Attention deficit hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots, or whether separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations.
To determine, using a multivariate familial factor analysis approach, whether one or more familial factors underlie the slow and variable reaction times (RTs), impaired response inhibition and choice impulsivity that are associated with ADHD.
An ADHD and control sibling-pair design.
Belgium, Germany, Ireland, Israel, Spain, Switzerland and the United Kingdom.
The sample consisted of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with ADHD combined subtype), and 345 control participants.
Main Outcome Measures
Performance on a four-choice RT task, a go/no-go inhibition task and a choice-delay task.
The final model consisted of two familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98-100% of the familial influences on mean RT and RT variability. The second smaller factor, reflecting 12.5% of the familial variance of ADHD, captured 62-82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model, due to poor fit.
The findings suggest the existence of two familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the two cognitive impairments is consistent with recent theoretical models – a developmental model and an arousal-attention model – on two separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally-sensitive interventions.
This paper describes a 16-month health education pilot program based on diffusion of innovation and social network theories. The program was implemented by volunteer community liaisons for the purposes of increasing awareness of and support for HIV vaccine research in minority populations. This theoretically driven pilot program allowed the liaisons to integrate delivery of the HIV vaccine research messages created for the program into their existing activities and routines. Through training in participatory engagement, volunteers were able to tailor and adapt an HIV prevention message for their communities. Process evaluation data showed that the acceptance of participatory engagement and HIV vaccine message dissemination far exceeded expectations. The anticipated number of community members to receive the message was estimated at 500 with 10 volunteer liaisons or 50 per person. However, the actual number of people reached was 644, with only 7 volunteer liaisons, or an average of 92 persons per liaison, almost double the original number. Further research is recommended to analyze the specific behavioral changes that can come from the use of social networks in HIV vaccine research awareness within minority populations.
Obesity is a public health concern. Yet the identification of adiposity-related genetic variants among United States (US) Hispanics, which is the largest US minority group, remains largely unknown.
To interrogate an a priori list of 47 (32 overall body mass and 15 central adiposity) index single-nucleotide polymorphisms (SNPs) previously studied in individuals of European descent among 3494 US Hispanic women in the Women's Health Initiative SNP Health Association Resource (WHI SHARe).
Cross-sectional analysis of measured body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were inverse normally transformed after adjusting for age, smoking, center and global ancestry. WC and WHR models were also adjusted for BMI. Genotyping was performed using the Affymetrix 6.0 array. In the absence of an a priori selected SNP, a proxy was selected (r2⩾0.8 in CEU).
Six BMI loci (TMEM18, NUDT3/HMGA1, FAIM2, FTO, MC4R and KCTD15) and two WC/WHR loci (VEGFA and ITPR2-SSPN) were nominally significant (P<0.05) at the index or proxy SNP in the corresponding BMI and WC/WHR models. To account for distinct linkage disequilibrium patterns in Hispanics and further assess generalization of genetic effects at each locus, we interrogated the evidence for association at the 47 surrounding loci within 1 Mb region of the index or proxy SNP. Three additional BMI loci (FANCL, TFAP2B and ETV5) and five WC/WHR loci (DNM3-PIGC, GRB14, ADAMTS9, LY86 and MSRA) displayed Bonferroni-corrected significant associations with BMI and WC/WHR. Conditional analyses of each index SNP (or its proxy) and the most significant SNP within the 1 Mb region supported the possible presence of index-independent signals at each of these eight loci as well as at KCTD15.
This study provides evidence for the generalization of nine BMI and seven central adiposity loci in Hispanic women. This study expands the current knowledge of common adiposity-related genetic loci to Hispanic women.
obesity; Hispanic; women; genetics; generalization
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
dementia; Lewy; Parkinson; amyloid; PiB
Triploidy occurs in 2 to 3% of conceptuses and accounts for approximately 20% of chromosomally abnormal first-trimester miscarriages. As such, triploidy is estimated to occur in 1 of 3,500 pregnancies at 12 weeks', 1 in 30,000 at 16 weeks', and 1 in 250,000 at 20 weeks' gestation. We present a series of four cases of second-trimester triploidy diagnosed at our center within a 1-year timeframe. This is remarkable, as the delivery volume at our institution is roughly 2,500/y. All patients were at least 19 weeks' gestation, with multiple abnormalities identified on prenatal ultrasound at 18 to 20 weeks' gestation; all fetuses had lethal anomalies, but anomalies were not consistent between cases. All patients elected for induction of labor before 24 weeks' gestational age. Two of the four cases had amniocentesis and chromosome analysis prior to delivery, and two cases had chromosome analysis performed on fetal tissue after delivery. All fetuses were examined following delivery. This case series demonstrates that the diagnosis of triploidy may not be obvious based on ultrasound and physical examination findings and highlights the importance of routine chromosome analysis on all prenatal diagnoses of multiple congenital anomalies prior to consideration of more complex genetic testing.
triploidy; ultrasound; phenotype; second trimester
Carcinomas in children are rare and have not been well studied.
We conducted a population-based case–control study and examined associations between birth characteristics and childhood carcinomas diagnosed from 28 days to 14 years during 1980–2004 using pooled data from five states (NY, WA, MN, TX, and CA) that linked their birth and cancer registries. The pooled data set contained 57 966 controls and 475 carcinoma cases, including 159 thyroid and 126 malignant melanoma cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
White compared with ‘other' race was positively associated with melanoma (OR=3.22, 95% CI 1.33–8.33). Older maternal age increased the risk for melanoma (ORper 5-year age increase=1.20, 95% CI 1.00–1.44), whereas paternal age increased the risk for any carcinoma (OR=1.10per 5-year age increase, 95% CI 1.01–1.20) and thyroid carcinoma (ORper 5-year age increase=1.16, 95% CI 1.01–1.33). Gestational age <37 vs 37–42 weeks increased the risk for thyroid carcinoma (OR=1.87, 95% CI 1.07–3.27). Plurality, birth weight, and birth order were not significantly associated with childhood carcinomas.
This exploratory study indicates that some birth characteristics including older parental age and low gestational age may be related to childhood carcinoma aetiology.
paediatric; carcinoma; melanoma; thyroid; risk
Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.
Multivariate familial models were run on data from 1265 individuals aged 6–18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice–delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).
Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41–0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80–87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.
The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.
ADHD; cognitive; heritability; IQ; intermediate phenotype
While activation of serum complement mediates antibody-initiated vascular allograft injury, increasing evidence indicates that complement also functions as a modulator of alloreactive T cells. We tested whether blockade of complement activation at the C5 convertase step affects T cell-mediated cardiac allograft rejection in mice. The anti-C5 mAb BB5.1, which prevents the formation of C5a and C5b, synergized with sub-therapeutic doses of CTLA4Ig to significantly prolong the survival of C57BL/6 heart grafts that were transplanted into naive Balb/c recipients. Anti-C5 mAb treatment limited the induction of donor-specific IFNγ-producing T cell alloimmunity without inducing Th2 or Th17 immunity in vivo and inhibited primed T cells from responding to donor antigens in secondary mixed lymphocyte responses. Additional administration of anti-C5 mAb to the donor prior to graft harvest further prolonged graft survival and concomitantly reduced both the in vivo trafficking of primed T cells into the transplanted allograft and decreased expression of T cell chemoattractant chemokines within the graft. Together these results support the novel concept that C5 blockade can inhibit T cell-mediated allograft rejection through multiple mechanisms, and suggest that C5 blockade may constitute a viable strategy to prevent and/or treat T cell-mediated allograft rejection in humans.
complement; C5; transplant rejection; T cell; CTLA4Ig
Both amyloid-β (Aβ) deposition and brain atrophy are invariably associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear.
We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by PET imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD.
One hundred and nineteen older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural MR. Regression models were used to relate PiB retention to cortical thickness and hippocampal volume.
We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aβ deposition.
We conclude that Aβ deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment.
Clinical notes summarize interactions that occur between patients and healthcare providers. With adoption of electronic health record (EHR) and computer-based documentation (CBD) systems, there is a growing emphasis on structuring clinical notes to support reusing data for subsequent tasks. However, clinical documentation remains one of the most challenging areas for EHR system development and adoption. The current manuscript describes the Vanderbilt experience with implementing clinical documentation with an EHR system. Based on their experience rolling out an EHR system that supports multiple methods for clinical documentation, the authors recommend that documentation method selection be made on the basis of clinical workflow, note content standards and usability considerations, rather than on a theoretical need for structured data.
Computer based documentation; electronic health records; medical informatics applications; computerized medical records systems; user-computer interface
BACKGROUND AND PURPOSE
We have developed PC HYPRFlow, a comprehensive MRA technique that includes a whole-brain CE dynamic series followed by PC velocity-encoding, yielding a time series of high-resolution morphologic angiograms with associated velocity information. In this study, we present velocity data acquired by using the PC component of PC HYPRFlow (PC-VIPR).
MATERIALS AND METHODS
Ten healthy volunteers (6 women, 4 men) were scanned by using PC HYPRFlow and 2D-PC imaging, immediately followed by velocity measurements by using TCD. Velocity measurements were made in the M1 segments of the MCAs from the PC-VIPR, 2D-PC, and TCD examinations.
PC-VIPR showed approximately 30% lower mean velocity compared with TCD, consistent with other comparisons of TCD with PC-MRA. The correlation with TCD was r = 0.793, and the correlation of PC-VIPR with 2D-PC was r = 0.723.
PC-VIPR is a technique capable of acquiring high-resolution MRA of diagnostic quality with velocity data comparable with TCD and 2D-PC. The combination of velocity information and fast high-resolution whole-brain morphologic angiograms makes PC HYPRFlow an attractive alternative to current MRA methods.
Little has been reported on socioeconomic (SES) patterns of risk for most forms of childhood cancer.
Population-based case–control data from epidemiological studies of childhood cancer conducted in five US states were pooled and associations of maternal, paternal and household educational attainment with childhood cancers were analysed. Odds ratios (ORs) and 95% confidence intervals were estimated using logistic regression, controlling for confounders.
Although there was no association with parental education for the majority of cancers evaluated, there was an indication of a positive association with lower education for Hodgkin's and Burkitt's lymphoma and Wilm's tumour, with the ORs ranging from 1.5 to >3.0 times that of more educated parents. A possible protective effect was seen for lower parental education and astrocytoma and hepatoblastoma, with ORs reduced by 30 to 40%.
These study results should be viewed as exploratory because of the broad nature of the SES assessment, but they give some indication that childhood cancer studies might benefit from a more thorough assessment of SES.
childhood cancer; socioeconomic status; epidemiology
We report on the image quality obtained by using fast contrast-enhanced whole-brain 4D radial MRA with 0.75-second temporal resolution, isotropic submillimeter spatial resolution, and velocity encoding (HYPRFlow). Images generated by HYPR-LR by using the velocity-encoded data as the constraining image were of diagnostic quality. In addition, we demonstrate that measurements of shear stress within the middle cerebral artery can be derived from the high-resolution 3D velocity data.
The transcription factor p63 is required for proper epidermal barrier formation and maintenance. Herein, we used chromatin immunoprecipitation coupled with DNA sequencing to identify novel p63 target genes involved in normal human epidermal keratinocyte (NHEKs) growth and differentiation. We identified over 2000 genomic sites bound by p63, of which 82 were also transcriptionally regulated by p63 in NHEKs. Through the discovery of interleukin-1-α as a p63 target gene, we identified that p63 is a regulator of epithelial–mesenchymal crosstalk. Further, three-dimensional organotypic co-cultures revealed TCF7L1, another novel p63 target gene, as a regulator of epidermal proliferation and differentiation, providing a mechanism by which p63 maintains the proliferative potential of basal epidermal cells. The discovery of new target genes links p63 to diverse signaling pathways required for epidermal development, including regulation of paracrine signaling to proliferative potential. Further mechanistic insight into p63 regulation of epidermal cell growth and differentiation is provided by the identification of a number of novel p63 target genes in this study.
cytokines; FGF10; GM-CSF; KGF; p53; p73
Maternally reported congenital abnormalities (CAs) were examined in a case–control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls.
Results and conclusions
Germ cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1–55.1), but not with any other specific CA in either sex.
germ cell tumours; paediatrics; congenital abnormalities
A new mouse mutant, punk rocker (allele symbol Kcne1pkr), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1pkr mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21.
The human ortholog of the gene responsible for audiogenic seizure susceptibility in Frings and BUB/BnJ mice (mouse gene symbol Mass1) recently was shown to underlie Usher syndrome type IIC (USH2C). Here we report that the Mass1frings mutation is responsible for the early onset hearing impairment of BUB/BnJ mice. We found highly significant linkage of Mass1 with ABR threshold variation among mice from two backcrosses involving BUB/BnJ mice with mice of strains CAST/EiJ and MOLD/RkJ. We also show an additive effect of the Cdh23 locus in modulating the progression of hearing loss in backcross mice. Together, these two loci account for more than 70% of the total ABR threshold variation among the backcross mice at all ages. The modifying effect of the strain-specific Cdh23ahl variant may account for the hearing and audiogenic seizure differences observed between Frings and BUB/BnJ mice, which share the Mass1frings mutation. During postnatal cochlear development in BUB/BnJ mice, stereocilia bundles develop abnormally and remain immature and splayed into adulthood, corresponding with the early onset hearing impairment associated with Mass1frings. Progressive base–apex hair cell degeneration occurs at older ages, corresponding with the age-related hearing loss associated with Cdh23ahl. The molecular basis and pathophysiology of hearing loss suggest BUB/BnJ and Frings mice as models to study cellular and molecular mechanisms underlying USH2C auditory pathology.
Hearing loss; Mouse inbred strain; Frings; BUB/BnJ; VLGR1; USH2C; Mass1; Cdh23
Dementia is a common syndrome in the geriatric population. Subsequent impairment of cognitive functioning impacts the patient’s mobility, ADLs, and IADLs. It is suggested that older persons with lower levels of cognition are less likely to achieve independence in ADLs and ambulation (1–2). Frequently, nursing home residents are viewed as too frail or cognitively impaired to benefit from exercise rehabilitation. Often, persons with Mini Mental State Score (MMSE) score below 25 are excluded from physical rehabilitation programs. However, Diamond (3) and Goldstein (4) concluded that geriatric patients with mild to moderate cognitive impairment were just as likely as cognitively intact patients to improve in functional abilities as a result of participation in exercise rehabilitation programs.
The objective of this study is to compare, through a meta-analysis endurance and strength outcomes of Cognitively Impaired (MMSE <23) and Cognitively Intact (MMSE >24) older adults who participate in similar exercise programs.
Published articles were identified by using electronic and manual searches. Key search words included exercise, training, strength, endurance, rehabilitation, cognitive impairment, cognition, Mini Mental State Exam (MMSE), older adult, aged, and geriatrics. Articles were included if the were from RCTs or well-designed control studies.
A total of 41 manuscripts met the inclusion criteria. We examined 21 exercise trials with cognitively impaired individuals (CI=1411) and 20 exercise trials with cognitively intact individuals (IN=1510). Degree of cognitive impairment is based on the reported MMSE score. Moderate to large effect sizes (ES = dwi, Hedges gi) were found for strength and endurance outcomes for the CI groups (dwi = .51, 95% CI=. 42–.60), and for the IN groups (dwi =. 49, 95% CI=. 40 –.58). No statistically significant difference in ES was found between the CI and IN studies on strength (t=1.675, DF= 8, P=.132), endurance (t=1.904, DF= 14, P=.078), and combined strength and endurance effects (t=1.434, DF= 56, P=. 263).
These results suggest that cognitively impaired older adults who participate in exercise rehabilitation programs have similar strength and endurance training outcomes as age and gender matched cognitively intact older participants and therefore impaired individuals should not be excluded from exercise rehabilitation programs.
Older adult; cognition; physical rehabilitation; strength; endurance; training
The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of
continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis
(RRMS). The objective of this study was to evaluate up to 15 years of GA as a
sole disease-modifying therapy. Two hundred and thirty-two patients received at
least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%,
Ongoing cohort) continued as of February 2008. Patients were evaluated every 6
months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were
8.6 ±5.2, 4.81 ±3.69, and 13.6 ± 1.3 years and
mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing
cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs)
maintained a decline from 1.12±0.82 at baseline to 0.25 ±
0.34 per year; 57% had stable/improved EDSS scores (change ± 0.5
points); 65% had not transitioned to secondary progressive multiple sclerosis
(SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA
therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43
± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not
transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion,
multiple sclerosis patients with mean disease duration of 22 years administering
GA for up to 15 years had reduced relapse rates, and decreased disability
progression and transition to SPMS. There were no long-term safety issues.
disability; Expanded Disability Status Scale; glatiramer acetate; long-term; relapsing-remitting multiple sclerosis; secondary progressive multiple sclerosis
To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI).
Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc‐HMPAO. Clinical outcome after a 5‐year follow‐up period was heterogeneous.
Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer's disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer's disease within the follow‐up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer's disease were also included for purposes of comparison. The group of patients with Alzheimer's disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion.
These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.
epigenetics; T cell; autoimmunity; interferon; methylation; lupus
Multiple Sclerosis (MS) is an autoimmune inflammatory disease that presents clinically with a range of symptoms including motor, sensory, and cognitive dysfunction as well as demyelination and lesion formation in brain and spinal cord. A variety of animal models of MS have been developed that share many of the pathological hallmarks of MS including motor deficits (ascending paralysis), demyelination and axonal damage of central nervous system (CNS) tissue. In recent years, neuropathic pain has been recognized as a prevalent symptom of MS in a majority of patients. To date, there have been very few investigations into sensory disturbances in animal models of MS. The current work contains the first assessment of hind paw mechanical allodynia (von Frey test) over the course of a relapsing-remitting myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE) rat model of MS and establishes the utility of this model in examining autoimmune induced sensory dysfunction. We demonstrate periods of both decreased responsiveness to touch that precedes the onset of hind limb paralysis, and increased responsiveness (allodynia) that occurs during the period of motor deficit amelioration traditionally referred to as symptom remission. Furthermore, we tested the ability of our recently characterized anti-inflammatory IL-10 gene therapy to treat the autoimmune inflammation induced behavioral symptoms and tissue histopathological changes. This therapy is shown here to reverse inflammation induced paralysis, to reduce disease associated reduction in sensitivity to touch, to prevent the onset of allodynia, to reverse disease associated loss of body weight, and to suppress CNS glial activation associated with disease progression in this model.
The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.
High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using PEDCHECK and MERLIN, and extended DR3 haplotypes were analysed.
With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (≥99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four ‘sentinel’ SNPs (rs2157678 ‘T’, rs3130380 ‘A’, rs3094628 ‘C’ and rs3130352 ‘T’). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 × 10−5, OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association.
The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.
8.1 haplotype; extended haplotypes; major histocompatibility complex; T1DGC; type 1 diabetes