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1.
Phys Rev Lett ; 129(26): 262501, 2022 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-36608181

RESUMO

The one-neutron knockout from ^{52}Ca in inverse kinematics onto a proton target was performed at ∼230 MeV/nucleon combined with prompt γ spectroscopy. Exclusive quasifree scattering cross sections to bound states in ^{51}Ca and the momentum distributions corresponding to the removal of 1f_{7/2} and 2p_{3/2} neutrons were measured. The cross sections, interpreted within the distorted-wave impulse approximation reaction framework, are consistent with a shell closure at the neutron number N=32, found as strong as at N=28 and N=34 in Ca isotopes from the same observables. The analysis of the momentum distributions leads to a difference of the root-mean-square radii of the neutron 1f_{7/2} and 2p_{3/2} orbitals of 0.61(23) fm, in agreement with the modified-shell-model prediction of 0.7 fm suggesting that the large root-mean-square radius of the 2p_{3/2} orbital in neutron-rich Ca isotopes is responsible for the unexpected linear increase of the charge radius with the neutron number.

2.
Phys Rev Lett ; 126(25): 252501, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34241497

RESUMO

Direct proton-knockout reactions of ^{55}Sc at ∼220 MeV/nucleon were studied at the RIKEN Radioactive Isotope Beam Factory. Populated states of ^{54}Ca were investigated through γ-ray and invariant-mass spectroscopy. Level energies were calculated from the nuclear shell model employing a phenomenological internucleon interaction. Theoretical cross sections to states were calculated from distorted-wave impulse approximation estimates multiplied by the shell model spectroscopic factors, which describe the wave function overlap of the ^{55}Sc ground state with states in ^{54}Ca. Despite the calculations showing a significant amplitude of excited neutron configurations in the ground-state of ^{55}Sc, valence proton removals populated predominantly the ground state of ^{54}Ca. This counterintuitive result is attributed to pairing effects leading to a dominance of the ground-state spectroscopic factor. Owing to the ubiquity of the pairing interaction, this argument should be generally applicable to direct knockout reactions from odd-even to even-even nuclei.

3.
Phys Rev Lett ; 123(14): 142501, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31702209

RESUMO

Exclusive cross sections and momentum distributions have been measured for quasifree one-neutron knockout reactions from a ^{54}Ca beam striking on a liquid hydrogen target at ∼200 MeV/u. A significantly larger cross section to the p_{3/2} state compared to the f_{5/2} state observed in the excitation of ^{53}Ca provides direct evidence for the nature of the N=34 shell closure. This finding corroborates the arising of a new shell closure in neutron-rich calcium isotopes. The distorted-wave impulse approximation reaction formalism with shell model calculations using the effective GXPF1Bs interaction and ab initio calculations concur our experimental findings. Obtained transverse and parallel momentum distributions demonstrate the sensitivity of quasifree one-neutron knockout in inverse kinematics on a thick liquid hydrogen target with the reaction vertex reconstructed to final state spin-parity assignments.

4.
Phys Rev Lett ; 122(7): 072502, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30848641

RESUMO

The first γ-ray spectroscopy of ^{52}Ar, with the neutron number N=34, was measured using the ^{53}K(p,2p) one-proton removal reaction at ∼210 MeV/u at the RIBF facility. The 2_{1}^{+} excitation energy is found at 1656(18) keV, the highest among the Ar isotopes with N>20. This result is the first experimental signature of the persistence of the N=34 subshell closure beyond ^{54}Ca, i.e., below the magic proton number Z=20. Shell-model calculations with phenomenological and chiral-effective-field-theory interactions both reproduce the measured 2_{1}^{+} systematics of neutron-rich Ar isotopes, and support a N=34 subshell closure in ^{52}Ar.

5.
Heredity (Edinb) ; 116(4): 362-71, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26647653

RESUMO

Most species are structured and influenced by processes that either increased or reduced gene flow between populations. However, most population genetic inference methods assume panmixia and reconstruct a history characterized by population size changes. This is potentially problematic as population structure can generate spurious signals of population size change through time. Moreover, when the model assumed for demographic inference is misspecified, genomic data will likely increase the precision of misleading if not meaningless parameters. For instance, if data were generated under an n-island model (characterized by the number of islands and migrants exchanged) inference based on a model of population size change would produce precise estimates of a bottleneck that would be meaningless. In addition, archaeological or climatic events around the bottleneck's timing might provide a reasonable but potentially misleading scenario. In a context of model uncertainty (panmixia versus structure) genomic data may thus not necessarily lead to improved statistical inference. We consider two haploid genomes and develop a theory that explains why any demographic model with structure will necessarily be interpreted as a series of changes in population size by inference methods ignoring structure. We formalize a parameter, the inverse instantaneous coalescence rate, and show that it is equivalent to a population size only in panmictic models, and is mostly misleading for structured models. We argue that this issue affects all population genetics methods ignoring population structure which may thus infer population size changes that never took place. We apply our approach to human genomic data.


Assuntos
Genética Populacional , Modelos Genéticos , Densidade Demográfica , Demografia , Genoma Humano , Genômica , Haploidia , Humanos
6.
J Nutr Health Aging ; 27(8): 597-606, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37702330

RESUMO

INTRODUCTION: Oropharyngeal dysphagia (OD) is an underdiagnosed medical condition with a high prevalence in populations such as patients with frailty, neurological disease, or head and neck pathology. Potential barriers to its diagnosis include lack of (or low) awareness of the existence and severity of the condition, the hidden nature of the condition within the 'normal ageing' process, clinical limitations, and socioeconomic reasons. Consequently, an effective treatment is not systematically offered in a timely manner, and complications, such as dehydration and respiratory infections or aspiration pneumonia, can arise. To overcome this issue, the early use of screening questionnaires to identify people at risk of swallowing disorders represents the cornerstone of preventive medicine. Several screening tools have been created but few are widely used in clinical practice. The Eating Assessment Tool-10 (EAT-10) was developed as a quick, easy-to-understand, and self-administered screening tool for OD. METHODS: A literature review was conducted in five databases with no restrictions on the language, date of publication, or design of the study to identify aspects of the validation, applicability, and usefulness of EAT-10. RESULTS AND CONCLUSIONS: Transcultural adaptation and translation studies, as well as studies involving various types of patients with dysphagia in different settings have shown the validity and reliability of EAT-10 in relation to the gold standard and other validation tools. The use of this standardised screening tool could be used as a primary screening instrument of dysphagia in routine clinical practice across a wide range of diseases and settings and thereby increase the likelihood of early diagnosis and management of a condition that lead to serious complications and impaired quality of life.


Assuntos
Transtornos de Deglutição , Fragilidade , Humanos , Transtornos de Deglutição/diagnóstico , Qualidade de Vida , Reprodutibilidade dos Testes , Bases de Dados Factuais
7.
Microbiol Spectr ; 9(1): e0014521, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34106579

RESUMO

Upon Kaposi's Sarcoma-associated herpesvirus (KSHV) lytic reactivation, rapid and widespread amplification of viral DNA (vDNA) triggers significant nuclear reorganization. As part of this striking shift in nuclear architecture, viral replication compartments are formed as sites of lytic vDNA production along with remarkable spatial remodeling and the relocalization of cellular and viral proteins. These viral replication compartments house several lytic gene products that coordinate viral gene expression, vDNA replication, and nucleocapsid assembly. The viral proteins and mechanisms that regulate this overhaul of the nuclear landscape during KSHV replication remain largely unknown. KSHV's ORF20 is a widely conserved lytic gene among all herpesviruses, suggesting it may have a fundamental contribution to the progression of herpesviral infection. Here, we utilized a promiscuous biotin ligase proximity labeling method to identify the proximal interactome of ORF20, which includes several replication-associated viral proteins, one of which is ORF59, the KSHV DNA processivity factor. Using coimmunoprecipitation and immunofluorescence assays, we confirmed the interaction between ORF20 and ORF59 and tracked the localization of both proteins to KSHV replication compartments. To further characterize the function of ORF20, we generated an ORF20-deficient KSHV and compared its replicative fitness to that of wild-type virus. Virion production was significantly diminished in the ORF20-deficient virus as observed by supernatant transfer assays. Additionally, we tied this defect in viable virion formation to a reduction in viral late gene expression. Lastly, we observed an overall reduction in vDNA replication in the ORF20-deficient virus, implying a key role for ORF20 in the regulation of lytic replication. Taken together, these results capture the essential role of KSHV ORF20 in progressing viral lytic infection by regulating vDNA replication alongside other crucial lytic proteins within KSHV replication compartments. IMPORTANCE Kaposi's Sarcoma-associated herpesvirus (KSHV) is a herpesvirus that induces lifelong infection, and as such, its lytic replication is carefully controlled to allow for efficient dissemination from its long-term reservoir and for the spread of the virus to new hosts. Viral DNA replication involves many host and viral proteins, coordinating both in time and space to successfully progress through the viral life cycle. Yet, this process is still not fully understood. We investigated the role of the poorly characterized viral protein ORF20, and through proximity labeling, we found that ORF20 interacts with ORF59 in replication compartments and affects DNA replication and subsequent steps of the late viral life cycle. Collectively, these results provide insights into the possible contribution of ORF20 to the complex lytic DNA replication process and suggest that this highly conserved protein may be an important modulator of this key viral mechanism.


Assuntos
Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/metabolismo , Proteínas Virais/metabolismo , Ativação Viral , Replicação Viral , Replicação do DNA , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8/genética , Humanos , Ligação Proteica , Proteínas Virais/genética
8.
Science ; 185(4156): 1049-53, 1974 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-4605043

RESUMO

Reoviruslike particles were visualized by electron microscopy in stool filtrates prepared from stools of infants and young children with severe acute gastroenteritis. Patients who had such particles in their stools and whose paired acute and convalescent serums were tested developed an antibody response to the reoviruslike agent, which was measured by immune electron microscopy and by complement fixation. The reoviruslike agent was antigenically related to the epizootic diarrhea of infant mice virus and the Nebraska calf diarrhea virus.


Assuntos
Diarreia Infantil/microbiologia , Fezes/microbiologia , Reoviridae/isolamento & purificação , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Pré-Escolar , Testes de Fixação de Complemento , Diarreia/veterinária , Diarreia Infantil/diagnóstico , Gastroenterite/diagnóstico , Gastroenterite/microbiologia , Humanos , Técnicas Imunológicas , Lactente , Camundongos , Microscopia Eletrônica , Reoviridae/imunologia , Doenças dos Roedores/microbiologia , Testes Sorológicos
9.
Br J Pharmacol ; 154(7): 1465-73, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18536749

RESUMO

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/toxicidade , Quinolinas/toxicidade , Córtex Suprarrenal/citologia , Córtex Suprarrenal/efeitos dos fármacos , Aldosterona/sangue , Animais , Anticolesterolemiantes/toxicidade , Corticosterona/sangue , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
10.
Physiol Res ; 57(3): 379-384, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17552869

RESUMO

Chronic volume overload (VO) on the left ventricle (LV) augments redox stress and activates matrix metalloproteinase (MMP) which causes the endocardial endothelial-myocyte (EM) disconnection leading to myocardial contractile dysfunction. VO-induced MMP-9 activation impairs cardiac functions, in part by endothelial endocardial apoptosis, but the role of MMP-9 on EM functions remains obscure. We conjecture that chronic VO activates MMP-9 and causes EM uncoupling. Arteriovenous fistula (AVF) was created in genetically identical wild type (WT) mice (FVB/NJ) and MMP-9 knockout mice (MMP-9KO, FVB.Cg-MMP9(tm1Tvu)/J). Sham-operated mice were used as controls. Before experimentation the phenotype analysis of MMP-9KO mice was carried out. In-gel-gelatin zymography for MMP-9 activation was performed on LV homogenates. The EM functions were determined on LV rings using tissue myobath. We report a decrease in MMP-9 activity in left ventricular myocardial extracts in MMP-9 deficient mice after AVF. The responses to drugs affecting cardiac functions (acetylcholine (Ach), nitroprusside and bradykinin) were attenuated in AVF mice suggesting the impairment of EM coupling. Interestingly, the EM functions were restored in the MMP-9 deficient mice after AVF. We suggest a direct cause-and-effect relationship between MMP-9 activation and EM uncoupling in LV myocardium after chronic VO and the possible involvement of MMP-9 in myocardial contractile performance.


Assuntos
Células Endoteliais/enzimologia , Insuficiência Cardíaca/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Contração Miocárdica , Miocárdio/enzimologia , Função Ventricular Esquerda , Acetilcolina/farmacologia , Animais , Derivação Arteriovenosa Cirúrgica , Bradicinina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Ativação Enzimática , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/enzimologia , Ventrículos do Coração/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/deficiência , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Nitroprussiato/farmacologia , Fenótipo , Função Ventricular Esquerda/efeitos dos fármacos
12.
J Perinatol ; 36(12): 1029-1033, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27416322

RESUMO

OBJECTIVE: To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. STUDY DESIGN: Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. RESULTS: An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety. CONCLUSIONS: For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development.


Assuntos
Ensaios Clínicos como Assunto/métodos , Hipertensão Pulmonar/tratamento farmacológico , Biomarcadores/análise , Criança , Pré-Escolar , Antagonistas dos Receptores de Endotelina/uso terapêutico , Teste de Esforço , Humanos , Lactente , Recém-Nascido , Consumo de Oxigênio/fisiologia , Pirimidinas/uso terapêutico , Padrões de Referência , Reprodutibilidade dos Testes , Citrato de Sildenafila/uso terapêutico , Sulfonamidas/uso terapêutico , Vasodilatadores/uso terapêutico
13.
J Neurosci ; 21(11): 3849-59, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-11356873

RESUMO

The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and one of its receptors (PAC(1)) are expressed in embryonic neural tube, where they appear to regulate neurogenesis and patterning. We now show that PAC(1) gene expression is also present in neonatal rats in the ventricular and subventricular zones and in the optic chiasm, areas that are rich in oligodendrocyte (OL) progenitors (OLP). Because actions of PACAP on OLP have not been reported, we examined the effects of PACAP on the proliferation of purified OLP in culture and on myelinogenesis in cerebellar slices. Northern analyses on total RNA from purified glial cell subtypes revealed an abundant 7 kb hybridizing transcript in OLP, which was confirmed to correspond to the PAC(1) receptor by reverse transcription-PCR. The presence of this receptor was also corroborated by radioligand binding and cAMP assay. In cultured OL, receptor density decreased during maturation but was partially counterbalanced by the appearance of sites that bound both PACAP and the related peptide vasoactive intestinal peptide. PACAP increased DNA synthesis in OLP cultures almost twofold and increased the bromodeoxyuridine-labeling index in O4-positive OLP. PACAP treatment also resulted in decreased sulfate incorporation into sulfatide in cultures of differentiating OL. The PACAP effect on sulfatide synthesis was fully reproduced in a cerebellar explant model. These findings indicate that PACAP may act at two stages during OL development to (1) stimulate proliferation and (2) delay maturation and/or myelinogenesis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , DNA/metabolismo , Neuropeptídeos/metabolismo , Oligodendroglia/citologia , Células-Tronco/metabolismo , Animais , Animais Recém-Nascidos , Ligação Competitiva/efeitos dos fármacos , Bromodesoxiuridina , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/metabolismo , Ventrículos Cerebrais/cirurgia , Expressão Gênica , Hibridização In Situ , Técnicas In Vitro , Bainha de Mielina/metabolismo , Neuropeptídeos/farmacologia , Quiasma Óptico/citologia , Quiasma Óptico/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , RNA Mensageiro/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Receptores do Hormônio Hipofisário/biossíntese , Receptores do Hormônio Hipofisário/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/efeitos dos fármacos
14.
J Clin Oncol ; 16(6): 2065-9, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9626205

RESUMO

PURPOSE: It has been suggested that age is associated with chemotherapy-related death in patients with non-Hodgkin's lymphoma (NHL) treated with doxorubicin-containing chemotherapy. The purpose of this study was to evaluate the relative influence of increasing age and other clinical parameters on the occurrence of treatment-related death in elderly patients with intermediate- or high-grade NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS: A retrospective study of patients 60 years of age or older with intermediate- or high-grade NHL treated with CHOP chemotherapy in a single cancer center. The following variables were recorded: age (60 to 69, 70 to 79, and 80 to 94 years), histology (Working Formulation [WF] D, E, F, G, and H), Ann Arbor stage, B symptoms, extranodal involvement, bulky disease (> 7 cm), performance status (Eastern Cooperative Oncology Group [ECOG] scale), International Prognostic Index (IPI score), serum lactate dehydrogenase (LDH) level and doxorubicin relative dose-intensity (RDI). The relationship between these features and treatment-related death was assessed in univariate and multivariate logistic regression analysis. RESULTS: From 1982 to 1991, 267 consecutive patients were treated. Median age was 70 years (range, 60 to 94 years). There were 35 toxic deaths. Sixty-three percent of the deaths occurred after the first cycle. Infection accounted for 82% of the toxic deaths. In the univariate analysis, the features associated with an increased risk of toxic death were ECOG performance status 2 to 4 (relative risk [RR], 7.82), B symptoms (RR, 3.38), diffuse large-cell histology (RR, 3.06), bulky disease (RR, 2.58), serum levels of LDH (RR, 2.53), and IPI score (RR, 2.46). The age groups did not show significance. In the regression model, performance status 2 to 4 was the only independent predictor of treatment-related death (RR, 3.52; 95% confidence interval [CI], 2.98 to 4.06). CONCLUSION: Our results show that in elderly patients with NHL treated with doxorubicin-based chemotherapy the risk for treatment-related death is associated with poor performance status rather than with increasing chronologic age.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Vincristina/efeitos adversos , Vincristina/uso terapêutico
15.
J Clin Oncol ; 16(7): 2352-8, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9667250

RESUMO

PURPOSE: Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkin's lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS: We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS: Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION: CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.


Assuntos
Envelhecimento/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma não Hodgkin/sangue , Masculino , Concentração Máxima Permitida , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Vincristina/administração & dosagem
16.
J Perinatol ; 35(10): 867-74, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26248129

RESUMO

OBJECTIVES: Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. STUDY DESIGN: We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. RESULTS: We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. CONCLUSION: The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials.


Assuntos
Ácidos Araquidônicos/administração & dosagem , Suplementos Nutricionais/normas , Ácidos Docosa-Hexaenoicos/administração & dosagem , Fórmulas Infantis/normas , Testes de Inteligência/normas , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes
17.
NeuroRehabilitation ; 37(4): 719-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26639934

RESUMO

BACKGROUND: The Test of Memory Malingering (TOMM) is an instrument used to assess purposeful embellishment or fabrication of memory difficulties for personal gain. Although the TOMM can be use in non-English speaking cultures, it has not been validated in Spanish-speaking Central and South American contexts. OBJECTIVE: To generate normative data on TOMM across 7 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 2,266 healthy adults who were recruited from Argentina, Bolivia, Chile, Mexico, Paraguay, Peru, and Puerto Rico. Each subject was administered the TOMM as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: t-tests did not show significant differences in TOMM performance between men and women in any countries of the TOMM Trial 1 or 2. As a result, gender-adjusted norms were not generated. CONCLUSIONS: The results from this study will have a large impact on the practice of neuropsychology in Latin America, as this is the first normative multicenter study to create norms for the TOMM in this global region.


Assuntos
Simulação de Doença/diagnóstico , Simulação de Doença/psicologia , Transtornos da Memória/diagnóstico , Transtornos da Memória/psicologia , Testes Neuropsicológicos/normas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Escolaridade , Feminino , Humanos , Idioma , América Latina , Masculino , Pessoa de Meia-Idade , Valores de Referência , Análise de Regressão , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
18.
NeuroRehabilitation ; 37(4): 591-624, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26639926

RESUMO

OBJECTIVE: To generate normative data on the Stroop Test across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the Stroop Test, as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 14-36% of the variance in Stroop Word scores, 12-41% of the variance in the Stoop Color, 14-36% of the variance in the Stroop Word-Color scores, and 4-15% of variance in Stroop Interference scores. Although t-tests showed significant differences between men and women on the Stroop test, none of the countries had an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to create norms for the Stoop Test in a Spanish-Speaking sample. This study will therefore have important implications for the future of neuropsychology research and practice throughout the region.


Assuntos
Cor , Teste de Stroop/normas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Testes de Percepção de Cores , Escolaridade , Feminino , Humanos , Idioma , América Latina , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
19.
NeuroRehabilitation ; 37(4): 501-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26639925

RESUMO

OBJECTIVE: To generate normative data on the Boston Naming Test (BNT) across 10 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,779 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the BNT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained between 3-32% of the variance in BNT scores. Although t-tests showed significant differences between men and women for Mexico, Argentina, Chile, Cuba, Guatemala, and Bolivia on the BNT, none of the six countries had an effect size larger than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to generate norms for the BNT; this study will have substantial repercussions for the practice of neuropsychology throughout the global region.


Assuntos
Testes Neuropsicológicos/normas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Interpretação Estatística de Dados , Feminino , Humanos , Idioma , América Latina , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
20.
NeuroRehabilitation ; 37(4): 625-38, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26639927

RESUMO

OBJECTIVE: To generate normative data on the Symbol Digit Modalities Test (SDMT) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and, Puerto Rico. Each subject was administered the SDMT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models explained 29-56% of the variance in SDMT scores. Although there were gender differences on the SDMT in Mexico, Honduras, Paraguay, and Guatemala, none of the four countries had an effect size greater than 0.3. As a result, gender-adjusted norms were not generated. CONCLUSIONS: This is the first normative multicenter study conducted in Latin America to create norms for the SDMT; this study will have an impact on the future practice of neuropsychology throughout the global region.


Assuntos
Testes Neuropsicológicos/normas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Escolaridade , Feminino , Humanos , Idioma , América Latina , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
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