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51.
Cristiana Mayer Ilya Lipkovich Alex Dmitrienko 《Statistics In Biopharmaceutical Research》2015,7(4):272-282
This article provides a summary of the results of a recent survey in the pharmaceutical and device industry on the current practice and common issues in the identification and analysis of subgroups. The survey was part of a cross-industry effort sponsored by the Quantitative Sciences in the Pharmaceutical Industry (QSPI) for two purposes: (1) to identify general practices in how statistical subgroup analyses are planned and conducted in clinical trials and (2) collect information on similarities and differences across the prespecified types of subgroup analyses in terms of most common challenges, methodologies, and other characteristics. The survey results help integrate good practices and create a unifying framework for subgroup analyses in industry encompassing those in discovery/early phases directed to biomarkers identification and those at later stages for exploratory, confirmatory, or post hoc evaluations. Results from this survey identify the number one challenge to be the lack of power related to the sample size and number of subgroups tested. The findings further highlight an unmet need for intensified educational efforts focused on sharing statistical methodologies, experiences, and knowledge on the most appropriate approaches for identifying and analyzing subgroups. The scientific debate among industry, regulators and academia should continue to find solutions to unresolved challenges and perceived difficulties of subgroup analyses in clinical trials. 相似文献
52.
Catena C Novello M Lapenna R Baroselli S Colussi G Nadalini E Favret G Cavarape A Soardo G Sechi LA 《Journal of hypertension》2005,23(9):1617-1631
Although adequate control of blood pressure is of basic importance in cardiovascular prevention in hypertensive patients, correction of additional risk factors is an integral part of their management. In addition to classical risk factors, epidemiological research has identified a number of other conditions that might significantly contribute to cardiovascular risk in the general population and might achieve specific relevance in patients with high blood pressure. In fact, more than 20% of patients with premature cardiovascular events do not have any of the traditional risk factors and, although effective intervention on blood pressure and additional risk factors has significantly reduced cardiovascular morbidity and mortality, the contribution to stroke, coronary artery disease and renal failure is still unacceptably high. Evaluation of new risk factors may further expand our capacity to predict atherothrombotic events when these factors are included along with the traditional ones in the assessment of global cardiovascular risk in hypertensive patients. Because it could be anticipated that the role of these novel factors will become increasingly evident in the future, researchers with an interest in hypertension and physicians dealing with problems related to cardiovascular prevention should give them appropriate consideration. This review summarizes the basic biology and clinical evidence of two emerging risk factors that are reciprocally related and contribute to the development and progression of organ damage in hypertension: the prothrombotic state and lipoprotein(a). 相似文献
53.
Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas 下载免费PDF全文
Bellan C Lazzi S Hummel M Palummo N de Santi M Amato T Nyagol J Sabattini E Lazure T Pileri SA Raphael M Stein H Tosi P Leoncini L 《Blood》2005,106(3):1031-1036
The normal counterpart of the neoplastic B cells in Burkitt lymphoma (BL) is still unclear. Based on immunoglobulin gene rearrangement studies, some authors suggest an origin from germinal center cells and others from memory B cells. However, most of these studies rely on cell lines or on a small series of cases. To help clarify the cell of origin of BL, semi-nested polymerase chain reaction (PCR) was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (V(H)) genes, and the resultant amplificates were sequenced for comparison with known germline V(H) segments. The results of this approach revealed that all cases (15 endemic BL [eBL], 10 sporadic BL [sBL], and 6 AIDS-related BL) harbor mutated V(H) genes, with different mutation ranges among the 3 types of BL. The eBL and AIDS-related forms showed considerably higher mutation rates than the sBL form (5.1%, 5.4%, and 1.5%, respectively). The mutations in eBL and AIDS-related BL also showed signs of antigen selection, whereas no signs of antigen selection were found in sBL. Finally, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations in any of the cases analyzed. Given that one of the main differences between eBL and AIDS-related BL on the one hand and sBL on the other hand is the association with Epstein-Barr virus (EBV), we compared EBV-positive and EBV-negative BLs independently of their geographic origin and HIV status. The differences in the number of somatic mutations and antigen selection were even more evident when this approach was used. According to our molecular results, it appears that EBV-positive and EBV-negative BL may originate from 2 distinct subsets of B cells, pointing to a particular role for the germinal-center reaction in the pathogenesis of these tumors. The different types of C-MYC translocation reported in BL may also be related to the different stages of B-cell maturation. 相似文献
54.
Elisabetta Pisu Alessandra Lombardi Daniela De Benedictis Chiarella Bozzo Enrico Chiara Cristiana Baggiore Alberto Bruno Laura Cravero Gianranco Pagano Gianfranco Lenti 《Acta diabetologica》1986,23(3):215-225
Summary Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes.
In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivityin vivo (hyperglycemic clamp) andin vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia
and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics
were slightly hyperinsulinemic during fasting (10.8±1.0vs 4.8±0.8 μU/ml in controls, p < 0.0005), with a significant reduction in early and late insulin secretion (14.0±1.5vs 20.8 ± 2.0 μU/ml, p<0.01 and 24.8±3.3vs 34.7±2.14 μU/ml, p<0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30±0.32vs 4.14±0.40, p<0.005). Endogenous glucose production was significantly increased (107±10.2vs 84±3.7 mg/m2 per min, p<0.025) and displayed a positive correlation with fasting glycemia (r=0.51, p<0.05). Insulin binding to monocytes
was significantly lower than in controls (2.36±0.22%vs 4.06±0.32%, p<0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1±2.8
μU/ml, p<0.0005vs controls) but, typically, lacked the early secretory phase (20.6±3.6 μU/mlvs baseline, n.s.). A similar increase of hepatic glucose production (107±11.2 mg/m2 per min, p<0.025vs controls, n.s.vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I=1.78±0.31, p<0.0005vs controls, n.s.vs non-obese diabetics) was found in moderately obsese diabetics, as well as a significant reduction of insulin binding to insolated
monocytes (2.62±0.4% p<0.01vs controls, n.s.vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics
are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral
insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect
as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate
obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.
This study was supported by a grant fromConsiglio Nazionale delle Ricerche, P.F. Medicina Preventiva, SP4,Malattie Degenerative, N. 84.02449.56. 相似文献
55.
Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders 总被引:3,自引:0,他引:3
Passamonti F Pietra D Malabarba L Rumi E Della Porta MG Malcovati L Bonfichi M Pascutto C Lazzarino M Cazzola M 《British journal of haematology》2004,126(5):650-656
The PRV-1 gene has been proposed as a marker of polycythaemia vera (PV). PRV-1 and NB1 are alleles of the polymorphic gene CD177, which belongs to the Ly-6/uPAR superfamily, and their coding regions differ at only four nucleotides. We studied neutrophil CD177 mRNA levels in normal subjects and in 235 patients with Ph-negative chronic myeloproliferative disorders (CMD), including PV, essential thrombocythaemia and myelofibrosis with myeloid metaplasia. Additional disease states were investigated for comparison. Highly variable neutrophil CD177 mRNA levels were observed in normal individuals. Neutrophils isolated from the bone marrow, or from peripheral blood following granulocyte colony-stimulating factor administration showed markedly higher CD177 expression than circulating granulocytes on steady state. Increased neutrophil CD177 mRNA levels were detected in all CMD. Elevated values were also found in reactive conditions and in disorders such as chronic myeloid leukaemia and myelodysplastic syndromes. In the differential diagnosis between PV and secondary erythrocytosis, the assay sensitivity was 68% while its specificity was 60%. These findings indicate that an elevated neutrophil CD177 mRNA level is not a specific marker for the diagnosis of PV nor for that of CMD. From a clinical viewpoint, neutrophil CD177 mRNA overexpression is rather a marker of abnormal neutrophil production and/or release in patients with CMD. 相似文献
56.
Stefano Mariano Marta Pardo Clelia Buccheri Placido Illiano Annalisa Adinolfi Sara Lucia M. Lo Russo Enrico Alleva Cristiana Carbone Walter Adriani 《Developmental psychobiology》2020,62(4):505-518
There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET–HET), was used. A second WT colony was derived and maintained (breeding WT–WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO–WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET–HET breeding led to reduced activity in HET females compared to WT rats (from WT–WT breeding). However, HET females from KO–WT breeding did not differ so much from WT rats (WT–WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET–HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT–WT). In their female offspring (HET, breeding HET–HET vs. WT, breeding WT–WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care. 相似文献
57.
58.
Valentina De Cosmi Alessandra Mazzocchi Veronica DOria Alessandro Re Giulia Carla Immacolata Spolidoro Gregorio P. Milani Cristiana Berti Silvia Scaglioni Claudia Giavoli Silvia Bergamaschi Giulia Rodari Eriselda Profka Roberto Colombo Carlo Agostoni 《Nutrients》2022,14(7)
Obese children are at high risk of developing vitamin D deficiency. Omega-3 polyunsaturated fatty acids and their derivatives might have a beneficial effect on vitamin D status of obese children, due to their anti-inflammatory action, and increasing its absorption. This multicenter, randomized, double-blind controlled study aims to investigate the effect of vitamin D and docosahexaenoic acid (DHA) co-supplementation for six months on vitamin D status, body composition, and metabolic markers of obese children with vitamin D deficiency. A total of 108 children were enrolled and 73 children completed the study: 33 were supplemented with an oral dose of 500 mg of DHA and 1200 IU/day of vitamin D3 and 41 were supplemented with 1200 IU/day of vitamin D3 + wheat germ oil. At the end of the study, more than 50% of the subjects improved their vitamin D status. However, co-supplementation was not more effective than vitamin D plus wheat germ oil. Fat mass percentage was significantly reduced, and body mass index improved in both groups, even if all the subjects were still obese at the end of the study. Children receiving both vitamin D and DHA presented a higher increase of DHA levels that could be relevant to prevent inflammatory-associated complications of obesity, but they had no effect on vitamin D levels. 相似文献
59.
60.
Helena Rebelo-de-Andrade Cristiana Pereira Marta Gíria Ema Prudêncio Maria Jo?o Brito Etelvina Calé Nuno Taveira 《Journal of clinical microbiology》2010,48(4):1391-1396
Human adenoviruses (AdVs) typically cause mild illnesses in otherwise healthy hosts. We investigated a pediatric outbreak of acute respiratory infection with fatal outcomes that occurred in Lisbon, Portugal, in 2004. Biological specimens were collected from 83 children attending two nurseries, a kinesiotherapy clinic, and the household of a nanny. Adenovirus infection was confirmed in 48 children by PCR and virus isolation. Most (96%) isolates were classified as being of subspecies B1. Phylogenetic analysis of fiber and hexon gene sequences revealed that most infants were infected with AdV serotype 3 (AdV3) strains. Infants attending one nursery harbored a new recombinant strain containing an AdV serotype 7 hexon and serotype 3 fiber (AdV7/3). Both the AdV3 and the AdV7/3 strains caused fatal infections. Two different serotype 3 strains were circulating in Lisbon in 2004, and the new AdV7/3 recombinant type originated from only one of those strains. These results demonstrate that recombination leads to the emergence of new adenovirus strains with epidemic and lethal potential.Human adenoviruses (HAdVs) have been associated with a wide spectrum of clinical diseases with respiratory and gastrointestinal symptoms (23, 32). Severe illness can occur in newborns, elderly individuals, and patients with underlying medical conditions. In otherwise healthy adults, infections caused by human adenoviruses do not represent a life-threatening clinical condition. Adenoviruses are characterized by a linear double-stranded DNA genome of 2 to 45 kbp that encodes 30 to 40 proteins (6). HAdV comprises 51 serotypes (HAdV-1 to HAdV-51), on the basis of type-specific antiserum-mediated neutralization of infectivity (10). The serotypes can be divided into seven species, named HAdV-A to HAdV-G, on the basis of hemagglutination inhibition and biochemical criteria (13). HAdV-B is further classified into subspecies B1 and B2, which use different cellular receptors for viral entry (29). These variants can be segregated by different geographic areas, time periods, and clinical conditions.Serotype identification is critical for epidemiological surveillance, the detection of new strains, assessment of treatment efficacy, and understanding the pathogenesis of HAdV. For example, acute respiratory disease is primarily caused by HAdV-B1 serotypes 3, 7, 16, and 21; HAdV-B2 serotypes 11 and 14; and HAdV-E serotype 4 (8, 23, 25, 28, 35, 38, 41). Respiratory infections caused by HAdV-B1 serotypes 3 and 7 (16) and HAdV-B2 serotype 14 (17) are potentially fatal. Neutralization tests are the classical reference method used for the typing of adenovirus and require virus isolation from infected organs or tissues (20). The main type-specific neutralizing epitope, the ɛ determinant, consists of loop 1 (L1) and loop 2 (L2) on the hexon protein, the major capsid protein and the most abundant structural protein (26). Cases of the failure of neutralization with the available antisera require extensive cross-neutralization studies to define a new HAdV type. To circumvent the practical problems associated with traditional serum neutralization studies, molecular methods for the typing of adenovirus have been established. Examples are restriction fragment length polymorphism (RFLP) analysis of adenoviral DNA (16), PCR-based assays (1, 36), and microarray-based methods (36). However, these methods cannot discriminate between all serotypes and do not allow detailed studies of molecular epidemiology and viral evolution to be performed.More recently, analysis of the nucleotide and amino acid sequences from different genes has shown that adenovirus species form three distinct phylogenetic clusters: HAdV-C belongs to cluster 1; HAdV-A and HAdV-F belong to cluster 2; and HAdV-B, HAdV-D, and HAdV-E belong to cluster 3 (6, 22). In addition, phylogenetic analysis of selected gene fragments has increasingly been used to classify human adenoviruses at the serotype and species levels (7, 19, 40), to detect cases of coinfection with multiple adenoviral species (36, 38), and to identify new recombinant strains formed between similar species (18, 37, 41) or different species (19). Finally, phylogenetic analysis has become an important tool in the epidemiological investigation of many disease outbreaks caused by adenovirus (11, 17, 27, 40, 41). In the present study, we have used epidemiological, virological, and molecular phylogenetic methods to investigate the causes and origin of a recent outbreak of acute respiratory infection in Lisbon, Portugal, that resulted in the deaths of two children. 相似文献