Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that manufacturing processes produce safe and effective products. A thorough understanding of the biological processes occurring during manufacture is fundamental to assuring these qualities and thus, their acceptability to regulators and clinicians. Leaders in both human pluripotent and somatic stem cells, were brought together with experts in clinical translation, bio-manufacturing and regulation, to discuss key issues in assuring appropriate manufacturing conditions for delivery of effective and safe products from these cell types. This report summarizes the key issues discussed and records consensus reached by delegates and emphasizes the need for accurate language and nomenclature in the scientific discourse around stem cells. Lay abstract Novel therapies derived from different kinds of precursor cells and stem cells are increasingly moving to clinical trials to restore tissue function in patients who have suffered injury or disease. The manufacture of these new therapies is unusually complex, which means that the manufacturing processes require great attention to assure they are safe and effective. This paper describes a conversation amongst experts in the field who are exploring therapeutic applications of two different kinds of stem cells (pluripotent stem cells and tissue-derived stem/precursor cells). It considers critical issues in developing the manufacturing process for each of these quite different cells types.
CONTEXTO: Doença arterial periférica é caracterizada pelo índice tornozelo-braquial (ITB) < 0,90, em indivíduos ≥ 40 anos, aumentando a prevalência com a idade. OBJETIVO: Detectar a prevalência de doença arterial periférica assintomática e sintomática, com introdução do ITB, associada a fatores de risco demarcados. MÉTODOS: Coorte descritiva identificada em unidade hospitalar terciária de angiologia, de dezembro de 2006 a dezembro de 2007, com idade ≥ 30 anos. Doenças pregressas e fatores de risco foram analisados associados à prevalência. ITB < 0,90 e questionário padronizado definiram doença arterial periférica sintomática com claudicação e assintomática com ausência de claudicação, ambas comparadas aos sem doença arterial periférica (ITB 0,90-1,30). A análise estatística utilizou programa SPSS, com significância de p < 0,05. RESULTADOS: Dos 407 pacientes, 248 apresentaram doença arterial periférica, sendo 52,2% do sexo feminino, com média de idade de 70,1±10,2 anos (p < 0,005). A prevalência de 60,9% (IC95% 56-66) foi subdividida em: assintomática, 10,1% (IC95% 6,3-13,8); e sintomática, 89,9% (IC95% 86,2-93,7). Destes, 32,2% (IC95% 26,4-38,1) apresentaram isquemia crítica. Ajustada por sexo e idade, a prevalência aumenta significativamente entre 55-74 anos, com predomínio do feminino (1,35:1) nos indivíduos acima de 74 anos. A prevalência dos assintomáticos e sintomáticos foi influenciada por tabagismo, hipertensão, diabéticos autorreferidos e confirmados, sobrepeso, infarto agudo do miocárdio e acidente vascular encefálico (p < 0,005). A média do ITB foi mais baixa nos sintomáticos (0,57±0,17) (p < 0,005). CONCLUSÃO: O ITB detectou doença arterial periférica com graus variáveis de gravidade associada a fatores de risco, identificando os assintomáticos não-claudicantes e os sintomáticos em unidade terciária.
CONTEXTO: A arterite de Takayasu é uma vasculite crônica, geralmente com diagnóstico tardio devido à pouca especificidade dos sintomas durante a fase inicial do acometimento vascular. A terapêutica de eleição é o uso de imunossupressores. O procedimento cirúrgico, quando necessário, é sempre evitado na fase aguda. OBJETIVO: Descrever alterações clínicas, laboratoriais e vasculares de arterite de Takayasu no período de 1977 a 2006. MÉTODO: A amostra compreendeu 36 pacientes - 10 brancos, 35 mulheres, idade média de 31,7 anos (±13,7), com prevalência significante na quarta década (p < 0,005). Evolução de 3 anos e período até o diagnóstico de 7,9 anos. Velocidade de hemossedimentação (VHS) e proteína C reativa (PCR) avaliaram atividade da doença, e o duplex scan aferiu a espessura médio- intimal da artéria carótida. RESULTADOS: Hipertensão arterial sistêmica e claudicação de membros superiores e inferiores foram ressaltados em 85,2, 69,5 e 30,5%, respectivamente. O resultado da VHS foi > 60 mm em 50% da amostra (p < 0,005). PCR mg/dL foi realizado em 18, variando de 0,4-25 na admissão para 0,11-1,9 na evolução. Doença auto-imune, tuberculose e HIV correlacionaram-se em 19,4, 8,3 e 2,7%, respectivamente. Lesões aórticas foram significativas em 22% (quatro oclusões, dois aneurismas infra-renais, um torácico). Em 19,4%, foram acometidas artérias renais e subclávias uma oclusão bilateral de carótidas, e em 25% os membros inferiores. A espessura médio-intimal da carótida comum foi estratificada em: > 3 mm, < 3 e > 1,7, < 1,7 e > 1,2 e < 1,2 mm, representando 41,6, 19,4, 8,37 e 30,50%, respectivamente (p < 0,005). Glicocorticóides foram utilizados em 61,1%, azatioprina em 16.6%, e associada a ciclofosfamida em 8,3%. Procedimento cirúrgico ou endovascular foi realizado em 30,5% com dois óbitos por complicações cardiovasculares. CONCLUSÕES: A VHS, PCR, e a espessura médio-intimal nas carótidas são importantes marcadores de acompanhamento da arterite de Takayasu. O período entre os sintomas e o diagnóstico deve ser abreviado, com redução da morbimortalidade.
Resumo A aviação civil vem apresentando aumento progressivo do número de voos regulares nos últimos 10 anos e, em função disso, mais passageiros estão sendo transportados em viagens aéreas (VAs). Associado a isso, há um aumento das doenças relacionadas às VAs, especialmente naquelas de longa duração. Uma das complicações mais temidas dos voos é o tromboembolismo venoso (TEV), mas a sua real incidência é de difícil mensuração devido à falta de consenso sobre, por exemplo, quanto tempo após o pouso podemos considerar que o TEV possa estar relacionado à VA realizada ou mesmo quanto tempo de voo pode ser considerado como de longa duração. Muito tem se discutido sobre os mecanismos fisiopatológicos do TEV relacionado às VAs, quais passageiros são os de maior risco e quais medidas profiláticas podemos adotar com segurança e eficácia. O objetivo desta revisão é esclarecer esses pontos e as condutas consensuais atuais.
The role of extracellular matrix (ECM) in the development and maintenance of the normal nervous tissue structure has been demonstrated. However, little is known about ECM modifications taking place in peripheral nerve pathology. This gap has prompted us to study the expression of several components of the peripheral nerve ECM in the major categories of human peripheral neuropathies. Normal and pathological sural nerve biopsies, including cases of CMT1, HNPP, CIDP and axonal neuropathies were studied by immunohistochemistry for the expression of collagen (COL) types I, III, IV, V, VI, laminin (LN), tenascin (TN), fibronectin (FN) and vitronectin (VN). The immunoreactivity of ECM proteins in pathologic nerves showed different patterns in relation to their distribution in normal nerves. Indeed, COL I and III, which are the main stromal components of the epineurium and endoneurium, respectively, showed increased expression in these compartments, generally in chronic neuropathies. COL IV, V, VI and LN localized mainly to basement membranes (BM) of Schwann cells, perineurial cells and blood vessels, showing increased deposition in the presence of BM redundancy. FN localized diffusely to the endoneurium and perineurium in control nerves and its expression increased in CIDP nerves. VN immunoreactivity was limited to several spots along the perineurium and epineurial vessels in normal nerve. However, in CIDP and in some cases of axonal neuropathy the VN signal was increased in the perineurium and appeared also in endoneurial vessels. Finally, TN was detected in the perineurium and the nodal/paranodal region in control nerve, while in some cases of CMT1 and CIDP it appeared to mark several internodes. These data, showing specific changes of the ECM components in peripheral neuropathies, suggest that a complex ECM remodeling is associated with mechanisms of nerve damage and repair. Supported by MURST‐COFIN 98 (n°86) and by CNR 98 (n°03081 CT04).
Varicose veins alternate areas of phlebosclerosis and hypertrophy of the vein wall. In this study, samples of long saphenous veins obtained from patients submitted for aortocoronary saphenous vein graft or for surgical resection of varicose saphenous veins were examined. Histologic changes in the intima, muscle, and adventitial layers were quantified. Thicknesses of the venous wall layers were obtained by linear measurements, and the volumetric density of the connective tissue in the muscle layer was determined by point counting. The muscle layer thickness was 300 +/- 13 and 581 +/- 25 microns in normal and varicose veins, respectively. A more severe connective tissue accumulation within the muscle bundles was found in the varicose condition. The volumetric density of the connective tissue in the circular muscle layer (CmC/MmC) showed also a marked difference between varicose (0.67 +/- 0.08) and normal veins (0.43 +/- 0.02), P < 0.05. The authors suggest that the varicose condition is associated with a connective tissue uniform accumulation among muscle cells in the circular muscle layer.
Demyelination and Schwann cell (SC) proliferation are hallmarks of hypertrophic demyelinating neuropathies, of which Charcot‐Marie‐Tooth type 1 A (CMT1A) neuropathy is the typical example. In CMT1A, an altered dosage of the PMP22 gene determines a defect of myelination and an abnormal SC phenotype, characterized by hyperplasia and abnormal differentiation. The Epidermal Growth Factor (EGF) family of proteins, including EGF and neuregulins, and their receptors, namely EGFr and the erbB family, control growth and development of SC. Their expression in mature SC is down‐regulated but, during Wallerian degeneration or chemical myelinolysis, these receptors are transiently over‐expressed, suggesting a potential autocrine mechanism. On the other hand, neuregulin 1 inhibits SC myelination and induces demyelination and SC dedifferentiation and proliferation. These effects might play a role in the pathogenesis of hypertrophic demyelinating neuropathies. We have therefore immunolocalized EGF, EGFr and the erbB receptors (erbB 2, 3 and 4) in sural nerve biopsies from patients with CMT1A as compared to chronic inflammatory demyelinating neuropathy (CIDP) nerve biopsies and to normal nerves, in order to evaluate if the expression of these molecules is up‐ or down‐regulated in these disorders. Among CMT1A nerves, immunoreactivity for EGF, EGFr, erbB2 and erbB3 was moderately to markedly increased in SC, particularly in onion bulbs, in most cases, while a mild to moderate expression of erbB 4 in SC cytoplasm was observed in a few cases. On the other hand in CIDP, which shares with CMT1A histopathological features such as de‐remyelination and SC hyperplasia, only the expression of erbB 3 was up‐regulated in a minority of cases. Since in SC the functional neuregulin receptor is a heterodimer, composed by erbB2 and erbB3, the parallel up‐regulation of these two molecules in CMT1A may bear a functional significance. This would be confirmed if an overexpression of neuregulins could be demonstrated, along with our finding of an increased expression of EGF and its receptor. In conclusion, it can be hypothesized that, in CMT1A, a persistent activation of neuregulin signaling pathways not only is indicative of SC dedifferentiation but also may contribute to demyelination and onion bulb formation or maintenance.
Case Report: A 20-year-old man presented for evaluation following an episode of painless injury in which he almost amputated his thumb. Upon further questioning, the patient reported he rarely experienced physical (including visceral) pain and his mother provided support to his history recalling incidents occurring as a child. He does not experience itching either. His neurologic and general medical history was otherwise negative. His neurologic and general examination were unremarkable except for the inability to perceive painful (pinprick, pressure on Achilles' tendons), hot and cold stimuli over his entire body, with some relative sparing over his chest, abdomen and back. Nerve conduction studies and needle examinations were normal. Quantitative sensory testing revealed normal threshold to vibration, relatively elevated threshold to cold and insensitivity to heat and pain. Autonomic reflex screen and thermoregulatory sweat test were normal. Sural nerve biopsy showed normal myelinated and unmyelinated fibers. MRI of head and cervical spine, and extensive laboratory testing were unremarkable. Conclusion: This patient differs from any other case described in the literature of pain insensitivity or pain indifference. Suspecting a central pathology, we prescribed naltrexone and retested his heat-pain sensation after treatment. He perceived the probe as hotter. Unfortunately, he suffered unacceptable dysthymia from the medication and stopped it. RAT IN VIVO MODELS OF TAXANES' PERIPHERAL NEUROTOXICITY FOLLOWING CHRONIC INTRAVENOUS ADMINISTRATION
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