Dynamic contrast-enhanced magnetic resonance imaging and blood oxygenation level-dependent magnetic resonance imaging for the assessment of changes in tumor biology with treatment

Functional magnetic resonance imaging (MRI) techniques are rapidly gaining importance as methods of exploring the pathophysiological properties of breast carcinomas. In the neoadjuvant setting where the primary tumor remains in situ, functional MRI is able to noninvasively evaluate microenvironmental features such as blood flow and oxygenation. Dynamic contrast-enhanced MRI provides information on tumor vascularity with evidence suggesting a role in predicting response to neoadjuvant chemotherapy. The spatial heterogeneity of response to anti-angiogenic and vascular disrupting agents can also be depicted. There is preliminary data supporting blood oxygenation level-dependent MRI as a potential marker of tumor oxygenation, with the ability to characterize tissue oxygenation changes with neoadjuvant chemotherapy. Additionally, advanced MR sequences such as diffusion-weighted MRI and MR spectroscopy have the potential to provide information relating to cellularity and metabolism, respectively.     

Circadian Activity Rhythms and Mortality: The Study of Osteoporotic Fractures

OBJECTIVES: To determine whether circadian activity rhythms are associated with mortality in community‐dwelling older women. DESIGN: Prospective study of mortality. SETTING: A cohort study of health and aging. PARTICIPANTS: Three thousand twenty‐seven community‐dwelling women from the Study of Osteoporotic Fractures cohort (mean age 84). MEASUREMENTS: Activity data were collected using wrist actigraphy for a minimum of three 24‐hour periods, and circadian activity rhythms were computed. Parameters of interest included height of activity peak (amplitude), midline estimating statistic of rhythm (mesor), strength of activity rhythm (robustness), and time of peak activity (acrophase). Vital status, with cause of death adjudicated through death certificates, was prospectively ascertained. RESULTS: Over an average of 4.1 years of follow‐up, there were 444 (14.7%) deaths. There was an inverse association between peak activity height and all‐cause mortality rates, with higher mortality rates observed in the lowest activity quartile (hazard ratio (HR)=2.18, 95% confidence interval (CI)=1.63–2.92) than in the highest quartile after adjusting for age, clinic site, race, body mass index, cognitive function, exercise, instrumental activity of daily living impairments, depression, medications, alcohol, smoking, self‐reported health status, married status, and comorbidities. A greater risk of mortality from all causes was observed for those in the lowest quartiles of mesor (HR=1.71, 95% CI=1.29–2.27) and rhythm robustness (HR=1.97, 95% CI=1.50–2.60) than for those in the highest quartiles. Greater mortality from cancer (HR=2.09, 95% CI=1.04–4.22) and stroke (HR=2.64, 95% CI=1.11–6.30) was observed for later peak activity (after 4:33 p.m.; >1.5 SD from mean) than for the mean peak range (2:50–4:33 p.m.). CONCLUSION: Older women with weak circadian activity rhythms have higher mortality risk. If confirmed in other cohorts, studies will be needed to test whether interventions (e.g., physical activity, bright light exposure) that regulate circadian activity rhythms will improve health outcomes in older adults.     

Prognostic effect of coronary flow reserve in women versus men with chest pain syndrome and normal dipyridamole stress echocardiography

The aim of this study was to investigate the prognostic effect of coronary flow reserve (CFR) on left anterior descending artery (LAD) in women and men with chest pain of unknown origin and normal stress echocardiogram. The study population consisted of 1,660 patients (906 women, 754 men) with chest pain syndrome, no wall motion abnormality on echocardiogram at rest, and dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echocardiogram negative for wall motion criteria. All had undergone stress echocardiography with combined evaluation of CFR on LAD by Doppler. A CFR value ≤2.0 was considered abnormal. Median duration of follow-up was 19 months (interquartile range 10 to 34). Abnormal CFR was assessed in 171 women (19%) and 147 men (19%, p = 0.80). During follow-up, 80 events (20 deaths, 13 ST-elevation myocardial infarctions, and 47 non-ST-elevation myocardial infarctions) occurred. In addition, 128 patients underwent revascularization and were censored. CFR ≤2.0 on LAD was independently associated with prognosis in women (hazard ratio [HR] 16.48, 95% confidence interval [CI] 7.17 to 37.85, p <0.0001) and in men (HR 6.23, 95% CI 3.42 to 11.33, p <0.0001). Antianginal therapy at time of testing (HR 2.11, 95% CI 1.14 to 3.90, p = 0.02) was also a multivariable prognostic predictor in men. Four-year event rate associated with CFR values ≤2.0 and >2.0 were, respectively, 27% and 2% in women (p <0.0001) and 42% and 8% in men (p <0.0001). In conclusion, decreased CFR on LAD is associated with markedly increased risk in women and men with chest pain syndrome and a normal result of dipyridamole stress echocardiography. Conversely, preserved CFR on LAD predicts excellent survival, particularly in women.     

Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults

BackgroundInformation is scarce regarding the effect of dietary protein type, with specific focus on the lysine-to-arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans.ObjectiveDetermine the effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults.DesignRandomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 years, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30% E fat, 50% E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL) cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT).ResultsNo differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (?24%, P = 0.001) and triglycerides (?23%, P = 0.001), and small but significant differences in fasting (?3%, P = 0.003) and postprandial (?3%, P = 0.018) apo AI, and fasting adiponectin concentrations (+7%, P = 0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P = 0.020 for both).ConclusionsDiets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity.     

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox–5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.     

Identification,isolation and characterization of process-related impurities in Rizatriptan benzoate

Three process-related impurities were observed in routine monitoring of the samples by HPLC. These impurities were identified by LC–MS. One of the impurities, Imp-3 [rizatriptan-2,5-dimer] was reported in literature. Other two impurities were isolated by preparative HPLC and characterized by NMR, Mass and IR. Pure impurities obtained by isolation were co-injected with Rizatriptan benzoate sample to confirm the retention times in HPLC. Structure elucidation of these impurities by spectral data has been discussed in detail. These impurities were identified as 4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-1,2-dimer] and [4,4-bis-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)-ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-2,2-dimer].     

CHANGES in SKIN TANNING ATTITUDES Fashion Articles and Advertisements in the Early 20th Century

Historical reviews suggest that tanning first became fashionable in the 1920s or 1930s. To quantitatively and qualitatively examine changes in tanning attitudes portrayed in the popular women''s press during the early 20th century, we reviewed summer issues of Vogue and Harper''s Bazaar for the years 1920, 1927, 1928, and 1929. We examined these issues for articles and advertisements promoting skin tanning or skin bleaching and protection. We found that articles and advertisements promoting the fashionable aspects of tanned skin were more numerous in 1928 and 1929 than in 1927 and 1920, whereas those promoting pale skin (by bleaching or protection) were less numerous. These findings demonstrate a clear shift in attitudes toward tanned skin during this period.NUMEROUS STUDIES HAVE linked exposure to ultraviolet (UV) light to both melanoma^1–4 and nonmelanoma skin cancers.^2–4 The incidence of skin cancers has risen dramatically over the past century,^5–7 and this is largely attributed to increased exposure to UV light from the sun. Despite public education initiatives aimed at preventing skin cancer,⁸ many individuals continue to tan, citing such reasons as the relationship between tanning and physical and emotional health, an active lifestyle, and physical beauty.⁹From a historical perspective, tanning as a fashion trend is a relatively new phenomenon, first noted in the 20th century. Earlier, pale skin was often perceived as a mark of beauty, wealth, and refinement, whereas tanned skin was considered to be typical of manual laborers.¹⁰ In the early 20th century, European and American women took precautions to maintain a light skin tone. Parasols and large hats were considered essential summer accessories.¹¹ Magazines in the early 20th century advertised powders that would conceal a tan as well as numerous bleach treatments, such as Bleachine Cream, which was featured in an advertisement by Elizabeth Arden in the July 1, 1920, issue of Vogue as “A mild but effective preparation for removing tan. Nourishing as well as whitening. Excellent for the hands.”¹² Toxic lead-based cosmetics, which date back to ancient Roman society, and other types of body powders were commonly used to lighten and augment fair skin during this era.^9,13Although it is well-known that social attitudes changed from sun protection to sun seeking during the first half of the 20th century, the exact year for such a cultural shift has remained obscure. Previous reviews on this subject suggest that the trend began in the late 1920s or early 1930s.^10,14 Magazines from the late 1920s reflect a clear shift in attitude, as illustrated in an article from a 1929 issue of Harper''s Bazaar: “Shall We Gild the Lily? There Is a Technique to a Good Tan—Whether by Fair Means or Fake!”¹⁵Open in a separate windowOpen in a separate windowJantzen swimsuit advertisement from (a) 1927 showing models with sun protection, including shawls, parasols, and wide-brimmed hats, and (b) 1929 depicting models in similar bathing suits, but now frolicking in the sun without sun protection.Illustrations by Frank Clark. Reprinted with permission of Jantzen.