Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain.

BACKGROUND AND PURPOSE: Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb-761 has anti-inflammatory properties and modulatory effects on key pain-related molecules. This study investigated the analgesic and anti-inflammatory effects of EGb-761 on carrageenan-induced inflammatory and hindpaw incisional pain. EXPERIMENTAL APPROACH: Adult male Wistar rats (n=6-10/group; 250-420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. EGb-761 (3, 10, 30, 100 or 300 mg kg(-1)), diclofenac (5 mg kg(-1)) or drug-vehicle was administered 3 h post-carrageenan/post-surgery. Hindpaw withdrawal latency (in seconds) to thermal stimulation, response threshold (in grams) to mechanical stimulation and paw volume were measured. KEY RESULTS: Carrageenan induced significant mechanical allodynia, thermal hyperalgesia and paw oedema at 6 h post-carrageenan, while paw incision surgery induced significant mechanical allodynia and thermal hyperalgesia at 6 and 24 h post-surgery. Administration of EGb-761 dose-dependently inhibited thermal hyperalgesia and was equally effective as diclofenac (5 mg kg(-1)) in both the carrageenan and hindpaw incision model. EGb-761 had no effect on carrageenan- or incision-induced mechanical allodynia or paw oedema. Diclofenac significantly reduced mechanical allodynia in both models and carrageenan-induced paw oedema. CONCLUSIONS AND IMPLICATIONS: EGb-761 dose-dependently alleviates acute inflammatory and surgically induced thermal hyperalgesia and is comparable to diclofenac, a commonly prescribed non-steroidal anti-inflammatory drug. This indicates that EGb-761 has analgesic potential in acute inflammatory pain.

Intra-operative injection of Patent Blue V dye to facilitate nodal staging in colorectal cancer.

OBJECTIVES: Routine histopathology may understage colorectal cancer by failing to detect involved lymph nodes. This study examined the feasibility of dye staining those lymph nodes most likely to harbour metastases. PATIENTS AND METHODS: Patent Blue V dye 2.5% was injected intra-operatively into left-sided colorectal carcinomas prior to resection in 19 patients. RESULTS: Blue-stained nodes were found in 12/19 patients (63%). Examination of blue-stained nodes alone correctly identified overall nodal status in 11 (92%) of these 12 patients. CONCLUSION: The technique needs to be refined further. Nonetheless, intra-operative lymph node staining using blue dye offers the prospect of improving the ease and accuracy of nodal staging in colorectal cancer.

Regression of columnar-lined (Barrett's) oesophagus with omeprazole 40 mg daily: results of 5 years of continuous therapy.

BACKGROUND: We have previously reported the effect of 2 years of omeprazole 40 mg daily on columnar-lined (Barrett's) oesophagus (CLO). AIMS: In the present study, follow-up has been extended to 5 years to assess the macroscopic and microscopic effects of continuing therapy. PATIENTS AND METHODS: The 23 patients have been followed for up to a further 3 years. Endoscopy with multiple biopsies was performed at the end of years 3, 4 and 5. RESULTS: Although there had been a statistically significant regression in the length of CLO after 2 years, there was no overall further measurable change after 5 years. However, one patient showed complete macroscopic and microscopic regression. The number and size of macroscopic squamous islands within the CLO continued to increase, and there was a further increase in microscopic squamous re-epithelialization of surface mucosa, gland ducts and Barrett's gland tissue. Low-grade dysplasia was found consistently in one patient in biopsies taken up to the end of year 3 but it could not be detected thereafter. CONCLUSIONS: Omeprazole 40 mg daily appears to have beneficial effects on CLO, although it rarely induces a complete regression. Whether the benefits will reduce the risk of malignant transformation is unknown.

Apoptotic and proliferative activity in the neoplastic progression of Barrett's oesophagus: a comparative study.

The balance between proliferation and apoptosis within a tissue is important in controlling its overall growth. When either or both are altered, uncontrolled cell proliferation can contribute to cancer. The aim of this study was to investigate apoptosis and proliferation in the progression from Barrett's oesophagus to adenocarcinoma. Fifty-one paraffin sections of Barrett's mucosa with both intestinal and gastric-type Barrett's mucosa, dysplasia, and adenocarcinoma, from 28 patients, were examined for apoptosis using haematoxylin and eosin (H&E)-stained sections counterstained immunohistochemically with CD45 to distinguish leucocytes from apoptotic bodies. Proliferation was detected by immunohistochemistry using the MIB-1 (Ki-67) antibody. There was an increase in proliferation in dysplastic and carcinomatous tissue compared with metaplastic tissue (p=0.0001). In dysplasia, proliferation was distributed throughout the basal-luminal axis, whereas in metaplasia, cell division was compartmentalized to the lower crypt (p<0.001). Conversely, there was a decrease in apoptosis in the upper crypt and luminal surface in dysplasia and adenocarcinoma compared with metaplasia (p<0.0008). There was a significant increase in apoptotic activity in intestinal-type Barrett's mucosa compared with gastric-type. There was a highly significant increase in the glandular proliferation to apoptosis ratio (GPAR) in the progression of metaplasia to dysplasia to adenocarcinoma (p=0.001). The shift in the GPAR in the progression of neoplastic change suggests that it may be a useful and sensitive marker of neoplastic change in Barrett's oesophagus, especially if the assessment of both apoptotic and proliferative activity in the mucosa can be made easier by more sophisticated technical methods.

The histopathology of treated Barrett's esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.

Columnar metaplasia of the lower esophageal epithelium (Barrett's esophagus) occurs in response to acid reflux, and its most important long-term complication is malignancy. In view of this, techniques are being explored for the eradication of Barrett's esophagus, and histopathologists will increasingly be required to assess response to these therapies in esophageal biopsy samples. The histopathologic features before and after treatment were studied in biopsy samples from 16 patients receiving omeprazole only, 10 treated by KTP laser photoablation, and five who underwent photodynamic therapy. All the treatment modalities resulted in histologic changes with at least partial squamous reepithelialization of the metaplastic columnar epithelium. The histologic findings suggest three main mechanisms for this: encroachment of adjacent squamous epithelium at the squamocolumnar junction, extension of epithelium from the submucosal gland duct to form squamous islands, and squamous metaplasia within the Barrett's columnar mucosa itself. The latter mechanism implies the existence of pluripotential stem cells within Barrett's mucosa. A relatively common finding was residual glandular mucosa, nonneoplastic and dysplastic, beneath squamous epithelium indicating the requirement for histologic confirmation of endoscopically suspected complete squamous reepithelialization with sufficiently deep biopsies.

Altered cadherin and catenin complexes in the Barrett's esophagus-dysplasia-adenocarcinoma sequence: correlation with disease progression and dedifferentiation.

The maintenance of adult tissue architecture is largely dependent on the function of cadherins. E-cadherin is expressed in most epithelia, although it may be co-expressed with P-cadherin in basal layers of stratified epithelia. Adhesive function of cadherins relies on interactions with catenins. Many reports have characterized reduced expression of cadherins and catenins in tumors, including those of the gastrointestinal tract. This study aimed to characterize expression of E- and P-cadherins, and the catenins, in the progression of Barrett's esophagus to adenocarcinoma. Immunohistochemical analysis and Western blotting were performed on paraffin-embedded and fresh-frozen tissue using antisera to the selected cadherins and catenins. The results of this study have shown inappropriate expression of cadherins and catenins in neoplastic Barrett's mucosa. There was a significant reduction of E-cadherin expression as the Barrett's metaplasia-dysplasia-adenocarcinoma sequence progressed (P < 0.01). In contrast, P-cadherin, expressed in basal layers of squamous esophagus, was usually absent from Barrett's and dysplasia but was expressed in 17 of 24 carcinomas, especially at the advancing tumor edge. Reduced expression of catenins was also seen, but in some specimens, immunoreactivity was observed in neoplastic nuclei, suggesting mediation of a nuclear function such as transcriptional regulation.

Photothermal laser ablation of Barrett's oesophagus: endoscopic and histological evidence of squamous re-epithelialisation.

BACKGROUND: Barrett's oesophagus is acquired by severe gastro-oesophageal reflux and is a premalignant condition. Acid suppression or anti-reflux surgery alone do not cause significant regression of the metaplastic mucosa nor reduce the malignant potential. Recent reports have suggested that the combination of mucosal ablation with acid suppression may result in squamous regeneration. AIMS: To destroy Barrett's mucosa by thermal ablation (in the setting of acid suppression) and so induce squamous regeneration. PATIENTS: Sixteen patients with non-dysplastic Barrett's oesophagus were recruited from a surveillance programme. All had been on a proton pump inhibitor. METHODS: At intervals, non-circumferential areas of columnar mucosa were ablated using the KTP laser. Acid suppression was obtained with 40 mg omeprazole daily. Multiple biopsy specimens were obtained for histological examination from ablated areas. RESULTS: Ablation of all areas of glandular mucosa resulted in squamous regeneration. The number of treatments required depended on the length of the Barrett's segment. In 11 patients there was evidence of squamous regeneration over remaining Barrett's glands (in some of the post-treatment biopsy specimens) whilst in nine patients squamous metaplasia was seen within Barrett's glands. CONCLUSION: Mucosal ablation of Barrett's oesophagus by laser, in the setting of acid suppression, results in squamous regeneration (though some burying of Barrett's glands did occur).

A clinico-pathological study of cutaneous leishmaniasis in British troops from Belize.

Thirty-four cases of cutaneous leishmaniasis contracted by British soldiers in Belize were studied. Pre- and post-treatment biopsies were taken from all patients. The range of histological appearances is described and the value of histological examination (including Giemsa staining and immunohistochemistry), cytological preparations and microbiological culture in diagnosis and clinical management assessed. Histology and culture were found to be complementary techniques in reaching a positive diagnosis, whilst cytological preparations were of no additional value. Histological examination of post-treatment biopsies merely confirmed the clinical impression of healing or non-healing whilst culture identified viable organisms in apparently healed lesions, which were subsequently re-treated.

Agminate Spitz naevi arising on hyperpigmented patches.

In 1948 Dr Sophie Spitz described criteria that distinguished juvenile melanoma from malignant melanoma. Since then the cases of eruptive Spitz naevi have been reported arising on normal skin, on lightly pigmented patches and on hypopigmented patches. There are only 12 reports of Spitz naevi arising on hyperpigmented patches: we describe here three further cases, all on the arms of children, seen in our department in a single year.

A clinico-pathological study of cutaneous leishmaniasis in British troops from Belize

Thirty-four cases of cutaneous leishmaniasis contracted by British soldiers in Belize were studied. Pre- and post-treatment biopsies were taken from all patients. The range of histological appearances is described and the value of histological examination (including Giemsa staining and immunohistochemistry), cytological preparations and microbiological culture in diagnosis and clinical management assessed. Histology and culture were found to be complementary techniques in reaching a positive diagnosis, whilst cytological preparations were of no additional value. Histological examination of post-treatment biopsies merely confirmed the clinical impression of healing or non-healing whilst culture identified viable organisms in apparently healed lesions, which were subsequently re-treated (AU)

Disseminated cutaneous granulomatous eruptions associated with myelodysplastic syndrome and acute myeloid leukaemia.

Two elderly male patients presented with similar, widespread, papular, granulomatous eruptions and developed myelodysplastic syndromes. The first showed histological features of diffuse granuloma annulare and had mild hypergammaglobulinaemia, slightly abnormal liver function and a leucoerythroblastic anaemia. He developed acute myeloid leukaemia (AML) secondary to a background myelodysplastic syndrome and was treated with combination chemotherapy during which his eruption settled; his AML and his skin are in remission 1 year later. The second developed a myelodysplastic syndrome and a similar rash with histological features of papular cutaneous sarcoidosis but no systemic abnormalities apart from mild hypergammaglobulinaemia, cutaneous anergy to multiple recall antigens and activation of circulating monocytes. He has remained well but his rash and myelodysplastic syndrome have persisted. These cases are interesting because of the striking similarity of their granulomatous eruptions and their associated haematological abnormalities. Patients with such disseminated, granulomatous cutaneous infiltrations should be investigated to exclude associated haematological abnormalities if there is any abnormality of their peripheral blood picture.

Calcium dependence of A-CAM function in human renal epithelium.

Previously we have used immunocytochemistry to identify A-CAM as a major cell adhesion molecule in human renal tubular epithelium. In this study, we demonstrate the calcium dependence of cell-cell adhesion and A-CAM function in cultured human renal epithelial cells. Separation of adjacent cells was seen within 1 min following sequestration of calcium from the culture medium with EDTA. This loss of intracellular adhesion in low calcium conditions was accompanied by the disappearance of A-CAM immunoreactivity. The changes were reversible and on return to normal calcium concentrations, A-CAM immunoreactivity reappeared and cell adhesion was re-established. The time course of this recovery was slow, taking 2-3 h. These results demonstrate the calcium dependence of cell adhesion in cultured human renal epithelial cells and confirm the adhesive function of the immunoreactive A-CAM molecule.

Malignant hidradenoma--a case report demonstrating insidious histological and clinical progression.

A histologically benign hidradenoma, occurring in a 15-year-old female inadequately excised at first procedure, recurred locally over the course of 11 years and exhibited first local and subsequently regional metastatic spread. The insidious progression was associated with increasing cytological atypia and alteration of epithelial antigenic expression. In view of the rarity of malignant sweat-gland tumours and consequent lack of a specific treatment protocol, this case serves to emphasize the importance of adequate primary local excision, with histological confirmation of clearance, in the management of sweat-gland tumours.

Morphological evidence that A-CAM is a major intercellular adhesion molecule in human kidney.

We have used immunocytochemistry to identify the major primary adhesion molecule of the cadherin class in human kidney. In frozen sections of kidney, A-CAM was detected using the monoclonal antibody GC4 on the surface of renal tubular epithelial cells. Renal tubular epithelium did not express L-CAM. No cadherin reactivity was found on the glomerular epithelial cells. Cultured renal tubular epithelium was studied by immunofluorescence and immunogold methods. A-CAM was found at the contact points of adjacent epithelial cells, the phenotype of which was confirmed by the demonstration of cytokeratins using the antibody CAM 5.2. The A-CAM molecule in human kidney had an Mr of 130 kD in Western blotting experiments. These results lead us to conclude that A-CAM is the major cadherin of adult human renal epithelium.