Heat waves: health impacts

Durante o Verão de 2003, a Europa ocidental foi afectada por uma onda de calor sem precedentes, que provocou milhares de mortos. As ondas de calor são fenómenos climatéricos esporádicos mas recorrentes, caracterizadas por períodos de calor intenso,com duração de vários dias, e associadas a aumento da morbilidade e da mortalidade. A principal causa de morte directamente atribuível ao calor é o golpe de calor, mas uma onda de calor provoca um aumento da mortalidade por todas as causas, sobretudo por doença cardiovascular e respiratória. Os estudos epidemiológicos revelam que o excesso de óbitos associado ao calor se concentra em grupos de risco definidos. Os idosos, os doentes crónicos e os indivíduos socialmente isolados são particularmente vulneráveis. O ar condicionado é o principal factor protector contra os efeitos pejorativos do calor sobre a saúde. As ondas de calor têm efeitos sobre a saúde indirectos, determinando a descompensação de uma doença crónica, ou directos, provocando doenças relacionadas com o calor (DRC). As DRC clássicas incluem, por ordem de gravidade crescente, exantemas, cãibras, síncope, exaustão pelo calor e golpe de calor. O golpe de calor é uma emergência médica caracterizada pela instalação súbita de hipertermia e disfunção neurológica central.O tratamento do golpe de calor consiste em arrefecimento corporal imediato e medidas de suporte de funções vitais. Mesmo com terapêutica agressiva, a mortalidade do golpe de calor é elevada e as sequelas neurológicas são frequentes nos sobreviventes. A mortalidade e morbilidade associadas às ondas de calor podem ser prevenidas através da adopção de medidas comportamentais individuais, como a utilização de ar condicionado e o aumento da ingestão de líquidos. O desenvolvimento de sistemas de alerta e planos de intervenção e a redução do stress térmico no ambiente constituem outras medidas adaptativas. No futuro, prevê-se um acréscimo da mortalidade relacionada com o calor devido ao envelhecimento populacional e crescimento da população urbana e ao antecipado aumento do número e da intensidade das ondas de calor determinado pelo aquecimento global. As consequências sanitárias de futuras ondas de calor poderão ser limitadas através de melhoramentos dos sistemas de vigilância e intervenção. É essencial que os profissionais de saúde estejam preparados para reconhecer, During the summer of 2003, record high temperatures were reported across Europe, causing thousands of casualties. Heat waves are sporadic recurrent events, characterised by intense and prolonged heat, associated with excess mortality and morbidity. The most frequent cause of death directly attributable to heat is heat stroke but heat waves are known to cause increases in all-cause mortality, specially circulatory and respiratory mortality. Epidemiological studies demonstrate excess casualties cluster in specific risk groups. The elderly, those with chronic medical conditions and the socially isolated are particularly vulnerable. Air conditioning is the strongest protective factor against heat-related disorders. Heat waves cause disease indirectly, by aggravating chronic disorders, and directly, by causing heat-related illnesses (HRI). Classic HRI include skin eruptions, heat cramps, heat syncope, heat exhaustion and heat stroke. Heat stroke is a medical emergency characterised by hyperthermia and central nervous system dysfunction. Treatment includes immediate cooling and support of organ-system function. Despite aggressive treatment, heat stroke is often fatal and permanent neurological damage is frequent in those who survive. Heat related illness and death are preventable through behavioural adaptations, such as use of air conditioning and increased fluid intake. Other adaptation measures include heat emergency warning systems and intervention plans and environmental heat stress reduction. Heat related mortality is expected to rise as a consequence of the increasing proportion of elderly persons, the growing urban population, and the anticipated increase in number and intensity of heat waves associated with global warming. Improvements in surveillance and response capability may limit the adverse health conditions of future heat waves. It is crucial that health professionals are prepared to recognise, prevent and treat HRI and learn to cooperate with local health agencies.publishersversionpublishe

A simple method to measure sulfonation in man using paracetamol as probe drug

Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index-PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual's sulfonator status. To the best of our knowledge, our method provides the first standardised in vivo empirical measure of an individual's phenol sulfonation capability and of its intraindividual variability. EUDRA-CT 2016-001395-29, NCT03182595 June 9, 2017.publishersversionpublishe

Behçet syndrome and Crohn’s disease – what are the differences?

Behçet syndrome (BS) is a variable vessel vasculitis that has pleiotropic manifestations. A 43-year-old male with a previous diagnosis of Crohn’s disease (CD) presented with deep venous thrombosis and bilateral superficial femoral artery aneurysms. A diagnosis of BS was made, and the patient was treated aggressively with immunosuppressive therapy and bilateral bypass surgery, attaining a favourable outcome. CD has many features that overlap with BS, and it may be challenging to distinguish between these two conditions, as our case illustrates. Nonetheless, the combination of venous thrombosis and arterial aneurysms should point the clinician towards a diagnosis of BS

In vivo phenotyping of sultia enzymes in man implications for precision medicine

Introduction:Sulfotransferase enzymes (SULT) catalyzesulfoconjugation of drugs, as well as endogenousmediators, gut microbiota metabolites and environmental xenobiotics. To address the limitedevidence on sulfonation activity from clinical research, we conceiveda clinical metabolic phenotypingmethod using paracetamol,a drug with significant metabolism by SULT1A1 and SULT1A3, as a probe substrate. Our aim was to estimate sulfonation capabilityof phenolic compounds and study its intra and interindividual variabilityin vivoin man. Population and Methods: This thesis included two separate clinical trials:Clinical trial “Variability of Sulfotransferase 1A1 Activity in Humans: An Approach to Improve Predictive Drug Response –Part I: Analysis of Intraindividual Variation in Healthy Adults”(EudraCT nº 2016-001395-29)was approved by the Portuguese National Ethics Committee. We recruited 36 healthy adults (12 men and 24 women, 12 on oral contraceptives). Baseline samples were collected. Subjects received 1 g of oral paracetamol on three different occasions and had blood and urine samples collected after 2 hours. Paracetamol (P) and its metabolites (sulfate, glucuronate, cysteine-S-conjugate and mercapturate) were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry(LC-HRMS). Paracetamol sulfonation index (PSI) was used to express SULT activity. PSI was calculated for urine (uPSI) and plasma (pPSI) samples. Twenty-nine subjects were genotyped for SULT1A1and genotypes were compared to phenotype measured with PSI.We measured expression of SULT1A1 and SULT1A3 in whole blood samples. Non-targeted metabolomics was performed in 27 pre-dose urine samples and 33 pre-dose plasma samples using LC-MS. LC-MS raw data was preprocessed using XCMS (R package xcms 3.6.2). Data was normalized by total area, centered and unit variance-scaled. Principal Component Analysis (PCA) was performed to assess the main sources of the variance of the data. Partial Least Square (PLS) analysis was performed to evaluate the correlation between the metabolites and the PSI using SIMCA (MKS Umetrics, Umeå, Sweden Umetrics, version 16.0.1). Metabolite annotation was performed by matching MSMS data against metabolomics databases (Metlin,HMDB).Clinical Trial “Variability of Sulfotransferase 1A1 Activity in Humans: An Approach to Improve Predictive Drug Response –Part II: Analysis of Interindividual Variation in Hypertensive Patients”(EudraCT 2019-002266-12)was approved by the Portuguese National Ethics Committee. We recruited 37patients with arterial hypertension. Baseline samples were collected. Subjects were phenotyped with the metabolic ratio PSI using paracetamol as probe drug, as previously described. PSI was calculated for urine (uPSI) samples.Both cohorts were combined to explore interindividual variability.Means, standard deviations, frequencies and percentages were used to describe the population under study.Multiple linear regression models wereperformed to study the role of several measurementsin the association withPSI. The linear regression model assumptions, namely the residuals homocedasticity and normality were checked and confirmed for all models obtained. 95% confidence intervals for the model’s coefficient estimates were obtained and presented. A confidence level of =0.05 was used throughout. Results:PSI was defined as the ratio between paracetamol sulfate (PS) and the sum of PS, paracetamol glucuronate (PG) and P: PSI=PS/(PS+PG+P). PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. SULT1A1 exhibitedgenetic variation. We found a prevalence of 0.24 for the SULT1A1*2 allele, the most common SULT1A1 variant allele.Only two individuals possessed the allele SULT1A1*3. We found no association of genotype with expression or phenotype measuredwith uPSI.SULT1A3 was found to be correlated with uPSI.In untargeted analysis, PCA showed an influence of sex and contraceptive use on the baselinemetabolic profile. A PLS model was built between the pre-dose metabolic profile and the uPSI (R2(X)=0.249, R2(Y)=0.898, Q2=0.535, p=0.016). A total of 22 features in urine were selected as the most relevant ions of the PLS model (variable importance of the projection (VIP) value >2.0). Although no conclusive metabolite annotation was achievedfor any of the ions, MSMS information led as to elucidate that one of the metabolites was a glucuronidated metabolite. This metabolite increased with the PSI.In hypertensive patients, uPSI retained the capacity to segregate high and low sulfonators. Logistic regression revealed the influence of eGFR and of the presence of autoimmune disease on uPSI.Combining both cohorts, we found a coefficient of variation of uPSI between individuals of 21.9%. Logistics regression revealed an influence of age and of plasma creatinine on uPSI.Using the antimodewe defined 0.44 as the cut-offvalue between low and high sulfonate conjugators phenotypes. We did not detect differences between both phenotypes.Discussion: Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measureof an individual’ssulfonator status.For the first time we have unveiled the presence of SULT1A1genetic variants in a Portuguese population and we did not find a genotype-phenotype relation. In the population studied, we have found an association between an individual’s baseline urinary metabolite profile and PSI, suggesting it could be used to estimate and compare sulfonation capacity between individuals.We discovered a modest interindividual variability of phenol sulfonation phenotype measured with uPSI. We detected an influence of plasma creatinine and age on uPSI that is yet to be understood. Conclusion: To the best of our knowledge, PSIprovides the first standardized in vivo empirical measure of an individual’s phenol sulfonation capability and of its intraindividual and interindividual variability.Furthermore, we have established the basis for the identification of a biomarker of sulfonation that could be useful for predicting sulfonator status from baseline metabolic profile. Both these initiatives constitute relevant tools in precision medicine