A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

Mammography interval and breast cancer mortality in women over the age of 75.

The purpose of this study is to evaluate the relationship between mammography interval and breast cancer mortality among older women with breast cancer. The study population included 1,914 women diagnosed with invasive breast cancer at age 75 or later during their participation in the Women's health initiative, with an average follow-up of 4.4 years (3.1 SD). Cause of death was based on medical record review. Mammography interval was defined as the time between the last self-reported mammogram 7 or more months prior to diagnosis, and the date of diagnosis. Multivariable adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) for breast cancer mortality and all-cause mortality were computed from Cox proportional hazards analyses. Prior mammograms were reported by 73.0 % of women from 7 months to ≤2 year of diagnosis (referent group), 19.4 % (>2 to <5 years), and 7.5 % (≥5 years or no prior mammogram). Women with the longest versus shortest intervals had more poorly differentiated (28.5 % vs. 22.7 %), advanced stage (25.7 % vs. 22.9 %), and estrogen receptor negative tumors (20.9 % vs. 13.1 %). Compared to the referent group, women with intervals of >2 to <5 years or ≥5 years had an increased risk of breast cancer mortality (HR 1.62, 95 % CI 1.03-2.54) and (HR 2.80, 95 % CI 1.57-5.00), respectively, p trend = 0.0002. There was no significant relationship between mammography interval and other causes of death. These results suggest a continued role for screening mammography among women 75 years of age and older.

Blood pressure variability and brain morphology in elderly women without cardiovascular disease.

OBJECTIVE: To examine the relationship between blood pressure (BP) variability (BPV), brain volumes, and cognitive functioning in postmenopausal women with few modifiable cardiovascular risk factors. METHODS: Study participants consisted of postmenopausal women enrolled in the Women's Health Initiative Memory MRI study (WHIMS-MRI) without cardiovascular disease, diabetes mellitus, hypertension, or current smoking at baseline (1996-1999). BP readings were taken at baseline and each annual follow-up visit. BPV was defined as the SD associated with a participant's mean BP across visits and the SD associated with the participant's regression line with BP regressed across visits. Brain MRI scans were performed between 2004 and 2006. Cognitive functioning was assessed at baseline and annually thereafter with the Modified Mini-Mental State Examination (3MSE) scoring until 2008. The final sample consisted of 558 women (mean age 69 years, median follow-up time [interquartile range] 8 [0.8] years). RESULTS: In adjusted models including mean systolic BP, women in the highest tertile of systolic BPV had lower hippocampal volumes and higher lesion volumes compared to women in the lowest tertile. No relationship between BPV and 3MSE scoring was detected. CONCLUSIONS: In postmenopausal women with few modifiable cardiovascular risk factors, greater visit-to-visit systolic BPV was associated with reductions in hippocampal volume and increases in lesion volumes at later life. These data add evidence to the emerging importance of BPV as a prognostic indicator even in the absence of documented cardiovascular risk factors.

Evaluation of an adult immunization composite measure in the Indian Health Service.

BACKGROUND: Government agencies, healthcare accreditation bodies and quality improvement organizations support the development of new quality measures. Composite quality measures use more than one measure to develop a broader assessment of healthcare system function. Currently, no composite measures for adult immunization coverage exist. Development of such measures could facilitate improvements in adult immunization coverage by focusing on measurement of receipt of all age-recommended vaccines. METHODS: We recruited five Indian Health Service (IHS) and Tribal health clinics to pilot an Adult Immunization Composite Measure (AICM). Data were collected monthly over seven months using a pre-programmed electronic health record (EHR) reporting tool (IHS sites); Tribal sites used third-party software or a programmable EHR reporting function. Data collected included: number of adults aged 19 years and over who were active users of the facility with at least two visits in the last three years; the cumulative number fully immunized per age-based recommendations for tetanus toxoid-containing vaccines, pertussis, zoster and pneumococcal vaccines; and the percent immunized for the AICM and for each individual vaccine. Coverage was calculated for three age groups: 19-59 years; 60-64 years; and 65 years and older. RESULTS: All sites reported aggregate immunization data monthly from patient EHR records. For all adults 19 years and older, AICM coverage ranged from 49% to 87% at the end of the report period. Two sites showed increases in AICM coverage ≥ 3%. Improvements in zoster vaccine coverage accounted for most of the increase observed. One site specifically focused on improving zoster coverage as a result of using the AICM. CONCLUSIONS: We demonstrated the feasibility of implementing a composite measure of adult immunization coverage. This is the first measure capable of monitoring immunization completeness, coverage improvement and overall adult vaccine program effectiveness for adults who receive all recommended, age-based vaccines.

Usefulness of the ratio of orbital fat to total orbit area in mild-to-moderate thyroid-associated ophthalmopathy.

OBJECTIVE: To identify a useful predictor of thyroid-associated ophthalmopathy (TAO) from orbital CT images; to evaluate the orbital fat and extraocular muscle area ratio as a CT-derived measure; and to investigate the correlations between this ratio and the clinical manifestations in mild-to-moderate TAO. METHODS: Between January 2012 and March 2013, 44 patients with TAO and 23 controls were studied prospectively. All of the patients underwent ophthalmic examinations, including clinical activity score, exophthalmometry, clinical photographs, alternate prism and cover test, duction and version test, Hess screen test, binocular single vision test, thyroid function tests and orbital CT. The cross-sectional areas of the four rectus muscles, superior oblique muscle, optic nerve and total orbit area were calculated in the coronal view 6 mm posterior from the posterior pole of globe. RESULTS: The cross-sectional area measured on orbital CT showed increased orbital fat in patients with TAO and an increased orbital fat to total orbit area ratio (fat/orbit) in TAO with retraction and proptosis. There were significant correlations between fat/orbit and margin reflex distance 1 (p = 0.022), margin reflex distance 2 (p = 0.013) and the exophthalmometric value (p = 0.007). CONCLUSION: The orbital fat to total orbit area ratio (fat/orbit) is a useful diagnostic index in mild-to-moderate TAO. ADVANCES IN KNOWLEDGE: The orbital CT offers a useful diagnostic index in TAO.

Changes in the glutathione status of plasma, liver and muscle following exhaustive exercise in rats.

Our results show that following physical exercise to exhaustion, the levels of reduced glutathione are increased in the plasma, but decreased in both the liver and skeletal muscle of rats. Levels of glutathione disulfide are increased in all 3 tissues. Our results are consistent with a mechanism in which the liver may be dumping reduced glutathione into the plasma in an attempt to deliver it to those tissues that need it the most: in this case, skeletal muscle.

Acoustic reflex abnormalities in cranial-cervical dystonia.

Previous anatomic and physiologic studies suggest brainstem dysfunction in cranial-cervical dystonia. To further explore this, we studied suprathreshold acoustic reflex waveforms in 15 such patients. A unique feature of this technique is its ability to reject movement artifacts before averaging the acoustic reflex waveforms. Thirteen patients (87%) showed some abnormality in reflex waveform morphology. There were both amplitude and latency abnormalities. These findings support the hypothesis that cranial-cervical dystonia reflects dysfunction of the brainstem.

Activated retinitis pigmentosa peripheral lymphocytes adhere to and alter cultured human retinal pigment epithelial cells.

Interleukin-2 receptor (IL-2R) is an activation molecule that, when expressed on peripheral blood lymphocyte (PBL) membranes, indicates the secretion of IL-2 and initiation of an immune system activation cascade. Comparing the average of IL-2R expression in 34 patients with retinitis pigmentosa (RP) syndrome (561 +/- 282 cells/mm3; mean +/- standard deviation) with 35 age-matched normal subjects (194 +/- 39 cells/mm3), it was found that those with RP had greater numbers of IL-2R-positive cells (P less than 0.001). The increased amounts of IL-2R on PBL of 29 RP and the homotypic self-aggregation of RP PBL by phase and scanning electron microscopy led to the study of the interaction of RP PBL with cultured human postmortem retinal pigment epithelial cells (RPE). A direct correlation was found between the amount of IL-2R expression and the numbers of RP lymphocytes adhering to RPE monolayers. However, the adherence effect was not unique to RP syndrome but appeared to be a nonspecific result of lymphocyte activation. Greater adherence to RPE than normal also was observed in PBL from disease control subjects with elevated IL-2R values and in PBL stimulated by the mitogen, concanavalin A (Con-A). In addition, RPE monolayers were destroyed by Con-A-stimulated PBL that showed 95-98% IL-2R expression. Similar, but less serious effects, occurring in RPE cells after 1 wk's cocultivation with RP PBL, suggested that activated RP lymphocytes can be cytotoxic to RPE during prolonged contact. Because macrophage-like cells and class II major histocompatibility complex expression have been found in RP-affected retinas, immune-mediated cytopathologic effects may contribute to retinal degeneration in RP.

Stepwise risk stratification soon after acute myocardial infarction.

A stepwise rise stratification procedure sequentially combining historical and clinical characteristics and treadmill exercise test results was applied to 702 consecutive men aged less than or equal to 70 years who were alive 21 days after acute myocardial infarction (MI). Historical characteristics alone (prior MI and prior angina or recurrence of pain in the coronary care unit) identified 10% of patients with the highest rate of reinfarction and death within 6 months (18%). Clinical contraindications to exercise testing identified another 40% of patients with an intermediate rate of cardiac events (6.4%). In the 50% of patients who underwent treadmill testing 3 weeks after MI, the rate of cardiac events within 6 months was 4.4%: 3.9% in patients with a negative test and 9.7% in patients with a positive test (ischemic ST-segment depression greater than or equal to 0.2 mV and a peak heart rate less than or equal to 135 beats/min). Patients with negative treadmill tests, who comprised 46% of patients less than or equal to 70 years and 53% of patients less than or equal to 60 years, had a cardiac death rate of less than 2% in the 6 months after MI. The stepwise classification procedure correctly classified 72% of patients with hard medical events within 6 months. Thus, most patients who experience subsequent cardiac events are correctly classified on the basis of historical and clinical risk characteristics. In patients without these risk characteristics, early treadmill testing is useful for further discriminating high-risk from very low risk patients.

Comparative value of maximal treadmill testing, exercise thallium myocardial perfusion scintigraphy and exercise radionuclide ventriculography for distinguishing high- and low-risk patients soon after acute myocardial infarction.

The prognostic value of symptom-limited treadmill exercise electrocardiography, exercise thallium myocardial perfusion scintigraphy and rest and exercise radionuclide ventriculography was compared in 117 men, aged 54 +/- 9 years, tested 3 weeks after a clinically uncomplicated acute myocardial infarction (MI). During a mean follow-up period of 11.6 months, 8 men experienced "hard" medical events (cardiac death, nonfatal ventricular fibrillation or recurrent MI) and 14 were hospitalized for unstable angina pectoris, congestive heart failure or coronary bypass surgery (total of 22 combined events). By multivariate analysis (Cox proportional hazards model), peak treadmill work load and the change in left ventricular ejection fraction (EF) during exercise were significant (p less than 0.01) predictors of hard medical events; these 2 risk factors and recurrent ischemic chest pain in the coronary care unit were also significantly predictive (p less than 0.001) for combined events. A peak treadmill work load of 4 METs or less or a decrease in EF of 5% or more below the value at rest during submaximal effort distinguished 22 high-risk patients (20% of the study population) from 89 low-risk patients. The rate of hard medical events within 12 months was 23% (5 of 22 patients), vs 2% (2 of 89 patients) in the high- and low-risk patient subsets, respectively (p less than 0.001). Thus, in patients who underwent evaluation 3 weeks after a clinically uncomplicated MI, exercise radionuclide ventriculography contributed independent prognostic information to that provided by symptom-limited treadmill testing and was superior to exercise thallium scintigraphy for this purpose.

Medically directed at-home rehabilitation soon after clinically uncomplicated acute myocardial infarction: a new model for patient care.

Medically directed at-home rehabilitation was compared with group rehabilitation which began 3 weeks after clinically uncomplicated acute myocardial infarction (AMI) in 127 men, mean age 53 +/- 7 years. Between 3 and 26 weeks after AMI, adherence to individually prescribed exercise was equally high (at least 71%), the increase in functional capacity equally large (1.8 +/- 1.0 METs) and nonfatal reinfarction and dropout rates equally low (both 3% or less) in the 66 men randomized to home training and the 61 men randomized to group training. No training-related complications occurred in either group. The low rate of reinfarction and death (5% and 1%, respectively) in the study as a whole, which included 34 patients with no training and 37 control patients, reflected a stepwise process of clinical evaluation, exercise testing at 3 weeks and frequent telephone surveillance of patients who underwent exercise training. Medically directed at-home rehabilitation has the potential to increase the availability and to decrease the cost of rehabilitating low-risk survivors of AMI.

Cost-benefit analysis of early return to work after uncomplicated acute myocardial infarction.

The economic consequences of an Occupational Work Evaluation designed to identify low risk patients recovering from uncomplicated acute myocardial infarction (AMI) and hasten their return to work was evaluated in a randomized trial. Two hundred one employed, clinically low risk men recovering from AMI were randomized to undergo an intervention (intervention group, 99 patients) consisting of an Occupational Work Evaluation or to receive usual care (usual care group, 102 patients). The time to return to work was reduced from 75 days in usual care patients to 51 days in intervention patients (p less than 0.002). Significant differences were found between groups for medical costs and occupational income during follow-up. Total medical costs per patient were lower in the intervention patients than in the usual care patients in the 6 months after AMI ($2,970 vs $3,472). Occupational income per patient was higher in intervention patients than in the usual care group in the 6 months after AMI ($9,655 vs $7,553). The per capita benefit accounting for medical costs and occupational income was $6,685 for intervention patients and $4,081 for usual care patients. Projected to the greater than 300,000 low risk, employed survivors of AMI annually in this country, the savings generated by the Occupational Work Evaluation could yield an annual economic benefit greater than 800 million dollars.

Auditory P300 abnormalities and leukocyte activation in HIV infection.

To evaluate whether P300 testing might serve as a screening modality for the early detection of HIV-related neuropathology, we tested 26 HIV-infected men (23 without neurologic symptoms, 2 with peripheral neuropathy, 1 with AIDS-associated dementia) and 15 controls. Although they had no overt neurologic symptoms, the P300 latency was delayed or undetectable in 30% of patients without clinically evident neurologic disease. P300 latencies did not correlate with peripheral blood CD4 T-cell count, serum quinolinic acid or p24 antigen levels, or the numbers of activated peripheral blood monocytes. Three individuals with abnormal P300 latencies had been HIV-seropositive for < or = 1 year, suggesting that delayed evoked responses detect early neurologic dysfunction. P300 responses do not predict imminent dementia. In only one previously asymptomatic individual with abnormal P300 waveforms have overt neurologic symptoms developed during a 2-year followup. Extended longitudinal studies will be necessary to define the predictive value of P300 latencies in the development of AIDS-related dementia. However, the sensitivity, quantitative nature, and speed of administration of this test suggest that it may be useful for identification of early neurologic involvement in HIV infection.

A case of congenital inverse Duane's retraction syndrome.

Inverse Duane's retraction syndrome is very uncommon. Congenital cases are even more unusual. A 6-year-old girl with convergent squint along with severe restriction on abduction is described. On attempted abduction, a narrowing of the palpebral fissure, upshoot and retraction of the eyeball were observed. Brain and orbit MRI demonstrated no intracranial or intraorbital mass, fracture, or entrapment of the medial rectus. Forced duction test was strongly positive. The primary lesion was found to be a tight medial rectus with shortening and soft tissue contracture. Surgical tenotomy of the medial rectus led to successful postoperative motility, but some limitation at full adduction and abduction persisted. This is a case reported with congenital medial rectus shortening, suggesting that this condition may be one of the etiologies of the rare inverse Duane's retraction syndrome.

Neuro-Behcet's disease presenting with isolated unilateral lateral rectus muscle palsy.

The authors present the clinical findings of a 30-year-old female and a 29-year-old male who both had isolated unilateral lateral rectus muscle palsy in neuro-Behcet's disease. The clinical feature related to isolated abduscens nerve palsy was identified by CT, systemic assessment and extraocular examination. These patients' constellation of findings appear to be unique: it does not follow any previously reported pattern of ocular manifestations of neuro-Behcet's disease.

Acquired pendular nystagmus with voluntary inhibition.

This report documents a case of voluntary inhibition of acquired pendular nystagmus after head trauma. A 30-year-old male developed oscillopsia and decreased visual acuity, as well as findings of acquired pendular nystagmus with voluntary inhibition after head trauma. The EOG finding was horizontal 18-20 Hz bilateral symmetrical pendular nystagmus in all directions of gaze at near and distant fixation. Nystagmus did not change with 14 Prism Diopter base-out prisms on both eyes, but it was possible to abolish it intentionally. Baclofen and Clonazepam had no effect in improving the patient's symptoms and EOG finding.

Speech-spectrum analysis of Mandarin: implications for hearing-aid fittings in a multi-ethnic society.

Using similar recording and analysis techniques, the long-term average speech spectra of English and Mandarin were compared in order to identify difference that might influence hearing-aid fitting strategies. Despite the well-documented pitch contour differences between English and Mandarin, no significant difference was found in the long-term average spectral analysis. Implications for hearing-aid prescription are discussed.

Case studies in binaural interference: converging evidence from behavioral and electrophysiologic measures.

We present four case reports of elderly hearing-impaired persons demonstrating a binaural interference effect. Performance measures were poorer when stimulation was binaural than when it was monaural. In the first case the effect is shown for aided speech recognition scores. In the second case it is shown in topographic brain maps of the middle-latency auditory evoked potential. In the third and fourth cases it is shown for both aided speech recognition and the middle-latency response. The effect may be analogous to the phenomenon of binocular rivalry in the visual domain.

Asymmetries in topographic brain maps of auditory evoked potentials in the elderly.

We compared topographic brain maps of the middle response (MR) and late response (LR) auditory evoked potentials in two groups of elderly males. Subjects were categorized on the basis of the performance of the poorer hearing ear on the Synthetic Sentence Identification (SSI) test. Evoked potentials, obtained in response to 1000-Hz tone pips and tone bursts, were recorded under three conditions of sound stimulation:binaural (BIN), left ear only (LE), and right ear only (RE). Comparisons of the topographic brain maps generated by the two groups revealed significant asymmetry in the MR of the experimental group. LE stimulation produced a larger response over the right hemisphere, and RE stimulation produced a larger response over the left hemisphere. This asymmetry was not observed in the experimental group with binaural stimulation, or in the control group in any of the three stimulation conditions. An analogous asymmetry was not recognized in the LR in either group for any of the three sound conditions. Results are interpreted in relation to the recently proposed model of multiple middle latency generators.

Electrophysiologic indices of Stroop and Garner interference reveal linguistic influences on auditory and visual processing.

The purpose of this study was to examine linguistic influences on the auditory and visual processing of words both behaviorally and electrophysiologically. Our task yielded measures of the effect of irrelevant semantic content (Stroop interference) and of the effect of irrelevant linguistic variability (Garner interference). The behavioral results allow us to assess whether the linguistic and nonlinguistic dimensions of verbal stimuli are processed dependently or independently. The electrophysiologic results allow us to determine where any processing interactions are arising, particularly regarding perceptual versus postperceptual underpinnings, and to evaluate the similarity and dissimilarity between the two interference effects. Results show pronounced Stroop and Garner interference both behaviorally and electrophysiologically, indicating linguistic influences on auditory and visual processing. Subjects could not ignore the irrelevant linguistic dimension and attend selectively to the physical dimension of either spoken or written words. The results indicate that the physical and linguistic dimensions of words are not processed independently. With regard to the stage of processing underlying the interference effects, our results suggest that both Stroop and Garner interference involve multiple stages of processing. The two interference effects are not duplicate measures, however, and different electrophysiologic signatures were observed. Stroop interference is characterized by perceptual and postperceptual components. Similar electrophysiologic patterns within the auditory and visual modalities suggest that each interference effect is tapping similar processes for spoken and written stimuli.