Sean S. Kohles

Plasma Levels of Polychlorinated Biphenyls, Non-Hodgkin Lymphoma, and Causation

Polychlorinated biphenyls (PCBs) are synthetic chlorinated hydrocarbons that have extensively polluted the environment and bioaccumulated in the food chain. PCBs have been deemed to be probable carcinogens by the Environmental Protection Agency, and exposure to high levels of PCBs has been consistently linked to increased risk of non-Hodgkin lymphoma (NHL). In the present article we present a forensic epidemiologic evaluation of the causal relationship between NHL and elevated PCB levels via application of the Bradford-Hill criteria. Included in the evaluation is a meta-analysis of the results of previously published case-control studies in order to assess the strength of association between NHL and PCBs, resulting in an odds ratio in which the lowest percentile PCB concentration (quartile, quintile, or tertile) has been compared with the highest percentile concentration in the study groups. The weight-adjusted odds ratio for all PCB congeners was 1.43 with a 95% confidence interval of 1.31 to 1.55, indicating a statistically significant causal association with NHL. Because of the lack of an unexposed comparison group, a rationale for the use of a less than 2.0 relative risk causal contribution threshold is presented herein, including an ecologic analysis of NHL incidence and PCB accumulation (as measured by sales volume) over time. The overall results presented here indicate a strong general causal association between NHL and PCB exposure.

An inverse method for predicting tissue-level mechanics from cellular mechanical input

Extracellular matrix (ECM) provides a dynamic three-dimensional structure which translates mechanical stimuli to cells. This local mechanical stimulation may direct biological function including tissue development. Theories describing the role of mechanical regulators hypothesize the cellular response to variations in the external mechanical forces on the ECM. The exact ECM mechanical stimulation required to generate a specific pattern of localized cellular displacement is still unknown. The cell to tissue inverse problem offers an alternative approach to clarify this relationship. Developed for structural dynamics, the inverse dynamics problem translates measurements of local state variables (at the cell level) into an unknown or desired forcing function (at the tissue or ECM level). This paper describes the use of eigenvalues (resonant frequencies), eigenvectors (mode shapes), and dynamic programming to reduce the mathematical order of a simplified cell-tissue system and estimate the ECM mechanical stimulation required for a specified cellular mechanical environment. Finite element and inverse numerical analyses were performed on a simple two-dimensional model to ascertain the effects of weighting parameters and a reduction of analytical modes leading toward a solution. Simulation results indicate that the reduced number of mechanical modes (from 30 to 14 to 7) can adequately reproduce an unknown force time history on an ECM boundary. A representative comparison between cell to tissue (inverse) and tissue to cell (boundary value) modeling illustrates the multiscale applicability of the inverse model.

A case-control study of cerebellar tonsillar ectopia (Chiari) and head/neck trauma (whiplash)

Primary objective: Chiari malformation is defined as herniation of the cerebellar tonsils through the foramen magnum, also known as cerebellar tonsillar ectopia (CTE). CTE may become symptomatic following whiplash trauma. The purpose of the present study was to assess the frequency of CTE in traumatic vs non-traumatic populations. Study design: Case-control. Methods and procedures: Cervical MRI scans for 1200 neck pain patients were reviewed; 600 trauma (cases) and 600 non-trauma (controls). Half of the groups were scanned in a recumbent position and half were scanned in an upright position. Two radiologists interpreted the scans for the level of the cerebellar tonsils. Main outcomes and results: A total of 1195 of 1200 scans were read. CTE was found in 5.7% and 5.3% in the recumbent and upright non-trauma groups vs 9.8% and 23.3% in the recumbent and upright trauma groups (p = 0.0001). Conclusions: The results described in the present investigation are first to demonstrate a neuroradiographic difference between neck pain patients with and without a recent history of whiplash trauma. The results of prior research on psychosocial causes of chronic pain following whiplash are likely confounded because of a failure to account for a possible neuropathologic basis for the symptoms.

The μPIVOT: an integrated particle image velocimeter and optical tweezers instrument for microenvironment investigations

A novel instrument to manipulate and characterize the mechanical environment in and around microscale objects in a fluidic environment has been developed by integrating two laser-based techniques: micron-resolution particle image velocimetry (μPIV) and optical tweezers (OT). This instrument, the μPIVOT, enables a new realm of microscale studies, yet still maintains the individual capabilities of each optical technique. This was demonstrated with individual measurements of optical trap stiffness (∼70 pN μm(-1) for a 20 μm polystyrene sphere and a linear relationship between trap stiffness and laser power) and fluid velocities within 436 nm of a microchannel wall. The integrated device was validated by comparing computational flow predictions to the measured velocity profile around a trapped particle in either a uniform flow or an imposed, gravity-driven microchannel flow (R(2) = 0.988, RMS error = 13.04 μm s(-1)). Interaction between both techniques is shown to be negligible for 15 μm to 35 μm diameter trapped particles subjected to fluid velocities from 50 μm s(-1) to 500 μm s(-1) even at the highest laser power (1.45 W). The integrated techniques will provide a unique perspective toward understanding microscale phenomena including single-cell biomechanics, non-Newtonian fluid mechanics and single particle or particle-particle hydrodynamics.

The relationship between vehicle roof crush and head, neck and spine injury in rollover crashes

BACKGROUND It is well established that rollover crashes are associated with a higher risk of serious injury and death than other types of crashes. Some of the most serious injuries that can result from a rollover crash are those to the head, neck and spine. The mechanism of injury to these body parts in a rollover is a matter of dispute in the literature. Some authors have concluded that the magnitude of vehicle roof deformation or vertical roof crush resulting from a rollover crash is not causally associated with head and neck injury severity, while others offer support for a causal association between roof crush and the degree of injury. A better understanding of the cause of serious injuries resulting from rollover crashes is important for improving injury prevention. METHODS This study utilized data from the National Automotive Sampling System--Crashworthiness Data System (NASS-CDS) for the years 1997 through 2007. Both cross-sectional and matched case-control designs along with a new composite injury metric termed the Head, Neck and Spine New Injury Severity Score (HNS-NISS) were used to analyze these data. RESULTS The cross-sectional analysis demonstrated a 64% (95% CI: 26-114%) increase in the odds of a life-threatening injury as estimated by the HNS-NISS with every 10 cm of increased roof crush. The results of the matched case-control analysis demonstrated a 44% (95% CI: 8-91%) increase in the odds of sustaining any injury to the head, neck or spine with every 10 cm increase in roof crush. CONCLUSION These results lend statistical support to a causal association between roof crush and head, neck and spine injury severity. Though they do not constitute definitive proof, they do contradict previously published theories suggesting that roof deformation is unrelated to such injuries.

Esophageal injury in fatal rear-impact collisions

Neck injuries resulting from motor vehicle collisions (MVC), often referred to as whiplash trauma and injury, often demonstrate little or no evidence of significant tissue damage. In rare instances, however, serious injury to the anterior neck organ injuries can result from such trauma. The present study describes esophageal injury associated with rear-impact collisions, based on a unique case report, review of the scientific literature and a query in the National Automotive Sampling System (NASS) database of the US National Highway Traffic Safety Administration. The Medline search and present case study totaled five cases of rear-impact collision-related serious esophageal injury (laceration or rupture). In the four published cases all patients survived, whereas in the presented case study, the patient died due to mediastinitis and sepsis. The NASS query revealed an additional three cases out of a total of 55,926 investigated crashes. All three cases were associated with fatalities. Although no anatomical or bioengineering studies have presented data on the behavior of the esophagus during rear-impact whiplash loading, sudden tensile and/or compressive forces is the likely explanation of injury, often in combination with a local fracture of a vertebral body. In these 8 cases significant esophageal injury carried a substantial (50%) risk of mortality. Clinicians should be aware of the potential for significant complications in the whiplash trauma-exposed patient who complains of chest pain, mid-thoracic pain, discomfort in the neck and throat, respiratory distress, or hoarseness. For those forensic specialists involved in whiplash cases these study results highlight the need to consider esophageal injuries as a rare but potential consequence of whiplash trauma.

Forensic Epidemiologic and Biomechanical Analysis of a Pelvic Cavity Blowout Injury Associated with Ejection from a Personal Watercraft (Jet-Ski)

Jet‐propelled personal watercraft (PWC) or jet‐skis have become increasingly popular. The means of propulsion of PWC, which is a jet of water forced out of small nozzle at the rear of the craft, combined with a high risk of falling off of the seat and into close proximity with the water jet stream, raise the potential for a unique type of injury mechanism. The most serious injuries associated with PWC falls are those that occur when the perineum passes in close proximity to the jet nozzle and the high‐pressure water stream enters the vaginal or rectal orifice. We describe the forensic investigation into a case of an anovaginal “blowout” injury in a passenger who was ejected from the rear seat position of a PWC and subsequently suffered life‐threatening injuries to the pelvic organs. The investigation included a biomechanical analysis of the injury mechanism, a summary of prior published reports of internal pelvic injuries resulting from PWC falls as well as other water sports and activities, and a comparison of the severity of the injuries resulting from differing mechanisms using the New Injury Severity Score (NISS). The mean (±standard deviation [SD]) NISS values for reported PWC injuries [not including the NISS of 38 in this case study] were 11.2 (±9.5), while the mean value for reported water‐skiing falls was half that of the PWC group at 5.6 (±5.2). It was concluded that the analyzed injuries were unique to a PWC ejection versus other previously described non‐PWC‐associated water sport injuries. It is recommended that PWC manufacturers help consumers understand the potential risks to passengers with highly visible warnings and reduce injury risk with revised seat design, and/or passenger seat “deadman” switches.

Serious head and neck injury as a predictor of occupant position in fatal rollover crashes

Serious head and neck injuries are a common finding in fatalities associated with rollover crashes. In some fatal rollover crashes, particularly when ejection occurs, the determination of which occupant was driving at the time of the crash may be uncertain. In the present investigation, we describe the analysis of rollover crash data from the National Automotive Sampling System-Crashworthiness Data System for the years 1997 through 2007 in which we examined the relationship between a serious head and neck injury in an occupant and a specified degree of roof deformation at the occupants seating position. We found 960 occupants who qualified for the analysis, with 142 deaths among the subjects. Using a ranked composite head and neck injury score (the HNISS) we found a strong relationship between HNISS and the degree of roof crush. As a result of the analysis, we arrived at a predictive model, in which each additional unit increase in HNISS equated to an increased odds of roof crush as follows: for ≥8 cm of roof crush compared with <8 cm by 4%, for ≥15 cm of roof crush compared to <8 cm by 6% and for ≥30 cm of roof crush compared to <8 cm by 11%. We describe two hypothetical scenarios in which the model could be applied to the real world investigation of occupant position in a rollover crash-related fatality.

Assessing specific causation of mesothelioma following exposure to chrysotile asbestos-containing brake dust

Abstract Background: The question of whether chrysotile asbestos-containing brake dust can plausibly serve as a cause of mesothelioma in an exposed individual has become a matter of heated debate in the medical literature despite multiple international, federal, and state governmental agencies acknowledging a causal association. Objectives: We describe and provide an analysis of various industry and academic perspectives contributing to the debate. Methods: A framework is presented for evaluating the general and specific causal relationship between brake dust exposure and mesothelioma utilizing the principles of forensic epidemiology, and by applying the Bradford–Hill criteria. Results and conclusions: We conclude that there is a “net” of evidence favoring a causal relationship between brake dust-associated chrysotile exposure and mesothelioma. The industry-sponsored position that there is insufficient evidence to support a contiguous “chain” of causation is specious from both a methodologic and evidentiary perspective. Finally, we suggest a semiquantitative approach for the evaluation of individual causation in putative cases of mesothelioma with a history of significant brake dust exposure.

A cell-matrix model of anabolic and catabolic dynamics during cartilage biomolecule regulation

Physiologic regulation of extracellular matrix (ECM) in articular cartilage tissue is controlled by cellular and molecular mechanisms which are not fully understood. It has been observed that the synthesis of the ECM structural molecules, glycosaminoglycan and collagen are promoted by growth factors such as IGF-1 and TGF-β. Concomitant ECM degradation is promoted by a variety of cytokines such as IL-1. The clinical need for reparative therapies of articular cartilage is linked with its poor intrinsic healing capacity. The following modelling approach was applied to engineered cartilage as a platform for exploring cartilage biology and to introduce a predictive tool as a bioinformatic support system supporting regenerative therapies. Systems biology was adapted through a mathematical framework producing a computational intelligence paradigm to explore a controlled phasic regulatory influence of the inhibition and production of ECM biomolecules. Model outcomes describe a steady synthesis of ECM as a dependence on a cyclic influence of the catabolic action of proteases and anabolic action of growth factors. This relationship is shown quantitatively in a governing harmonic equation representing the simplified biological mechanisms of biomolecule homeostasis.