The Pathway from Anatomy and Physiology to Diagnosis: A Developmental Perspective on Swallowing and Dysphagia.

Dysphagia results from diverse and distinct etiologies. The pathway from anatomy and physiology to clinical diagnosis is complex and hierarchical. Our approach in this paper is to show the linkages from the underlying anatomy and physiology to the clinical presentation. In particular, the terms performance, function, behavior, and physiology are often used interchangeably, which we argue is an obstacle to clear discussion of mechanism of pathophysiology. We use examples from pediatric populations to highlight the importance of understanding anatomy and physiology to inform clinical practice. We first discuss the importance of understanding anatomy in the context of physiology and performance. We then use preterm infants and swallow-breathe coordination as examples to explicate the hierarchical nature of physiology and its impact on performance. We also highlight where the holes in our knowledge lie, with the ultimate endpoint of providing a framework that could enhance our ability to design interventions to help patients. Clarifying these terms, and the roles they play in the biology of dysphagia will help both the researchers studying the problems as well as the clinicians applying the results of those studies.

The Impact of Varying Nipple Properties on Infant Feeding Physiology and Performance Throughout Ontogeny in a Validated Animal Model.

Infant feeding requires successful interactions between infant physiology and the maternal (or bottle) nipple. Within artificial nipples, there is variation in both nipple stiffness and flow rates, as well as variation in infant physiology as they grow and mature. However, we have little understanding into how infants interact with variable nipple properties to generate suction and successfully feed. We designed nipples with two different stiffnesses and hole sizes and measured infant feeding performance through ontogeny using a pig model. We evaluated their response to nipple properties using high-speed X-Ray videofluoroscopy. Nipple properties substantially impacted sucking physiology and performance. Hole size had the most profound impact on the number of sucks infants took per swallow. Pressure generation generally increased with age, especially in nipples where milk acquisition was more difficult. However, most strikingly, in nipples with lower flow rates the relationship between suction generation and milk acquisition was disrupted. In order to design effective interventions for infants with feeding difficulties, we must consider how variation in nipple properties impacts infant physiology in a targeted manner. While reducing flow rate may reduce the frequency an infant aspirates, it may impair systems involved in sensorimotor integration.

The contractile patterns, anatomy and physiology of the hyoid musculature change longitudinally through infancy.

All mammalian infants suckle, a fundamentally different process than drinking in adults. Infant mammal oropharyngeal anatomy is also anteroposteriorly compressed and becomes more elongate postnatally. While suckling and drinking require different patterns of muscle use and kinematics, little insight exists into how the neuromotor and anatomical systems change through the time that infants suckle. We measured the orientation, activity and contractile patterns of five muscles active during infant feeding from early infancy until weaning using a pig model. Muscles not aligned with the long axis of the body became less mediolaterally orientated with age. However, the timing of activation and the contractile patterns of those muscles exhibited little change, although variation was larger in younger infants than older infants. At both ages, there were differences in contractile patterns within muscles active during both sucking and swallowing, as well as variation among muscles during swallowing. The changes in anatomy, coupled with less variation closer to weaning and little change in muscle firing and shortening patterns suggest that the neuromotor system may be optimized to transition to solid foods. The lesser consequences of aspiration during feeding on an all-liquid diet may not necessitate the evolution of variation in neuromotor function through infancy.

The Function of the Mammal Extrinsic Tongue Musculature in the Transition from Suckling to Drinking.

The transition from suckling to drinking is a developmental pathway that all mammals take. In both behaviors, the tongue is the primary structure involved in acquiring, transporting, and swallowing the liquid. However, the two processes are fundamentally different: during suckling, the tongue must function as a pump to generate suction to move milk, whereas during drinking, the tongue moves backwards and forwards through the mouth to acquire and move water. Despite these fundamental differences, we have little understanding of how tongues role varies between these behaviors. We used an infant pig model to investigate the relationships between anatomy, physiology, and function of the tongue to examine how lingual function is modulated in the transition from infancy to adulthood. We found that while some muscles were proportionally largest at birth, others were proportionally larger at the time of weaning. Furthermore, we found variation in tongue movements between suckling and drinking along both the mediolateral and anteroposterior axes, resulting in differences in tongue deformation between the two behaviors. The extrinsic tongue muscles also changed in function differently between drinking and suckling. Genioglossus increased its activity and turned on and off earlier in the cycle during drinking, whereas hyoglossus fired at lower amplitudes during drinking, and turned on and off later in the cycle. Together, the data highlight the significant need for high neuroplasticity in the control of the tongue at a young age in mammals and suggest that the ability to do so is key in the ontogeny and evolution of feeding in these animals.

Regional Variation in Contractile Patterns and Muscle Activity in Infant Pig Feeding.

At the level of the whole muscle, contractile patterns during activity are a critical and necessary source of variation in function. Understanding if a muscle is actively lengthening, shorting, or remaining isometric has implications for how it is working to power a given behavior. When feeding, the muscles associated with the tongue, jaws, pharynx, and hyoid act together to transport food through the oral cavity and into the esophagus. These muscles have highly coordinated firing patterns, yet also exhibit high levels of regional heterogeneity in both their timing of activity and their contractile characteristics when active. These high levels of variation make investigations into function challenging, especially in systems where muscles power multiple behaviors. We used infant pigs as a model system to systematically evaluate variation in muscle firing patterns in two muscles (mylohyoid and genioglossus) during two activities (sucking and swallowing). We also evaluated the contractile characteristics of mylohyoid during activity in the anterior and posterior regions of the muscle. We found that the posterior regions of both muscles had different patterns of activity during sucking versus swallowing, whereas the anterior regions of the muscles did not. Furthermore, the anterior portion of mylohyoid exhibited concentric contractions when active during sucking, whereas the posterior portion was isometric during sucking and swallowing. This difference suggests that the anterior portion of mylohyoid in infant pigs is functioning in concert with the tongue and jaws to generate suction, whereas the posterior portion is likely acting as a hyoid stabilizer during sucking and swallowing. Our results demonstrate the need to evaluate both the contractile characteristics and activity patterns of a muscle in order to understand its function, especially in cases where there is potential for variation in either factor within a single muscle.

Preterm Birth Impacts the Timing and Excursion of Oropharyngeal Structures during Infant Feeding.

Swallowing in mammals requires the precise coordination of multiple oropharyngeal structures, including the palatopharyngeal arch. During a typical swallow, the activity of the palatopharyngeus muscle produces pharyngeal shortening to assist in producing pressure required to swallow and may initiate epiglottal flipping to protect the airway. Most research on the role of the palatopharyngeal arch in swallowing has used pharyngeal manometry, which measures the relative pressures in the oropharynx, but does not quantify the movements of the structures involved in swallowing. In this study, we assessed palatopharyngeal arch and soft palate function by comparing their movements in a healthy population to a pathophysiological population longitudinally through infancy (term versus preterm pigs). In doing so, we test the impact of birth status, postnatal maturation, and their interaction on swallowing. We tracked the three-dimensional (3D) movements of radiopaque beads implanted into relevant anatomical structures and recorded feeding via biplanar high-speed videofluoroscopy. We then calculated the total 3D excursion of the arch and soft palate, the orientation of arch movement, and the timing of maximal arch constriction during each swallow. Soft palate excursion was greater in term infants at both 7 and 17 days postnatal, whereas arch excursion was largely unaffected by birth status. Maximal arch constriction occurred much earlier in preterm pigs relative to term pigs, a result that was consistent across age. There was no effect of postnatal age on arch or soft palate excursion. Preterm and term infants differed in their orientation of arch movement, which most likely reflects both differences in anatomy and differences in feeding posture. Our results suggest that the timing and coordination of oropharyngeal movements may be more important to feeding performance than the movements of isolated structures, and that differences in the neural control of swallowing and its maturation in preterm and term infants may explain preterm swallowing deficits.

Altered systemic serologic parameters in patients with silicone mammary implants.

BACKGROUND: The most common local complication in patients with silicone mammary implants (SMIs) is excessive peri-SMI connective tissue capsule formation and its subsequent contracture. However, considerable controversy remains as to whether these implants also cause systemic side effects. The present study was undertaken to identify possible alterations of serological markers in SMI patients that may herald systemic side effects. METHODS: We investigated several systemic serological parameters in 143 individuals, 93 of whom had received SMIs and 50 were controls. The patients were grouped according to the severity of capsular contracture (Baker scores I-IV) and the duration of SMI implants (less than 1 year, between 1 and 5 years, more than 5 years). We also included control groups (female blood donors, nurses with possible professional silicone exposure). Patients with breast cancer and subsequent SMI-reconstruction were excluded from the study since they are generally considered immunocompromised. The following parameters were determined: anti-neutrophil cytoplasmatic autoantibodies (cANCA), anti-nuclear autoantibodies (ANA), anti-cardiolipin antibodies (CL-Ab), rheumatoid factor (RF), complement components (C3, C4), circulating immune complexes (CIC), procollagen III (a marker of active fibrosis), anti-polymer antibodies (APA) and soluble intercellular adhesion molecule-1 (sICAM-1). RESULTS: The following parameters were increased in the sera of SMI patients: CIC, procollagen III, APA, sICAM-1. CONCLUSIONS: We found a set of parameters in serum that correlate with fibrosis development and the duration of the implants in otherwise healthy SMI carriers. Future studies will clarify whether these serological abnormalities will be useful in predicting clinical disease, and also further assess the sensitivity and specificity of these parameters. Our present recommendation as a result of this study is that SMI patients with persistent abnormal serological parameters should be monitored closely by a clinical team that includes rheumatologists.

Really old-palaeoimmunology: immunohistochemical analysis of extracellular matrix proteins in historic and pre-historic material.

In this review, we summarize data concerning the respective preservation and deterioration of antigenic determinants of various collagenous and non-collagenous extracellular matrix (ECM) proteins in palaeontologic material of different ages. ECM proteins are the major quantitative constituents of mammalian organisms and were, therefore, selected as important representative proteins for these analyses. The specimens, studied by immunofluorescence and immunohistochemical techniques, included the skin of 500-1500 year-old human mummies from Peru, skin and striated muscle from the 5300-year-old glacier mummy ("Iceman") from Tyrol, Austria, and a 50-million-year-old bat with preserved soft body parts from the fossil excavation site of Messel, Germany. In frozen sections of the former two sources, epitopes recognized by specific antibodies for triple-helical antigenic determinants of different types of collagen resistant against conventional proteases were preserved, while non-helical domains, as well as the non-collagenous ECM proteins, could no longer be demonstrated. The fossil bat, although showing evidence of fibrous, collagen-like structures in conventional histology, revealed no collagenous or non-collagenous ECM proteins by any technique. It later turned out that this was due to the replacement of the original soft parts in these fossils by lawns of bacteria. These studies introduced immunological techniques into palaeontology and opened new approaches for studying physiologically- and pathologically-altered structures in tissues of animals and humans of considerable historical age.

Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer.

AIMS: Tenascin-C (Tn-C) is an extracellular matrix glycoprotein that is upregulated in malignant tumours. Tn-C promotes cell growth, cell migration, and angiogenesis. It has been suggested to be a prognostic factor in various types of malignant tumours, but there is little information on its significance in bladder cancer with regard to overall survival (OS) and recurrence free survival (RFS). METHODS: Tn-C expression was studied in 106 patients with bladder cancer diagnosed between 1994 and 1997. Immunohistochemistry was performed using a monoclonal antibody against Tn-C. RFS and OS were estimated by the Kaplan-Meier method and compared by the log rank test in univariate analysis and by the Cox multistep regression method in multivariate analysis. RESULTS: Within the mean follow up period of 126 months, patients with diffuse Tn-C staining in the tumour stroma had a significantly worse OS than those with negative staining or only moderate Tn-C expression (p = 0.025). Patients with cytoplasmic expression of Tn-C had a significantly better OS than those without (p = 0.001). Multivariate analysis, taking into consideration age, grade, stage, tumour associated carcinoma in situ, progression, and Tn-C staining in tumour stroma, showed that only expression of Tn-C in invasive tumour cells was an independent positive prognostic factor for OS (p = 0.049). CONCLUSIONS: Tn-C may provide important prognostic information in bladder cancer depending on the expression pattern in the tumour stroma or cytoplasm of the tumour cells.

Differences between patients and medical professionals in the evaluation of aesthetic outcome following breast reconstruction with implants.

BACKGROUND AND AIM: Most studies on breast reconstruction evaluate different surgical techniques, types of implant or time of reconstruction. Moreover, evaluations are usually performed either by surgeons or by patients, but are rarely compared. We conducted a study on aesthetic outcome following breast reconstruction with implants comparing the evaluation by patients versus medical professionals. METHODS: Forty-seven patients, who had a breast reconstruction with implants between 2001 and 2010 (median follow-up 71 months), underwent a clinical examination, standardized photo documentation and filled out a questionnaire to evaluate their aesthetic result (rate 1 very good to 5 very poor). Photo documentation was independently evaluated by 18 medical professionals using the same evaluation instrument and the results were compared. Gender and patient aspects were taken into account. RESULTS: We found statistically significant differences between patients and medical professional ratings. The patient evaluation was better through all categories as compared to the evaluation by medical personnel. The degree of medical education or gender aspects did not significantly affect the professional ratings. Age at reconstruction, length of follow-up or primary versus secondary reconstruction did not seem to make a difference in the evaluations of the patients versus the medical professionals.. CONCLUSION: The differences between patient and expert opinion in rating of aesthetic results indicate that patient satisfaction is influenced by multiple factors and not only by good aesthetic outcome. Patient evaluation should therefore be carefully considered in treatment and outcome studies of breast reconstruction..

The vascular-associated lymphoid tissue: a new site of local immunity.

Recent data suggest that atherosclerosis might be a systemic (auto)immune reaction against heat shock protein 60, first occurring at notorious local predilection sites, i.e. the intima at arterial branching points. The local infiltration of mononuclear cells, mainly macrophage-derived foam cells, T cells and smooth-muscle cells in atheromatous plaques, have long been described. During the past few years, research has been concentrated on the early stages in the development of atherosclerosis, and on healthy arteries from young individuals unaffected by arterial disease. In this review, we summarize data characterizing pre-existing mononuclear cell infiltrations in healthy arteries from children and teenagers. These arterial accumulations at regions known to be predilection sites for the later development of atherosclerosis consist mostly of activated T cells, macrophages and dendritic cells, with only a few mast cells and virtually no B or natural killer cells. In analogy to the mucosa-associated lymphoid tissue, we termed these accumulations 'vascular-associated lymphoid tissue', and assumed a similar function as a local immunosurveillance system, monitoring the bloodstream for potentially harmful endogenous or exogenous antigens. In addition to the remarkable accumulation of mononuclear cells, the vascular-associated lymphoid tissue regions are characterized by a typical distribution of extracellular matrix proteins: collagen type I, collagen type III, fibronectin and tenascin are expressed preferentially in the vascular-associated lymphoid tissue region, whereas collagen type IV, collagen type V, collagen type VI and laminin show a homogenous distribution throughout all regions of the intima. Vascular adhesion molecules type 1, intercellular adhesion molecules type 1 and P-selectin are already present on the healthy endothelial cells of young children. Interactions between adhesion molecules, extracellular matrix components and cellular elements of the vascular-associated lymphoid tissue may provide the basis for the cellular accumulations in the vascular-associated lymphoid tissue regions and the possible development of atherosclerotic lesions later in life.