Takamasa Kayama

Global prevalence and major risk factors of diabetic retinopathy

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Clinical and Neuroradiological Features of Intracranial Vertebrobasilar Artery Dissection

BACKGROUND AND PURPOSE We sought to determine the clinical and neuroradiological features of intracranial vertebrobasilar artery dissection. METHODS The clinical features and MR findings of 31 patients (20 men and 11 women) with intracranial vertebrobasilar artery dissections confirmed by vertebral angiography were analyzed retrospectively. The vertebral angiography revealed the double lumen sign in 11 patients (13 arteries) and the pearl and string sign in 20 patients (28 arteries). RESULTS The patients ranged in age from 25 to 82 years (mean, 54.8 years). Clinical symptoms due to ischemic cerebellar and/or brain stem lesions were common, but in 3 cases the dissections were discovered incidentally while an unrelated disorder was investigated. Headache, which has been emphasized as the only specific clinical sign of vertebrobasilar artery dissection, was found in 55% of the patients. Intramural hematoma on T1-weighted images has been emphasized as a specific MR finding. The positive rate of intramural hematoma was 32%. Double lumen on 3-dimensional (3-D) spoiled gradient-recalled acquisition (SPGR) images after the injection of contrast medium was identified in 87% of the patients. The 3-D SPGR imaging method is considered useful for the screening of vertebrobasilar artery dissection. CONCLUSIONS Intracranial vertebrobasilar artery dissection is probably much more frequent than previously considered. Such patients may present no or only minor symptoms. Neuroradiological screening for posterior circulation requires MR examinations, including contrast-enhanced 3-D SPGR. Angiography may be necessary for the definite diagnosis of intracranial vertebrobasilar artery dissection because the sensitivity of the finding of intramural hematoma is not satisfactory.

Hsp70 Overexpression Sequesters AIF and Reduces Neonatal Hypoxic/Ischemic Brain Injury:

Apoptosis is implicated in neonatal hypoxic/ischemic (H/I) brain injury among various forms of cell death. Here we investigate whether overexpression of heat shock protein (Hsp) 70, an antiapoptotic protein, protects the neonatal brain from H/I injury and the pathways involved in the protection. Postnatal day 7 (P7) transgenic mice overexpressing rat Hsp70 (Tg) and their wild-type littermates (Wt) underwent unilateral common carotid artery ligation followed by 30 mins exposure to 8% O2. Significant neuroprotection was observed in Tg versus Wt mice on both P12 and P21, correlating with a high level of constitutive but not inducible Hsp70 in the Tg. More prominent injury was observed in Wt and Tg mice on P21, suggesting its continuous evolution after P12. Western blot analysis showed that translocation of cytochrome c, but not the second mitochondria-derived activator of caspase (Smac)/DIABLO and apoptosis-inducing factor (AIF), from mitochondria into cytosol was significantly reduced in Tg 24 h after H/I compared with Wt mice. Coimmunoprecipitation detected more Hsp70 bound to AIF in Tg than Wt mice 24 h after H/I, inversely correlating with the amount of nuclear, but not cytosolic, AIF translocation. Our results suggest that interaction between Hsp70 and AIF might have reduced downstream events leading to cell death, including the reduction of nuclear AIF translocation in the neonatal brains of Hsp70 Tg mice after H/I.

Prevalence and Risk Factors for Age-Related Macular Degeneration in an Adult Japanese Population : The Funagata Study

OBJECTIVE To describe the prevalence and risk factors for age-related macular degeneration (AMD) in a Japanese population and to compare these with data from a white population. DESIGN Population-based cross-sectional epidemiologic study. PARTICIPANTS A population-based sample of Japanese persons 35 years or older from Funagata, Japan. METHODS The Funagata study is a population-based study of 1758 (43% of eligible) Japanese persons 35 years or older from Funagata, Japan. In 2000 to 2002, 1625 (92.4%) participants had a nonmydriatic fundus photograph of one eye with sufficient quality for grading of AMD lesions, using the Wisconsin protocol. Age-standardized prevalence rates compared with the Blue Mountains Eye Study (BMES) population, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Risk factors were assessed by logistic regression. MAIN OUTCOME MEASURES Early and late AMD. RESULTS Of 1625 participants, early AMD and late AMD were present in 3.5% and 0.5%, respectively. Age-standardized early AMD prevalence in right eyes was 4.1%, similar to the corresponding prevalence of 4.4% in the BMES. For men, age-standardized prevalences of late AMD in right eyes were 1.1% and 1.2% in the BMES; for women, the corresponding prevalences were 0.3% and 2.1%, respectively. Increasing age (per 10 years; gender-adjusted OR, 2.27; 95% CI, 1.10-4.67) and current cigarette smoking (age- and gender-adjusted OR, 5.03; 95% CI, 1.00-25.47) were associated with late AMD. CONCLUSIONS In this Japanese population, prevalence of early AMD was similar to that for whites in the BMES. Although the late AMD prevalence was lower in Japanese women, in Japanese men it was similar to that in whites. This could have resulted from the substantially high proportion of Japanese men who are smokers. Cigarette smoking and increasing age were the 2 principal factors found associated with late AMD.

The Role of G-Protein-Coupled Receptor Kinase 5 in Pathogenesis of Sporadic Parkinson's Disease

Sporadic Parkinsons disease (sPD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the pathogenesis of the disease remains undetermined, phosphorylation of α-synuclein and its oligomer formation seem to play a key role. However, the protein kinase(s) involved in the phosphorylation in the pathogenesis of sPD has not been identified. Here, we found that G-protein-coupled receptor kinase 5 (GRK5) accumulated in Lewy bodies and colocalized with α-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of α-synuclein at the plasma membrane and induced translocation of phosphorylated α-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of α-synuclein. Genetic association study revealed haplotypic association of the GRK5 gene with susceptibility to sPD. The haplotype contained two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bound to YY1 (Yin Yang-1) and CREB-1 (cAMP response element-binding protein 1), respectively, and increased transcriptional activity of the reporter gene. The results suggest that phosphorylation of α-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.

Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome c release and subsequent DNA fragmentation after permanent focal ischemia

Although protective effects of heat shock protein 70 (HSP70) overproduction after ischemic injury have been shown both in vitro and in vivo in neurons, the mechanisms are not fully understood. The hypothesis of this study is that transgenic mice overexpressing HSP70 (HSP70 Tg) show reduced mitochondrial cytochrome c release into cytosol and diminished apoptotic cell death after permanent focal ischemia in comparison to wild-type (Wt) mice. Permanent middle cerebral artery occlusion (pMCAO) was produced by intraluminal suture cannulation in HSP70 Tg and Wt mice. DNA fragmentation was evaluated with DNA gel electrophoresis and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) 24 h after pMCAO. Mitochondrial cytochrome c release into cytosol was assessed with Western blotting and immunohistochemistry 4 h after pMCAO. Cytochrome c levels in the cytosolic fraction were significantly reduced and immunoreactivity of cytochrome c in both cortex and striatum was significantly less in HSP70 Tg mice compared with Wt mice after 4-h pMCAO. DNA laddering, which was clearly observed in Wt mice, was markedly attenuated in HSP70 Tg mice 24 h after pMCAO. The number of TUNEL-positive cells was significantly reduced in HSP70 Tg mice compared with Wt mice. Results are consistent with an association between overexpression of HSP70 and reduction of cytochrome c release with subsequent DNA fragmentation. This may contribute to the HSP70-mediated neuroprotective effect observed after cerebral ischemia.

Chemiluminescence in hypoxic brain--the second report: cerebral protective effect of mannitol, vitamin E and glucocorticoid.

The effect of vitamin E, betamethasone and mannitol upon a series of pathological free radical reactions within hypoxic brain tissue was evaluated by the chemiluminescence method. Hypoxia was induced by arterial hypoxemia (PaO2 17-22 mmHg) with normocapnia (PaCO2 28-38 mmHg) and normotension (MABP 100-140 mmHg). 4% O2-96% N2 mixed gas was used to obtain the lowered PaO2. In the untreated group, increased chemiluminescence was measured in the hypoxic state and the early stage of the initial post-hypoxic state. In the groups administered vitamin E, betamethasone, mannitol and a combination of them reduced chemiluminescence was detected. To explore the reaction stage at which the drugs act in lipid peroxidation, chemiluminescence spectra was analyzed using the brain homogenate with the drugs added. Intensity peaks of the spectra were around at 480, 520-530, 570, 620-640, 680-700 nm before addition of the drugs. All the intensity peaks diminished after addition of vitamin E and betamethasone, but very little decrease occurred after mannitol. The lowered chemiluminescence value may indicate the free radical scavenging action of vitamin E, betamethasone and mannitol in vivo. Chemiluminescence spectrum analysis shows that vitamin E and betamethasone act on the late chain reaction following hydroperoxide and mannitol acts on the early reaction--generation of active oxygens.

Lateral and Medial Medullary Infarction A Comparative Analysis of 214 Patients

Background and Purpose— No large-scale study has ever compared the clinical and radiological features of lateral medullary infarction (LMI) and medial medullary infarction (MMI). The aim of this study was to investigate them through the use of cooperatively collected cases. Methods— Medical information on all patients from 1996 to 2000 with medullary infarction (MI) proven by brain MR images at 35 stroke centers in the Tohoku district, Japan, was collected, and their clinical and radiological features were analyzed. Results— A total of 214 cases of MI were registered. They included 167 cases (78%) of LMI, 41 (19%) of MMI, and 6 (3%) of LMI plus MMI. The mean age of onset and the male-to-female ratio were 60.7 years and 2.7:1 in LMI and 65.0 years and 3.6:1 in MMI, respectively. The middle medulla was most frequently affected in LMI, and the upper medulla was most frequently affected in MMI. Dissection of the vertebral artery was observed in 29% of LMI and 21% of MMI. Prognosis, assessed by the Barthel Index, was favorable in both LMI and MMI. Diabetes mellitus was more frequently associated with MMI than with LMI. Conclusions— The present study surveyed a large number of MI cases and revealed that (1) the mean age of onset of MMI is higher than that of LMI, (2) the dissection of the vertebral artery is an important cause not only of LMI but also of MMI, and (3) diabetes mellitus is frequently associated with MMI.

Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK

Control of the cancer stem/initiating cell population is considered key to realizing the long‐term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to induce differentiation of glioma‐initiating cells having stem‐like properties and inhibit their tumor‐initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem‐like glioma‐initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP‐activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self‐renewing and tumor‐initiating cell population within established tumors, inhibited tumor formation by stem‐like glioma‐initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma‐initiating cells via the AMPK‐FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma‐initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells.

Subarachnoid Hemorrhage of Unknown Cause

After the institution of computed tomography (CT), 814 cases of spontaneous subarachnoid hemorrhage (SAH) were treated during a period of 6 years and 9 months (April 1978 through December 1984). In 9 (22.0%) of 41 patients whose cause of SAH was not determined by the first four-vessel study (cerebral panangiography), ruptured aneurysms were found by repeated four-vessel study. Thus, of 814 cases, only 32 (3.9%) were diagnosed as cases of unknown etiology at discharge. The 32 cases were monitored by follow-up examination for 5 to 67 months (median, 27.1 months) after onset. No recurrence of SAH was reported, and all patients were rehabilitated except 2 who suffered terminal carcinoma. A third follow-up four-vessel study was performed 8 to 44 months (median, 22.0 months) after the second study in 14 of the 16 patients with SAH initially demonstrated by CT. In 1 of these cases, an aneurysm found 9 months after the initial SAH was treated surgically. Ultimately, 31 cases (3.8%) were diagnosed as cases of SAH of unknown cause. This incidence is low when compared with those in previous reports. Because of the strict examination schedule including repeated angiography, the incidence is lower and the prognosis is relatively favorable.