Wolbachia, Cardinium and climate: an analysis of global data.

Bacterial endosymbionts are very common in terrestrial arthropods, but infection levels vary widely among populations. Experiments and within-species comparisons suggest that environmental temperature might be important in explaining this variation. To investigate the importance of temperature, at broad geographical and taxonomic scales, we extended a global database of terrestrial arthropods screened for Wolbachia and Cardinium. Our final dataset contained data from more than 117 000 arthropods (over 2500 species) screened for Wolbachia and more than 18 000 arthropods (over 800 species) screened for Cardinium, including samples from 137 different countries, with mean temperatures varying from -6.5 to 29.2°C. In insects and relatives, Cardinium infection showed a clear and consistent tendency to increase with temperature. For Wolbachia, a tendency to increase with temperature in temperate climates is counteracted by reduced prevalence in the tropics, resulting in a weak negative trend overall. We discuss the implications of these results for natural and introduced symbionts in regions affected by climate change.

Review and action plan for oral health improvement in Sheffield special schools.

A description of the process of a review of oral health improvement in special schools in Sheffield and the implementation of an action plan for these activities. Public health competencies encompassed: assessing the evidence on oral health and dental interventions, programmes and services; strategic leadership and collaborative working for health; oral health improvement.

Morphological and proteomic analysis of biofilms from the Antarctic archaeon, Halorubrum lacusprofundi.

Biofilms enhance rates of gene exchange, access to specific nutrients, and cell survivability. Haloarchaea in Deep Lake, Antarctica, are characterized by high rates of intergenera gene exchange, metabolic specialization that promotes niche adaptation, and are exposed to high levels of UV-irradiation in summer. Halorubrum lacusprofundi from Deep Lake has previously been reported to form biofilms. Here we defined growth conditions that promoted the formation of biofilms and used microscopy and enzymatic digestion of extracellular material to characterize biofilm structures. Extracellular DNA was found to be critical to biofilms, with cell surface proteins and quorum sensing also implicated in biofilm formation. Quantitative proteomics was used to define pathways and cellular processes involved in forming biofilms; these included enhanced purine synthesis and specific cell surface proteins involved in DNA metabolism; post-translational modification of cell surface proteins; specific pathways of carbon metabolism involving acetyl-CoA; and specific responses to oxidative stress. The study provides a new level of understanding about the molecular mechanisms involved in biofilm formation of this important member of the Deep Lake community.

Modulating effects of WT1 on interferon-ß-vitamin D association in MS.

OBJECTIVE: To investigate whether those genes involved in the vitamin D pathway modulate the relationship between 25-hydroxyvitamin D (25(OH)D) and IFN-ß, the relationship between IFN-ß and sun in predicting 25(OH)D, and the interaction between IFN-ß and 25(OH)D in modulating relapse risk in patients with MS. METHODS: Prospective cohort study of 169 participants with MS and genotype data followed 2002-2005. Gene-IFN-ß and gene-IFN-ß-sun interactions predicting 25(OH)D evaluated by multilevel mixed-effects linear regression. Gene-IFN-ß interactions with 25(OH)D in modulating in relapse risk assessed using survival analysis. RESULTS: The cohort was 71.6% female and of mean age 47.8. Two-independent intronic genotyped SNPs (rs10767935 and rs5030244) in WT1 significantly modified the IFN-ß-25(OH)D association after adjustment (P(interaction) = 0.001, 0.0002; P(adj) = 0.003, 0.006, respectively). There was a marked difference in the interaction between self-reported sun exposure and IFN-ß in predicting 25(OH)D by level of rs10767935, although this did not reach statistical significance. No SNPs modified the interaction between IFN-ß and 25(OH)D in predicting relapse. CONCLUSIONS: We have demonstrated that two-independent SNPs (rs10767935 and rs5030244) in WT1 modified the IFN-ß-25(OH)D association in patients with MS. Some evidence was shown for a difference in the sun-IFN-ß-25(OH)D association by level of rs10767935. These findings indicate that WT1 variants may play a role in altering the effects of IFN-ß on vitamin D in MS.

Transcriptomics of cortical gray matter thickness decline during normal aging.

INTRODUCTION: We performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging. METHODS: Transcriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 µm) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability. RESULTS: Transcripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT. CONCLUSION: Expression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

Linkage mapping of CVD risk traits in the isolated Norfolk Island population.

To understand the underlying genetic architecture of cardiovascular disease (CVD) risk traits, we undertook a genome-wide linkage scan to identify CVD quantitative trait loci (QTLs) in 377 individuals from the Norfolk Island population. The central aim of this research focused on the utilization of a genetically and geographically isolated population of individuals from Norfolk Island for the purposes of variance component linkage analysis to identify QTLs involved in CVD risk traits. Substantial evidence supports the involvement of traits such as systolic and diastolic blood pressures, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, body mass index and triglycerides as important risk factors for CVD pathogenesis. In addition to the environmental influences of poor diet, reduced physical activity, increasing age, cigarette smoking and alcohol consumption, many studies have illustrated a strong involvement of genetic components in the CVD phenotype through family and twin studies. We undertook a genome scan using 400 markers spaced approximately 10 cM in 600 individuals from Norfolk Island. Genotype data was analyzed using the variance components methods of SOLAR. Our results gave a peak LOD score of 2.01 localizing to chromosome 1p36 for systolic blood pressure and replicated previously implicated loci for other CVD relevant QTLs.

Sensory nerve excitability and neuropathy in end stage kidney disease.

BACKGROUND: Peripheral neuropathy is present in 65% of patients with end stage kidney disease (ESKD) starting dialysis. Studies of membrane potential and axonal ion channel function may help explain the pathophysiology. OBJECTIVES: To follow changes in median sensory axon excitability in patients with ESKD treated with haemodialysis, and correlate them with clinical rating scales and serum levels of potential neurotoxins. METHODS: Sensory nerve action potentials were recorded from the second digit following stimulation of the median nerve in 12 ESKD patients. Stimulus-response behaviour using two stimulus durations, threshold electrotonus to 100 ms polarising currents, a current-threshold relation, and recovery of excitability following supramaximal stimulation were recorded before, during, and after haemodialysis. Serum concentrations of potential neurotoxins were measured. RESULTS: Before dialysis, there were changes in nerve excitability consistent with axonal depolarisation: refractoriness was increased; superexcitability and depolarising threshold electrotonus were reduced. Following dialysis there were improvements in all indices, with correlations between excitability abnormalities and serum potassium measurements. Neuropathic symptoms correlated with excitability changes. CONCLUSIONS: Nerves are depolarised before haemodialysis in ESKD patients. The correlation of excitability abnormalities with potassium indicates that the achievement of normokalaemia should be a priority in treating such patients.

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes.

OBJECTIVE: To investigate levels of components of the alternative pathway of complement, and of two activation products, ASP and Bb, in persons ranging in insulin resistance both fasting and following the consumption of a high-fat, low-carbohydrate meal. SUBJECTS: Healthy controls (n = 17) and normoglycaemic first-degree relatives of patients with type II diabetes (n = 15). MEASUREMENTS: All subjects had normal glucose tolerance. Blood was collected for the measurement of plasma glucose, insulin, triglycerides and free fatty acids. Body composition was assessed with dual energy X-ray absorptiometry (DEXA) and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Basal and postprandial values over 6 h were determined for plasma C3, B, D, Bb and ASP. Basal levels of C1q, C4 and CRP were also determined. RESULTS: Controls did not differ significantly from the relatives of patients with type II diabetes for any metabolic parameter except in their degree of insulin resistance and central fat (kg). Across all subjects, basal levels of C3, but no other complement protein, were correlated with insulin resistance. Native complement proteins, but not ASP or Bb, were correlated with body mass index and the amount (kg) of central fat. Basal levels of C3 and factor B were significantly higher in the relatives group, whereas factor D and the classical pathway proteins C1q and C4 did not differ between the two groups. Postprandially, levels of factor D were significantly reduced in both groups. ASP levels also fell postprandially, the decline achieving significance in the relatives group. CONCLUSIONS: Elevated levels of C3 and factor B in the diabetic relatives group may have resulted from increased synthesis by adipose tissue. There was no evidence of alternative pathway activation in response to a fat meal in terms of ASP or Bb production, or significant consumption of C3 and factor B. These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat.

The postprandial response of adiponectin to a high-fat meal in normal and insulin-resistant subjects.

OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal. DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal. SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20). MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting. RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting. CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.

Negotiating and managing partnership in primary care.

In the UK public service organisations are increasingly working together in new partnerships, networks and alliances, largely stimulated by government legislation, which aims to encourage 'joined-up' policy-making. This is particularly prevalent in health-care where local government, health authorities and trusts, voluntary and community groups are extending existing, and developing new, forms of partnership, particularly around Health Improvement Programmes and new primary care organisations. This paper explores two main aspects of how these new interorganizational relationships are being developed and managed and is based on research conducted in one case study locality. First, the new structures of partnership in primary care are mapped out, together with discussion on why these particular patterns of relationship between statutory and voluntary sector organisations have emerged, exploring both centrally and locally determined influences. Secondly, the paper explores the tensions associated with working within new policy-making and management structures, and how the additional demands of audit, performance measurement and the sheer pace of change, pose a potential threat to the partnership process.

CL22 - a novel cationic peptide for efficient transfection of mammalian cells.

Condensing peptide-DNA complexes have great potential as nonviral agents for gene delivery. To date, however, such complexes have given transfection activities greatly inferior to adenovirus and somewhat inferior to cationic lipid-DNA complexes, even for cell lines and primary cells in vitro. We report here the identification of a novel condensing peptide, CL22, which forms DNA complexes that efficiently transfect many cell lines, as well as primary dendritic and endothelial cells. We report studies with sequence and structure variants that define some properties of the peptide that contribute to efficient transfection. We demonstrate that the superior transfection activity of CL22 compared with other DNA condensing peptides is conferred at a step after uptake of the complexes into cells. We show that CL22-DNA complexes have transfection activity that is at least equivalent to the best available nonviral agents.

Patient mood and carer strain during stroke rehabilitation in the community following early hospital discharge.

PURPOSE: Patient mood and carer stress were assessed for stroke patients in the community following early hospital discharge. METHOD: Patients had low Barthel Indices (13.0 (mean) +/- 4.9 (SD)) with high anxiety and depression scores, and carers had high stress scores, on starting rehabilitation. On starting rehabilitation, patient Barthel Indices correlated inversely with patient depression (r = -0.33, p < 0.02) and carer stress scores (r = -0.48, p < 0.001). RESULTS: During rehabilitation improvements occurred in patient Barthel Indices, patient anxiety scores and carer stress scores, but not in patient depression scores. Incremental increases in patient Barthel Indices during rehabilitation correlated with reductions in carer stress scores (r = -0.55, R2 = 29.4%, p < 0.001). Following early hospital discharge stroke patients display mood abnormalities which do not resolve during rehabilitation. CONCLUSION: Carer stress and patients depression scores are related to the severity of stroke-related disability. Strategies to address patient mood and carer stress should be present in community services providing early stroke rehabilitation.

Fechtner syndrome: physiologic analysis of macrothrombocytopenia.

Fechtner syndrome is a rare autosomal dominant disorder consisting of macrothrombocytopenia and leukocyte inclusions, associated with Alport's syndrome (hereditary nephropathy, sensorineural hearing loss, and ocular anomalies). We describe a 71-year-old Caucasian male with a history of hearing loss and asymptomatic macrothrombocytopenia incidentally noted in 1985. Several challenges to hemostasis were uneventful, including total hip arthroplasty. He subsequently developed progressive renal failure, with 'nil lesions' by light and electron microscopy, which was responsive to corticosteroid therapy. Eight family members are affected variably by either thrombocytopenia or renal failure. Laboratory testing gave the following results: hemoglobin, 10.2 g/dl; leukocytes, 5.0 x 109/l; platelets, 64 x 109/l (mean platelet volume, 13.3 fl; normal platelet volume, 7.6-10.8 fl). Peripheral blood smear revealed thrombocytopenia and leukocytes with inclusions. Electron microscopy of the buffy coat confirmed Fechtner inclusions within the patient's leukocytes. Whole mount and thin section electron microscopy revealed a population of large, although not giant, platelets. Despite thrombocytopenia, platelet aggregation was normal. Flow cytometry of dilute platelets revealed normal glycoprotein alphaII beta beta3 activation and alpha-granule p-selectin secretory response to 10 nmol/l human alpha-thrombin. Dense granule adenosine triphosphate secretory response to thrombin was likewise normal. This case illustrates that 'giant' platelets are not universally present in Fechtner syndrome cases, although the platelets are enlarged. Finally, renal pathology other than Alport's nephropathy may be associated with this syndrome.

C3a is made by proximal tubular HK-2 cells and activates them via the C3a receptor.

BACKGROUND: Some individual components of complement are synthesized by the kidney. However, it is not known whether these form functional pathways that are able to mediate more fundamental cellular events. We examined the ability of HK-2 tubular cells to produce an intact alternative pathway of complement and to respond to the C3a fragment thus produced through the C3a receptor. METHODS: The production of mRNA for alternative pathway components was detected by reverse transcription-polymerase chain reaction, whereas protein synthesis was investigated by probing Western blots of concentrated culture supernatants with polyclonal antisera. Levels of C3a and inositol phosphate produced by HK-2 cells were determined by radioimmunoassay, whereas those of transforming growth factor-beta1 (TGF-beta1) were measured by ELISA. Intracellular tyrosine phosphorylation in response to C3a was evaluated by Western blotting and chemiluminescence. RESULTS: HK-2 cells produce the complement polypeptides C3a, C3, and factors B and H. They also contain mRNA for all components of the alternative pathway and the C3a receptor. mRNA levels were up-regulated by interleukin-1alpha, interleukin-1beta, and tumor necrosis factor-alpha. Incubation of HK-2 cells with C3a led to an increase in intracellular inositol phosphate and to tyrosine phosphorylation of at least two proteins in a pertussis-toxin-sensitive fashion. C3a and C3a desarg also up-regulated the secretion of TGF-beta1 by these cells. CONCLUSION: HK-2 cells produce an intact alternative pathway of complement. In addition, both locally produced and urinary C3a have the potential to activate these cells, resulting in inflammatory events such as TGF-beta1 production.

Tenacious adhesion of Actinobacillus actinomycetemcomitans strain CU1000 to salivary-coated hydroxyapatite.

Adherence of Actinobacillus actinomycetemcomitans to hard-tissue surfaces was evaluated by comparing a phenotypically stable, well-maintained clinical isolate (strain CU1000) to Streptococcus gordonii G9B, an extensively studied oral-colonizing bacterium. Standard innocula of radiolabelled bacteria were added to saliva-coated hydroxyapatite (SHA) and the ratio of bound to unbound cells counted. Several other clinical isolates as well as laboratory strain Y4 were studied. In other experiments, cell detachment from SHA was compared in static and shaking vessels to calculate controlled desorption of cells over time. A sonic-displacement assay was used to measure avidity of binding to HA and SHA. To better define the attachment properties of CU1000, bacteria were treated with a variety of agents including detergents, salts and enzymes before or after incubation with SHA. Results indicated that CU1000 bound better than G9B (a minimum of 10-fold greater; p < or = 0.05) and did not desorb from SHA, while G9B desorbed to equilibrium in 4 h. Furthermore, Langmuir isotherm calculations indicated that, unlike G9B, CU1000 did not follow second-order adsorption kinetics and thus did not achieve saturation. In addition, of the agents tested only periodate reduced attachment and resulted in detachment of CU1000 from surfaces. These experiments suggest that clinical isolates of A. actinomycetemcomitans possess unique binding properties that promote adsorption to and impede desorption from SHA. The characteristics described for the actinobacillus in this study have been previously underestimated, appear to be mediated by glycoconjugates, and may resemble attachment described for several biofilm-forming, non-oral pathogens.

The influence of oral lipid loads on acylation stimulating protein (ASP) in healthy volunteers.

OBJECTIVES: To examine the hypothesis that a sustained rise in plasma acylation stimulating protein (ASP, C3a desarg) accompanies the elevation in triacylglycerol that follows the ingestion of an oral fat load. DESIGN: Following an overnight fast, blood samples were obtained from healthy volunteers while fasting and 15 min, 1, 2, 4, 6 and 8 h following ingestion of: (i) a liquid meal, rich in dairy fat (eight subjects) and (ii) a semi-liquid meal, with higher total fat content and rich in polyunsaturated fat (six subjects). SUBJECTS AND METHODS: Four male and four female volunteers (age range: 22-51 y; body mass index (BMI): 17.9-26.9 kg/m2) received the first meal. Six subjects (age range: 32-60 y; BMI: 18.0-28.4 kg/m2), including three from the first study, received the second meal using the same protocol. ASP and C5a were measured by radioimmunoassay (RIA) and the complement proteins C3, factor B and C5 by radial immunodiffusion or nephelometry. Tumour necrosis factor (TNF)-alpha was measured by enhanced ELISA, and plasma cholesterol and triacylglycerol by an automated enzymatic method. The presence of chylomicrons was assessed in post-prandial plasma samples taken after the second meal. RESULTS: There was no significant change in mean ASP concentration in either group at any time point, following ingestion of either meal. However, there was a significant positive linear trend in ASP following the second fat challenge (ANOVA; P < 0.05). There was also no change in complement proteins, plasma cholesterol or TNF-alpha. Plasma triacylglycerol rose significantly after the first and second meals (P < 0.05 and P < 0.001 at 2 h post-prandially); the mean maximum rise above the fasting level was 58 +/- 41% and 89 +/- 38% respectively (mean +/- s.d.). Chylomicrons were detected in samples taken from each subject after the second meal. Analysis of individual ASP data showed a sustained rise in one subject after the first meal and two subjects after the second meal. Substantial variation in ASP concentration was observed in samples taken in the first 2 h post-prandially. CONCLUSION: There was no significant change in ASP nor other complement proteins for either group of subjects following ingestion of the lipid loads. Individual data showed substantial variation in post-prandial ASP, but multiple plasma sampling did not define the basis for this variation.

Renoprotective differences between perindopril and enalapril in the diabetic hypertensive rat do not reflect glomerular angiotensin-converting enzyme activity.

1. The various angiotensin-converting enzyme inhibitors have structural differences which affect their affinities for the catalytic sites on converting enzyme. We postulated that such differences might result in differences in renoprotective efficacy. We investigated this in the diabetic spontaneous hypertensive rat. We also investigated whether these differences might reflect variations in glomerular or plasma angiotensin-converting enzyme activity. 2. One week after induction of diabetes, rats were started on antihypertensive therapy: enalapril, 10 mg.day-1.kg-1, or perindopril, 4 mg.day-1.kg-1, in the drinking water. After 3 months, the rats were killed, blood samples were taken and tissues were harvested. Angiotensin-converting enzyme activity in isolated glomeruli and plasma was measured by fluorimetric assay. Glomerular protein content was also determined. 3. Urinary protein excretion was significantly lower in perindopril-treated rats than in either controls (P < 0.0005) or enalapril-treated rats (P < 0.05). Glomerular protein content was also lower in perindopril-treated rats (P < 0.05 versus enalapril; P < 0.005 versus control). There was no difference in glomerular angiotensin-converting enzyme activity between the two inhibitors although both were lower than control values (enalapril P < 0.025; perindopril P < 0.025). Plasma angiotensin-converting enzyme activity was significantly lower in the perindopril group than in either control (P < 0.005) or the enalapril group (P < 0.01). 4. We conclude that in the spontaneous hypertensive rat with streptozotocin-induced diabetes, perindopril is more effective than enalapril in reducing proteinuria and glomerular protein accumulation. This difference does not result from differences in glomerular-converting enzyme activity.

Detection and quantification of the control proteins of the alternative pathway of complement in 3T3-L1 adipocytes.

The complement peptide C3a desarg is identical to acylation-stimulating protein (ASP), a human plasma protein that potently stimulates adipocyte triacylglycerol synthesis and glucose transport. Both human and murine adipocytes express mRNA and/or protein for the complement components C3 and factors B and D (adipsin) required to generate ASP. However, the regulatory mechanisms controlling this process are unknown. We have established a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique to demonstrate the presence in mouse 3T3-L1 adipocytes of mRNA for all components of the alternative pathway, including the control proteins factors I and H, CR1 and properdin. On differentiation, mRNA for C3 (fivefold) and factor D (> 50-fold) increased, whereas stimulation with tumour necrosis factor (TNF)-alpha and interleukin (IL) 1 beta led to eightfold increases in factor B mRNA. Metabolic labelling followed by immunoprecipitation showed that factor B protein is normally present in small quantities, and is greatly increased by cytokine stimulation. The larger quantities of C3 and H proteins present were little affected, whereas levels of C3a increased on cytokine stimulation. These results suggest that the rate-limiting step in the cytokine-induced production of ASP in adipocytes is factor B synthesis.

Acute but not chronic angiotensin-converting enzyme inhibition induces enzyme synthesis in the glomerulus of the spontaneously hypertensive rat.

1. Treatment with angiotensin-converting enzyme (ACE) inhibitors slows the rate of progression of nephropathy in the spontaneously hypertensive rat (SHR) with streptozotocin-induced diabetes. Paradoxically, however, chronic ACE inhibitor therapy has been reported to be associated with induction of ACE in the plasma. We sought to determine whether induction also occurred in the glomerulus. 2. Seven days after induction of diabetes rats were randomized to receive perindopril (4 mg/kg per day) in the drinking water or water alone. Blood glucoses were maintained 6-10 mmol/L by daily ultralente insulin. Rats were killed after 1 and 12 weeks of ACE inhibitor therapy and the kidneys were harvested. Angiotensin-converting enzyme activity was determined in isolated glomeruli before and after removal of perindopril and reconstitution with zinc sulphate. 3. After 1 week of ACE inhibitor therapy, glomerular ACE was significantly greater after removal of perindopril than either before its removal (P < 0.025) or in the untreated controls (P < 0.025). After 12 weeks of therapy, ACE activity was significantly lower in the perindopril-treated group than in the untreated controls (P < 0.025). There was no increase in ACE activity following removal of perindopril. 4. These studies suggest that short-term ACE inhibition is associated with induction of ACE in the glomerulus. However, there was no increase in ACE activity after removal of perindopril, suggesting that induction of synthesis of this enzyme in the glomerulus does not occur during chronic ACE inhibition.