Acute Clinical Manifestations Research Articles

Activation of cytokines corroborate with development of inflammation and autoimmunity in thromboangiitis obliterans patients

Thromboangiitis obliterans (TAO) is a segmental inflammatory occlusive disorder that affects the arm and leg arteries of young smokers. The immune system seems to play a critical role in the aetiology of TAO; however, knowledge of the aspects involved in the progression of vascular tissue inflammation and, consequently, the evolution of this disease is still limited. This study was carried out to investigate the cytokine levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-17 and IL-23 in the plasma of TAO patients presenting with acute clinical manifestations. The study included 20 TAO patients (n = 10 women; n = 10 men) aged 38-59 years under clinical follow-up, classified into two groups: (i) TAO former smokers (n = 11) and (ii) TAO active smokers (n = 9); the control groups included normal volunteer non-smokers (n = 10, active smokers (n = 10) and former smokers (n = 10). Patients' plasma samples were measured using the sandwich enzyme-linked immunosorbent assay. Statistical analyses were performed using the non-parametric Mann-Whitney U-test, with parameters significant at P < 0·05. The activities of all cytokines were different in groups of TAO patients when compared with normal controls, and decreased for control smokers. Increased levels of TNF-α, IL-1β, IL-4, IL-17 and IL-23 were significant in patients with TAO when compared to the controls (P < 0·005, all parameters). The results presented here indicate an increased production of cytokines in TAO, possibly contributing to the inflammatory response observed in the patients' vascular levels. In addition, the increased levels of IL-17 and IL-23 suggest that the disturbance of TAO is involved with mechanisms of autoimmunity. Thus, the discovery of IL-17 and its association with inflammation and autoimmune pathology has reshaped our viewpoint regarding the pathogenesis of TAO, which was based previously on the T helper type 1 (Th1)-Th2 paradigm.

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: Study protocol for a randomised controlled trial

BackgroundChildren with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain.Methods/designThis study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05.DiscussionThis clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting.Trial registrationCurrent Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20

Cerebral Vasospasm after Sub-arachnoid Hemorrhage as a Clinical Predictor and Phenotype for Genetic Association Study

A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study. The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies. Two hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906 600 single-nucleotide polymorphisms across the human genome. The four clinical manifestations were significantly associated with each other as P-values ranged from 3·31 × 10(-4) to 8·10 × 10(-15) . Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P = 3·39 × 10(-8) ). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic 'vasospasm', and angiographic vasospasm was 0·0017, 0·0017, and 0·19, respectively. Despite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage.

Sickle cell disease: acute clinical manifestations in early childhood and molecular characteristics in a group of children in Rio de Janeiro

ObjectivesTo describe clinical events of sickle cell disease and the correlation with β-globin haplotypes and α-thalassemia in under 6-year-old children.MethodsA retrospective study was conducted of under 6-year-old children from the neonatal screening program in Rio de Janeiro. Forty-eight male and 48 female children were enrolled in this study, 79 with sickle cell anemia and 17 with hemoglobin SC. The mean age was 29.9 (standard deviation = 20.9) months, 62 (16.2 ± 8.6) were aged between 0-3 years old and 34 (54.9 ± 11.3) were from 3-6 years old. Painful events, acute splenic sequestration, hemolytic crises, hand-foot and acute chest syndromes and infections were evaluated.ResultsThe events were more frequent in under 3-year-old children, 94% of children had at least one episode. Infection was the most common event affecting 88.5% of children. Acute splenic sequestration took place earlier, while painful crises and acute chest syndromes in under 6-year-old children. Thal-α 3.7 was observed in 20.9% of cases. Bantu was the most frequent haplotype found, followed by Benin. No correlation was observed between clinical events and β-globin haplotypes. Children with sickle cell anemia and α-thalassemia have less infectious events. No correlation was found among these polymorphisms and clinical events, however, the majority of children with Bantu/Bantu and without α-thalassemia had more clinical events.

Effect of Kuberaksha Patra Churna, Vriddhadaru Mula Churna and Kandughna Taila in Shlipada (Manifested filariasis)

At present there are effective drugs in eradicating microfilariae but treatments to control the progression of manifested filariasis, periodic adenolymphangitis (ADL) and lymphedema are not available in conventional system of medicine. So far National Ayurveda Research Institute for Vector-borne diseases, Vijayawada, has conducted many clinical trails on manifested filariasis patients with the classical Ayurvedic herbal, herbo-mineral drugs and found significant results on ADL, lymphedema and other acute and chronic clinical manifestations. An effort has been made to find the effect of Kuberaksha Patra Churna [Caesalpinia bonduc (L.) Roxb.], Vriddhadaru Mula Churna [Argyreia nervosa (Burm.f.) Boj.] and Kandughna Taila (oil prepared from 10 Ayurvedic drugs) in manifested filarial patients. Based on inclusion criteria 133 patients were included in three groups (45 in Gr.I, 45 in Gr.II and 43 in Gr.III) and 120 patients completed the study (40 in each group). In Gr. I Argyreia nervosa (Burm.f.) Boj. root powder, Caesalpinia bonduc (L.) Roxb. leaf powder mixed equally was given in the dose of 5 g twice a day for 30 days. In Gr.II along with Gr. I internal drugs Kandughna Taila was applied externally in sufficient quantity once a day for 30 days. Gr. III is a control study with Ayurvedic established drug ‘Nityananda Rasa’ 1 tablet thrice daily for 30 days. Group I and II drugs showed highly significant effect on lymphedema, lymphadenitis, lymphangitis, pain, tenderness, heaviness, deformity, fever and rigors (P<0.0001). Group III drug showed highly significant (P<0.0001) effect on lymphedema, deformity and heaviness; statistically significant (P=0.0018) on pain and tenderness; Significant effect on fever (P=0.0290), rigor (P=0.0290) and in lymphangitis (P=0.0384) and non-significant effect on lymphadenitis (P=0.1033). On statistical analysis effect of treatment on Hb and eosinophil count was found non-significant in three groups. On ESR, effect of treatment was found significant in Gr. III and non-significant in Gr. I and Gr. II.

Serum Levels of Gelatinase Associated Lipocalin as Indicator of the Inflammatory Status in Coronary Artery Disease

Background. Atherosclerosis is a chronic inflammatory disease and the acute clinical manifestations represent acute on chronic inflammation. Neutrophil gelatinase-associated lipocalin (NGAL) is found in the granules of human neutrophils, with many diverse functions. The aim of this study was to evaluate the hypothesis that levels NGAL in blood may reflect the inflammatory process in various stages of coronary artery disease. Methods. We studied 140 patients, with SA 40, UA 35, NSTEMI 40, and STEMI 25, and 20 healthy controls. Serum NGAL was measured upon admission and before coronary angiography. Results. Significant differences were observed in median serum-NGAL(ng/mL) between patients with SA (79.23 (IQR, 37.50–100.32)), when compared with UA (108.00 (68.34–177.59)), NSTEMI (166.49 (109.24–247.20)), and STEMI (178.63 (111.18–305.92)) patients and controls (50.31 (44.30–69.78)) with significant incremental value from SA to STEMI. We observed a positive and significant correlation between serum-NGAL and hs-CRP (spearman coefficient rho = 0.685, P < 0.0001) as well as with neutrophil counts (r = 0.511, P < 0.0001). Conclusions. In patients with coronary artery disease serum levels of NGAL increase and reflect the degree of inflammatory process. In patients with acute coronary syndromes, serum levels of NGAL have high negative predictive value and reflecting the inflammatory status could show the severity of coronary clinical syndrome.

Treatment of Acute Transverse Myelitis and Its Early Complications

Acute transverse myelitis (ATM) has many potential etiologies, but a significant proportion of cases are categorized as idiopathic despite thorough evaluation. Clinical presentation of ATM typically includes some combination of motor weakness, sensory symptoms, and bowel and bladder dysfunction. Prompt recognition, even before a final etiologic diagnosis is reached, is critical to initiating early therapeutic intervention to reduce the harmful effects of inflammation. Acute therapeutic options for ATM include corticosteroids, plasma exchange, IV immunoglobulin, and chemotherapeutic agents such as cyclophosphamide. In some instances, combinations of these therapies are used. This article examines the therapeutic approach to ATM and its various acute clinical manifestations.

Spontaneous talar and calcaneal fracture in rheumatoid arthritis: a case report

Rheumatoid arthritis (RA) leads to a progressive weakening of the skeleton which may result in bone fractures. However, spontaneous fractures (exclusive of stress fractures, vertebral collapse, and superficial articular fragmentation) in patients with rheumatoid arthritis have been only occasionally reported in the medical literature. A case of spontaneous talar and calcaneal fracture in rheumatoid arthritis is described. Bone lesions were identified on radiographs, MR images and scintigraphy in a patient with right ankle pain. The absence of episodes of acute trauma, and the presence of acute clinical manifestations should guide the clinical suspicion.

Myocardial edema underlies dynamic T-wave inversion (Wellens' ECG pattern) in patients with reversible left ventricular dysfunction

The Wellens' electrocardiogram (ECG) pattern of dynamic T-wave inversion in the anterior leads is observed in clinical conditions characterized by reversible left ventricular (LV) dysfunction (stunned myocardium), either ischemic or nonischemic. The pathophysiologic basis of this ECG pattern remains to be elucidated. The purpose of this study was to report the contrast-enhanced cardiac magnetic resonance (CE-CMR) findings in 4 cases of Wellens' ECG pattern associated with transient LV dysfunction from a variety of clinical conditions such as myocardial bridge, coronary artery dissection, cholecystitis, and takotsubo syndrome. All patients underwent CE-CMR at the time of acute clinical manifestations and after 6 to 8 weeks of follow-up to assess the presence and dynamics of LV myocardial changes. In all patients, the Wellens' ECG abnormalities were associated with increased signal intensity of the LV myocardium on T2-weighted sequences suggesting myocardial edema, in the absence of late enhancement on postcontrast sequences. Repolarization abnormalities and myocardial edema had a parallel time course with persistence beyond recovery of mechanical abnormalities. T-wave inversion was associated with transient prolongation of the QTc interval in all cases. The study results suggest that myocardial edema rather than systolic dysfunction underlies the Wellens' ECG pattern, regardless of the causative mechanism.

Thrombosis and Sickle Cell Disease

Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin, which has the unique property of polymerizing when deoxygenated. The pathophysiology of acute and chronic clinical manifestations of SCD have shown the central role of dense, dehydrated red cells in acute and chronic clinical manifestations of this pathology. Recent studies have indicated that SCD is characterized by a hypercoagulable state that contributes to the vaso-occlusive events in microcirculation, leading to acute and chronic sickle cell-related organ damage. This review discusses, in the context of SCD, (1) abnormalities in the coagulation system, (2) perturbation of platelet activation and aggregation, (3) vascular endothelial dysfunction, (4) the contribution of cell inflammatory responses, and (5) the connection with nitric oxide metabolism. We also review the available studies on the therapeutic approaches in clinical management of hypercoagulability in SCD.

Erysipelothrix Spp. Genotypes, Serotypes, and Surface Protective Antigen Types Associated with Abattoir Condemnations

The objective of the current study was to investigate characteristics of Erysipelothrix spp. from slaughter condemnations. Specimens from 70 carcasses with lesions suspect for swine erysipelas were collected at an abattoir in Iowa from October 2007 to February 2009. Erysipelothrix spp. were isolated from 59 of 70 carcasses (84.3%). Abattoir inspectors classified lesions as acute, subacute, or chronic; 8 of 8 (100%) were acute cases, 31 of 32 (96.9%) were subacute cases, and 20 of 30 (66.6%) were chronic cases that were isolation positive. The following serotypes were identified: 1a (40.7%; 24/59), 2 (49.2%; 29/59), 7 (1/59), 10 (1/59), 11 (1/59), and untypeable (5.1%; 3/59). Serotypes 1a and 2 were identified in pigs with acute, subacute, or chronic clinical manifestations, whereas serotypes 7, 10, and 11 were only present in chronic cases. Fifty-seven of the 59 isolates were determined to belong to E. rhusiopathiae, and 2 of 59 of the isolates were determined to be E. tonsillarum by multiplex real-time polymerase chain reaction. Surface protective antigen (spa) A was detected in all E. rhusiopathiae isolates but not in E. tonsillarum serotypes 7 and 10. The results of the present study indicate that E. rhusiopathiae serotypes 1a and 2 continue to be commonly isolated from condemned pig carcasses and that spaA is the exclusive spa type in U.S. abattoir isolates. Interestingly, E. tonsillarum, thought to be avirulent for swine, was isolated from systemic sites from 3.4% of the carcasses that were negative for E. rhusiopathiae, indicating the potential importance of this genotype in erysipelas pathogenesis.

Antitrombocitna terapija u sekundarnoj prevenciji

Platelet activation plays a critical role in thrombosis, a major pathophysiologic event responsible for the acute clinical manifestations of atherothrombotic diseases such as acute coronary syndrome, ischemic stroke/transient ischemic attack and peripheral artery disease. Treatment with the combination of aspirin plus P2Y12 antagonist (dual antiplatelet therapy) is an important strategy for preventing ischemic events in patients with acute coronary syndrome, including those undergoing percutaneous coronary intervention. However, patients receiving dual antiplatelet therapy remain at substantial risk of ischemic events because current agents do not interfere with all platelet activation pathways, allowing continued platelet activation via other pathways. The novel P2Y12 inhibitors, prasugrel and ticagrelor, demonstrated superior ischemic outcomes, versus clopidogrel, but event rates remain high, and major bleeding is increased. The use of a combination of proton-pump inhibitors and clopidogrel has recently been questioned due to pharmacological interaction, with possible implications and effects on clinical outcome in patients using this combination. Triple therapy (dual antiplatelet therapy plus a vitamin K antagonist) are recommended as first-line treatment during the initial phase of acute coronary syndrome in patients with atrial fibrillation. Triple therapy is associated with a three- to fourfold increase in major bleeding complications. The management of such patients is challenging owing to the fact that a good level of anticoagulation should be maintained during the acute and long-term phases of the disease.

Sickle‐cell disease in California: A population‐based description of emergency department utilization

Acute and chronic clinical manifestations of sickle-cell disease (SCD) lead to significant healthcare utilization, especially of the emergency department (ED). Limited population-level data are available in SCD with the ability to connect patients to visits, leaving us with minimal description of utilization patterns. Using ED discharge data with links between patients and visits, we sought to describe the California SCD population and its ED utilization patterns across facilities. Non-public California Office of Statewide Health Planning and Development data employ unique patient identifiers, linking patients, and visits. SCD patients of all ages are heavily reliant on Medicaid (46%). The majority of SCD Californians visit an ED more than once during a year (69%), but only a minority use more than one facility during a year (34%). However, adults with SCD have multiple visits and utilize multiple EDs in higher proportions than do children (72% vs. 60% and 40% vs. 21%, respectively). A higher proportion of visits to the ED are made by SCD adults, but a higher proportion of visits by children result in hospital admission. Uninsured adults outnumber uninsured children (16% vs. 5%). ED utilization by the California SCD population is described on a population level. Utilization patterns by adults point towards increased utilization in the population no longer eligible for Title V pediatric coverage for their disease. Further investigation using population-level socioeconomic and geographic correlates is warranted to evaluate the factors leading to ED utilization in SCD.

Antiplatelet therapy for atherothrombotic disease: How can we improve the outcomes?

Platelets play a key role in hemostasis but are also responsible for the formation of pathogenic thrombi underlying the acute clinical manifestations of vascular atherothrombotic disease. Platelets are activated by multiple pathways, including adenosine diphosphate (ADP), thromboxane A(2) (TXA(2)), and thrombin, ultimately leading to formation of platelet-rich thrombi that occlude the arterial lumen, resulting in ischemia and cardiovascular events. Current oral antiplatelet agents inhibit the TXA(2) (aspirin [ASA]) and ADP platelet activation pathways (P2Y(12) ADP receptor antagonists) and have demonstrated clinical efficacy for the reduction of morbidity and mortality in patients with atherothrombotic disease. However, these agents are associated with residual risk for thrombotic events, bleeding risk, and variability in response. Thus, there is a strong clinical need for novel antiplatelet therapies that decrease the risk of thrombotic events without exposing patients to increased risk of bleeding. This review describes the clinical safety and efficacy of ASA and P2Y(12) ADP receptor antagonists, the limitations of current antiplatelet therapy, and novel therapies in development, including newer P2Y(12) ADP receptor antagonists and protease-activated receptor (PAR-1) inhibitors.

Prevalência das manifestações clínicas iniciais da granulomatose de Wegener no Brasil: relato de seis casos e revisão da literatura

To describe the initial clinical manifestations of Wegener's Granulomatosis (WG) in Brazil. Retrospective analysis of six medical records of WG patients followed-up at the Rheumatology Department of Hospital Geral of Fortaleza (HGF), as well as a bibliographic survey of cases of WG in Brazil on LILACS, SciELO, and MEDLINE databases. The study identified 49 patients, 15 (31%) males and 34 (69%) females. Systemic disease was observed in 35 patients (73%): 28 adults, 5 children, and 2 teenagers. Limited disease was observed in 13 adults and 1 child. The average age of onset in adults was 42.2 years (18 to 65 years). Acute clinical manifestations, with the onset of symptoms less than three months before the diagnosis, were observed in 41% (20/49) of the patients, and the insidious presentation in 59% (29/49) of the patients. The prevalence of the initial clinical manifestations in adults with systemic disease (n = 28) was 64% (18/28), upper airways, 36% (10/28), lungs, 18% (5/28), kidneys, 25% (7/28), eyes, 11% (3/28) skin, 25% (7/28), musculoskeletal, and 7% (2/28), neurological. In adults (n = 13) with limited disease, prevalent symptoms included: upper airway, 84% (10/13), eyes, 23% (3/13), and lungs, 15% (2/13). The prevalence of the initial clinical manifestations of WG in Brazil was similar to that reported in the literature. The lack of specific symptoms may delay diagnosis cases with insidious presentation of the disease and increase the morbidity and mortality in acute disease.

In vitro effect of Bartonella birtlesii on mouse red cell viability

The genus Bartonella comprises a unique group of facultative intracellular bacteria that use arthropod transmission as a mammalian parasitism strategy. Common traits of Bartonellae are haemotropic infections in their mammal reservoir hosts without causing immediate detriment to the host. When they are accidentally introduced into the wrong host or into immunocompromised individuals, infection results in acute clinical manifestations. After intravenous inoculation and before stable blood colonisation, Bartonella sp. first infect a primary niche, which could be, according to current opinion, based on in vivo clinical manifestation and on in vitro evidence, the vascular endothelial cells [1]. From this primary niche, the bacteria then colonise the bloodstream. Bartonella-mediated bacteraemia has been investigated using the B. tribocorumrat infection model [2]. This study demonstrated that Bartonella associated with mature erythrocytes entered within erythrocytes and replicated until reaching about eight bacteria per cell. The number of intracellular bacteria remained constant for the remaining lifespan of the erythrocytes. Detailed investigation of the erythrocyte invasion process requires a suitable in vitro model for erythrocyte infection. In this study, we evaluated the effect of the mouse-adapted Bartonella birtlesii on viability of Balb ⁄C mouse erythrocytes maintained in different culture media, with the aim of establishing an appropriate medium to study in vitro red cell infection. MATERIAL AND METHODS

Chronic and acute clinical manifestations associated with systemic mineralization caused by ingestion of Nierembergia veitchii in sheep in southern Brazil

Enzootic calcinosis associated with Nierembergia veitchii ingestion occurs in sheep in southern Brazil, and has been described as a chronic disease. However, in recent years this plant has been associated with cases of acute disease and sudden death in sheep. Data from 12 sheep flocks affected by this toxicosis in southern Brazil, between 1990 and 2007, are described. Thirty-five sheep were necropsied. Twenty-four had a history of chronic disease with weight loss, stiff gait, tucked abdomen, kyphosis, and recumbency. Eleven sheep died suddenly with no prior history of severe illness. In all affected sheep, gross changes included poor body condition and widespread mineralization of several tissues, more prominent in blood vessels and heart valves. In addition, sheep that experienced sudden death had moderate to severe pulmonary edema. There was a distinct seasonal pattern to the clinical presentations, with chronic disease occurring in spring and summer and the acute cases dying in fall and winter. Stress of parturition or poor climatic/nutritional conditions may have precipitated the acute deaths.

Pathologies respiratoires aiguës et subaiguës d’origine toxique

Acute or subacute chemical-induced lung injury is rarely compound specific and is most often caused by an accidental occupational, domestic or environmental exposure to an inhaled chemical agent. The industrial disaster that happened in Bhopal in 1984, accidental poisoning with chlorine and petroleum hydrocarbons and also vesicant gases used during conflicts, are specific examples. Rarely, a chemical agent can cause lung damage by being ingested and reaching the lung through the systemic circulation (for example accidental or deliberate paraquat ingestion). Household accidents should not be underestimated. An important cause of household accidents is chlorine inhalation resulting from mixing bleach with acids such as the scale removers used to clean toilets. Chemical agents can provoke direct and/or indirect damage to the respiratory tract. The acute or subacute clinical manifestations resulting from inhalation of chemical agents are very varied and include inhalation fevers, acute non-cardiogenic pulmonary oedema, adult respiratory distress syndrome, reactive airways dysfunction syndrome and acute or subacute pneumonitis. The site and the severity of chemical-induced respiratory damage caused by inhaled chemical agents depend mainly on the nature and the amount of the agent inhaled. The immediate and long-term prognosis and possible sequelae are also variable. This review excludes infectious or immunologically induced acute respiratory diseases.

Parálisis periódica tirotóxica como forma de presentación de hipertiroidismo primario autoinmunitario. Utilidad del bloqueo betaadrenérgico no selectivo

A 40-year-old Caucasian man presented to the emergency room of our hospital with bilateral lower extremity weakness with onset 1 hour previously and concurrent hypokalemia. After dramatic clinical progression for the first 5 hours, the episode resolved once serum potassium levels were normalized. Laboratory data revealed primary hyperthyroidism, indicating a diagnosis of thyrotoxic periodic paralysis (TPP). Treatment consisted of potassium, propranolol and methimazole administration. Although the mainstay of therapy is potassium replacement, the role of propranolol in improving the acute clinical manifestations of TPP has yet to be adequately clarified.

PATHOPHISIOLOGY OF SICKLE CELL DISEASE AND NEW DRUGS FOR THE TREATMENT

A homozygous mutation in the gene for β globin, a subunit of adult hemoglobin A (HbA), is the proximate cause of sickle cell disease (SCD). Sickle hemoglobin (HbS) shows peculiar biochemical properties, which lead to polymerizing when deoxygenated. HbS polymerization is associated with a reduction in cell ion and water content (cell dehydration), increased red cell density which further accelerate HbS polymerization. Dense, dehydrated erythrocytes are likely to undergo instant polymerization in conditions of mild hypoxia due to their high HbS concentration, and HbS polymers may be formed under normal oxygen pressure. Pathophysiological studies have shown that the dense, dehydrated red cells may play a central role in acute and chronic clinical manifestations of sickle cell disease, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow in a variety of organs and tissue. The persistent membrane damage associated with HbS polymerization also favors the generation of distorted rigid cells and further contributes to vaso-occlusive crisis (VOCs) and cell destruction in the peripheral circulation. These damaged, dense sickle red cells also show a loss of phospholipid asymmetry with externalization of phosphatidylserine (PS), which is believed to play a significant role in promoting macrophage recognition with removal of erythrocytes (erythrophagocytosis). Vaso-occlusive events in the microcirculation result from a complex scenario involving the interactions between different cell types, including dense, dehydrated sickle cells, reticulocytes, abnormally activated endothelial cells, leukocytes, platelets and plasma factors such as cytokine and oxidized pro-inflammatory lipids. Hydroxycarbamide (hydroxyurea) is currently the only drug approved for chronic administration in adult patients with sickle cell disease to prevent acute painful crises and reduce the incidence of transfusion and acute chest crises. Here, we will focus on consolidated and experimental therapeutic strategies for the treatment of sickle cell disease, including: agents which reduce or prevent sickle cell dehydrationagents which reduce sickle cell-endothelial adhesive eventsnitric oxide (NO) or NO-related compoundsanti-oxidant agentsCorrection of the abnormalities ranging from membrane cation transport pathways to red cell-endothelial adhesive events, might constitute new pharmacological targets for treating sickle cell disease.