Cilia are found on most human cells and exist as motile cilia or non-motile primary cilia. Primary cilia play sensory roles in transducing various extracellular signals, and defective ciliary functions are involved in a wide range of human diseases. Centrosomes are the principal microtubule-organizing centers of animal cells and contain two centrioles. We observed that DNA damage causes centriole splitting in non-transformed human cells, with isolated centrioles carrying the mother centriole markers CEP170 and ninein but not kizuna or cenexin. Loss of centriole cohesion through siRNA depletion of C-NAP1 or rootletin increased radiation-induced centriole splitting, with C-NAP1-depleted isolated centrioles losing mother markers. As the mother centriole forms the basal body in primary cilia, we tested whether centriole splitting affected ciliogenesis. While irradiated cells formed apparently normal primary cilia, most cilia arose from centriolar clusters, not from isolated centrioles. Furthermore, C-NAP1 or rootletin knockdown reduced primary cilium formation. Therefore, the centriole cohesion apparatus at the proximal end of centrioles may provide a target that can affect primary cilium formation as part of the DNA damage response.
centrosome; DNA damage response; kizuna; C-NAP1; NEK2
Alcohol consumption and mammographic density are established risk factors for breast cancer. This study examined whether the association of mammographic density with breast cancer varies by alcohol intake. Mammographic density was assessed in digitized images for 1,207 cases and 1,663 controls from three populations (Japan, Hawaii, California) using a computer-assisted method. Associations were estimated by logistic regression. When comparing ever to never drinking, mean density was similar and consumption was not associated with breast cancer risk. However, within the Hawaii/Japan subset, women consuming >1 drink/day had a non-significantly elevated relative risk compared to never drinkers. Also in the Hawaii/Japan population, alcohol intake only modified the association between mammographic density and breast cancer in women consuming >1 drink/day (pinteraction=0.05) with significant risk estimates of 3.65 and 6.58 for the 2nd and 3rd density tertiles as compared to 1.57 and 1.61 for never drinkers in Hawaii/Japan. Although these findings suggest a stronger association between mammographic density and breast cancer risk for alcohol consumers, the small number of cases requires caution in interpreting the results.
breast cancer; alcohol; mammographic density; case-control study; pooling
Composition of dietary fatty acid intake, which influences cytokine production, may contribute to the development of non-Hodgkin’s lymphoma (NHL). Serum lipid levels may serve as biomarkers of inflammation associated with NHL risk.
We conducted a case-control analysis (275 cases and 549 controls) nested within the Multiethnic Cohort Study (whites, Japanese Americans, Latinos, African Americans, and Native Hawaiians) to examine the association of pre-diagnostic, erythrocyte membrane phospholipid fatty acid composition and serum cholesterol and triglyceride (TG) concentrations with the risk of NHL. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) by tertiles of biomarker concentrations.
Higher total saturated fatty acids (SFA) were associated with an increase in NHL risk (ORT3 vs. T1=1.57 [95% CI: 1.03-2.39]; ptrend=0.01), whereas no associations were detected for total n-3 or n-6 polyunsaturated fatty acids. Inverse associations were observed for total cholesterol (TC; OR T3 vs. T1=0.51 [95% CI: 0.35, 0.74]; ptrend <0.0001) and high-density lipoprotein cholesterol (HDL-C; OR T3 vs. T1=0.47 [95% CI: 0.31, 0.71]; ptrend =0.0001) but not for low-density lipoprotein cholesterol or TG. Adjustment for the use of lipid-lowering medication did not modify the results substantially.
This prospective biomarker investigation offers supportive evidence for an adverse effect of higher erythrocyte membrane SFA levels on NHL risk, but preclinical effects cannot be excluded. Inverse relations between pre-diagnostic, circulating TC and HDL-C and NHL risk may be due to reverse causation or a result of protective actions of these lipids and lipoproteins.
non-Hodgkin lymphoma; fatty acids; serum lipids; multiethnic population; nested case-control study
Arterial stiffness decreases with weight loss in overweight/obese young adults. We aimed to determine the mechanisms by which this occurs.
We evaluated carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV) in 344 young adults (23% male, BMI 25–40 kg/m2) at baseline, 6, and 12 months in a behavioral weight loss intervention. Linear mixed models were used to evaluate associations between weight loss and arterial stiffness and to examine whether improvements in obesity-related factors explained these associations.
At 6 months (7% mean weight loss), there was a significant median decrease of 47.5 cm/s in cfPWV (p<0.0001) and a mean decrease of 11.7 cm/s in baPWV (p=0.049). At 12 months (6% mean weight loss), only cfPWV remained reduced. In models adjusting for changes in mean arterial pressure and obesity-related factors, changes in BMI (p=0.01) and common carotid artery diameter (p=0.003) were positively associated with change in cfPWV. Reductions in heart rate (p<0.0001) and C-reactive protein (p=0.02) were associated with reduced baPWV and accounted for the association between weight loss and reduced baPWV.
Weight loss is associated with reduced cfPWV independently of changes in established hemodynamic and cardiometabolic risk factors, but its association with reduced baPWV is explained by concurrent reductions in heart rate and inflammation.
arterial stiffness; obesity; lifestyle modification
Diabetes distress is a general term that refers to the emotional burdens, anxieties, frustrations, stressors and worries that stem from managing a severe, complex condition like Type 1 diabetes. To date there has been limited research on diabetes-related distress in younger people with Type 1 diabetes. This qualitative study aimed to identify causes of diabetes distress in a sample of young adults with Type 1 diabetes.
Semi-structured interviews with 35 individuals with Type 1 diabetes (23–30 years of age).
This study found diabetes related-distress to be common in a sample of young adults with Type 1 diabetes in the second phase of young adulthood (23–30 years of age). Diabetes distress was triggered by multiple factors, the most common of which were: self-consciousness/stigma, day-to-day diabetes management difficulties, having to fight the healthcare system, concerns about the future and apprehension about pregnancy. A number of factors appeared to moderate distress in this group, including having opportunities to talk to healthcare professionals, attending diabetes education programmes and joining peer support groups. Young adults felt that having opportunities to talk to healthcare professionals about diabetes distress should be a component of standard diabetes care.
Some aspects of living with diabetes frequently distress young adults with Type 1 diabetes who are in their twenties. Clinicians should facilitate young adults’ attendance at diabetes education programmes, provide them with opportunities to talk about their diabetes-related frustrations and difficulties and, where possible, assist in the development of peer-support networks for young adults with diabetes.
Young adult; Distress; Qualitative; Type 1 diabetes; Emerging adulthood
To prospectively examine alterations in working memory (WM) –associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging.
Patients and Methods
Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx−; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx− and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001.
At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx−), with prominent alterations in the frontal lobes bilaterally.
Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.
Centrosomes, the principal microtubule-organising centres in animal cells, contain centrins, small, conserved calcium-binding proteins unique to eukaryotes. Centrin2 binds to xeroderma pigmentosum group C protein (XPC), stabilising it, and its presence slightly increases nucleotide excision repair (NER) activity in vitro. In previous work, we deleted all three centrin isoforms present in chicken DT40 cells and observed delayed repair of UV-induced DNA lesions, but no centrosome abnormalities. Here, we explore how centrin2 controls NER. In the centrin null cells, we expressed centrin2 mutants that cannot bind calcium or that lack sites for phosphorylation by regulatory kinases. Expression of any of these mutants restored the UV sensitivity of centrin null cells to normal as effectively as expression of wild-type centrin. However, calcium-binding-deficient and T118A mutants showed greatly compromised localisation to centrosomes. XPC recruitment to laser-induced UV-like lesions was only slightly slower in centrin-deficient cells than in controls, and levels of XPC and its partner HRAD23B were unaffected by centrin deficiency. Interestingly, we found that overexpression of the centrin interactor POC5 leads to the assembly of linear, centrin-dependent structures that recruit other centrosomal proteins such as PCM-1 and NEDD1. Together, these observations suggest that assembly of centrins into complex structures requires calcium binding capacity, but that such assembly is not required for centrin activity in NER.
While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3’,5’-monophosphate (cAMP) signaling may contribute to schizophrenia pathology. As cAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor-detection thresholds to two odorants that differ in the degree to which they activate intracellular cAMP were assessed in clinical risk and low-risk participants.
Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n = 17) and controls at low risk for developing psychosis (n = 15). Citralva and lyral are odorants that differ in cAMP activation; citralva is a strong cAMP activator and lyral is a weak cAMP activator.
The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy.
This study extends prior findings of an odor-specific hyposmia implicating cAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of cAMP signaling may be present during the psychosis prodrome.
schizophrenia prodrome; ultra high risk; cAMP; adenosine cyclase; DISC1
Self-monitoring for weight loss has traditionally been performed with paper diaries. Technologic advances could reduce the burden of self-monitoring and provide feedback to enhance adherence.
To determine if self-monitoring diet using a PDA only or the PDA with daily tailored feedback (PDA+FB), was superior to using a paper diary on weight loss and maintenance.
The Self-Monitoring and Recording Using Technology (SMART) Trial was a 24-month RCCT; participants were randomly assigned to one of three self-monitoring groups.
From 2006 to 2008, 210 overweight/obese adults (84.8% female, 78.1% white) were recruited from the community. Data were analyzed in 2011.
Participants received standard behavioral treatment for weight loss which included dietary and physical activity goals, encouraged the use of self-monitoring, and was delivered in group sessions.
Main outcome measures
Percentage weight change at 24 months, adherence to self-monitoring over time.
Study retention was 85.6%. The mean percentage weight loss at 24 months was not different among groups (paper diary: −1.94% [95% CI= −3.88, 0.01], PDA: −1.38% [95% CI= – 3.38, 0.62], PDA+FB: –2.32% [95% CI= –4.29, −0.35]); only the PDA+FB group (p=0.02) demonstrated a significant loss. For adherence to self-monitoring, there was a time-by-treatment group interaction between the combined PDA groups and the paper diary group (p=0.03) but no difference between PDA and PDA+FB groups (p=0.49). Across all groups, weight loss was greater for those who were adherent ≥60% versus <30% of the time, p<0.001.
PDA+FB use resulted in a small weight loss at 24 months; PDA use resulted in greater adherence to dietary self-monitoring over time. However, for sustained weight loss, adherence to self-monitoring is more important than the method used to self-monitor. A daily feedback message delivered remotely enhanced adherence and improved weight loss, which suggests that technology can play a role in improving weight loss.
Brain gray matter alterations have been reported in cross-sectional magnetic resonance imaging (MRI) studies of breast cancer patients after cancer treatment. Here we report the first prospective MRI study of women undergoing treatment for breast cancer, with or without chemotherapy, as well as healthy controls. We hypothesized that chemotherapy-associated changes in gray matter density would be detectable 1 month after treatment, with partial recovery 1 year later. Participants included breast cancer patients treated with (CTx+, N = 17) or without (CTx–, N = 12) chemotherapy and matched healthy controls (N = 18). MRI scans were acquired at baseline (after surgery but before radiation, chemotherapy, and/or anti-estrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1). Voxel-based morphometry (VBM) was used to evaluate gray matter density differences between groups and over time. There were no between-group gray matter differences at baseline. Group-by-time interactions showed declines from baseline to M1 in both cancer groups relative to controls. Within-group analyses indicated that at M1 relative to baseline the CTx+ group had decreased gray matter density in bilateral frontal, temporal, and cerebellar regions and right thalamus. Recovery was seen at Y1 in some regions, although persistent decreases were also apparent. No significant within-group changes were found in the CTx– or control groups. Findings were not attributable to recency of cancer surgery, disease stage, psychiatric symptoms, psychotropic medication use, or hormonal treatment status. This study is the first to use a prospective, longitudinal approach to document decreased brain gray matter density shortly after breast cancer chemotherapy and its course of recovery over time. These gray matter alterations appear primarily related to the effects of chemotherapy, rather than solely reflecting host factors, the cancer disease process, or effects of other cancer treatments.
Adjuvant chemotherapy; Brain; Breast cancer; Magnetic resonance imaging; Neuroimaging
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth.
BACKGROUND AND PURPOSE
IL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development.
In vitro the potency, specificity and species selectivity of CAT-354 was assayed in TF-1 cells, human umbilical vein endothelial cells and HDLM-2 cells. The ability of CAT-354 to modulate disease-relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT-354 was tested on human IL-13-induced air pouch inflammation in mice, ovalbumin-sensitization and challenge in IL-13 humanized mice and antigen challenge in cynomolgus monkeys.
CAT-354 has a 165 pM affinity for human IL-13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL-13. CAT-354 did not neutralize human IL-4. In vitro CAT-354 functionally inhibited IL-13-induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT-354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia.
CONCLUSIONS AND IMPLICATIONS
CAT-354 is a potent and selective IL-13-neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.
CAT-354; IL-13; IgG4; preclinical development for asthma; uncontrolled asthma; therapeutic antibody; asthma treatment
Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2μM of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p<0.05) demonstrating synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p<0.05) and revealed 29 common genes affected by both signaling. Among the genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heat-shock and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways.
Colon cancer; FAK; gene expression; hyaluronan; silenced RNA; viability
The association of mammographic breast density with breast cancer risk may vary by adiposity. To examine effect modification by body mass index (BMI), the authors standardized mammographic density data from four case-control studies (1994–2002) conducted in California, Hawaii, and Minnesota, and Gifu, Japan. The 1,699 cases and 2,422 controls included 45% Caucasians, 40% Asians, and 9% African-Americans. Using ethnic-specific BMI cut points, 34% were classified as overweight and 19% as obese. A single reader assessed density from mammographic images using a computer-assisted method. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) while adjusting for potential confounders. Modest heterogeneity in the relation between percent density and breast cancer risk across studies was observed (pheterogeneity = 0.08). Cases had a greater age-adjusted mean percent density than controls: 31.7% versus 28.5%, respectively (p <0.001). Relative to <20 percent density, the ORs for >35 were similar across BMI groups whereas the OR for 20–35 was slightly higher in overweight (OR = 1.69, 95% CI: 1.28, 2.24) and obese (OR = 1.62, 95% CI: 1.12, 2.33) than in normal weight women (OR = 1.49, 95% CI: 1.11, 2.01). Furthermore, limited evidence of effect modification by BMI of the OR per 10% increase in percent density (pinteraction = 0.06) was observed, including subgroup analyses by menopausal status and in analyses that excluded women at the extremes of the BMI scale. Our findings indicate little, if any, modification by BMI of the effects of breast density on breast cancer risk.
Adiposity; breast cancer incidence; body mass index; ethnicity; mammographic density; risk factor
The Women on the Move through Activity and Nutrition (WOMAN) study was designed to test whether a nonpharmacological intervention including qualitative and quantitative dietary changes to induce weight loss and increased physical activity levels would reduce blood triglyceride levels and number of low-density lipoprotein particles (LDL-P). Such decreases in lipoproteins and other risk factors could reduce or slow progression of subclinical cardiovascular disease (CVD). Study participants were randomized to either the intervention (Lifestyle Change) or assessment (Health Education) group. Most of the intervention ended at the 30-month visit. The last 48-month examination was completed in 9/2008. There was very substantial weight loss and increased exercise during the first 30 months of the trial resulting in significant decreases in CV risk factors. Most of the intervention effect was lost through 48 months. Weight loss was 3.4 kg in Lifestyle Intervention and 0.2 kg in the Health Education at 48 months (P = 0.000). There were no significant changes at 48 months in lipid levels, blood pressure (BP), glucose, insulin, or in the subclinical measures of coronary calcium, carotid intima media thickness, or plaque. There was a significant decrease in long-distance corridor walk time in the Lifestyle vs. Health Education groups. Significant lifestyle changes can be achieved that result in decreases in CV risk factors. Whether such changes reduce CV outcomes is still untested in clinical trials of weight loss or exercise. Long-term maintenance of successful lifestyle changes, weight loss and reduced risk factors is the hurdle for lifestyle interventions attempting to prevent CV and other chronic diseases.
To examine the individual and combined associations of leisure-time physical activity and sleep with cardiovascular risk factors in postmenopausal women.
We analyzed cross-sectional 48-month follow-up data from 393 participants of the Woman on the Move through Activity and Nutrition (WOMAN) Study, a behavioral weight loss trial. Leisure-time physical activity data were collected with the past year Modifiable Activity Questionnaire; sleep data were collected with the Pittsburgh Sleep Quality Index. We compared physical activity and sleep categories using ANOVA, post hoc Scheffe tests, and multivariate analyses based on groups above/below median leisure-time physical activity level, above/below below sleep quality value = 5, and above/below sleep duration of 7 hrs/day.
The average sleep quality and sleep duration did not significantly differ between women with high and low physical activity levels. When comparing women with good sleep quality, higher physical activity levels were associated lower BMI (2.0 kg/m2; 0.3, 3.6), waist circumference (6.3 cm; 1.7, 10.9), and total body fat (2.1 %; 0.3, 4.0) (p<0.05). When comparing participants with poor sleep quality, highly active women had lower trunk fat, total body fat, and insulin levels than less active women (p<0.05). In multivariate analysis, physical activity was significantly associated with HDL, trunk fat, and total body fat after controlling for sleep quality, sleep duration, age, hormone therapy, smoking, and BMI.
The combined associations of leisure-time physical activity and sleep suggest that cardiovascular risk factors were more favorable in highly active women relative to less active women regardless of sleep.
Physical activity; sleep; cardiovascular risk factors; menopause
Mammographic density is strongly and consistently associated with breast cancer risk. To determine if this association was modified by reproductive factors (parity and age at first birth), data were combined from four case-control studies conducted in the United States and Japan. To overcome the issue of variation in mammographic density assessment among the studies, a single observer re-read all the mammograms using one type of interactive thresholding software. Logistic regression was used to estimate odds ratios (OR) while adjusting for other known breast cancer risk factors. Included were 1699 breast cancer cases and 2422 controls, 74% of whom were postmenopausal. A positive association between mammographic density and breast cancer risk was evident in every group defined by parity and age at first birth (OR per doubling of percent mammographic density ranged between 1.20 and 1.39). Nonetheless, the association appeared to be stronger among nulliparous than parous women (OR per doubling of percent mammographic density = 1.39 vs 1.24; P-interaction = 0.054). However, when examined by study location, the effect modification by parity was apparent only in women from Hawaii and when examined by menopausal status, it was apparent in postmenopausal, but not premenopausal, women. Effect modification by parity was not significant in subgroups defined by body mass index or ethnicity. Adjusting for mammographic density did not attenuate the OR for the association between parity and breast cancer risk by more than 16.4% suggesting that mammographic density explains only a small proportion of the reduction in breast cancer risk associated with parity. In conclusion, this study did not support the hypothesis that parity modifies the breast cancer risk attributed to mammographic density. Even though an effect modification was found in Hawaiian women, none was found in women from the other three locations.
Breast neoplasms; mammographic density; reproductive factors; epidemiology; risk factor; effect modification
Women gain visceral fat during pregnancy. Studies examining the impact of breastfeeding on maternal body composition are inconclusive. We examined the extent to which breastfeeding was associated with visceral adiposity in a sample of US women. This was a cross-sectional analysis of 351 women aged 45–58 years, who were free of clinical cardiovascular disease and had not used oral contraceptives or hormone replacement therapy in the 3 months prior to enrollment in the Study of Women’s Health Across the Nation (SWAN)-Heart Study (2001–2003). History of breastfeeding was self-reported. Computed tomography was used to assess abdominal adiposity. Among premenopausal/early-peri-menopausal mothers, those who never breastfed had 28% greater visceral adiposity (95% confidence interval (CI): 11–49, P = 0.001), 4.7% greater waist-hip ratio (95% CI: 1.9–7.4, P < 0.001), and 6.49 cm greater waist circumference (95% CI: 3.71–9.26, P < 0.001) than mothers who breastfed all of their children for ≥3 months in models adjusting for study site; age; parity; years since last birth; socioeconomic, lifestyle, and family history variables; early adult BMI; and current BMI. In comparison to women who were nulliparous, mothers who breastfed all of their children for ≥3 months had similar amounts of visceral fat (P > 0.05). In contrast, premenopausal/early-peri-menopausal mothers who had never breastfed had significantly greater visceral adiposity (42% (95% CI: 17–70), P < 0.001), waist circumference (6.15 cm (95% CI: 2.75–9.56), P < 0.001), and waist-hip ratio (3.7% (95% CI: 0.69–6.8), P = 0.02) than nulliparous women. No significant relationships were observed among late peri-menopausal/postmenopausal women. In conclusion, until menopause, mothers who did not breastfeed all of their children for ≥3 months exhibit significantly greater amounts of metabolically active visceral fat than mothers who had breastfed all of their children for ≥3 months.
The metabolic syndrome (MetS) is associated with an increase in breast cancer risk. In this study, we evaluated whether the MetS was associated with an increase in percent mammographic density (MD), a breast cancer risk factor. We used linear regression and mixed models to examine the cross-sectional and longitudinal associations of the MetS and components of the MetS to percent MD in 790 pre- and early perimenopausal women enrolled in the Study of Women’s Health Across the Nation (SWAN). In cross-sectional analyses adjusted for body mass index (BMI), modest inverse associations were observed between percent MD and the MetS (β = −2.5, SE = 1.9, p = 0.19), abdominal adiposity (β = −4.8, SE = 1.9, p = 0.01) and raised glucose (β = −3.7, SE = 2.4, p = 0.12). In longitudinal models adjusted for covariates including age and BMI, abdominal adiposity (β = 0.34, SE = 0.17, p = 0.05) was significantly positively associated with slower annual decline in percent MD with time. In conclusion, our results do not support the hypothesis that the MetS increases breast cancer risk via a mechanism reflected by an increase in percent MD.
adiposity; body mass index; breast cancer risk factor; mammographic density; metabolic syndrome
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
A systematic review, with or without a meta-analysis, should be undertaken to determine if the research question of interest has already been answered before a new trial begins. There has been limited research on how systematic reviews are used within the design of new trials, the aims of this study were to investigate how systematic reviews of earlier trials are used in the planning and design of new randomised trials.
Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) between 2006 and 2008 were obtained. This included the: commissioning brief (if appropriate), outline application, minutes of the Board meeting in which the outline application was discussed, full application, detailed project description, referee comments, investigator response to referee comments, Board minutes on the full application and the trial protocol. Data were extracted on references to systematic reviews and how any such reviews had been used in the planning and design of the trial.
50 randomised trials were funded by NIHR HTA during this period and documentation was available for 48 of these. The cohort was predominately individually randomised parallel trials aiming to detect superiority between two treatments for a single primary outcome. 37 trials (77.1%) referenced a systematic review within the application and 20 of these (i.e. 41.7% of the total) used information contained in the systematic review in the design or planning of the new trial. The main areas in which systematic reviews were used were in the selection or definition of an outcome to be measured in the trial (7 of 37, 18.9%), the sample size calculation (7, 18.9%), the duration of follow up (8, 21.6%) and the approach to describing adverse events (9, 24.3%). Boards did not comment on the presence/absence or use of systematic reviews in any application.
Systematic reviews were referenced in most funded applications but just over half of these used the review to inform the design. There is an expectation from funders that applicants will use a systematic review to justify the need for a new trial but no expectation regarding further use of a systematic review to aid planning and design of the trial. Guidelines for applicants and funders should be developed to promote the use of systematic reviews in the design and planning of randomised trials, to optimise delivery of new studies informed by the most up-to-date evidence base and to minimise waste in research.
Systematic review; Meta-analysis; Randomised controlled trial; Planning; Design
In vivo and direct imaging of the murine spinal cord and its vasculature using multimodal (optical and acoustic) imaging techniques could significantly advance preclinical studies of the spinal cord. Such intrinsically high resolution and complementary imaging technologies could provide a powerful means of quantitatively monitoring changes in anatomy, structure, physiology and function of the living cord over time after traumatic injury, onset of disease, or therapeutic intervention. However, longitudinal in vivo imaging of the intact spinal cord in rodent models has been challenging, requiring repeated surgeries to expose the cord for imaging or sacrifice of animals at various time points for ex vivo tissue analysis. To address these limitations, we have developed an implantable spinal cord window chamber (SCWC) device and procedures in mice for repeated multimodal intravital microscopic imaging of the cord and its vasculature in situ. We present methodology for using our SCWC to achieve spatially co-registered optical-acoustic imaging performed serially for up to four weeks, without damaging the cord or induction of locomotor deficits in implanted animals. To demonstrate the feasibility, we used the SCWC model to study the response of the normal spinal cord vasculature to ionizing radiation over time using white light and fluorescence microscopy combined with optical coherence tomography (OCT) in vivo. In vivo power Doppler ultrasound and photoacoustics were used to directly visualize the cord and vascular structures and to measure hemoglobin oxygen saturation through the complete spinal cord, respectively. The model was also used for intravital imaging of spinal micrometastases resulting from primary brain tumor using fluorescence and bioluminescence imaging. Our SCWC model overcomes previous in vivo imaging challenges, and our data provide evidence of the broader utility of hybridized optical-acoustic imaging methods for obtaining multiparametric and rich imaging data sets, including over extended periods, for preclinical in vivo spinal cord research.
To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder (RCBD) and comorbid substance abuse and/or dependence.
A 6-month, double-blind, parallel group comparison was carried out in recently manic/hypomanic/mixed patients who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy.
Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%; nonresponse: 25%; intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% relapsed (24% into depression and 76% into a manic/hypomanic/mixed episode), 26% completed the study, and 19% were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (p=NS). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% and 53%, respectively. The rate of depressive relapse in both arms was 13%, while the rate of relapse into a manic, hypomanic, or mixed episode was 44% for lithium monotherapy and 40% for the combination of lithium and divalproex.
A small subgroup of patients in this study stabilized after six months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of RCBD in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.
Bipolar disorder; Rapid cycling; Dual-diagnosis; Substance use disorder; Maintenance trial; Placebo-controlled trial; Lithium; Divalproex; Combination pharmacotherapy
Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the EPR-3, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.
Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.
Twenty-six established asthma investigators, who are part of the NIH-supported Inner City Asthma Consortium (ICAC), participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma using the Asthma Control Evaluation (ACE) trial. CASI was validated using the Inner City Anti-IgE Therapy for Asthma (ICATA) trial.
CASI scores include five domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At ACE enrollment, CASI ranged from 0 to 17 with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than symptoms alone.
CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity, and provide a composite clinical characterization of asthma.
Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity