study, we focused on and elucidated the inhibitory effect of 6-O-α-(4-O-α-D-Glucuronyl)-D-glucosyl-ß-CyD (GUG-ß-CyD) on TTR amyloid formation. Tryptophan (Trp) fluorescence and (1)H-NMR spectroscopy analyses indicated that GUG-ß-CyD stabilized TTR conformation via interaction with the hydrophobic amino acids of TTR. Moreover, GUG-ß-CyD suppressed TTR deposition in transgenic rats possessing a human ATTR V30M gene in vivo. Collectively, these data indicate that GUG-ß-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.

Possible enhancing mechanisms for gene transfer activity of glucuronylglucosyl-ß-cyclodextrin/dendrimer conjugate.

We previously reported that glucuronylglucosyl-ß-cyclodextrin (GUG-ß-CyD) conjugate with polyamidoamine starburst dendrimer (GUG-ß-CDE conjugate) with the average degree of substitution (DS) of cyclodextrin (CyD) of 1.8 (GUG-ß-CDE conjugate (DS 1.8)), showed remarkably higher gene transfer activity than α-CyD/dendrimer conjugate (α-CDE conjugate (DS 1.2)) and ß-CyD/dendrimer conjugate (ß-CDE conjugate (DS 1.3)) in vitro and in vivo. In this study, to clarify the enhancing mechanism for high gene transfer activity of GUG-ß-CDE conjugate (DS 1.8), we investigated the physicochemical properties, cellular uptake, endosomal escape and nuclear translocation of the plasmid DNA (pDNA) complexes as well as pDNA release from the complexes. The particle size, ζ-potential and cellular uptake of GUG-ß-CDE conjugate (DS 1.8)/pDNA complex were mostly comparable to those of α-CDE conjugate (DS 1.2) and ß-CDE conjugate (DS 1.3). Meanwhile, GUG-ß-CDE conjugate (DS 1.8)/pDNA complex was likely to have high endosomal escaping ability and nuclear localization ability in A549 and RAW264.7 cells. In addition, the pDNA condensation and decondensation abilities of GUG-ß-CDE conjugate (DS 1.8) were lower and higher than that of α-CDE conjugate (DS 1.2) or ß-CDE conjugate (DS 1.3), respectively. These results suggest that high gene transfer activity of GUG-ß-CDE conjugate (DS 1.8) could be, at least in part, attributed to high endosomal escaping ability, nuclear localization ability and suitable pDNA release from its complex.

Peak-less hypoglycemic effect of insulin glargine by complexation with maltosyl-ß-cyclodextrin.

Long-acting insulin products are desired that provide sustained blood glucose lowering without blood glucose level peaks. In the present study, to obtain the more desirable blood glucose lowering effect of long-acting insulin products, we investigated the effect of maltosyl-ß-cyclodextrin (G(2)-ß-CyD) on physicochemical properties and pharmacokinetics/pharmacodynamics of insulin glargine, which is the one of the most widely used insulin analog. G(2)-ß-CyD increased the solubility and suppressed the aggregation of insulin glargine in phosphate buffer at 9.5, probably due to the interaction of G(2)-ß-CyD with aromatic residues of the insulin glargine such as tyrosine. In addition, the dissolution rates of insulin glargine from its precipitates were increased by a complexation with G(2)-ß-CyD. Subcutaneous administration of an insulin glargine solution with G(2)-ß-CyD to rats gradually decreased blood glucose levels and provided a sustained blood glucose lowering effect without showing the glucose level peaks. These results suggest that G(2)-ß-CyD can be a useful excipient for sustained release and a truly peak-less formulation of insulin glargine.

Potential use of glucuronylglucosyl-ß-cyclodextrin/dendrimer conjugate (G2) as a DNA carrier in vitro and in vivo.

In this study, we evaluated the polyamidoamine starburst dendrimer (dendrimer, generation 2: G2) conjugate with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-ß-cyclodextrin (GUG-ß-CDE (G2)) as a gene transfer carrier. The in vitro gene transfer activity of GUG-ß-CDE (G2, degree of substitution (DS) of cyclodextrin (CyD) 1.8) was remarkably higher than that of dendrimer (G2) conjugate with α-CyD (α-CDE (G2, DS 1.2)) and that with ß-CyD(ß-CDE (G2, DS 1.3)) in A549 and RAW264.7 cells. The particle size, ζ-potential, DNase I-catalyzed degradation, and cellular association of plasmid DNA (pDNA) complex with GUG-ß-CDE (G2, DS 1.8) were almost the same as those of the other CDEs. Fluorescent-labeled GUG-ß-CDE (G2, DS 1.8) localized in the nucleus 6 h after transfection of its pDNA complex in A549 cells, suggesting that nuclear localization of pDNA complex with GUG-ß-CDE (G2, DS 1.8), at least in part, contributes to its high gene transfer activity. GUG-ß-CDE (G2, DS 1.8) provided higher gene transfer activity than α-CDE (G2, DS 1.2) and ß-CDE (G2, DS 1.3) in kidney with negligible changes in blood chemistry values 12 h after intravenous injection of pDNA complexes with GUG-ß-CDE (G2, DS 1.8) in mice. In conclusion, the present findings suggest that GUG-ß-CDE (G2, DS 1.8) has the potential for a novel polymeric pDNA carrier in vitro and in vivo.

Effects of Selected Anionic ß-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats.

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of ß-cyclodextrin sulfate (Sul-ß-CyD) and sulfobutylether ß-cyclodextrin (SBE7-ß-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-ß-CyD and SBE7-ß-CyD increased solubility of insulin glargine. SBE7-ß-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-ß-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-ß-CyD, but not Sul-ß-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-ß-CyD could be a useful excipient for sustained release of insulin glargine.

[Relationship between living arrangements and stroke in Sano-Kosei General Hospital].

We retrospectively reviewed the relationship between living arrangements and stroke in Sano-Kosei General Hospital, for the 3-year period from December, 2007 to November, 2010. The proportion of live-alone among stroke patients was 14.9% (131/877). The indirect standardized live-alone ratio (95% confidence interval), compared with Sano city's live-alone ratio as a standard group, was 1.34 (1.13-1.60). Among live-alone patients with stroke, sex ratio showed no significant difference (p=0.46). Comparing live-alones with non-live-alones in stroke patients, the mean age of live-alones was younger for men, but older for women (p<0.001). There was no significant difference between living arrangements and diseases risk factors. However, on the point of the mean number of risk factors, live-alones tended to have more risk factors than non-live-alones (p=0.032). Therefore, living arrangements are considered as an important factor for prevention of stroke.

Effect of sulfobutyl ether-ß-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-ß-cyclodextrin (SBE4-ß-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-ß-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-ß-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-ß-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-ß-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-ß-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-ß-CyD can be a useful excipient for sustained release of insulin glargine.

Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis.

TTR (transthyretin), a ß-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various branched ß-CyDs, GUG-ß-CyD [6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-ß-CyD] showed potent inhibition of TTR amyloid formation. Far-UV CD spectra analysis showed that GUG-ß-CyD reduced the conformational change of TTR in the process of amyloid formation. In addition, tryptophan fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-ß-CyD stabilized the TTR conformation via interaction with the hydrophobic amino acids of TTR, especially tryptophan. Moreover, GUG-ß-CyD exerted its inhibitory effect by reducing TTR deposition in transgenic rats possessing a human variant TTR gene in vivo. Collectively, these results indicate that GUG-ß-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.

Potential use of gamma-cyclodextrin polypseudorotaxane hydrogels as an injectable sustained release system for insulin.

The development of injectable hydrogels for protein delivery is a major challenge. In this study, insulin/alpha-cyclodextrin (alpha-CyD) and gamma-CyD polypseudorotaxane (PPRX) hydrogels were prepared through inclusion complexation between high molecular weight poly(ethylene glycol) (PEG) and CyDs. The alpha-CyD and gamma-CyD PPRX hydrogels were formed by inserting one PEG chain in the alpha-CyD cavity and two PEG chains in the gamma-CyD cavity. Insulin/CyD PPRX hydrogel formation was based on physical crosslinking induced by self-assembling without chemical crosslinking reagent. The supramolecular structures of insulin/CyD PPRX hydrogels were confirmed with (1)H nuclear magnetic resonance ((1)H NMR), X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release study showed that the release rate of insulin from the CyDs PPRX hydrogels decreased in the order of gamma-CyD PPRX hydrogel>alpha-CyD PPRX hydrogel. This decrease was controlled by the addition of CyDs to the medium. The serum insulin level after subcutaneous administration of gamma-CyD PPRX hydrogel to rats was significantly prolonged, accompanying with an increase in the area under serum concentration-time curve, which was clearly reflected in the prolonged hypoglycemic effect. In conclusion, these results suggest the potential use of gamma-CyD PPRX hydrogel as an injectable sustained release system for insulin.