RESUMO
Organ transplantation is a modern medical success story. However, since its inception it has been limited by the need for pharmacological immunosuppression. Regulatory cellular therapies offer an attractive solution to these challenges by controlling transplant alloresponses through multiple parallel suppressive mechanisms. A number of cell types have seen an accelerated development into human trials and are now on the threshold of a long-awaited breakthrough in personalized transplant therapeutics. Here we assess recent developments with a focus on the most likely candidates, some of which have already facilitated successful immunosuppression withdrawal in early clinical trials. We propose that this may constitute a promising approach in clinical transplantation but also evaluate outstanding issues in the field, providing cause for cautious optimism.
Assuntos
Transplante de Órgãos , Tolerância ao Transplante , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Tolerância Imunológica , Terapia de ImunossupressãoRESUMO
Over the last two decades, an additional and important role for B cells has been established in immune regulation. Preclinical studies demonstrate that regulatory B cells (Breg) can prolong allograft survival in animal models and induce regulatory T cells. Operationally tolerant human kidney transplant recipients demonstrate B-cell-associated gene signatures of immune tolerance, and novel therapeutic agents can induce Bregs in phase I clinical trials in transplantation. Our rapidly expanding appreciation of this novel B-cell subtype has made the road to clinical application a reality. Here, we outline several translational pathways by which Bregs could soon be introduced to the transplant clinic.
Assuntos
Linfócitos B Reguladores , Animais , Humanos , Tolerância Imunológica , Linfócitos T Reguladores , Tolerância ao Transplante , Transplante HomólogoAssuntos
Vacinas contra COVID-19 , COVID-19 , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , Diálise Renal , SARS-CoV-2 , Reino Unido , VacinaçãoRESUMO
BACKGROUND: Pharmaceutical expenditure is currently rising by 16% per annum in China, greater in recent years. Initiatives to moderate growth include drug pricing regulations, essential medicine lists and encouraging generic prescribing. These are principally concentrated in hospitals, which currently account for over 80% of total pharmaceutical expenditure. However, no monitoring of prescribing and perverse incentives encouraging physicians and hospitals to profit from drug procurement encourages irrational prescribing. This includes greater utilisation of originators versus generics as well as injectables when cheaper oral equivalents are available. The objective of the paper is to assess changes in proton pump inhibitor (PPI) utilisation and expenditure in China as more generics become available including injectables. METHODS: Observational retrospective study of PPI utilisation and procured expenditure between 2004 and 2013 in the largest teaching hospital in Chongqing District as representative of China. RESULTS: Appreciable increase in PPI utilisation during the study period rising 10.4 fold, with utilisation of generics rising faster than originators. Oral generics reached 84% of total oral preparations in 2013 (defined daily dose basis), with generic injectables 93% of total injectables by 2013. Injectables accounted for 42% of total PPI utilisations in 2008 and 2009 before falling to below 30%. Procured prices for oral preparations reduced over time (-34%). Generic oral omeprazole in 2010 was 87% below 2004 originator prices, mirroring reductions seen in Western Europe. Injectable prices also decreased over time (-19%). However, injectables typically 4.3 to 6.8 fold more expensive than equivalent orals - highest for injectable lansoprazole at 13.4 to 18.0 fold. High utilisation of more expensive oral PPIs as well as injectables meant that PPI expenditure increased 10.1 fold during the study period. Lower use of injectables, and only oral generic omeprazole, would result in accumulated savings of CNY249.65 million, reducing total accumulated expenditure by 84%. CONCLUSIONS: Encouraging to see high utilisation of generic PPIs and low prices for oral generics. However, considerable opportunities to enhance prescribing efficiency through greater use of oral generic omeprazole.
Assuntos
Omeprazol/uso terapêutico , Padrões de Prática Médica/tendências , Inibidores da Bomba de Prótons/uso terapêutico , Administração Oral , China , Custos de Medicamentos , Uso de Medicamentos , Medicamentos Genéricos/economia , Medicamentos Genéricos/uso terapêutico , Previsões , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/economia , Gastos em Saúde , Humanos , Injeções Intravenosas , Padrões de Prática Médica/economia , Inibidores da Bomba de Prótons/economia , Estudos RetrospectivosRESUMO
Renal Angiomyolipoma (renal AML) is a benign clonal neoplasm with a incidence of 0.3-3%, occurring as isolated sporadic entity or in association with Tuberous sclerosis (TS) in 80% cases. Multiple, bilateral renal AML are considered diagnostic of Tuberous sclerosis. Wunderlich's syndrome, a urological emergency is a spontaneous nontraumatic bleeding into subcapsular and or peri-renal space and is a life threatening complication of renal AML occurring in 10% cases which has to be timely diagnosed and treated. Here, we present an unusual case of TS with bilateral, multifocal renal AML in a 25-year-old female who presented with Wunderlich's syndrome, which is a rare but life threatening complication that has to be suspected, timely diagnosed and treated. We have discussed the importance of early diagnosis, timely treatment, follow up and education of patient and relatives of the possible complications associated.
RESUMO
BACKGROUND: There have been multiple reforms in South Africa to conserve resources including policies to enhance generic use, such as compulsory generic substitution and copayments. However, there are concerns with the limited knowledge of their impact. OBJECTIVE: The objective was to determine utilization and expenditure of different proton pump inhibitors (PPIs). METHODOLOGY: A retrospective drug utilization study was conducted on a prescription database of a medical aid administrator in 2010. RESULTS: The limited prescribing of single-sourced PPIs accounted for 21.5% of total prescriptions. The limited use of originators omeprazole and lansoprazole accounted for 1.8 and 1.4% of total prescriptions for the molecule, respectively. Generic prices accounted for 36-68% of the originator in 2010. Patients received on average 2.91 PPI prescriptions during the year. CONCLUSION: Policies to enhance prescribing of generics appear working. Opportunities exist to further lower generic prices given low prices in some European countries.
Assuntos
Medicamentos Genéricos/provisão & distribuição , Padrões de Prática Médica/estatística & dados numéricos , Inibidores da Bomba de Prótons/provisão & distribuição , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Medicamentos Genéricos/economia , Feminino , Humanos , Lactente , Recém-Nascido , Lansoprazol/economia , Lansoprazol/provisão & distribuição , Masculino , Pessoa de Meia-Idade , Omeprazol/economia , Omeprazol/provisão & distribuição , Padrões de Prática Médica/economia , Setor Privado/estatística & dados numéricos , Inibidores da Bomba de Prótons/economia , Estudos Retrospectivos , África do Sul , Adulto JovemRESUMO
OBJECTIVES: To (1) evaluate educational needs of clinical students at Al-Quds University Medical School in the West Bank; (2) address these needs where possible using synchronous distance learning, with clinicians in Oxford providing case-based tutorials to undergraduates in the West Bank via an online platform (WizIQ) and (3) assess the impact of this education. DESIGN: Review of online OxPal Medlink database for tutorials held between March 2012 and April 2013. Needs assessment and evaluation of student and tutor experiences through online questionnaires, focus groups and semi-structured interviews. SETTING: Oxford University Hospitals, Oxford, UK, and Al-Quds University Medical School, Abu Dies, Palestine. PARTICIPANTS: Doctors at Oxford University Hospitals and fourth-, fifth- and sixth-year medical students and faculty members at Al-Quds Medical School. MAIN OUTCOME MEASURES: Number of tutorials, student participation, student-rated satisfaction and qualitative feedback from tutors and students. RESULTS: Students demonstrated strong theoretical knowledge but struggled to apply this in presentation-based scenarios. Between March 2012 and April 2013, 90 tutorials were delivered to 60 students. Feedback: >95% respondents rated tutorials as 'Excellent' or 'Good' and 'Very' or 'Fairly' relevant to their future practice in Palestine. Students reported the programme had modified their approach to patients but requested better synchronization with concurrent attachments and clarification of learning outcomes. CONCLUSIONS: OxPal Medlink is a novel, web-based distance-learning partnership designed to overcome some of the challenges to local medical education in the occupied Palestinian territories. Evaluation of the first year indicates teaching is relevant to local practice and of high quality. This approach may have the potential to strengthen local capacity for medical education.
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In recent years, substantial advances in T-cell immunosuppressive strategies and their translation to routine clinical practice have revolutionized management and outcomes in autoimmune disease and solid organ transplantation. More than 80 diseases have been considered to have an autoimmune etiology, such that autoimmune-associated morbidity and mortality rank as third highest in developed countries, after cardiovascular diseases and cancer. Solid organ transplantation has become the therapy of choice for many end-stage organ diseases. Short-term outcomes such as patient and allograft survival at 1 year, acute rejection rates, as well as time course of disease progression and symptom control have steadily improved. However, despite the use of newer immunosuppressive drug combinations, improvements in long-term allograft survival and complete resolution of autoimmunity remain elusive. In addition, the chronic use of nonspecifically targeted immunosuppressive drugs is associated with significant adverse effects and increased morbidity and mortality. In this article, we discuss the current clinical tools for immune suppression and attempts to induce long-term T-cell tolerance induction as well as much-needed future approaches to produce more short-acting, antigen-specific agents, which may optimize outcomes in the clinic.
Assuntos
Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Órgãos/métodos , Linfócitos T , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Inibidores de Calcineurina , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Janus Quinase 3/antagonistas & inibidores , Piperidinas , Proteína Quinase C/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Quinazolinas/farmacologia , Receptores de Citocinas/antagonistas & inibidores , Receptores de Citocinas/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Imunologia de Transplantes/imunologia , Tolerância ao Transplante/imunologiaRESUMO
BACKGROUND: Leukocyte depletion at the time of transplantation with alemtuzumab (Campath-1H) has been demonstrated to be a potential strategy for reducing long-term exposure to immunosuppressive drugs. Although the impact of alemtuzumab treatment on the immune system has been explored, the effects of long-term immunosuppressive therapy in alemtuzumab-treated patients still need to be elucidated. METHODS: T-regulatory cells and Th1/Th17 responses were assessed by flow cytometry and real-time polymerase chain reaction more than 4 years after transplantation in 10 kidney recipients treated with alemtuzumab induction. Seven patients were converted to sirolimus monotherapy at 12 months posttransplant, whereas the remaining three patients with history of graft rejection were treated with sirolimus and mycophenolate mofetil. In addition, we sorted and expanded interleukin (IL)-17A-producing CCR6CD4 T cells and assessed their susceptibility to suppression by regulatory T (Treg) cells in in vitro suppression tests. RESULTS: Three years of mammalian target of rapamycin inhibitor monotherapy correlates with an increase in the number of IL-17A producing cells, compared with patients treated with sirolimus and mycophenolate mofetil. In these patients, IL-17A expression was compensated for by an increase in Treg cell frequency and number. In addition, we demonstrated that both proliferation and cytokine production by Th17 cells can be effectively regulated by Treg cells. CONCLUSIONS: Our results demonstrate that history of rejection and long-term maintenance immunosuppression has an impact on the number of circulating Treg and Th17 cells. However, more importantly, we have shown that Treg cells can effectively regulate Th17cells both in vitro and in vivo.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antineoplásicos/farmacologia , Imunossupressores/farmacologia , Células Th17/fisiologia , Alemtuzumab , Anticorpos Monoclonais Humanizados , Rejeição de Enxerto/prevenção & controle , Humanos , Interleucina-17/biossíntese , Transplante de Rim/imunologia , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologia , Receptores CCR6/análise , Sirolimo/farmacologia , Linfócitos T Reguladores/fisiologiaRESUMO
Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.
Assuntos
Biomarcadores/sangue , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Doença Aguda , Quimiocinas/sangue , Doença Crônica , Células Endoteliais/imunologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Humanos , Interferon gama/sangue , Isoanticorpos/sangue , Antígeno Ki-1/sangue , Ativação Linfocitária , MicroRNAs/sangue , MicroRNAs/genética , Monitorização Imunológica/métodos , Imunologia de TransplantesRESUMO
Clinical experience of learning a new technique of minimally surgery for total knee arthroplasty is presented. Close monitoring of the technique, pitfalls, learning tips, and tricks are discussed. A "learning phase" is identified as approximately 10 months or 21 knee replacements using minimally invasive technique. It took 50 operations before the surgical time equaled the open technique. There was no incidence of increased complications during the learning phase. Functional results such as stair climbing, walking distance, and walking with aids was significantly better after minimally invasive technique than after standard technique.