Shorter preschool, leukocyte telomere length is associated with obesity at age 9 in Latino children.

The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages.

Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial.

BACKGROUND: The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. PATIENTS AND METHODS: We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). RESULTS: A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. CONCLUSIONS: Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

Race/ethnic differences in AD survival in US Alzheimer's Disease Centers.

OBJECTIVE: Survival after Alzheimer disease (AD) is poorly understood for patients of diverse race/ethnic groups. We examined whether nonwhite AD patients (African American, Latino, Asian, American Indian) had different rates of survival compared with white AD patients. METHODS: The National Alzheimer's Coordinating Center (NACC) cataloged data from more than 30 Alzheimer's Disease Centers in the United States from 1984 to 2005. Patients aged 65 years or older with a diagnosis of possible/probable AD were included (n = 30,916). Survival was calculated using Cox proportional hazards models with a primary outcome of time to death. Secondary outcomes of this study were neuropathologic characteristics on an autopsied subsample (n = 3,017). RESULTS: The 30,916 AD patients in the NACC were followed up for 2.4 +/- 2.9 years (mean age 77.6 +/- 6.5 years; 65% women; 19% nonwhite [12% African American, 4% Latino, 1.5% Asian, 0.5% American Indian, and 1% other]). Median survival was 4.8 years. African American and Latino AD patients had a lower adjusted hazard for mortality compared with white AD patients (African American hazard ratio [HR] 0.85, 95% CI 0.74 to 0.96; Latino HR 0.57, 95% CI 0.46 to 0.69). Asians and American Indians had similar adjusted hazards for mortality compared with white AD patients (p > 0.10 for both). African American and Latino autopsied AD patients had similar neuropathologic characteristics compared with white AD patients with similar clinical severity. CONCLUSIONS: African American and Latino Alzheimer disease (AD) patients may have longer survival compared with white AD patients. Neuropathology findings did not explain survival differences by race. Determining the underlying factors behind survival differences may lead to longer survival for AD patients of all race/ethnic backgrounds.

Pegfilgrastim +/- ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study.

BACKGROUND: TAC (docetaxel/doxorubicin/cyclophosphamide) is associated with high incidences of grade 4 neutropenia and febrile neutropenia (FN). This analysis compared the efficacies of four regimens for primary prophylaxis of FN and related toxic effects in breast cancer patients receiving neoadjuvant TAC. PATIENTS AND METHODS: Patients with stage T2-T4 primary breast cancer were scheduled to receive 6-8 cycles of TAC. Primary prophylaxis was: ciprofloxacin 500 mg orally twice daily on days 5-14 (n = 253 patients; 1478 cycles), daily granulocyte colony-stimulating factor (G-CSF) (filgrastim 5 microg/kg/day or lenograstim 150 microg/m(2)/day) on days 5-10 (n = 377; 2400 cycles), pegfilgrastim 6 mg on day 2 (n = 305; 1930 cycles), or pegfilgrastim plus ciprofloxacin (n = 321; 1890 cycles). RESULTS: Pegfilgrastim with/without ciprofloxacin was significantly more effective than daily G-CSF or ciprofloxacin in preventing FN (5% and 7% versus 18% and 22% of patients; all P < 0.001), grade 4 neutropenia, and leukopenia. Pegfilgrastim plus ciprofloxacin completely prevented first cycle FN (P < 0.01 versus pegfilgrastim alone) and fatal neutropenic events. CONCLUSION: Ciprofloxacin alone, or daily G-CSF from day 5-10 (as in common practice), provided suboptimal protection against FN and related toxic effects in patients receiving TAC. Pegfilgrastim was significantly more effective in this setting, especially if given with ciprofloxacin.

Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients--a double-blind, randomized study.

BACKGROUND: Classical hormone replacement therapy for hot flashes is contraindicated in breast cancer especially in endocrine responsive disease. PATIENTS AND METHODS: In a double-blind, randomized phase III study, breast cancer patients suffering from hot flashes at least twice a day, who were not taking any medication against hypertension and depression received either clonidine 0.075 mg twice a day or venlafaxine 37.5 mg twice a day for 4 weeks. The primary end point was defined as the frequency of hot flashes after 4 weeks of treatment. A self-reported 1-week hot flash and other symptom questionnaire were kept before the start of treatment until the end of treatment course. RESULTS: From April 2002 to October 2004, 80 patients were recruited of whom 64 were assessable for efficacy analyses. Thirty-three received clonidine and 31 venlafaxine, nine patients stopped early because of side-effects and seven withdrew consent. At the end of treatment week 4, the median hot flash frequency dropped by 7.6 hot flashes per day for patients receiving venlafaxine and 4.85 hot flashes per day for those receiving clonidine (P = 0.025). CONCLUSION: Venlafaxine is significantly more effective in reducing the frequency of hot flashes in breast cancer patients than clonidine.

Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions.

The cytolytic activity of NK cells is tightly regulated by inhibitory receptors specific for MHC class I Ags. We have investigated the composition of signal transduction molecules in the supramolecular activation clusters in the MHC class I-regulated cytolytic and noncytolytic NK cell immune synapses. KIR2DL3-positive NK clones that are specifically inhibited in their cytotoxicity by HLA-Cw*0304 and polyclonal human NK cells were used for conjugate formation with target cells that are either protected or are susceptible to NK cell-mediated cytotoxicity. Polarization of talin, microtubule-organizing center, and lysosomes occurred only during cytolytic interactions. The NK immune synapses were analyzed by three-dimensional immunofluorescence microscopy, which showed two distinctly different synaptic organizations in NK cells during cytolytic and noncytolytic interactions. The center of a cytolytic synapse with MHC class I-deficient target is comprised of a complex of signaling molecules including Src homology (SH)2-containing protein tyrosine phosphatase-1 (SHP-1). Closely related molecules with overlapping functions, such as the Syk kinases, SYK, and ZAP-70, and adaptor molecules, SH2 domain-containing leukocyte protein of 76 kDa and B cell linker protein, are expressed in activated NK cells and are all recruited to the center of the cytolytic synapse. In contrast, the noncytolytic synapse contains SHP-1, but is lacking other components of the central supramolecular activation cluster. These findings indicate a functional role for SHP-1 in both the cytolytic and noncytolytic interactions. We also demonstrate, in three-cell conjugates, that a single NK cell forms a cytolytic synapse with a susceptible target cell in the presence of both susceptible and nonsusceptible target cells.

Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study.

OBJECTIVE: To examine the association between postmenopausal hormone replacement therapy (HRT) and the trajectory of global cognitive change with age. METHODS: The Modified Mini-Mental State Examination (MMSE) was administered to a population sample of 2,073 nondemented, community-dwelling female residents of Cache County, UT, aged 65 and older. Current and past HRT and other medications at a baseline interview and at follow-up 3 years later were assessed. Between interviews, a telephone Women's Health Questionnaire was administered to assess initial exposure, duration, and recency of HRT. Generalized estimating equation marginal models were used to evaluate the cross-sectional and longitudinal relations of HRT and modified MMSE score. Also assessed were effects with multivitamins and calcium supplements as exposures likely to reflect a "healthy lifestyle" among HRT users. Model covariates included the presence of APOE epsilon4 alleles, age, education, concurrent depression, several chronic diseases, and self-perceived general health. RESULTS: Age, lower education, depression, and APOE epsilon4 were all associated with lower baseline modified MMSE scores. With these covariates in the model, lifetime HRT use was associated with better baseline modified MMSE scores and a slower rate of decline. Stratification by APOE genotype did not alter these effects. Apparent benefits with HRT were attenuated but remained significant after elimination of scores from participants with incident dementia. A significant interaction between age and HRT indicated the strongest effects in women aged 85 and older. Measures of age at initial use of HRT, duration, and recency of exposure did not improve the models. No effects were seen with the "healthy lifestyle" control exposures. CONCLUSIONS: In a population cohort of older women, lifetime HRT exposure was associated with improved global cognition and attenuated decline over a 3-year interval. Improvements were greatest in the oldest old.

The declining prevalence of hepatitis B virus infection among Asian and Pacific Islander children.

PURPOSE: This article provides a review of the literature on the decline of hepatitis B virus (HBV) infection in Asian and Pacific nations having universal hepatitis B immunization programs. METHODS: Papers on the epidemiology of HBV infection and hepatitis B immunization programs in Asian and Pacific nations were located by searching MEDLINE and libraries for publications in English, and by contacting hepatitis B experts. PRINCIPAL FINDINGS: High endemicity for HBV in Asian and Pacific nations was partly caused by a cycle of high infectiousness, perinatal transmission, and chronic infection from early ages. Higher prevalence of infection has been found in men, some families, communities, and ethnic groups, and in people with high risk behaviors and situations, such as attending day care, getting injections, or sharing personal items. Incidence of acquisition of infection is about 2%-5% per year. Prevalence of HBV infection was declining in some nations before commencing hepatitis B immunization programs, probably because of improvements in medical practices and living conditions. Twenty-seven of 34 Pacific and East and Southeast Asian nations have attained >70% hepatitis B vaccination coverage in infants, and twelve have documented reducing infection or liver cancer to fractions of their former rates. But the immunization programs may be causing natural selection of mutant hepatitis B viruses, necessitating study of the mutants, and modification of serological tests and vaccines. CONCLUSIONS: Practical implications for U.S. health professionals are: increasing HBV screening and hepatitis B vaccination of adolescents and adults from Asian and Pacific nations can prevent many infections and disease cases; most children coming from high coverage Asian and Pacific nations will be immune and few infected; we can learn much from these successful programs; and we should still make efforts to immunize Asian and Pacific children in the United States, and help Asian and Pacific nations which do not yet have highly successful hepatitis B immunization programs.

Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study.

UNLABELLED: AIMS AND SUBJECTS: We investigated the prospective relationship between thyroid status and the risk of dementia and Alzheimer's disease among a random sample of 1843 participants, aged 55 years and over, from the population-based prospective Rotterdam Study. METHODS: Thyroid status was measured at baseline (1990-93), through assessment of serum antibodies to thyroid peroxidase (TPO-Abs, positive: >10 IU/ml), serum TSH levels, and when TSH was abnormal (<0.4 or >4.0 mU/l), serum thyroxin levels (T4). At baseline and at follow up, after on average 2 years, participants were screened for dementia. Diagnoses were based on international criteria. RESULTS: Persons with reduced TSH levels at baseline had a more than threefold increased risk of dementia (RR = 3.5, 95%CI: 1.2-10.0) and of Alzheimer's disease (RR = 3.5, 95%CI: 1.1-11.5), after adjustment for age and sex. Among persons with reduced TSH levels, T4 levels appeared to be positively related to the risk of dementia (RR per SD increase = 2.9, 95%CI: 0.7-12.2), although none of those who became demented had a T4 level above the normal range (>140 nmol/l). The risk of dementia was especially increased in subjects with low TSH who were positive for TPO-Abs (RR = 23.7, 95%CI: 4.0-140). CONCLUSIONS: This is the first prospective study to suggest that subclinical hyperthyroidism in the elderly increases the risk of dementia and Alzheimer's disease.

Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study.

OBJECTIVE: To investigate the relation between head trauma and incidence of dementia in a prospective population-based study. BACKGROUND: Whether head trauma increases the risk of dementia and AD remains controversial. It has been suggested that the risk might be particularly increased for carriers of the APOE-epsilon4 allele. METHODS: The study population included 6645 participants of the prospective population-based Rotterdam Study, aged 55 years or older, who were free of dementia at baseline. Head trauma with loss of consciousness was measured at baseline by a self-report to a physician and detailed the number of head traumas, time since head trauma, and duration of loss of consciousness. The cohort was followed for incident dementia that was diagnosed according to international criteria. Logistic regression was used to calculate the risk of dementia after adjusting for age, gender, and education. RESULTS: No increased risk of dementia or AD was found for persons with a history of head trauma with loss of consciousness (relative risk [RR] for dementia = 1.0, 95% CI, 0.5-2.0; RR for AD = 0.8, 95% CI, 0.4-1.9). Multiple head traumas, time since head trauma, and duration of unconsciousness did not significantly influence the risk of dementia. In addition, the APOE-epsilon4 allele did not modify the relationship. CONCLUSIONS: This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly. In addition, this study does not concur with previous cross-sectional studies suggesting an interaction with the APOE genotype.