Biomedical subjects
A J Howie
Publications and source records attributed to A J Howie.
A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer.
The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 microg m(-2)by intravenous infusion plus GM-CSF 5 microg kg(-1)day(-1)by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21-188) days. Toxicity was generally NCI-CTG 0-2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71-184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted.
C9 immunohistology in detection of myocardial infarction.
Explore the source record for details and available documents.
Potential role for monocyte chemotactic protein-4 (MCP-4) in monocyte/macrophage recruitment in acute renal inflammation.
The CC chemokine, monocyte chemoattractant protein-4 (MCP-4), is an important chemoattractant for monocytes and T cells. Recent data indicate a role in renal inflammation. This study has used in situ hybridization and immunohistochemical analysis of cryostat sections of biopsy material taken from patients with acute renal allograft rejection and vasculitic glomerulonephritis to demonstrate renal expression of MCP-4, both at message and protein level. MCP-4 was primarily expressed at peritubular, periglomerular, and perivascular sites, irrespective of the inflammatory condition, and was associated with infiltrating CD3-positive lymphocytes and CD68-positive monocyte/macrophages. In addition, proximal tubular epithelial cells grown in culture from cortical fragments of human kidney showed low levels of constitutive MCP-4 expression, detectable by western blotting; this expression of MCP-4 was up-regulated in response to the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). CCR3-, CCR5- and CCR2-expressing leukocyte populations were identified at sites of MCP-4 expression. Double-staining techniques revealed that CC chemokine receptor-expressing cells were primarily CD68-positive. These studies suggest an important role for MCP-4 in the recruitment and retention of monocytes/macrophages in renal inflammation.
Th2 dominance in nasal mucosa in patients with Wegener's granulomatosis.
Wegener's granulomatosis initially affects upper respiratory tract organs including the nasal mucosa in more than 90% of patients. The inflammation is typically granulomatous with associated vasculitis. T lymphocytes are usually a prominent component of the leucocyte infiltrate. Previous studies using peripheral blood T cells have implicated IFN-gamma rich Th1-type responses. This study addressed the cytokine milieu in nasal mucosa from 10 patients with active Wegener's granulomatosis using immunohistochemistry. Increased levels of CD3+ T cells and eosinophils were present compared with normal and disease controls. There was increased expression of IL-4, down-regulation of IL-2 and no detectable IFN-gamma. There was increased expression of the chemokine receptor CCR3 by infiltrating cells, consistent with an IL-4 dominant, Th2-biased response. In contrast, renal biopsy tissue from 10 patients with active Wegener's granulomatosis showed expression of IL-2 and IL-4. The Th2-type environment within nasal mucosa, often the initial site of disease activity in Wegener's, is consistent with a local allergic response in these patients.
Renal cell carcinoma and malignant phase hypertension.
Many cross-sectional and follow-up studies of large numbers of patients with hypertension have demonstrated an increased prevalence and mortality from renal cancer. We report the details of three patients with renal cell carcinoma from a series of 254 consecutive patients with malignant phase hypertension, an excess over the expected number reported from several large published series with non-malignant hypertension. In view of this excess we investigated the prevalence of hypertension in a series of 192 consecutive patients who presented with a diagnosis of renal cell carcinoma, in comparison with a local unselected population screening survey. Hypertension was found in 43% of the renal carcinoma patients and 20% of the local population, also a clear excess. The mechanism of the association between renal cancer and malignant and non-malignant hypertension is unclear.
Prognostic value of simple measurement of chronic damage in renal biopsy specimens.
BACKGROUND: A simple method of measurement of chronic damage in renal biopsy specimens would be useful in clinical management, prognosis, comparisons between different centres and trials. METHODS: An interactive image analysis system was used to outline and measure areas of chronic damage in 247 renal biopsy specimens to give an index of chronic damage, expressed as a percentage of cortical cross-sectional area. Prognostic value was analysed by the Kaplan-Meier method to study time between biopsy and onset of permanent dialysis. RESULTS: There was no significant bias between measurements by the same observer or different observers. The index of chronic damage ranged from 0 to 90%. Increasing severity of chronic damage was associated with shortened renal survival. Each increase of 10% in the index increased the hazard ratio of risk of permanent dialysis by 1.5 times (95% confidence interval 1.4-1.7, P<0.001). CONCLUSIONS: A simple measure of chronic damage was a powerful indicator of prognosis. This is likely to be clinically useful in routine practice and trials.
Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase.
The mitochondrial enzyme 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) plays an important role in calcium homeostasis by catalyzing synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D(3), in the kidney. However, enzyme activity assays indicate that 1 alpha-hydroxylase is also expressed in a variety of extrarenal tissues; recent cloning of cDNAs for 1 alpha-hydroxylase in different species suggests that a similar gene product is found at both renal and extrarenal sites. Using specific complementary ribonucleic acid probes and antisera to 1 alpha-hydroxylase, we have previously reported the distribution of messenger ribonucleic acid and protein for the enzyme along the mouse and human nephron. Here we describe further immunohistochemical and Western blot analyses that detail for the first time the extrarenal distribution of 1 alpha-hydroxylase in both normal and diseased tissues. Specific staining for 1 alpha-hydroxylase was detected in skin (basal keratinocytes, hair follicles), lymph nodes (granulomata), colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex), and placenta (decidual and trophoblastic cells). Further studies using psoriatic skin highlighted overexpression of 1 alpha-hydroxylase throughout the dysregulated stratum spinosum. Increased expression of skin 1alpha-hydroxylase was also associated with sarcoidosis. In lymph nodes and skin from these patients 1 alpha-hydroxylase expression was observed in cells positive for the surface antigen CD68 (macrophages). The data presented here confirm the presence of protein for 1 alpha-hydroxylase in several extrarenal tissues, such as skin, placenta, and lymph nodes. The function of this enzyme at novel extrarenal sites, such as adrenal medulla, brain, pancreas, and colon, remains to be determined. However, the discrete patterns of staining in these tissues emphasizes a possible role for 1 alpha-hydroxylase as an intracrine modulator of vitamin D function in peripheral tissues.
ABC of arterial and vascular disease: vasculitis.
Explore the source record for details and available documents.
Glomerular prolapse as precursor of one type of segmental sclerosing lesions.
A distinctive segmental glomerular abnormality is confined to the region of the tubular opening. The hypothesis was that this followed prolapse of the tuft into the tubule. Analysis was made of 39 renal biopsy specimens with acute postinfective glomerulonephritis, later material from ten cases, four specimens from three women with pre-eclampsia, and 21 control specimens, with morphometry of glomeruli and immunohistological examination for immunoproteins and monocytes/macrophages. Prolapse was found in 14 specimens with acute postinfective glomerulonephritis, associated in eight with adhesion to Bowman's capsule and local alterations in the tuft, which together constitute early tip changes. Another three had early tip changes only and eight others had thin adhesions between the tuft and capsule next to the tubular opening. Later material confirmed this order of development and showed another late change, with sclerosed and hyaline material in the tuft and adhesion at the tubular origin. Findings in pre-eclampsia were comparable. Glomeruli were significantly larger in acute postinfective glomerulonephritis than in controls and were shown by others to be larger in pre-eclampsia than in normal pregnancy. Immunohistology showed IgM and a few foamy monocytes/macrophages in early tip changes but not in prolapsed loops. Glomerular prolapse appears to be a temporary consequence of acute enlargement of the tuft, probably causes mechanical damage to epithelial cells, and is a precursor of permanent structural changes near the tubular origin. This gives a unifying hypothesis to explain how these changes can be seen in acute postinfective glomerulonephritis, pre-eclampsia, and many other human and experimental renal disorders.
Role of nitric oxide in a toxin-induced model of haemolytic uraemic syndrome.
The role of nitric oxide in the pathogenesis of glomerular thrombotic microangiopathy was explored using an established rat model in which ricin with or without lipopolysaccharide induced glomerular thrombosis. Ricin alone caused a small rise in the plasma concentration of nitric oxide (control 9.2+/-0.7 microM, ricin 23.3+/-6.3 microM at 7 h). This increase occurred after the development of glomerular thrombosis. Nitric oxide synthase (NOS) activity in the kidney showed no significant change from control values (control 5.66+/-2.7 pmol/min per ml homogenate, ricin 7.52+/-1.8 pmol/min per ml homogenate, total activity). When ricin and lipopolysaccharide were administered together, calcium-independent NOS activity increased whereas calcium-dependent activity decreased (1.22+/-2.6 pmol/min per ml homogenate). The increase in calcium-independent NOS activity correlated with a high plasma concentration of interleukin-1beta in the ricin plus lipopolysaccharide group (4,036.83+/-1,001.5 pg/ml). These data indicate that thrombus formation in a rat model of haemolytic uraemic syndrome is independent of the effects of nitric oxide.
Renal pathological findings in infective endocarditis.
BACKGROUND: Accounts of renal pathological findings in infective endocarditis are mostly based on studies from many years ago. We reviewed a group of patients with infective endocarditis in the light of modern concepts of renal pathology, including the largest reported series of renal biopsies in this condition. METHODS: Renal tissue was available for retrospective study from 62 patients with confirmed infective endocarditis out of 354 diagnosed with the disease between 1981 and 1998 inclusive. Twenty patients had a renal biopsy and 42 a necropsy. RESULTS: Common renal lesions noted were localized infarcts in 31%, noted only in necropsy material, and acute glomerulonephritis in 26%, noted in biopsy and necropsy material. The commonest type of glomerulonephritis was vasculitic, without deposition of immunoproteins in glomeruli. Of the renal infarcts over half were due to septic emboli, mostly in patients infected with Staphylococcus aureus. Acute interstitial nephritis was found in 10% but was more common in biopsy material and seemed attributable to antibiotics. Renal cortical necrosis found in 10% was apparent only at necropsy. There were various other findings in the kidney. CONCLUSIONS: The kidneys are commonly affected in infective endocarditis by a variety of complications of clinical significance. The commonest type of glomerulonephritis does not appear to be attributable to deposition of immune complexes. A renal biopsy may be helpful in the investigation of renal impairment in a patient with infective endocarditis.
Percutaneous image-guided biopsy of lung nodules in the assessment of disease activity in Wegener's granulomatosis.
OBJECTIVE: In patients with known Wegener's granulomatosis (WG) and persistent chest radiographic abnormalities, assessment for disease activity is often difficult, prompting the need for histological diagnosis to determine appropriate treatment. Here we report the use of automated image-guided core needle biopsy of pulmonary lesions for the assessment of disease activity in WG, rather than for primary diagnosis. METHODS: Image-guided percutaneous core needle biopsy was performed on five occasions in four patients with thoracic WG and persistent radiographic abnormalities of the chest. Clinical features, indication for biopsy, radiographic abnormalities and pathological findings were recorded. RESULTS: Adequate pathological specimens were obtained, allowing exclusion of infection and tumour. Active chronic inflammation with or without vasculitis was demonstrated in each case, indicating the need for further immunosuppressive therapy. A small pneumothorax following biopsy in one case required no treatment. Follow-up chest imaging revealed a reduction in the extent of thoracic disease following therapy in all cases. CONCLUSIONS: The safety and diagnostic accuracy of image-guided core biopsy of thoracic lesions makes it a useful tool in the assessment of disease activity in WG patients with persistent chest radiographic lesions.
Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation.
Drug toxicity is one of the major problems in clinical immunosuppression. Combining two immunosuppressants in low or ineffective doses is an attractive strategy if it helps to reduce drug-related toxicity. We examined the immunosuppressive efficacy of brequinar (BQR) in combination with leflunomide (Lef) or tacrolimus (FK) in a heterotopic rat cardiac allotransplantation model. Abdominal heterotopic heart grafts (DA x LEW) were immunosuppressed from the time of transplantation and continued until the ninth posttransplant day (POD) in experiments examining prophylaxis of rejection treatment (PRT). In a separate series of experiments designed to test rescue treatment (RT), immunosuppression was begun on POD 4 and continued for 10 days; transplanted rats were sacrificed the following day intentionally. Cardiac rejection was monitored by palpation and documented by light microscopy. Immunosuppressive drugs (BQR 3 mg/kg and 12 mg/kg; BQR 3 mg/kg + Lef 5 mg/kg; BQR 3 mg/kg + FK 0.5 mg/kg) were given orally by gavage; thrice weekly according to the monotherapy or dual-therapy dosing protocol. Median survival time of the cardiac graft for controls (no treatment) was 5 days. BQR monotherapy 3 mg/kg (low dose) improved graft survival (P = 0.003); graft histology showed moderate acute rejection. BQR monotherapy 12 mg/kg (therapeutic dose) application in the PRT or RT treatment arms of the study design resulted in aortic-graft ruptures and clinical toxicity in each treatment arm due to overimmunosuppression; normal graft morphology was maintained. Successful rescue of rejecting grafts was histologically documented. Combining BQR with Lef or FK in the PRT protocol showed prolonged graft survival in both drug combination groups (median survival time, 14 days; P = 0.009 and 0.014, respectively). Using an identical combination protocol for RT, all grafts achieved a 14-day graft survival; cardiac histology showed reversible moderate acute rejection. BQR given in the presence of Lef or FK not only prevented acute rejection but intercepted it so long as it was administered; grafts were rejected within 4 days of stopping immunosuppression in the PRT study. These combinations using low or subtherapeutic doses may be important for controlling transplant rejection and rescuing ongoing graft rejection. The need for continuing treatment in this strongly allogeneic model is highlighted.
T lymphocyte adhesion mechanisms within inflamed human kidney: studies with a Stamper-Woodruff assay.
Renal inflammatory conditions are characterized by mononuclear cell recruitment to sites of inflammation. We have developed a modified Stamper-Woodruff assay system to analyze mechanisms of functional T cell adhesion to cryostat sections of renal biopsy material from patients with vasculitic glomerulonephritis (GN) and acute allograft rejection. Peripheral blood T cells adhered to intraglomerular, periglomerular, and tubulointerstitial regions of the cortex. Blocking monoclonal antibodies against tissue expressed ICAM-1, VCAM-1, and the CS-1 domain of fibronectin (CS-1Fn) differentially attenuated T cell adhesion. Glomerular adhesion in vasculitic GN and tubulointerstitial adhesion in acute rejection were particularly sensitive to both anti-ICAM-1 and anti-VCAM-1 antibodies, indicating a prominent role for ICAM-1 and VCAM-1 at glomerular sites in vasculitis and at tubulointerstitial sites in rejection. Furthermore, using KL/4 cells (LFA-1 expressing) and Jurkat cells (VLA-4 expressing), we demonstrated specific LFA-1/ICAM-1- and VLA-4/VCAM-1-mediated interactions within glomerular and tubulointerstitial compartments. Jurkat cells also adhered to VCAM-1-free sites, and binding was inhibitable by anti-CS-1Fn antibody, thereby demonstrating a role for VLA-4/fibronectin interactions especially at intraglomerular sites in acute rejection where VCAM-1 is notably absent. We therefore propose a prominent functional role for ICAM-1, VCAM-1, and CS-1 domain fibronectin in T cell recruitment to the inflamed kidney.
Effect of donor-specific transfusion in combination with FK 506 in rat cardiac allotransplantation.
Explore the source record for details and available documents.
A laboratory model of toxin-induced hemolytic uremic syndrome.
BACKGROUND: Verocytotoxin-producing (Shiga-like toxin-producing) Escherichia coli infection is the principal cause of hemolytic uremic syndrome (HUS). The pathogenesis is unclear, and there is a need for animal models. These are impeded by the different distribution of verocytotoxin receptors between species. We have circumvented this restriction using ricin, which gains entry into cells via various galactose receptors. Like verocytotoxin, ricin specifically cleaves a single adenine from ribosomal RNA. METHODS: Rats were given ricin at a dose of 6.7 micrograms/100 g body wt, with or without lipopolysaccharide at 10 micrograms/100 g body wt. Lipopolysaccharide alone or saline were used as controls. Changes in glomerular filtration rate, hematological parameters, histology, and plasma cytokine concentrations were measured. RESULTS: Extensive glomerular thrombosis, pyknotic nuclei, and an infiltration of ED1-positive cells into glomeruli were observed eight hours after an injection of ricin. Other vascular beds were unaffected. Histologic changes were preceded by oliguric renal failure, hemolysis, and thrombocytopenia. Ricin produced a rise in plasma concentrations of monocyte chemotactic protein-1, > tumor necrosis factor-alpha, > interleukin-1 beta, > interleukin-6. Interferon-gamma showed a small increase at the end of the experiment. CONCLUSIONS: Ricin induces glomerular thrombotic microangiopathy, closely resembling that which occurs in verocytotoxin-producing E. coli-induced HUS. As in HUS, high concentrations of proinflammatory cytokines are present, which are probably a result of cytokine superinduction by the toxin.
Definition of 'focal segmental glomerulosclerosis'.
Explore the source record for details and available documents.