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Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim-/- ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR. Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim-/- mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation. These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.
Assuntos
Proteínas Reguladoras de Apoptose , Gliose , Neurônios , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/fisiologia , Morte Celular , Gliose/patologia , Camundongos , Neurônios/metabolismo , RetinaRESUMO
BACKGROUND AND AIMS: The present study was designed to assess the differences in cognitive plasticity, cognitive functioning and quality of life (QoL) in young-old and old-old adults, and to determine whether variables related to QoL can predict cognitive plasticity in old age. METHODS: The study population consisted of 215 people living in sheltered accommodation for elderly people in southern Spain. Participants were divided into two groups according to age: young-old aged (between 65 and 80 years) and old-old (81 and above). Participants were assessed by means of cognitive performance tests, a QoL questionnaire, and the auditory verbal learning test-learning potential (AVLT-LP) as a measure of cognitive plasticity. RESULTS: No significant differences were found in cognitive plasticity between the young-old and old-old adults, although the former performed better on immediate and sustained verbal recall. Likewise, no significant inter-group differences arose in most of the QoL variables. However, differences in cognitive plasticity did appear as a function of the level of cognitive functioning of the old adults, and cognitive functioning has been shown to be the best predictor of cognitive plasticity in old age. CONCLUSIONS: Differences in cognitive plasticity between young-old and old-old adults only appear when the cognitive functioning of individuals is taken into account, rather than their age group. The variables cognitive functioning, social integration and education level appear to be the best predictors of cognitive plasticity in old age.
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Envelhecimento/psicologia , Cognição , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Cognição/fisiologia , Feminino , Humanos , Modelos Lineares , Masculino , EspanhaRESUMO
This work examines the possible behaviour of Neanderthal groups at the Cueva Des-Cubierta (central Spain) via the analysis of the latter's archaeological assemblage. Alongside evidence of Mousterian lithic industry, Level 3 of the cave infill was found to contain an assemblage of mammalian bone remains dominated by the crania of large ungulates, some associated with small hearths. The scarcity of post-cranial elements, teeth, mandibles and maxillae, along with evidence of anthropogenic modification of the crania (cut and percussion marks), indicates that the carcasses of the corresponding animals were initially processed outside the cave, and the crania were later brought inside. A second round of processing then took place, possibly related to the removal of the brain. The continued presence of crania throughout Level 3 indicates that this behaviour was recurrent during this level's formation. This behaviour seems to have no subsistence-related purpose but to be more symbolic in its intent.
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Homem de Neandertal , Animais , Herbivoria , Crânio , Arqueologia , Espanha , MamíferosRESUMO
FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5-15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor kappaB (NF-kappaB), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75(NTR), in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-kappaB-mediated control of neurite growth in developing neurons.
Assuntos
Encéfalo/fisiologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Fatores de Crescimento Neural/metabolismo , Neuritos/fisiologia , Neurogênese/fisiologia , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Morte Celular/fisiologia , Diferenciação Celular/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos , Neurônios Motores/fisiologia , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso , Neuroglia/metabolismo , Células PC12 , Ratos , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/metabolismo , Gânglio Cervical Superior/embriologia , Gânglio Cervical Superior/crescimento & desenvolvimento , Gânglio Cervical Superior/fisiologiaRESUMO
Gait impairments in Alzheimer's disease (AD) result from structural and functional deficiencies that generate limitations in the performance of activities and restrictions in individual's biopsychosocial participation. In a translational way, we have used the conceptual framework proposed by the International Classification of Disability and Health Functioning (ICF) to classify and describe the functioning and disability on gait and exploratory activity in the 3xTg-AD animal model. We developed a behavioral observation method that allows us to differentiate qualitative parameters of psychomotor performance in animals' gait, similar to the behavioral patterns observed in humans. The functional psychomotor evaluation allows measuring various dimensions of gait and exploratory activity at different stages of disease progression in dichotomy with aging. We included male 3xTg-AD mice and their non-transgenic counterpart (NTg) of 6, 12, and 16 months of age (n = 45). Here, we present the preliminary results. The 3xTg-AD mice show more significant functional impairment in gait and exploratory activity quantitative variables. The presence of movement limitations and muscle weakness mark the functional decline related to the disease severity stages that intensify with increasing age. Motor performance in 3xTg-AD is accompanied by a series of bizarre behaviors that interfere with the trajectory, which allows us to infer poor neurological control. Additionally, signs of physical frailty accompany the functional deterioration of these animals. The use of the ICF as a conceptual framework allows the functional status to be described, facilitating its interpretation and application in the rehabilitation of people with AD.
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Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients.
Assuntos
Autofagia/fisiologia , Neurônios Motores/patologia , Músculo Esquelético/patologia , Atrofia Muscular Espinal/patologia , Animais , Feminino , Humanos , Masculino , Camundongos , Neurônios Motores/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/metabolismoRESUMO
Apoptosis plays an important role during development, control of tissue homeostasis and in pathological contexts. Apoptosis is executed mainly through the intrinsic pathway or the death receptor pathway, i.e., extrinsic pathway. These processes are tightly controlled by positive and negative regulators that dictate pro- or anti-apoptotic death receptor signaling. One of these regulators is the Fas Apoptotic Inhibitory Molecule (FAIM). This death receptor antagonist has two main isoforms, FAIM-S (short) which is the ubiquitously expressed, and a longer isoform, FAIM-L (long), which is mainly expressed in the nervous system. Despite its role as a death receptor antagonist, FAIM also participates in cell death-independent processes such as nerve growth factor-induced neuritogenesis or synaptic transmission. Moreover, FAIM isoforms have been implicated in blocking the formation of protein aggregates under stress conditions or de-regulated in certain pathologies such as Alzheimer's and Parkinson's diseases. Despite the role of FAIM in physiological and pathological processes, little is known about the molecular mechanisms involved in the regulation of its expression. Here, we seek to investigate the post-transcriptional regulation of FAIM isoforms by microRNAs (miRNAs). We found that miR-206, miR-1-3p, and miR-133b are direct regulators of FAIM expression. These findings provide new insights into the regulation of FAIM and may provide new opportunities for therapeutic intervention in diseases in which the expression of FAIM is altered.
RESUMO
The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Proteínas Inibidoras de Apoptose/metabolismo , Plasticidade Neuronal , Animais , Proteínas Reguladoras de Apoptose/genética , Caspase 3/metabolismo , Células Cultivadas , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Camundongos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ligação Proteica , Ratos , Receptores de AMPA/metabolismo , UbiquitinaçãoRESUMO
Intracellular calcium (Ca(2+)) concentration determines neuronal dependence on neurotrophic factors (NTFs) and susceptibility to cell death. Ca(2+) overload induces neuronal death and the consequences are thought to be a probable cause of motoneuron (MN) degeneration in neurodegenerative diseases. In the present study, we show that membrane depolarization with elevated extracellular potassium (K(+)) was toxic to cultured embryonic mouse spinal cord MNs even in the presence of NTFs. Membrane depolarization induced an intracellular Ca(2+) increase. Depolarization-induced toxicity and increased intracellular Ca(2+) were blocked by treatment with antagonists to some of the voltage-gated Ca(2+) channels (VGCCs), indicating that Ca(2+) influx through these channels contributed to the toxic effect of depolarization. Ca(2+) activates the calpains, cysteine proteases that degrade a variety of substrates, causing cell death. We investigated the functional involvement of calpain using a calpain inhibitor and calpain gene silencing. Pre-treatment of MNs with calpeptin (a cell-permeable calpain inhibitor) rescued MNs survival; calpain RNA interference had the same protective effect, indicating that endogenous calpain contributes to the cell death caused by membrane depolarization. These findings suggest that MNs are especially vulnerable to extracellular K(+) concentration, which induces cell death by causing both intracellular Ca(2+) increase and calpain activation.
Assuntos
Potenciais da Membrana/fisiologia , Neurônios Motores/fisiologia , Medula Espinal/citologia , Análise de Variância , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/metabolismo , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Proteínas com Homeodomínio LIM , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Neurônios Motores/efeitos dos fármacos , Fatores de Crescimento Neural/farmacologia , Cloreto de Potássio/farmacologia , RNA Interferente Pequeno/farmacologia , Fatores de Tempo , Fatores de TranscriçãoRESUMO
BACKGROUND: To estimate the agreement between observers on the detection of goitre by palpation in the school population because it is considered a variability test. METHODS: For five months, during 2001/2002, the presence of goitre was studied in across-section sample of 845 school children (for 6 to 14 years old) from 18 school centres in a Health Area in Valentian Community. The exploration was always carried out by the same two observers. The thyroid size was established in 6 degrees. It was considered goitre since 0B inclusive. The agreement was assessed in relation to age, sex, IBM, and the exploration date. The Kappa Index was used as a measure of agreement. RESULTS: The global prevalence of goitre was 40,4% according to the first observer and 36,8% to the second one. The agreement between observers was high, with a Kappa Index of 0.83 and it was similar in relation to sex, IBM, and the exploration date. It was smaller in the youngest children (six and seven years old) than in the oldest ones (from 12 to 14). CONCLUSIONS: An excellent interobserver agreement in clinic assessment of goitre by palpation in a school children population was achieved. The least concordance was seen in youngest group. It would be advisable to include the study of agreement in the protocol of endemic goitre study.
Assuntos
Bócio/diagnóstico , Bócio/epidemiologia , Palpação , Adolescente , Criança , Estudos Transversais , Humanos , Variações Dependentes do Observador , PrevalênciaRESUMO
Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neurons are generally resistant to death induction through DRs and rather their activation promotes neuronal outgrowth and branching. These results suppose the existence of DRs antagonists expressed in the nervous system. Fas apoptosis inhibitory molecule (FAIM(S)) was first identified as a Fas antagonist in B-cells. Soon after, a longer alternative spliced isoform with unknown function was identified and named FAIM(L). FAIM(S) is widely expressed, including the nervous system, and we have shown previously that it promotes neuronal differentiation but it is not an anti-apoptotic molecule in this system. Here, we demonstrate that FAIM(L) is expressed specifically in neurons, and its expression is regulated during the development. Expression could be induced by NGF through the extracellular regulated kinase pathway in PC12 (pheochromocytoma cell line) cells. Contrary to FAIM(S), FAIM(L) does not increase the neurite outgrowth induced by neurotrophins and does not interfere with nuclear factor kappaB pathway activation as FAIM(S) does. Cells overexpressing FAIM(L) are resistant to apoptotic cell death induced by DRs such as Fas or tumor necrosis factor R1. Reduction of endogenous expression by small interfering RNA shows that endogenous FAIM(L) protects primary neurons from DR-induced cell death. The detailed analysis of this antagonism shows that FAIM(L) can bind to Fas receptor and prevent the activation of the initiator caspase-8 induced by Fas. In conclusion, our results indicate that FAIM(L) could be responsible for maintaining initiator caspases inactive after receptor engagement protecting neurons from the cytotoxic action of death ligands.
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Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Apoptose/fisiologia , Proteínas Inibidoras de Apoptose/fisiologia , Neurônios/metabolismo , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/fisiologia , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/fisiologia , Células Cultivadas , Regulação da Expressão Gênica/fisiologia , Variação Genética/fisiologia , Humanos , Camundongos , Neurônios/patologia , Células PC12 , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Ratos , Receptores de Morte Celular/genéticaRESUMO
Tropomyosin-related kinase A (TrkA) receptor mediates the effects exerted by nerve growth factor on several subpopulations of neuronal cells. Ligand binding to TrkA induces receptor autophosphorylation on several tyrosine residues and the activation of signaling cascades. In this study, we describe a new site relevant for TrkA regulation, the tyrosine 701 (Y701), which is important for receptor trafficking and activation. Y701 replacement by aspartate or phenylalanine reduces receptor internalization rate and decreases the colocalization and association of TrkA with clathrin heavy chain, demonstrating that Y701 constitutes a YxxPhi (YRKF701-704) trafficking motif relevant for the regulation of receptor endocytosis. In accordance with this hypothesis, the colocalization of Y701 mutant receptors with a lysosomal marker is also reduced giving support to the involvement of the YRKF701-704 motif in the lysosomal targeting of TrkA receptors. Contrary to what was expected, substitution of Y701 for an Asp in order to mimic phosphorylation, impairs TrkA ability to mediate nerve growth factor-induced differentiation, although the mutant receptor retains its in vitro kinase activity. This is the first evidence that a Tyr residue can simultaneously regulate TrkA receptor trafficking and activity.
Assuntos
Receptor trkA/metabolismo , Tirosina/metabolismo , Subunidades gama do Complexo de Proteínas Adaptadoras/metabolismo , Animais , Ácido Aspártico/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Cadeias Pesadas de Clatrina/metabolismo , Imunoprecipitação/métodos , Proteínas de Membrana Lisossomal/metabolismo , Mutação/fisiologia , Células PC12 , Transporte Proteico/fisiologia , Ratos , Transfecção/métodosRESUMO
INTRODUCTION: research into memory in geriatrics and gerontology has become increasingly important in recent years. However, various studies have shown that not all aspects or types of memory are affected in the same way or with the same severity by old age. OBJECTIVES: the present study aimed to establish differential profiles in objective and subjective memory associated with old age with a view to establishing criteria that could be used to distinguish between age-associated memory loss and pathological memory loss, thus aiding diagnosis of cognitive impairment. MATERIAL AND METHODS: a total of 143 participants between 60 and 98 years of age were evaluated using a battery of tests comprising the validated Spanish version of the Mini-Mental State Examination [Lobo's Mini-Examen Cognoscitivo (MEC)], diverse tests for objective memory [the auditory verbal learning test of learning potential (AVLT-LP) and a working memory test], and the subjective memory questionnaire. RESULTS AND CONCLUSIONS: significant differences were found between distinct age groups in different measures of subjective and objective memory. In general terms, persons who complained most about memory problems were not those with poorer performance on objective memory tests. The results show that measures of subjective and objective memory assess different aspects of memory.
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Envelhecimento/fisiologia , Memória/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Psicológicos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Tetrahydrobiopterin (BH4), cofactor of phenylalanine hydroxylase, can be used to treat a subset of phenylketonuria (PKU) patients as it results in a reduction in blood phenylalanine levels. The molecular basis of the response appears to be multifactorial. METHOD: A standard BH4 loading test (20 mg/kg) was performed. Genotyping was performed by DGGE and sequencing analysis. Expression analysis of the D129G mutation was performed in E. coli (expression as fusion protein MBP-PAH) and in a human hepatoma cell line with an N-terminal FLAG epitope. RESULTS: We report the positive response and long-term treatment of a patient functionally hemizygous for the D129G mutation in the phenylalanine hydroxylase gene. Expression in the prokaryotic system revealed partial activity and a decreased binding affinity for BH4 of the mutant protein. In the eukaryotic system the mutant protein shows reduced stability. CONCLUSION: The D129G mutation which confers a BH4-responsive phenotype, has a decreased binding affinity for BH4.
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Biopterinas/análogos & derivados , Mutação/genética , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Biopterinas/farmacologia , Análise Mutacional de DNA , Genótipo , Humanos , Recém-Nascido , Triagem Neonatal , Óxido Nítrico Sintase/metabolismo , Fenótipo , Fenilalanina , Fenilalanina Hidroxilase/metabolismo , Conformação Proteica , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Sex cord tumor with annular tubules is an extremely uncommon gonadal stromal neoplasm. It represents 0.05-0.6% of all ovarian tumors, according to series. An unusual case is presented in a 6-year-old girl, detected as a result of an isosexual peripheral precocious puberty. The highlight of this case is that no mass attached to the ovary was found, but only a gonadal asymmetry without radiological signs of malignancy. After confirming the presence of tumoral cells by intraoperative biopsy, unilateral salpingo-oophorectomy with ipsilateral para-aortic and pelvic lymphadenectomy was performed. Afterwards, the evolution of the patient was favorable.
El tumor de los cordones sexuales con túbulos anulares es una neoplasia del estroma gonadal muy infrecuente. Representa el 0,05-0,6% de todos los tumores ováricos, según series. Se presenta un caso especialmente inusual, en una niña de 6 años, detectado a raíz de una pubertad precoz periférica isosexual. Su interés radica en que no se halló ninguna masa anexa al ovario, sino únicamente una asimetría gonadal, sin signos radiológicos de malignidad. Se realizó una salpingo-ooforectomía unilateral con linfadenectomía pélvica y paraaórtica ipsilateral, por vía laparoscópica, tras confirmarse la presencia de células tumorales en la biopsia intraoperatoria. La evolución posterior de la paciente fue favorable.
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Neoplasias Ovarianas/complicações , Puberdade Precoce/etiologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Criança , Feminino , Humanos , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologiaRESUMO
Fas Apoptosis Inhibitory Molecule (FAIM) is an evolutionarily highly conserved death receptor antagonist, widely expressed and known to participate in physiological and pathological processes. Two FAIM transcript variants have been characterized to date, namely FAIM short (FAIM-S) and FAIM long (FAIM-L). FAIM-S is ubiquitously expressed and serves as an anti-apoptotic protein in the immune system. Furthermore, in neurons, this isoform promotes NGF-induced neurite outgrowth through NF-кB and ERK signaling. In contrast FAIM-L is found only in neurons, where it exerts anti-apoptotic activity against several stimuli. In addition to these two variants, in silico studies point to the existence of two additional isoforms, neither of which have been characterized to date. In this regard, here we confirm the presence of these two additional FAIM isoforms in human fetal brain, fetal and adult testes, and placenta tissues. We named them FAIM-S_2a and FAIM-L_2a since they have the same sequence as FAIM-S and FAIM-L, but include exon 2a. PCR and western blot revealed that FAIM-S_2a shows ubiquitous expression in all the tissues and cellular models tested, while FAIM-L_2a is expressed exclusively in tissues of the nervous system. In addition, we found that, when overexpressed in non-neuronal cells, the splicing factor nSR100 induces the expression of the neuronal isoforms, thus identifying it as responsible for the generation of FAIM-L and FAIM-L_2a. Functionally, FAIM-S_2a and FAIM-L_2a increased neurite outgrowth in response to NGF stimulation in a neuronal model. This observation thus, supports the notion that these two isoforms are involved in neuronal differentiation. Furthermore, subcellular fractionation experiments revealed that, in contrast to FAIM-S and FAIM-L, FAIM-S_2a and FAIM-L_2a are able to localize to the nucleus, where they may have additional functions. In summary, here we report on two novel FAIM isoforms that may have relevant roles in the physiology and pathology of the nervous system.
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Proteínas Reguladoras de Apoptose/metabolismo , Isoformas de Proteínas/metabolismo , Processamento Alternativo , Animais , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Éxons , Humanos , Conformação de Ácido Nucleico , Células PC12 , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estabilidade Proteica , RNA Mensageiro/química , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , TermodinâmicaRESUMO
Low response rates and concerns about safety have limited the implementation of treatment for chronic hepatitis C (CHC) in patients with HIV infection. The efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin in HIV-infected patients with CHC were evaluated in a prospective, open-label, multicenter study. Sixty patients with persistently high transaminases, positive HCV-RNA, CD4 count > or = 300 cells/microl, and HIVRNA <10,000 copies/ml were included. Patients were given peg-IFN 80-150 microg/week plus ribavirin 800-1200 mg/day. Treatment was scheduled for 24 weeks for genotypes 2/3 and 48 weeks for genotypes 1/4. In an intent- to-treat analysis, 16 (26.7%) patients achieved a sustained virological response (SVR). Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events. Negative predictive values for SVR on the basis of HCV-RNA decline between baseline and week 4 were 100% for 1- and 2-log10 fall, and positive predictive values were 40% and 58.3% for 1- and 2-log10 fall, respectively. CD4 fell by a median of 216 cells during treatment, but no HIV-associated complications occurred. In conclusion, treatment with peg-IFN alpha-2b plus ribavirin is safe and clears RNA-HCV in about one-quarter of HIV-infected patients with CHC. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment. Assessment of HCV-RNA at week 4 may help guide early therapeutic decision making.
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Infecções por HIV/complicações , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Modelos Logísticos , Masculino , Polietilenoglicóis , Estudos Prospectivos , RNA Viral/sangue , Proteínas Recombinantes , Ribavirina/efeitos adversos , Resultado do Tratamento , Replicação ViralRESUMO
Disulfiram and calcium carbimide are two alcohol deterrants widely used in alcoholism treatment, however, there exist great concerns over their safety. Reports on hepatotoxicity, mainly related to disulfiram therapy, have been published. The hepatotoxic potential of calcium carbimide is less well characterized. Here, we describe four cases of liver damage related to this therapeutic group that were submitted to a Registry of hepatotoxicity and point out the limitations that we face when prescribing these compounds. A reassessment of the role of these compounds in the management of alcohol dependence is clearly needed.
Assuntos
Dissuasores de Álcool/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Cianamida/efeitos adversos , Dissulfiram/efeitos adversos , Fígado/efeitos dos fármacos , Adulto , Interações Medicamentosas , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVE: Correct utilization of source isolation (SI) in hospitals is important to take advantage of hospital resources. The objective of this work was to evaluate the utilization of SI considering the appropriateness of isolation length-stay. PATIENTS AND METHOD: During a period of 19 months a prospective observational study was carried out among non-critical inpatients who underwent SI in a university hospital. The information was obtained from Admission Unit data, daily ward rounds and review of case history records. RESULTS: A total of 239 SIs were identified, summarizing 2,589 days in isolation (median: 8 days, range: 1-56 days). These data supposed a cumulative incidence of 6.74 isolations by 1,000 admissions, and an incidence density of 1.08 isolations by 1,000 inpatient-day. 36.8% of SIs were considered incorrectly used, meaning a total of 703 inappropriate stays in isolation (27.1% of all stays carried out in SI). Surgical wound infections prompted inappropriate isolations with a greater frequency (45.2%), mainly after hip and knee prosthesis implantation interventions (42.9% and 17.9%, respectively). CONCLUSIONS: It is necessary to develop quality criteria and indicators in order to implement quality improvement actions to optimize SI length-stay management.