Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 low-risk essential thrombocythemia patients (CALR-mutated n=271, JAK2V617F-mutated n=162) who were on antiplatelet therapy or observation only. After a 2215 person-years follow-up free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 vs. 1.8 x1000 patient-years, p=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; p=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated than in JAK2V617F-mutated essential thrombocythemia (median time 5 years and 9.8 years, respectively; p=0.0002) usually to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Prevention of bacterial translocation using β-(1-3)-D-glucan in small bowel ischemia and reperfusion in rats

To investigate the role of β-(1-3)-D-glucan on 99mTc labelled Escherichia coli translocation and cytokines secretion in rats submitted to small bowel ischemia/reperfusion injury. Methods: Five groups (n=10 each) of Wistar rats were subjected to control(C), sham(S), group IR subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R), and group I/R+glucan subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R) and injected with 2mg/Kg intramuscular. Translocation of labelled bacteria to mesenteric lymph nodes, liver, spleen, lung and serum was determined using radioactivity/count and colony forming units/g(CFU/g). Serum TNFα, IL-1β, IL-6, IL-10 were measured by ELISA. Results: CFU/g and radioactivity/count were higher in I/R than in I/R+glucan rats. In C, S and S+glucan groups, bacteria and radioactivity/count were rarely detected. The I/R+glucan rats had enhancement of IL-10 and suppressed production of serum TNFα, IL-1β and, IL-6, compared to I/R untreated animals. Conclusion: The β-(1-3)-D-glucan modulated the production of pro-inflammatory and anti-inflammatory cytokines during bowel ischemia/reperfusion, and attenuated translocation of labelled bacteria

Prevention of bacterial translocation using β-(1-3)-D-glucan in small bowel ischemia and reperfusion in rats

To investigate the role of β-(1-3)-D-glucan on 99mTc labelled Escherichia coli translocation and cytokines secretion in rats submitted to small bowel ischemia/reperfusion injury. Methods: Five groups (n=10 each) of Wistar rats were subjected to control(C), sham(S), group IR subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R), and group I/R+glucan subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R) and injected with 2mg/Kg intramuscular. Translocation of labelled bacteria to mesenteric lymph nodes, liver, spleen, lung and serum was determined using radioactivity/count and colony forming units/g(CFU/g). Serum TNFα, IL-1β, IL-6, IL-10 were measured by ELISA. Results: CFU/g and radioactivity/count were higher in I/R than in I/R+glucan rats. In C, S and S+glucan groups, bacteria and radioactivity/count were rarely detected. The I/R+glucan rats had enhancement of IL-10 and suppressed production of serum TNFα, IL-1β and, IL-6, compared to I/R untreated animals. Conclusion: The β-(1-3)-D-glucan modulated the production of pro-inflammatory and anti-inflammatory cytokines during bowel ischemia/reperfusion, and attenuated translocation of labelled bacteria

Découverte de nouveaux marqueurs pharmacogénomiques de la maladie du greffon contre l'hôte en transplantation de cellules souches hématopoïétiques

La transplantation de cellules souches hématopoïétiques (CSH) constitue une avenue thérapeutique potentiellement curative pour plusieurs cancers hématologiques comme la leucémie. L’utilisation d’une thérapie immunosuppressive pour prévenir la maladie du greffon contre l’hôte (GvHD) est un déterminant majeur du succès de la greffe. Malgré tout, cette complication survient chez 25 à 50% des transplantés et est une cause majeure de mortalité. L’optimisation du régime d’immunosuppression est un facteur facilement modifiable qui pourrait améliorer le pronostic des patients. Particulièrement, les polymorphismes du génome du donneur ou du receveur dans les voies pharmacogénomiques des immunosuppresseurs pourraient influencer l’exposition et l’action de ces médicaments, de même que le pronostic du patient. Le profilage de 20 pharmacogènes prioritaires chez des paires de donneurs-receveurs en greffe de CSH a permis d’identifier des variations génétiques liées au risque de la GvHD aiguë. Principalement, le statut génétique du receveur pour les protéines ABCC1 et ABCC2, impliquées dans le transport du méthotrexate (MTX), ainsi que des cibles moléculaires de ce médicament (ATIC et MTHFR) ont été associées au risque de GvHD aiguë. Similairement, le NFATc1, codant pour une cible moléculaire de la cyclosporine, augmentait lui aussi le risque de la maladie. Les porteurs de deux génotypes à risque et plus étaient particulièrement prédisposés à développer cette complication. Par surcroît, le statut génétique du donneur influençait également le pronostic du receveur après la greffe. Entre autres, des allèles protecteurs ont été identifiés dans les voies liées au transport (SLC19A1) et à l’action du MTX (DHFR). Inversement, NFATc2 a été associé à une augmentation du risque de GvHD aiguë. Afin de mieux comprendre les associations observées entre ces marqueurs génétiques et le risque de GvHD aiguë, une étude prospective innovante est en cours chez des greffés de CSH. Cette étude permettra d’étudier comment la génétique du patient ou du donneur peut influencer la pharmacocinétique et la pharmacodynamie des immunosuppresseurs, de même que leurs liens avec la GvHD aiguë. Ces paramètres sont quantifiés grâce à des approches analytiques que nous avons mises au point afin de répondre aux besoins spécifiques et uniques de cette étude. Les approches proposées dans cette thèse sont complémentaires aux méthodes classiques de suivi des immunosuppresseurs et pourraient aider à optimiser la pharmacothérapie du patient. Une meilleure identification des patients à haut risque de GvHD aiguë avant la greffe, basée sur des marqueurs pharmacogénomiques identitaires, pourrait guider le choix de la prophylaxie immunosuppressive, et ainsi améliorer l’issue clinique de la greffe.

Antibioterapia profilática na extração de terceiros molares inclusos

Contextualização: A extração de terceiros molares é um dos atos clínicos mais realizados em Cirurgia Oral. A presença de um terceiro molar incluso pode estar na origem de uma variedade de complicações. Pericoronarite, cáries dentárias e doença periodontal são algumas das indicações para extração de terceiros molares inclusos. A antibioterapia profilática para a prevenção de complicações pós-operatórias como a alveolite e a infeção do local cirúrgico é ainda um assunto que gera alguma controvérsia, particularmente em indivíduos saudáveis. Objetivo: Estudar a necessidade da antibioterapia profilática na extração de terceiros molares e os seus potenciais riscos e benefícios. Materiais e Métodos: Foi efetuada uma pesquisa bibliográfica na base de dados da MEDLINE/PubMed e no motor de busca da ResearchGate. Adicionalmente, foram coletados artigos de interesse da bibliografia recolhida e consultados alguns livros de forma a complementar a informação obtida. Conclusão: Não existe um consenso no que toca à profilaxia antibiótica na extração de terceiros molares. Os médicos dentistas devem, por isso, efetuar uma avaliação cuidada do estado clínico de cada paciente de forma a tomar uma decisão consciente relativamente à administração de antibióticos com o intuito de prevenir complicações pós-operatórias da cirurgia de terceiros molares inclusos.

Variations in chemoprophylaxis for meningococcal disease: a retrospective case note review, analysis of routine prescribing data and questionnaire of general practitioners

BACKGROUND: Invasive meningococcal disease is a significant cause of mortality and morbidity in the UK. Administration of chemoprophylaxis to close contacts reduces the risk of a secondary case. However, unnecessary chemoprophylaxis may be associated with adverse reactions, increased antibiotic resistance and removal of organisms, such as Neisseria lactamica, which help to protect against meningococcal disease. Limited evidence exists to suggest that overuse of chemoprophylaxis may occur. This study aimed to evaluate prescribing of chemoprophylaxis for contacts of meningococcal disease by general practitioners and hospital staff. METHODS: Retrospective case note review of cases of meningococcal disease was conducted in one health district from 1st September 1997 to 31st August 1999. Routine hospital and general practitioner prescribing data was searched for chemoprophylactic prescriptions of rifampicin and ciprofloxacin. A questionnaire of general practitioners was undertaken to obtain more detailed information. RESULTS: Prescribing by hospital doctors was in line with recommendations by the Consultant for Communicable Disease Control. General practitioners prescribed 118% more chemoprophylaxis than was recommended. Size of practice and training status did not affect the level of additional prescribing, but there were significant differences by geographical area. The highest levels of prescribing occurred in areas with high disease rates and associated publicity. However, some true close contacts did not appear to receive prophylaxis. CONCLUSIONS: Receipt of chemoprophylaxis is affected by a series of patient, doctor and community interactions. High publicity appears to increase demand for prophylaxis. Some true contacts do not receive appropriate chemoprophylaxis and are left at an unnecessarily increased risk

Spondylodiscitis as Complication of Transrectal Ultrasonography-guided Prostate Biopsy: a Case Report

A 61-year-old man presented with high fever, and severe back and abdominal pain following transrectal ultrasonography (TRUS)-guided prostate biopsy. Diagnosis of spondylodiscitis and psoas abscesses was made based on MRI images of the lumbar tract of the spine. Six-month broad-spectrum antibiotic treatment and immobilization with a girdle overcame the disease without any relapse at the 1-year follow-up. Spondylodiscitis after TRUS-guided prostate biopsy is a rare event, which is not yet included as a major complication of the procedure. It is probably due to the presence of fluoroquinolone-resistant bacteria in faeces. It is, therefore, important to highlight this possibility and to stress the use of targeted antibiotic prophylaxis after rectal flora swabbing with selected antibiotics at sufficient concentrations to be effective.

Prevention of bacterial translocation using β-(1-3)-D-glucan in small bowel ischemia and reperfusion in rats

To investigate the role of β-(1-3)-D-glucan on 99mTc labelled Escherichia coli translocation and cytokines secretion in rats submitted to small bowel ischemia/reperfusion injury. Methods: Five groups (n=10 each) of Wistar rats were subjected to control(C), sham(S), group IR subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R), and group I/R+glucan subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R) and injected with 2mg/Kg intramuscular. Translocation of labelled bacteria to mesenteric lymph nodes, liver, spleen, lung and serum was determined using radioactivity/count and colony forming units/g(CFU/g). Serum TNFα, IL-1β, IL-6, IL-10 were measured by ELISA. Results: CFU/g and radioactivity/count were higher in I/R than in I/R+glucan rats. In C, S and S+glucan groups, bacteria and radioactivity/count were rarely detected. The I/R+glucan rats had enhancement of IL-10 and suppressed production of serum TNFα, IL-1β and, IL-6, compared to I/R untreated animals. Conclusion: The β-(1-3)-D-glucan modulated the production of pro-inflammatory and anti-inflammatory cytokines during bowel ischemia/reperfusion, and attenuated translocation of labelled bacteria

Prophylactic antibiotics for the prevention of cellulitis

Background: Cellulitis of the lower leg accounts for 2-3% of hospital admissions (Cox et al, 1998), with an average length of in-patient stay of nine days. Studies have reported that up to half of these patients suffer further episodes (Cox et al, 1998; Dupuy et al, 1999). Reducing the recurrence of cellulitis could therefore have a significant impact on both patient morbidity and NHS costs. Aims: To assess whether prophylactic antibiotics prescribed after an episode of cellulitis of the leg results in fewer subsequent attacks and reduced health service costs (PATCH prophylactic antibiotics for the treatment of cellulitis at home). Methods: This article describes two related studies in which participants are randomised to receive either 12 months of prophylaxis (PATCH I) or six months of prophylaxis (PATCH II). The PATCH I study recruits only patients with recurrent disease defined as two or more episodes of cellulitis in the last three years. PATCH II has more open criteria and includes patients with a first episode of cellulitis and also participants with recurrent disease. It is expected that 260 patients will be recruited into PATCH I and 400 patients into PATCH II.

Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment.

OnabotulinumtoxinA for hemicrania continua: open label experience in 9 patients

BACKGROUND: Hemicrania continua is a strictly unilateral, continuous headache, typically mild to moderate in severity, with severe exacerbations commonly accompanied by cranial autonomic features and migrainous symptoms. It is exquisitely responsive to Indomethacin. However, some patients cannot tolerate treatment, often due to gastrointestinal side effects. Therapeutic alternatives are limited and controlled evidence lacking. METHODS: We present our experience of nine patients treated with OnabotulinumtoxinA for hemicrania continua. All patients were injected using the PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) protocol for migraine. RESULTS: Five of nine patients demonstrated a 50% or more reduction in moderate to severe headache days with OnabotulinumtoxinA with a median reduction in moderate to severe headache days of 80%. Patient estimate of response was 80% or more in five subjects. The median and mean duration of response in the five responders was 11 and 12 weeks (range 6-20 weeks). Improvements were also seen in headache-associated disability CONCLUSIONS: OnabotulinumtoxinA adds a potential option to the limited therapeutic alternatives available in hemicrania continua.

Prevention of bacterial translocation using β-(1-3)-D-glucan in small bowel ischemia and reperfusion in rats

To investigate the role of β-(1-3)-D-glucan on 99mTc labelled Escherichia coli translocation and cytokines secretion in rats submitted to small bowel ischemia/reperfusion injury. Methods: Five groups (n=10 each) of Wistar rats were subjected to control(C), sham(S), group IR subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R), and group I/R+glucan subjected to 45 min of bowel ischemia/60 min of reperfusion(I/R) and injected with 2mg/Kg intramuscular. Translocation of labelled bacteria to mesenteric lymph nodes, liver, spleen, lung and serum was determined using radioactivity/count and colony forming units/g(CFU/g). Serum TNFα, IL-1β, IL-6, IL-10 were measured by ELISA. Results: CFU/g and radioactivity/count were higher in I/R than in I/R+glucan rats. In C, S and S+glucan groups, bacteria and radioactivity/count were rarely detected. The I/R+glucan rats had enhancement of IL-10 and suppressed production of serum TNFα, IL-1β and, IL-6, compared to I/R untreated animals. Conclusion: The β-(1-3)-D-glucan modulated the production of pro-inflammatory and anti-inflammatory cytokines during bowel ischemia/reperfusion, and attenuated translocation of labelled bacteria

A Case of Internal Carotid Artery Thrombosis associated with Thalidomide Administration in Multiple Myeloma

Thalidomide is an effective chemotherapeutic agent used to achieve remission in multiple myeloma. However, its administration is associated with several adverse effects including venous thromboembolism, while arterial thrombosis has also, although rarely, been described in the literature. We report a case of internal carotid artery occlusion within 1 week of starting thalidomide with prophylactic low molecular weight heparin in a patient who had no other prothrombotic risk factors. It is not known why this complication occurs despite the administration of anticoagulant prophylaxis. The role of factor VIII, von Willebrand factor antigen levels and fibrinogen in multiple myeloma patients should be studied in order to determine if these factors should be targeted in future prophylactic treatment.

Dietary supplements based on borututu: wich is the most suitable choice for bioactive purposes?

Borututu ( Cochlospermum angolensis Welw.) is a widespread tree in Angola used since antiquity by traditional healers for the prevention and treatment of hepatic diseases and for the prophylaxis of malaria [1]. This plant is mostly consumed as infusions but is also available as dietary supplements, such as piiis, capsules, and syrups, among others. In the present study, the aim was to evaluate the proximate composition and energetic contribution of borututu as weii as its composition in hydrophilic (sugars and organic acids) and lipophilic (fatty acids and tocopherols) compounds, given the fact that this plant is directly introduced in some dietary supplements. Furthermore, the bioactivity (antioxidant, hepatoprotective and antimicrobial activities) of three different formulations of borututu (infusion, pills, and syrup) was assessed and compared, and since plant beneficial properties are often ascribed to phenolic compounds [2], the phenolic profile of the formulations was also analysed. Carbohydrates (88 g/100 g) and fat (2.5 g/100 g) were the major and tl1e minor components of the studied borututu dry barks, respectively, with an energetic contribution of 384 kcal/100 g. Fructose was the most abundant sugar (1.3 g/100 g), foilowed by sucrose, trehalose and glucose (1.1, 0.98 and 0.79 g/100 g, respectively). Oxalic (0.70 g/100 g), malic (0.63 g/100 g) and citric (0.57 g/100 g) acids were present in higher amounts but shikimic and fumaric acids were also detected. Among the fatty acids found in borututu, a prevalence of saturated fatty acids (SF A; 48.2%) was observed, whereas polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids were detected in relative percentages of 30.9% and 20.8%, respectively. P-tocopherol was the most abundant of the four isoforms found in the sample, foiiowed by o-, a- and y-tocopherol, present in concentrations of 597,43, 3.7 and 2.0 g/100 g, respectively. Borututu infusion revealed the highest antioxidant activity, with EC50 values ranging from 20 to 600 J.lg/mL and was the only formulation inhibiting the growth of an HepG2 ceii line, with a Gl5o value of 146 J.lg/mL. This formulation.also revealed the best antimicrobial capacity and proved to be able to inhibit the growth of Escherichia coli, E. coli ESBL, Staphylococcus aureus and Pseudomonas aeruginosa, with MIC values of 50, 6.2, 1.6 and 25 mg!mL, respectively. Pills revealed activity against some of the studied bacterial strains and the syrup did not reveal antimicrobial activity at the studied concentration. Eilagic acids, methyl ellagic acids, eucaglobulinlglobulusin B and (epi)gaiiocatechin-0-gallate were the compounds present in all the different formulations. The highest concentration of phenolic compounds was found in the infusion extract. Protocatechuic acid was the most abundant phenolic compound in the infusions, the only preparation where it was detected, whereas ( epi)gaiiocatechin- 0-gallate was the main phenolic in the pills and eucaglobulinlglobulusin in the syrup. In a general way, borututu proved to be a good source of phytochemicals such as phenolic compounds, with the infusions revealing the best bioactive properties.

Phenolic profile and antimicrobial activity of dietary supplements based on Cochlospermum angolensis Welw.

Cochlospermum angolensis Welw. (borututu) is a widespread tree in Angola that belongs to the Cochlospermaceae family. Its bark infusion is used in the traditional medicine of Angola for the treatment of jaundice, hepatic diseases and for the prophylaxis of malaria [1]. In the present work, three formulations based on this plant (infusion, pills, and syrup) were characterized by HPLC-DAD-ESI/MS regarding phenolic composition, and evaluated by their in vitro antimicrobial activity against isolates of multiresistant bacteria (Escherichia coli, Escherichia coli spectrum extended producer of β-lactamases (ESBL), Proteus mirabilis, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa). The infusion and pills revealed the highest variety of phenolic compounds, with eleven compounds identified. Protocatechuic acid was only present in infusions, being the most abundant compound, while (epi)gallocatechin-O-gallate and eucaglobulin/globulusin were the main molecules identified in pills and syrup, respectively. Methyl ellagic acids, eucaglobulin/globulusin B (Fig. 1) and (epi)gallocatechin-O-gallate were found in all the formulations. The infusion revealed antimicrobial activity against all the studied bacteria with the exception of P. mirabilis whereas the pills revealed activity in E. coli ESBL and MRSA. No significant antimicrobial activity was detected in the syrup, in agreement with its low concentrations of phenolic compounds. None of the tested formulations inhibited P. mirabilis. Considering the obtained results, C. angolensis infusion can be considered a good source of phenolic compounds as well as a good antimicrobial agent.