Host parasite response in nerve in leprosy.

Nerve granulomas occur at all points across the leprosy spectrum. Studies have been made using experimental models in which mycobacteria were injected directly in the sciatic or posterior tibial nerve of the guinea pig. Clinical and electrophysiological studies demonstrated axonal damage which was confirmed by morphometric studies showing disrupted myelin sheaths and in places complete demyelination. Further immunohistological studies showed a complete disappearance of staining for certain neuropeptides. The role of Schwann cells has also been investigated. Schwann cells in nerves affected by mycobacterial granulomas, both experimental and in leprosy patients were not demonstrated to be MHC class II positive suggesting that they did not play a role in antigen presentation. Macrophages in leprosy granulomas were shown to contain TNF alpha, suggesting that this cytokine played a role in axonal damage. The role of mycobacterial heat-shock protein in nerve granulomas has not as yet been determined. The localized nature of granulomas in leprosy nerves and nerves with experimental mycobacterial granulomas has been studied by a process of excision and repair with muscle grafts. Marked recovery has been demonstrated by clinical, electrophysiological, morphometric and immuno-histochemical techniques, the latter demonstrating a return of neuropeptide production.

Sir James Paget and his contributions to pathology.

Sir James Paget's Lectures on Surgical Pathology, published in 1853, was based on Lectures given at the Royal College of Surgeons of England in the previous six years. It makes use of the pathological material collected by John Hunter in the late eighteenth century which was housed in the College. It expands the principles of pathophysiology enunciated by Hunter using microscopic observations. The first half of the book covers mainly inflammation and repair; the second is involved in a description of tumours with particular emphasis on the difference between benign and malignant growths. This book indicates a concept of pathology before the realization of the role of infectious organisms. However, there is some inkling of the contagious nature of syphilis and variola following on Hunter's work. The concept, current at that time, that tuberculosis was related to cancer is expressed. This work acts as a bridge between the pathology of John Hunter and that of the present time.

Genetic analysis of experimental allergic encephalomyelitis in mice.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that exhibits many pathologic similarities with multiple sclerosis. While products of the MHC are known to control the development of EAE, it is clear that non-MHC products also influence susceptibility. The chromosomal locations of these were investigated in selective crosses between MHC class II-compatible, EAE-susceptible Biozzi ABH, and low responder nonobese diabetic (NOD) mice. The disease was dominant and highly influenced by gender in the backcross one (BC1) generation. Female mice were significantly more susceptible than male mice. Segregation of disease frequency of female animals in this cross suggested that EAE was controlled by a major locus. Although microsatellite-based exclusion mapping indicated that a number of regions on chromosomes 5, 6, 7, 8, 9, 10, 11, 12, 13, and 18 showed evidence of linkage (p < 0.05) compared with expected random distributions of alleles, disease susceptibility was most strongly linked (p < 0.001) to chromosome 7. However, by selectively analyzing animals that were either severely affected or almost normal, additional susceptibility loci were mapped on chromosomes 18 and 11 that were linked (p < 0.001) to resistance and the development of severe disease, respectively. The data indicate a major locus on chromosome 7, affecting initiation and severity of EAE that is probably modified by several other unlinked loci. These localizations may provide candidate loci for the analysis of human autoimmune-demyelinating disease.

Bleomycin and FK 565 enhance the release of GM-CSF from LPS-stimulated BALB/c peritoneal macrophages.

The anti-tumour antibiotic Bleomycin, the experimental immunostimulatory tripeptide FK 565, and the immunosuppressive agent Cyclosporin A were examined for their in vitro effects on the release of the haemopoietic cytokine Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) from LPS stimulated BALB/c adherent peritoneal macrophages. FK 565 and Bleomycin produced an increase in GM-CSF release indicating that these agents are capable of stimulating peritoneal macrophage populations. Cyclosporin A was found to have no effect.

Syphilitic caries of the skull--the changing face of medicine.

This paper describes the specimens of caries sicca of calvaria due to syphilis in the collections of the Museums of the Royal College of Surgeons of England. The condition appears not to have been uncommon in the nineteenth century. The mechanism of bone destruction is discussed as is also the role of secondary infection and treatment with mercury.

Inflammation: John Hunter's "A treatise on the blood, inflammation and gun-shot wounds".

John Hunter's A Treatise on the Blood, Inflammation and Gunshot Wounds was published in 1794. Throughout the nineteenth century this was considered the most important study of inflammation and has been widely quoted since. After a section on the nature of blood and the circulatory system, in which he describes the vascular supply in detail, he passes on to an extensive survey of inflammation. This is based mainly on his wide clinical experience, including that as a military surgeon. He, however, supplements this with a number of experiments, some of which are classic. He bases his observations on the four cardinal signs of Celsus (redness, heat, swelling and pain). Inflammation is then divided into three main groups: adhesive, suppurative and ulcerative. He discusses the nature of pus and the formation and treatment of abscesses. He describes his experiments on the transplantation of tissues under the general heading of adhesive inflammation. This, he states, underlies the union of wounds and thus the union of tissues after transplantation. Although unaware of the role of infecting organisms as a cause of inflammation, he makes observations on inflammation in smallpox, venereal infections and tuberculosis. He relates these to his observations on inflammatory aspects of wound healing. Lister was particularly influenced by Hunter's observations in the development of antisepsis. As well as the local effect of inflammation, Hunter was concerned with the constitutional effects such as fever.

Effect of anticancer drugs on the release of TGF-beta in vitro.

Some conventional and experimental anticancer drugs were tested for their effect on Concanavalin A (Con A)-induced Transforming Growth Factor-beta (TGF-beta) release from BALB/c splenocytes, lipopolysaccharide (LPS)-induced TGF-beta release from Nude mouse splenocytes and BALB/c peritoneal exudate cells stimulated by LPS in vitro. When 5 x 10(6) BALB/c and Nude mouse splenocytes/ml stimulated with 1 microgram/ml Con A, 50ng/ml LPS respectively, and 5 x 10(6)/ml peritoneal exudate cells stimulated with 50ng/ml LPS were incubated with various non-cytotoxic concentrations of the vinca alkaloid Vincristine, there was an inhibition of the release of TGF-beta in culture supernatants of both BALB/c splenocytes and peritoneal exudate cells. But, in Nude mouse Vincristine did not alter the release of TGF-beta. The antitumour antibiotic Bleomycin, the immunoactive peptide FK565 and the immunosuppressive agent Cyclosporin A (CsA) were found to have no effect on the release of TGF-beta from all culture supernatants.

Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins.

Tumor necrosis factor (TNF) activity was inhibited during the development of actively-induced, chronic relapsing experimental allergic encephalomyelitis (CREAE) in Biozzi AB/H mice, using a mouse TNF-specific (TN3.19.12) antibody and bivalent human p55 and p75 TNF receptor-immunoglobulin (TNFR-Ig) fusion proteins. The development of disease could be inhibited when repeated doses of antibody were administered prior to the anticipated onset. It has now also been shown that a therapeutic effect is evident even when antibody is administered after the onset of clinical signs, further indicating an important role for TNF in pathogenic effector mechanisms in CREAE. Although biologically-active TNF was not detected in the circulation, TNF-alpha was detected in lesions within the central nervous system (CNS). This suggested that the CNS may be the main site for TNF-specific immunomodulation and was supported by the observation that intracranial injection was significantly more potent than that administered systemically, for both antibody and TNFR-Ig fusion proteins. The fusion proteins were as effective as antibody at doses 10-100-fold lower than that used for antibody, reflecting their higher neutralizing capacity in vitro. Although treatment was not curative and relapse inevitably occurred in this model if treatment was not sustained, the data indicate that anti-TNF immunotherapy, especially within the CNS, can inhibit CREAE and may, therefore, be useful in the control of human neuroimmunological diseases.

A morphological and functional assessment of Mycobacterium leprae-induced nerve damage in a guinea-pig model of leprous neuritis.

Nerve damage, resembling that caused by Mycobacterium leprae in man, was created by the injection of cobalt-irradiated M. leprae organisms into the tibial nerve of guinea-pigs. Assessment of nerve damage was made by clinical, electrophysiological and morphometric means at intervals up to 13 weeks after injection. Quantitative immunohistochemical analysis of neuropeptide-containing fibres in the skin of the foot was also carried out. Significant nerve damage occurred 3 weeks after injection of M. leprae organisms. Motor and sensory functional loss peaked at 5 weeks after injection, and there was a significant decrease of peptide-immunoreactive nerves in all skin compartments. The nerve damage was self-limiting and functional recovery had occurred by 13 weeks. The model shows many of the features found in the nerve damage of treated leprosy patients.

Denatured muscle grafts for nerve repair in an experimental model of nerve damage in leprosy. 2. Recovery of peripheral peptide-containing nerves assessed by quantitative immunohistochemical study.

A marked depletion of neuropeptide-immunoreactive nerves, a consequence of the nerve damage which is commonly found in leprosy, has been reported in peripheral tissues of leprosy patients and of a leprosy animal model. The aim of this study was to investigate peripheral reinnervation following a denatured autologous muscle graft in an animal model of leprosy nerve damage. Possible reinnervation of the foot-pad skin was studied by immunohistochemistry using antisera to the neuronal marker protein gene product 9.5 (PGP), the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and the C-flanking peptide of neuropeptide Y (CPON). The extent of the reinnervation process was assessed by image analysis quantification at different time points. At 8 weeks after muscle grafting, there were small numbers of immunoreactive nerves (p < 0.05). At 12, 16, and 20 weeks postoperatively there was a gradual increase in all immunostaining. At 20 weeks, no significant difference was found for PGP-, CGRP-, and SP-immunoreactive nerves in the epidermal and subepidermal layers compared to control (contralateral) tissue. In experimental tissue the recovery of immunoreactive nerves around sweat glands took longer (up to 12 weeks) than in other skin compartments, but after that time the recovery was rapid and at 20 weeks no difference was measured for VIP-immunoreactive nerves in comparison with controls. Around blood vessels, the recovery of CGRP- and CPON-immunoreactive fibers was slow, and at 20 weeks a difference with control samples (p < 0.01) was noted. In the same area, there was no significant difference for PGP immunoreactivity between controls and tissues at 20 weeks. In contrast, the immunoreactive nerve bundles in the dermis showed a faster recovery than nerves in other skin areas, with amounts similar to controls at 20 weeks. The significant recovery of immunoreactive nerves, in particular of those containing sensory neuropeptide, is consistent with the described functional recovery.

Denatured muscle grafts for nerve repair in an experimental model of nerve damage in leprosy. 1. A functional and morphometric study.

The effectiveness of denatured autologous muscle grafts for nerve repair in an experimental model of leprosy was assessed. Nerve damage resembling that caused by Mycobacterium leprae in humans was induced by the injection of cobalt-irradiated M. leprae into the tibial nerve of guinea pigs. At the time of maximum functional loss, caused by the formation of a granuloma within the nerve, the area of damage was excised and a denatured autologous muscle graft was used to repair the nerve. Assessment of nerve regeneration through the graft was made using clinical, electrophysiological and microscopic morphometric analysis at intervals up to 20 weeks. The results were compared with regeneration after grafting of a normal nerve. Clinically, some motor and sensory recovery occurred in all of the graft recipients in the normal nerve by 8 weeks, and by 11 weeks in the recipients of grafts in the granulomatous nerve. Full sensory recovery occurred in all but one animal by 20 weeks. Motor function recovered to near normal levels at 14 weeks after repair of the normal nerve but, at 20 weeks, there was variation in motor recovery after repair of the granulomatous nerve. Electrophysiology showed increased conduction velocity of the nerve fibers at each time-point. The conduction velocity at 8 weeks after grafting of the normal nerve was similar to that at 12 weeks after grafting of the granulomatous nerve. Morphometry showed an increasing number of myelinated fibers repopulating the distal nerve up to 20 weeks. Myelin fiber numbers, at this time, were one third of normal after repair of the granulomatous nerve and two thirds after repair of the normal nerve.(ABSTRACT TRUNCATED AT 250 WORDS)