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1.  Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation 
Translational Psychiatry  2014;4(11):e482-.
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg−1), morphine (20 mg kg−1) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (−9.5 s, P<0.01 and −7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity—although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
PMCID: PMC4259992  PMID: 25386959
2.  Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women's health initiative 
Multivitamin use is common in the United States. It is not known whether multivitamins with minerals supplements (MVM) used by women already diagnosed with invasive breast cancer would affect their breast cancer mortality risk. To determine prospectively the effects of MVM use on breast cancer mortality in postmenopausal women diagnosed with invasive breast cancer, a prospective cohort study was conducted of 7,728 women aged 50–79 at enrollment in the women's health initiative (WHI) in 40 clinical sites across the United States diagnosed with incident invasive breast cancer during WHI and followed for a mean of 7.1 years after breast cancer diagnosis. Use of MVM supplements was assessed at WHI baseline visit and at visit closest to breast cancer diagnosis, obtained from vitamin pill bottles brought to clinic visit. Outcome was breast cancer mortality. Hazard ratios and 95 % confidence intervals (CIs) for breast cancer mortality comparing MVM users to non-users were estimated using Cox proportional hazard regression models. Analyses using propensity to take MVM were done to adjust for potential differences in characteristics of MVM users versus non-users. At baseline, 37.8 % of women reported MVM use. After mean post-diagnosis follow-up of 7.1 ± 4.1 (SD) years, there were 518 (6.7 %) deaths from breast cancer. In adjusted analyses, breast cancer mortality was 30 % lower in MVM users as compared to non-users (HR = 0.70; 95 % CI 0.55, 0.91). This association was highly robust and persisted after multiple adjustments for potential confounding variables and in propensity score matched analysis (HR = 0.76; 95 % CI 0.60–0.96). Postmenopausal women with invasive breast cancer using MVM had lower breast cancer mortality than non-users. The results suggest a possible role for daily MVM use in attenuating breast cancer mortality in women with invasive breast cancer but the findings require confirmation.
PMCID: PMC3902175  PMID: 24104882
Breast cancer; Multivitamins; Vitamins; Women's health initiative; WHI; Breast cancer mortality
3.  Characterization of Cervicofacial Lymphnodes - A Clinical and Ultrasonographic Study 
Background: Lymph nodes undergo reactive changes in response to a wide variety of stimuli, the most common cause being inflammatory and immune reactions, apart from primary malignant neoplasms and metastatic tumours. It is well accepted that a clinical examination alone cannot be considered diagnostic to justify the involvement of cervicofacial lymph nodes especially deep and small nodes. Ultrasonography is an easy, reproducible, non invasive, non-ionizing imaging modality to evaluate cervicofacial lymph nodes.
Aim: The present study was devised with an aim of comparing the clinical and ultrasonographic features of cervicofacial lymphadenopathy.
Materials and Methods: The subjects for the study were selected from the patients who visited the outpatient department with clinically palpable lymph nodes. Fifty two patients were included in the study and they were divided into 4 groups; group I (subjects with odontogenic infections), group II (subjects with non odontogenic oral conditions), group III (subjects with tuberculosis) and group IV (subjects with head and neck carcinomas). A detailed case history was recorded and a thorough clinical examination was carried out for all subjects. The cervicofacial lymph nodes were palpated and examined. Ultrasonographic examination of cervicofacial lymph nodes was carried out and recorded. The statistical analysis was done using chi square test.
Result and Conclusion: Most of the subjects considered for the study showed cervicofacial lymphadenopathy associated with odontogenic causes, specific infections like tuberculosis and head and neck malignancies. The lymph nodes showed varied clinical features. The ultrasonographic features such as number, size, shape, short axis/long axis ratio, border sharpness, hilum, echogenicity, distribution of the internal echoes, intranodal necrosis, matting or soft tissue edema were evaluated. The results were tabulated and statistical analysis was done.
PMCID: PMC4190788  PMID: 25302262
Cervicofacial lymphnodes; Lymphadenopathy; Ultrasonography
4.  What Big Size You have! Using Effect Sizes to Determine the Impact of Public Health Nursing Interventions 
Applied Clinical Informatics  2013;4(3):434-444.
The Omaha System is a standardized interface terminology that is used extensively by public health nurses in community settings to document interventions and client outcomes. Researchers using Omaha System data to analyze the effectiveness of interventions have typically calculated p-values to determine whether significant client changes occurred between admission and discharge. However, p-values are highly dependent on sample size, making it difficult to distinguish statistically significant changes from clinically meaningful changes. Effect sizes can help identify practical differences but have not yet been applied to Omaha System data.
We compared p-values and effect sizes (Cohen’s d) for mean differences between admission and discharge for 13 client problems documented in the electronic health records of 1,016 young low-income parents. Client problems were documented anywhere from 6 (Health Care Supervision) to 906 (Caretaking/parenting) times.
On a scale from 1 to 5, the mean change needed to yield a large effect size (Cohen’s d≥0.80) was approximately 0.60 (range = 0.50 – 1.03) regardless of p-value or sample size (i.e., the number of times a client problem was documented in the electronic health record).
Researchers using the Omaha System should report effect sizes to help readers determine which differences are practical and meaningful. Such disclosures will allow for increased recognition of effective interventions.
PMCID: PMC3799213  PMID: 24155795
Nursing informatics; public health nursing; methods
5.  Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison 
Diabetes Therapy  2014;5(1):1-41.
To compare the safety and efficacy of the dipeptidylpeptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and inadequate glycemic control.
Systematic review of randomized controlled trials (RCTs), health economic evaluation studies, systematic reviews, and meta-analyses, followed by primary Bayesian mixed treatment comparison meta-analyses (MTCs), and secondary frequentist direct-comparison meta-analyses using a random-effects model. Outcomes were reported as weighted mean change from baseline, or odds ratio (OR) with 95% credible interval.
Data sources
MEDLINE, MEDLINE In-Process, EMBASE, and BIOSIS via Dialog ProQuest; Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews via EBSCO; four diabetes and two technical congress abstracts; and health technology assessment organization websites.
Eligibility criteria
Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment.
Data extraction and analysis
Title/abstracts were reviewed for eligibility, followed by full-text review of publications remaining after first pass. A three-person team filtered articles and an independent reviewer checked a random selection (10%) of filtered articles. Data extraction and quality assessment of studies were also independently reviewed. Five DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) were compared via meta-analysis (where data were available) as monotherapy, dual therapy (plus metformin, sulfonylurea, pioglitazone, or insulin), and triple therapy (plus metformin/sulfonylurea).
The review identified 6,601 articles; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis. MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin (HbA1c) or body weight, or the proportions of patients achieving HbA1c <7% or experiencing a hypoglycemic event, apart from in patients on alogliptin plus metformin, who achieved HbA1c <7% more frequently than those treated with saxagliptin plus metformin [OR 6.41 (95% CI 3.15–11.98) versus 2.17 (95% CI 1.56–2.95)].
This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes, either as monotherapy or combination therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s13300-014-0061-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4065303  PMID: 24664619
Alogliptin; DPP-4 inhibitor; Glycosylated hemoglobin; Linagliptin; Mixed treatment comparison; Saxagliptin; Sitagliptin; Type 2 diabetes mellitus; Vildagliptin
6.  Comparative Evaluation of the Efficiency of Four Ceramic Finishing Systems 
Aim: To compare the effect of four different finishing systems and diamond paste on ceramic roughness with the objectives of evaluating the roughness of ceramic surface of prepared specimens after abrasion, finishing and polishing.
Materials & Methods: A total of 50 test specimens were fabricated in the form of discs of diameter 13mm and 0.6mm thickness. Test specimens were then randomly distributed into five groups of 10 and coded. All the test specimens were then abraded with 125μm diamond in unidirectional motion to create surface roughness that will simulate occlusal or incisal correction. The values were recorded and the specimens were then finished using the various finishing systems. multiple range tests by Duncan's procedure. One way Anova was used to calculate the p-value
Results:After fini shing, the Ra,Rq,Rz and Rt values showed a tendency to decline to levels much inferior to the values obtained after the preparation of the specimens. Ra values of group III specimens were slightly higher and the increase was significant. The highest Rt value [5.29] obtained after polishing is below the lowest roughness values [7.42] obtained after finishing the specimens.
Conclusions: Finishing and polishing procedures have a significant role in reducing the roughness of ceramics.Following abrasion with diamond point to simulate clinical adjustment the roughness values doubled when compared to the initial reading.Ra, Rq,Rz and Rt values suggest that Sof lex is the most efficient of all the systems tested followed by auto glazing.After the final diamond paste polishing, sof lex group specimens showed the best finish and auto glazed specimens showed a value almost as equal to the so flex group.
How to cite this article: Aravind P, Razak PA, Francis PG, Issac JK, Shanoj RP, Sasikumar TP. Comparative Evaluation of the Efficiency of Four Ceramics Finishing Systems. J Int Oral Health 2013; 5(5):59-64.
PMCID: PMC3845286  PMID: 24324306
Ceramic; Finishing Systems; Randomized Clinical Trial
7.  Separation of cognitive impairments in attention deficit hyperactivity disorder into two familial factors 
Archives of general psychiatry  2010;67(11):1159-1167.
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.
PMCID: PMC3770932  PMID: 21041617
8.  The Community Liaison Program: a health education pilot program to increase minority awareness of HIV and acceptance of HIV vaccine trials 
Health Education Research  2012;27(4):746-754.
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.
PMCID: PMC3529630  PMID: 22327809
9.  Generalization of adiposity genetic loci to US Hispanic women 
Nutrition & Diabetes  2013;3(8):e85-.
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.
PMCID: PMC3759132  PMID: 23978819
obesity; Hispanic; women; genetics; generalization
10.  Brain amyloid and cognition in Lewy body diseases 
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.
PMCID: PMC3725259  PMID: 22693110
dementia; Lewy; Parkinson; amyloid; PiB
11.  Second-Trimester Diagnosis of Triploidy: A Series of Four Cases 
AJP Reports  2012;3(1):37-40.
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.
PMCID: PMC3699153  PMID: 23943708
triploidy; ultrasound; phenotype; second trimester
13.  Birth characteristics and childhood carcinomas 
British Journal of Cancer  2011;105(9):1396-1401.
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.
PMCID: PMC3241539  PMID: 21915125
paediatric; carcinoma; melanoma; thyroid; risk
14.  The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ 
Psychological medicine  2010;41(4):861-871.
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.
PMCID: PMC3430513  PMID: 20522277
ADHD; cognitive; heritability; IQ; intermediate phenotype
15.  Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice 
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.
PMCID: PMC3128644  PMID: 21668627
complement; C5; transplant rejection; T cell; CTLA4Ig
17.  Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly 
Annals of neurology  2011;69(6):1032-1042.
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.
PMCID: PMC3117980  PMID: 21437929
18.  Generating Clinical Notes for Electronic Health Record Systems 
Applied Clinical Informatics  2010;1(3):232-243.
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.
PMCID: PMC2963994  PMID: 21031148
Computer based documentation; electronic health records; medical informatics applications; computerized medical records systems; user-computer interface
19.  Velocity Measurements in the Middle Cerebral Arteries of Healthy Volunteers Using 3D Radial Phase-Contrast HYPRFlow: Comparison with Transcranial Doppler Sonography and 2D Phase-Contrast MR Imaging 
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).
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.
PMCID: PMC3133942  PMID: 20947642
20.  Parental educational attainment as an indicator of socioeconomic status and risk of childhood cancers 
British Journal of Cancer  2010;103(1):136-142.
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.
PMCID: PMC2905284  PMID: 20531410
childhood cancer; socioeconomic status; epidemiology
21.  Fast Whole-Brain 4D Contrast-Enhanced MR Angiography with Velocity Encoding Using Undersampled Radial Acquisition and Highly Constrained Projection Reconstruction: Image-Quality Assessment in Volunteer Subjects 
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.
PMCID: PMC2974026  PMID: 20223884
22.  Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation 
Cell Death & Disease  2010;1(9):e74-.
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.
PMCID: PMC3000738  PMID: 21151771
cytokines; FGF10; GM-CSF; KGF; p53; p73
23.  Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study 
British Journal of Cancer  2009;101(3):518-521.
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.
PMCID: PMC2720246  PMID: 19603020
germ cell tumours; paediatrics; congenital abnormalities
24.  A new spontaneous mouse mutation in the Kcne1 gene 
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.
PMCID: PMC2862908  PMID: 11003695
25.  The Mass1frings mutation underlies early onset hearing impairment in BUB/BnJ mice, a model for the auditory pathology of Usher syndrome IIC 
Genomics  2005;85(5):582-590.
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.
PMCID: PMC2855294  PMID: 15820310
Hearing loss; Mouse inbred strain; Frings; BUB/BnJ; VLGR1; USH2C; Mass1; Cdh23

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