CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5' and 3' ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. METHODS: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. RESULTS: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. CONCLUSIONS: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

The spatial structure of Phanerozoic marine animal diversity.

The global fossil record of marine animals has fueled long-standing debates about diversity change through time and the drivers of this change. However, the fossil record is not truly global. It varies considerably in geographic scope and in the sampling of environments among intervals of geological time. We account for this variability using a spatially explicit approach to quantify regional-scale diversity through the Phanerozoic. Among-region variation in diversity is comparable to variation through time, and much of this is explained by environmental factors, particularly the extent of reefs. By contrast, influential hypotheses of diversity change through time, including sustained long-term increases, have little explanatory power. Modeling the spatial structure of the fossil record transforms interpretations of Phanerozoic diversity patterns and their macroevolutionary explanations. This necessitates a refocus of deep-time diversification studies.

Circulating low-density lipoprotein ceramide concentrations increase in Holstein dairy cows transitioning from gestation to lactation.

Low-density lipoprotein (LDL) ceramide causes insulin resistance in obese diabetic nonruminants. Because previous work suggests that liver-derived ceramide may impair insulin action in postpartum cows, our objectives were to characterize peripartal changes in lipoprotein ceramides. We further studied the effects of prepartum adiposity on lipoprotein ceramide levels. Twenty-eight pregnant Holstein cows (parity = 3.65 ± 1.62) with lean (body condition score, BCS = 2.97 ± 0.16; body weight, BW = 630 ± 55.2 kg; n = 15) or overweight (BCS = 3.93 ± 0.27; BW = 766 ± 46.1 kg; n = 13) body condition 28 d before expected parturition were evaluated. Sampling occurred on d -20.5 ± 1.74, -13.8 ± 1.71, -7.84 ± 4.07, -6.71 ± 1.00, -3.92 ± 0.64, and -1.28 ± 0.61 (before parturition); daily until d 8 postpartum; and on d 10, 12, 14, 21, and 28. Adipose tissue and liver were biopsied on d -7.84 ± 4.07 and 10. Postpartum insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp. Lipoprotein fractions were isolated using liquid chromatography. Sphingolipids were quantified using mass spectrometry. Data were analyzed using a mixed model with repeated measures. Overweight cows had a higher BCS and BW at enrollment relative to lean cows, but BCS and BW were similar postpartum. Overweight cows lost more body condition (0.97 ± 0.36 vs. 0.55 ± 0.16 BCS units) and BW (291 ± 67.3 vs. 202 ± 54.5 kg) during transition relative to lean cows. Adipocyte volume and counts declined from prepartum to postpartum (50.4 and 13.7%, respectively), and adipocyte volume was greater (48.2%) in overweight cows prepartum relative to lean cows. Although DMI was comparable between BCS groups, milk yield tended to be greater in overweight cows. Plasma free fatty acid and ß-hydroxybutyrate and liver lipid levels were 40, 16, and 37% greater, respectively, in overweight cows compared with lean cows. Glucose infusion rate during the hyperinsulinemic-euglycemic clamp tended to be lower in overweight cows. Ceramide levels within triacylglycerol-rich lipoprotein fractions declined postpartum, whereas LDL ceramide increased postpartum. Overweight cows had lower triacylglycerol-rich lipoprotein C16:0-ceramide levels relative to lean cows. Prepartum LDL C24:0-ceramide levels were greater in overweight cows relative to lean cows. Independent of prepartum adiposity, we concluded that serum LDL ceramide levels are elevated in early-lactation cows experiencing adipose tissue free fatty acid mobilization and hepatic steatosis.

Flumazenil in intensive care. The duration of arousal after an assessment dose.

The effect of an assessment dose of the benzodiazepine antagonist flumazenil was studied in 20 patients in an intensive care unit. The patients had been sedated with alfentanil and midazolam, and were ready to be weaned from mechanical ventilation. In 10 patients flumazenil was titrated just to produce full arousal whilst the midazolam infusion was continued; flumazenil administration was repeated one hour later after the infusion of midazolam had been stopped. In another 10 patients, flumazenil was administered only once, coinciding with the cessation of sedation. The duration of full arousal in both groups was less than 15 minutes in 75% of patients given a single dose of flumazenil (median dose 0.4 mg) although some effect persisted for up to 60 minutes. The cardiovascular effects of arousal were transient and probably not clinically significant. A brief duration of action is advantageous if the patient is found still to require sedation.

Assessment of oxygenation in the critically ill.

This paper reviews the physiology and pathology of oxygen transport from the atmosphere to the cells in critically ill patients. A thorough understanding of this allows a rational approach to monitoring and managing an hypoxic patient in the intensive care setting.

South Birmingham Coronary Prevention Project: a district approach to the prevention of heart disease.

The South Birmingham Coronary Prevention Project is described, in which health checks by practice nurses in GPs' surgeries are combined with direct patient access to a secondary referral system. Where appropriate, health check attenders are offered the choice of either (a) counselling by the practice nurse, (b) direct referral to their GP, or (c) direct referral to secondary intervention, including specialist dietary advice for patients with high (greater than 6.5 mmol/l) serum cholesterol, stress management training for mild hypertension (diastolic blood pressure greater than 90 less than 105 mmHg), and smoking cessation groups. Significant reductions in blood pressure (p less than 0.005) and serum cholesterol levels (p less than 0.001) have been achieved. Further, substantial numbers of smokers have ceased since attending smoking cessation groups. This multidisciplinary approach to the identification and modification of risk factors for coronary heart disease may provide a powerful adjunct to wider ranging population interventions.

Therapeutic progress in intensive care--rational use of vasoactive and inotropic drugs in the intensive care unit.

Vasoactive (vasodilating and vasoconstricting) and inotropic drugs are widely used in intensive therapy. Major progress in their use in recent years has been due to a greater understanding of the physiological derangements of the critically ill. This progress is the consequence of improved standards of haemodynamic monitoring in the intensive therapy unit (ITU). In addition the introduction of accurate and reliable syringe pumps, to administer small volumes of fluid accurately, has enabled the easy use of drugs to manipulate physiological parameters. An understanding of the basic anatomy and physiology of the cardiovascular system (CVS) is essential to an understanding of the methods used for monitoring and measurement (1). Logical therapeutic interventions follow from consideration of these measured and derived parameters.

A multi-disciplinary approach to the prevention of coronary heart disease.

The South Birmingham Coronary Prevention Project is described, in which health checks by practice nurses in GPs' surgeries are combined with direct patient access to a secondary referral system. Where appropriate, health check attenders are offered the choice of either counselling by the practice nurse, direct referral to their GP, or direct referral to secondary intervention, including dietary advice for patients with high serum cholesterol, stress management training for mild hypertension, and smoking cessation groups run by specialist workers. Further developments of the project may be toward increasing areas of nurses intervention, for example running lipid clinics, and combining with Look After Your Heart! in the workplace. Progress in each of these areas is described and discussed.

Additional blood-gas variables for the rational control of oxygen therapy. With allowance for shifts of the oxygen dissociation curve.

When a sample of arterial blood is analysed for oxygen tension and, using a modern oximeter, for haemoglobin concentration and saturation, it is possible to calculate the position of the oxygen dissociation curve and two new variables: "P95" and "C(a-x)O2". P95 is the tension at which the haemoglobin would be 95% saturated and can, therefore, constitute a target tension for near-maximum arterial content of oxygen. C(a-x)O2 (the "conditional extraction" of oxygen) is the amount of oxygen, in ml/dl blood, which can be extracted from the arterial blood for a hypothetical mixed-venous oxygen tension PxO2. It is explained how it is possible to estimate the adequacy of tissue oxygenation by comparing any available estimate of the required extraction (normally about 5 ml dl-1) with conditional extractions calculated for three hypothetical values of PxO2 covering the clinical range. Methods of calculation are given. For accurate results at high arterial saturations, a peripheral venous sample may be required in addition to the arterial sample.

The effects of formulation and addition of adrenaline to cocaine for haemostasis in intranasal surgery.

Twenty patients presenting for submucous resection of the nasal septum under general anaesthesia were randomly allocated to four groups to receive either 1.0 ml 25% cocaine HCl in paraffin paste, 1.0 ml 25% cocaine HCl combined with 0.1% adrenaline in paraffin paste, 4.0 ml aqueous 4% cocaine HCl combined with 0.05% adrenaline or 4.0 ml aqueous 4% cocaine HCl on ribbon gauze applied to the nasal mucosa. Mean intraoperative blood loss was significantly decreased when the 25% cocaine 0.1% adrenaline combination in paraffin paste was used (11 (SD 8) ml, 60 (SD 30) ml, P less than 0.05, for adrenaline and plain paste respectively). Combination of adrenaline with cocaine in the aqueous formulation was not associated with a significant decrease in blood loss compared with aqueous cocaine alone (75 (SD 51), 96 (SD 66) ml respectively). Cocaine adrenaline paste and plain cocaine paste were associated with higher mean maximum cocaine blood concentrations (1.6 (SD 1.4), 2.0 (SD 1.5) micrograms/ml respectively) when compared with aqueous cocaine adrenaline and aqueous cocaine alone (0.03 (SD 0.003), 0.5 (SD 0.3) microgram/ml respectively). Heart rate and blood pressure changes were similar in all four groups and cardiovascular toxicity was not observed. One ml of topical intranasal 25% cocaine HCl with 0.1% adrenaline in paraffin paste provided the best haemostasis for nasal septal surgery.

Minimum volume of discard for valid blood sampling from indwelling arterial cannulae.

The volume of discard for valid blood sampling from indwelling femoral (leader cath) and radial (Venflon) arterial cannulae (with internal volume of cannula plus connecting tubing of approximately 2 ml) was investigated by analysing sequential 2-ml aliquots of 10-ml samples. The aliquots were analysed for pH, carbon dioxide tension, oxygen tension, standard bicarbonate, haemoglobin concentration, haemoglobin oxygen saturation and potassium concentration. Analysis of variance showed that, for these variables and these catheters, a valid blood sample was obtained after discarding 4 ml, but not after only 2 ml. The haemoglobin concentration, as measured by a Corning oximeter, provided good warning of inadequate discard.

Pulse oximetry. An assessment in anaesthetised dental patients.

The applications of a pulse oximeter were studied in dental day case surgery using nasal mask anaesthesia. Changes in arterial oxygen saturation were sensitively and rapidly detected, in the absence of cyanosis. Impaired oxygenation can be detected before cyanosis develops.

Bronchial intubation. A comparison between polyvinyl chloride and red rubber double lumen tubes.

Red rubber and polyvinyl chloride bronchial double lumen tubes were compared. Polyvinyl chloride tubes are easier to pass quicker to position and cause less damage to the mucosa of the respiratory tract than the red rubber equivalents.

The validity of oxygen content calculations.

Blood oxygen content calculated from haemoglobin concentration, measured haemoglobin oxygen saturation and measured oxygen tension was compared with three other methods of estimating oxygen content. These other methods were those of Van Slyke and Zander, which are direct methods, and a method using Kelman's equation to estimate the saturation from measured oxygen tension and hence content. The coefficients of correlation (corr coeff) (r) were 0.9050 (n = 22), 0.9919 (n = 24) and 0.9862 (n = 25) for the respective methods when compared with oxygen content calculated using measured saturation. The Van Slyke method proved to be imprecise in our hands. The direct measurement using the oxygen cuvette of Zander gave oxygen content values similar to those estimated from measured saturation. The oxygen content calculated from pO2 alone when compared to that derived from measured saturation had a corr coeff (r) of 0.9862 (n = 25), but the high residual standard deviation (So) of 6.939 ml/l indicates that the practice of calculating oxygen content from oxygen tension alone is imprecise. We conclude that oxygen content may be satisfactorily estimated by the Zander method when it becomes generally available, but until then the measurement of oxygen saturation is a necessary prerequisite to the estimation of blood oxygen content.