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Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners., peer-reviewed

Acne, hidradenitis suppurativa and hyperhidrosis are three distinct skin disorders. In this article, the key clinical features, medical associations and important aspects of management are highlighted.

AimTo determine the risk of myocardial infarction (MI) associated with pattern, frequency, and intensity of alcohol consumption, type of alcoholic beverage, and the combined effect of alcohol and smoking on risk of MI, inflammation, and lipid profile.MethodA total of 423 cases with a first MI and 465 controls from the Maltese Acute Myocardial Infarction (MAMI) Study were analysed. Data was collected through an extensive interviewer-led questionnaire, along with measurements of various blood parameters. Medians and the Mann–Whitney test were used to assess effect of different drinking patterns, frequency, intensity, and smoking and drinking combinations on hs-CRP and lipid profile. Odds ratios, adjusted for the conventional risk factors of MI (AdjORs), were calculated as an estimate of the relative risk of MI.ResultsRegular alcohol consumption protected against MI [AdjOR 0.6 (95% CI 0.4–0.9)] while daily binge drinking increased risk [AdjOR 5.0 (95% CI 1.6–15.0)] relative to regular drinkers who did not binge drink. Whereas moderate weekly consumption of wine protected against MI, high weekly consumption of beer conveyed a deleterious effect. Alcohol consumption decreased risk of MI independent of smoking status. Frequent alcohol consumption was associated with higher HDL-, non-HDL-, total cholesterol and triglycerides, and lower hs-CRP. Total and HDL-cholesterol increased and BMI decreased with increasing quantity of weekly alcohol consumption relative to the non-regular drinkers. The effect of smoking on lipid profile and hs-CRP was less pronounced in current drinkers than in those who were non-regular drinkers.ConclusionThe protective effect of alcohol consumption was dependent on the pattern, frequency, type, and intensity of alcohol consumed. Alcohol modified the effects of smoking on the lipid profile. Regular drinking attenuated the effect of smoking on hs-CRP and lipid profile.

BackgroundCD4+ small/medium-sized pleomorphic T-cell lymphoma (SMPTCL) is a controversial primary cutaneous lymphoma, in which the candidate neoplastic cells express a follicular T-helper phenotype. We describe 16 cases of SMPTCL and compare expression of PD-1, CXCL-13 and ICOS in these tumors with 40 dermatitis cases. MethodsHistopathologic examination and immunocytochemistry were performed for 16 tumors and 40 assorted dermatitis cases. ResultsAll but one patient presented with solitary lesions. Each biopsy revealed a dense nodular non-epitheliotropic infiltrate of atypical T-cells. Neoplastic cells were CD3+/CD4+/CD8(-)/CD30(-). Cutaneous recurrence occurred in one patient over a median follow up of 8months (range 5-36). All tumors widely expressed PD-1 and ICOS to a lesser extent. CXCL-13 stained much fewer cells. Of the dermatitis cases, PD-1 (most numerous) and ICOS labeled lymphoid cells in all cases, albeit fewer than in the tumors, and CXCL-13 was negative in 32. A rosette pattern of PD-1 expression was identified in all the SMPTCL cases but not in dermatitis. ConclusionsThere remains uncertainty about the appropriate nosological status of SMPTCL, which some authors consider to be a pseudolymphoma. However, this study suggests a significant difference in the prevalence and pattern of follicular T-helper cell markers between this tumor and lymphoid proliferations known to be reactive.

The thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) are important medications for cancer and inflammatory disorders. They are also widely prescribed as immunosuppressants in organ transplant patients. Their metabolism results in the incorporation of 6-TG into patients' DNA, and this increases skin sensitivity to incident UVA. Unlike the canonical DNA bases, which do not absorb UVA to a significant degree, DNA 6-TG is a strong UVA chromophore. It acts as a Type II UVA photosensitizer, and the combination of 6-TG and UVA treatment induces a synergistic toxicity in cultured human cells. Here, we review some of the damage that this interaction causes. Photochemical activation of DNA 6-TG triggers DNA and protein oxidation; it induces DNA breakage, DNA crosslinking, oxidation of DNA bases and the covalent attachment of proteins to DNA. Many of these photochemical DNA lesions are difficult for cells to deal with, and we review the evidence linking thiopurine immunosuppression with genome instability and the high incidence of skin cancer in organ transplant recipients.

The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.

Thiopurines have diverse clinical applications and their long-term use as anti-rejection drugs in transplant patients has been associated with a significantly increased risk of various types of cancer. Although they are slowly being replaced by a new generation of non-thiopurine immunosuppressants, it is anticipated that their use in the management of inflammatory and autoimmune diseases will continue to increase. Therapy-related cancer will remain a potential consequence of prolonged treatment for these generally non-life-threatening conditions. Understanding how thiopurines contribute to the development of cancer will facilitate clinical decisions about the potential risks to patients of long-term treatment for chronic inflammatory disorders.

Objective To investigate the effect of passive smoking, active smoking and smoking cessation on inflammation, lipid profile and the risk of myocardial infarction (MI), Methods A total of 423 cases with a first MI and 465 population controls from the Maltese Acute Myocardial Infarction (MAMI) Study were analysed. Data were collected through an interviewer-led questionnaire, and morning fasting blood samples were obtained. ORs adjusted for the conventional risk factors of MI (aORs) were calculated as an estimate of the relative risk of MI. The influence of smoking on biochemical parameters was determined among controls., Results Current smokers had a 2.7-fold (95%CI 1.7 to 4.2) and ex-smokers a 1.6-fold (95%CI 1.0 to 2.4) increased risk of MI. Risk increased with increasing pack-years and was accompanied by an increase in highsensitivity C reactive protein levels and an abnormal lipid profile. Smoking cessation was associated with lower triglyceride levels. Exposure to passive smoking increased the risk of MI (aOR 3.2 (95% CI 1.7 to 6.3)), with the OR being higher for individuals exposed to passive smoking in a home rather than in a public setting (aOR 2.0 (95% CI 0.7 to 5.6) vs aOR 1.2 (95% CI 0.7 to 2.0)). Passive smoke exposure was associated with higher levels of total cholesterol, triglycerides and total cholesterol:high-density lipoprotein cholesterol ratio compared with individuals not exposed to passive smoking., Conclusions Both active and passive smoking are strong risk factors for MI. This risk increased with increasing pack-years and decreased with smoking cessation. Such effects may be partly mediated through the influence of smoking on inflammation and lipid metabolism., peer-reviewed

Objectives: To investigate the risk of myocardial infarction (MI) attributed to diabetes. Methods: Questionnaire data and samples from 429 cases with MI and 434 controls from the Maltese Acute Myocardial Infarction (MAMI) Study were analysed. HbA1c estimation was performed on EDTA plasma using ion-exchange HPLC (Bio-Rad Variant II Analyzer). For cases this was assayed at time of MI. Uncontrolled diabetes was deemed present in self-reported diabetics who had HbA1c levels higher than 6.5% and controlled diabetes in self-reported diabetics who had normal HbA1c levels (≤6.5%). Undiagnosed diabetics were subjects with elevated HbA1c levels who did not report being diabetic. Odds ratios (AdjOR) were adjusted for age, gender, smoking, drinking alcohol, hypertension, hypercholesterolaemia and BMI. Results: Diabetes was reported in 13.7% of controls out of which 9.2% were uncontrolled. An additional 2.5% of controls have previously undiagnosed diabetes. The risk of MI was higher in undiagnosed [AdjOR 3.5(95%CI 1.6-7.8)] and in uncontrolled diabetics [AdjOR 2.7(95%CI 1.6-4.5)] when compared to non-diabetics. Controlled diabetics showed no increased risk of MI [AdjOR 0.9(95%CI 0.4-2.1)]. An elevated HbA1c level was associated with a 3-fold increased risk of MI [AdjOR 3.0(95%CI 1.9-4.7)]. Self-reported diabetes was associated with a 2-fold risk [AdjOR 2.1(95%CI 1.4-3.2)]. The median duration of diabetes in women with MI was longer than in controls (15 years versus 8 years, p

The title of Torjesen’s article could be misleading.1 Sentinel node biopsy (SNB) is a staging tool used to provide patients with the best available information,2 and is a well established prognostic test. Our research shows that patients want information on prognosis.3 Lymph node status is the most meaningful prognostic indicator and SNB the most sensitive …

Azathioprine is associated with enhanced skin photosensitivity to ultraviolet A (UVA) and leads to incorporation of 6-thioguanine (6-TG) into DNA of dividing cells. Unlike canonical DNA, 6-TG DNA is damaged by UVA, which comprises more than 90% of the ultraviolet reaching earth. Skin photosensitivity to UVA and UVB was measured in 48 kidney transplant patients immunosuppressed either by azathioprine (n = 32) or mycophenolate (n = 16). In 23 patients, azathioprine was subsequently replaced by mycophenolate and skin photosensitivity, DNA 6-TG content in peripheral blood mononuclear cells, and susceptibility to UVA-induced DNA damage were monitored for up to 2 years. The mean minimal erythema dose to UVA on azathioprine was twofold lower than on mycophenolate. Three months after replacing azathioprine by mycophenolate mofetil, the minimal erythema dose to UVA had increased from 15 to 25 J/cm(2) (p < 0.001) accompanied by reduced DNA 6-TG content. P53 protein expression in irradiated skin indicated reduced susceptibility to UVA-induced DNA damage. 6-TG DNA in peripheral blood mononuclear cells remained measurable for over 2 years. Replacing azathioprine selectively reduced the skin photosensitivity to UVA, attenuated UVA-induced skin DNA damage, and is likely based on incorporated 6-TG in DNA.

Nine members of a family with a high incidence of duodenal ulcer disease were studied by interview, examination of hospital records, endoscopy, and antral biopsy. Helicobacter pylori was confirmed by CLO test, histology and culture. DNA extraction from pure isolates of H pylori was possible in six family members and strain typing was performed by restriction fragment length polymorphism. DNA restriction digestion was followed by vacublotting and then DNA hybridisation, using a cDNA probe complimentary to H pylori rRNA cistrons. Eight of the nine family members were H pylori positive by CLO test and histology. Five had duodenal ulcer disease. Three family members (one from each generation) harboured clonal variants of a single parent strain of H pylori but only two had duodenal disease. The other three members harboured different strains. Intrafamilial clustering of clonal variants of H pylori occurs in some duodenal ulcer disease families. Family members however, may develop duodenal disease irrespective of the colonising strain.

We present a patient with an unusual enterocutaneous syndrome. Long-term, low-dose acitretin treatment has stabilized the development of gastrointestinal lesions while synchronously reducing cutaneous morbidity.

Aims: To analyse measures of adiposity and risk of myocardial infarction (MI) in a Mediterranean European Population. Methods: A total of 308 MI cases and 437 controls from the Maltese Acute Myocardial Infarction (MAMI) study had hip and waist circumferences measured per WHO guidelines. BMI and Waist-Hip Ratio (WHR) were analysed using WHO cutoffs. Odds ratios adjusted for common risk factors (adjOR) were calculated. Differences between groups were evaluated using the Kruskal-Wallis test. Results: A similar median BMI between male cases and controls (29.2, 28.7, p =0.05) and a similar prevalence of obesity (41.4%, 38.2%) resulted in an AdjOR of 1.2 (95%CI 0.6-2.4). AdjOR was similar in females despite a higher prevalence of obesity in cases (52.9%, N=37) than in controls (32.8%, N=45). Waist circumference (0.94, 1.00, p

Objectives: To investigate the effect of alcohol consumption and of passive and active smoking on the risk of myocardial infarction (MI). Methods: Data on 429 cases with MI and 434 controls was obtained through an interviewer-led questionnaire as part of the Maltese Acute Myocardial Infarction (MAMI) Study. Regular alcohol drinkers were defined as subjects having at least one drink per week for one year and binge drinkers as having six or more drinks on one occasion this last year. Current smokers were excluded from the analysis of passive smoking. Odds ratios (AdjOR) were adjusted for age, gender, smoking/drinking alcohol, hypertension, diabetes, hypercholesterolaemia and BMI. Results: Regular alcohol drinkers were protected against MI [AdjOR 0.6 (95%CI 0.4-0.8)]. The risk of MI associated with binge drinking varies with the frequency, reaching an AdjOR of 5.8 (95%CI 1.2-27.1) in daily binge drinkers. The AdjOR for current smokers was 3.1 (95%CI 2.0-4.9) and for ex-smokers 1.6 (95%CI 1.1-2.4). Passive smoking also increased the risk of MI [AdjOR 3.0 (95%CI 1.7-5.4)]. Passive smoke exposure in a home setting had a greater deleterious effect [AdjOR 2.8 (95%CI 1.6-4.7)] than exposure in a public setting [AdjOR 1.4 (95%CI 0.9-2.2)]. While periods of 1 hour or longer of passive smoke exposure were found to be deleterious in both the investigated settings, exposure for less than 1 hour was only a risk factor in a home setting. Conclusion: The effect of alcohol consumption on the risk for MI varies from protective to extremely deleterious depending on the frequency of drinking. Daily binge drinking is associated with a high risk of MI. Smoking, even passive smoking, is a risk factor of MI. The effect of passive smoking on the risk of MI is greater in a home than in a public setting.

Haematemesis in the elderly patient is a life-threatening condition. When the degree of blood loss is severe enough to warrant intervention by surgery or endoscopic means, the risk is even greater. We describe such a case, where treatment was further complicated as the bleeding point was in a hiatus hernia. The bleeding was successfully controlled by non-invasive means using an infusion of a somatostatin analogue.

OBJECTIVES--(a) to determine the efficacy of papaveretum in treating pain when administered early to patients presenting with acute abdominal pain and (b) to assess its effect on subsequent diagnosis and management. DESIGN--Prospective, randomised, placebo controlled study. SETTING--Walsgrave Hospital, Coventry. SUBJECTS--100 consecutive patients with clinically significant abdominal pain who were admitted as emergencies to a surgical firm. INTERVENTIONS--Intramuscular injection of up to 20 mg papaveretum or an equivalent volume of saline. OUTCOME MEASURES--Pain and tenderness scores, assessment of patient comfort, accuracy of diagnosis, and management decisions. RESULTS--Median pain and tenderness scores were lower after papaveretum (pain score 8.3 in control group and 3.1 in treatment group, p < 0.0001; tenderness score 8.1 in control group and 5.1 in treatment group, p < 0.0001). Forty eight patients were deemed to be comfortable after papaveretum compared with nine after saline. Incorrect diagnoses and management decisions applied to two patients after papaveretum compared with nine patients after saline. CONCLUSION--Early administration of opiate analgesia to patients with acute abdominal pain can greatly reduce their pain. This does not interfere with diagnosis, which may even be facilitated despite a reduction in the severity of physical signs. These patients should not be denied effective treatment.

We describe a safe method of percutaneous renal transplant biopsy using real time ultrasound guidance. The method provides a good histological sample, is straightforward and has a low complication rate.

Une observation: une femme de 53 ans, atteinte d'hypertension, d'insuffisance cardiaque, d'insuffisance vasculaire peripherique et d'angor presente une aggravation de ces troubles et une anurie. Le rein droit est atrophique et le rein gauche normal. Apres 2 j d'essais de traitement de l'anurie le diagnostic d'obstruction de l'artere renale gauche est fait, et l'operation, 72 h apres le debut de l'anurie, est efficace