Douglas Wilson

A multicentre study into the reliability of steroid receptor immunocytochemical assay quantification

Qualitative and semiquantitative assessments of oestrogen receptor and progesterone receptor positivity determined on previously immunocytochemically stained slides were performed by eight independent assessors. Concordance between assessments of steroid receptor status was good (24/25, 96%). Interassessor variations in estimates of positive immunostaining levels were high, varying by between 10 and 75% for individual slides. In 2 cases estimates for the same section ranged between 15% nuclei positive and 90% nuclei positive. Wide variations were also recorded for slides stained for progesterone receptors. Results using an assessment procedure combining staining intensity and percentage positivity estimates were also subject to marked discordance. A computerised image analysis system, also used to assess slides gave results similar to the mean manually determined percentage positivity values. It is suggested that quality control of steroid receptor immunocytochemical quantification be considered and that automated image analysis may represent an accurate and valid means of achieving this.

Renal failure in lithium-treated bipolar disorder: a retrospective cohort study.

Objective Lithium users are offered routine renal monitoring but few studies have quantified the risk to renal health. The aim of this study was to assess the association between use of lithium carbonate and incidence of renal failure in patients with bipolar disorder. Methods This was a retrospective cohort study using the General Practice Research Database (GPRD) and a nested validation study of lithium exposure and renal failure. A cohort of 6360 participants aged over 18 years had a first recorded diagnosis of bipolar disorder between January 1, 1990 and December 31, 2007. Data were examined from electronic primary care records from 418 general practices across the UK. The primary outcome was the hazard ratio for renal failure in participants exposed to lithium carbonate as compared with non-users of lithium, adjusting for age, gender, co-morbidities, and poly-pharmacy. Results Ever use of lithium was associated with a hazard ratio for renal failure of 2.5 (95% confidence interval 1.6 to 4.0) adjusted for known renal risk factors. Absolute risk was age dependent, with patients of 50 years or older at particular risk of renal failure: Number Needed to Harm (NNH) was 44 (21 to 150). Conclusions Lithium is associated with an increased risk of renal failure, particularly among the older age group. The absolute risk of renal failure associated with lithium use remains small.

Food Antioxidants and Their Anti-Inflammatory Properties: A Potential Role in Cardiovascular Diseases and Cancer Prevention

Mediterranean-style diets caused a significant decline in cardiovascular diseases (CVDs) in early landmark studies. The effect of a traditional Mediterranean diet on lipoprotein oxidation showed that there was a significant reduction in oxidative stress in the intervention group (Mediterranean diet + Virgin Olive Oil) compared to the low-fat diet group. Conversely, the increase in oxidative stress causing inflammation is a unifying hypothesis for predisposing people to atherosclerosis, carcinogenesis, and osteoporosis. The impact of antioxidants and anti-inflammatory agents on cancer and cardiovascular disease, and the interventive mechanisms for the inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis were explored. Following the Great Oxygen Event some 2.3 billion years ago, organisms have needed antioxidants to survive. Natural products in food preservatives are preferable to synthetic compounds due to their lower volatility and stability and generally higher antioxidant potential. Free radicals, reactive oxygen species, antioxidants, pro-oxidants and inflammation are described with examples of free radical damage based on the hydroxyl, nitric oxide and superoxide radicals. Flavonoid antioxidants with 2- or 3-phenylchroman structures such as quercetin, kaempferol, myricetin, apigenin, and luteolin, constituents of fruits, vegetables, tea, and wine, which may reduce coronary disease and cancer, are described. The protective effect of flavonoids on the DNA damage caused by hydroxyl radicals through chelation is an important mechanism, though the converse may be possible, e.g., quercetin. The antioxidant properties of carotenoids, which are dietary natural pigments, have been studied in relation to breast cancer risk and an inverse association was found with plasma concentrations: higher levels mean lower risk. The manipulation of primary and secondary human metabolomes derived especially from existing or transformed gut microbiota was explored as a possible alternative to single-agent dietary interventions for cancer and cardiovascular disease. Sustained oxidative stress leading to inflammation and thence to possibly to cancer and cardiovascular disease is described for spices and herbs, using curcumin as an example of an intervention, based on activation of transcription factors which suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

Utility of Biomarkers in the Differential Diagnosis of Heart Failure in Older People: Findings from the Heart Failure in Care Homes (HFinCH) Diagnostic Accuracy Study

Background The performance of biomarkers for heart failure (HF) in older residents in long-term care is poorly understood and has not differentiated between left ventricular systolic dysfunction (LVSD) and HF with preserved ejection fraction (HFpEF). Methods This is the first diagnostic accuracy study in this population to assess the differential diagnostic performance and acceptability of a range of biomarkers against a clinical diagnosis using portable echocardiography. A total of 405 residents, aged 65–100 years (mean 84.2), in 33 UK long-term care facilities were enrolled between April 2009 and June 2010. Results For undifferentiated HF, BNP or NT-proBNP were adequate rule-out tests but would miss one in three cases (BNP: sensitivity 67%, NPV 86%, cut-off 115 pg/ml; NT-proBNP: sensitivity 62%, NPV 87%, cut-off 760 pg/ml). Using higher test cut-offs, both biomarkers were more adequate tests of LVSD, but would still miss one in four cases (BNP: sensitivity 76%, NPV 97%, cut-off 145 pg/ml; NT-proBNP: sensitivity 73%, NPV 97%, cut-off 1000 pg/ml). At these thresholds one third of subjects would test positive and require an echocardiogram. Applying a stricter ‘rule out’ threshold (sensitivity 90%), only one in 10 cases would be missed, but two thirds of subjects would require further investigation. Biomarkers were less useful for HFpEF (BNP: sensitivity 63%, specificity 61%, cut-off 110 pg/ml; NT-proBNP: sensitivity 68%, specificity 56%, cut-off 477 pg/ml). Novel biomarkers (Copeptin, MR-proADM, and MR-proANP) and common signs and symptoms had little diagnostic utility. Conclusions No test, individually or in combination, adequately balanced case finding and rule-out for heart failure in this population; currently, in-situ echocardiography provides the only adequate diagnostic assessment. Trial Registration Controlled-Trials.com ISRCTN19781227

Carcinoembryonic antigen (CEA) in patients with breast cancer

Abstract Plasma CEA concentrations were measured in normal women and in patients with both primary and advanced breast carcinoma by means of a radioimmunoassay utilising rabbit anti-CEA antiserum. Fifty-five per cent of women with primary breast cancer had detectable levels of CEA (> 0.1 U/ml), as compared to 13% in a random selection of the female population. The incidence of detectable CEA levels in benign conditions of the breast was less than 10% , but the largest incidence of detectable levels of CEA (70%) was in the group of patients with advanced breast carcinoma. In patients with primary cancer, no correlation was observed between the plasma CEA levels and either the presence of oestradiol- 17 β receptor proteins in the tumours or the menstrual status of the patient. The effect of anti-oestrogen therapy on plasma CEA concentration in patients with advanced breast cancer was studied. A greater proportion of patients classified as clinical non-responders showed increased plasma CEA concentrations and fewer showed decreased CEA levels than in the case of the patients who responded to treatment.

Evaluation of luteal-phase salivary progesterone levels in women with benign breast disease or primary breast cancer.

Salivary progesterone concentrations were determined in premenopausal parous women with a mean age of ca. 40 yr who had a history of either benign breast disease (n = 15) or primary breast cancer (n = 15) and in a group of age-matched healthy women (n = 15). Saliva samples were collected at 09.00 and 21.00 hr daily for one complete menstrual cycle and progesterone concentration was measured by radioimmunoassay. Characteristic luteal-phase progesterone profiles were observed in all subjects in each of the three groups but no statistical intergroup differences could be demonstrated for age-matched subjects in each group. These studies indicated that ovarian dysfunction, as judged from salivary progesterone concentrations, was not apparent in older premenopausal women with a history of benign breast disease or primary breast cancer when compared with age-matched controls.

Bimodal age-frequency distribution of epitheliosis in cancer mastectomies relevance to preneoplasia

A census of epitheliosis in 500 consecutive cancer mastectomies has been carried out. The probability of concurrence of this phenomenon with cancer has a bimodal age‐frequency distribution. It is high in cancer mastectomies from women in their early 40s, low in the late 50s and high again in the elderly. Epitheliosis during the reproductive life span is regarded as a reversible ovary‐dependent abnormality. It is greatly increased in the premenopausal cancerous breast and it is thought that it carries increased risk for cancer initiation. In contrast the probability of epitheliosis in the breast in the elderly cancer patient is only slightly greater than in “noncancerous” post mortem breasts of similar age. Much of this “epitheliosis” may represent, in fact, indolent autonomous cancer though a small proportion could be epitheliosis supported by extraovarian estrogen.

Achieving high quality colonoscopy: using graphical representation to measure performance and reset standards

Aim  Completeness and thoroughness of colonoscopy are measured by the caecal intubation rate (CIR) and the adenoma detection rate (ADR). National standards are ≥ 90% and ≥ 10% respectively. Variability in CIR and ADR have been demonstrated but comparison between individuals and units is difficult. We aimed to assess the performance of colonoscopy in endoscopy units in the northeast of England.

Nutrition in Transition from Homo sapiens to Homo economicus

The food and nutrient intake among Paleolithic Homo sapiens, hunter-gatherers and among Asian and Homo economicus Western populations shows marked variations. Economic development and affluence may be associated with a decrease in the consumption of omega-3 fatty acids, vitamins, antioxidants and amino acids and significant increase in the intakes of carbohydrates, (mainly refined), fat (saturated, trans fat and linoleic acid) and salt compared to the Paleo- lithic period. The protein or amino acid intake was 2.5 fold greater (33 vs. 13%) in the Paleolithic diet Homo sapiens compared to modern Western diet consumed by Homo economicus populations. Approximately 10,000 years ago, prior to the Agricultural Revolution, our diet was based on an enormous variety of wild plants. However, today about 17% of plant species provide 90% of the worlds food supply which is mainly contributed by grains produced by fertilizer based on rapidly grown crops which may result in a decrease in nutrient density and increase in energy. Wheat, corn and rice ac- count for three fourths of the worlds grain production on which humans are dependent for their food supply. Grains are high in omega-6 fatty acids and carbohydrates and low in omega-3 fatty acids and antioxidants compared to leafy green vegetables. It has been estimated that diet of Homo sapiens was characterized by higher intakes by essential and non- essential amino acids, calcium, potassium, magnesium, flavonoids and w-3 fatty acids whereas modern Western diet of Homo economicus has excess of energy-rich refined carbohydrates, w-6, trans fat and saturated fat and low in protective nutrients. The consumption of such diets in wealthy countries in conjunction with sedentary behavior is associated with increased prevalence of morbidity and mortality due to noncommunicable diseases (NCDs).

Salivary cortisol and dehydroepiandrosterone sulphate levels in postmenopausal women with primary breast cancer

Cortisol and dehydroepiandrosterone sulphate (DHAS) were measured in saliva from postmenopausal women with primary breast cancer and a control group of comparable age. Specimens were collected at 2-hr intervals during wake-span for two consecutive days, and circadian rhythmicity was demonstrated for each of the hormones in both populations. The marginally elevated levels of cortisol and lower levels of DHAS associated with the cancer group, and the larger inter-subject variation, make it unlikely that these hormone measurements would be of value in identifying women at risk of developing breast cancer.