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1.
J Biol Regul Homeost Agents ; 35(3 Suppl. 1): 155-166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34289675

RESUMO

It is widely recognized that the physiology of childbirth labor largely depends on the interaction between three factors: a) the force generated by uterine contractions; b) the structure and characteristics of the birth canal and c) the fetus. Harmony between these three variables determines the initiation of maternal dynamic phenomena and the establishment of an optimal maternal-fetal balance in which both warrant for a correct delivery timing. The present study considered the above known factors and assessed if any other factor, still not recognized, could also play a role, and eventually modify the timing of delivery during the expulsive period. In particular, we focused our attention on the role played by the temporomandibular joint and dental occlusion on maternal body balance and on the stability of muscular reflected forces. The importance of assessing the temporomandibular function and the dental occlusion lies in the fact that any alteration in chewing or in temporomandibular joint (TMJ) mobility and occlusion brings to relevant modifications on the vertebral column and pelvic girdle. Our hypothesis is based on the evidence that those women who have any kind of alteration in their dental occlusion, can have an altered capability of pushing during the expulsive period, as the force applied on the pelvic floor is not expressed. Moreover, recent studies have highlighted a relationship between temporomandibular dysfunctions and sleep apnea syndrome and between sleep apnea syndromes and pregnancy. These relationships are explored in this study.


Assuntos
Oclusão Dentária , Contração Uterina , Feminino , Humanos , Gravidez , Articulação Temporomandibular
6.
Clin Transl Oncol ; 22(6): 844-851, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31392645

RESUMO

BACKGROUND: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression. METHODS: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC). RESULTS: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs). CONCLUSION: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Itália , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida , Resultado do Tratamento
10.
J Transl Med ; 17(1): 74, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849967

RESUMO

BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated. METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS). RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001). CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.


Assuntos
Antígenos de Neoplasias/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Queratina-19/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Fosfopiruvato Hidratase/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
11.
Br J Cancer ; 116(1): 36-43, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27898657

RESUMO

BACKGROUND: VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed. METHODS: The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted. RESULTS: Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately. CONCLUSIONS: The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Química do Sangue/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Padrão de Cuidado , Análise de Sobrevida
12.
Expert Opin Pharmacother ; 17(9): 1197-205, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27055148

RESUMO

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an uncommon, aggressive cancer, derived from pleural mesothelial cells, that has a close relationship to asbestos exposure. To date, MPM prognosis is poor and very few treatment options are available for both localized and advanced MPM. AREAS COVERED: The standard of care is still chemotherapy with platinum derivates and antifolate agents. In the last few years, several new agents have been studied on the basis of mesothelioma carcinogenesis and invasiveness mechanisms; however, the recent results are poor and few drugs have been tested in phase III trials because of toxicity or because they did not improve patient outcomes. The aim of this review is to focus on the current available treatment for MPM through the analysis of the results comes from the phase III trials and to discuss the future perspectives in the pathogenesis, diagnosis and treatment. EXPERT OPINION: Many compounds are currently under investigation in different subsets of patients. Interesting data have come from preliminary studies on immunotherapy, but randomized studies are needed to confirm the preliminary positive results of this new strategy. A better comprehension of MPM pathogenesis should be obtained to improve and develop new diagnostic tools and target therapies.


Assuntos
Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Terapias em Estudo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/tendências , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/tendências , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Mesotelioma Maligno , Neoplasias Pleurais/diagnóstico , Prognóstico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
13.
Int J Clin Pract ; 68(8): 995-1000, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24852701

RESUMO

BACKGROUND: A high incidence of erectile dysfunction (ED) among patients with obstructive sleep apnoea syndrome (OSAS) has been reported, with a strong correlation between obstructive sleep apnoea, ED, and quality of life (QOL), and it has been estimated that 10-60% of patients with OSAS suffer from ED. In this prospective randomised controlled trial, we investigated 82 men with ED consecutively who were referred to the outpatient clinic for sleep disorders and had severe OSAS (AHI> 30 events/h) without any other comorbidities as a possible cause of ED. The aim of this study was to evaluate and compare the efficacy of sildenafil vs. continuous positive airway pressure (CPAP) in men with ED and severe OSAS. METHODS: Eighty-two patients were randomised to two main treatment groups: group 1 patients (n = 41) were treated with 100-mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 patients (n = 41 men) were treated with only nasal CPAP during night time sleep. Both groups were evaluated with the same questionnaires (International Index of Erectile Function-EF domain; Sex Encounter Profile; Erectile Dysfunction Inventory Treatment Satisfaction) 12 weeks after treatment. RESULTS: In patients receiving sildenafil treatment, 58.2% of those who attempted sexual intercourses were successful compared to 30.4% in the CPAP group. The mean number of successful attempts per week was significantly higher in the sildenafil group compared with the CPAP group (2.9 vs. 1.7, respectively; p < 0.0001). The mean IIEF-EF domain scores were significantly higher in the sildenafil group compared with the CPAP group (p < 0.0001). The overall satisfaction rate was 68% with sildenafil treatment and 29% with CPAP treatment. CONCLUSIONS: This study confirms that severe OSAS is strongly associated with erectile dysfunction. CPAP and sildenafil (100 mg) are safe and effective therapies for OSAS-related ED patients. In the present study sildenafil was more effective than CPAP in treating ED associated with OSAS, as indicated by a significantly higher rate of successful attempts at intercourse and higher IIEF-EF domain scores. Our study, to date, is the only that has investigated sildenafil in patients with severe OSAS.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/estatística & dados numéricos , Disfunção Erétil/tratamento farmacológico , Piperazinas/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Síndromes da Apneia do Sono/tratamento farmacológico , Vasodilatadores/uso terapêutico , Adulto , Coito/fisiologia , Terapia Combinada , Pressão Positiva Contínua nas Vias Aéreas/normas , Disfunção Erétil/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Citrato de Sildenafila/administração & dosagem , Síndromes da Apneia do Sono/terapia , Inquéritos e Questionários , Vasodilatadores/administração & dosagem
14.
Scr Med (Brno) ; 80(4): 157-166, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19122770

RESUMO

BIOCOS, the project aimed at studying BIOlogical systems in their COSmos, has obtained a great deal of expertise in the fields of blood pressure (BP) and heart rate (HR) monitoring and of marker rhythmometry for the purposes of screening, diagnosis, treatment, and prognosis. Prolonging the monitoring reduces the uncertainty in the estimation of circadian parameters; the current recommendation of BIOCOS requires monitoring for at least 7 days. The BIOCOS approach consists of a parametric and a non-parametric analysis of the data, in which the results from the individual subject are being compared with gender- and age-specified reference values in health.Chronobiological designs can offer important new information regarding the optimization of treatment by timing its administration as a function of circadian and other rhythms.New technological developments are needed to close the loop between the monitoring of blood pressure and the administration of antihypertensive drugs.

15.
Biomed Pharmacother ; 59 Suppl 1: S86-91, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16275513

RESUMO

This study aimed at examining any relation between the circadian variation in blood pressure (BP) in human pregnancy and fetal growth. A prospective study included 52 pregnant women monitored during the third trimester of pregnancy. There were 33 uncomplicated pregnancies with normal fetal growth (Group 1) and 19 pregnancies complicated by intrauterine growth retardation (IUGR), confirmed at birth (Group 2). Ten women (five in each group) had pregnancy-induced hypertension. All women were hospitalized and followed a similar daily routine. BP was recorded with an automatic wearable device. Measurements were obtained every 20 min for 24 +/- 1 h. BP profiles were analyzed by conventional statistical methods and by cosinor, involving the least squares fit of cosine curves with an anticipated period (24 h) to the data. BP parameters, fetal outcome, demographic and obstetric characteristics were compared between the two groups. Logistic regression and multivariate analyses were used to assess factors putatively associated with fetal outcome. The circadian amplitude of diastolic BP was found to be larger in normotensive women with IUGR. As gauged by odds ratios (OR), the circadian amplitude of diastolic BP (OR = 1.7, 95% CI: 1.1-2.8; P = 0.03) and hematocrit (OR = 1.4, 95% CI: 1.0-1.9; P = 0.04) were the only variables positively and independently associated with IUGR. In the presence of maternal hypertension, the circadian amplitude of systolic BP was negatively associated with IUGR (OR = 0.7, 95% CI: 0.5-1.0; P = 0.03). A larger circadian variation in diastolic BP, rather than a difference in the mean value of systolic or diastolic BP, was found to be statistically significantly associated with IUGR. This study adds another condition in which the circadian BP amplitude constitutes a harbinger of elevated risk, apart from an association with a shortened lifespan in the absence or presence of malignant hypertension and with an increased risk of stroke and nephropathy reported earlier.


Assuntos
Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Desenvolvimento Fetal/fisiologia , Gravidez/fisiologia , Adulto , Monitorização Ambulatorial da Pressão Arterial , Índice de Massa Corporal , Peso Corporal/fisiologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Recém-Nascido , Modelos Logísticos
16.
Ultrasound Obstet Gynecol ; 25(5): 468-72, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15849804

RESUMO

OBJECTIVE: To assess whether the addition of four-dimensional (4D) ultrasound to a conventional two-dimensional (2D) scan in the second/third trimester of pregnancy facilitates maternal recognition of specific fetal structures and movements and causes an emotional impact, as subjectively perceived by the woman. METHODS: Fifty-two women were randomly assigned to 2D ultrasound only (Group 1), while 48 women underwent 2D plus 4D ultrasound (Group 2). All the women completed two questionnaires. One questionnaire listed the fetal structures and movements that the women had recognized during the 2D scan or, for those women who also underwent a 4D scan, during the combination of the two; the other questionnaire required the women to score on an analog scale whether they had seen all the fetal parts and movements that they wished to see, whether they were satisfied with the scan, and if the scan had changed for the better their perception of the fetus. A subgroup of 46 women completed the Maternal Antenatal Attachment Scale (MAAS) designed to measure antenatal emotional attachment. RESULTS: Similar percentages of women in the two groups visualized fetal structures and movements, but facial expressions and hand-to-mouth movements were twice as likely to be seen with 4D ultrasound, although this difference did not reach statistical significance. The percentage of women who reported that they had seen all the fetal parts and movements that they wished to see, and of those who were satisfied overall with the scan, were similar in the two groups. There was no difference in the percentage of women who felt that the scan had changed for the better their perception of the fetus. Although the MAAS scores were similar in the two groups, there were more women with positive quality, intensity and global attachment among those who had undergone a 4D scan. Women who had seen all the fetal parts and movements they wished to see (whether with 2D or 2D plus 4D) answered more frequently that the scan had changed for the better their perception of the fetus. CONCLUSION: This randomized study indicates that the addition of 4D ultrasound does not change significantly the perception that women have of their baby nor their antenatal emotional attachment compared with conventional 2D ultrasound.


Assuntos
Emoções , Imageamento Tridimensional , Relações Materno-Fetais , Satisfação do Paciente , Gravidez/psicologia , Ultrassonografia Pré-Natal/métodos , Gravação em Vídeo , Adulto , Feminino , Humanos , Imageamento Tridimensional/psicologia , Razão de Chances , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Ultrassonografia Pré-Natal/psicologia
17.
Curr Top Microbiol Immunol ; 285: 175-98, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15609504

RESUMO

Viruses use the host cellular machinery to translate viral proteins. Similar to cellular proteins directed to the secretory pathway, viral (glyco)proteins are synthesized on polyribosomes and targeted to the endoplasmic reticulum (ER). For viruses that encode polyproteins, folding of the individual proteins of the precursor often is coordinated. Translocation and the start of folding coincide and are assisted by cellular folding factors present in the lumen of the ER. The protein concentration a newborn protein finds in this compartment is enormous (hundreds of mg/ml) and the action of molecular chaperones is essential to prevent aggregation. Viral envelope proteins also undergo the cellular quality control mechanisms, which ensure, with variable stringency, that only proteins with the correct structure will proceed through the secretory pathway. Proteins that are misfolded, or not yet folded, are retained in the ER until they reach the native conformation or until their retrotranslocation into the cytosol for degradation. Peculiar characteristic of viruses is their ability to interfere with the cellular machinery to ensure virus production and, moreover, to pass through the body unobserved by the host immune system. This section describes some mechanisms of genetic variation and viral immune evasion that involve the secretory pathway.


Assuntos
Chaperonas Moleculares/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas da Matriz Viral/biossíntese , Vírus/metabolismo , Animais , Retículo Endoplasmático/metabolismo , Glicosilação , Humanos , Dobramento de Proteína , Proteínas da Matriz Viral/metabolismo
18.
J Hypertens ; 19(9): 1659-64, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11564987

RESUMO

OBJECTIVE: Atrial natriuretic peptide (ANP) increases are reported during normal pregnancy, but the relation to arterial pressure and the renin-angiotensin system is debatable. We assessed whether normotensive pregnancies with intrauterine growth retardation (IUGR) present an alteration of maternal ANP levels. DESIGN: A total of 11 pregnant women with IUGR, in the absence of any other maternal or fetal pathology, entered the study during the third trimester. They were compared with 12 healthy pregnant women of similar age and characteristics. We monitored all subjects for blood pressure (BP), ANP, aldosterone and plasma renin activity (PRA), under the same conditions for 24 h. All subjects were submitted to the same regimen of life; with homogeneous dark : light periods, salt intake and meal times. METHODS: BP was monitored at 20 min intervals for 24 h and blood tests performed at six time points during the 24 h. EDTA plasma samples were immediately centrifuged. Hormone assays were performed by radioimmunoassay. Koch's nonparametric two-way analysis of variance (ANOVA) was used to compare the hormone time-dependent profiles in the two groups. Circadian rhythms were assessed by cosinor analysis. RESULTS: The IUGR group was characterized by higher ANP values compared to normal pregnancy, (205 +/- 24 versus 146 +/- 21 pg/ml: P < 0.05) but not significant differences were shown for PRA, aldosterone and BP circadian rhythms. CONCLUSIONS: This study shows higher ANP values in human pregnancy complicated by IUGR, with presence of normal BP, aldosterone and PRA profiles.


Assuntos
Aldosterona/sangue , Fator Natriurético Atrial/sangue , Pressão Sanguínea , Ritmo Circadiano , Retardo do Crescimento Fetal/fisiopatologia , Renina/sangue , Adulto , Feminino , Retardo do Crescimento Fetal/sangue , Humanos , Masculino , Gravidez , Terceiro Trimestre da Gravidez , Valores de Referência
19.
J Gerontol A Biol Sci Med Sci ; 56(5): M304-24, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11341244

RESUMO

Biological cycles with relatively long and some unusual periods in the range of the half-week, the half-year, years, or decades are being discovered. Their prior neglect constituted a confounder in aging and much other research, which then"flew blind" concerning the uncertainties associated with these cycles when they are not assessed. The resolution of more about 10-year and other cycles, some reported herein, replaces the admission of complete unpredictability, implied by using the label "secularity." Heretofore unaccounted-for variability becomes predictable insofar as it proves to be rhythmic and is mapped systematically to serve as a battery of useful reference values. About 10-year cycles in urinary 17-ketosteroid excretion and in heart rate and its variability, among others, are aligned with cycles of similar length in mortality from myocardial infarction. Associations accumulate between cycles of natural physical time structures, chronomes such as the 10.5-year (circadecennian) Schwabe and the 21-year (circavigintunennian) Hale cycles of solar activity, and chronomes in biota. There are about 50-year (circasemicentennian) cycles in mortality from stroke in Minnesota and in the Czech Republic and also in human morphology at birth, the latter result reducing the likelihood that these cycles are purely human made. Associations among large populations warrant long-term systematic coordinated sampling of natural physical and biological variables of interest for the design of countermeasures against already documented elevated risks of stroke, myocardial infarction, and other catastrophic diseases, notably in elderly adults. New findings will be introduced against the background of the documented value of mapping rhythms in medicine and gerontology. In both these fields, rhythms promise the seeming paradox of better care for less.


Assuntos
Envelhecimento/fisiologia , Fenômenos Cronobiológicos/fisiologia , 17-Cetosteroides/urina , Idoso , Frequência Cardíaca/fisiologia , Humanos , Infarto do Miocárdio/mortalidade , Periodicidade , Acidente Vascular Cerebral/mortalidade
20.
FASEB J ; 14(5): 769-78, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10744633

RESUMO

Many aberrant or unassembled proteins synthesized in the endoplasmic reticulum (ER) are degraded by cytosolic proteasomes. To investigate how soluble glycoproteins destined for degradation are retrotranslocated across the ER membrane, we analyzed the fate of two IgM subunits, mu and J, retained in the ER by myeloma cells that do not synthesize light chains. Degradation of mu and J is prevented by proteasome inhibitors, suggesting that both chains are retrotranslocated to be disposed of by proteasomes. Indeed, when proteasomes are inhibited, some deglycosylated J chains that no longer contain intrachain disulfide bonds accumulate in the cytosol. However, abundant glycosylated J chains are still present in the ER at time points in which degradation would have been almost complete in the absence of proteasome inhibitors, suggesting that retrotranslocation and degradation are coupled events. This was confirmed by protease protection and cell fractionation assays, which revealed that virtually all mu chains are retained in the ER lumen in a glycosylated state when proteasomes are inhibited. Association with calnexin correlated with the failure of mu chains to dislocate to the cytosol. Taken together, these results suggest that active proteasomes are required for the extraction of Ig subunits from the ER, though the requirements for retrotranslocation may differ among individual substrates.


Assuntos
Cisteína Endopeptidases/metabolismo , Cadeias J de Imunoglobulina/metabolismo , Cadeias mu de Imunoglobulina/metabolismo , Complexos Multienzimáticos/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Calnexina , Calreticulina , Inibidores de Cisteína Proteinase/farmacologia , Citosol/enzimologia , Citosol/imunologia , Retículo Endoplasmático/imunologia , Glicosilação , Cadeias J de Imunoglobulina/química , Cadeias mu de Imunoglobulina/química , Cinética , Camundongos , Oxirredução , Complexo de Endopeptidases do Proteassoma , Ribonucleoproteínas/metabolismo , Solubilidade , Células Tumorais Cultivadas
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