Adhesion molecules, such as platelet-endothelial adhesion molecule-1 (PECAM-1), platelet selectin (P-selectin), endothelial selectin (E-selectin), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), are localized on the membranes of activated platelets and leukocytes and on the vascular endothelium. Recently, we measured serum levels of soluble (s) forms of adhesion molecules in adults,18 to 26 years old, with autism spectrum disorder (ASD) and observed low levels of sPECAM-1 and sP-selectin. A subsequent study showed a similar result in children two to four years old with ASD. However, information about school age (five to seventeen years old) ASD subjects is required to determine whether adhesion molecules are also reduced in individuals with ASD in this age range.
Twenty-two subjects with high-functioning ASD and 29 healthy age-matched controls were recruited. ELISA was used for sPECAM-1, and a suspension array system was used for sP-selectin, sE-selectin, sICAM-1 and sVCAM-1 measurements. We found that serum levels of sPECAM-1 (U = 91.0, P<0.0001 by Mann–Whitney U test) and sVCAM-1 (U = 168.0, P = 0.0042) were significantly lower in ASD subjects than in controls. Subsequently, we examined the correlations between serum levels of either sPECAM-1 or sVCAM-1 and clinical variables including Autism Diagnostic Interview - Revised subscores and our previous cytokine profile data from the same ASD subjects. However, we did not find any significant correlations between them.
The present results, taken together with previous results, suggest that sPECAM-1 may play a role in the generation and development of ASD, beginning in childhood and lasting until adulthood.
Autism; Human serum; Adhesion molecules; Platelet-endothelial adhesion molecule-1; Platelet selectin; Endothelial selectin; Intracellular adhesion molecule-1; Vascular cell adhesion molecule-1
Accumulating evidence suggests that dysfunction in the glutamatergic system may underlie the pathophysiology of autism. The anterior cingulate cortex (ACC) has been implicated in autism as well as in glutamatergic neurotransmission. We hypothesized that alterations in the glutamate-glutamine cycle in the ACC might play a role in the pathophysiology of autism.
We performed Western blot analyses for the protein expression levels of enzymes in the glutamate-glutamine cycle, including glutamine synthetase, kidney-type glutaminase, liver-type glutaminase, and glutamate dehydrogenases 1 and 2, in the ACC of postmortem brain of individuals with autism (n = 7) and control subjects (n = 13).
We found that the protein levels of kidney-type glutaminase, but not those of the other enzymes measured, in the ACC were significantly lower in subjects with autism than in controls.
The results suggest that reduced expression of kidney-type glutaminase may account for putative alterations in glutamatergic neurotransmission in the ACC in autism.
Autism; Glutamate; Glutaminase; Glutamate-glutamine cycle; Anterior cingulate cortex
Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.
We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.
Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.
Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities.
Hyperactivity; Neurodevelopmental disorder; Psychiatric disorder; Reelin; Transgenic rat; Vldlr
The neurobiological basis of autism remains poorly understood. The diagnosis of autism is based solely on behavioural characteristics because there are currently no reliable biological markers. To test whether the anterior pituitary hormones and cortisol could be useful as biological markers for autism, we assessed the basal serum levels of these hormones in subjects with autism and normal controls.
Using a suspension array system, we determined the serum levels of six anterior pituitary hormones, including adrenocorticotropic hormone and growth hormone, in 32 drug-naive subjects (aged 6 to 18 years, all boys) with autism, and 34 healthy controls matched for age and gender. We also determined cortisol levels in these subjects by enzyme-linked immunosorbent assay. Serum levels of adrenocorticotropic hormone, growth hormone and cortisol were significantly higher in subjects with autism than in controls. In addition, there was a significantly positive correlation between cortisol and adrenocorticotropic hormone levels in autism.
Our results suggest that increased basal serum levels of adrenocorticotropic hormone accompanied by increased cortisol and growth hormone may be useful biological markers for autism.
Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.
Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the expression of axon-guidance proteins.
The mRNA and protein expression of axon-guidance proteins, including ephrin (EFN)A4, eEFNB3, plexin (PLXN)A4, roundabout 2 (ROBO)2 and ROBO3, were examined in the anterior cingulate cortex and primary motor cortex of autistic brains (n = 8 and n = 7, respectively) and control brains (n = 13 and n = 8, respectively) using real-time reverse-transcriptase PCR (RT-PCR) and western blotting. Real-time RT-PCR revealed that the relative expression levels of EFNB3, PLXNA4A and ROBO2 were significantly lower in the autistic group than in the control group. The protein levels of these three genes were further analyzed by western blotting, which showed that the immunoreactive values for PLXNA4 and ROBO2, but not for EFNB3, were significantly reduced in the ACC of the autistic brains compared with control brains.
In this study, we found decreased expression of axon-guidance proteins such as PLXNA4 and ROBO2 in the brains of people with autism, and suggest that dysfunctional axon-guidance protein expression may play an important role in the pathophysiology of autism.
Accumulating evidence suggests that dysregulation of the immune system is
involved in the pathophysiology of autism spectrum disorders (ASD). The aim
of the study was to explore immunological markers in peripheral plasma
samples from non-medicated subjects with high-functioning ASD.
A multiplex assay for cytokines and chemokines was applied to plasma samples
from male subjects with high-functioning ASD (n = 28)
and matched controls (n = 28). Among a total of 48
analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5,
IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in
subjects with ASD compared with the corresponding values of matched controls
after correction for multiple comparisons.
The results suggest that abnormal immune responses as assessed by multiplex
analysis of cytokines may serve as one of the biological
trait markers for ASD.
Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.
A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.
The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.
Vacuolar-type ATPases (V-ATPases) exist in various cellular membranes of many organisms to regulate physiological processes by controlling the acidic environment. Here, we have determined the crystal structure of the A3B3 subcomplex of V-ATPase at 2.8 Å resolution. The overall construction of the A3B3 subcomplex is significantly different from that of the α3β3 sub-domain in FoF1-ATP synthase, because of the presence of a protruding ‘bulge' domain feature in the catalytic A subunits. The A3B3 subcomplex structure provides the first molecular insight at the catalytic and non-catalytic interfaces, which was not possible in the structures of the separate subunits alone. Specifically, in the non-catalytic interface, the B subunit seems to be incapable of binding ATP, which is a marked difference from the situation indicated by the structure of the FoF1-ATP synthase. In the catalytic interface, our mutational analysis, on the basis of the A3B3 structure, has highlighted the presence of a cluster composed of key hydrophobic residues, which are essential for ATP hydrolysis by V-ATPases.
crystal structure; FoF1; proton pump; rotary motor; V-ATPase
Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications.
We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus.
These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.
We previously interrogated the transcriptome in heart tissue from LmnaH222P/H222P mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38α signaling. Biochemical analysis of hearts from LmnaH222P/H222P mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of LmnaH222P/H222P mice with the p38α inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38α may be useful in the treatment of this disease.
Intraductal carcinoma of the prostate is a marker of aggressive disease. However, intraductal carcinoma exists on a morphologic continuum with high grade prostatic intraepithelial carcinoma (PIN) and distinguishing intraductal carcinoma from PIN is a common diagnostic dilemma with significant clinical implications. We evaluated whether immunostains for PTEN and ERG can sensitively identify intraductal carcinoma and accurately distinguish it from high grade PIN. A combined immunostain for PTEN, ERG, p63 and CK903 was developed and validated. Radical prostatectomy specimens with lesions meeting criteria for intraductal carcinoma (n=45), intraductal cribriform proliferations falling short of intraductal carcinoma (n=15), and PIN lesions (n=39) were retrospectively identified and assessed for PTEN and ERG. Cytoplasmic PTEN loss was identified in 84% (38/45) of the intraductal carcinoma and 100% (15/15) of intraductal cribriform proliferation cases. In contrast, cytoplasmic PTEN loss was never observed in PIN (0/39) (p<0.0001). Of the 53 cases of intraductal carcinoma or intraductal cribriform proliferation with cytoplasmic PTEN loss, it was homogeneously lost in 42 cases (79%). Weak, focal nuclear positivity for PTEN was retained in 31 of these 42 cases (74%). ERG expression was identified in 58% (26/45) of intraductal carcinoma and 67% (10/15) of intraductal cribriform proliferations compared to 13% (5/39) of PIN. Concordance between the PTEN/ERG status of the intraductal carcinoma lesions and the concurrent invasive carcinoma was high (>95% and p<0.0001 for each), and substantially less for PIN and the concurrent invasive tumor (83% for PTEN and 67% for ERG; p=NS for each). Cytoplasmic PTEN loss occurs in the majority of intraductal carcinoma and intraductal cribriform proliferation cases. Cytoplasmic PTEN loss was never observed in PIN (100% specificity). Our study identifies PTEN loss as a potentially useful marker to distinguish intraductal carcinoma from PIN and provides a plausible molecular explanation for why intraductal carcinoma is associated with poor prognosis.
Prostatic adenocarcinoma; intraductal carcinoma; PTEN; ERG; immunohistochemistry
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population.
We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2−R3HDML−HNF4A, rs6467136 near GCCI−PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis.
With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10-4, OR = 1.05, 95% confidence interval: 1.02–1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits.
These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.
Nonsyndromic orofacial clefts are common birth defects whose etiology is influenced by complex genetic and environmental factors and gene–environment interactions. Although these risk factors are not yet fully elucidated, it is known that alterations in transforming growth factor-beta (TGFβ) signaling can cause craniofacial abnormalities, including cleft palate, in mammals. To elucidate the downstream targets of TGFβ signaling in palatogenesis, we analyzed the gene expression profiles of Tgfbr2fl/fl;Wnt1-Cre mouse embryos with cleft palate and other craniofacial deformities resulting from the targeted inactivation of the Tgfbr2 gene in their cranial neural crest (CNC) cells. Relative to controls, palatal tissues obtained from Tgfbr2fl/fl;Wnt1-Cre mouse embryos at embryonic day 14.5 (E14.5) of gestation have a robust gene expression signature reflective of known defects in CNC-derived mesenchymal cell proliferation. Groups of differentially expressed genes (DEGs) were involved in diverse cellular processes and components associated with orofacial clefting, including the extracellular matrix, cholesterol metabolism, ciliogenesis, and multiple signaling pathways. A subset of the DEGs are known or suspected to be associated with an increased risk of orofacial clefting in humans and/or genetically engineered mice. Based on bioinformatics analyses, we highlight the functional relationships among differentially expressed transcriptional regulators of palatogenesis as well as transcriptional factors not previously associated with this process. We suggest that gene expression profiling studies of mice with TGFβ signaling defects provide a valuable approach for identifying candidate mechanisms by which this pathway controls cell fate during palatogenesis and its role in the etiology of human craniofacial abnormalities.
TGFβ SIGNALING; CLEFT PALATE; MICROARRAY; GENE EXPRESSION PROFILING
Vacuolar ATPases (V-ATPases) function as proton pumps in various cellular membrane systems. The hydrophilic V1 portion of the V-ATPase is a rotary motor, in which a central-axis DF complex rotates inside a hexagonally arranged catalytic A3B3 complex by using ATP hydrolysis energy. We have previously reported crystal structures of Enterococcushirae V-ATPase A3B3 and A3B3DF (V1) complexes; the result suggested that the DF axis induces structural changes in the A3B3 complex through extensive protein-protein interactions. In this study, we mutated 10 residues at the interface between A3B3 and DF complexes and examined the ATPase activities of the mutated V1 complexes as well as the binding affinities between the mutated A3B3 and DF complexes. Surprisingly, several V1 mutants showed higher initial ATPase activities than wild-type V1-ATPase, whereas these mutated A3B3 and DF complexes showed decreased binding affinities for each other. However, the high ATP hydrolysis activities of the mutants decreased faster over time than the activity of the wild-type V1 complex, suggesting that the mutants were unstable in the reaction because the mutant A3B3 and DF complexes bound each other more weakly. These findings suggest that strong interaction between the DF complex and A3B3 complex lowers ATPase activity, but also that the tight binding is responsible for the stable ATPase activity of the complex.
Using a very high-resolution oligonucleotide array for copy number variant (CNV) screening of samples comprising schizophrenic patients, we detected a novel CNV within the critical region (NCBI36/hg18, Chr7: 158,630,410–158,719,410) previously shown to be associated with schizophrenia. We investigated the association between the novel CNV identified in the current study and schizophrenia. Three independent samples were used: (1) Screening set, 300 Japanese schizophrenic patients (53.28 ± 14.66 years); (2) Confirmation set, 531 schizophrenic patients (46.03 ± 12.15 years); and (3) 711 healthy controls (47.12 ± 11.03 years). All subjects enrolled in the study were Japanese. Chromosomal position was determined using fluorescence in situ hybridization. We identified a novel duplication within the region associated with schizophrenia identified on 7q36.3 that is adjacent to VIPR2 and is not associated with schizophrenia. In the Japanese population, the 35-kb region that harbors the common, novel CNV should be excluded from the region associated with schizophrenia on 7q36.3.
High fat diet (HFD) is prevalent in many modern societies and HFD-induced metabolic condition is a growing concern worldwide. It has been previously reported that HFD clearly worsens cognitive function in amyloid precursor protein (APP) transgenic mice. On the other hand, we have demonstrated that voluntary exercise in an enriched environment is an effective intervention to rescue HFD-induced β-amyloid (Aβ) deposition and memory deficit. However, it had been unclear whether consumption of HFD after exercising abolished the beneficial effect of exercise on the inhibition of Alzheimer's disease (AD) pathology. To examine this question, we exposed wild type (WT) and APP mice fed with HFD to exercise conditions at different time periods. In our previous experiment, we gave HFD to mice for 20 weeks and subjected them to exercise during weeks 10–20. In the present study, mice were subjected to exercise conditions during weeks 0–10 or weeks 5–15 while being on HFD. Interestingly, we found that the effect of exercise during weeks 0–10 or weeks 5–15 on memory function was not abolished in WT mice even if they kept having HFD after finishing exercise. However, in APP transgenic mice, HFD clearly disrupted the effect of exercise during weeks 0–10 or weeks 5–15 on memory function. Importantly, we observed that the level of Aβ oligomer was significantly elevated in the APP mice that exercised during weeks 0–10: this might have been caused by the up-regulation of Aβ production. These results provide solid evidence that continuation of exercise is necessary to rescue HFD-induced aggravation of cognitive decline in the pathological setting of AD.
Mating processes of local demes and spatial genetic structure of island populations at the self-incompatibility (S-) locus under negative frequency-dependent selection (NFDS) were evaluated in Prunus lannesiana var. speciosa in comparison with nuclear simple sequence repeat (SSR) loci that seemed to be evolutionarily neutral. Our observations of local mating patterns indicated that male–female pair fecundity was influenced by not only self-incompatibility, but also various factors, such as kinship, pollen production and flowering synchrony. In spite of the mating bias caused by these factors, the NFDS effect on changes in allele frequencies from potential mates to mating pollen was detected at the S-locus but not at the SSR loci, although the changes from adult to juvenile cohorts were not apparent at any loci. Genetic differentiation and isolation-by-distance over various spatial scales were smaller at the S-locus than at the SSR loci, as expected under the NFDS. Allele-sharing distributions among the populations also had a unimodal pattern at the S-locus, indicating the NFDS effect except for alleles unique to individual populations probably due to isolation among islands, although this pattern was not exhibited by the SSR loci. Our results suggest that the NFDS at the S-locus has an impact on both the mating patterns and the genetic structure in the P. lannesiana populations studied.
self-incompatibility; S-alleles; Prunus; paternity; SSR; negative frequency-dependent selection
Precise effects of albuminuria and low estimated glomerular filtration rate (eGFR) on cardiovascular mortality, all-cause mortality, and renal events in diabetic patients are uncertain.
Materials and Methods
A systematic review was conducted of the literature through MEDLINE, EMBASE, and CINHAL from 1950 to December 2010. Cohort studies of diabetic patients providing adjusted relative risk (RR) of albuminuria and eGFR for risks of cardiovascular mortality, all-cause mortality, and renal events were selected. Two reviewers screened abstracts and full papers of each study using standardized protocol.
We identified 31 studies fulfilling the criteria from 6546 abstracts. With regard to the risk of cardiovascular mortality, microalbuminuria (RR 1.76, 95%CI 1.38–2.25) and macroalbuminuria (RR 2.96 95%CI 2.44–3.60) were significant risk factors compared to normoalbuminuria. The same trends were seen in microalbuminuria (RR 1.60, 95%CI 1.42–1.81), and macroalbuminuria (RR 2.64, 95%CI 2.13–3.27) for the risk of all-cause mortality, and also in microalbuminuria (RR 3.21, 95%CI 2.05–5.02) and macroalbuminuria (RR 11.63, 95%CI 5.68–23.83) for the risk of renal events. The magnitudes of relative risks associated with low eGFR along with albuminuria were almost equal to multiplying each risk rate of low eGFR and albuminuria. No significant factors were found by investigating potential sources of heterogeneity using subgroup analysis.
High albuminuria and low eGFR are relevant risk factors in diabetic patients. Albuminuria and low eGFR may be independent of each other. To evaluate the effects of low eGFR, intervention, or race, appropriately designed studies are needed.
We report our findings in two siblings with late-onset cone–rod dystrophy (CRD) with no visible macular degeneration.
Cases and methods
Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs) were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes.
These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years.
cone-rod dystrophy; peripheral cone dystrophy; occult macular dystrophy; late onset; macular degeneration; negative ERG
Large genomic copy number variations (CNVs) have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.
To detect novel CNVs increasing susceptibility to schizophrenia, utilizing two ethnically homogeneous discovery cohorts and replication in large samples.
Genetic association study of microarray data.
DNA samples were collected at nine sites from different countries.
Two discovery cohorts were comprised of: a) 790 cases (schizophrenia and schizoaffective disorder) and 1347 controls of Ashkenazi Jewish descent; and b) 662 trios (offspring affected with schizophrenia or schizoaffective disorder) from Bulgaria. Replication datasets consisted of 12,398 cases and 17,945 controls.
Main outcome measure
Statistically increased rate of specific CNVs in cases versus controls.
One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 out of 13,850 cases (0.094%) and in 3 out of 19,954 controls (0.015%), Fisher Exact p = 0.0014; OR = 6.25 (95%CI = 1.78 – 21.93).
Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains nine genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional eight genes. Our findings add a new locus to the list of CNVs that increase risk to develop schizophrenia.
Inland and transitional aquatic systems play an important role in global carbon (C) cycling. Yet, the C dynamics of wetlands and floodplains are poorly defined and field data is scarce. Air-water fluxes in the wetlands of Doñana Natural Area (SW Spain) were examined by measuring alkalinity, pH and other physiochemical parameters in a range of water bodies during 2010–2011. Areal fluxes were calculated and, using remote sensing, an estimate of the contribution of aquatic habitats to gaseous transport was derived. Semi-permanent ponds adjacent to the large Guadalquivir estuary acted as mild sinks, whilst temporal wetlands were strong sources of (−0.8 and 36.3 ). Fluxes in semi-permanent streams and ponds changed seasonally; acting as sources in spring-winter and mild sinks in autumn (16.7 and −1.2 ). Overall, Doñana's water bodies were a net annual source of (5.2 ). Up–scaling clarified the overwhelming contribution of seasonal flooding and allochthonous organic matter inputs in determining regional air-water gaseous transport (13.1 ). Nevertheless, this estimate is about 6 times < local marsh net primary production, suggesting the system acts as an annual net sink. Initial indications suggest longer hydroperiods may favour autochthonous C capture by phytoplankton. Direct anthropogenic impacts have reduced the hydroperiod in Doñana and this maybe exacerbated by climate change (less rainfall and more evaporation), suggesting potential for the modification of C sequestration.
Recent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population.
Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis.
Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5×10−8) only for BD (P = 9.4×10−9) and psychosis (P = 2.0×10−10). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1×10−7 for psychosis), this signal weakened when the samples size was increased by including data from a Caucasian population (P = 4.3×10−3).
We found 3p21.1 (including PBRM1, strong linkage disequilibrium made it difficult to pinpoint the risk genes) and SP8 as risk loci for BD, SCZ and psychosis. Further replication studies will be required for conclusive results.
On August 9th 2012, we published an original research article in Scientific Reports, concluding that artificial radionuclides released from the Fukushima Dai-ichi Nuclear Power Plant exerted genetically and physiologically adverse effects on the pale grass blue butterfly Zizeeria maha in the Fukushima area. Immediately following publication, many questions and comments were generated from all over the world. Here, we have clarified points made in the original paper and answered questions posed by the readers.
The following points were clarified. (1) There are many advantages to using the pale grass blue butterfly as an indicator species. (2) The forewings of the individuals collected in Fukushima were significantly smaller than in the northern and southern localities. (3) We observed growth retardation in the butterflies from the Fukushima area. (4) The aberrant colour patterns in the butterflies obtained in the Fukushima area were different from the colour patterns induced by temperature and sibling crosses but similar to those induced by external and internal exposures to the artificial radionuclides and by a chemical mutagen, suggesting that genetic mutations caused the aberrations. (5) This species of butterfly has been plentiful in Fukushima area for at least half a century. We here present specimens collected from Fukushima Prefecture before the accident. (6) Mutation accumulation was detected by the increase in the abnormality rates from May 2011 to September 2011. (7) The abnormal traits were heritable. (8) Our sampling localities were not affected by the tsunami. (9) We used a high enough number of samples to obtain statistically significant results. (10) The standard rearing method was followed, producing normal adults in the control groups. (11) The exposure experiments successfully reproduced the results of the field work. This species of butterfly is vulnerable to long-term low-dose internal and external exposures; however, insect cells are known to be resistant to short-term high-dose irradiation. This discrepancy is reconcilable based on the differences in the experimental conditions.
We are just beginning to understand the biological effects of long-term low-dose exposures in animals. Further research is necessary to accurately assess the possible biological effects of the accident.
Abnormality rate; Artificial radionuclides; Colour pattern; Fukushima nuclear accident; Long-term low-dose radiation exposure; Pale grass blue butterfly; Zizeeria maha