Pyrrolizidine alkaloid toxicity in livestock: a paradigm for human poisoning?

Livestock poisoning, primarily liver damage, caused by consumption of plants containing 1,2-dehydropyrrolizidine ester alkaloids (dehydroPAs), and the corresponding N-oxides, is a relatively common occurrence worldwide. Because of the economic impact, extensive investigations of such episodes have been performed, particularly in Australia, South Africa the United States and, more recently, South America. Plant species most commonly involved are members of the families Boraginaceae, Asteraceae and Leguminosae. These may be native species that periodically flourish under particular climatic conditions or introduced species that thrive in the absence of natural control factors such as herbivory and competition. Contamination of grain crops with dehydroPA-producing plants has resulted in large-scale incidents of food poisoning in humans, with high morbidity and mortality, especially in Africa and in central and south Asia, with recent episodes in Afghanistan and possibly Ethiopia. Attention has recently focused on the potential for low levels of dehydroPAs to contaminate many food products in developed countries, possibly leading to progressive, chronic diseases that may not include overt hepatotoxicity. This overview examines the potential for better control of exposure and means of monitoring dehydroPA intake by extrapolation of knowledge gained from animal studies to the human situation.

A little-known aspect of Arthur Conan Doyle (1859-1930): the call of India and a debt to Walter Scott (1771-1832).

This paper recalls the early life of Dr Arthur Conan Doyle when his writing centred briefly on India. The significance of a young female skeleton given to the museum of the Royal College of Surgeons of Edinburgh in 1879 is reviewed. Morphometric and genetic evidence is provided to show that the skeleton originated in the Andaman Islands. It is suggested that Doyle saw it during his undergraduate or early postgraduate years, leading him to introduce an Andaman Islander into his novel The Sign of the Four, published in 1890. Like his inspiring predecessor Walter Scott, Doyle wrote of India but did not visit the country: both authors learned indirectly of the Indian Raj and the Indian Medical Service. Doyle knew of the convict colony established after the Sepoy Mutiny of 1857 at Port Blair, capital of the Andamans, but the reason he chose an Islander to commit murder in London has, until now, remained contentious.

Intra-articular hyaluronate in experimental rabbit osteoarthritis can prevent changes in cartilage proteoglycan content.

OBJECTIVE: The purpose of this study was to determine the effects of intra-articular injections of high molecular weight (2000 kDa) sodium hyaluronate (HA) on the progression of articular cartilage degeneration in a rabbit partial medial meniscectomy model of osteoarthritis. DESIGN: Six experimental groups included normal, sham operated, and operated and injected animals, the latter injected once-weekly (for two weeks or twelve weeks, beginning four weeks after surgery) with either 1% (w/v) HA or phosphate buffered saline (PBS). Following assessment of gross morphology, serial adjacent blocks of full-depth articular cartilage were prepared from the tibial condyle for analysis of total water, hydroxyproline, DNA and proteoglycan (uronic acid) content, as well as the ratio of galactosamine to glucosamine. Samples were sub-divided into inner (medial) and outer (lateral) regions. RESULTS: No morphological differences were recognized between joints injected with PBS and those receiving HA. When analysed biochemically, there were no significant differences in hydration, hydroxyproline or DNA content between the experimental groups. In contrast, HA injection did affect changes in proteoglycan content. Expressed per tissue dry weight, uronic acid content in the operated group injected with PBS for two weeks was lower than normal (P<0.02), a result not seen in the corresponding HA injected group. After 12 weeks of PBS injections, uronic acid content (per dry weight) was higher than normal (P<0.01), an effect again not observed in the corresponding HA injected group. Results for the galactosamine: glucosamine ratio showed a reduction after 12 weeks of injections, but no differences between PBS and HA injected groups. CONCLUSIONS: Once-weekly, intra-articular injection of high molecular weight HA can prevent changes in proteoglycan content in tibial condylar articular cartilage, compared to PBS injected controls, in the rabbit partial meniscectomy model of osteoarthritis.

A cascade thermoacoustic engine.

A cascade thermoacoustic engine is described, consisting of one standing-wave stage plus two traveling-wave stages in series. Most of the acoustic power is produced in the efficient traveling-wave stages. The straight-line series configuration is easy to build and allows no Gedeon streaming. The engine delivers up to 2 kW of acoustic power, with an efficiency (the ratio of acoustic power to heater power) of up to 20%. An understanding of the pressure and volume-velocity waves is very good. The agreement between measured and calculated powers and temperatures is reasonable. Some of the measured thermal power that cannot be accounted for by calculation can be attributed to Rayleigh streaming in the two thermal buffer tubes with the largest aspect ratios. A straightforward extension of this work should yield cascade thermoacoustic engines with efficiencies of around 35-40% of the Carnot efficiency.

Henry Wade (1876-1955) and cancer research: early years in the life of a pioneer of urological surgery.

This paper describes the microscopic studies of human and experimental cancers made by Henry Wade during the years 1904-9. William Ford Robertson, his mentor, and Wade claimed to have discovered a microbial cause of human cancer. The claim was at once fiercely disputed. Wade turned to the investigation of a transmissible sarcoma of the dog, during which he demonstrated an early form of immune transplant rejection. He also undertook studies of Hodgkin's disease. Later in life, Wade established urological surgery at the Royal Infirmary of Edinburgh and became President of the Royal College of Surgeons of Edinburgh.

Early twentieth century surgical urology: the 1909-1939 experience of Henry Wade.

This historical review uses the experience of Henry Wade (1876-1955) to examine the state of surgical urology in the early decades of the twentieth century. For 50 years, Wade was a central figure in the life of the Royal College of Surgeons of Edinburgh. His work epitomises Scottish surgery in the years between 1909 and 1939. Wade adopted every available technique to arrive at the precise diagnosis of urinary tract disease. An exact clinical history and examination were followed by the testing of the urine, the analysis of the blood, radiography and cystoscopy. During his time, urological surgery was revolutionised by the advent of excretion pyelography. Soon afterwards, blood transfusion and the first antibacterial agents began to transform prognosis. Nevertheless, the urological scene was still dominated by the hazards of prostatectomy, the high frequency of renal tuberculosis, and the challenges of bladder and renal cancer. The virtual impossibility of eradicating malignant prostatic tumours, much less common in a population where the mean expectation of life for males was 20 to 30 years less than now, relegated this insidious disorder to a small place in his practice. In 30 years of active consultant life, Wade brought to surgical urology the skills, integrity, knowledge and determination that had already led him to prominence in the fields of cancer research and in orthopaedic and military surgery.

Sacral and iliac articular cartilage thickness and cellularity: relationship to subchondral bone end-plate thickness and cancellous bone density.

OBJECTIVES: To measure the thickness and cellularity of adult human sacral and iliac articular cartilages and the thickness and density of the subchondral bones. METHODS: The right sacroiliac joints of 15 adult patients were examined post-mortem. HOME (Highly Optimized Microscope Environment) microscopy was used to measure articular cartilage and subchondral bone end-plate thickness. Conventional morphometric techniques were employed to estimate cartilage cellularity and cancellous bone density. RESULTS: Sacral articular cartilage was thicker than iliac (1.81 vs 0.80 mm, P<0.001). Iliac cartilage cell density in all zones was higher than sacral. The overall mean was 31.19 x 10(-3) vs. 23.23 x 10(-3)/mm(3), P<0.001. Superficial zones contained more cells than middle and deep zones but there were large differences between the cell numbers of the middle and deep zones of both sacral and iliac cartilages. Iliac subchondral bone end-plates were thicker than sacral (0.36 vs 0.23 mm, P<0.001). The thickness of these plates was related inversely to that of the overlying articular cartilages. Iliac subchondral cancellous bone was twice as dense as sacral (22.07 vs. 12.05%, P<0.001), a ratio recognized anteriorly, centrally and posteriorly. CONCLUSIONS: Adult human sacral cartilage is thick and of low cell density. It rests upon a thin bone end-plate supported by porous, cancellous bone. Iliac cartilage and bone display the converse proportions. The identification of these variables may assist understanding of normal sacroiliac joint function and the interpretation of tissue changes in the spondylarthropathies.

McDowell's saucer.

The pioneer American ovariotomist McDowell studied anatomy in Edinburgh under John Bell. McDowell returned to Kentucky in 1793 with a set of porcelain. One saucer from his set was donated to the College in 1994.

Histopathologic evidence that sacroiliitis in ankylosing spondylitis is not merely enthesitis.

OBJECTIVE: To systematically study the histopathology of sacroiliitis in ankylosing spondylitis (AS) at 5 different stages of the disease. METHODS: Two independent observers assessed 75 microscopic features in the sacroiliac (SI) joints in 12 cases of AS (5 biopsies, 7 autopsies) and in 22 control cases (all autopsies). RESULTS: In AS, synovitis, pannus formation, myxoid marrow, superficial cartilage destruction, enthesitis, intraarticular fibrous strands, new bone formation, and bony ankylosis were significantly more frequent than in control cases, in which there was more endochondral bone within deep-zone articular cartilage. Cartilaginous fusion occurred in both groups, but much earlier in AS. There was no residual synovium when the joint lumen was totally occluded. Mild but destructive synovitis and myxoid subchondral bone marrow were the earliest changes identified in AS. These lesions destroyed the adjacent articular tissues, a loss that was followed to varying degrees by fibrous scarring, woven bone, and new cartilage. The original cartilages also fused, and chondral fusion was the predominant mode of ankylosis. Both the original and the reparative cartilaginous tissues were replaced by bone. Active enthesitis occurred in 2 advanced and 3 late cases; fibrous scar tissue, presumed to represent previous enthesitis, was observed in all stages except the earliest. Paraarticular bone was at first dense, and later porotic. CONCLUSION: In the sacroiliitis of AS, two findings predominate: 1) synovitis and subchondral bone marrow changes offer a more rational explanation for widespread joint destruction than does enthesitis; and 2) an unusual form of chondroid metaplasia contributes to ankylosis.

Anisotropic response of the human knee joint meniscus to unconfined compression.

The response of meniscal tissue to axial, radial and circumferential compressive forces was measured at physiologically relevant levels of load in eight pairs of human knee joint menisci. Compression was unconfined and uniaxial. Stress strain data were fitted to a two-parameter exponential model. The tissue was found to be significantly stiffer to axial compressive forces than to radial and circumferential forces. No significant difference was found between the responses to circumferential and radial forces.

Radial fibre proportions in human knee joint menisci. Measurement by scanning optical microscopy.

The proportions of medial and lateral knee joint menisci represented by radially orientated collagen (COL) were measured in 42 specimens from 24 hospital patients examined post-mortem. Images of the fibre bundles were obtained by the 488-nm laser confocal scanning of hydrated, fixed radial blocks taken from the anterior, middle and posterior regions of the menisci after staining with picro-Sirius red. Measurements of the percentage of each image occupied by fluorescent, doubly refractile COL were made by means of a Kontron IBAS image analyser, after interactive segmentation. In areas adjoining the outer, lateral parts of both the medial and lateral menisci, the proportion of all samples identified as radial COL was 7.56 +/- 0.28%. The corresponding figure for areas near the inner, medial edges of the menisci was 17.80 +/- 0.80%. However, no relationship was demonstrable between age and sex and meniscal radial fibre optical density, and there was no difference between the proportion of radial fibres in the anterior, middle or posterior regions.

Advances in the microscopy of osteoarthritis.

This review describes recent contributions made by microscopy to the understanding of osteoarthritis, a clinical syndrome the pathological features of which are well defined by classical white light microscopy. The fluorescence and reflected light, conventional and scanning optical microscopy of excised osteoarthritic tissue preparations, from human and animal sources, has enabled the identification of cell proteins such as S100, of matrix components such as the proteoglycans and collagens, and of adhesion molecules including fibronectin, the integrins and tenascin. Comparable microscopic studies have been made of cell and tissue culture preparations of osteoarthritic cartilage and synovium. Scanning optical microscopy also allows the rapid measurement, in hydrated osteoarthritic tissues, of cell density, cell size, surface roughness and other parameters. The importance of water in sustaining the physical attributes of cartilage is accepted and new forms of electron microscopy can play important parts in the study of unfixed osteoarthritic cartilage. These methods include the low temperature scanning electron microscopy and electron probe x-ray microanalysis of hydrated bulk material and the high resolution transmission electron microscopy of low temperature replicas of cartilage surfaces. Understanding of osteoarthritis has been facilitated by these advances and will continue to be enhanced as new techniques of microscopy evolve.

Problems and paradigms in joint pathology.

This short review outlines aspects of joints relevant to current problems in articular, connective tissue disease and describes the pathology of rheumatoid arthritis and osteoarthrosis. The synovial joints display greatly varying degrees of anatomical specialisation. There is also heterogeneity of microscopic structure, to illustrate which the synovial components of the sacroiliac joints are considered. The chondron is regarded as a functional unit of hyaline articular cartilage but the responses of this tissue in disease are strongly influenced by its avascularity and by the need for chondrocytes to communicate with each other and with their local and systemic environments. Hyaline cartilage is capable of molecular replacement or substitution but not of repair by regeneration; it can, however, be replaced by fibrocartilage. The bearing surfaces of hyaline articular cartilage are never planar or smooth. Rheumatoid arthritis is a paradigm of connective tissue disease. It is not only a systemic disorder which may abbreviate life but, characteristically, is an aseptic form of symmetric polyarthritis. The inheritance of HLA-DR beta 1 and of female sex predispose to rheumatoid arthritis but the cause is unknown; it may be viral. Central to the disease is destruction of articular cartilage by sustained inflammation in which activated macrophages and TH cells, possibly of restricted clonality, combine to release cytokines, proteinases and the mediators of inflammation. Osteoarthrosis is a synovial joint syndrome, not a single disease. It is characterised by a loss of and change in the composition of cartilage proteoglycans leading to failure of normal responses to stress. The results include cartilage fibrillation and loss, bone exposure and a clinical syndrome of pain and disability. Rare forms of heritable chondrodysplasia lead to premature osteoarthrosis but, in most instances, the cause of osteoarthrosis appears to be either excess, inappropriate or insufficient mechanical demand, or traumatic, infective, inflammatory, endocrine or metabolic disease. There remain idiopathic ('primary') cases in which no cause is demonstrable.

Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Impact of confocal scanning optical microscopy on pathological practice.

This review outlines some recent advances likely to influence the hospital laboratory practice of light microscopy, a technique that remains the cornerstone of all surgical pathology. The principal advances are confocal scanning optical ('indirect view') microscopy, to which this short account is restricted, and tandem scanning ('direct view') microscopy.

Articular cartilage fibrillation and permeability to Light Green SF dye. A method for the detection of pre-microscopic disease?

We describe a method which may be useful for the selection of samples for the study of early fibrillation in human articular cartilage. Blocks of cartilage and bone were cut post-mortem from the medial tibial condyles of 29 male and 31 female subjects and the grade of fibrillation was assessed from sections. Contiguous, unfixed blocks of cartilage from the same surface were immersed in a solution of the dye Light Green SF. Sections of these blocks were cut and the rate of penetration of the dye measured at 30 equidistant points across the condylar surface. The relationship between the grade of fibrillation and the rate of dye diffusion was then determined. We demonstrated a significant correlation between the two variables. This technique may make it possible to detect a pre-fibrillary state in apparently normal specimens.