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CD2, a cell surface glycoprotein expressed on T cells and natural killer cells, can couple to signaling pathways that result in T cell proliferation. An Src-like protein tyrosine kinase, p56lck, coprecipitates with CD2, and perturbation of CD2 by monoclonal antibodies results in an increase in the activity of p56lck, suggesting that an interaction with p56lck contributes to CD2-mediated signaling. Herein, we investigate the mechanism by which CD2 associates with p56lck. We demonstrate that CD2 and p56lck associate when coexpressed in nonlymphoid cells, that this association requires the cytoplasmic domain of CD2, and that the SH3 domain of p56lck mediates its interactions with CD2. Using truncation mutants of CD2, we identify two regions in the cytoplasmic domain of CD2 involved in binding p56lck. Each region contains a proline-rich sequence that, in the form of a synthetic peptide, directly binds p56lck. Thus, proline-rich sequences in the cytoplasmic domain of CD2 allow this transmembrane receptor to bind to the SH3 domain of p56lck.

The MRC OX-44 molecule, which is expressed on all peripheral leukocytes, identifies the subset of thymocytes capable of proliferating in response to alloantigens and lectins (Paterson, D.J., J.R. Green, W.A. Jefferies, M. Puklavec, and A.F. Williams. 1987. J. Exp. Med. 165:1). When we isolated monoclonal antibodies (mAbs) on the basis of their ability to activate the phosphatidylinositol signaling pathway in RNK-16 cells (a rat leukemia line with natural killer activity), three of the resulting mAbs recognized the OX-44 molecule. Addition of these mAbs to RNK-16 elicits protein tyrosine phosphorylation, generates inositol phosphates, and increases the concentration of cytoplasmic free calcium. These responses require the addition of intact mAb and are not observed with F(ab')2 fragments. One of these mAbs (7D2) is mitogenic for freshly isolated rat splenic T cells and synergizes with a mAb to the T cell antigen receptor in this activation. A 50-60-kD glycoprotein coprecipitates with the OX-44 molecule from RNK-16 cells and rat splenic T cells. Peptide mapping and reprecipitation studies indicate that the coprecipitating molecule is CD2. Thus, the OX-44 molecule can couple to multiple signaling pathways and associates with CD2 on both RNK-16 and rat T cells.

STUDY OBJECTIVE: To investigate the efficacy and safety of a fully human monoclonal antibody recognizing the chemokine interleukin (IL)-8 in patients with COPD. DESIGN: Randomized, double-blind, parallel-group, placebo-controlled trial. SETTING: Eighteen clinics/hospitals in the United States. PATIENTS: One hundred nine patients with stable COPD. INTERVENTIONS: Three IV infusions of either monoclonal antibody recognizing IL-8 (800-mg loading dose; 400-mg subsequent doses) or active buffer solution administered monthly over a 3-month period. MEASUREMENTS AND RESULTS: The differences in the transition dyspnea index (TDI) total score, the primary outcome measure, between fully human monoclonal IgG(2) antibody directed against IL-8 and placebo were 0.8, 1.0, 0.8, and 0.3 at week 2 (p = 0.046) and months 1 to 3, respectively. At all time points, the proportion of patients achieving >/= 1 point improvement in the TDI was greater for the monoclonal antibody group compared with the placebo group: 28% vs 11% at week 2 (p = 0.028). There were no significant differences observed for lung function, health status, 6-min walking distance, and adverse events between groups. CONCLUSIONS: The results of this phase 2 study suggest that neutralization of IL-8 with monoclonal antibody therapy may improve dyspnea in patients with COPD. These results support the further investigation of monoclonal antibody therapy targeting IL-8 for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Ligation of the CD2 co-stimulatory receptor on human T lymphocytes induces tyrosine phosphorylation and activation of the Tec-family tyrosine kinase, ITK. To examine whether any of several proline-rich (PR) stretches of the CD2 cytoplasmic tail are necessary for ITK activation we introduced wild-type and mutated versions of rat CD2, each missing at least one PR stretch of the tail, into human Jurkat T leukemia cells. The influence of cytoplasmic tail mutations was then studied following stimulation of transfectants with the rat CD2 mAb pair, OX54/OX55. As predicted, wild-type rat CD2 was able to activate ITK in Jurkat cells. In addition, a truncation mutant, lacking the most membrane-distal PR stretch, PR6, was able to activate ITK. By contrast, all other studied truncation mutants, each of which is missing at least PR4-PR6, were unable to induce ITK activation. Of deletion mutants, deletion of the membrane-proximal PR stretches, PR1-PR3, did not impair rat CD2-mediated ITK activation. However, additional deletion of PR4 from a tail missing PR1 and PR2, deletion of PR2 and PR4, and deletion of PR4 alone from rat CD2 abrogated an ability to activate ITK. Thus, these results identify PR4 as an element of the CD2 tail that is required for activation of ITK. Furthermore, we show that, unlike wild-type rat CD2, PR4-deleted rata CD2 is unable to induce IL-2 secretion from Jurkat cells. This is consistent with the view that PR4-mediated activation of ITK is important for downstream signaling events induced by CD2 co-stimulation. [ABSTRACT FROM PUBLISHER]

Charged residues on the surface of proteins are critical for both protein stability and interactions. However, many proteins contain binding regions with a high net charge that may destabilize the protein but are useful for binding to oppositely charged targets. We hypothesized that these domains would be marginally stable, as electrostatic repulsion would compete with favorable hydrophobic collapse during folding. Furthermore, by increasing the salt concentration, we predict that these protein folds would be stabilized by mimicking some of the favorable electrostatic interactions that take place during target binding. We varied the salt and urea concentrations to probe the contributions of electrostatic and hydrophobic interactions for the folding of the yeast SH3 domain found in Abp1p. The SH3 domain was significantly stabilized with increased salt concentrations due to Debye-Huckel screening and a nonspecific territorial ion-binding effect. Molecular dynamics and NMR show that sodium ions interact with all 15 acidic residues but do little to change backbone dynamics or overall structure. Folding kinetics experiments show that the addition of urea or salt primarily affects the folding rate, indicating that almost all the hydrophobic collapse and electrostatic repulsion occur in the transition state. After the transition state formation, modest yet favorable short-range salt bridges are formed along with hydrogen bonds, as the native state fully folds. Thus, hydrophobic collapse offsets electrostatic repulsion to ensure this highly charged binding domain can still fold and be ready to bind to its charged peptide targets, a property that is likely evolutionarily conserved over 1 billion years., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Objective: To clarify the selection of medical therapy following transsphenoidal surgery in patients with acromegaly, based on growth hormone (GH)/insulin-like growth factor 1 (IGF-1) response and glucometabolic control. Methods: We carried out a systematic literature review on three of the best studied and most practical predictive markers of the response to somatostatin analogues (SSAs): somatostatin receptor (SSTR) expression, tumor morphologic classification, and T2-weighted magnetic resonance imaging (MRI) signal intensity. Additional analyses focused on glucose metabolism in treated patients. Results: The literature survey confirmed significant associations of all three factors with SSA responsiveness. SSTR expression appears necessary for the SSA response; however, it is not sufficient, as approximately half of SSTR2-positive tumors failed to respond clinically to first-generation SSAs. MRI findings (T2-hypo-intensity) and a densely granulated phenotype also correlate with SSA efficacy, and are advantageous as predictive markers relative to SSTR expression alone. Glucometabolic control declines with SSA monotherapy, whereas GH receptor antagonist (GHRA) monotherapy may restore normoglycemia. Conclusion: We propose a decision tree to guide selection among SSAs, dopamine agonists (DAs), and GHRA for medical treatment of acromegaly in the postsurgical setting. This decision tree employs three validated predictive markers and other clinical considerations, to determine whether SSAs are appropriate first-line medical therapy in the postsurgical setting. DA treatment is favored in patients with modest IGF-1 elevation. GHRA treatment should be considered for patients with T2-hyperintense tumors with a sparsely granulated phenotype and/or low SSTR2 staining, and may also be favored for individuals with diabetes. Prospective analyses are required to test the utility of this therapeutic paradigm. Abbreviations: DA = dopamine agonist; DG = densely granulated; GH = growth hormone; GHRA = growth hormone receptor antagonist; HbA1c = glycated hemoglobin; IGF-1 = insulin-like growth factor-1; MRI = magnetic resonance imaging; SG = sparsely granulated; SSA = somatostatin analogue; SSTR = somatostatin receptor.

Objectives: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities., Methods: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×10 6 , 3×10 6 or 10×10 6 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood., Results: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×10 6 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high., Conclusion: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×10 6 tolDC but no systemic clinical or immunomodulatory effects were detectable., Trial Registration Number: NCT01352858., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Vaccination generating a robust memory population of CD8 + T cells may provide protection against cancer. However, immune therapies for cancer are influenced by the local tumour immune microenvironment. An infiltrate of T cells into tumours of people with colorectal cancer has proven to be a significant indicator of good prognosis., Methods: We used an intracaecal mouse model of cancer to determine whether a protective immune response against a mucosal gut tumour could be generated using a systemic intervention. We investigated the generation of murine memory CD8 + T cells using a sustained antigen release vaccine vehicle (chitosan gel; Gel + OVA) containing the model antigen ovalbumin, chitosan gel alone (Gel) or conventional dendritic cell vaccination (DC + OVA) using the same protein antigen., Results: Following vaccination with Gel + OVA, CD8 + T cell memory populations specific for ovalbumin protein were detected. Only vaccination with Gel + OVA gave decreased tumour burden compared to unvaccinated or DC + OVA-vaccinated mice in the intracaecal cancer challenge model., Conclusion: These results indicate that subcutaneous vaccination with Gel + OVA generates a population of functional CD8 + memory T cells in lymphoid tissue able to protect against intracaecal tumour challenge. Vaccination with chitosan gel may be valuable in anti-cancer treatment at both peripheral and mucosal sites.

Biologic therapies have been licensed to treat rheumatic diseases for more than a decade. In parallel, they have gained acceptance in a variety of non-rheumatic diseases, where their impact has been no less revolutionary. In this Review, we examine the application of biologics in a number of non-rheumatic autoimmune and inflammatory disorders-psoriasis, inflammatory bowel disease, uveitis, asthma, diabetes, congestive cardiac failure and multiple sclerosis. In particular, we have sought information, or lessons, that could influence their application in rheumatic diseases. For example, we highlight the potential to stratify asthma into groups that might require different targeted approaches, and focus on some of the less common adverse events associated with biologic therapies in multiple sclerosis. Similarly, we examine type 1 diabetes mellitus in the context of potential therapeutic induction of immune tolerance. Working collaboratively, across specialties, there is significant synergy to be gained in regard to understanding how biologic therapies work, how best to use them, and the adverse effects we should be conscious of.

Background: Increased oxidative stress may play a role in morbidity and mortality of patients with renal failure. Most studies have examined serum markers of oxidation, but it is unclear whether oxidative stress is involved in skeletal muscle atrophy., Methods: This study examined markers of oxidative stress in the skeletal muscle of 10 haemodialysed patients and 10 control subjects. Biopsies from the quadriceps femoris were analysed for reduced and oxidized glutathione, protein thiols, malonaldehyde and heat shock proteins (HSP27, HSP60 and HSP70), superoxide dismutase and catalase activities. A novel microdialysis procedure was used to examine hydroxyl radical activity in the interstitial fluid of the tibialis anterior., Results: Patients had muscle atrophy with a reduced diameter of both type I and II fibres (by 15 and 20%, respectively). Muscle microdialysates contained 2,3- and 2,5-dihydroxybenzoates formed from salicylate indicating hydroxyl radical activity, with no differences between patients and control subjects. Muscle protein thiol and oxidized glutathione contents were unchanged in patients, but malonaldehyde content was reduced. In contrast, total muscle glutathione and heat shock protein contents were increased. Muscle superoxide dismutase activity was unchanged, but catalase activity was reduced in patients., Conclusions: The muscle of patients undergoing haemodialysis undergoes some adaptive responses in total glutathione content, heat shock protein content and catalase activity that are potentially related to chronic oxidative stress. However, there is no evidence of gross oxidation, nor any clear relationship between oxidative stress and muscle fibre atrophy, arguing against a direct role of oxidants in the degenerative processes.

Background: Muscle dysfunction, which contributes to morbidity in patients on haemodialysis, has several manifestations and a number of possible causes. We applied the non-invasive techniques of (31)P-magnetic resonance spectroscopy ((31)P-MRS), magnetic resonance imaging (MRI) and near-infrared spectroscopy (NIRS) to calf muscle of dialysed patients to define the abnormalities in muscle cross-sectional area (CSA), contractile efficiency, mitochondrial function and vascular O(2) supply., Methods: We performed (31)P-MRS/NIRS/MRI studies on the lateral gastrocnemius during isometric plantarflexion and recovery in 23 male patients on haemodialysis (age 24-71 years; haemoglobin 9.9-14.2 g/dl; bicarbonate 17-30 mmol/l; urea reduction ratio 53-77%; parathyroid hormone 1-95 U/l) and 15 male controls (age 29-71 years). To understand the relationships between calf CSA and body mass we also performed MRI only in a further six male patients and 18 male controls., Results: In patients, exercise duration was 30+/-11% lower than in controls. Muscle CSA was lower by 26+/-5%, but contractile efficiency (force/CSA/ATP turnover) was normal. Slowing of post-exercise phosphocreatine (PCr) recovery implied a 22+/-5% defect in effective 'mitochondrial capacity'. That PCr recovery was slow relative to NIRS recovery suggests that this is largely an intrinsic mitochondrial problem (not the result of impaired O(2) supply), one which, furthermore, correlated with CSA. Urea reduction ratio showed a negative correlation with body mass and CSA, but none with PCr rate constant., Conclusions: The relationships to urea reduction ratio reflect the effect of muscle mass on dialysis efficiency, rather than direct effects on muscle CSA or metabolism. The relationship between PCr recovery and calf CSA suggests a role for the mitochondrial defect, whatever its cause, in the development of muscle wasting, although a common cause (e.g. physical inactivity) for both abnormalities cannot be ruled out.

Aims: To determine the prevalence of proteinuira and enzymuria among a cohort of subjects exposed to hexachlorobutadiene (HCBD) in their homes and to determine whether there was a change in observed effects when exposure ceased., Methods: Residents underwent a health check, which included a panel of urinary markers of both glomerular and tubular origin, within two months of cessation of long term exposure to HCBD and again at least 10 months after exposure ceased. Analysis of the results was performed to determine if there was any early evidence of renal effects, and to ascertain whether changes in these parameters occurred after exposure to HCBD ceased., Results: Tubular proteinuria and enzymuria were increased in the initial health check and significantly decreased after the residents had left their homes for about 10 months. As the early renal tubular markers improved when exposure ceased it is anticipated that the long term nephrotoxic risk will be minimal, but the carcinogenic risk remains unknown., Conclusions: Results show there was a renal effect which improved when subjects left their homes. This suggests there was a local environmental factor responsible for the observations. This is consistent with the predicted toxicological effects of HCBD from animal studies.

The link between increased QT dispersion and cardiac death in subjects with diabetes and arterial disease is well recognised. Corrected QT dispersion was studied in subjects with end stage renal failure on haemodialysis. Thirty one stable, chronic subjects on haemodialysis had 12-lead electrocardiograms (ECGs) taken before and after a single haemodialysis session. The QT interval was measured manually in each and the corrected QT and corrected QT dispersion calculated. Serum concentrations of potassium, calcium, and magnesium were measured at the same time as ECG acquisition. Corrected QT dispersion increased from a mean (SEM) 90.6 (5.8) to 117.7 (10.2) ms (p=0.002). Serum potassium and magnesium decreased from 5.0 (0.14) to 3.5 (0.09) mmol/l and 0.95 (0.04) to 0.89 (0.09) mmol/l respectively, while serum calcium increased from 2.56 (0.04) to 2.77 (0.04) mmol/l. Intradialytic weight fell by a mean of 2.1 kg. There was no significant correlation between the change in QTc dispersion and the changes in measured serum anions or the subjects' weight during dialysis. Corrected QT dispersion was higher in subjects on haemodialysis than previously suggested normal values, and was significantly increased by haemodialysis. This reflects increased inhomogeneous ventricular repolarisation, which may lead to an increased risk of arrhythmias and sudden death. Studies looking at QT dispersion in subjects on dialysis should standardise the timing of ECG recordings taken with respect to dialysis.

The case report in this review illustrates an acute myocardial infarction in a young adult probably due to arterial thrombosis that can be attributed to a hypercoagulable state resulting from the nephrotic syndrome. Although rare, acute myocardial infarction should be considered in young adults presenting with chest pain. A detailed clinical history may help to identify the aetiology, and guide subsequent management, but diagnostic coronary angiography is essential. Careful risk factor modification and treatment of the underlying cause should reduce the incidence of recurrent cardiac events.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed therapies for acute and chronic pain in the elderly. NSAIDs are effective in treating many disorders, but their use often is limited by toxicities, especially gastrointestinal and renal toxicity. COX-2 inhibitors are a major therapeutic advance, providing the analgesic and anti-inflammatory activity of NSAIDs, with a significant improvement in gastrointestinal safety. These new agents may be ideal therapies for older patients at risk for NSAID-related gastrointestinal toxicity.

Aims: To ascertain the incidence of hyponatraemia, and the impact of an icodextrin-based dialysis solution regime on hyponatraemia, in diabetic and non-diabetic patients using peritoneal dialysis (PD)., Methods: Following severe hyponatraemia, resulting in neurological sequelae, in two diabetic patients who were on icodextrin-based PD for established renal failure, we reviewed the results of all our PD patients. Data was gathered retrospectively, from our database and case notes, on plasma sodium, haematocrit, dry weight estimation, plasma albumin and residual renal function. Patients using icodextrin-based solutions were compared with a random selection of patients using dextrose-based peritoneal solutions. We also compared diabetic patients on and off icodextrin with their non-diabetic counterparts using the same dialysis regime. The data were analysed using the paired Student's t-test., Results: Plasma sodium was significantly lower in all patients using icodextrin-based solutions compared with those patients on dextrose-based PD. Plasma sodium was also found to fall in all patients following the initiation of an icodextrin-based PD regime. The fall in plasma sodium was statistically significant in diabetic and non-diabetic patients, but only fell below the laboratory reference range in the diabetic patients., Conclusions: Icodextrin-based PD is a risk factor for hyponatraemia and may produce clinically relevant symptoms if, as in our two cases, the hyponatraemia is compounded by other factors.

The GRB10 gene encodes a growth suppressor and maps to human chromosome 7p11.2-p13. Maternal duplication (matdup) of this region has recently been associated with Silver-Russell syndrome (SRS), which is characterised by pre- and postnatal growth restriction, craniofacial dysmorphism and lateral asymmetry. Maternal uniparental disomy for chromosome 7 (mUPD7) occurs in approximately 7% of SRS patients. Exposure of a recessive allele due to isodisomy has been ruled out in five mUPD7 cases, suggesting genomic imprinting as the basis for disease. Assuming SRS patients with matdup of 7p11.2-p13 and mUPD7 share a common aetiology, this would implicate a maternally expressed gene from this interval, which is involved in growth inhibition. Murine Grb10 was identified as a maternally expressed gene by subtractive hybridisation using normal and androgenetic mouse embryos. Grb10 maps to the homologous region of proximal mouse chromosome 11, for which mUPD incurs reduced birthweight. A role for GRB10 in SRS was evaluated by determining its imprinting status in multiple human foetal tissues using expressed polymorphisms, and by screening the coding region for mutations in 18 classic non-mUPD7 SRS patients. Maternal repression of GRB10 was observed specifically in the developing central nervous system including brain and spinal cord, with biallelic expression in peripheral tissues. This is in contrast to mouse Grb10, and represents the first example of opposite imprinting in human and mouse homologues. While a role for GRB10 in mUPD7 SRS cases can not be ruled out on the basis of imprinting status, no mutations were identified in the patients screened.

Modulation of biotransformation by genetic traits may be important in determining environmentally-induced nephrotoxicity. We conducted a case-control study to investigate the role of occupational hydrocarbon exposure, along with polymorphisms of the genes coding for N-acetyltransferase 2 (NAT2) and glutathione S-transferase mu (GSTmu), in the development of idiopathic membranous glomerulonephritis (IMGN). Patients (n=36) with biopsy-proven IMGN were matched with healthy controls for age, gender, and geographical area. Lifetime hydrocarbon exposure was assessed by a validated questionnaire. The polymorphisms of the NAT2 and GSTmu genes (GSTM1) were defined by use of a polymerase chain reaction on white-cell DNA from peripheral blood. Exposure to hydrocarbons was significantly greater in patients with IMGN than in controls (mean+/-SEM hydrocarbon exposure score 11 003+/-2955.7 vs. 4352+/-1418, p<0.02). NAT2 acetylator status was identical in patients and controls with 23 (63.9%) fast and 13 (36.1%) slow acetylators in each group. GSTmu was present in 15 (41.7%) patients and 16 (44.4%) controls. While occupational exposure to hydrocarbons remains a likely factor in its pathogenesis, further work is required to identify the genetic polymorphisms that modulate the risk of IMGN.

Substance abuse has been increasing steadily in the UK and some other countries. Recent evidence suggests more than 40% of young people have tried illicit drugs at some time. There are numerous medical consequences to recreational drug use, and a physician should always consider substance abuse in any unexplained illness. The renal complications of drug abuse are also becoming more frequent, and may encompass a spectrum of glomerular, interstitial and vascular diseases. Although some substances are directly nephrotoxic, a number of other mechanisms are also involved. These effects are often chronic and irreversible, but occasionally acute with possible recovery. The rapid growth of illicit drug use is clearly a major public health problem. We review the commonly used substances of abuse and their associations with renal disease.

Women with functioning transplanted kidneys often become fertile again. Indeed, renal function, endocrine status and libido rapidly improve after renal transplantation, and 1:50 women of childbearing age become pregnant. However, there is concern regarding the haemodynamic changes of pregnancy, which could lead to a decline in graft function (temporary or permanent). We examined obstetric data and renal parameters in 29 patients and 33 pregnancies. Mean serum creatinine and creatinine clearance remained stable throughout pregnancy and 1 year postpartum. However, there was a significant increase in proteinuria from a mean of 0.45 g/24 h around the time of conception to 1.11 g/24 h at delivery (p<0.05). The proteinuria resolved to baseline levels at 3 months postpartum. We highlight certain parameters to be considered before conception to allow a good obstetric outcome and prolong stable renal function: serum creatinine <150 micromol/l, proteinuria <1 g/day, absence of histological evidence of chronic allograft rejection, controlled blood pressure (140/90) and stability of maintenance immunosuppression.

Evidence exists that in certain groups of workers exposed to volatile organic chemicals, there is subclinical renal damage and dysfunction. Also, there is activation of biological mechanisms that are suggested links between volatile organic chemical exposure and renal disease. Notably, the workers studied are employed in factories where exposures are considered controlled, with on-site professional health and safety management. Recent studies continue to indicate an increased risk of renal disease in those exposed to volatile organic chemicals.

Hydrocarbon exposure has been shown to play an important role in the development of renal dysfunction in several occupational settings. In this study, renal screening was performed in a group of paint sprayers with exposure to hydrocarbon-based paints, recruited from a car manufacturing plant where personal protective equipment was widely used. The hydrocarbon exposure scores and various markers of renal injury were compared between these subjects and a group of paint sprayers from a previous study who did not use personal protective equipment regularly. Cumulative hydrocarbon exposure scores were calculated from a validated questionnaire. Serum creatinine, urinary total protein, albumin, transferrin, retinol-binding protein, and N-acetylglucosaminidase were evaluated, Both groups experienced heavy hydrocarbon exposure but sprayers who regularly used personal protective equipment had significantly reduced exposure scores due to improved skin and respiratory protection. A significant number of sprayers from both groups had elevated levels of serum creatinine. Interestingly, urinary N-acetylglucosaminidase activity, a marker of proximal tubular damage, was abnormal in a significant proportion of sprayers in the unprotected group but normal in those with improved protection. Our results are in keeping with the hypothesis that hydrocarbon exposure through paint spraying may result in active proximal tubular damage which may be reduced by improvement of protection at the worksite. However, renal impairment independent of tubular injury may result from chronic paint exposure, even with improved protection.

We reported two cases of chronic bronchiectasis and rapidly progressive necrotizing glomerulonephritis/severe renal failure which were also positive for anti-myeloperoxidase antibody, and followed their treatment and outcome. Immunosuppressive therapy was complicated by superimposed chest infection in both cases. Nonetheless, cautious use of immunosuppressive and antibiotic therapy reversed dialysis-dependent renal failure in one of the two cases.

Hydrocarbon (HC) exposure can play a role in the development of chronic glomerulonephritis (GN). Interindividual variations in various metabolizing enzymes may influence HC biotransformation, and hence susceptibility to HC-associated GN. We evaluated the role of human genotypic polymorphism in HC-associated GN, in 41 patients (30 male, 11 female) with primary GN (17 diffuse mesangial proliferative GN, 12 focal segmental GN, 11 membranous GN, one membranoproliferative GN) and 60 (46 male, 14 female) healthy controls. Genotypic polymorphisms of (CYP) P450 2D6 (CYP2D6), glutathione S-transferases mu (GSTM1) and theta (GSTT1) and N-acetyltransferase (NAT-2) were determined using polymerase chain reaction analysis of white-blood-cell DNA. HC exposure scores were determined using a validated questionnaire, and were significantly elevated in GN patients compared to controls. While no significant differences in the various genotypic frequencies were observed in the GN group overall, compared to controls, there was a significant increase in GSTM1 null (n = 10) to GSTM1 wild type (n = 1), and NAT fast (n = 10) to slow (n = 1) acetylators, in the membranous GN group compared to controls (p < 0.05). These results suggest a possible role for GSTM1 null and NAT fast acetylator in the development of HC-associated membranous GN.

A patient probably acquired hepatitis B virus (HBV) from a transfused infected unit of fresh frozen plasma. She had been on regular haemodialysis for four months before her infection was discovered. One hundred and seventy-six patients and 304 staff contacts were screened and there were no secondary cases. At donation the infected blood donor was hepatitis B surface antigen (HBsAg) negative but subsequently proved to be anti-hepatitis B core (HBc)-positive and positive for HBV DNA. Consideration should be given to screening blood donations for anti-HBc in addition to HBsAg. Vigilance needs to be maintained on dialysis units against sporadic cases of hepatitis B. All staff should be immunized and be able to demonstrate protective levels of anti-HBs.

Objective: To provide quantitative estimates of exposure to benzene for cases and controls in an epidemiology study to investigate the risk of leukaemia in petroleum distribution workers., Methods: Work histories were obtained for cases and controls together with detailed information on the distribution sites. For each job in the work history, an estimate of exposure (parts per million (ppm)) was obtained by multiplying a measure derived from exposure data by modifying factors to reflect the differences between the conditions that existed at the time of measurement and those at the time of interest. The modifying factors used related to job activity, the number of road tankers loaded, the benzene content of the gasoline, the mixture of products handled, temperature, and loading technology. Cumulative exposures for each case and control were obtained by multiplying the exposure estimates for each job by the duration of time in the respective jobs, and summing these over all jobs in the work history. Peak exposure and exposure through dermal contact were quantitatively classified for each job., Results: Measured exposures were obtained for 30 job categories, and ranged from 0.003 to 8.20 ppm. 40% of work histories were assigned background exposures, with a further 34% assigned the exposure estimate for a driver carrying out top submerged loading of motor fuel into road tankers. Cumulative exposures ranged from < 1 to > 200 ppm-years, although 81% were < 5 ppm-years. Comparison of the exposure estimates for selected jobs with data from sources not used in the study showed similar results., Conclusion: The estimates of exposure to benzene in this study provide a sound basis for the epidemiological analyses.

Significant numbers of workers (14%) chronically exposed to volatile organic chemicals commonly found in spray paints had elevated levels of uncharacterized antibodies to collagen IV, a basement membrane protein. No increased frequency of subjects with positive results for anti-glomerular basement membrane antibodies (anti-GBM) was found in this group. These anti-GBM antibodies are directed against a specific epitope on the non-collagenous domain (NC1) of the α3 chain of collagen IV. Anti-GBM antibodies are diagnostic for Goodpasture's syndrome that has been reported to occur following acute inhalation of volatile substances. In another group of workers, exposed both dermally and by inhalation to petroleum-based oil mists, 5% had positive results for antiGBM antibodies. We conclude that the measurement of general, uncharacterized antibodies to collagen IV may be a useful indicator of basement membrane damage in workers occupationally exposed to volatile organic chemicals.

Background: Muscle weakness is a common but unexplained feature of dialysis patients. This study investigated the prevalence and causes of muscle weakness in dialysis patients by examining the quadriceps muscle force and contractile properties., Methods: The quadriceps femoris was studied in terms of force, force-frequency curve, and speed of muscle relaxation in 49 dialysis patients and 27 healthy subjects. In addition nutritional, haematological, biochemical, and histological assessments were performed, and steps of force generation were analysed to reach the possible mechanisms leading to the observed weakness., Results: Muscle weakness, though invariable as a symptom, was subtle or absent on clinical examination. Quadriceps force measurements, however, revealed unequivocal weakness in most of the patients (71%). The quadriceps muscle was weaker (317 +/- 115 versus 460 +/- 159 N, P < 0.01) compared to healthy individuals, but there was no evidence of impaired excitation-contraction coupling (0.79 +/- 0.05 versus 0.76 +/- 0.07, P = 0.1). Among dialysis patients the older and the malnourished (n = 23) were the weaker but there was no relationship to the type or duration of dialysis. The serum albumin was the only biochemical parameter related to the muscle force (r = 0.6, P = 0.01). The other most prominent abnormality of quadriceps muscle function observed in this study was slowing of relaxation (patients versus controls; 8.7 +/- 1.8% versus 10.8 +/- 1.1% force loss/10 ms, P < 0.0001) particularly in the malnourished group (malnourished versus well nourished; 8.3 +/- 2.1 versus 9.4 +/- 0.95, P = 0.03). Muscle histology was investigated (n = 12) and revealed that type II fibres were mildly atrophic in 40% of the biopsies in most areas, but predominantly type IIB. Although type IIB fibre areas are slightly smaller in the dialysis patients compared to the controls, this was not statistically significant (3025 +/- 578 versus 4406 +/- 1582, P = 0.1) except in the malnourished group compared to the well-nourished dialysis patients (2092 +/- 304 versus 4346 +/- 1496, P = 0.04), and in the malnourished dialysis patients type IIB fibre area was significantly correlated to the strength (r = 0.6, P = 0.02)., Conclusions: The only significant predictor of loss of muscle strength and abnormality of relaxation in this study was the nutritional state. A regular assessment of the nutritional state is required to ensure adequate nutrition to prevent the observed abnormalities of the skeletal muscles.

We report the case of a 49-year-old female with severe Goodpasture's syndrome, staghorn calculus, and subacute thyroiditis. Despite the use of a combined therapy with corticosteroid, cyclophosphamide, azathioprine and plasma exchange, we were unable to suppress the disease activity or normalize the anti-glomerular basement membrane (GBM) antibody levels. Disease remission with a parallel reduction in anti-GBM antibody titer was only achieved after sequential bilateral nephrectomy.

Soluble endothelial leucocyte adhesion molecule-1 (ELAM-1) has been shown to act as a neutrophil chemoattractant and may also represent a specific marker of endothelial cell damage or activation. Nine patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis (p-ANCA: n = 4, c-ANCA: n = 5) were prospectively monitored for disease activity by serial serum ELAM-1, C-reactive proteins (CRPs), von Willebrand factor (vWF) and ANCA levels. Six patients presented acutely with biopsy-proven renal vasculitis. One patient on dialysis, one in remission with stable renal function and one renal transplant patient developed clinical and serological relapse. Seven patients had abnormally high ELAM-1 (>60 ng/ml) levels at presentation. These fell within normal limits a week following pulse methyl prednisolone therapy. This preceded a fall in CRP, vWF and subsequent clinical remission. p-ANCA serology remained positive in 3 cases. One patient relapsed with rising ELAM-1 levels. Two patients developed erroneously positive ANCA serology but serum ELAM-1 remained normal. Six patients with chronic renal impairment of non-vasculitic origin who presented acutely with septicaemia had normal serum ELAM-1 levels (mean +/- SD: 31 +/- 10 ng/ml) at presentation and during the subsequent clinical course. These preliminary findings are encouraging, especially when ELAM-1 is combined with ANCA monitoring in vasculitis. However, further data from larger controlled studies are needed to validate the utility of ELAM-1 in the monitoring of patients with vasculitis.