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Background. Tissue transglutaminase (TG2), a cross-linking enzyme, modulates deposition of extracellular matrix protein in renal fibrosis. This study aimed to examine TG2 and its cross-link productε(γ-glutamyl)-lysine in the Fisher-Lewis rat renal transplantation (RTx) model of chronic allograft nephropathy (CAN).Materials and Methods. Left renal grafts from male Fisher and Lewis were transplanted into Lewis rats, generating allografts and isografts, respectively. Blood pressure, renal function, and proteinuria were monitored for up to 52 weeks. At termination, CAN was assessed in the renal tissue by light and electron microscopy, TG2 andε(γ-glutamyl)-lysine by immunofluorescence, and the urinaryε(γ-glutamyl)-lysine by high performance liquid chromatography.Results. Compared to the isograft, the allografts were hypertensive, proteinuric, and uraemic and developed CAN. Extracellular TG2 (glomerulus:64.55±17.61versus2.11±0.17,P<0.001; interstitium:13.72±1.62versus3.19±0.44,P<0.001),ε(γ-glutamyl)-lysine (glomerulus:21.74±2.71versus1.98±0.37,P<0.01; interstitium:37.96±17.06versus0.42±0.11,P<0.05), TG2 enzyme activity (1.09±0.13versus0.41±0.03 nmol/h/mg protein,P<0.05), TG2 mRNA (20-fold rise), and urinaryε(γ-glutamyl)-lysine (534.2±198.4 nmol/24 h versus57.2±4.1 nmol/24 h,P<0.05) levels were significantly elevated in the allografts and showed a positive linear correlation with tubulointerstitial fibrosis.Conclusion. CAN was associated with upregulation of renal TG2 pathway, which has a potential for pharmacological intervention. The elevated urinaryε(γ-glutamyl)-lysine, measured for the first time in RTx, is a potential biomarker of CAN.

Wound infection in the setting of immunosuppressed state such as renal transplantation (RT) causes significant morbidity from sepsis, prolongs hospital stay and is expensive. Vacuum-assisted closure (VAC) therapy is a new technique of management of wound based on the principle of application of controlled negative pressure. The aim of this study was to assess the efficacy of VAC therapy in the management of wound infection following RT.This is a prospective study of a cohort of 180 consecutive RTs performed over a period of 4 years, where the data were retrieved from a prospectively maintained computerised database and case-notes.9 of 180 (5%) patients developed wound infection following RT which led to cavitations and dehiscence with copious discharge, and refused to heal with conventional treatment. All 9 cases were treated with VAC therapy. The VAC system was removed after a median of 9 (range 3-30) days when discharge from the wound ceased. Four patients were discharged home with portable VAC device and managed on an outpatient basis, where the system was removed after a median 5.5 (range 3-7) days. The median hospital stay after initiation of VAC therapy was significantly shorter (5, range 2-12 days) than on conventional treatment prior to VAC therapy (11, range, 5-20 days) (p=0.003). Complete healing was achieved in all cases.The use of VAC therapy is an effective and safe adjunct to conventional and established treatment modalities for the management of wound infection and dehiscence following RT. Key words: Renal transplantation, wound infection, vacuum-assisted closure therapy.

Femoral nerve palsy has been reported after percutaneous ilioinguinal field infiltration with general anaesthesia for inguinal herniorrhaphy. The mechanism whereby this could occur was studied in cadaver dissections. It was found that the plane between the transversus abdominis muscle and the transversalis fascia was continuous laterally with the tissue plane deep to the iliacus fascia, which is the plane containing the femoral nerve. Injection of methylene blue 1 ml into this plane resulted in pooling of dye around the femoral nerve. Femoral nerve palsy may result from infiltration of a sufficient volume of local anaesthetic into the plane between the transversus abdominis muscle and the transversalis fascia with tracking of the injectate deep to the iliacus fascia to affect the femoral nerve. This finding has important implications for the performance of a percutaneous ilioinguinal field block particularly in day surgery provision.

Summary A case of adenocarcinoma of the sigmoid colon, presenting as a testicular mass, is described. At sigmoid colectomy widespread metastases were found and only palliative care could be offered thereafter. The incidence and age of such a presentation and manner of spread of the occult primary are discussed.

Summary A case of adenomatous polyp occurring at a ureterocaecal anastomosis, 25 years after urinary diversion following a total cystectomy for carcinoma of the bladder, is reported. Bilateral nephrectomy for chronic pyelonephritis was carried out 25 years after the initial surgery and, following this, a sinus formed at the incision at the right loin. A sinogram showed contrast filling the right ureter and caecum, and outlined a lobulated filling defect at the ureterocaecal anastomosis. Subsequent histology revealed a dysplastic tubulovillous adenoma. The clinical presentation and management of tumours at the ureterointestinal junction are discussed.

A study was performed to test the hypothesis that renal allograft recipients are at high risk of developing anal human papillomavirus (HPV) infection and anal intraepithelial neoplasia (AIN). A total of 133 renal allograft recipients and 145 control patients underwent anoscopy and biopsy. A polymerase chain reaction was used to detect HPV16 DNA in biopsy samples. A histological diagnosis of anal HPV infection or AIN was made in 32 allograft recipients (HPV infection, five; AIN I, 20; AIN II, three; AIN III, three; AIN III and anal cancer, one). One subject with AIN was detected in the control group. HPV16 DNA was detected in 47 and 12.4 per cent of anal biopsies in the allograft and control groups respectively. Renal allograft recipients are at high risk of developing anal HPV infection and neoplasia (P

To assess the surgical workload on a renal unit, with particular reference to non-transplant-related surgery and to assess the workload in relation to surgical staffing levels.Prospective audit of all surgical procedures carried out on patients in acute or chronic renal failure, and on transplanted patients, within a one year period.A purpose-built renal unit serving a population of 1.7 million.The number of surgical procedures, both transplant and non-transplant-related, according to type and severity, with particular reference to the levels of surgical staffing.Transplant-related surgery accounted for only 6.5 per cent of the total surgical workload (general, vascular and renal) of the 'transplant surgeons'. Taking into account only the renal-related workload, transplant-related surgery accounted for just 16.5 per cent of the workload, the remainder being related to vascular access and peritoneal access for dialysis, and general surgical procedures on patients in renal failure and transplanted patients. The surgical workload undertaken by a relatively small number of staff was high, representing 531 Intermediate Equivalents per Service Equivalent Value per annum.When assessing workload and adequacy of surgical staffing on a Renal Unit, care should be taken to account for all surgical activity on renal patients and not just that related to transplantation since only 16.5 per cent of the surgical workload is transplant-related.

Histology of pancreas transplant rejection is complicated by non-specific appearances related to undrained exocrine secretions. Using a rat model of pancreas transplantation with exocrine drainage into the urinary tract, morphology of acute rejection has been studied with minimal interference from non-specific change. Unmodified acute rejection was complete after 7-9 days. Intralobular lymphocytic infiltration, which differentiated allografts from isografts, was present 5 days after transplantation and lymphocytic infiltration of islets and blood vessel walls developed between 5th and 7th days. Cyclosporin A immunosuppression of allografts resulted in marked attenuation of the cellular infiltrate. The nature of the infiltrate and its suppression with cyclosporin A indicated an allograft reaction.

The healing of visceral and parietal peritoneum has been investigated using conventional light microscopy, Hautchen preparations, and by using 1 μ sections of epoxy-resin-embedded material to follow the activity of peritoneal macrophages labelled with polystyrene spheres (0.79 μ in diameter). Healing has been found to occur rapidly and for the most part without adhesion formation. Parietal peritoneum and caecum are covered by a new mesothelial membrane in 8 days, while the liver is covered in 7 days. It has not been possible to support the theory that peritoneal macrophages are transformed into mesothelial cells via fibroblasts. The results obtained in the present investigation suggest that the new mesothelial layer is derived directly from the subperitoneal fibroblast.

The healing of visceral and parietal peritoneum has been investigated in the immature animal by both light and electron microscopy. Healing has been found to occur more rapidly in the immature animal when compared with the adult animal. Parietal peritoneum was covered by a new mesothelium in 7 days, while the liver was covered in 5 days. The new mesothelium developed from subperitoneal perivascular connective-tissue cells but it was not possible to determine whether these were primitive mesenchymal cells or fibroblasts. The findings are discussed in relation to the pathogenesis of peritoneal adhesions.

Increased platelet-derived growth factor in the kidneys of cyclosporin-treated rats. We have examined the histological changes and the distribution of immunoreactive platelet-derived growth factor (PDGF) in the kidneys of Sprague-Dawley rats injected with cyclosporin A (CsA, 25 mg/kg/day). Control rats were injected with the olive oil vehicle alone. Groups of rats were killed after 1, 2, 3, 4 weeks of injection and 8 weeks after a 4 week period of injection. Additional controls included groups of rats injected with different doses of CsA and a group of rats subjected to chronic renal ischemia by partial ligation of the aorta. CsA-treated rats gained weight more slowly than olive oil-treated controls (45%, P < 0.05). In rats injected with CsA, a significant increase in serum creatinine concentration (64 ± 2 µmol/liter vs. 39 ± 1 µmol/liter, P < 0.01) and a reduction in creatinine clearance rates (0.23 ± 0.07 ml/min/100 g body wt vs. 0.43 ± 0.07 ml/min/100 g body wt, P < 0.01) occurred after 3 weeks. After 1 week of CsA treatment, segments of the walls of some afferent and intralobular arterioles were thickened and stained strongly by the periodic acid Schiff (PAS) procedure. Immunostainable PDGF-BB and PDGF-AB were detected within short segments of the afferent and intralobular arterioles of the kidneys of CsA-treated rats and in the kidneys subjected to renal ischemia but not in tissue from other control animals. No PAS staining or immunostaining was evident in CsA treated kidneys eight weeks after the discontinuation of treatment. We conclude that CsA-induced ischemia results in increased accumulation of PDGF in the walls of renal arterioles.

Cyclosporine enhances the expression of TGF-β in the juxtaglomerular cells of the rat kidney. The mediators of cyclosporine (CsA) nephrotoxicity remain ill defined. In this study, we describe evidence of increased amounts of transforming growth factor-beta (TGF-β) in the kidneys of adult male Wistar rats treated with CsA (5 to 25 mg/kg/day) for four weeks. Localization of TGF-β was undertaken immunocytochemically at both light and electron microscope levels and Northern blot analysis was applied to detect changes in transcription of TGF-β. In control rats, weak to moderate immunostaining for TGF-β was observed, in the juxtaglomerular arterioles. CsA treatment resulted in a dose-dependent increase in the number of stained afferent and interlobular arterioles and in the intensity of staining. The number of stained afferent arterioles increased from a control value of 0.21 ± 0.08/mm2 cortex to 0.84 ± 0.15/mm2 cortex, P < 0.01, and to 1.12 ± 0.10/mm2 cortex, P < 0.01, in rats treated with CsA 12.5 mg/kg/day and 25 mg/kg/day, respectively. The number of interlobular arterioles stained for TGF-β increased from a control value of 0.07 ± 0.05/mm2 to 0.31 ± 0.02/mm2, P < 0.05, and 0.39 ± 0.07/mm2, P < 0.01, in rats treated with CsA, 12.5 mg/kg/day and 25 mg/kg/day, respectively. At the electron microscope level, TGF-β was localized exclusively within the granular cells of the juxtaglomerular arterioles. Northern blot analysis suggested that this enhanced staining is due to increased transcription of TGF-β1. We have therefore observed an association between TGF-β and CsA-induced nephrotoxicity. While this does not establish a causal link, it leads us to postulate that TGF-β, alone or in combination with other growth factors, may play a role in the pathogenesis of CsA induced nephrotoxicity.

Summary Clinical and experimental studies have suggested that noxythiolin and aprotinin may prevent intraperitoneal adhesion formation. A comparison was therefore made of their efficacy in preventing the reformation of adhesions following surgical lysis in a controlled trial using rats. Neither noxythiolon nor aprotinin had any significant benefit over surgical lysis alone. The mortality rate was high in the noxythiolin-treated group.

Total and differential leucocyte counts were performed on 175 patients with a provisional diagnosis of acute appendicitis. Ninety-six per cent of patients with acute appendicitis had either an abnormal total or differential leucocyte count. Four of 24 patients operated on with a normal leucocyte count had acute appendicitis. It is concluded that leucocytosis of above 10 000/mm3 or a differential in excess of 75 per cent neutrophils supports the clinical diagnosis of acute appendicitis and that routine estimation of the leucocyte count is a useful investigation. While a normal leucocyte count does not exclude even a perforated appendicitis, such a count should prompt further review of the diagnosis, especially in the presence of an atypical history or minimal physical signs.

A method has been developed for measuring fibrinolytic activity in a single layer of cells--for example, venous endothelium or peritoneal mesothelium. A single layer of cells was collected on a gelatin disc, incubated on a fibrin plate for 24 h, and the resulting area of lysis measured. This was converted to a measure of fibrinolytic activity expressed in Ploug units of urokinase by reference to areas of lysis created by standard amounts of urokinase placed on similar fibrin plates. The method has been used for measuring fibrinolytic activity in venous endothelium and peritoneal mesothelium and has demonstrated that the activity in a single layer of endothelial cells is only about one-quarter of that in an equivalent area of whole vein wall. It has also shown that peritoneal fibrinolytic activity is reduced after peritoneal trauma. This method maybe useful in the investigation of the fibrinolytic system in a variety of pathological conditions--for example, thrombosis and intraperitoneal adhesions.

The healing of peritoneal wounds has been studied using a fibrin slide technique. Normal peritoneal mesothelium shows fibrinolytic activity. During the first 48 hours of healing fibrinolytic activity is absent from the wound surface but thereafter gradually increases until 8 days, when peritoneal regeneration is complete. At this time the activity is much greater than that in normal mesothelium. The results suggest that fibrinolytic activity of regenerating mesothelial cells will allow them to penetrate into and lyse fibrinous adhesions before fibroplasia occurs, thus preventing the formation of permanent fibrous adhesions.

Observations have been made by light and electron microscopy of the development of peritoneal adhesions in the rat following abdominal surgery. Essentially the changes which occurred were those which are seen in healing by fibrosis, except that in many areas of adhesions numerous eosinophils were observed by electron microscopy. In areas where eosinophils were numerous little proliferation of fibro-blasts was seen. Conversely in sites where fibroplasia and collagen formation were well advanced no eosinophils were seen. The role of the eosinophil in the development of adhesions is discussed and it is suggested that the presence of eosinophiis with their associated anti-histamine activity may hold in check the proliferation of fibroblasts while a new mesothelium is formed and thus prevent adhesion formation.

Forty-four general surgical patients were included in a prospective, randomized double-blind controlled trial of ascorbic acid (500 mg b.d.) or placebo for 7 days before operation. This was to test the hypothesis that vitamin C may reduce the instance of deep venous thrombosis postoperatively. Venous blood samples were taken before entering the trial, just immediately before surgery, on the day of operation and on three further occasions at 3-day intervals postoperatively for leucocyte ascorbic acid concentration (LAC). Venous thrombosis was diagnosed using the 125I-fibrinogen test and the leg scans interpreted by Roberts' criteria. There was no significant difference in the incidence of DVT between the treatment and placebo groups. In those with DVT (n = 23) the mean LAC on the day of operation was not significantly different from that in those without DTV. However, on the sixth and ninth postoperative days LAC levels were significantly lower in the DVT group. These results suggest that the administration of ascorbic acid preoperatively does not reduce the incidence of DVT, but a striking decrease in the LAC levels in the DVT patients in in keeping with the hypothesis that the initial event in the pathogenesis of DVT is adherence of leucocytes to the venous endothelium.

A total of 108 orthotopic liver transplants have been carried out in the Cambridge/King9s College Hospital series. Over 13 years, changes in patient selection, immunosuppression, and surgical and anaesthetic techniques have led to a steady improvement in results. Results obtained in the last 22 patients indicated that over half survive for one year. Although at considerable risk during the operation, patients with non-malignant cirrhotic diseases who survive one year have a good long-term chance of survival

Fresh specimens of human peritoneum collected from heart-beating cadaver organ donors have been examined by transmission electron microscopy. Samples were taken from the anterior abdominal wall and from the surfaces of the liver, stomach and diaphragm. The mesothelium consisted of a single layer of flattened cells generally 2.5 microns to 3 microns thick. These were joined by tight junctions and desmosomes to form a continuous sheet. The cells rested on a prominent basement membrane deep to which was a layer of fibrous connective tissue. This layer was more compact under the mesothelium from the abdominal wall and liver than elsewhere. Long microvilli projected from apical surface of the cells. In many cases these covered the entire surface but sometimes they were more profuse at the edges of the cells near the intercellular junctions. The cells possessed a well-developed cytoskeleton of intermediate filaments which coursed through the cytoplasm in thick bundles. The cells also had a well-developed rough endoplasmic reticulum and Golgi apparatus. Numerous smooth-surfaced and coated vesicles could be seen adjacent to the plasmalemma at all surfaces, providing evidence of considerable pinocytotic activity. There was little regional variation in the structure of the mesothelium. We found no evidence of pores passing through the layer although, on the liver, cisternae were present between the cells and these were often occupied by lymphocytes.

The healing of parietal and visceral peritoneum has been studied by the techniques of enzyme histochemistry in an attempt to define more precisely the type of cell responsibile for forming the new mesothelium. The changes occurring in the distribution of the following enzymes throughout the course of healing have been investigated: acid phosphatase, alkaline phosphatase, ATPase and non-specific esterase. Regenerating mesothelial cells have been found to have several enzyme histochemical properties in common with subperitoneal connective tissue cells. It has not been possible to distinguish between primitive mesenchymal cells and subperitoneal fibroblasts by the histochemical techniques used in this study and therefore the study has not been fruitful in determining whether the new mesothelium arises from primitive mesenchymal cells or subperitoneal fibroblasts. The present study does, however, lend weight to the view that the new mesothelium is not derived from peritoneal macrophages.

The effect of two absorbable haemostatic materials, oxidized cellulose gauze (Surgicel) and absorbable gelatin sponge (Sterispon) has been investigated in relation to intraperitoneal adhesion formation using the rat as experimental animal. Neither oxidized cellulose gauze nor absorbable gelatin sponge was associated with an increased incidence of adhesions. On the contrary, oxidized cellulose gauze was associated with a decreased incidence of adhesions. If haemostatic material is required in the peritoneal cavity, oxidized cellulose gauze may be preferable to absorbable gelatin sponge since it is associated with a lower incidence of adhesions.

An ultrastructure study was undertaken in an attempt to confirm the finding, obtained by light microscopy, that the new mesothelium arose by metaplasia of subperitoneal fibroblasts and not by transformation of peritoneal macrophages and to assess the role of detached mesothelial cells in peritoneal regeneration. A total of 80 adult male Sprague-Dawley rats weighing 220-250 grams was used. During the early stages of the healing process, macrophages were the predominant type of cell on the wound surface, but cells resembling primitive mesenchymal cells were occasionally observed. Gradual primitive mesenchymal cells and cells resembling proliferating fibroblasts became more numerous on the wound surface, while the number of macrophages decreased. By the 8th day following the operation a continuous layer of mesothelial cells was present on the wound surface. They resembled the underlying fibroblasts in nuclear and cytoplasmic characteristics, except that the mesothelial cells possessed microvilli and junctional complexes. There was no evidence in support of the theories that the new mesothelium arises from transformation of peritoneal macrophages or that is arises by seeding of mesothelial cells from adjacent peritoneal surfaces. The new mesothelium arises from subperitoneal connective tissues. As yet it has not been possible to determine conclusively whether these are primitive mesenchymal cells or fibroblasts.

Summary We report what we believe is the first recorded case of Mondor’s disease associated with metastatic lung cancer presenting in the breast. An association between Mondor’s disease and primary breast cancer has been described previously. In patients with Mondor’s disease and primary breast cancer has been described previously. In patients with Mondor’s disease the possibility of underlying carcinoma, either primary or secondary, must be considered.