Abstract

Forensic aspects related to pediatric pathology: medicolegal aspects of pediatric head injuries.

Roger W. Byard

The evaluation of head trauma in infants is often complex and contentious. Difficulties arise at all levels and problems result from inadequate investigations, poorly documented autopsy findings and contradictory interpretations of lesions. Head injuries in infants are particularly difficult to evaluate given a paucity of external findings, unique anatomy and poorly understood mechanisms of initial injury. Double blind trials involving head injury infants are not possible, and animal and mechanical models have been criticised. The older literature often relied upon uncorroborated histories of injury, and extrapolation was often made from small numbers of cases. The role of the expert is unenviable. Opinions are requested on the degree of force required to cause injuries and on possible mechanisms, resulting in protracted debate over possible contributions of factors to the fatal episode. If an infant or young child has died from a head injury that is not explainable by carers or by a close analysis of the environment where the child was injured, inflicted injury must be strongly suspected. The evaluation of these cases requires full scene examination by trained investigators, careful review of the family and infant's history, complete autopsy by a forensic pathologist with experience in pediatrics (or by a combination of forensic and pediatric pathologists), adequate tissue sampling and full neuropathological evaluation of brains and spinal cords by a specialised neuropathologist, with the use of special stains for evidence of occult trauma or disease. Defects in any of these areas may make subsequent medicolegal evaluation difficult, if not impossible.

A Vertical Challenge: Role of Desmoglein 1 in Epidermal Morphogenesis.

Spiro Getsios, Linda J. Sheu, Rachel L. Dusek, Cory L. Simpson,
Mona L. Cornwell, Todd Gocken, Susan E. Crawford, and Kathleen J. Green

Desmoglein 1 (Dsg1) is an essential adhesion molecule present in the desmosomes of differentiated keratinocytes. Consequently, blisters form in the upper epidermal cell layers when Dsg1 is targeted by autoimmune antibodies or bacterial proteases. As this desmosomal cadherin subtype is first expressed when keratinocytes enter a pathway of terminal differentiation, we tested whether Dsg1 has additional functions that regulate human epidermal morphogenesis using organotypic raft cultures. Chronic cleavage of the Dsg1 extracellular domain by the bacterial toxin, ETA, disrupted keratinocyte adhesion but did not prevent the formation of a stratified epithelium. In contrast, RNAi-mediated silencing of Dsg1 expression profoundly inhibited the vertical expansion of the epidermis, leading to the development of thinner raft cultures. Surprisingly, alterations in keratinocyte proliferation or cell death were not responsible for these stunted epidermal structures. Instead, Dsg1 was required for the progression of keratinocytes through the transitional stages of epidermal development. In the absence of Dsg1, proliferating keratinocytes remained largely confined to the basal layer but the terminal differentiation process was accelerated in the subpopulation of epidermal cell that had undergone stratification resulting in poorly formed intermediate layers. The onset of Dsg1 expression allowed for the enhanced migration of keratinocytes out of the basal layer and ultimately led to the complete recovery of epidermal architecture. These results support the idea that Dsg1 is required for the morphogenetic development of intermediate epidermal cell layers and complements its adhesive functions in human keratinocytes.

The potential value of targeting remodeling for AF therapy

Stanley Nattel

Over the last 10 years, we have learned about the crucial importance of atrial remodeling in the creation of a substrate for AF. Atrial tachycardia produces a predominantly electrical form of remodeling, with shortened refractory periods that favour the initiation and maintenance multiple circuit reentry. Heart failure, valve disease and other neurohumoral/stretch activating paradigms promote atrial fibrosis and conduction abnormalities that stabilize atrial reentry. With an awareness of the importance of remodeling has come an interest in remodeling prevention as an AF-preventing approach. Drugs with T-type Ca2＋-channel blocking activity (general combined with some L-type inhibition) like amiodarone may owe some of their efficacy to prevention of atrial tachycardia remodeling. Renin-angiotensin inhibitors partially prevent structural remodeling associated with congestive heart failure and prevent AF development in patients with left ventricular dysfunction. Statin drugs are potent antioxidants with anti-inflammatory properties and appear to prevent both atrial tachycardia-induced and heart failure-associated remodeling. There is some clinical evidence for the usefulness of statins in AF prevention, but the results are variable and prospective controlled trials are needed to assess whether statins have value in AF prevention and, if so, in what population. Much work needs to be done to define the mechanisms by which various classes of drugs can prevent atrial remodeling and to indicate the types of AF in which they are most effective, but the approach as a whole appears very promising.

Electropathology of the pulmonary veins

Stanley Nattel

The landmark work of Michel Haissaguerre identified the pulmonary veins (PVs) as being a key site of atrial arrhythmogenesis in some AF patients. The classical observations were in relatively young patients without organic heart disease, who showed frequent atrial ectopy and paroxysmal AF, with little tendency towards chronicization of AF. Subsequently, a wide range of procedures targeting PVs, including PV isolation and circumferential PV ablation, have been applied successfully to an increasingly large variety of AF patients. Basic research findings on potential mechanisms of PV arrhythmogenesis have varied. Some laboratories have found evidence of abnormal focal activity in normal and tachycardia-remodeled PVs, but others have not been able to reproduce these observations. A variety of PV properties favoring reentry, including particularities of fiber orientation and coupling, as well as in action potential properties, have been described. We have modeled these mathematically and shown that they can result in a tendency for PV reentry. Experimental and clinical studies have also pointed to the occurrence of PV reentry. There is evidence for an important role of autonomic factors in PV arrhythmogenesis. The PVs may be more susceptible than left atrial tissue to arrhythmogenic responses upon autonomic nerve stimulation. In addition, autonomic ganglia are located on the epicardial surface near PV ostia, and their destruction during PV ablation may contribute to the efficacy of PV ablation procedures. At present, the participation of PVs in AF appears to involve multiple important factors that may work quite differently in different AF populations.