• Sleep Debt Makes the Brain Hypersensitive to Food Cues
• “Metabolically Healthy Obesity”: What's the Risk?
• Endometriosis Is Averted by Breast-Feeding
• Does Cutting Dietary Fat Affect Breast Cancer Outcomes?
• High-Fat Diets Were Associated with Lower 7-Year Mortality
• Insulin Pump Superior to Insulin Injection for Type 1 Diabetes Mellitus
• Preserving Ovarian Function in Young Women with Breast Cancer
• Comorbidities Delay Multiple Sclerosis Diagnosis and Increase Mortality
• Understanding the Pathogenesis of Alzheimer Disease
• Systolic Blood Pressure, Cognition, and Race
• Antidepressant Use During Pregnancy may Raise Risk for Psychiatric Illness in Offspring
Sleep 2017 Aug 21
Sleep Debt Makes the Brain Hypersensitive to Food Cues
Ordinary levels of sleep debt, even in people who aren't aware that they need sleep, increases appetite and brain reactivity to visual food stimuli.
Obesity is a major public health problem and is associated with lack of sleep in epidemiological studies. In sleep laboratories, total sleep deprivation increased activation in the brain's reward network, but researchers have not previously addressed the effects of everyday sleep debt on brain activation.
This laboratory study enrolled 15 normal-weight healthy participants reporting an average in-home sleep time of 7.3 hours. In the extended sleep (ES) period, they were allowed to sleep freely (≤12 hours/day) for 9 days. All participants initially increased their sleep time and then decreased it to an average of 8.5 hours by the 9th night (measured with wrist actigraph and sleep diary), indicating that at baseline they had sleep debt. Subsequently, all underwent 39 hours of total sleep deprivation (TSD). Daily energy intake was controlled throughout the study.
Self-reported morning appetite levels were the lowest after ES and the highest at baseline and after TSD. Functional magnetic resonance imaging was conducted during 8-hour fasting while participants viewed food and nonfood images. In analyses controlling for appetite levels, amygdala and insula activity while viewing food images compared with nonfood images was highest at baseline, reduced after ES, and, in the insula, increased again after TSD. However, ratings of desire for individual food stimuli did not change; the brain activity measure was more sensitive to changes in sleep status.
COMMENT: Even everyday levels of sleep debt may increase overeating risk, as indicated by subjective changes in appetite and objectively measured brain reactivity to food stimuli in regions important for emotional processing. In obesity and binge-eating prevention and treatment, providers should encourage adequate sleep and alert people that even mild sleep deprivation can increase risk for overeating. Further research into the clinical significance of brain reactivity to food cues is warranted.
CITATION(S): Katsunuma R et al. Unrecognized sleep loss accumulated in daily life can promote brain hyperreactivity to food cue. Sleep 2017 Aug 21; [e-pub].
(http://dx.doi.org/10.1093/sleep/zsx137)
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J Am Coll Cardiol 2017 Sep 19; 70:1429
“Metabolically Healthy Obesity”: What's the Risk?
Over 5 years, these individuals faced elevated risks for developing metabolic abnormalities and cardiovascular disease.
Overweight and obese individuals can be “metabolically healthy” (i.e., without hypertension, diabetes, or hyperlipidemia), but does this protect them from cardiovascular events? In an analysis of approximately 3.5 million patients in the U.K., investigators sought to understand the interplay of body-mass index (BMI) and metabolic dysfunction.
Over a mean follow-up of 5 years, metabolically healthy obese individuals (BMI, ≥30 kg/m2), compared with metabolically healthy normal-weight individuals, had significantly higher risks for coronary heart disease (hazard ratio, 1.49), cerebrovascular disease (HR, 1.07), and heart failure (HR, 1.96) but not peripheral vascular disease after adjustment for confounders. In contrast, approximately 10% of the normal-weight population had ≥1 metabolic risk factor at baseline, which placed them at increased risk for all four cardiovascular endpoints. A significant minority of metabolically healthy obese individuals developed metabolic risk factors during the study (diabetes 5.6%; hypertension, 10.5%; hyperlipidemia, 11.5%). Underweight individuals (BMI, <18.5 kg/m2), even nonsmokers, also appeared to have increased risk for some endpoints.
COMMENT: “Metabolically healthy” obesity still conferred significant cardiovascular risk, most notably an almost 50% increase in coronary heart disease and an almost twofold increase in heart failure. Obesity combined with metabolic risk factors was associated with the worst prognosis. Still, editorialists note that the findings call into question the concept of metabolically benign obesity. Metabolically healthy obese individuals also had a substantial risk for developing metabolic risk factors. Clearly, obesity and metabolic factors — and the complex interplay between the two — need to be addressed to minimize risk. The number of normal-weight individuals with metabolic risk factors prompted editorialists to call for robust screening. The finding in underweight individuals is not clearly understood.
CITATION(S): Caleyachetty R et al. Metabolically healthy obese and incident cardiovascular disease events among 3.5 million men and women. J Am Coll Cardiol 2017 Sep 19; 70:1429.
(http://dx.doi.org/10.1016/j.jacc.2017.07.763)
http://www.onlinejacc.org/content/70/12/1429?ijkey=
a7ee8e7070ec6246e1e439caa8d8f1e659660c18&keytype2=tf_ipsecsha
Bea JW and Sweitzer NK.More appropriate cardiovascular risk screening through understanding complex phenotypes: Mind the gap. J Am Coll Cardiol 2017 Sep 19; 70:1438. (http://dx.doi.org/10.1016/j.jacc.2017.07.742)
http://www.onlinejacc.org/content/70/12/1438?ijkey=
2190baaeaa461d8f8816ddd12240219eae662826&keytype2=tf_ipsecsha
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BMJ 2017 Aug 29; 358:j3778
Endometriosis Is Averted by Breast-Feeding
Large U.S. cohort study provides more evidence that longer duration of breast-feeding protects women against endometriosis.
Endometriosis, a common cause of chronic pelvic pain, affects about 10% of U.S. women and has no known cure. To study whether breast-feeding decreases women's risk for developing endometriosis, investigators analyzed data from 72,394 women who gave birth one or more times after enrolling in the Nurses' Health Study II, a prospective cohort study that began in 1989.
Incident laparoscopically confirmed endometriosis (self-reported) was more common among women who breast-fed for <1 month after delivery than women who breast-fed for longer durations. For each pregnancy, every 3-month increase in mean duration of exclusive breast-feeding per pregnancy was associated with a 14% decreased risk for endometriosis (hazard ratio, 0.86, 95% confidence interval, 0.81–0.90; P<0.001 for trend).
COMMENT: Given that lactation suppresses ovulation, it is biologically plausible that breast-feeding would prevent endometriosis. While it's rarely easy for new mothers to breast-feed — and some women, or their infants, are simply unable to do so — this study adds to the growing list of reasons why it's critically important that women who want to breast-feed receive prompt, high-quality lactation support. Recent evidence indicates that women who breast-feed are less likely to develop hypertension, diabetes, cardiovascular disease, and certain cancers (e.g., NEJM JW Womens Health Dec 2016 and Obstet Gynecol 2016; 128:1095), and may also be less likely to develop autoimmune conditions such as rheumatoid arthritis and multiple sclerosis. In addition, breast-feeding offers long-term benefits for infants' health.
CITATION(S): Farland LV et al. History of breast feeding and risk of incident endometriosis: Prospective cohort study.BMJ 2017 Aug 29; 358:j3778.
(http://dx.doi.org/10.1136/bmj.j3778)
http://www.bmj.com/content/358/bmj.j3778?ijkey=
1d1d94841e4cf745a007e899da573eb21ca76eb6&keytype2=tf_ipsecsha
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J Clin Oncol 2017 Sep 1; 35:2919
Does Cutting Dietary Fat Affect Breast Cancer Outcomes?
Women's Health Initiative randomized trial findings suggest lowering dietary fat also lowers mortality after breast cancer.
In the Women's Health Initiative dietary modification trial, investigators randomized women beginning in 1993 (age range, 50–70) to usual diet or a diet characterized by reduced fat and increased fruit, vegetables, and grains. Results at a median of 8 years indicated that fewer deaths from breast cancer occurred in women assigned to this dietary modification. The current report extends follow-up to a median of 16 years, focusing on the impact of dietary modification on deaths from breast cancer as well as overall mortality in participants with breast cancer diagnoses.
Although most breast cancer characteristics were similar between groups, a significantly smaller proportion of cancers in the dietary modification participants were of the poor-prognosis, estrogen-receptor–positive, progesterone-receptor–negative type. During the extended follow-up, among 3030 participants with incident breast cancer, deaths attributed to breast cancer were modestly (but not significantly) less common in the dietary modification group. However, overall mortality after breast cancer was significantly lower among women in the dietary modification group (234 vs. 443 deaths; hazard ratio, 0.82; P=0.01). Adjustment for weight change during the dietary intervention did not alter these findings.
COMMENT: The authors note that a favorable effect of this dietary intervention on cardiovascular mortality could have contributed to their findings. Furthermore, they point out that chemotherapy and radiation therapy can contribute to cardiovascular mortality in breast cancer patients. Whether the reduced overall mortality among women with incident breast cancer was caused by a direct positive effect of the dietary modification on breast cancer characteristics, or whether the benefits were not oncologic, these findings provide additional evidence for the benefits of a plant-based, low-fat diet.
CITATION(S): Chlebowski RT et al. Low-fat dietary pattern and breast cancer mortality in the Women's Health Initiative randomized controlled trial. J Clin Oncol 2017 Sep 1; 35:2919.
(http://dx.doi.org/10.1200/JCO.2016.72.0326)
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Lancet 2017 Aug 28
High-Fat Diets Were Associated with Lower 7-Year Mortality
Higher fat and lower carbohydrate intake was associated with lower mortality and no change in adverse cardiovascular events in this global study.
Standard dietary advice to restrict total fat and saturated fatty acids (<30% and <10% of total energy, respectively) is based largely on a few observational studies conducted years ago in North America and Europe. However, recent meta-analyses have shown no association, or an inverse relation, between saturated fatty acid intake and total mortality and adverse cardiovascular (CV) events.
Researchers conducted detailed analyses of the diets of more than 135,000 people with a range of income levels in 18 countries on five continents. Participants were sorted into quintiles based on percentage of dietary energy derived from carbohydrates; protein; and total, saturated, monounsaturated, and polyunsaturated fats. Median follow-up was 7.4 years.
After adjustment for education, smoking, physical activity, diabetes, urban versus rural location, total energy intake, and geographic region, higher carbohydrate intake was associated with higher risk for overall mortality and non-CV–related death but was not associated with major adverse CV events assessed individually or as a group. Conversely, higher intakes of total, saturated, monounsaturated, and polyunsaturated fats were associated with lower risk for overall and non-CV–related death and were not associated with adverse CV events (other than an inverse relation between saturated fat intake and stroke).
COMMENT: Data from this large, diverse international cohort does not support current dietary guidelines that recommend restricting total and saturated fats. The findings suggest that people who eat high carbohydrate diets might benefit from substituting fats for some of their carbohydrates.
CITATION(S): Dehghan M et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): A prospective cohort study. Lancet 2017 Aug 28; [e-pub].
(http://dx.doi.org/10.1016/S0140-6736(17)32252-3)
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JAMA 2017 Oct 10; 318:1358
Insulin Pump Superior to Insulin Injection for Type 1 Diabetes Mellitus
Insulin pump therapy was associated with lower rates of severe hypoglycemia and ketoacidosis and better glycemic control compared with insulin injection therapy in a pediatric population.
Nearly half of children with type 1diabetes mellitus (T1DM) are now treated with insulin pump therapy. Conflicting data exist about the safety and efficacy of pump therapy compared with frequent insulin injections.
In a multinational, population-based study in Europe, researchers prospectively compared safety and efficacy outcomes in approximately 10,000 children, adolescents, and young adults (aged <20 years) with T1DM receiving insulin therapy and an equal-sized, propensity-matched cohort receiving ≥4 daily doses of injected insulin. The overall mean age was 14 years and minimum disease duration was 1 year (median, 4 years).
After a follow-up of 12 months, results were as follows:
- Rates of severe hypoglycemia, hypoglycemic coma, ketoacidosis, severe ketoacidosis (pH <7.1 or blood bicarbonate <5 mmol/L) were significantly lower in the insulin pump cohort compared with the insulin injection cohort.
- Total daily insulin dose and HbA1clevel were lower in those treated via pump versus injection.
- Daily frequency of glucose monitoring was greater in those treated with insulin pumps.
- Body-mass index was similar between groups.
Outcomes were similar among the larger unmatched cohort of over 30,000 youth with T1DM undergoing the two different regimens.
COMMENT: Insulin pump therapy is superior to frequent daily insulin injections in preventing severe complications and improving overall glycemic control in children, adolescents, and young adults with type 1 diabetes mellitus. Hopefully this therapy will be available for all children and youth with type 1 diabetes until a cure for the disease is found.
CITATION(S): Karges B et al. Association of insulin pump therapy vs insulin injection therapy with severe hypoglycemia, ketoacidosis, and glycemic control among children, adolescents, and young adults with type 1 diabetes. JAMA 2017 Oct 10; 318:1358.
(https://jamanetwork.com/journals/jama/article-abstract/2656808)
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Ann Oncol Med 2017 Aug 1; 28:1811
Preserving Ovarian Function in Young Women with Breast Cancer
The gonadotropin-releasing hormone agonist goserelin reduced the risk for chemotherapy-induced ovarian insufficiency in premenopausal women with early-stage disease.
Balancing strategies to reduce the risk for disease recurrence while optimizing fertility preservation is a critical tension when caring for young women with early-stage breast cancer. To determine whether the use of the gonadotropin-releasing hormone agonist goserelin reduces the risk for chemotherapy-induced premature ovarian insufficiency (POI) in women with early breast cancer, investigators conducted a prospective, randomized study (OPTION) of 202 premenopausal patients (median age, 38 years) with stage I–III disease (about 44% estrogen receptor positive) receiving neoadjuvant or adjuvant chemotherapy.
Patients received six to eight cycles of cyclophosphamide, an anthracycline, or both, with or without a taxane. In addition, they were randomized to receive goserelin (starting 1–2 weeks prior to chemotherapy and continued every 3–4 weeks until chemotherapy was complete) or nothing (control group). Hormone levels were checked after cycle 3, after the final cycle, at 9 months, at 12 months, and annually thereafter. The primary endpoint was the rate of amenorrhea, defined as no menses between 12 and 24 months following randomization along with an elevated level of follicle stimulating hormone (FSH).
The rate of amenorrhea between 12 and 24 months was lower in the goserelin group than in the control group (22% vs. 38%; P=0.015), as were FSH levels at 12 months (P=0.027) and 24 months (P=0.001). The prevalence of POI was also lower with goserelin (18.5% vs. 34.8%; P=0.048), especially in women 40 or younger.
COMMENT: These results suggest that the rate of POI can be reduced in young women receiving adjuvant chemotherapy for breast cancer. Less clear is the effect of goserelin on follicle reserve and on the ability of women to get pregnant following chemotherapy. Nevertheless, this approach should be discussed with young breast cancer patients planning to receive adjuvant chemotherapy.
CITATION(S): Leonard RCF et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: The Anglo Celtic Group OPTION trial. Ann Oncol 2017 Aug 1; 28:1811.
(http://dx.doi.org/10.1093/annonc/mdx184)
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Neurology 2017 Sep 20; 10.1212/WNL.0000000000004508
Comorbidities Delay Multiple Sclerosis Diagnosis and Increase Mortality
Patients with chronic medical illnesses were twice as likely as patients without these illnesses to be diagnosed after a 5- to 10-year delay.
To investigate the interaction between comorbidities and diagnosis of multiple sclerosis (MS), researchers used the Danish Multiple Sclerosis Registry, which contained 8862 eligible patients with MS onset between 1980 and 2005. Of those, 79 had two or more medical comorbidities.
Average time to MS diagnosis was 4 years. Patients with cardiac, pulmonary, cerebrovascular, diabetes, or cancer comorbidities were significantly more likely than those without these comorbidities to have an MS diagnostic delay of ≥10 years. The association held for cardiac and pulmonary comorbidities for a delay of 5 to 10 years. Comorbid autoimmune disease did not lead to a delay in MS diagnosis. Mortality was increased for MS patients with psychiatric, diabetes, cancer, cerebrovascular disease, or cardiovascular comorbidities.
COMMENT: Although many patients with MS are otherwise healthy, the 10% to 20% with preexisting illnesses can be more challenging to diagnose. This challenge may not seem intuitive, perhaps because some of these patients are already seeking medical care and are being evaluated regularly. We do not know why a delay is taking place, whether owing to patients not reporting symptoms, a propensity for the treating physician to only focus on their specific disease, or a willingness to write off neurologic problems as consequences of their primary diagnosis. Whether this delay in MS diagnosis has been reduced during the last 10 years as more treatments and education have become available would be interesting to determine. We are taught about Occam's razor in medical school for creating differential diagnoses, but we should always consider that patients can have more than one disease.
CITATION(S): Thormann A et al. Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality. Neurology 2017 Sep 20; 10.1212/WNL.0000000000004508; [e-pub]. (http://dx.doi.org/10.1212/WNL.0000000000004508)
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Nature 2017 Sep 28; 549:523
Understanding the Pathogenesis of Alzheimer Disease
Tau protein interacts with apolipoprotein E4 to enhance neurotoxicity.
Previous research has incriminated three molecules in the pathogenesis of Alzheimer disease (AD): β-amyloid peptide, tau protein, and a particular form of apolipoprotein E (apoE) — apoE4. ApoE4 interacts with β-amyloid to enhance its neurotoxicity. In a new study, researchers assessed the interaction between apoE4 and tau protein.
Using mice that were genetically engineered to make large amounts of human tau protein plus human apoE4, apoE3, apoE2 or no apoE protein, researchers evaluated deposition of tau and other pathological features. The mice that produced apoE4 developed markedly more deposits of tau, greater brain atrophy, and greater brain inflammation than did mice that made apoE2 or apoE3. Mice that made no apoE protein were protected against these changes. Brain immune system cells (microglia) were extracted from the different strains of mice. Those from apoE4-producing mice were most likely to respond to antigenic challenges by producing inflammatory molecules. When glial cells from apoE4-producing mice were placed in a dish with neurons, they produced more inf lammatory molecules and more readily caused neuronal death than did glial cells from other mouse strains.
COMMENT: This study demonstrates that — independent of β-amyloid — tau and apoE4 proteins can cause neurodegeneration. The study also suggests that inflammation plays an important role in neurodegeneration. This report will encourage investigation into more interventions that target tau, apoE4, and inflammation as a means of preventing and treating not only AD but also other “tauopathies,” such as frontotemporal dementia and chronic traumatic encephalopathy.
CITATION(S): Shi Y et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017 Sep 28; 549:523. (http://dx.doi.org/10.1038/nature24016)
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JAMA Neurol 2017 Aug 21
Systolic Blood Pressure, Cognition, and Race
Lowering systolic blood pressure to ≤120 mm Hg may benefit cognition.
Target systolic blood pressure (SBP) recommendations have ranged from <150 mm Hg for older adults to <120 mm Hg for cardiovascular risk reduction. Black people may have more risks associated with hypertension. To investigate associations among SBP, cognition, and race, researchers analyzed 10-year data from 1657 older adults (mean age, 74 years; 47.3% nonwhite race) receiving hypertension treatment and participating in the Health Aging and Body Composition study. Outcomes included mean scores of global cognition with the Modified Mini-Mental State Examination (3MSE) and a test of visuomotor speed, attention, set-shifting, and memory with the Digit Symbol Substitution Test (DSST).
Mean baseline cognitive scores were 89.8 for the 3MSE and 34.3 for the DSST. The 10-year decrease in adjusted cognitive scores was largest for those with SBP ≥150 mm Hg (−3.7 points on the 3MSE and −6.2 points on the DSST) and smallest for those with SBP ≤120 mm Hg (−3.0 on the 3MSE, −5.0 on the DSST). Compared with white people, black people had lower baseline 3MSE and DSST scores and a greater 10-year decrease in 3MSE scores. Black people had a significantly greater difference than white people in cognitive scores between SBP ≥150 mm Hg and ≥120 mm Hg (−0.08 vs. −0.05 for the 3MSE and −0.13 vs. −0.07 for the DSST).
COMMENT: Targeting lower blood pressures may slow the cognitive decline in older adults, and SBP ≤120 mm Hg may be a reasonable target for cognition, especially in black people. Replicating these results using more-comprehensive neuropsychological testing and correlating the results with daily functioning would further support more-aggressive blood pressure management to protect cognition.
CITATION(S): Hajjar I et al. Association of JNC-8 and SPRINT systolic blood pressure levels with cognitive function and related racial disparity. JAMA Neurol 2017 Aug 21; [e-pub].
(http://dx.doi.org/10.1001/jamaneurol.2017.1863)
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BMJ 2017 Sep 6; 358:j3668
Antidepressant Use During Pregnancy May Raise Risk for Psychiatric Illness in Offspring
But the excess risk seems largely related to maternal psychiatric illness.
Antidepressant use during pregnancy has been shown to be relatively safe regarding teratogenicity and effects on the pregnancy, but interest in long-term neurobehavioral effects (e.g., possible increased risk for autism) continues to grow. In a prospective cohort study, investigators used Danish registry data to examine psychiatric diagnoses in 905,383 offspring born from 1998 through 2012 and followed for up to 16.5 years. Maternal antidepressant use was categorized as none, discontinued before pregnancy, continued, or new.
Cumulative incidence of psychiatric diagnoses in offspring (including autism, mood disorders, somatoform disorders, and behavioral disorders) was 8.0% in the nonuse group, 11.5% in the discontinuation group, 13.6% in the continuation group, and 14.5% in the new-use group. In analyses adjusted for confounding by indication, overall risk for psychiatric disorders was higher in the continuation group than the discontinuation group (hazard ratio, 1.3). Mothers who continued to use antidepressants had more-severe psychiatric illness. The population-attributable fraction for continuous use was 0.5% of all cases. Risk was higher with longer duration of use and with polytherapy. Paternal antidepressant use was associated with modestly raised risk.
COMMENT: Although animal studies of the neurobehavioral outcomes of fetal antidepressant exposure suggest mechanisms for such effects, this study indicates that the maternal psychiatric illness driving antidepressant use may inherently account for much — albeit not all — of this risk. At 0.5%, the fraction of cases attributable to antidepressant use is substantially lower than what would be attributable to parental psychiatric illness. As the authors note, current guidelines advising continued antidepressant use for more-severely ill mothers and discontinuation only in those with minimal illness should not be changed because of these findings.
CITATION(S): Liu X et al. Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ 2017 Sep 6; 358:j3668.
(http://dx.doi.org/10.1136/bmj.j3668)
http://www.bmj.com/content/358/bmj.j3950?ijkey=
a32c69ce8737e5e0af1ab5d40382950aaf04974e&keytype2=tf_ipsecsha
Nordeng H et al. Prenatal exposure to antidepressants and increased risk of psychiatric disorders: How can we disentangle the effects of antidepressants from the underlying risks? BMJ 2017 Sep 6; 358:j3950.
(http://dx.doi.org/10.1136/bmj.j3950)
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