American Journal of Physical Medicine & Rehabilitation: December 2006 - Volume 85 - Issue 12 - p 950 doi: 10.1097/01.phm.0000245816.76165.b2
The prion diseases, or transmissible spongiform encephalopathies, are a group of fatal neurodegenerative disorders which occur in animals and man [4]. The first of these to be identified was the disease in sheep known as scrapie, which is endemic in many parts of the world including Europe and the USA. Scrapie has been extensively studied in experimental models to investigate the nature of the unique transmissible agents responsible for this group of disorders. Early studies revealed that the scrapie agent had a unique spectrum of physical and chemical properties, with a marked resistance to conventional forms of microbial inactivation. In 1982, Prusiner published the prion hypothesis [62], which states that the transmissible agent responsible for this group of disorders is composed of a modified host protein, prion protein, which in humans is encoded by a gene on chromosome 20. Accumulation of the abnormal isoform of the prion protein (PrPres) in the brain is a characteristic feature of all prion diseases, and the detection of this abnormal protein is now of major importance in their diagnosis [40, 58, 59].
Forensic medicine and neuropathology not infrequently come together in the investigation of cases of sudden death, which in a small but significant number of instances is due to intracranial pathology rather than cardiovascular disease. Clinical information may help to provide the cause of an unexpected death but may be absent in circumstances that are unexplained.
Understanding the pathological cause of disease is a fundamental goal in all areas of medicine. An understanding of what is going wrong allows a rational approach to developing preventive and therapeutic interventions. In the pathological characterisation of diseases associated with dementia there have been great advances in understanding that, in the long term, promise insights leading to therapy.
In recent years, head injury has lost its Cinderella status in the neuroscience world, as advances in the understanding of the cellular pathology have opened up the very real possibility of therapeutic intervention. For pathologists, a direct consequence of this has been that not only can much more of the tissue damage resulting from trauma now be appreciated on light microscopy, thanks to the development of immunocytochemical markers, but also there are often greater expectations of the autopsy and brain examination in a head injury case. This chapter describes a modern approach to head injury for non-neuropathologists, then addresses the specific problem of axonal injury, and finally tackles a rather specialist subject about which there is very little published information — namely, non-accidental head injury in infants.
Postmortem examination of peripheral nerve and skeletal muscle will often provide useful information for understanding clinical conditions in which neuromuscular features are present. A common misconception is that postmortem sampling of nerves, and particularly muscle, is of limited value because of autolytic change and loss of enzyme activity. Many of the histochemical techniques used for the analysis of muscle biopsies, however, can be used even if there is a postmortem delay of several days. Simple morphology may also be informative, even in muscle samples taken from a 3,200-year-old mummy, which allowed the diagnosis of trichinella infection (de Boni et al. 1977). A neuromuscular disorder may be either the primary disease which has led to the death of the individual or a complication of a systemic disorder, e. g. paraneoplastic diseases or critical illness myoneuropathy. Many skeletal muscle disorders also affect cardiac muscle, e.g. muscular dystrophies and mitochondrial myopathies, which can lead to conduction defects, cardiomyopathy and sudden cardiac death. Involvement of respiratory muscles may result in respiratory failure. Involvement of bulbar muscles predisposes to choking; this occurs in neurogenic disorders, such as motor neuron disease and in myopathic disorders, including the muscular dystrophies. As in all autopsies, a clear understanding of the underlying pathology is of great educational value to clinicians and helps in explaining the cause of death to family members.
The histological distinction between Spitz naevus (Spitz 1948) and a small group of melanomas which resemble Spitz naevus and which are therefore often referred to colloquially as “Spitzoid melanomas” (Smith et al. 1989; Chan et al. 1999) is notoriously difficult and may occasionally be impossible. In the past decades, the recognition of variants of Spitz naevus has resulted in a marked expansion of its clinical and histological spectrum. The differential diagnostic problem is compounded by the fact that like Spitz naevus, Spitzoid melanoma preferentially affects the younger age-groups and may even occur in very young children (Mehregan and Mehregan 1993). In a series of 23 melanomas occurring in children up to 15 years of age, Barnhill (1998) considered three cases to represent Spitzoid melanomas, and a further nine cases were designated “atypical Spitz tumours” (see below), while only six of the cases showed the histology of usual adult-type melanoma. Although there is some evidence to suggest that, as a group, “Spitzoid melanoma” has a more favourable prognosis than other melanomas of similar thickness, there is no doubt that individual examples of Spitzoid melanoma can progress beyond locoregional disease and can kill the patient. A correct diagnosis is therefore of eminent importance. In this brief review, I shall discuss the salient features of Spitz naevi and Spitzoid melanomas, with special emphasis on potential pitfalls and on diagnostically helpful features.
In the past, studies on malignant lymphomas of the skin focused mostly on mycosis fungoides and other T-cell lymphomas. In recent years, thanks to constant progress being made in immunology and molecular biology, it was recognised that B-cell lymphomas arising primarily in the skin, i.e. primary cutaneous B-cell lymphomas (PCBCLs), represent a distinct and very important group of extranodal lymphomas [1]. They occur far more frequently than is generally believed. The widespread use of immunohistochemical and molecular genetic techniques revealed that many of the cases classified in the past as cutaneous B-cell pseudolymphomas in fact represent low-grade malignant B-cell lymphomas of the skin [2, 3].
Although opportunistic infections are important causes of morbidity and mortality, noninfectious conditions frequently make substantial contributions to the disease course. Patients with HIV infection are at increased risk for neoplastic diseases, both by decreased immunological response to abnormal cells and by increased susceptibility to infection by viruses. However, they do not have an increased incidence of the most common tumours affecting the general population, such us breast, colon, and prostate carcinoma.
In the past few decades, molecular virology has led to a dramatic increase in our knowledge of the structure and biology of viruses. For a long time, the identification of infectious organisms had been based on the isolation and cultivation of the pathogen, i.e., growth of the infectious agent in conditioned media or cell cultures, or on the in situ detection in affected tissues, mainly by chromogenic reactions (e. g., Ziehl-Neelsen staining). These methods depend essentially on the replication of pathogens or on the presence of a relatively high number of infectious agents in the affected tissue. Therefore, they are of little use for the detection of infections agents which cannot be cultured, grow poorly, or are present in small numbers in the affected tissue. Molecular biology provided the methodological background for new approaches to the identification of viral components, in particular by employing so-called sequence-based molecular methods (SBMM). SBMM are independent of the replication and isolation of the pathogen. Furthermore, the sensitivity of in vitro nucleic acid amplification techniques allows the detection of very small amounts of viral sequences, even in archival tissue specimens. Thus, SBMM extended dramatically the tools used to search for previously unidentified patho-gens and to detect viral sequences for diagnostic purposes (Relman 1998; Fredricks and Relman 1999).
The spectrum of infection in solid organ-transplant recipients has widened over the last decade as the numbers of patients transplanted and the diversity of procedures undertaken has increased. Some of these infections are only described in a handful of case reports, but for others a pattern has emerged of relatively common infections, occurring at specific times during the post-transplant period (see Table 1 and Fig. 1).
During wound healing and fibrocontractive diseases, clinical and experimental investigations have shown that fibroblastic cells acquire some morphological and biochemical features similar to those of smooth muscle cells [33]. These modified fibroblasts, called myofibroblasts, express de novo α-SM actin temporarily during wound healing and permanently in fibrotic situations, such as hypertrophic scars or fibromatosis. Myofibroblasts are thought to be involved in contraction and have been observed in practically all fibrotic conditions involving retraction and reorganization of connective tissues [32].
Since its discovery in granulation tissue of healing wounds, now over a quarter of a century ago [22], the myofibroblast has been described in: (1) normal tissue; (2) diverse responses to injury and repair phenomena; (3) quasi-neoplastic proliferative conditions; (4) the stromal response to certain forms of neoplasia; and (5) benign and malignant neoplasms (for review [49]). In practical terms, the surgical pathologist is a daily witness to this panoply of myofibroblastic proliferation. An appropriate evaluation of the myofibroblast with regard to neoplasia is impossible without identifying briefly where these cells occur, and without defining this unique cell.
Current evidence suggests that fibroblasts undergo phenotypic modulation during several physiologic and pathologic conditions, such as wound healing and fibrocontractive diseases [29]. These phenotypically altered fibroblasts develop cytoskeletal features similar to those of smooth muscle cells (SMCs), including the expression of α-smooth muscle actin (α-SMA), which is a contractile isoform of actin and, hence, they have been denoted as myofibroblasts [8]. The myofibroblast is thought to contribute to the process of wound contraction, as well as contractile phenomena observed during fibrotic diseases. However, little is known about the mechanisms responsible for phenotypic modulation of fibroblasts and the expression of α-SMA. Several types of growth factors and cytokines that are locally released from inflammatory and stromal cells at wound sites, as well as components of the extracellular matrix, have been studied to evaluate their role in fibroblastic differentiation. A likely candidate for regulation of α-SMA is transforming growth factor-β (TGF-β) [7], a potent regulator of matrix remodeling. This regulation may be achieved in part by modulation of cell-matrix interactions.KeywordsMonolayer CultureWound ContractionHuman Gingival FibroblastIntracellular TensionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
From the contents:Cellular and molecular biology of fibroblast and myofibroblast. Some historical and philosophical reflections on the myofibroblast concept. Transcription regulation of the desmin and SM22 genes in vascular concept. Modulation of myofibroblast and smooth muscle phenotypes in the lung. Role of platelet-derived growth factors in angiogenesis and alveogenesis. TGFB gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis.
