Mercury (Hg) Exposure in Breast-Fed Infants and Their Mothers and the Evidence of Oxidative Stress

The objective of this work was to assess exposure to mercury (Hg) and its induction of oxidative stress in 155 healthy lactating Saudi mothers and their infants. Samples of breast milk and blood were collected from the mothers, while urine was taken from both infants and mothers. Both urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured in mothers and infants as biomarkers of oxidative stress. The mean concentration of Hg in breast milk was 1.19 μg/L (range 0.012–6.44 μg/L) with only one mother having Hg >4 μg/L, the upper limit established by the US Agency for Toxic Substance and Disease Registry. However, 57.4 % had Hg ≥1 μg/L, the background level for Hg in human milk. The mean urinary Hg corrected for creatinine (Hg-C) in mothers and infants was 1.47 and 7.90 μg/g creatinine, respectively, with a significant correlation between the two (p?<?0.001). Urinary Hg levels over 5 μg/g creatinine (the background level in an unexposed population) were found in 3.3 % of mothers and 50.1 % of infants. None of the mothers had total blood Hg above the US Environmental Protection Agency’s maximum reference dose of 5.8 μg/L. No correlation was noted between urinary Hg in infants and Hg in breast milk (p?>?0.05). Hg in breast milk, though, was associated with Hg in blood (p?<?0.001), suggesting the efficient transfer of Hg from blood to milk. Hg in the breast milk of mothers and in the urine of infants affected the excretion of urinary MDA and 8-OHdG, respectively, in a dose-related manner. These findings reveal for the first time lactational exposure to Hg-induced oxidative stress in breast-fed infants, which may play a role in pathogenesis, particularly during neurodevelopment. This will also contribute to the debate over the benefits of breast milk versus the adverse effects of exposure to pollutants. Nevertheless, breastfeeding should not be discouraged, but efforts should be made to identify and eliminate the source of Hg exposure in the population.     

Differences in muscle function during walking and running at the same speed

Individual muscle contributions to body segment mechanical energetics and the functional tasks of body support and forward propulsion in walking and running at the same speed were quantified using forward dynamical simulations to elucidate differences in muscle function between the two different gait modes. Simulations that emulated experimentally measured kinesiological data of young adults walking and running at the preferred walk-to-run transition speed revealed that muscles use similar biomechanical mechanisms to provide support and forward propulsion during the two tasks. The primary exception was a decreased contribution of the soleus to forward propulsion in running, which was previously found to be significant in walking. In addition, the soleus distributed its mechanical power differently to individual body segments between the two gait modes from mid- to late stance. In walking, the soleus transferred mechanical energy from the leg to the trunk to provide support, but in running it delivered energy to both the leg and trunk. In running, earlier soleus excitation resulted in it working in synergy with the hip and knee extensors near mid-stance to provide the vertical acceleration for the subsequent flight phase in running. In addition, greater power output was produced by the soleus and hip and knee extensors in running. All other muscle groups distributed mechanical power among the body segments and provided support and forward propulsion in a qualitatively similar manner in both walking and running.     

Musculotendon lengths and moment arms for a three-dimensional upper-extremity model

Generating muscle-driven forward dynamics simulations of human movement using detailed musculoskeletal models can be computationally expensive. This is due in part to the time required to calculate musculotendon geometry (e.g., musculotendon lengths and moment arms), which is necessary to determine and apply individual musculotendon forces during the simulation. Modeling upper-extremity musculotendon geometry can be especially challenging due to the large number of multi-articular muscles and complex muscle paths. To accurately represent this geometry, wrapping surface algorithms and/or other computationally expensive techniques (e.g., phantom segments) are used. This paper provides a set of computationally efficient polynomial regression equations that estimate musculotendon length and moment arms for thirty-two (32) upper-extremity musculotendon actuators representing the major muscles crossing the shoulder, elbow and wrist joints. Equations were developed using a least squares fitting technique based on geometry values obtained from a validated public-domain upper-extremity musculoskeletal model that used wrapping surface elements (Holzbaur et al., 2005). In general, the regression equations fit well the original model values, with an average root mean square difference for all musculotendon actuators over the represented joint space of 0.39 mm (1.1% of peak value). In addition, the equations reduced the computational time required to simulate a representative upper-extremity movement (i.e., wheelchair propulsion) by more than two orders of magnitude (315 versus 2.3 s). Thus, these equations can assist in generating computationally efficient forward dynamics simulations of a wide range of upper-extremity movements.     

Pre-swing deficits in forward propulsion,swing initiation and power generation by individual muscles during hemiparetic walking

Clinical studies of hemiparetic walking have shown pre-swing abnormalities in the paretic leg suggesting that paretic muscle contributions to important biomechanical walking subtasks are different than those of non-disabled individuals. Three-dimensional forward dynamics simulations of two representative hemiparetic subjects with different levels of walking function classified by self-selected walking speed (i.e., limited community=0.4–0.8 m/s and community walkers=>0.8 m/s) and a speed-matched control were generated to quantify individual muscle contributions to forward propulsion, swing initiation and power generation during the pre-swing phase (i.e., double support phase proceeding toe-off). Simulation analyses identified decreased paretic soleus and gastrocnemius contributions to forward propulsion and power generation as the primary impairment in the limited community walker compared to the control subject. The non-paretic leg did not compensate for decreased forward propulsion by paretic muscles during pre-swing in the limited community walker. Paretic muscles had the net effect to absorb energy from the paretic leg during pre-swing in the community walker suggesting that deficits in swing initiation are a primary impairment. Specifically, the paretic gastrocnemius and hip flexors (i.e., iliacus, psoas and sartorius) contributed less to swing initiation and the paretic soleus and gluteus medius absorbed more power from the paretic leg in the community walker compared to the control subject. Rehabilitation strategies aimed at diminishing these deficits have much potential to improve walking function in these hemiparetic subjects and those with similar deficits.     

A Method for Numerical Simulation of Single Limb Ground Contact Events: Application to Heel-Toe Running

The objective of this work was to develop a method to simulate single-limb ground contact events, which may be applied to study musculoskeletal injuries associated with such movements. To achieve this objective, a three-dimensional musculoskeletal model was developed consisting of the equations of motion for the musculoskeletal system, and models for the muscle force generation and ground contact elements. An optimization framework and a weighted least-squares objective function were presented that generated muscle stimulation patterns that optimally reproduced subject-specific movement data. Experimental data were collected from a single subject to provide initial conditions for the simulation and tracking data for the optimization. As an example application, a simulation of the stance phase of running was generated. The results showed that the average difference between the simulation and subject's ground reaction force and joint angle data was less than two inter-trial standard deviations. Further, there was good agreement between the model's muscle excitation patterns and experimentally collected electromyography data. These results give confidence in the model to examine musculoskeletal loading during a variety of landing movements and to study the effects of various factors associated with injury. Limitations were examined and areas of improvement for the model were presented.     

Design and analysis of orthogonally compliant features for local contact pressure relief in transtibial prostheses

A very attractive advantage of manufacturing prosthetic sockets using solid freeform fabrication is the freedom to introduce design solutions that would be difficult to implement using traditional manufacturing techniques. Such is the case with compliant features embedded in amputee prosthetic sockets to relieve contact pressure at the residual limb-socket interface. The purpose of this study was to present a framework for designing compliant features to be incorporated into transtibial sockets and manufacturing prototypes using selective laser sintering (SLS) and Duraform material. The design process included identifying optimal compliant features using topology optimization algorithms and integrating these features within the geometry of the socket model. Using this process, a compliant feature consisting of spiral beams and a supporting external structure was identified. To assess its effectiveness in reducing residual limb-socket interface pressure, a case study was conducted using SLS manufactured prototypes to quantify the difference in interface pressure while a patient walked at his self-selected pace with one noncompliant and two different compliant sockets. The pressure measurements were performed using thin pressure transducers located at the distal tibia and fibula head. The measurements revealed that the socket with the greatest compliance reduced the average and peak pressure by 22% and 45% at the anterior side distal tibia, respectively, and 19% and 23% at the lateral side of the fibula head, respectively. These results indicate that the integration of compliant features within the socket structure is an effective way to reduce potentially harmful contact pressure and increase patient comfort.     

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.     

Kinetic characterization of the oxidation of esculetin by polyphenol oxidase and peroxidase

Esculetin has been described as an inhibitor of tyrosinase and polyphenol oxidase and, therefore, of melanogenesis. In this work, we demonstrate that esculetin is not an inhibitor but a substrate of mushroom polyphenol oxidase (PPO) and horseradish peroxidase (POD), enzymes which oxidize esculetin, generating its o-quinone. Since o-quinones are very unstable, the usual way of determining the enzymatic activity (slope of recordings) is difficult. For this reason, we developed a chronometric method to characterize the kinetics of this substrate, based on measurements of the lag period in the presence of micromolar concentrations of ascorbic acid. The catalytic constant determined was of the same order for both enzymes. However, polyphenol oxidase showed greater affinity (a lower Michaelis constant) than peroxidase for esculetin. The affinity of PPO and POD towards oxygen and hydrogen peroxide was very high, suggesting the possible catalysis of both enzymes in the presence of low physiological concentrations of these oxidizing substrates. Taking into consideration optimum pHs of 4.5 and 7 for POD and PPO respectively, and the acidic pHs of melanosomes, the studies were carried out at pH 4.5 and 7. The in vivo pH might be responsible for the stronger effect of these enzymes on L-tyrosine and L-3,4-dihydroxyphenylanaline (L-DOPA) (towards melanogenesis) and on cumarins such as esculetin towards an alternative oxidative pathway.     

Snoring and aortic dimension in Marfan syndrome

Recent reports suggest that self-reported snoring, which is a feature of obstructive sleep apnea, is associated with aortic enlargement in Marfan syndrome (MFS). Objective assessment of snoring although lacking, could provide a rational for OSA screening in MFS patients. Our goal in this study was to examine the association between objective measurements of snoring with OSA and aortic size in persons with MFS. Consecutive persons with MFS who reported snoring were recruited at Johns Hopkins, completed the Epworth Sleepiness Scale (ESS) and underwent overnight polysomnography during which inspiratory sound was captured. We measured breath-by-breath peak decibel levels and snoring was defined as flow limitation with sound?≥?40 dB(A). OSA was defined as an apnea–hypopnea-index (AHI)?≥?15 or AHI: 5–15 and ESS?>?10. Participants’ aortic data were collated to ascertain aortic root diameter. Regression models were used to determine the relationship of snoring breath% with OSA and aortic root diameter. In our cohort (M|F:13|16, Age: 37.0?±?15.5 years, Aortic diameter; 38.9?±?4.8 mm), a 1-unit increase in snoring breath percentage increased the odds of having OSA by 5% in both the unadjusted (OR?=?1.05, p?=?0.040) model, and a model adjusted for age and sex (OR?=?1.05, p?=?0.048). Similarly, a 10-unit increase in snoring breath percentage was associated with a 1 mm increase in contemporaneous aortic-root-diameter in both unadjusted (β?=?0.09, p?=?0.007), and adjusted (β?=?0.08, p?=?0.023) models. Objective snoring assessment could provide a means for identifying persons with MFS who need sleep studies, who may also be at risk for more severe aortic disease.