Soft tissue tumours

Any soft tissue swelling beneath the deep fascia should be considered a sarcoma until proven otherwise. As the most important factor in the primary treatment of these cancers is the adequacy of the primary surgical resection, it is vital to diagnose these malignant tumours pre-operatively. The modern treatment of soft tissue sarcomas may involve all modalities, but the most important aspect of treatment of a primary localised sarcoma is wide excisional surgery preserving limb function. Radiotherapy is a vital adjunct in high-grade tumours, or in tumours whose resectability is limited either by size or anatomical proximity to vital structures. Apart from a few chemosensitive sarcomas, the role of chemotherapy is limited to treatment of metastatic disease where documented response rates are no greater than 30%. As 50% of patients with high-grade sarcomas will die from metastatic disease, improvements in survival rates will only come from improvements in response to systemic therapy. No controlled trials have shown any survival benefit for adjuvant chemotherapy, although a recent meta-analysis of published data has shown a trend to increased survival at two years. Multicentre randomised trials are ongoing. The prognosis of these lesions is highly variable, but is intimately related to the anatomical site (i.e., resectability), and also the grade and size of the tumour.     

Crystal structure of ICAM-2 reveals a distinctive integrin recognition surface

Recognition by integrin proteins on the cell surface regulates the adhesive interactions between cells and their surroundings. The structure of the 'I' domain that is found in some but not all integrins, has been determined. However, the only integrin ligands for which structures are known, namely fibronectin and VCAM-1, are recognized by integrins that lack I domains. The intercellular adhesion molecules ICAM-1, 2 and 3 are, like VCAM-1, members of the immunoglobulin superfamily (IgSF), but they are recognized by an I domain-containing integrin, lymphocyte-function-associated antigen 1 (LFA-1, or CD11a/CD18). Here we present the crystal structure of the extracellular region of ICAM-2. The glutamic acid residue at position 37 is critical for LFA-1 binding and is proposed to coordinate the Mg2+ ion in the I domain; this Glu 37 is surrounded by a relatively flat recognition surface and lies in a beta-strand, whereas the critical aspartic acid residue in VCAM-1 and fibronectin lie in protruding loops. This finding suggests that there are differences in the architecture of recognition sites between integrins that contain or lack I domains. A bend between domains 1 and 2 of ICAM-2 and a tripod-like arrangement of N-linked glycans in the membrane-proximal region of domain 2 may be important for presenting the recognition surface to LFA-1. A model of ICAM-1 based on the ICAM-2 structure provides a framework for understanding its recognition by pathogens.     

Evaluation of the Short Parkinson's Evaluation Scale: a new friendly scale for the evaluation of Parkinson's disease in clinical drug trials

The extensive use of the Unified Parkinson's Disease Rating Scale (UPDRS) has revealed low interrater reliability in some items and redundancy in others. In view of these shortcomings, we have structured a new scale that includes a zero-to three-point scale for each item in the evaluation of PD. The mental axis includes memory, thought disorders, and depression. Activities of daily living (ADL) includes eight items: speech, eating, feeding, dressing, hygiene, handwriting, walking, and turning in bed. The motor examination includes eight items: speech, tremor, rest and posture, rigidity, finger tapping, arising from chair, gait, and postural stability. Complications of therapy were also included: dyskinesias, dystonia, motor fluctuations, and freezing episodes, collected by history. In addition, a global scoring for motor fluctuations that should complement the Hoehn and Yahr Scale was incorporated. In this report, we present a statistical analysis of the ADL, motor evaluation, and complications of therapy sections. Concerning the interrater reliability mean, Kendall's W values were >0.9 for most of the items in the Short Parkinson's Evaluation Scale (SPES). Kendall's W <0.8 (motor evaluation) was found for two items of the SPES and nine items of the UPDRS. The mean interrater reliability for both scales across all seven centers (seven Kendall's W for seven centers) (Mann-Whitney test) showed no statistical differences between the scales. Spearman's correlations between items of both scales were significant. Factor analysis of the SPES and UPDRS data revealed a four-factor solution that explained approximately 60% of the data. All participating centers found the SPES easier to apply and quicker to complete, when compared with the UPDRS. The results obtained strongly favor the introduction of SPES for clinical practice.     

The neuroregulatory properties of L-DOPA. A review of the evidence and potential role in the treatment of Parkinson's disease

Accumulating evidence suggests that L-dihydroxyphenylalanine (L-DOPA) has neurotransmitter-like and/or neuromodulatory properties in the CNS. Such evidence is based on a wide range of findings including the existence of specific L-DOPAergic neurons in several regions of the CNS, neurotransmitter-like characteristics and specific pharmacological effects. This review attempts to outline the main evidence for this conception and to relate such findings to L-DOPA treatment effects in Parkinson's disease. In this context L-DOPA in itself has been shown to potentiate D2 receptor-mediated effects, inhibit acetylcholine release and increase the release of L-glutamate, neuropharmacological effects which can be linked to treatment side-effects in advanced Parkinson's disease. It is suggested that supersensitive L-DOPA-mediated effects contribute to the pathogenesis underlying L-DOPA-induced motor complications in advanced Parkinson's disease. However, since specific L-DOPA receptors have yet to be identified, the assessment of the relative importance of L-DOPA-mediated effects in this clinical context must be regarded as incomplete.     

Slow skeletal troponin I gene transfer, expression, and myofilament incorporation enhances adult cardiac myocyte contractile function

The functional significance of the developmental transition from slow skeletal troponin I (ssTnI) to cardiac TnI (cTnI) isoform expression in cardiac myocytes remains unclear. We show here the effects of adenovirus-mediated ssTnI gene transfer on myofilament structure and function in adult cardiac myocytes in primary culture. Gene transfer resulted in the rapid, uniform, and nearly complete replacement of endogenous cTnI with the ssTnI isoform with no detected changes in sarcomeric ultrastructure, or in the isoforms and stoichiometry of other myofilament proteins compared with control myocytes over 7 days in primary culture. In functional studies on permeabilized single cardiac myocytes, the threshold for Ca2+-activated contraction was significantly lowered in adult cardiac myocytes expressing ssTnI relative to control values. The tension-Ca2+ relationship was unchanged from controls in primary cultures of cardiac myocytes treated with adenovirus containing the adult cardiac troponin T (TnT) or cTnI cDNAs. These results indicate that changes in Ca2+ activation of tension in ssTnI-expressing cardiac myocytes were isoform-specific, and not due to nonspecific functional changes resulting from overexpression of a myofilament protein. Further, Ca2+-activated tension development was enhanced in cardiac myocytes expressing ssTnI compared with control values under conditions mimicking the acidosis found during myocardial ischemia. These results show that ssTnI enhances contractile sensitivity to Ca2+ activation under physiological and acidic pH conditions in adult rat cardiac myocytes, and demonstrate the utility of adenovirus vectors for rapid and efficient genetic modification of the cardiac myofilament for structure/function studies in cardiac myocytes.     

The soluble alpha-mannosidases of Drosophila melanogaster

The alpha-mannosidases are implicated in both the catabolism of carbohydrates and the N-linked glycosylation pathway in insects, but little is known of the biochemistry of these glycosidases. In order to study the soluble alpha-mannosidases of Drosophila melanogaster we have used artificial fluorogenic substrates for detection of activity in situ following non-denaturing gel electrophoresis. This approach also permitted examination of the mannosidases present in different tissues and the sensitivity of the enzymes to known mannosidase inhibitors. Fluorogenic substrates were also used to determine the pH optima of partly purified mannosidases. We report that D. melanogaster contains several soluble alpha-mannosidase activities. Acidic mannosidases were detected in the gut, fat body and haemolymph of third-instar larvae. The major activity detected in larval guts was a neutral mannosidase presumed to be involved in digestion.     

Studies on the hypodermosis affecting red deer in central and southern Spain

From November 1992 to February 1993, 455 red deer (Cervus elaphus) were surveyed in order to estimate the prevalence of warble fly (Hypoderma actaeon) larvae under the skin of this ungulate species. Material came from Montes de Toledo, Sierra Morena, Sierra de Alcaraz, and Sierras de Cazorla, Segura y Las Villas Natural Park (central and southern Spain). We observed a prevalence of 92%, with a mean +/- SD intensity of 35.7 +/- 41.3 grubs per parasitized host; there was a maximum of 317 larvae per host. No significant differences in prevalence by host sex were found, although significant differences were observed in prevalences among different host age classes. The main location of feeding larvae in deer was in the back tissues.     

Transplantectomy today: indications and complications

Analysis of the indications for transplantectomy and its complications over a 12-year period. Over a total of 159 failure grafts, we performed 53 transplantectomies (33.3%). The percentage of complications was 16.9%. Three patients died (5.6%) during the more or less immediate post-operative period. In our experience, consistent and prolonged maintenance of immunosuppression should avoid the need for transplantectomy in a high percentage of grafts. Only 15 transplantectomies were made on 104 failure grafts after 6 months (14.4%). Our short but successful experience with embolization of 2 rejected grafts confirms the validity of this conservative alternative versus conventional surgical transplantectomy in selected cases.     

Gastrointestinal autonomic nerve tumors. A clinicopathological, immunohistochemical, and ultrastructural study of 12 cases

The gastrointestinal autonomic nerve tumor (GAN tumor) is an uncommon stromal tumor of the intestinal tract and retroperitoneum first described by Herrera and associates in 1984. Distinction of GAN tumors from other gastrointestinal stromal tumors is based on electron microscopic findings. Thus far there have been 12 reported cases. We present an additional 12 GAN tumors, identified by us during 4 years. There were seven male and five female patients and they ranged in age from 10 to 85 years (mean: 58 years). Sites of the tumors were stomach (three), jejunum (two), ileum (four), mesentery (one), and retroperitoneum (two). Eight of the tumors measured > 10 cm in greatest dimension. Usually well circumscribed, the neoplasms were tan to light pink, sometimes hemorrhagic, and soft. There was a variety of histologic patterns including fascicles, palisades, and whorls. Mitotic activity varied from 0 to 23 mitosis per 10 high-power fields (HPF). Using a panel of 10 immunohistochemical stains, only vimentin was consistently positive. There was neuron-specific enolase reactivity in six and S-100 protein reactivity in two cases. All muscle markers were negative. Ultrastructural studies showed neuron-like cells with long axonic cytoplasmic processes ending in bulbous synapse-like structures containing dense-core neurosecretory granules and clear vesicles. Basement membrane was absent. These features are reminiscent of ganglia of the intestinal autonomic nervous system. The patients were followed for 5-125 months (mean of 26 months). Tumor recurred or metastasized to the liver in seven patients (58%) and four patients died with tumor. There were correlations between tumor size (> 10 cm), mitotic count (at least five per 10 HPF), and aggressive behavior.