The effect of fibre cell remodelling on the power and optical quality of the lens.

Vertebrate eye lenses are uniquely adapted to form a refractive index gradient (GRIN) for improved acuity, and to grow slowly in size despite constant cell proliferation. The mechanisms behind these adaptations remain poorly understood. We hypothesize that cell compaction contributes to both. To test this notion, we examined the relationship between lens size and shape, refractive characteristics and the cross-sectional areas of constituent fibre cells in mice of different ages. We developed a block-face imaging method to visualize cellular cross sections and found that the cross-sectional areas of fibre cells rose and then decreased over time, with the most significant reduction occurring in denucleating cells in the adult lens cortex, followed by cells in the embryonic nucleus. These findings help reconcile differences between the predictions of lens growth models and empirical data. Biomechanical simulations suggested that compressive forces generated from continuous deposition of fibre cells could contribute to cellular compaction. However, optical measurements revealed that the GRIN did not mirror the pattern of cellular compaction, implying that compaction alone cannot account for GRIN formation and that additional mechanisms are likely to be involved.

Weight gain in early pregnancy and risk of gestational diabetes mellitus among Latinas.

AIM: To evaluate the association between gestational weight gain (GWG) in early pregnancy and incidence of abnormal glucose tolerance (AGT) and gestational diabetes mellitus (GDM) among Latinas. METHODS: We conducted a retrospective cohort study of 2039 Latinas using pooled data from two medical centres in Massachusetts. Gestational weights were abstracted from medical records and GWG was categorized as low, appropriate and excessive according to 2009 Institute of Medicine Guidelines. Diagnosis of AGT and GDM was confirmed by study obstetricians. RESULTS: A total of 143 women (7.0%) were diagnosed with GDM and 354 (17.4%) with AGT. After adjusting for age and study site, women with low GWG up to the time of GDM screen had a lower odds of GDM (OR: 0.51, 95% CI: 0.29-0.92). Among overweight women, women with excessive first-trimester GWG had 2-fold higher odds of AGT (OR: 1.96, 95% CI: 1.17-3.30) and GDM (OR: 2.07, 95% CI: 1.04-4.12) compared to those with appropriate GWG; however, these findings were not significant among normal weight or obese women. CONCLUSION: Among Latinas, low GWG up to the time of GDM screen was associated with lower odds of AGT and GDM, while excessive GWG among overweight women was associated with higher odds. Findings highlight need for interventions in early pregnancy to help women meet GWG guidelines and to moderate GWG among overweight Latinas.

Moderate intensity sports and exercise is associated with glycaemic control in women with gestational diabetes.

AIM: To assess the association of regular, unsupervised sports and exercise during pregnancy, by intensity level, with glycaemic control in women with gestational diabetes (GDM). METHODS: Prospective cohort study of 971 women who, shortly after being diagnosed with GDM, completed a Pregnancy Physical Activity Questionnaire assessing moderate and vigorous intensity sports and exercise in the past 3 months. Self-monitored capillary glucose values were obtained for the 6-week period following the questionnaire, with optimal glycaemic control defined≥80% values meeting the targets<5.3mmol/L for fasting and <7.8mmol/L 1-hour after meals. Logistic regression estimated the odds of achieving optimal control; linear regression estimated activity level-specific least square mean glucose, as well as between-level mean glucose differences. RESULTS: For volume of moderate intensity sports and exercise ([MET×hours]/week), the highest quartile, compared to the lowest, had significantly increased odds of optimal control (OR=1.82 [95% CI: 1.06-3.14] P=0.03). There were significant trends for decreasing mean 1-hour post breakfast, lunch and dinner glycaemia with increasing quartile of moderate activity (all P<0.05). Any participation in vigorous intensity sports and exercise was associated with decreased mean 1-hour post breakfast and lunch glycaemia (both P<0.05). No associations were observed for fasting. CONCLUSION: Higher volumes of moderate intensity sports and exercise, reported shortly after GDM diagnosis, were significantly associated with increased odds of achieving glycaemic control. Clinicians should be aware that unsupervised moderate intensity sports and exercise performed in mid-pregnancy aids in subsequent glycaemic control among women with GDM.

A pregnancy lifestyle intervention to prevent gestational diabetes risk factors in overweight Hispanic women: a feasibility randomized controlled trial.

AIMS: To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women, with the aim of reducing risk factors for gestational diabetes mellitus. METHODS: Women were randomized either to a lifestyle intervention (n = 33, 48.5%), consisting of a culturally and linguistically modified, motivationally targeted, individually tailored 6-month prenatal programme, or to standard care (n = 35, 51.5%). Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity, decrease saturated fat and increase dietary fibre. Outcomes included gestational weight gain, infant birth weight and biomarkers associated with insulin resistance. RESULTS: Patient retention up to delivery was 97% in both study groups. The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity, but differences between groups were not significant (mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week; P = 0.88). Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group (mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week) and declined in the standard care group (-0.8 ± 0.8 metabolic equivalent of task h/week; P = 0.04). The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the standard care group; however, these differences were not statistically significant. There were no statistically significant differences in biomarkers of insulin resistance between groups. CONCLUSIONS: Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women. The intervention protocol can readily be translated into clinical practice in underserved and minority populations.

Perceived psychosocial stress and glucose intolerance among pregnant Hispanic women.

AIM: Prior literature suggests a positive association between psychosocial stress and the risk of diabetes in non-pregnant populations, but studies during pregnancy are sparse. We evaluated the relationship between stress and glucose intolerance among 1115 Hispanic (predominantly Puerto Rican) prenatal care patients in Proyecto Buena Salud, a prospective cohort study in Western Massachusetts (2006-2011). METHODS: Cohen's Perceived Stress Scale (PSS-14) was administered in early (mean = 12.3 weeks gestation; range 4.1-18 weeks) and mid- (mean = 21.3 weeks gestation; range 18.1-26 weeks) pregnancy. Participants were classified as having a pregnancy complicated by gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance, based on the degree of abnormality on glucose tolerance testing between 24 and 28 weeks of gestation. RESULTS: The prevalence of gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance was 4.1%, 7.2%, and 14.5%, respectively. Absolute levels of early or mid-pregnancy stress were not significantly associated with glucose intolerance. However, participants with an increase in stress from early to mid-pregnancy had a 2.6-fold increased odds of gestational diabetes mellitus (95% confidence intervals: 1.0-6.9) as compared to those with no change or a decrease in stress after adjusting for age and pre-pregnancy body mass index. In addition, every one-point increase in stress scores was associated with a 5.5mg/dL increase in screening glucose level (ß=5.5; standard deviation=2.8; P=0.05), after adjusting for the same variables. CONCLUSION: In this population of predominantly Puerto Rican women, stress patterns during pregnancy may influence the risk of glucose intolerance.

Mechanical forces in cerebral cortical folding: a review of measurements and models.

Folding of the cerebral cortical surface is a critical process in human brain development, yet despite decades of indirect study and speculation the mechanics of the process remain incompletely understood. Leading hypotheses have focused on the roles of circumferential expansion of the cortex, radial growth, and internal tension in neuronal fibers (axons). In this article, we review advances in the mathematical modeling of growth and morphogenesis and new experimental data, which together promise to clarify the mechanical basis of cortical folding. Recent experimental studies have illuminated not only the fundamental cellular and molecular processes underlying cortical development, but also the stress state and mechanical behavior of the developing brain. The combination of mathematical modeling and biomechanical data provides a means to evaluate hypothesized mechanisms objectively and quantitatively, and to ensure that they are consistent with physical law, given plausible assumptions and reasonable parameter values.

Associations between race, lifecourse socioeconomic position and prevalence of diabetes among US women and men: results from a population-based panel study.

BACKGROUND: Few studies have examined the degree to which racial disparities in the development of diabetes are accounted by differences in lifecourse socioeconomic position (SEP). We assessed the association between race, lifecourse SEP measures and prevalence of diabetes in a representative US sample of black and white adults. METHODS: A generalised estimating equations approach was used with a sample of 3497 adults from the Americans' Changing Lives study. Sex-specific models were calculated to compute prevalence ratios (PR) for associations of race and SEP with self-reported diagnoses of diabetes. RESULTS: For men, childhood and adult SEP were unrelated to diabetes, and adjustment for lifecourse SEP had little effect on the excess diabetes in blacks (PR=1.56, 95% CI 1.11 to 2.21). Adjustment for measures of lifecourse SEP reduced the PR for the association between race and diabetes in women from 1.96 (95% CI 1.52 to 2.54) to 1.40 (95% CI 1.04 to 1.87) with the respondent's education responsible for most of the reduction in the association. However, diabetes was also inversely associated with father's education, and low SEP throughout the lifecourse was associated with a nearly threefold increase in diabetes (PR=2.89, 95% CI 2.10 to 3.99). CONCLUSIONS: Racial disparities in diabetes existed among both men and women, but lifecourse SEP was related to diabetes only among women. The pathway and cumulative hypotheses for lifecourse SEP effects on diabetes may be especially salient for women.

Physical activity before and during pregnancy and risk of abnormal glucose tolerance among Hispanic women.

AIM: Women diagnosed with abnormal glucose tolerance and gestational diabetes mellitus are at increased risk for subsequent type 2 diabetes, with higher risks in Hispanic women. Studies suggest that physical activity may be associated with a reduced risk of these disorders; however, studies in Hispanic women are sparse. METHODS: We prospectively evaluated this association among 1241 Hispanic participants in Proyecto Buena Salud. The Pregnancy Physical Activity Questionnaire was used to assess pre, early, and mid pregnancy physical activity. Medical records were abstracted for pregnancy outcomes. RESULTS: A total of 175 women (14.1%) were diagnosed with abnormal glucose tolerance and 57 women (4.6%) were diagnosed with gestational diabetes. Increasing age and body mass index were strongly and positively associated with risk of gestational diabetes. We did not observe statistically significant associations between total physical activity or meeting exercise guidelines and risk. However, after adjusting for age, BMI, gestational weight gain, and other important risk factors, women in the top quartile of moderate-intensity activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio=0.48, 95% Confidence Interval 0.27-0.88, Ptrend=0.03) as compared to those in the lowest quartile. Similarly, women with the highest levels of occupational activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio=0.48, 95% Confidence Interval 0.28-0.85, Ptrend=0.02) as compared to women who were unemployed. CONCLUSION: In this Hispanic population, total physical activity and meeting exercise guidelines were not associated with risk. However, high levels of moderate-intensity and occupational activity were associated with risk reduction.

A cortical folding model incorporating stress-dependent growth explains gyral wavelengths and stress patterns in the developing brain.

In humans and many other mammals, the cortex (the outer layer of the brain) folds during development. The mechanics of folding are not well understood; leading explanations are either incomplete or at odds with physical measurements. We propose a mathematical model in which (i) folding is driven by tangential expansion of the cortex and (ii) deeper layers grow in response to the resulting stress. In this model the wavelength of cortical folds depends predictably on the rate of cortical growth relative to the rate of stress-induced growth. We show analytically and in simulations that faster cortical expansion leads to shorter gyral wavelengths; slower cortical expansion leads to long wavelengths or even smooth (lissencephalic) surfaces. No inner or outer (skull) constraint is needed to produce folding, but initial shape and mechanical heterogeneity influence the final shape. The proposed model predicts patterns of stress in the tissue that are consistent with experimental observations.

A POROELASTIC MODEL FOR CELL CRAWLING INCLUDING MECHANICAL COUPLING BETWEEN CYTOSKELETAL CONTRACTION AND ACTIN POLYMERIZATION.

Much is known about the biophysical mechanisms involved in cell crawling, but how these processes are coordinated to produce directed motion is not well understood. Here, we propose a new hypothesis whereby local cytoskeletal contraction generates fluid flow through the lamellipodium, with the pressure at the front of the cell facilitating actin polymerization which pushes the leading edge forward. The contraction, in turn, is regulated by stress in the cytoskeleton. To test this hypothesis, finite element models for a crawling cell are presented. These models are based on nonlinear poroelasticity theory, modified to include the effects of active contraction and growth, which are regulated by mechanical feedback laws. Results from the models agree reasonably well with published experimental data for cell speed, actin flow, and cytoskeletal deformation in migrating fish epidermal keratocytes. The models also suggest that oscillations can occur for certain ranges of parameter values.

Perspectives on biological growth and remodeling.

The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years. Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation. In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development.

A walking model to assess the onset of analgesia in osteoarthritis knee pain.

OBJECTIVE: To assess a walking model utilizing a set of standardized treadmill walks to measure acute analgesic response in osteoarthritis (OA) of the knee. DESIGN: Randomized, double-blind, placebo-controlled, multiple dose, three-period crossover study. Patients > or =45 years of age (N=22) with symptomatic knee OA were randomized to naproxen 500 mg bid, tramadol/acetaminophen 37.5 mg/325 mg in forced titration, or placebo in each of three periods. Patients performed multiple 20-minute treadmill walks on Day 1 and Day 3 at a consistent self-selected pace predetermined at screening. Pain intensity (PI) during the walks was assessed on an 11-point numerical rating scale at 0, 3, 6, 9, 12, 15, 18, and 20 min. The primary endpoint was the time-weighted average (TWA) change from baseline PI on Day 3 for the two self-paced walks for the active treatments vs placebo. Time to moderate pain (TTMP) was a key secondary endpoint. RESULTS: Compared with placebo, the TWA change from baseline PI on Day 3 was significantly better with tramadol/acetaminophen (P=0.043) but not with naproxen (P=0.089). TWA change from baseline on Day 1 was also significantly better with both tramadol/acetaminophen (P=0.001) and naproxen (P=0.048) compared with placebo. TTMP was significantly better for tramadol/acetaminophen and naproxen than placebo (P<0.001 to P=0.015) for walks on Day 1 after a single dose and on Day 3. CONCLUSIONS: This novel OA pain model was able to discriminate both tramadol/acetaminophen and naproxen from placebo after single and multiple doses. ClinicalTrials.gov identifier: NCT00772967.

A 2-D model of flow-induced alterations in the geometry, structure, and properties of carotid arteries.

Evidence from diverse investigations suggests that arterial growth and remodeling correlates well with changes in mechanical stresses from their homeostatic values. Ultimately, therefore, there is a need for a comprehensive theory that accounts for changes in the 3-D distribution of stress within the arterial wall, including residual stress, and its relation to the mechanisms of mechanotransduction. Here, however, we consider a simpler theory that allows competing hypotheses to be tested easily, that can provide guidance in the development of a 3-D theory, and that may be useful in modeling solid-fluid interactions and interpreting clinical data. Specifically, we present a 2-D constrained mixture model for the adaptation of a cylindrical artery in response to a sustained alteration in flow. Using a rule-of-mixtures model for the stress response and first order kinetics for the production and removal of the three primary load-bearing constituents within the wall, we illustrate capabilities of the model by comparing responses given complete versus negligible turnover of elastin. Findings suggest that biological constraints may result in suboptimal adaptations, consistent with reported observations. To build upon this finding, however, there is a need for significantly more data to guide the hypothesis testing as well as the formulation of specific constitutive relations within the model.

Approach to quantify the mechanical behavior of the intact embryonic chick heart.

The heart undergoes remarkable changes during embryonic development due to genetic programing and epigenetic influences such as mechanical loads. An important goal is to develop mathematical models that describe and predict the influence of mechanics on cardiac development, yet the data needed to develop such models remain scant. In particular, prior data from embryonic hearts have come from one-dimensional tests, which reveal well the general characteristic behaviors but are not sufficient for quantifying the complex material behavior exhibited by most soft tissues. We developed a computer-controlled system for quantifying in vitro the multiaxial, regionally dependent mechanical response of the intact embryonic chick heart to controlled distension pressures; such tests have not been accomplished heretofore but promise to contribute to our understanding for they better mimic the native loading conditions and geometry. Calibration of the device indicated that distending the hearts using low flow rates avoids significant viscous losses and thereby allows pressure to be measured directly over small ranges (0-2 mmHg) with good resolution (0.01 mm Hg). Likewise, an on-line video system allows two-dimensional strains to be measured regionally by tracking the motions of triplets of closely spaced (100 microm) microspheres to reasonable resolution (2.5 microm/pixel). Illustrative data from 18 hearts show the utility of the new system, confirm previous findings with regard to the strong viscoelastic response of the stage 18 embryonic chick heart, and provide guidance for the design of future experiments.

Theoretical and experimental study of growth and remodeling in the developing heart.

A theoretical model is presented for growth and remodeling in the developing embryonic heart. The model is a thick-walled tube composed of two layers of orthotropic pseudoelastic material. The analysis includes stress and strain dependent volumetric growth, with changes in material properties specified to reflect the evolving structure of the heart wall. For use in model validation, experimental measurements of ventricular opening angles are reported for 3-4-day old chick embryos under control and pressure overload conditions. Owing to changes in residual stress in the overloaded heart, the opening angle decreased from 31 +/- 10 degrees to -8 +/- 12 degrees (mean +/- SD) within 12 h and then increased slightly. The opening angle at 12 h was significantly less than the control value. With an appropriate choice of parameters, the model yields reasonable agreement with these and other published opening angle data, as well as with temporal changes in lumen radius, wall thickness, epicardial strains, and pressure-volume curves during development before and after birth.

Exercise and diabetes.

As rates of diabetes mellitus and obesity continue to increase, physical activity continues to be a fundamental form of therapy. Exercise influences several aspects of diabetes, including blood glucose concentrations, insulin action and cardiovascular risk factors. Blood glucose concentrations reflect the balance between skeletal muscle uptake and ambient concentrations of both insulin and counterinsulin hormones. Difficulties in predicting the relative impact of these factors can result in either hypoglycemia or hyperglycemia. Despite the variable impact of exercise on blood glucose, exercise consistently improves insulin action and several cardiovascular risk factors. Beyond the acute impact of physical activity, long-term exercise behaviors have been repeatedly associated with decreased rates of type 2 diabetes. While exercise produces many benefits, it is not without risks for patients with diabetes mellitus. In addition to hyperglycemia, from increased hepatic glucose production, insufficient insulin levels can foster ketogenesis from excess concentrations of fatty acids. At the opposite end of the glucose spectrum, hypoglycemia can result from excess glucose uptake due to either increased insulin concentrations, enhanced insulin action or impaired carbohydrate absorption. To decrease the risk for hypoglycemia, insulin doses should be reduced prior to exercise, although some insulin is typically still needed. Although precise risks of exercise on existing diabetic complications have not been well studied, it seems prudent to consider the potential to worsen nephropathy or retinopathy, or to precipitate musculoskeletal injuries. There is more substantive evidence that autonomic neuropathy may predispose patients to arrhythmias. Of clear concern, increased physical activity can precipitate a cardiac event in those with underlying CAD. Recognizing these risks can prompt actions to minimize their impact. Positive actions that are part of exercise programs for diabetic patients emphasize SMBG, foot care and cardiovascular functional assessment. SMBG provides critical information on the impact of exercise and is recommended for all patients before, during and after exercise. More frequent monitoring (and for longer periods following exercise) is recommended for those with hypoglycemia unawareness or those performing high-intensity exercise. Preventing the sequelae of an exercise-induced severe hypoglycemic reaction can be as simple as carrying glucose tablets or gel, a diabetic identification bracelet or card, or exercising with an individual who is aware of the circumstances. In addition to blood glucose concentrations, proper foot care is critical to people with diabetes who exercise and includes considering type of shoe, type of exercise, inspection of skin surfaces and appropriate evaluation and treatment of lesions (calluses and others). Those with severe neuropathy can consider alternatives to weight-bearing exercises. Precipitation of clinical CAD is of great concern for all diabetic patients participating in exercise activities. Although a sufficiently sensitive and specific screening test for coronary disease has not been identified, those planning an exercise program of moderate intensity or greater should be evaluated. Initial cardiac assessment should include exercise testing as well as identifying risk for autonomic neuropathy. In addition to noting maximal heart rate and blood pressure as well as ischemic changes, exercise tolerance testing can identify anginal thresholds and patients with asymptomatic ischemia. Those without symptoms should be counseled regarding target pulse rates to avoid inducing ischemia. Ischemic changes need to be evaluated for either further diagnostic testing or pharmacological intervention. For patients with diabetes mellitus, the overall benefits of exercise are clearly significant. Clinicians and patients must work together to maximize these benefits while minimizing risks for negative consequences. Identifying and preventing potential problems beforehand can reduce adverse outcomes and promote this important approach to healthy living.

Colorectal cancer screening participation: comparisons with mammography and prostate-specific antigen screening.

OBJECTIVES: The relation of personal characteristics, health and lifestyle behaviors, and cancer screening practices to current colorectal cancer (CRC) screening was assessed and compared with those factors' relation to current mammography screening in women and prostate-specific antigen (PSA) screening in men. METHODS: A cross-sectional random-digit-dialed telephone survey of 954 Massachusetts residents aged 50 and older was conducted. RESULTS: The overall prevalence of current CRC screening was 55.3%. Logistic regression results indicated that family history of CRC (odds ratio [OR] = 1.98; 95% confidence interval [CI] = 1.02, 3.86), receiving a regular medical checkup (OR = 3.07; 95% CI = 2.00, 4.71), current screening by mammography in women and PSA in men (OR = 4.40; 95% CI = 2.94, 6.58), and vitamin supplement use (OR = 1.87; 95% CI = 1.27, 2.77) were significant predictors of CRC screening. CONCLUSIONS: Health and lifestyle behaviors were related to increased current CRC, mammography, and PSA screening. Personal factors independently related to CRC screening were not consistent with those related to mammography and PSA screening. This lack of consistency may reflect different stages of adoption of each type of screening by clinicians and the public.

Biomechanics of cardiovascular development.

It long has been known that mechanical forces play a role in the development of the cardiovascular system, but only recently have biomechanical engineers begun to explore this field. This paper reviews some of this work. First, an overview of the relevant biology is discussed. Next, a mechanical theory is presented that can be used to model developmental processes. The theory includes the effects of finite volumetric growth and active contractile forces. Finally, applications of this and other theories to problems of cardiovascular development are discussed, and some future directions are suggested. The intent is to stimulate further interest among engineers in this important area of research.