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IntroductionWith the pressing need to develop treatments that slow or stop the progression of Alzheimers disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease. Methods and AnalysisThe New Therapeutics in Alzheimers disease study (NTAD) aims to identify a biomarker set from magneto/electro-encephalographic that is sensitive to disease and progression over one year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimers disease and 30 healthy controls aged between 50 and 85 years. Repeat measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and magnetic resonance imaging) of participants with Alzheimers disease or mild cognitive impairment will be taken at baseline and at one year. To assess reliability of magneto/electro-encephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimers disease will undergo repeat magneto/electro-encephalographic two weeks after baseline. Clinical and cognitive assessment will be repeated at 2 years. Linear mixed models of baseline and longitudinal change in neurophysiology are the primary analyses of interest, supported by Bayesian inference. Additional outputs will include relative effect sizes for physiological markers, atrophy and cognitive change and the respective numbers needed to treat each arm of simulated clinical trials of a future disease modifying therapy. Ethics and disseminationThe study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group. STRENGTHS AND LIMITATIONS OF THIS STUDYO_ST_ABSStrengthsC_ST_ABSO_LINTAD is a longitudinal, multicentre study of magneto/electro-encephalographic measures of Alzheimers disease progression C_LIO_LINTAD assesses the test-retest reliability of magneto/electro-encephalographic parameters C_LIO_LIAll participants with early-stage Alzheimers disease or mild cognitive impairment will be amyloid-positive C_LI LimitationsO_LIAttrition during follow up may limit inferences C_LIO_LIRecruitment is from volunteer panels and clinical services that may not reflect national diversity of people affected by Alzheimers disease C_LI

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

Objective To report the effect of bevacizumab versus dexamethasone on hard exudates (HEX) in diabetic macular oedema (DME). Design Post hoc analysis of 24-month data from the Randomised clinical trial of BEVacizumab OR DEXamethasone for diabetic macular oedema (BEVORDEX) phase 2 multicentre randomised clinical trial. Eyes with centre-involving DME resistant to or unlikely to benefit from macular laser therapy were included. Eyes were randomly assigned to bevacizumab every 4 weeks or Ozurdex dexamethasone implant (DEX) every 16 weeks, both as required. The 68 eyes from 48 patients that completed 24-month follow-up were analysed. Two masked graders assessed extent and location of HEX on baseline, 12-month and 24-month foveal-centred colour fundus photographs using validated grading software. Results Macular HEX was present in 60% of study eyes. Of these, 21 eyes were treated with DEX and 20 eyes with bevacizumab. Both treatments led to reduction in area of macular HEX at 12 months and 24 months. There was greater regression of HEX from the foveal centre in DEX-treated eyes (median change +890 µm, IQR=1040 µm) than bevacizumab-treated eyes (median change +7.0 µm, IQR=590 µm) at 12 months (p=0.04) but the difference was no longer statistically significant (p=0.10) by 24 months (DEX +1400 µm, IQR=1590 µm; bevacizumab +20 µm, IQR=2680 µm). Reassuringly, no study eye developed HEX at the foveal centre, a visually devastating consequence of diabetic maculopathy. Conclusions Bevacizumab and DEX were effective in reducing area of HEX in eyes with DME. DEX provided more rapid regression of HEX from the foveal centre although bevacizumab-treated eyes started to catch up by 24 months. Distance from the foveal centre as well as total area of macular HEX should be assessed when evaluating treatments for foveal-threatening HEX. Trial registration number NCT01298076; Post-results.

Objective To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME). Design Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076). Participants We enrolled 88 eyes of 61 patients with center-involving DME. Methods Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation. Main Outcome Measures The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire. Results Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant–treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 μm for bevacizumab eyes and by 187 μm for dexamethasone implant eyes ( P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups. Conclusions Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant–treated eyes lost vision, mainly because of cataract.

Background Diabetic macular oedema (DMO) is the commonest cause of vision loss in people with diabetes. Laser photocoagulation can be effective in the treatment of DMO; however, its mechanism of action is still poorly understood. A better understanding of these mechanisms may allow the development of therapeutic approaches that could avoid the deleterious adverse events associated with photocoagulation. Methods We have used proteomic techniques to identify the protein changes induced by threshold intensity retinal laser treatment in a rodent model of diabetic retinopathy. Retinae were obtained from diabetic Dark Agouti rats 8 weeks following laser treatment. Extracted proteins from lasered and non-lasered diabetic retinae were separated and compared using two-dimensional gel electrophoresis. Results Image analysis revealed 24 protein spots with decreased expression after laser treatment and 9 spots with increased expression. On lasered retinal gels, four spots were uniquely expressed, with eight unique spots on non-lasered gels. Twenty-two protein spots of interest were identified using matrix-assisted desorption ionization-mass spectrometry with database matching. Following laser, Wnt-5 beta, LEK-1, GADPH, claudin-12 and calretinin were significantly down-regulated in expression. Conclusions The present study provides a proteomic insight into the underlying biological basis for the therapeutic effects of laser for DMO. We provide further evidence of the involvement of Wnt pathway signalling in the neural retina in DMO, and for up to 2 months following laser treatment. Changes in LEK-1 and claudin-12 may have effector roles, and changes in glyceraldehyde-3-phosphate dehydrogenase and calretinin may reflect the altered retinal microenvironment resulting from laser treatment.

Most acute cases of central serous chorioretinopathy resolve spontaneously with minimal visual impairment. The small percentage of eyes developing chronic or recurrent disease that do warrant treatment is often difficult to control. Emergent investigations and treatments have added to the established options available to manage these cases. Optical coherence tomography has proved valuable for both imaging subtle fundoscopic findings and monitoring disease progression. Fluorescein angiography aids identification of pigment epithelial leaks and targets the use of argon laser treatment if outside the fovea. Fluorescein angiography also assists differentiation from other choroidal pathologies such as choroidal neovascularization and polypoidal choroidal vasculopathy. Where the diagnosis is uncertain, indocyanine green angiography can demonstrate classic midphase hyperpermeability. This is also useful to guide the application of photodynamic therapy. Newer treatments such as intravitreal anti-vascular endothelial growth factor are as yet unproven.

Central serous chorioretinopathy (CSCR) is a common retinal cause of vision loss. This review surveys the epidemiology, risk factors, clinical presentation, natural history and pathophysiology of CSCR. Studies suggest an annual incidence rate of 10 per 100 000 in men, with CSCR occurring six times more commonly in men compared with women. Most acute CSCR cases resolve spontaneously within 2-3 months. Prognosis is highly dependent on presenting visual acuity; patients with initial visual acuities of 6/6 remain at that level, while patients with initial visual acuities of less than 6/9 recover on average two to three Snellen lines over the next few years. The main risk factors for CSCR are systemic corticosteroid use, type A personality, pregnancy and endogenous Cushing's syndrome. The pathophysiology of CSCR remains obscure, although disorders in both the choroidal circulation and retinal pigment epithelium are implicated.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Diabetes is an increasingly common condition and hence, managing dying patients with diabetes as a co-morbidity will become a frequent challenge. It is uncertain whether there is net beneficence in preventing hyperglycaemia in diabetic patients during the terminal phase or whether the distress involved in administering therapy and blood glucose monitoring may outweigh this ordeal. Since there is no available evidence upon which to base clinical decisions, a semi-structured questionnaire based around three clinical vignettes was sent to consultants in diabetes and palliative care in the UK. There was consensus of opinion from both groups of consultants that treatment and monitoring should be stopped in patients with type 2 diabetes, once in the terminal phase. There was less consensus regarding management of type 1 diabetes. Practical issues were raised by both groups of consultants and clinical guidelines are suggested.

Antibodies reactive with peptide epitopes on the core protein of MUC1 epithelial mucin have been demonstrated in some patients with adenocarcinomas. Because these epitopes can be exposed on MUC1 in the serum of healthy women, we measured concentrations of MUC1-reactive antibodies in the serum of healthy pregnant and non-pregnant women, and in patients with benign and malignant ovarian tumours. Antibodies were measured in an enzyme-linked immunosorbent assay utilising a synthetic peptide corresponding to a 105-amino-acid segment of the MUC1 tandem repeat region (5.25 repeats). MUC1-reactive antibodies were always of an IgM isotype and concentrations were highest in young healthy women and declined progressively with age (P = 0.0006) concomitantly with increasing serum MUC1 levels (P = 0.003). Regardless of age, antibody levels were lower in cancer patients than in healthy women (P

Amiodarone is used to treat life-threatening cardiac arrhythmias. Amiodarone-induced pulmonary toxicity (APT) can be difficult to diagnose. APT may result in increased mucus production and mucin expression. Thus, serum mucin-1 was evaluated as a marker for amiodarone-induced pulmonary toxicity. Concentrations of mucin-1 in peripheral blood were determined using cancer-associated serum antigen (CASA) assay in patients taking amiodarone. Eight of ten patients who developed major amiodarone toxicity had high serum CASA levels. Patients with toxicity had a significantly higher mean rank CASA concentration compared with those without major toxicity. CASA shows potential as a marker for amiodarone-induced toxicity, particularly pulmonary toxicity.

The Prostate-Specific Antigen (PSA) and the Cancer-Associated Serum Antigen (CASA) assay for the MUC1 mucin were compared in the serum of 303 patients with malignant or benign prostatic disease. Using cutpoints of 4, 10, and 20 mu g/l, PSA was elevated in 93%, 81%, and 64% of patients with prostate cancer (n = 113), with corresponding specificities of 55%, 84%, and 96% in benign prostate disease (prostatic hyperplasia or prostatitis, n = 190). Using the recommended cutpoint of 4 Units/ml, CASA was elevated in 38% of patients with prostate cancer, with a specificity of 91% in benign disease. PSA and CASA showed a poor correlation in prostate cancer (r = 0.367) and benign disease (r = 0.158), and CASA was elevated in some PSA negative samples. Used together; PSA greater than or equal to 20 mu g/l and CASA greater than or equal to 4 kU/l gave perfect specificity in benign disease, with a corresponding sensitivity of 29% (positive and negative predictive values of 100% and 70%, respectively). However, this combination gave no improvement over the use of PSA alone, with sensitivity 47% when the cutpoint was raised to give perfect specificity. These data suggest that CASA is of little use as an adjunct to PSA in the differentiation of benign and malignant prostate disease.

Tropical spastic paraparesis (TSP) is a retroviral disease characterized predominantly by a chronic myelopathy and progressive leg weakness. Four patients from the northern coast of Colombia with chronic spastic paraparesis and serum positivity for antibodies to human T cell lymphotropic virus type 1 by enzyme-linked immunosorbent assay and Western blot are reported. All patients had mixed ethnic origins (white, black, and amerindian). This is the first report of TSP on the Caribbean coast of Colombia. This study extends the geographic boundaries of TSP in the Caribbean basin.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Many extrahepatic manifestations of hepatitis C have been described, including renal disease and vasculitis. We describe the novel finding of intimal hyperplasia associated with severe ischaemic events in two patients with hepatitis C. The combination of genotype 1a hepatitis C virus, rapidly progressive mesangiocapillary glomerulonephritis and intimal hyperplasia with ischaemic sequelae, may represent a new syndrome.

Background Gene delivery is a rapidly expanding field with potential applications to every human organ system. Recently, adenoviruses have been used as efficient vectors for in vivo gene transfer into the myocardium. These methods, however, have shown a sharp decline of gene expression after 1 week. To test the hypothesis that an immune-effector mechanism is involved in this decline, we compared the results after injection of adenovirus-5 carrying the β-galactosidase gene (Adβ-gal) into the left ventricular myocardium of athymic nude rats (NDRs) versus immunocompetent Sprague-Dawley rats (SDRs). Methods and Results Adβ-gal (5.0×10 9 PFU/mL) was injected into the left ventricle of NDRs (n=16) and SDRs (n=22). Hearts were harvested, embedded in paraffin, and sectioned and stained for β-gal activity, hematoxylin and eosin and picrosirius red at 4, 21, 35, 85, and 120 days. Representative samples were immunostained with antibodies directed at inflammatory markers. β-gal activity was quantified by digital planimetry and expressed as area of staining (%±SEM). Peak β-gal activity was highest at 4 days, with NDRs displaying significantly greater staining (83±3.0% versus 54±8.0%; P =.03). SDRs sustained a rapid drop in activity, such that at 35 (1±0.19%) and 85 (1±0.4%) days, only occasional cells stained positive and by 120 days (0.3±0.0%), activity had been extinguished. NDRs continued to show transgene expression at all time periods (35 and 85 days, 25±7.1% and 7.4±2.7%, respectively) and was still readily detected at 120 days. An inflammatory response was limited in NDRs compared with SDRs, in which there was intense mononuclear cell infiltration, with collagen deposition and scar formation. Immunostaining identified the majority of these inflammatory cells as not being of lymphocyte lineage, although small numbers of lymphocytes and phagocytic and activated plasma cells were identified. Conclusions Our data suggest that immune-effector mechanisms can severely affect the expression of genes delivered by adenovirus. The present model provides efficient gene expression for at least 120 days without significant inflammatory reaction.

This is the first comparison of the three mucin based tests CA15-3, CASA, and MSA, and the cytokeratin-related TPS assay in breast cancer. The mucin markers were superior to TPS in receiver-operator analysis, though no marker was of use in the diagnosis of malignancy due to low sensitivity. Using cutpoints that gave 95% specificity in benign disease (n = 83), corresponding sensitivities in pre-treatment breast cancer (n = 123: 13 in situ, 54 stage I, 45 stage II, 4 stage III, 7 stage IV) were 17% (CA15-3), 16% (CASA), 13% (MSA), and 8% (TPS), with a strong relationship between marker levels and disease stage. These assays did not always detect the same patients, and the use of CA15-3 combined with CASA gave the highest sensitivity (23%), though this was not significantly better than the use of CA15-3 alone. Despite detecting similar antigens, these assays can show markedly different responses in some patients, indicating that one mucin-based test cannot be substituted for another.

The serum markers CA125, CASA and TPS were compared, with particular reference to the clinical applications of these tumor markers in the management of patients with ovarian cancer (discrimination of benign and malignant disease; indicating prognosis; predicting preclinical recurrence). (i) Using recommended cut-off points, CASA (greater than or equal to 4 U ml(-1)) and TPS (greater than or equal to 80 U l(-1))showed similar sensitivities in ovarian carcinoma (56% and 57% respectively), though these were lower than with CA125 (85% greater than or equal to 35U m l(-1)). The combined use of CA125 with either CASA or TPS at higher cut-off points excluding benign disease (CA125 >345 U ml(-1); CASA >6 U ml(-1); TPS>359 Ul(-1)) improved the discrimination of ovarian cancer from benign adnexal masses (100% positive predictive value with 65% of ovarian cancers detected with CA125-CASA, 61% with CA125-TPS vs 46% with CA125 alone). The combined preoperative use of these markers may therefore assist the general gynecologist in avoiding potentially difficult oncologic surgery. (ii) TPS was the best preoperative indicator of prognosis, possibly due to its association with cell proliferation, while CASA was superior as a postoperative prechemotherapeutic prognostic indicator, possibly due to it being a more accurate indicator of residual disease than the other markers, or the surgeons' assessment. Similarly, CASA gave the best differentiation of patients with minimal residual disease (

The serum MUC1 markers CASA and CA 15-3 were compared with CA 125 in the serum of patients with ovarian cancer and in pregnant women. Used individually, CASA and CA 15-3 gave sensitivities of 54 and 56% in pre-operative ovarian carcinoma (n = 50), though these were lower than with CA 125 (84%). CASA levels were elevated in 3 women with a negative CA 125, while CA 15-3 was elevated in 2 of these women. The combined use of CA 125 with CASA or CA 15-3 led to the preclinical detection of recurrence in 4/5 patients, with mean lead times of 3.6 and 4.3 months, respectively. Of particular interest was the marked difference in reactivity observed with CASA and CA 15-3 in some patients, despite both assays utilising monoclonal antibodies (MAbs) that react with the MUC1 mucin. CA 15-3 and CASA showed a lower than expected correlation in patients with ovarian cancer (r = 0.70), with some patients having high concentrations of one mucin marker and low concentrations of another. Furthermore, different marker profiles were observed when monitoring the progress of patients with these markers. Marked differences between CA 15-3 and CASA were also observed in the serum of pregnant women (n = 10), where CASA showed marked elevation (mean 33.6 times cutpoint) and CA 15-3 did not (mean 0.88 times cutpoint). These data suggest that the specificities of the MAbs used in these assays affect the glycoform of MUC1 detected, and that it should not be assumed that all MUC1 assays will behave in the same manner.

This paper argues that the viable systems model can be used by managers to understand and control their organizations.

In December 1993 the NSW Health Department was notified that two patients had presented with acute hepatitis C five and seven weeks after undergoing minor surgical procedures in the same operating session at a Sydney private hospital early that year. Neither case had other risk factors for acute hepatitis C.

Sera from 86 well controlled diabetics were examined for the presence of immune complexes. Thirty-six patients were receiving standard insulins, 19 monocomponent preparations, 24 oral hypoglycaemic agents and seven dietary restriction alone. Three methods were used to detect complexes: measurement of complement components, a Clq binding assay (BA) and the Raji cell radioimmunoassay (RIA). Complement components were normal in all patients. Eleven (31%) of the group on standard insulins had a positive Raji cell RIA; none had an abnormal Clq-BA. One patient on monocomponent therapy had a mildly positive Raji cell RIA; Clq-BA was negative in each patient of this group. Thirteen (54%) of the patients on oral hypoglycaemic agents were positive on one or both assays while one patient on diet alone was abnormal on both assays. These data show that immune complex production is common in both insulin-requiring and non-insulin-requiring diabetics and that this phenomenon is strikingly less frequent in patients on monocomponent insulins. Such observations could bear relevance to the pathogenesis of microvascular complications in diabetes.

The MUC1 epithelial mucin is a transmembrane glycoprotein that is frequently but variably over-expressed by adenocarcinomas. It is used as a diagnostic serum tumour marker and is a candidate target for tumour immunotherapy. Peritoneal fluid (PF) samples from ovarian cancer patients were investigated for their ability to modulate MUC1 expression in 6 ovarian cancer cell lines which showed a range from very low to high endogenous MUC1 expression. Cell lines were cultured in 20% PF for 4 days, fixed in situ and MUC1 assayed by ELISA. MUC1 expression was stimulated by some PF samples in 5 of 6 lines tested. MUC1 expression in the PE04 cell line (very low endogenous expression) was increased by 35 of 36 PFs tested (p < 0.05); stimulation varied between PFs but was greater than with 100 IU/mL hu-r-gamma-interferon. Western blotting confirmed the stimulation of MUC1 in PE04 cells and FACS showed an increase in the proportion of cells expressing MUC1. The active factor was partially purified by gel filtration and was shown to stimulate PE04 cells in a dose-dependent manner. Concentrations of IL1beta, IL4, IL6, IL8, IL10, TNF-alpha, TGF-beta and GM-CSF were often very high in PF and varied substantially between different PF samples but did not correlate with the degree of MUC1 stimulatory activity.