Spinal Muscular Atrophy (SMA) is caused by mutation or deletion of the Survival Motor Neuron 1 (SMN1), which encodes cell-ubiquitous SMN protein. Although classified as a neuromuscular disease, a range of systemic pathologies is reported in SMA patients. Despite a clear understanding of the genetics, the role of SMN protein in SMA pathogenesis is somewhat unclear, especially in tissues outside the CNS. Here, we describe failed liver development in response to reduced SMN levels, in a Taiwanese mouse model of severe SMA. Molecular analysis revealed significant changes in proteins involved in cell cycling and blood homeostasis including coagulation prior to motor neuron pathology. With SMN being directly associated with some of these proteins, this indicates primary liver pathology in SMA. Study of livers obtained from two other mouse models of SMA; severe SMNΔ7 and intermediate 2B, which have slightly higher SMN levels than Taiwanese SMA mice, also revealed significant overlapping pathologies, suggestive of high intrinsic susceptibility of the liver to SMN decrease. Proteomic study of pre-symptomatic 2B/- liver revealed significant perturbations in mitochondrial bioenergetics, which could account for metabolic defects in SMA patients. Vascular changes can be observed in mouse models of SMA and even skeletal muscle of severe SMA patients. Although Taiwanese SMA liver showed no morphological changes to its vasculature, it does have impairments in several key vascular signaling molecules, including VEGF and Tie-2. Furthermore, we report for the first time significant vascular changes in a zebrafish model of SMA, that could be associated with defective neuronal-vascular signaling and is supported by preliminary findings in the Taiwanese SMA retina. This thesis uncovers perturbations in several clinically relevant signalling pathways directly linked to SMN decrease, independent of the motor neurone pathology. Taken together this work emphasises the importance of a systemic therapy in SMA.

Orientadores: Joyce Maria Annichino-Bizzacchi, Rodrigo Nogueira Angerami / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T02:16:10Z (GMT). No. of bitstreams: 1 Orsi_FernandaLoureirodeAndrade_D.pdf: 6021232 bytes, checksum: e409b42632a9af01efbd442e6f2db91f (MD5) Previous issue date: 2013 / Resumo: Os casos de dengue são classificados em dengue clássica (DC) e febre hemorrágica da dengue (FHD). Embora a DC seja considerada uma manifestação não grave da dengue, algumas complicações clínicas podem ser encontradas neste grupo, em particular as complicações hemorrágicas. Entretanto, as causas de sangramentos na DC não estão esclarecidas. Desta forma, o objetivo deste estudo foi realizar uma avaliação abrangente dos possíveis mecanismos fisiopatológicos que podem contribuir para a tendência hemorrágica da dengue. Este é um estudo de caso-controle que incluiu adultos com dengue durante o período de defervescência da doença e controles saudáveis. Foram avaliadas as células do sangue periférico, os marcadores da resposta inflamatória, da permeabilidade microvascular, da ativação de células endoteliais e da fibrinólise e a geração de trombina nos pacientes e controles. Foram incluídos 26 adultos com DC e sangramento, 33 adultos com DC sem complicações, 8 adultos com FHD e 67 controles saudáveis. A gravidade e extensão dos sangramentos foram semelhantes entre os pacientes classificados como DC e os classificados como FHD. Pacientes com DC com sangramento e FHD tinham menor contagem de plaquetas em comparação aos com DC sem sangramento. Fator de necrose tumoral (TNF-?), trombomodulina (TM) e fator de von Willebrand (FVW) estavam aumentados nos grupos de dengue em relação aos controles. A atividade e antígeno da ADAMTS 13 estavam diminuídos, em particular nos pacientes com DC não complicada. Houve tendência ao aumento do fator de crescimento do endotélio vascular (VEGF-A) apenas nos pacientes com FHD, mas a diferença não foi estatisticamente significativa. Houve, porém, alterações significativas dos receptores solúveis do VEGF-A (sVEGF-R1 e sVEG-R2). Os níveis plasmáticos do sVEGF-R1 estavam aumentados e de sVEGF-R2 estavam diminuídos nos pacientes, principalmente nos com FHD. A relação VEGF-A/VEGF-R2 estava significativamente elevada nos casos de FHD em relação aos controles e aos outros grupos de dengue. Os níveis plasmáticos do ativador tecidual do plasminogênio (tPA) e dímero-D (DD) estavam significativamente elevados em pacientes com DC e sangramento e nos com FHD; sendo que os níveis séricos de PAI-1 não diferiram entre os grupos. Os pacientes com DC com sangramento e FHD apresentaram também menor geração de trombina. Estes resultados permitem concluir que a DC pode manifestar-se com hemorragias espontâneas associadas a diversos distúrbios da hemostasia, na ausência de sinais clínicos ou laboratoriais de aumento da permeabilidade vascular. Os principais distúrbios da hemostasia encontrados foram trombocitopenia, hiperfibrinólise e hipocoagulabilidade. Desta forma, a DC compreende um grupo heterogêneo de doentes que podem apresentar uma coagulopatia complexa e potencialmente grave / Abstract: Dengue has been classified according to disease severity into dengue fever (DF) and dengue hemorrhagic fever (DHF). Although DF is considered a non-severe manifestation of dengue, it represents a heterogeneous group of patients with varied clinical complications, particularly, bleeding complications. However, the causes of bleedings in DF have not been fully addressed. Thus, the aim of this study was to perform a comprehensive evaluation of possible pathophysiological mechanisms that could contribute to the bleeding tendency in DF and DHF. This is a case-control study that enrolled adults with DF without bleeding, DF and bleeding complications and DHF during the defervescence period. Healthy controls were also included. Peripheral blood counts, inflammatory, microvascular permeability, fibrinolysis, endothelial cell activation markers, and thrombin generation were evaluated in patients and controls. We included 26 adults with DF and bleeding, 33 adults with DF without complications, 8 adults with DHF and 67 healthy controls. The severities of the bleeding episodes were similar between patients with DC and DHF. Patients with DF with bleedings and DHF had lower platelet counts than DF without bleeding. Levels of the tumoral necrosis factor (TNF)-?, thrombomodulin (TM) and von Willebrand factor (VWF) were significantly increased in dengue groups than in healthy controls, but similar among patients. Plasma levels of the soluble receptor 1 of the vascular endothelial growth factor (sVEGR-R1) were increased and plasma levels of sVEGF-R2 were decreased in patients with DF and bleedings and in patients with DHF. In DHF patients presented a non-significant increased in vascular endothelial growth factor (VEGF-A) serum levels and a significantly higher VEGF/sVEGF-R2 ratio. Plasma levels of tissue plasminogen activator (tPA) and D-dimer (DD) were significantly increased in patients with bleedings, regardless of the dengue classification, while PAI-1 was similar between groups. Patients with DHF and DF with bleeding complications had reduced thrombin formation. In conclusion, DF can manifest with spontaneous bleedings without clinical and laboratory signs of increased vascular permeability. Spontaneous bleeding was associated with thrombocytopenia, excessive fibrinolysis and reduced thrombin in both DF with bleeding and DHF groups. These coagulopaties were not significantly present in DF without bleeding. DF is a heterogeneous group of patients that may present with a complex and potentially severe coagulation disorders / Doutorado / Clinica Medica / Doutora em Clínica Médica

Thesis (MScMedSc)--Stellenbosch University, 2012. / Bibliography / ENGLISH ABSTRACT: Background: In the era of antiretroviral therapy (ART), the risk of acquired immune deficiency syndrome (AIDS) related deaths has decreased and people living with Human Immunodeficiency Virus (HIV) now have prolonged life spans. However, an increasing trend of non-AIDS associated deaths has been reported despite adequate control of viral loads. HIV infection is established as a chronic inflammatory condition which is associated with an increased risk for thrombosis. Thus HIV infected patients are at a higher risk of developing cardiovascular disease (CVD) and other inflammatory-associated complications. Inflammation is linked with thrombosis and promotes the formation of thrombin, which plays an important role in platelet activation. Furthermore, activated platelets have been shown to play a key role during infection and the inflammatory process, particularly by mediating interactions between cells of innate immunity. Soluble markers of platelet activation have been shown to be increased in HIV-infection. However, these have not been well documented by flow cytometry. P-selectin CD62P is stored in the alpha granules of platelets and is expressed on the surface only upon platelet activation. This facilitates interaction with other blood cells and the endothelium. Activated platelets may play a role in HIV-induced atherosclerosis through the expression and release of mediators that induce endothelial activation and support the adhesion of leukocytes to the inflamed vessel wall. Fibrinogen is a precursor of the blood coagulatory protein fibrin and the degradation of fibrin to D-dimer is a measure of the formation and the subsequent dissolution of blood clots. In HIV infected patients, chronic inflammation induces the up-regulated expression of tissue factor (TF) on monocytes which triggers the activation of the clotting cascade and increases the level of D-dimers. Methods: This pilot study consisted of ART naïve patients and all platelet flow analyses were carried out on whole blood. In this study, a total of 57 adult South Africans were recruited from a clinic in the Western Cape. These included 32 HIV positive patients and 25 HIV negative individuals. The levels of platelet activation and platelet function were investigated using a novel platelet cytometry assay. The method was optimized to ensure minimal platelet activation: no centrifugation or red blood cell (RBC) lysis steps were performed. The platelet-specific markers CD41a and CD42b were used to ensure gating on platelets only. CD62P expression was used to evaluate platelet activation and these levels were correlated with Fibrinogen, hsCRP, Ddimer, CD4 counts and viral load. Furthermore, platelet function was evaluated by investigating the response of platelets to endogenous agonists which included adenosine diphosphate(ADP) and arachidonic acid (AA) at varying concentrations. Results:This study demonstrated higher baseline levels of CD62P expression in treatment naïve HIV positive patients as compared to uninfected controls (mean %CD62P 71.74 ± 2.18 vs control 54.52 ± 2.42; p=<0.0001). In addition it was shown that %CD62P expression correlated directly with platelet counts (r=0.374, p=0.042). Platelet counts showed an inverse correlation with viral loads (give values) Fibrinogen levels correlated with the absolute WCC (r=0.659, p=0.0021); absolute neutrophil count (r=0.619, p=0.0105); absolute monocyte count (0.562, p=0.0235) and hsCRP (r=0.688 p=0.0011). In addition, fibrinogen showed a strong negative correlation with CD4 counts (r=-0.594, p=0.0014) and therefore, may be a valuable marker of both disease progression and risk of thrombosis in treatment naïve HIV positive patients. HsCRP levels correlated with the absolute neutrophil counts (r=0.392, p=0.0005). The HIV Group showed an overall hyper-response to ADP at a concentration 0.025 μM as compared to uninfected controls (62.34 ± 9.7 vs control 36.90 ± 5.7, p=0.0433). Conclusions: In this study we describe a novel Flow Cytometry technique that may be used to evaluate the levels of platelet activation and platelet function in HIV infected patients. In addition we report a cost-effective panel in the form of fibrinogen, WCC and platelets that may be valuable in predicting the progression of HIV infection to AIDS or other inflammatory- associated complications in treatment naïve HIV infected patients. Platelet counts showed an inverse correlation with viral loads and a direct correlation with the level of activated platelets. These findings taken together suggest the potential prognostic value of platelet activation and platelet counts in the context of asymptomatic HIV infected patients. Our findings suggest WCC and Fibrinogen may be used to evaluate the inflammatory profile of individual HIV infected patients. This may have a direct impact on HIV patient management prior to initiation of antiretroviral therapy and valuable in monitoring responses to treatment. Further, we present a novel flow cytometry based platelet functional assay and suggest the use of ADP at a concentration of 0.025 μM to evaluate platelet function optimally in HIV infected patients. The utilization of the novel Flow Cytometry technique as described in this study would add significant value in the assessment of thrombotic risk and disease progression in HIV infected patients and may additionally prove to be of value in other chronic inflammatory conditions. / AFRIKAANSE OPSOMMING: Voorkennis: In die era van antiretrovirale terapie (ART), het die risiko van vigs-verwante sterftes verminder en mense wat nou met volle naam (MIV) leef, het ‘n verlengde lewensduur. Nogtans, word 'n toenemende neiging van nie-vigs geassosieer sterftes berig wat hoofsaaklik toegeskryf word aan trombotiese toestande. MIV-infeksie word as 'n chroniese inflammatoriese toestand beskou met ʼn verhoogde trombose risiko geassosieer word. Dus, MIV-besmette pasiënte het 'n hoër risiko om kardiovaskulêre siekte (CVD) te ontwikkel ongeag of hulle ARV naïef is of op behandeling is nie. Inflammasie word geassosieer met trombose en bevorder die vorming van trombien, wat 'n belangrike rol in plaatjie aktivering speel. Verder, word daar bewys dat geaktiveerde bloedplaatjies 'n belangrike rol speel tydens infeksie en die inflammatoriese proses.Hulle bemiddel interaksies tussen die selle van ingebore immuniteit. Daar word bewys dat oplosbare merkers van plaatjie aktivering verhoog is in MIV-infeksie, maar die bewyse is nie so goed gedokumenteer deur vloeisitometrie nie. P-selectin (CD62P) word gestoor in die alfa korrels van plaatjies en word uitgedruk op die oppervlak slegs wanneer plaatjies geaktivering word; daardeur fasilitering dit die interaksie met ander bloedselle en die endoteel. Geaktiveerde plaatjies kan ook 'n rol in MIV-geïnduseerde aterosklerose speel deur middel van die uitdrukking en vrylating van bemiddelaars wat endoteel aktivering induseer asook die adhesie van leukosiete aan die ontsteekte vat wand ondersteun.. Fibrinogeen, 'n voorloper van die bloed koagulatories proteïen fibrin en die degradasie van fibrin na D-dimeer is' n maatstaf van die vorming en die daaropvolgende ontbinding van bloedklonte. Kroniese inflammasie in MIVbesmette pasiënte, induseer die op-gereguleerde uitdrukking van weefsel faktor (TF) op monosiete wat die aktivering van die stolling kaskade inisieer en die D-dimere vlakke verhoog. Metodes: Hierdie loodsstudie bestaan uit ART naïewe pasiënte en al die plaatjie vloei ontleding was op vol bloed uitgevoer. In hierdie studie, 'n totaal van 57 volwasse Suid-Afrikaners was van' n kliniek in die Wes-Kaap gewerf. Dit sluit 32 MIV-positiewe pasiënte en 25 MIV negatiewe individue in. Die vlakke van plaatjie aktivering en plaatjie funksie was ge ondersoek deur middel van 'n nuwe plaatjie sitometrie toets. Die metode was geoptimaliseer om minimale plaatjie aktivering te verseker: dus geen sentrifugering of volle naam (RBS) liseer stappe was gebruik nie. Die plaatjie-spesifieke merkers, CD41a en CD42b was gebruik om te verseker dat slegs bloedplaatjes gekies word. Die uitdrukking van CD62P was gebruik vir die evaluering van plaatjie aktivering en hierdie vlakke was gekorreleer met fibrinogeen, hsCRP, D-dimeer, CD4- tellings en virale lading. Verder, was plaatjie funksie geëvalueer deur die reaksie van plaatjies aan endogene agoniste wat ADP en AA by wisselende konsentrasies insluit te ondersoek. Results: Hierdie studie het getoon hoër basislyn vlakke van CD62P uitdrukking in behandeling naïewe MIV-positiewe pasiënte in vergelyking met onbesmette beheermaatreëls (beteken% CD62P 71,74 ± 2,18 vs beheer 54,52 ± 2,42, p <0.0001). Daar is ook getoon dat% CD62P uitdrukking direk gekorreleer met plaatjie tellings (r = 0,374, p = 0,042). Plaatjie tellings het 'n omgekeerde korrelasie met virale ladings (gee waardes) fibrinogeen vlakke korreleer met die absolute WCC (r = 0,659, p = 0,0021), absolute neutrofiel telling (r = 0,619, p = 0,0105); absolute monosiet telling (0,562, p = 0,0235) en hsCRP (r = 0,688 p = 0,0011). Daarbenewens, fibrinogeen het 'n sterk negatiewe korrelasie met 'n CD4-tellings (r = -0,594, p = 0,0014) en daarom kan 'n waardevolle merker van beide die siekte en die risiko van trombose in behandeling naïewe MIV-positiewe pasiënte. HsCRP vlakke gekorreleer met die absolute neutrofiel tellings (r = 0,392, p = 0,0005). Die MIV-groep het 'n algehele hiper-reaksie op die ADP by 'n konsentrasie 0,025 μM in vergelyking met onbesmette beheermaatreëls (62,34 ± 9,7 vs beheer 36,90 ± 5.7, p = 0,0433). Gevolgtrekkings: In hierdie studie beskryf ons 'n roman vloeisitometrie tegniek wat gebruik kan word om die vlakke van Plaatjie aktivering en plaatjie funksie in die MIV-besmette pasiënte te evalueer. Verder het ons 'n verslag van 'n koste-effektiewe paneel in die vorm van fibrinogeen, WCC en plaatjies wat waardevol kan wees in die voorspelling van die vordering van MIVinfeksie tot VIGS of ander inflammatoriese-verwante komplikasies in die behandeling naïewe MIV-besmette pasiënte. Plaatjie tellings het 'n omgekeerde korrelasie met die virale laste en 'n direkte verband met die vlak van geaktiveerde bloedplaatjies. Hierdie bevindinge saam, dui op die moontlike prognostiese waarde van Plaatjie aktivering en die plaatjie tel in die konteks van die asimptomatiese MIV-geïnfekteerde pasiënte. Ons bevindinge dui daarop WCC en fibrinogeen kan gebruik word om die inflammatoriese profiel van individuele MIV-geïnfekteerde pasiënte te evalueer. Dit kan 'n direkte impak op MIV pasiënt vooraf aan die inisiasie van antiretrovirale terapie en waardevolle in die monitering van die reaksie op behandeling. Verder bied ons 'n roman vloeisitometrie gebaseer plaatjie funksionele toets en dui op die gebruik van die ADP teen 'n konsentrasie van 0,025 μM plaatjie funksie optimaal te evalueer in MIVgeïnfekteerde pasiënte. Die benutting van die roman vloeisitometrie tegniek soos beskryf in hierdie studie sal 'n beduidende waarde toevoeg in die beoordeling van die die trombotiese risiko en die siekte in MIV-geïnfekteerde pasiënte en kan addisioneel bewys van waarde te wees in 'n ander chroniese inflammatoriese toestande. / National Reserach Foundation

Aproximadamente 5,8 milhões de pessoas morrem anualmente vítimas de trauma no mundo. A reposição volêmica inicial dos pacientes graves politraumatizados com choque hemorrágico tem características distintas hoje quando comparada à proposta não mais do que uma década atrás. A infusão reduzida de fluidos associada à transfusão precoce de hemoderivados é o padrão adotado em portadores de hemorragia maciça, no que se chama na literatura de damage control resuscitation (DCR). Entretanto, a administração precoce de componentes do sangue, implica em limitações de armazenamento, transporte, disponibilidade, compatibilidade, reações transfusionais e custo. Assim, estratégias medicamentosas que possam beneficiar o paciente politraumatizado no tratamento do sangramento devem ser desenvolvidas. As pesquisas atuais buscam medidas que possam agir na resposta inflamatória e na coagulopatia envolvidas nas lesões traumáticas e no choque hemorrágico. Desta forma, decidiu- se avaliar o potencial da administração precoce de Pentoxifilina (PTX) em associação com Ringer lactato (RL) e seus efeitos na coagulopatia associada ao trauma. Foi utilizado modelo experimental suíno de choque hemorrágico e politrauma. Foram utilizados 23 suínos, machos, da raça Landrace, com peso médio de 28,5 kg randomizados em 3 grupos: Controle (n=5), RL (n=5) e PTX (n=7). Os animais foram submetidos à anestesia geral, exceto o grupo controle, a uma fratura de fêmur, seguido de choque hemorrágico controlado e, por fim, uma lesão hepática como hemorragia não controlada. Foram analisados parâmetros hemodinâmicos, laboratoriais e gasometria, testes de coagulação padrão e tromboelastometria. Os animais submetidos ao experimento apresentaram taquicardia, hipotensão arterial, hipotermia, acidose, redução de hemoglobina e alteração nos testes de coagulação e viscoelásticos. O lactado no tempo Final mostrou-se mais elevado no grupo PTX, quando comparado ao grupo RL (p=0,01). Os dados da tromboleastometria não mostraram diferença entre os grupos submetidos ao experimento. No tempo Final, observou-se uma redução do fibrinogênio menor no grupo tratado com PTX, quando comparado ao grupo RL (p < 0,01). A análise dos efeitos da pentoxifilina associada à reanimação volêmica sugere melhora dos níveis de fibrinogênio após sua administração seguindo a hemorragia e trauma / Approximately 5.8 million people die each year victim of trauma worldwide. The initial volume replacement of severely injured patients with hemorrhagic shock has different characteristics today than a decade before. Low-volume fluid resuscitation associated with early transfusion of blood products is the standard adopted in patients with massive hemorrhage, so called damage control resuscitation (DCR). However, early administration of blood components implies limitations in storage, transport, availability, compatibility, transfusion reactions, and cost. Thus, drug strategies that may benefit the severely injured patient in the treatment of bleeding should be developed. Current research seeks measures that can modulate the inflammatory response and coagulopathy involved in traumatic injuries and hemorrhagic shock. Therefore, we decided to evaluate the role of early administration of Pentoxifylline (PTX) in association with RL and its effects on coagulopathy and traumatic inflammatory response. A porcine model of multiple trauma and hemorrhagic shock was used. Twenty-three Landrace male pigs were used, with a mean weight of 28.5 kg randomized into three groups: Control (n=5), RL (n=5), and PTX (n=7). The animals were submitted to general anesthesia (except the control group), femur fracture, followed by controlled hemorrhagic shock, and, finally, a hepatic injury (as uncontrolled hemorrhage simulation). Hemodynamic parameters, laboratory tests, standard coagulation tests and thromboelastometry were analyzed. The animals submitted to the experiment presented tachycardia, hypotension, hypothermia, acidosis, hemoglobin decrease and impaired coagulation and viscoelastic tests. Lactate levels at the end of the experiment were higher in the PTX group when compared to RL (p=0,01). Data extracted from thromboelastometric tests have shown no difference between the groups submitted to the protocol. Fibrinogen reduction (consumption) were significantly lower in the PTX group when compared to RL (p < 0,01). The analysis of pentoxifylline effects suggests less fibrinogen consumption after PTX administration

Trauma é a maior causa de óbito entre adultos jovens no Brasil e no mundo, considerado um problema grave de saúde mundial. Atualmente, o controle da hemorragia é feito com uma reanimação hemostática, que preconiza a hipotensão permissiva, limita o uso de cristalóides, estimula o uso precoce de hemoderivados e medicamentos que possam minimizar o sangramento. Entretanto, a administração precoce de componentes do sangue, apresenta limitações de armazenamento, transporte, disponibilidade, compatibilidade, reações transfusionais e custo. Assim, devem ser desenvolvidas estratégias medicamentosas que possam beneficiar o paciente politraumatizado no tratamento do sangramento e na coagulopatia traumática. Por isso, decidiuse avaliar o efeito da administração precoce de N-acetilcisteína (NAC) e do ácido tranexâmico (TXA) em associação com Ringer lactato e seus efeitos na coagulação. Foi utilizado modelo experimental de choque hemorrágico e politrauma em 36 suínos, machos, da raça Landrace, com peso médio de 28,34 kg e distribuídos em cinco grupos: Controle (n=5), Ringer lactato (n=5), NAC (n=6), TXA (n=6) e NAC+TXA (n=6). Os animais foram submetidos à anestesia geral, fratura de fêmur, choque hemorrágico controlado e, por fim, a uma lesão hepática com hemorragia não controlada. Foram analisados os parâmetros fisiológicos, testes laboratoriais e tromboelastometria. Todos os animais submetidos ao experimento apresentaram taquicardia, hipotensão arterial, hipotermia, acidose, redução de plaquetas e hemoglobina e alteração nos testes de coagulação e viscoelásticos. O grupo NAC+TXA apresentou melhora do pH e excesso de base nas fases mais tardias do experimento quando comparados com os demais grupos (p < 0,05). No tempo Final, observou-se uma redução do fibrinogênio menor no grupo tratado com NAC+TXA. Na análise da tromboelastometria, os grupos tratados com TXA e NAC+TXA apresentaram o ML menor do que os tratados apenas com Ringer lactato ou NAC (p < 0,05). As análises do estudo sugerem um efeito benéfico da NAC em associação com TXA na melhora da acidose e fibrinólise. / Trauma is the major cause of death among young adults in Brazil and is considered a worldwide public health problem. Today, hemorrhage control begins with a homeostatic approach which preconizes permissive hypotension, limits the use of crystalloids, uses early transfusion and drugs that can minimize bleeding. However, early administration of blood components implies concerns, which includes storage, transport, availability, compatibility, transfusion reactions and cost. Therefore, there must be strategies that could bring benefits to the patient victim of trauma with bleeding and traumatic coagulopathy. Thus, it was decided to evaluate the potential of early administration of N-acetylcysteine (NAC) and Tranexamic Acid (TXA) associated or not to Ringer lactate and its potential benefits in coagulopathy. A model of multiple trauma and hemorrhagic shock previously described was used to evaluate these aspects in 36 male pigs, Landrace race, with an average weight of 28,34 kg and randomized into five groups: Control (n=5), Ringer lactate (n=5), NAC (n=6), TXA (n=6) and NAC + TXA (n=6). The animals were submitted to general anesthesia, a femur fracture, followed by controlled hemorrhagic shock, and an uncontrolled hepatic hemorrhage. Physiological parameters, standard laboratory tests and thromboelastometry were analyzed. All the animals showed tachycardia, low blood pressure, hypothermia, acidosis, lower platelets and hemoglobina levels and viscoelastics tests. The group NAC + TXA showed improvement in pH and base excess at the final phase of the experiment when compared with the others groups (p < 0.05). At the final phase, fibrinogen was lower reduced in the NAC + TXA group. In the thromboelastometry, the groups TXA and NAC + TXA had lower ML (Maximum Lysis) than the groups Ringer lactate and NAC. The study suggests a beneficial effect of NAC in association with TXA in improving acidosis and fibrinolysis

Trauma é a maior causa de óbito entre adultos jovens no Brasil e no mundo, considerado um problema grave de saúde mundial. Atualmente, o controle da hemorragia é feito com uma reanimação hemostática, que preconiza a hipotensão permissiva, limita o uso de cristalóides, estimula o uso precoce de hemoderivados e medicamentos que possam minimizar o sangramento. Entretanto, a administração precoce de componentes do sangue, apresenta limitações de armazenamento, transporte, disponibilidade, compatibilidade, reações transfusionais e custo. Assim, devem ser desenvolvidas estratégias medicamentosas que possam beneficiar o paciente politraumatizado no tratamento do sangramento e na coagulopatia traumática. Por isso, decidiuse avaliar o efeito da administração precoce de N-acetilcisteína (NAC) e do ácido tranexâmico (TXA) em associação com Ringer lactato e seus efeitos na coagulação. Foi utilizado modelo experimental de choque hemorrágico e politrauma em 36 suínos, machos, da raça Landrace, com peso médio de 28,34 kg e distribuídos em cinco grupos: Controle (n=5), Ringer lactato (n=5), NAC (n=6), TXA (n=6) e NAC+TXA (n=6). Os animais foram submetidos à anestesia geral, fratura de fêmur, choque hemorrágico controlado e, por fim, a uma lesão hepática com hemorragia não controlada. Foram analisados os parâmetros fisiológicos, testes laboratoriais e tromboelastometria. Todos os animais submetidos ao experimento apresentaram taquicardia, hipotensão arterial, hipotermia, acidose, redução de plaquetas e hemoglobina e alteração nos testes de coagulação e viscoelásticos. O grupo NAC+TXA apresentou melhora do pH e excesso de base nas fases mais tardias do experimento quando comparados com os demais grupos (p < 0,05). No tempo Final, observou-se uma redução do fibrinogênio menor no grupo tratado com NAC+TXA. Na análise da tromboelastometria, os grupos tratados com TXA e NAC+TXA apresentaram o ML menor do que os tratados apenas com Ringer lactato ou NAC (p < 0,05). As análises do estudo sugerem um efeito benéfico da NAC em associação com TXA na melhora da acidose e fibrinólise. / Trauma is the major cause of death among young adults in Brazil and is considered a worldwide public health problem. Today, hemorrhage control begins with a homeostatic approach which preconizes permissive hypotension, limits the use of crystalloids, uses early transfusion and drugs that can minimize bleeding. However, early administration of blood components implies concerns, which includes storage, transport, availability, compatibility, transfusion reactions and cost. Therefore, there must be strategies that could bring benefits to the patient victim of trauma with bleeding and traumatic coagulopathy. Thus, it was decided to evaluate the potential of early administration of N-acetylcysteine (NAC) and Tranexamic Acid (TXA) associated or not to Ringer lactate and its potential benefits in coagulopathy. A model of multiple trauma and hemorrhagic shock previously described was used to evaluate these aspects in 36 male pigs, Landrace race, with an average weight of 28,34 kg and randomized into five groups: Control (n=5), Ringer lactate (n=5), NAC (n=6), TXA (n=6) and NAC + TXA (n=6). The animals were submitted to general anesthesia, a femur fracture, followed by controlled hemorrhagic shock, and an uncontrolled hepatic hemorrhage. Physiological parameters, standard laboratory tests and thromboelastometry were analyzed. All the animals showed tachycardia, low blood pressure, hypothermia, acidosis, lower platelets and hemoglobina levels and viscoelastics tests. The group NAC + TXA showed improvement in pH and base excess at the final phase of the experiment when compared with the others groups (p < 0.05). At the final phase, fibrinogen was lower reduced in the NAC + TXA group. In the thromboelastometry, the groups TXA and NAC + TXA had lower ML (Maximum Lysis) than the groups Ringer lactate and NAC. The study suggests a beneficial effect of NAC in association with TXA in improving acidosis and fibrinolysis

INTRODUÇÃO: a albumina sérica reduzida em pacientes em diálise peritoneal (DP) é associada à aterosclerose, causa de morte mais comum entre esses pacientes. Semelhantemente à síndrome nefrótica, supõe-se que a perda de proteínas conjuntamente a de fatores de regulação da hemostasia leva ao estímulo da síntese hepática de fatores pró-coagulantes, como o fibrinogênio, deslocando o equilíbrio hemostático em direção ao estado pró-trombótico. Pacientes em DP apresentam valores séricos elevados de marcadores da ativação endotelial e fatores pró-coagulantes, quando comparados a pacientes em hemodiálise (HD). A tromboelastografia (TEG) é um método que avalia propriedades do sangue global e dinâmica da coagulação, fornecendo, por meio de um traçado, valores absolutos do tempo de formação de fibrina (K), a agregação plaquetária (amplitude máxima - AM), a firmeza do coágulo (G), entre outros dados. Por final, classifica a coagulação em normal, hipocoagulante ou hipercoagulante segundo o índice de coagulação (IC) apresentado, sendo assim útil no diagnóstico precoce de coagulopatias. Por ser pouco utilizado em pacientes com DRC, utilizou-se o TEG na avaliação da hemostasia dos pacientes em diálise peritoneal automatizada (DPA) e investigou-se a relação com a perda de proteínas, bem como outras condições clínicas inerentes ao tratamento dialítico. MÉTODOS: este estudo foi do tipo transversal que incluiu pacientes estáveis em DPA. Foram obtidos dados demográficos, clínicos e bioquímicos de rotina do prontuário médico eletrônico. Adicionalmente, foram avaliados a coagulometria, a hemostasia primária [antitrombina (AT), proteína S, fator VIII (FVIII), fator IX (FIX), fator V (FV), fibrinogênio e dímero-D] e o TEG. Os pacientes foram submetidos ao teste de equilíbrio peritoneal (PET), a avaliação da perda de proteínas para a solução de diálise (PSD) e a absorção de glicose. O estado nutricional dos pacientes foi avaliado por meio de métodos objetivos e subjetivos. RESULTADOS: vinte pacientes (38±16 anos de idade, 55% mulheres, 22,4±14,8 meses em DPA, 40% de glomerulopatia, 70% transportadores médio lento/lento e em bom estado nutricional) foram incluídos no estudo. O FVIII e FIX elevados em 85% e 50% da amostra, respectivamente. O fibrinogênio (553,8±100,5 mg/dL) e o dímero-D (720 (520-1940) ug/L) foram elevados em mais da metade dos pacientes. O TEG revelou 55% dos pacientes hipercoagulantes, 45%, normais, e nenhum era hipocoagulante. Os pacientes hipercoagulantes foram caracterizados por um tempo K menor (1,3±0,4 vs. 1,8±0,3 minutos, p=0,007); AM (72,1±2,4 vs. 64,7±3,6 mm, p=0,000) e G (13,1±1,6 vs. 9,3±1,5 K, p= p=0,000) elevados, também alterados em 78% e 33%, respectivamente, nos pacientes com coagulação normal. Pacientes hipercoagulantes também apresentaram maiores valores de plaquetas (251±28 vs. 214±51 mil/mm³, p=0,038), que se correlacionou positivamente com AM/G (r=0,594, p=0,006), enquanto a proteína C foi menor (108±12 vs. 117±20 %, p=0,034) e a AT se correlacionou positivamente com o tempo K (r=0,635, p=0,011). Não houve diferença de albumina sérica, PSD, cinética de creatinina e estado nutricional entre os grupos normal e hipercoagulante. Os pacientes hipercoagulantes, entretanto, apresentaram menores valores de hemoglobina (10,3±1,4 g/dL vs. 12,0±1,1 g/dL; p=0,007), que se correlacionou negativamente com AM/G (r=-0,673, p=0,001), bem como o hematócrito (31±4 % vs. 36±3 %; p=0,010), que também se correlacionou negativamente com AM/G (r=-0,640; p=0,002). CONCLUSÃO: demonstramos que pacientes em DPA estáveis apresentaram uma tendência pró-trombótica caracterizada pela hiperfunção plaquetária e maior força de coágulo. Mesmo não havendo linearidade na relação com a hemostasia a perda de proteínas pode ter contribuído para a hipercoagulabilidade nesses pacientes. Entretanto, os eritrócitos reduzidos representaram um fator de confusão para o resultado do / INTRODUCTION: reduced serum albumin in patients on peritoneal dialysis (PD) is associated to atherosclerosis that is the leading cause of death. Similarly to nephrotic syndrome they lose protein; it is assumed that together with regulating factors of haemostasis this loss leads to liver synthesizes of procoagulants factors, such as fibrinogen, shifting the hemostatic equilibrium to a prothrombotic state. Patients on PD present elevated serum markers of endothelial activation and coagulant factors when compared with hemodialysis (HD) patients. Thromboelastography (TEG) is a method that evaluate blood properties through coagulation\'s global and dynamic perspectives, providing through a trace absolute values of fibrin\'s time formation (K), platelet aggregation (maximum amplitude - MA), clot strength (G), among other data. Finally it classifies the coagulation in normal, hypocoagulant or hypercoagulant according to the coagulation index (CI), so that it is useful in the early diagnosis of coagulopathies. TEG is not often used in patients with CKD, because of this we chose to use TEG for hemostatic evaluation in patients on APD and investigated its relation with protein loss as well as other clinical conditions intrinsic to the dialytic therapy. METHODS: this was a cross-sectional study that included stable patients on automated peritoneal dialysis (APD). Demographic, clinical and routine biochemical data were obtained from electronic medical chart. Additionally the coagulometry, primary hemostasis [antithrombin (AT), protein S, factor VIII (FVIII), factor IX (FIX), factor V (FV), fibrinogen and D-dimer] and TEG were evaluated. Patients were submitted to peritoneal equilibrium test (PET), protein loss to dialysis solution (PDS) and glucose absorption evaluations. Patients nutritional status was evaluated by objective and subjective methods. RESULTS: twenty patients (38±16 years old, 55% women, 22.4±14.8 months on APD, 40% of glomerulopathy, 70% slow average/slow transporters and well nourished) were included in this study. FVIII and FIX were elevated in 85% and 50% of the sample, respectively. Fibrinogen (553.8±100.5 mg/dL) and D-dimer (720 (520-1940) ug/L) were elevated in over half of the patients. TEG showed 55% of the patients hypercoagulant, 45% were normal and nobody was hypocoagulant. Hypercoagulant patients were characterized by a lower K-time (1.3±0.4 vs. 1.8±0.3 minutes; p=0.007); elevated MA (72.1±2.4 vs. 64.7±3.6 mm; p=0.000) and G (13.1±1.6 vs. 9.3±1.5 K; p= p=0.000); altered too in 78% and 33%, respectively, in normal coagulation patients. Hypercoagulant patients presented too higher values of platelet count (251±28 vs. 214±51 mil/mm³, p=0,038), but within the normal range, that correlated positively with MA/G (r=0.594; p=0.006) while protein C was lower (108±12 vs. 117±20 %; p=0,034) and AT correlated positively with K-time (r=0.635; p=0.011). There was no difference to serum albumin, PDS, creatinin kinetic and nutritional status between hypercoagulant and normal groups. However hypercoagulant patients presented lower values of hemoglobin (10.3±1.4 g/dL vs. 12.0±1.1 g/dL; p=0.007); that correlated negatively with MA/G (r=-0.673; p=0.001), as well as hematocrit (31±4 % vs. 36±3 %; p=0,010), which also correlated negatively with MA/G (r=-0.640; p=0.002). CONCLUSION: we demonstrated that stable patients on APD presented a prothrombotic tendency characterized by platelet hyperfuntion and clot strength. Even though there was no linearity in relation to hemostasis; protein loss may have contributed to the hypercoagulability in these patients. However reduced erythrocytes were a confounding factor in the TEG analysis

INTRODUÇÃO: a albumina sérica reduzida em pacientes em diálise peritoneal (DP) é associada à aterosclerose, causa de morte mais comum entre esses pacientes. Semelhantemente à síndrome nefrótica, supõe-se que a perda de proteínas conjuntamente a de fatores de regulação da hemostasia leva ao estímulo da síntese hepática de fatores pró-coagulantes, como o fibrinogênio, deslocando o equilíbrio hemostático em direção ao estado pró-trombótico. Pacientes em DP apresentam valores séricos elevados de marcadores da ativação endotelial e fatores pró-coagulantes, quando comparados a pacientes em hemodiálise (HD). A tromboelastografia (TEG) é um método que avalia propriedades do sangue global e dinâmica da coagulação, fornecendo, por meio de um traçado, valores absolutos do tempo de formação de fibrina (K), a agregação plaquetária (amplitude máxima - AM), a firmeza do coágulo (G), entre outros dados. Por final, classifica a coagulação em normal, hipocoagulante ou hipercoagulante segundo o índice de coagulação (IC) apresentado, sendo assim útil no diagnóstico precoce de coagulopatias. Por ser pouco utilizado em pacientes com DRC, utilizou-se o TEG na avaliação da hemostasia dos pacientes em diálise peritoneal automatizada (DPA) e investigou-se a relação com a perda de proteínas, bem como outras condições clínicas inerentes ao tratamento dialítico. MÉTODOS: este estudo foi do tipo transversal que incluiu pacientes estáveis em DPA. Foram obtidos dados demográficos, clínicos e bioquímicos de rotina do prontuário médico eletrônico. Adicionalmente, foram avaliados a coagulometria, a hemostasia primária [antitrombina (AT), proteína S, fator VIII (FVIII), fator IX (FIX), fator V (FV), fibrinogênio e dímero-D] e o TEG. Os pacientes foram submetidos ao teste de equilíbrio peritoneal (PET), a avaliação da perda de proteínas para a solução de diálise (PSD) e a absorção de glicose. O estado nutricional dos pacientes foi avaliado por meio de métodos objetivos e subjetivos. RESULTADOS: vinte pacientes (38±16 anos de idade, 55% mulheres, 22,4±14,8 meses em DPA, 40% de glomerulopatia, 70% transportadores médio lento/lento e em bom estado nutricional) foram incluídos no estudo. O FVIII e FIX elevados em 85% e 50% da amostra, respectivamente. O fibrinogênio (553,8±100,5 mg/dL) e o dímero-D (720 (520-1940) ug/L) foram elevados em mais da metade dos pacientes. O TEG revelou 55% dos pacientes hipercoagulantes, 45%, normais, e nenhum era hipocoagulante. Os pacientes hipercoagulantes foram caracterizados por um tempo K menor (1,3±0,4 vs. 1,8±0,3 minutos, p=0,007); AM (72,1±2,4 vs. 64,7±3,6 mm, p=0,000) e G (13,1±1,6 vs. 9,3±1,5 K, p= p=0,000) elevados, também alterados em 78% e 33%, respectivamente, nos pacientes com coagulação normal. Pacientes hipercoagulantes também apresentaram maiores valores de plaquetas (251±28 vs. 214±51 mil/mm³, p=0,038), que se correlacionou positivamente com AM/G (r=0,594, p=0,006), enquanto a proteína C foi menor (108±12 vs. 117±20 %, p=0,034) e a AT se correlacionou positivamente com o tempo K (r=0,635, p=0,011). Não houve diferença de albumina sérica, PSD, cinética de creatinina e estado nutricional entre os grupos normal e hipercoagulante. Os pacientes hipercoagulantes, entretanto, apresentaram menores valores de hemoglobina (10,3±1,4 g/dL vs. 12,0±1,1 g/dL; p=0,007), que se correlacionou negativamente com AM/G (r=-0,673, p=0,001), bem como o hematócrito (31±4 % vs. 36±3 %; p=0,010), que também se correlacionou negativamente com AM/G (r=-0,640; p=0,002). CONCLUSÃO: demonstramos que pacientes em DPA estáveis apresentaram uma tendência pró-trombótica caracterizada pela hiperfunção plaquetária e maior força de coágulo. Mesmo não havendo linearidade na relação com a hemostasia a perda de proteínas pode ter contribuído para a hipercoagulabilidade nesses pacientes. Entretanto, os eritrócitos reduzidos representaram um fator de confusão para o resultado do / INTRODUCTION: reduced serum albumin in patients on peritoneal dialysis (PD) is associated to atherosclerosis that is the leading cause of death. Similarly to nephrotic syndrome they lose protein; it is assumed that together with regulating factors of haemostasis this loss leads to liver synthesizes of procoagulants factors, such as fibrinogen, shifting the hemostatic equilibrium to a prothrombotic state. Patients on PD present elevated serum markers of endothelial activation and coagulant factors when compared with hemodialysis (HD) patients. Thromboelastography (TEG) is a method that evaluate blood properties through coagulation\'s global and dynamic perspectives, providing through a trace absolute values of fibrin\'s time formation (K), platelet aggregation (maximum amplitude - MA), clot strength (G), among other data. Finally it classifies the coagulation in normal, hypocoagulant or hypercoagulant according to the coagulation index (CI), so that it is useful in the early diagnosis of coagulopathies. TEG is not often used in patients with CKD, because of this we chose to use TEG for hemostatic evaluation in patients on APD and investigated its relation with protein loss as well as other clinical conditions intrinsic to the dialytic therapy. METHODS: this was a cross-sectional study that included stable patients on automated peritoneal dialysis (APD). Demographic, clinical and routine biochemical data were obtained from electronic medical chart. Additionally the coagulometry, primary hemostasis [antithrombin (AT), protein S, factor VIII (FVIII), factor IX (FIX), factor V (FV), fibrinogen and D-dimer] and TEG were evaluated. Patients were submitted to peritoneal equilibrium test (PET), protein loss to dialysis solution (PDS) and glucose absorption evaluations. Patients nutritional status was evaluated by objective and subjective methods. RESULTS: twenty patients (38±16 years old, 55% women, 22.4±14.8 months on APD, 40% of glomerulopathy, 70% slow average/slow transporters and well nourished) were included in this study. FVIII and FIX were elevated in 85% and 50% of the sample, respectively. Fibrinogen (553.8±100.5 mg/dL) and D-dimer (720 (520-1940) ug/L) were elevated in over half of the patients. TEG showed 55% of the patients hypercoagulant, 45% were normal and nobody was hypocoagulant. Hypercoagulant patients were characterized by a lower K-time (1.3±0.4 vs. 1.8±0.3 minutes; p=0.007); elevated MA (72.1±2.4 vs. 64.7±3.6 mm; p=0.000) and G (13.1±1.6 vs. 9.3±1.5 K; p= p=0.000); altered too in 78% and 33%, respectively, in normal coagulation patients. Hypercoagulant patients presented too higher values of platelet count (251±28 vs. 214±51 mil/mm³, p=0,038), but within the normal range, that correlated positively with MA/G (r=0.594; p=0.006) while protein C was lower (108±12 vs. 117±20 %; p=0,034) and AT correlated positively with K-time (r=0.635; p=0.011). There was no difference to serum albumin, PDS, creatinin kinetic and nutritional status between hypercoagulant and normal groups. However hypercoagulant patients presented lower values of hemoglobin (10.3±1.4 g/dL vs. 12.0±1.1 g/dL; p=0.007); that correlated negatively with MA/G (r=-0.673; p=0.001), as well as hematocrit (31±4 % vs. 36±3 %; p=0,010), which also correlated negatively with MA/G (r=-0.640; p=0.002). CONCLUSION: we demonstrated that stable patients on APD presented a prothrombotic tendency characterized by platelet hyperfuntion and clot strength. Even though there was no linearity in relation to hemostasis; protein loss may have contributed to the hypercoagulability in these patients. However reduced erythrocytes were a confounding factor in the TEG analysis

Background: Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application. Aims: To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia. Methods: Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding. Results: Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7–3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12). Conclusions: This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.

Thesis (M. Tech.) -- Central University of Technology, Free State, 2007 / Cerebrovascular disease and coronary heart disease (CHD) are of the most important causes of morbidity and mortality amongst South Africans. The risk factor prevalence for stroke and CHD becomes altered by changes in lifestyle, including diet. In general it is suggested that lifestyle management should be the first choice when having to treat patients with increased cardiovascular risk. The prudent low-fat, high-fibre diet is regarded as an apparently healthy diet. It is suspected that this diet is effective for the control of known coronary risk factors as well as raised clotting factors. Research studies have shown the addition of dietary fibre to the diet as a promising therapeutic agent for the limited control of known coronary risk factors. The physiological effects of dietary fibre in humans are significantly influenced by the degree to which fibre is fermented in the colon. Fermentation results in the production of short-chain fatty acids (SCFAs); acetate, propionate and butyrate. The aim of this study was to examine the possible effects of different combinations of short-chain fatty acids on some metabolic risk markers. In this study a group of westernised African male volunteers was recruited and randomly assigned to three groups. Group one received a placebo. Group two received a supplement containing 50% acetate and 50% propionate. Group three received a SCFA supplement in the ratio of 70% acetate, 15% propionate and 15% butyrate. Supplementation was sustained for a period of six weeks. Blood samples were drawn during the different visits. At baseline the study group represented a group of black African men without any apparent metabolic or physical abnormalities. All measured variables fell within the normal range. In the placebo group, there was a statistically significant decrease in plasma fibrinogen levels from baseline to the end of supplementation. In the acetatepropionate supplement study group a statistically significant decrease in factor VIII (from 91.1 ± 11.2 to 90.9 ± 8.3%, respectively), and ATIII (from 114.3 ± 13.1 to 108.34 ± 9.5%), as well as a statistically significant decrease in low-density lipoprotein cholesterol (LDL-C) from 3.10 ± 0.79 to 2.64 ± 0.73 mmol/L. The significant increase in %HDL-C from 26.3 ± 6.5 to 30.2 ± 9.3% should also be noted. Both triglycerides (8%) and plasma fibrinogen (2%) showed a statistically significant increase. However, these changes are of no clinical significance. For the high-acetate supplement study group (with the addition of butyrate), a statistically significant decrease in factor VII (from 102.5 ± 13.7 to 101.1 ± 6.4%), VIII (from 92.6 ± 12.8 to 87.6 ± 6.0%), ATIII (from 109.2 ± 16.0 to 103.0 ± 9.9%) as well as fibrin monomer concentration (from 13.9 ± 2.2 to 12.1 ± 3.6 mg/L), were measured. Fibrin network compaction increased significantly from 14.2 ± 4.6 to 13.7 ± 4.0%. Other changes include a statistically significant increase in the serum-TC of 4.2%. From the results it is evident that the acetate-propionate supplement, with exclusion of butyrate, has a beneficial effect on metabolic parameters when compared to a highacetate- propionate supplement. The results do provide evidence of a possible therapeutic application for the propionate-acetate containing supplement. The specific mechanism should, however, still be investigated. It can be concluded from this study that acetate, propionate and butyrate each have different effects on human metabolism. It is evident that the use of a mixture of acetate and propionate may have a beneficial effect on patients at risk of developing CVD. Further studies that investigate the optimum ratio of these two products may lead to the development of a naturally derived therapeutic product for the prevention or treatment of CVD in black African men, as well as the population at large.