RESUMO
Similar to human chronic lymphocytic leukemia (CLL), the de novo New Zealand Black (NZB) mouse model has a genetically determined age-associated increase in malignant B-1 clones and decreased expression of microRNAs miR-15a and miR-16 in B-1 cells. In the present study, lentiviral vectors were employed in vivo to restore miR-15a/16, and both the short-term single injection and long-term multiple injection effects of this delivery were observed in NZB. Control lentivirus without the mir-15a/16 sequence was used for comparison. We found that in vivo lentiviral delivery of mir-15a/16 increased miR-15a/16 expression in cells that were transduced (detected by GFP expression) and in sera when compared with control lentivirus treatment. More importantly, mice treated with the miR-expressing lentivirus had decreased disease. The lentivirus had little systemic toxicity while preferentially targeting B-1 cells. Short-term effects on B-1 cells were direct effects, and only malignant B-1 cells transduced with miR-15a/16 lentivirus had decreased viability. In contrast, long-term studies suggested both direct and indirect effects resulting from miR-15a/16 lentivirus treatment. A decrease in B-1 cells was found in both the transduced and non-transduced populations. Our data support the potential use of systemic lentiviral delivery of miR-15a/16 to ameliorate disease manifestations of CLL.
Assuntos
Lentivirus/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , MicroRNAs/genética , Animais , Modelos Animais de Doenças , Terapia Genética , Leucemia Linfocítica Crônica de Células B/patologia , CamundongosRESUMO
OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Eletromiografia/métodos , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Metionina/genética , Estimulação Magnética Transcraniana/métodos , Valina/genéticaRESUMO
Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.
Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Condicionamento Físico Animal/fisiologia , Animais , Peso Corporal/fisiologia , Ventrículos do Coração/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Norepinefrina/metabolismo , Tamanho do Órgão/fisiologia , Ratos , Ratos WistarRESUMO
We evaluated 48 archival cases of acute erythroleukemia and divided them into 3 groups: M6a, corresponding to the traditional French-American-British M6 category; M6b, which is pure erythroleukemia; and M6c, in which myeloblasts and pronormoblasts each account for more than 30% of cells by the French-American-British exclusion criteria. No significant differences were noted among the subtypes for ratio of males to females; age; or exposure to toxins, alcohol, or both. However, compared with the patients in the M6a group, patients in the M6b and M6c groups demonstrated a statistically significant increase in cytogenetic aberrations, proliferation markers (proliferating cell nuclear antigen and Ki67), and ringed (type III) sideroblasts. Marked survival differences were noted between the M6a (30.1 +/- 29.5 months) and M6b (3.15 +/- 4.2 months) groups, with patients in the M6c group demonstrating an intermediate prognosis (10.5 +/- 12.7 months). Chemotherapeutic regimens induced remission in all treated patients in the M6a and M6c groups but did not appear to affect the M6b group. However, the patients in the M6c group remained in remission for a significantly shorter period of time than did patients in the M6a group. Overall, survival appeared to depend on the ratio of pronormoblasts to myeloblasts at diagnosis and demonstrated a rapid decline with increasing pronormoblast and decreasing myeloblast counts. We must, therefore, devise chemotherapeutic regimens that target both blastic components of this disease.
Assuntos
Divisão Celular , Citogenética , Leucemia Eritroblástica Aguda/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Aberrações Cromossômicas , Eritrócitos/patologia , Feminino , Granulócitos/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Cariotipagem , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Antígeno Nuclear de Célula em Proliferação/análiseRESUMO
We report a case of mammary duct carcinoma with a prominent lipid-rich, sebaceous-like component, occurring in a 55 yr old white male. The patient presented with a painless, subareolar left breast mass and the diagnosis of malignancy was made by fine needle aspiration. Subsequent modified radical mastectomy revealed an infiltrating and in situ ductal carcinoma with dermal invasion and numerous vacuolated sebaceous-like tumor cells, positive for neutral lipid by Oil Red O stain. We propose that this case represents an unusual variant of lipid-secreting breast carcinoma. To the best of our knowledge, this subtype of mammary carcinoma is unprecedented in male breast.
Assuntos
Neoplasias da Mama Masculina/química , Carcinoma Ductal de Mama/química , Lipídeos/química , Glândulas Sebáceas/patologia , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Glândulas Sebáceas/químicaRESUMO
Acute erythroleukemia is an aggressive leukemia derived from a multipotential stem cell. Three subtypes have been described: (1) M6a with greater than or equal to 30% blasts of the nonerythrocytic component, (2) M6b with greater than or equal to 30% pronormoblasts of the erythrocytic elements, and (3) M6c with greater than or equal to 30% blasts and greater than or equal to 30% pronormoblasts by the aforementioned exclusion criteria. The poor prognosis associated with this disorder positively correlates with a high pronormoblast:myeloblast ratio; unfavorable cytogenetic aberrations; a high proliferative index; and the presence of P-glycoprotein expression (multidrug resistance phenotype). Chemotherapeutic regimens directed toward these specific parameters should be devised in order to improve the characteristically poor outcome of this patient population.
Assuntos
Leucemia Eritroblástica Aguda/patologia , Doença Aguda , Aberrações Cromossômicas , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , PrognósticoRESUMO
This is a case of a long-term Connecticut resident who presented with both human granulocytic ehrlichiosis and Lyme disease. The etiologic agents and the probability of coinfection are discussed.
Assuntos
Ehrlichiose/complicações , Doença de Lyme/complicações , Idoso , Animais , Comorbidade , Connecticut , Ehrlichia/isolamento & purificação , Ehrlichiose/transmissão , Feminino , Humanos , Ixodes , Doença de Lyme/transmissãoRESUMO
OBJECTIVE: Moderate alcohol consumption is related to a reduction of mortality. However, this phenomenon is not well established in the elderly, especially in the presence of chronic heart failure (CHF). The aim of the study was to verify the effect of moderate alcohol consumption on 12-year mortality in elderly community-dwelling with and without CHF. SETTINGS: community-dwelling from 5 regions of Italy. PARTICIPANTS: A cohort of 1332 subjects aged 65 and older. MEASUREMENT: Mortality after 12-year follow-up in elderly subjects (≥65 years old) with and without CHF was studied. Moderate alcohol consumption was considered ≤250 ml/day (drinkers). RESULTS: In the absence of CHF (n=947), mortality was 42.2% in drinkers vs. 53.7% in non-drinker elderly subjects (p=0.021). In contrast, in the presence of CHF (n=117), mortality was 86.5% in drinkers vs. 69.7% in non-drinker elderly subjects (p=0.004). Accordingly, Cox regression analysis shows that a moderate alcohol consumption is protective of mortality in the absence (HR=0.79; CI 95% 0.66-0.95; p<0.01) but it is predictive of mortality in the presence of CHF (HR=1.29; CI 95% 1.05-1.97; p<0.05). CONCLUSIONS: Our data demonstrates that moderate alcohol consumption is associated with an increased long-term mortality risk in the elderly in the presence of CHF.
Assuntos
Consumo de Bebidas Alcoólicas/mortalidade , Etanol/efeitos adversos , Insuficiência Cardíaca/mortalidade , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Etanol/administração & dosagem , Feminino , Humanos , Itália/epidemiologia , Masculino , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVES: The oscillation model of Parkinson disease (PD) states that, in the subthalamic nucleus (STN), increased θ (4-10 Hz) and ß (11-30 Hz) frequencies were associated with worsening whereas γ frequencies (31-100 Hz) were associated with improvement of motor symptoms. However, the peak STN frequency in each band varied widely from subject to subject. We hypothesized that STN deep brain stimulation (DBS) at individualized γ frequencies would improve whereas θ or ß frequencies would worsen PD motor signs. METHODS: We prospectively studied 13 patients with PD. STN local field potential (LFP) was recorded after electrode implantations, in the OFF and then in ON dopaminergic medication states while patients performed wrist movements. Six individual peak frequencies of the STN LFP power spectra were obtained: the greatest decrease in θ and ß and greatest increase in γ frequencies in the ON state (MED) and during movements (MOVE). Eight DBS frequencies were applied including 6 MED and MOVE frequencies, high frequency (HF) used for chronic stimulation, and no stimulation. The patients were assessed using the motor Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: STN DBS at γ frequencies (MED and MOVE) and HF significantly improved mUPDRS scores compared to no stimulation and both γ frequencies were not different from HF. DBS at θ and ß frequencies did not worsen mUPDRS scores compared to no stimulation. CONCLUSION: Short-term administration of STN DBS at peak dopamine-dependent or movement-related γ frequencies were as effective as HF for reducing parkinsonian motor signs but DBS at θ and ß frequencies did not worsen PD motor signs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN DBS at patient-specific γ frequencies and at usual high frequencies both improved mUPDRS scores compared to no stimulation and did not differ in effect.
Assuntos
Estimulação Encefálica Profunda/métodos , Doença de Parkinson/terapia , Núcleo Subtalâmico/cirurgia , Adulto , Idoso , Antiparkinsonianos/uso terapêutico , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Movimento/fisiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Medicina de Precisão , Selegilina/uso terapêutico , Núcleo Subtalâmico/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVE: The pedunculopontine nucleus region (PPNR) is being investigated as a target for deep brain stimulation (DBS) in Parkinson disease (PD), particularly for gait and postural impairment. A greater understanding of how PPNR activities and oscillations are modulated with voluntary movements is crucial to the development of neuromodulation strategies. METHODS: We studied 7 patients with PD who underwent DBS electrode implantations in the PPNR. PPNR local field potential and EEG were recorded while patients performed self-paced wrist and ankle movements. RESULTS: Back-averaging of the PPNR recording showed movement-related potentials before electromyography onset. Frequency analysis showed 2 discrete movement-related frequency bands in the theta (6- to 10-Hz) and beta (14- to 30-Hz) ranges. The PPNR theta band showed greater event-related desynchronization with movements in the ON than in the OFF medication state and was coupled with the sensorimotor cortices in the ON state only. Beta event-related desynchronization was observed in the PPNR during the premovement and movement execution phases in the OFF state. In contrast, premovement PPNR beta event-related synchronization occurred in the ON state. Moreover, beta band coherence between the PPNR and the midline prefrontal region was observed during movement preparation in the ON but not the OFF state. CONCLUSIONS: Activities of PPNR change during movement preparation and execution in patients with PD. Dopaminergic medications modulate PPNR activities and promote the interactions between the cortex and PPNR. Beta oscillations may have different functions in the basal ganglia and PPNR, and may be prokinetic rather than antikinetic in the PPNR.
Assuntos
Movimento/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Idoso , Gânglios da Base/fisiologia , Sincronização Cortical , Interpretação Estatística de Dados , Estimulação Encefálica Profunda , Eletrodos Implantados , Eletroencefalografia , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiologia , Rede Nervosa/fisiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/cirurgia , Córtex Somatossensorial/fisiologia , Núcleo Subtalâmico/fisiologiaAssuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Meningite Criptocócica/etiologia , Mieloma Múltiplo/complicações , Transplante de Medula Óssea/efeitos adversos , Cryptococcus neoformans , Feminino , Humanos , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/tratamento farmacológico , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Transplante Autólogo/efeitos adversosAssuntos
Leucemia Eritroblástica Aguda/patologia , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Citarabina/uso terapêutico , Citogenética , Daunorrubicina/uso terapêutico , Evolução Fatal , Humanos , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genéticaAssuntos
Artrite Reumatoide/complicações , Púrpura Trombocitopênica Idiopática/complicações , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/fisiopatologiaAssuntos
Distúrbios Distônicos/fisiopatologia , Eletroencefalografia , Globo Pálido/fisiopatologia , Tálamo/fisiopatologia , Adulto , Braço/fisiologia , Sincronização Cortical , Estimulação Encefálica Profunda , Eletromiografia , Feminino , Humanos , Movimento/fisiologia , Rede Nervosa/fisiopatologia , Putamen/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Núcleos Ventrais do Tálamo/fisiopatologia , Punho/fisiologiaRESUMO
BACKGROUND: The elderly are characterized by a high prevalence of chronic heart failure (CHF) and frailty, which is a complex interaction of physical, psychological and social impairment. This study aimed to examine the predictive role of frailty on long-term mortality in elderly subjects with CHF. MATERIALS AND METHODS: The study assessed long-term mortality after 12-year follow up in 120 subjects with CHF and 1139 subjects without CHF, selected in 1992, from a random sample of the elderly population in the Campania region of Italy. Frailty was assessed according to a 'Frailty Staging System'. RESULTS: Subjects with CHF were prevalently female (60%) and older than 75 years (mean 75.9 +/- 6.7); subjects without CHF were prevalently female (56.4%) and younger than 75 years (mean 74.0 +/- 6.3). In subjects with and without CHF stratified into classes of frailty there was a statistically significant increase in age, comorbidity, disability and low social support, and a decrease in MMSE score. Moreover, death progressively increased more with frailty in subjects (70.0% to 94.4%, P < 0.03) than in those without (43.8.% to 88.3%, P < 0.0001) CHF. The Kaplan-Meier analysis shows that at 9 years the probability of survival progressively decreased as frailty increased (45.5% to 0%) in subjects with CHF and from 62.8% to 25.9% in subjects without CHF. The Cox regression analysis indicated that frailty is predictive of mortality in the multivariate model adjusted for several variables including sex and age in subjects with and without CHF. Moreover, the analysis showed that frailty is more predictive of mortality in elderly subjects with CHF when it was analyzed either as continuous (1.48 vs. 1.36) or as a dummy (3 vs. 1 = 1.62 vs. 1.24) variable. CONCLUSIONS: Thus mortality among elderly subjects with or without CHF increases with frailty. Moreover, frailty is more predictive of long-term mortality in elderly subjects with than in those without CHF. Hence, frailty represents a new independent variable for predicting long-term mortality in elderly subjects with CHF.
Assuntos
Idoso Fragilizado , Insuficiência Cardíaca/mortalidade , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Itália , Masculino , Análise Multivariada , Análise de SobrevidaRESUMO
We report a rare case of testicular histiocytoid hemangioma. Pathological features and differential diagnosis of this neoplasm are discussed.
Assuntos
Hemangioma/patologia , Neoplasias Testiculares/patologia , Adulto , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
Acute erythroleukemia (FAB M6) is a rare heterogeneous disease with an increase in red cell precursors and myeloblasts. Three subsets have been described: M6A (myeloblast-rich erythroleukemia); M6B (proerythroblast-rich erythroleukemia); and M6C (myeloblast- and proerythroblast-rich mixed variant). This study was undertaken to define and compare the clinical courses and survival outcomes among M6A, M6B, and M6C variants of erythroleukemia. Sixty-nine cases of M6 leukemia were categorized as consisting of >/=50% erythroid of all nucleated cells and M6A with >/=30% myeloblasts/nonerythroid component; M6B with >/=30% proerythroblasts/erythroid component; and M6C with >/=30% myeloblasts and >/=30% proerythroblasts. The demographics, cell type distribution, and survival (mean +/- sd) of these groups were compared. There were 32 M6A, 26 M6B, and 11 M6C patients. No significant difference was seen among the groups in age, sex, or treatment. Compared to M6A, both the M6B (P< 0.0001) and M6C (P< 0.0001) variants showed a statistically significant increase in the percentage of bone marrow erythroid cells, proerythroblasts, and the proerythroblasts/erythroid ratios. Comparing the groups for survival, M6B (3 +/- 3.6 months) versus M6A (25 +/- 28 months), P< 0. 002, and M6C (10 +/- 13 months) versus M6A, P< 0.01 had a poorer prognosis. Calculating the proerythroblasts as a component of total bone marrow erythroids provides a complimentary method for delineating the pure red cell erythroleukemia (M6B) and mixed variant (M6C), similar to that for the myeloid/erythroid (M6A) leukemia. Now that it is possible to delineate erythroleukemia subtypes, innovative treatments are indicated to target the malignant erythroid population, which is resistant to myeloid-based therapies.