Implications of sulfotransferase activity in interindividual variability in drug response: clinical perspective on current knowledge.

The interindividual variability in drug response is a major issue in clinical practice and in drug development. Sulfoconjugation is an important Phase II reaction catalyzed by cytosolic sulfotransferases (SULTs), playing a major role in homeostatic functions, xenobiotic detoxification, and carcinogen bioactivation. SULT display wide interindividual variability, explained only partially by genetic variation, suggesting that other non-genetic, epigenetic, and environmental influences could be major determinants of variability in SULT activity. This review focuses on the factors known to influence SULT variability in expression and activity and the available evidence regarding the impact of SULT variability on drug response.

Operative Hysteroscopy Intravascular Absorption Syndrome - A Life-Threatening Complication.

Operative hysteroscopy intravascular absorption (OHIA) syndrome is a rare and potentially life-threatening complication related to irrigation fluid systemic absorption during hysteroscopy. It can lead to severe electrolyte disturbances, cerebral and pulmonary oedema, dysrhythmias and coagulopathy. We present the case of a 30-year-old woman who underwent a hysteroscopic myomectomy. After absorbing 2.5 l of normal saline, she experienced haemodynamic instability, respiratory distress and severe metabolic acidosis, initially mistaken for an anaphylactic or haemorrhagic shock. Insufficient monitoring of fluid deficit and irrigation fluid pressures contributed to the condition. This case underscores the importance of recognising OHIA and its risk factors to enable timely intervention and prevent adverse outcomes. Close fluid balance monitoring is vital in hysteroscopic surgeries to mitigate OHIA development. LEARNING POINTS: OHIA syndrome occurs due to the systemic absorption of the irrigation fluid used during hysteroscopic procedures.The presentation is diverse with encephalopathy, pulmonary oedema, dysrhythmias, electrolyte disturbances and coagulopathy.Fluid balance and irrigation fluid pressures should be monitored during hysteroscopic procedures to mitigate OHIA development.

Moyamoya Disease and Syndrome in Caucasian Patients.

Moyamoya disease is a unique cerebrovascular disease characterized by narrowing of the terminal portion of internal carotid arteries and circle of Willis, with consequent development of a network of collateral vessels in response to brain ischemia. Moyamoya vascular pattern can be idiopathic (Moyamoya disease), is more likely to occur in individuals of Asian ascent and in the pediatric age, or is associated with other diseases (Moyamoya syndrome). We present two cases of stroke in young adults, where workup revealed Moyamoya-type vascular changes. The first case report is of a 42-year-old woman presenting with hemorrhagic stroke, with classic angiographic findings of Moyamoya disease, otherwise asymptomatic. The second case concerns a 36-year-old woman admitted with ischemic stroke; besides the typical angiographic pattern of Moyamoya, the patient was diagnosed with antiphospholipid antibody syndrome and Graves' disease, two conditions known to be associated with this vasculopathy. These case reports illustrate the need to consider this entity in the etiological evaluation of ischemic and hemorrhagic cerebrovascular events, even in Western countries, since management and secondary prevention require specific approaches.

Ascending Aortic Thrombus With Peripheral Embolization.

Thoracic aortic mural thrombi are rare in clinical practice, especially in non-aneurysmatic or non-atherosclerotic vessels. They are typically located in the descending aorta, and less frequently in the aortic arch, abdominal aorta, and ascending aorta. Although they are a rare cause of arterial embolization, this is their main manifestation. We present the case of a 48-year-old man, with no cardiovascular risk factors or history of trauma, who presented with acute arterial ischemia of the right upper limb. From the initial investigation, we highlight the presence of a pedunculated mass in the distal portion of the ascending aorta with signs of instability. Due to the risk of additional embolization, the patient was submitted to urgent surgery, with excision of the aortic defect, implantation of a tubular prosthesis as well as thrombo-embolectomy of the right brachial artery. The etiological evaluation of mural aortic thrombi is challenging and implies the exclusion of some prothrombotic conditions known to predispose to arterial thrombosis. This is a rare case that emphasizes the importance of considering the aorta as a possible source of peripheral embolization, even when there is no significant atherosclerotic or aneurysmatic disease.

Levofloxacin-Induced Acute Pancreatitis.

Drug-induced pancreatitis is a rare entity accounting for less than 2% of acute pancreatitis (AP). Quinolones are commonly used antimicrobials with occasional reports of pancreatitis. We present the case of a 74-year-old man who was diagnosed with acute cystitis five days before hospital admission and was treated with levofloxacin (LVF). Two days after initiating LVF he experienced fever, severe abdominal pain, and nausea. The initial assessment revealed leukocytosis, elevated C-reactive protein, and a significant elevation of amylase and lipase. On abdominal ultrasound, the head of the pancreas revealed an hypoechogenic region suggestive of inflammatory edema. A diagnosis of AP was established. The drug was withdrawn along with supportive care, with complete resolution of the symptoms. No other probable causes of AP were found after further investigation. Although rare, LVF-induced pancreatitis should be considered when managing a patient with AP. Increasing physician awareness is vital to the prompt recognition of this entity.

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.

Medicines for the Treatment Of COVID-19: Awaiting the Evidence.

The novel severe acute respiratory syndrome coronavirus 2 is the cause of Coronavirus Disease 2019, a new illness with no effective treatment or vaccine that has reached pandemic proportions. In this document, we analyze how health authorities and agencies around the world position themselves regarding the off-label use of repurposed drugs or new investigational drugs to treat Coronavirus Disease 2019. We review the most promising candidate medicines, including available evidence, clinical recommendations and current options for access. Our concluding remarks stress the importance of administering off-label and investigational drugs in the setting of clinical trials, or at least in standardized scenarios, to generate as much scientific knowledge as achievable while engaging in the best efforts to treat patients and save lives.

O novo severe acute respiratory syndrome coronavírus 2 é a causa da doença por coronavírus 2019, uma doença emergente, sem tratamento eficaz nem vacina, que alcançou proporções de pandemia. Neste documento, analisamos a forma como as autoridades e agências de saúde em todo o Mundo se posicionam em relação ao uso de fármacos off-label ou novos produtos de investigação para o tratamento da doença por coronavírus 2019. Revemos os fármacos mais promissores, incluindo a evidência disponível, as recomendações clínicas e as atuais opções de acesso a estes medicamentos. Concluímos enfatizando a importância de administrar fármacos em uso off-label e produtos de investigação em contexto de ensaios clínicos, ou pelo menos em circunstâncias padronizadas, para que se gere o máximo possível de conhecimento científico a mesmo tempo que se concentram esforços em tratar doentes e salvar vidas.

Malabsorption Due to Chronic Giardiasis as a Presenting Symptom of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency that presents with a broad spectrum of clinical manifestations. We report the case of a 33-year-old man, initially referred to the outpatient internal medicine clinic for anemia. At the evaluation, the patient complained of diarrhea and unintentional weight loss for the last six months. He had no known medical conditions, but his previous medical history highlighted recurrent respiratory infections since childhood and also oral ulcers. The investigation identified iron-deficiency anemia caused by a malabsorption syndrome due to chronic giardiasis (Giardia lamblia cysts identified in fecal culture and Giardia lamblia trophozoites identified in the villi epithelium). Further investigation revealed bilateral bronchiectasis and splenomegaly. Suspecting CVID, a serum protein electrophoresis was performed, which showed a flattening of the gamma region, corresponding to a severe deficit of immunoglobulin (Ig) G, IgA, and IgM. A deficiency in the production of IgG in response to immunizations was confirmed, and the other causes of hypogammaglobulinemia were excluded. Therefore, a diagnosis of CVID was established. Malabsorption due to chronic giardiasis is a rare cause of iron deficiency anemia and an unusual presentation of CVID.

Hypertrophic cardiomyopathy--two atypical forms diagnosed by cardiac CT.

Hypertrophic cardiomyopathy is a relatively common genetic disease (prevalence of 0.2%), with a clinical spectrum that ranges from absence of symptoms to presentation as sudden cardiac death. Atypical forms are a diagnostic challenge and recent cardiac imaging techniques, such as cardiac CT and magnetic resonance imaging, can make an important contribution. We present a review of this disease based on two case reports.

Anecdotal Response to Amphotericin in a Patient with Probable Susac Syndrome: Implications in the Pathogenesis.

Susac syndrome is a rare, probably immune-mediated endotheliopathy presenting with encephalopathy, sensorineural hearing loss and retinal arterial occlusions. A 33-year-old female with Susac syndrome was worsening despite high-dose steroids so a brain biopsy was performed which suggested a possible fungal infection. Treatment with amphotericin B resulted in prompt reversal of symptoms and radiological findings, and no further symptoms occurred during 8 years of follow-up. A diagnosis of fungal infection was not confirmed. The etiology of Susac syndrome is unknown and this anecdotal observation suggests that an infectious agent susceptible to amphotericin might have caused or triggered Susac syndrome in this patient.

A síndrome de Susac é uma endoteliopatia rara, provavelmente imunomediada que se apresenta com a tríade sindromática de encefalopatia, surdez neurosensorial e oclusões de ramos arteriais da retina. Apresenta-se o caso de uma mulher de 33 anos com o diagnóstico de síndrome de Susac que agravou sob terapêutica imunossupressora, pelo que se decidiu pela realização de uma biópsia cerebral, que levantou a suspeita de uma possível infeção fúngica. O tratamento com anfotericina B resultou numa recuperação clínica e imagiológica rápida e não se verificou recorrência de sintomas num período de seguimento de oito anos. O diagnóstico de meningoencefalite fúngica não foi confirmado. A etiologia da síndrome de Susac é desconhecida. A observação fortuita da resposta terapêutica deste caso sugere que um agente infecioso suscetível à anfotericina B possa ter causado ou desencadeado esta síndrome, nesta doente.

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. LEARNING POINTS: Behçet syndrome is a variable vessel vasculitis of unknown aetiology that has pleiotropic manifestations.Crohn's disease has many overlapping features with Behçet syndrome, namely gastrointestinal, cutaneous, articular, ocular and cardiac manifestations.The combination of venous thrombosis and arterial aneurysms should point the clinician towards a diagnosis of Behçet syndrome.

Myelitis and Polyradiculoneuropathy With Severe Pain: Unusual Neurological Manifestations as Presenting Symptoms of Brucellosis.

Brucellosis, an endemic zoonosis in Portugal, is a multisystem disease, presenting with neurological manifestations in up to 25% of cases. Neurobrucellosis diagnostic criteria include evidence of central nervous system invasion, either by documenting increased blood-brain barrier permeability that normalizes after treatment or by Brucella isolation. We report 2 patients with systemic brucellosis presenting with neurological symptoms: A 28-year-old female with progressive hemiparesis associated with severe refractory thoracic and lumbar pain, whose spinal magnetic resonance imaging identified longitudinally extensive myelitis. Brucella agglutination test was positive in blood; however, cerebrospinal fluid cytochemical, serological testing, and cultures were negative. A 58-year-old male with intermittent fever in the evening, associated with severe refractory cervical and lumbar spinal and radicular pain. Blood workup identified leukocytosis, elevated inflammatory markers and positive Brucella agglutination test. Cerebrospinal fluid presented mild protein increase and negative serological testing and cultures. Electromyogram revealed demyelinating polyradiculoneuropathy. In both cases, antibiotic therapy induced symptom resolution. Despite the neurological presentation, no evidence of direct nervous system infection was found. An indirect mechanism appears to be involved, such as a parainfectious syndrome or circulating endotoxins release by the bacteria. Brucellosis should be considered in patients presenting with inflammatory neurological symptoms in endemic regions. Prompt diagnosis and treatment are important as chronic infection has significant morbidity.

[Heat waves: health impacts]. / Ondas de calor. Impacto sobre a saúde.

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.

[Internal medicine consultation]. / Consulta intra-hospitalar de medicina interna.

The Internal Medicine consultation plays an important part in the activity of the Medicine Department. This activity is seldom quantified and is usually underestimated. In order to assess the work load represented by this service, the authors designed a prospective study to quantify and analyse the characteristics of the 556 consecutive consultations performed during 12 months. Over half the requests for observation were received after 4 p.m. and 18% were requested urgently; 96,8% were answered on the same day. Of the consultations, 33% came from the Orthopaedics and Trauma Department, 18% from the General Surgery Department and 17% from the Surgical Intermediate Care Unit. Cardio-vascular, infectious and neurological pathology accounted for most of the calls. During the regular working hours, there was'nt a direct contact with the patient's physician in 54% of the consultations. This activity represents an important additional work load to the Internist, with increasing relevance in the improvement of medical care. Our results highlight the need to establish a general medicine consultation service in every Internal Medicine Department and to include this activity in future educational programs.