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Genomic techniques enable diagnosis and management of children and young adults with sarcomas by identifying high-risk patients and those who may benefit from targeted therapy or participation in clinical trials. Objective: to analyze the performance of an NGS gene panel for the clinical management of pediatric sarcoma patients. We studied 53 pediatric and young adult patients diagnosed with sarcoma, from two Spanish centers. Genomic data were obtained using the Oncomine Childhood Cancer Research Assay, and categorized according to their diagnostic, predictive, or prognostic value. In 44 (83%) of the 53 patients, at least one genetic alteration was identified. In 80% of these patients, the diagnosis was obtained ( n = 11) or changed ( n = 9), and thus genomic data affected therapy. The most frequent initial misdiagnosis was Ewing's sarcoma, instead of myxoid liposarcoma ( FUS-DDDIT3 ), rhabdoid soft tissue tumor ( SMARCB1 ), or angiomatoid fibrous histiocytoma ( EWSR1-CREB1 ). In our series, two patients had a genetic alteration with an FDA-approved targeted therapy, and 30% had at least one potentially actionable alteration. NGS-based genomic studies are useful and feasible in diagnosis and clinical management of pediatric sarcomas. Genomic characterization of these rare and heterogeneous tumors also helps in the search for prognostic biomarkers and therapeutic opportunities.

Hereditary spherocytosis arises from alterations in the genes encoding red blood cell membrane proteins. Although its diagnosis is mostly clinical, recent advances in next-generation sequencing (NGS) technologies have allowed for a faster cost-effective gene-based diagnosis. We report the case of a boy with spherocytic anemia and development delay in whom a de novo 2.84-Mb deletion at chromosome 14 including SPTB (ß-spectrin gene) was identified by array-based comparative genomic hybridization. This alteration, consistent with de novo spherocytosis, was missed by a NGS gene panel. When associated with other symptoms, especially neurologic, NGS may not be appropriate to genetically diagnose spherocytic anemia.

Soil moisture and compaction, and source of N and bovine urine can reduce methane (CH 4 ) rates from agricultural soils. However, the magnitude of the effect is unknown in tropical soil under different conditions, as well as the potential of different urine-N concentration, volume, and sources of N in such an effect. This study aimed to investigate the effects of different soil conditions (moist, dry, compacted, moist-dung, moist-dung-compacted), N concentration in urine (2.5, 5.0, 10.0, and 15.0 g N L -1 ), volume of urine (25, 50, 100, and 200 ml kg -1 dry soil), and source of N (ammonium, nitrate, and urea) on CH 4 emissions. A tropical Ferralsol soil from marandu-grass pasture was incubated during 106 days and the CH 4 concentration determined by gas chromatography. The CH 4 rates varied significantly according to the soil conditions when manipulated the urine-N (p < 0.01) and averaged 0.75, - 0.50, 1.14, 6.23, and 8.17 μg C-CH 4 m -2  h -1 for the moist, dry, compacted, moist-dung, and moist-dung-compacted soil, respectively, and, not responded to the level of N (p = 0.73) averaging 2.57 μg C-CH 4 m -2  h -1 . When evaluated, the volumes of urine cumulative CH 4 averages were - 0.52, - 1.24, - 0.88, 14.48, and 18.56 μg C-CH 4 m -2  h -1 for the moist, dry, compacted, moist-dung, and moist-dung-compacted, respectively. Soils were affected by soil treatments (p < 0.001) but not by urine volumes (p = 0.30). The source of N did not influence the CH 4 rates (p = 0.1) averaging 0.88, - 1.26, and - 1.19 μg C-CH 4 m -2  h -1 respectively, for urea, nitrate, and ammonium. The CH 4 fluxes in tropical Ferralsols are controlled by the soil characteristics and dung addition.

Development of highly active photocatalysts is mandatory for more widespread application of this alternative environmental technology. Synthesis of photocatalysts, such as anatase TiO 2 , with more reactive, non-equilibrium, crystallographic facets is theoretically justified by a more efficient interfacial charge transfer to reactive adsorbed species, increasing quantum efficiency of photocatalyst. Air and vacuum calcinations of protonated trititanate nanotubes lead to their transformation to anatase nanorods. The nanorods synthesized by air calcination demonstrate photo-oxidation of NO gas more than three times superior to the one presented by the benchmark P-25 photocatalyst. This performance has been explained in terms of 50% higher specific surface area and, more importantly, through the predominance of more reactive, non-equilibrium, {001} crystallographic facets of the anatase nanorods. These facets present a high density of undercoordinated Ti cations, which favors adsorption of reactant species, and strained Ti-O-Ti bonds, leading to more efficient photo-oxidation reactions. Reduced Ti species, such as Ti 3+ , were not observed in the as-obtained nanorods, while reactive adsorbed molecules are scarce on the nanorods obtained through vacuum calcination. Dip-coating of TiO 2 anatase nanorods (air calcined) over soda-lime glass plates was used to prepare visible light transparent, superhydrophilic and highly adherent photocatalytic coatings with homogenously distributed nanopores.

Early recognition of ventricular fibrillation (VF) and electrical therapy are key for the survival of out-of-hospital cardiac arrest (OHCA) patients treated with automated external defibrillators (AED). AED algorithms for VF-detection are customarily assessed using Holter recordings from public electrocardiogram (ECG) databases, which may be different from the ECG seen during OHCA events. This study evaluates VF-detection using data from both OHCA patients and public Holter recordings. ECG-segments of 4-s and 8-s duration were analyzed. For each segment 30 features were computed and fed to state of the art machine learning (ML) algorithms. ML-algorithms with built-in feature selection capabilities were used to determine the optimal feature subsets for both databases. Patient-wise bootstrap techniques were used to evaluate algorithm performance in terms of sensitivity (Se), specificity (Sp) and balanced error rate (BER). Performance was significantly better for public data with a mean Se of 96.6%, Sp of 98.8% and BER 2.2% compared to a mean Se of 94.7%, Sp of 96.5% and BER 4.4% for OHCA data. OHCA data required two times more features than the data from public databases for an accurate detection (6 vs 3). No significant differences in performance were found for different segment lengths, the BER differences were below 0.5-points in all cases. Our results show that VF-detection is more challenging for OHCA data than for data from public databases, and that accurate VF-detection is possible with segments as short as 4-s.

Purpose: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established., Methods: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases., Results: Among incident FL cases, educational level (χ(2) p = 0.021) and height (χ(2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95% CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases., Conclusions: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status.

Background: Fast and accurate quality estimation of the electrocardiogram (ECG) signal is a relevant research topic that has attracted considerable interest in the scientific community, particularly due to its impact on tele-medicine monitoring systems, where the ECG is collected by untrained technicians. In recent years, a number of studies have addressed this topic, showing poor performance in discriminating between clinically acceptable and unacceptable ECG records., Methods: This paper presents a novel, simple and accurate algorithm to estimate the quality of the 12-lead ECG by exploiting the structure of the cross-covariance matrix among different leads. Ideally, ECG signals from different leads should be highly correlated since they capture the same electrical activation process of the heart. However, in the presence of noise or artifacts the covariance among these signals will be affected. Eigenvalues of the ECG signals covariance matrix are fed into three different supervised binary classifiers., Results and Conclusion: The performance of these classifiers were evaluated using PhysioNet/CinC Challenge 2011 data. Our best quality classifier achieved an accuracy of 0.898 in the test set, while having a complexity well below the results of contestants who participated in the Challenge, thus making it suitable for implementation in current cellular devices.

T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1(+) T-ALLs. Sequencing reveals that >20% of monoallelic TAL1(+) patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5' to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.

Purpose: The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL., Participants and Methods: Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples., Results: Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis., Conclusion: High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

Early detection of ventricular fibrillation (VF) and rapid ventricular tachycardia (VT) is crucial for the success of the defibrillation therapy. A wide variety of detection algorithms have been proposed based on temporal, spectral, or complexity parameters extracted from the ECG. However, these algorithms are mostly constructed by considering each parameter individually. In this study, we present a novel life-threatening arrhythmias detection algorithm that combines a number of previously proposed ECG parameters by using support vector machines classifiers. A total of 13 parameters were computed accounting for temporal (morphological), spectral, and complexity features of the ECG signal. A filter-type feature selection (FS) procedure was proposed to analyze the relevance of the computed parameters and how they affect the detection performance. The proposed methodology was evaluated in two different binary detection scenarios: shockable (FV plus VT) versus nonshockable arrhythmias, and VF versus nonVF rhythms, using the information contained in the medical imaging technology database, the Creighton University ventricular tachycardia database, and the ventricular arrhythmia database. sensitivity (SE) and specificity (SP) analysis on the out of sample test data showed values of SE=95%, SP=99%, and SE=92% , SP=97% in the case of shockable and VF scenarios, respectively. Our algorithm was benchmarked against individual detection schemes, significantly improving their performance. Our results demonstrate that the combination of ECG parameters using statistical learning algorithms improves the efficiency for the detection of life-threatening arrhythmias.

MYC is a potent oncogene involved in ∼70% of human cancers, inducing tumorigenesis with high penetrance and short latency in experimental transgenic models. Accordingly, MYC is recognized as a major driver of T-cell acute lymphoblastic leukemia (T-ALL) in human and zebrafish/mouse models, and uncovering the context by which MYC-mediated malignant transformation initiates and develops remains a considerable challenge. Because MYC is a very complex oncogene, highly dependent on the microenvironment and cell-intrinsic context, we generated transgenic mice (tgMyc(spo)) in which ectopic Myc activation occurs sporadically (<10(-6) thymocytes) within otherwise normal thymic environment, thereby mimicking the unicellular context in which oncogenic alterations initiate human tumors. We show that while Myc(+) clones in tgMyc(spo) mice develop and initially proliferate in thymus and the periphery, no tumor or clonal expansion progress in aging mice (n = 130), suggesting an unexpectedly low ability of Myc to initiate efficient tumorigenesis. Furthermore, to determine the relevance of this observation in human pathogenesis we analyzed a human T-ALL case at diagnosis and relapse using the molecular stigmata of V(D)J recombination as markers of malignant progression; we similarly demonstrate that despite the occurrence of TAL1 and MYC translocations in early thymocyte ontogeny, subsequent oncogenic alterations were required to drive oncogenesis. Altogether, our data suggest that although central to T-ALL, MYC overexpression per se is inefficient in triggering the cascade of events leading to malignant transformation., (Copyright © 2013 Wiley Periodicals, Inc.)

Rhythmic feeding in rabbit pups is a natural model to study food entrainment because, similar to rodents under a schedule of food restriction, these animals show food-anticipatory activity (FAA) prior to daily nursing. In rodents, several brain systems, including the orexinergic system, shift their activity to the restricted feeding schedule, and remain active when subjects are hungry. As the lamina terminalis and regions of the preoptic area participate in the control of behavioral arousal, it was hypothesized that these brain regions are also activated during FAA. Thus, the effects of daily milk ingestion on FOS protein expression in the organum vasculosum of lamina terminalis (OVLT), median preoptic nucleus (MnPO), and medial preoptic area (MPOA) were examined using immunohistochemistry before and after scheduled time of nursing in nursed and fasted subjects. Additionally, FOS expression was explored in orexin (ORX) cells in the lateral hypothalamic area and in the supraoptic nucleus (SON) because of their involvement in arousal and fluid ingestion, respectively. Pups were entrained by daily nursing, as indicated by a significant increase in locomotor behavior before scheduled time of nursing in both nursed and fasted subjects. FOS was significantly higher in the OVLT, MnPO, and MPOA at the time of nursing, and decreased 8 h later in nursed pups. In fasted subjects, this effect persisted in the OVLT, whereas in the MnPO and MPOA, values did not drop at 8 h later, but remained at the same level or higher than those at the time of scheduled nursing. In addition, FOS was significantly higher in ORX cells during FAA in nursed pups in comparison with 8 h later, but in fasted subjects it remained high during most fasting time points. Additionally, OVLT, SON, and ORX cells were activated 1.5 h after nursing. We conclude that the OVLT, MnPO, and MPOA, but not SON, may participate in FAA, as they show activation before suckling of periodic milk ingestion, and that sustained activation of the OVLT, MnPO, and MPOA by fasting may contribute to the high arousal state associated with food deprivation. In agreement with this, ORX cells also remain active after expected nursing, which is consistent with reports in other species.

Leukemias harboring MLL translocations are frequent in children and adults, and respond poorly to therapies. The receptor tyrosine kinase FLT3 is highly expressed in these leukemias. In vitro studies have shown that pediatric MLL-rearranged ALL cells are sensitive to FLT3 inhibitors and clinical trials are ongoing to measure their therapeutic efficacy. We sought to determine the contribution of Flt3 in the pathogenesis of MLL-rearranged leukemias using a myeloid leukemia mouse model. Bone marrow from Flt3 null mice transduced with MLL-ENL or MLL-CBP was transplanted into host mice and Flt3 (-/-) leukemias were compared to their Flt3 wild type counterparts. Flt3 deficiency did not delay disease onset and had minimal impact on leukemia characteristics. To determine the anti-leukemic effect of FLT3 inhibition we studied the sensitivity of MLL-ENL leukemia cells to the FLT3 inhibitor PKC412 ex vivo. As previously reported for human MLL-rearranged leukemias, murine MLL-ENL leukemia cells with higher Flt3 levels were more sensitive to the cytotoxicity of PKC412. Interestingly, Flt3 deficient leukemia samples also displayed some sensitivity to PKC412. Our findings demonstrate that myeloid leukemias induced by MLL-rearranged genes are not dependent upon Flt3 signaling. They also highlight the discrepancy between the sensitivity of cells to Flt3 inhibition in vitro and the lack of contribution of Flt3 to the pathogenesis of MLL-rearranged leukemias in vivo.

In rabbit pups, nursing by the mother is the prevailing entraining signal for their circadian rhythms during at least the first two weeks of life. Therefore, they are considered a natural model of food anticipatory activity. However, the photic entrainment of the circadian system in rabbit pups during this developmental stage is not well understood. The present study examined the retinal projections to the suprachiasmatic nucleus (SCN) and the functional responses of the SCN to light exposure. Using the anterograde tracer cholera toxin-B, we examined the retinal projections to the SCN at postnatal days (PD) 1, 9, 19 and in adult animals. The results revealed that the retinal projections were present at PD1 with a bilateral symmetry, and with a contralateral tendency at PD19 and adults. We also explored the response of the SCN to a light pulse by assessing the induction of FOS protein, a marker of neuronal activation, at PD1, 12, 19 and in adults. Light-induced FOS was observed during day and night at PD1, but mainly during night at PD12, 19 and adults. We conclude that in the SCN there is a "gating" mechanism to FOS induction by light that develops several days after birth, as in other mammals, and in the rabbit is already present at PD12. Moreover, in contrast to other altricial mammals, the circadian visual system, although not essential for entraining the rhythm during first two weeks of life, is present and functional in rabbit pups from birth., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Rabbit pups represent a natural model of food anticipatory activity (FAA). FAA is the behavioral output of a putative food entrainable oscillator (FEO). It had been suggested that the FEO is comprised of a distributed system of clocks that work in concert in response to gastrointestinal input by food. Scheduled food intake synchronizes several nuclei in the brain, and the hypothalamus has received particular attention. On the contrary, brainstem nuclei, despite being among the brain structures to first receive food cues, have been scarcely studied. Here we analysed by immunohistochemistry possible oscillation of FOS and PER1 proteins through a complete 24-h cycle in the dorsal vagal complex (DVC) and parabrachial nucleus (PBN) of 7-8-day-old rabbit pups scheduled to nurse during the night (02:00 h) or day (10:00 h), and also in fasted subjects to explore the possible persistence of oscillations. We found a clear induction of FOS that peaks 1.5 h after nursing in all nuclei studied. PER1 was only synchronized in the PBN, reaching highest values 12 h after nursing. Only PER1 oscillations persisted, with a shift, in fasted subjects. We conclude that the DVC nuclei are probably more related to the transmission of food cues to other brain regions, but that the PBN participates in the integration of information essential for FAA. Our results support previous findings suggesting that the DVC nuclei, but not PBN, are not essential for FAA. We suggest that PBN is a key component of the proposed distributed system of clocks involved in FAA., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Rabbit pups ingest food, in this case milk, once a day with circadian periodicity and are a natural model of food anticipatory activity. During nursing, several sensory systems receive information about properties of the food, one of them being the olfactory system, which has received little attention in relation to synchronization by food. In addition, the olfactory bulb has a circadian pacemaker that exhibits rhythms independently of the suprachiasmatic nucleus, but the biological functions of these rhythms are largely unknown. In the present contribution, we hypothesized that circadian suckling of milk synchronizes rhythms in the olfactory bulb. To this aim we explored by immunohistochemistry, rhythms of FOS and PER1 proteins, as indicators of activation and reporter of oscillations, respectively, through a complete 24-h cycle in periglomerular, mitral and granular cell layers of both the main and the accessory olfactory bulb. Subjects were 7-day-old rabbit pups scheduled to nurse during the night (02:00 h) or day (10:00 h), and also fasted subjects, to explore the possible persistence of oscillations. In the three layers of the main olfactory bulb, FOS was high at time of nursing, then further increased 1.5 h afterward, and then decreased to increase again in advance of the next nursing bout. This pattern persisted, without the postprandial increase, in fasted subjects with a shift in subjects nursed at 02:00. PER1 was increased 2-8 h after nursing and this increase persisted in most cell layers, with a shift, in fasted subjects. In the accessory olfactory bulb we only observed a consistent pattern of FOS expression in the mitral cell layer of nursed subjects, similar to that of the main olfactory bulb. We conclude that the main olfactory bulb is synchronized during milk ingestion, but during fasting its oscillations perhaps are modulated by the suprachiasmatic nucleus, as proposed for rodents.

Nursing in the rabbit is under circadian control, and pups have a daily anticipatory behavioral arousal synchronized to this unique event, but it is not known which signal is the main entraining cue. In the present study, we hypothesized that food is the main entraining signal. Using mother-deprived pups, we tested the effects of artificial feeding on the synchronization of locomotor behavior, plasma glucose, corticosterone, c-Fos (FOS) and PERIOD1 (PER1) rhythms in suprachiasmatic, supraoptic, paraventricular and tuberomammillary nuclei. At postnatal day 1, an intragastric tube was placed by gastrostomy. The next day and for the rest of the experiment, pups were fed with a milk formula through the cannula at either 02:00 h or 10:00 h [feeding time = zeitgeber time (ZT)0]. At postnatal days 5-7, pups exhibited behavioral arousal, with a significant increase in locomotor behavior 60 min before feeding. Glucose levels increased after feeding, peaking at ZT4-ZT12 and then declining. Corticosterone levels were highest around the time of feeding, and then decreased to trough concentrations at ZT12-ZT16, increasing again in anticipation of the next feeding bout. In the brain, the suprachiasmatic nucleus had a rhythm of FOS and PER1 that was not significantly affected by the feeding schedule. Conversely, the supraoptic, paraventricular and tuberomammillary nuclei had rhythms of both FOS and PER1 induced by the time of scheduled feeding. We conclude that the nursing rabbit pup is a natural model of food entrainment, as food, in this case milk formula, is a strong synchronizing signal for behavioral, hormonal, metabolic and neural parameters., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Background/aims: Anemia is common in patients with chronic kidney disease (CKD). Recently, the erythropoiesis-stimulating agent/hemoglobin level (ESA/Hb) index emerged as a new factor associated with increased morbidity and mortality in this population. In this study, we evaluated the factors that influence the ESA/Hb index in a pre-dialysis CKD population., Methods: Ninety-five patients were evaluated for clinical and laboratory parameters, nutritional status and ESA/Hb index. For comparison, we divided our population into 3 groups: G I--no ESA treatment, G II--patients with ESA/index below 50th percentile and G III--patients with ESA/Hb index above 50th percentile. We performed single and multiple regression models and logistic regression analysis., Results: In a multiple regression model, age (t = -3.456, P = 0.001), SGA (t = 2.059, P = 0.047), ferritin (t = 2.386, P = 0.027), Ca × P (t = 2.066, P = 0.043), TNF-α (t = 2.673, P = 0.009) and IL-6 (t = 2.939, P = 0.004) independently influenced the ESA/Hb index. At logistic regression analysis, gender, cardiovascular disease and TNF-α were independently associated with ESA/Hb higher than 50th percentile compared to the other patients (R(2) = 0.457)., Conclusion: In a pre-dialysis population, female gender, cardiovascular disease, malnutrition and inflammation are associated with a higher ESA/Hb index.

Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1. Furthermore, we show that posttranscriptional deregulation of MYC constitutes a major alternative pathway of MYC activation in T-ALL, operating partly via the PI3K/AKT axis through down-regulation of PTEN, and that NOTCH1(m) might play a dual transcriptional and posttranscriptional role in this process. Altogether, our data lend further support to the significance of therapeutic targeting of MYC and/or the PTEN/AKT pathways, both in GSI-resistant and identified NOTCH1-independent/MYC-mediated T-ALL patients.

Rabbit does nurse their litter once every 24h during the night. We hypothesized that corticosterone, ghrelin, leptin, and metabolites such as glucose, liver glycogen, and free fatty acids could be affected in the pups by the time at which does nurse them. Therefore, we measured these parameters in pups nursed at 02:00 h (nighttime for the doe) to compare them with results from a previous study where does nursed at 10:00 h, during daytime. From postnatal day 7, pups were sacrificed either just before their scheduled time of nursing or at 4, 8, 12, 16, or 20 h after nursing (n=6 at each time point); additional pups were sacrificed at 4h intervals between 48 and 72 h after nursing to study the persistence of oscillations during fasting. All pups developed locomotor anticipatory activity to nursing. Corticosterone, ghrelin, and free fatty acids exhibited a rhythm that persisted in fasted pups. Glucose concentrations were lower in fasted than in nursed pups, and glycogen was only detected in nursed subjects. Leptin values were stable and low in nursed subjects but increased significantly in fasted subjects up to 72 h after the expected nursing time. The rhythm of ghrelin persisted during fasting, contrary to our previous findings in pups nursed during daytime (i.e., outside the natural time of nursing for this species). Therefore, in 7-day-old rabbit pups, night nursing is a strong zeitgeber for corticosterone, ghrelin, free fatty acids, and energy metabolites but not for leptin., (Copyright 2010 Elsevier Inc. All rights reserved.)

The increased mortality rate observed in patients with chronic kidney disease is related to the high prevalence of cardiovascular disease in this population. Recently, it has been shown that interventional therapy with statins and/or vitamin D could improve the outcomes of these patients. The aim of this study was to identify the risk factors for mortality in a group of patients with chronic kidney disease (stages 4 and 5--pre-dialysis) and verify whether vitamin D and statins could change the outcome. We included 95 patients (mean age--69.4) with stages 4 and 5 (pre-dialysis) of our "low-clearance" outpatient clinic, with an average eGFR of 16.9 ml/min and a mean follow-up of 24.1 months. Several biological, nutritional, laboratory and inflammatory parameters were analysed at baseline. Our population was divided into three groups: G-I, patients not medicated with either vitamin D or statins; G-II, patients medicated with either vitamin D or statins; and G-III, patients medicated with vitamin D and statins. We found (ANOVA) that the serum levels of pre-albumin (P = 0.018) and PTH (P = 0.03) were lower in G-I. Concerning the inflammatory parameters, G-I showed higher levels of hsCRP (P = 0.014) and a trend to higher IL-6 levels (P = 0.077). We found the actuarial survival at 30 months (Kaplan-Meier), to be 56.4% in G-I, 82.3% in G-II and 100% in G-III (log rank = 13.08 P = 0.0014). Using the Cox proportional hazards model, we found that the existence of coronary artery disease (P = 0.0001) and the absence of medication with vitamin D and/or statins (P = 0.005) independently influenced the mortality of our patients. In conclusion, we found, in our study, that patients under vitamin D and statins (with a synergistic effect) were less inflamed and showed a lower mortality rate.

Nursing in the rabbit is a circadian event during which mother and pups interact for a period of < 5 min every day. Here we explored behavioral and neuronal changes in the mother by analyzing the suprachiasmatic nucleus (SCN), and oxytocinergic (OT) neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). We maintained lactating does in a light-dark cycle (lights on at 07 : 00 hours; ZT0); they were scheduled to nurse during either the day (ZT03) or the night (ZT19). Groups of intact and nursing females was perfused, one at each 4-h point through a 24-h cycle. We explored, by immunohistochemistry, the PER1 expression and double-labeling, with OT antibody, of neurons in the PVN and SON at lactation on day 7. In the SCN, intact and lactating groups had peak PER1 expression at ZT11; however, there was a reduction in PER1 at peak time in the nursing groups. There was a locomotor activity rhythm with increased activity around the time of lights-on in intact subjects and around the time of suckling in lactating does. There was an induction of PER1 in OT cells in the PVN and SON that shifted in phase with timing of nursing. We further explored the maintenance of the PER1 expression in OT cells in nursing-deprived does and found a significant decrease at 24 and 48 h after the last nursing. We conclude that suckling induced PER1 in the PVN and SON, but not in the SCN, in nursing does, and also shifted their locomotor behavior.

Young rabbits are nursed every 24 h for a period of 3-5 min. As a consequence, pups are synchronized to this nursing event; this synchronization is characterized by increased locomotor activity and a peaking of core temperature and plasma corticosterone in anticipation of the daily meal. Ghrelin is a hormone suggested to play a role in meal initiation and to promote food intake. The present study explored the role of ghrelin in food-entrained conditions. Newborn rabbits were maintained in constant darkness and nursed once daily at 1000 by the lactating dam. On postnatal day 7, rabbits were killed at six different time points to complete a 24-h cycle. All pups developed locomotor rhythms entrained by mealtime and exhibited anticipatory activity. Food-entrained rhythms in plasma corticosterone and free fatty acids were observed even if two meals were omitted. In contrast, daily food-driven rhythms in stomach weight, plasma glucose, liver glycogen, and ghrelin did not persist when two meals were omitted. Peak ghrelin levels were observed at the moment in the cycle when the stomach weight was lowest, i.e., before initiation of anticipation. The present data are in agreement with previous data from rabbit pups maintained in light-dark conditions and provide evidence that 7- to 9-day-old rabbits in constant darkness can exhibit metabolic and hormonal rhythms mainly driven by the restricted daily nursing.

Introduction: Cardiovascular disease is the main cause of morbidity and mortality in chronic renal patients. Carotid intima-media thickness (CIMT) is one of the most accurate markers of atherosclerosis risk. In this study, the authors set out to evaluate a population of chronic renal patients to determine which factors are associated with an increase in intima-media thickness., Methods: We included 56 patients (F=22, M=34), with a mean age of 68.6 years, and an estimated glomerular filtration rate of 15.8 ml/min (calculated by the MDRD equation). Various laboratory and inflammatory parameters (hsCRP, IL-6 and TNF-alpha) were evaluated. All subjects underwent measurement of internal carotid artery intima-media thickness by high-resolution real-time B-mode ultrasonography using a 10 MHz linear transducer., Results: Intima-media thickness was used as a dependent variable in a simple linear regression model, with the various laboratory parameters as independent variables. Only parameters showing a significant correlation with CIMT were evaluated in a multiple regression model: age (p=0.001), hemoglobin (p=00.3), logCRP (p=0.042), logIL-6 (p=0.004) and homocysteine (p=0.002). In the multiple regression model we found that age (p=0.001) and homocysteine (p=0.027) were independently correlated with CIMT. LogIL-6 did not reach statistical significance (p=0.057), probably due to the small population size., Conclusion: The authors conclude that age and homocysteine correlate with carotid intima-media thickness, and thus can be considered as markers/risk factors in chronic renal patients.

H-trititanate nanotubes obtained by alkali hydrothermal treatment of TiO(2) followed by proton exchange were compared to their bulk H(2)Ti(3)O(7) counterpart with respect to their thermally induced structural transformation paths. As-synthesized and heat-treated samples were characterized by XRD, TEM/SAED, DSC and spectroscopy techniques, indicating that H(2)Ti(3)O(7) nanotubes showed the same sequence of structural transformations as their bulk counterpart obtained by conventional solid state reaction. Nanostructured H(2)Ti(3)O(7) converts into TiO(2)(B) via multistep transformation without losing its nanotubular morphology. The transformation occurs between 120 and 400 degrees C through topotactic mechanisms with the intermediate formation of nanostructured H(2)Ti(6)O(13) and H(2)Ti(12)O(25), which are more condensed layered titanates eventually rearranging to TiO(2)(B). Our results suggest that the intermediate tunnel structure H(2)Ti(12)O(25) is the final layered intermediate phase, on which TiO(2)(B) nucleates and grows. The conversion of nanostructured TiO(2)(B) into anatase is completed at a much lower temperature than its bulk counterpart and is accompanied by loss of the nanotubular morphology.

HOX genes, MEIS1, and FLT3 are frequently up-regulated in human myeloid leukemias. Meis1 cooperates with Hox genes to induce leukemias in mice, hypothetically the consequence of Meis1-induced Flt3 overexpression. To test this, we compared the properties of Flt3(-/-) and Flt3(+/+) progenitors transduced with Hoxa9 or Hoxa9/Meis1. In a myeloid clonogenic assay, Meis1 greatly enhanced the proliferation of Hoxa9-expressing cells, massively up-regulating Flt3 protein. However, the transforming potential of Hoxa9/Meis1 was unaltered in Flt3(-/-) cells. All mice that received Hoxa9/Meis1-transduced progenitors succumbed to rapid acute myeloid leukemias regardless of Flt3 genotype. Flt3 expression levels in leukemic blasts did not correlate with parameters reflecting their proliferative rate or their impaired differentiation. Furthermore, analysis of c-Myb expression levels in Hoxa9/Meis1-transformed cells showed that the up-regulation of this critical downstream effector was independent of Flt3. Altogether, our findings demonstrate that Flt3 is dispensable to the oncogenic cooperation of Meis1 with Hoxa9.

Anaemia and hypertension are common in patients with chronic renal insufficiency. The correction of anaemia with erythropoiesis stimulating agents (ESA) can improve survival and decrease the decline of renal function. Angiotensin converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (AIIRA) can also slow the progression of renal failure, but the blockade of the renin-angiotensin system can worsen anaemia. The aim of our study was to assess the impact of antihypertensive therapy (ACEI plus AIIRA) in the requirements of darbepoietin in a group of elderly predialysis patients. We included 71 patients (m = 39, f = 32), mean age of 76.3 years with a mean creatinine clearance of 17.5 ml/min. Patients were divided in two groups according to their antihypertensive therapy: G-I patients under ACEI or AIIRA therapy and G-II normotensive patients or hypertensive patients under antihypertensive drugs other than ACEI or AIIRA. The groups were compared regarding demographic, nutritional, biochemical and inflammatory parameters. We also compared the mean darbepoietin dose. In GI the mean dose of darbepoietin was higher than in GII (0.543 vs. 0.325 microg/kg/week, P = 0.032). We did not find any difference regarding other parameters analysed. We conclude that ACEI and AIIRA can increase the needs of darbepoietin in predialysis elderly patients. However, when formally indicated to treat hypertension in a specific patient, they should not be switched to another antihypertensive agent. Instead, in such cases, higher doses of ESA should be used, if necessary.

The importance of HOXA genes in T-cell acute lymphoblastic leukemia (T-ALL) has recently been recognized. We report a novel chromosomal translocation in a T-ALL patient that maps upstream of the HOXA13 gene and downstream of the BCL11B/CTIP2 locus. Analysis of HOXA gene transcription demonstrated massive expression of HOXA13, whereas the other HOXA genes were unaffected. A genomic rearrangement of the HOXA locus associated with exclusive expression of HOXA13 was observed in a second patient. This situation resembles chromosomal translocations activating genes of the TLX/HOX11 family in T-ALLs. To compare the leukemogenic properties of HOXA13 to that of TLX proteins, cohorts of lethally irradiated mice were transplanted with bone marrow transduced with a retroviral vector expressing TLX3 or HOXA13. Cells transduced with TLX3 or HOXA13 could not be detected in the peripheral blood of mice post-transplantation and none of the mice developed malignancies. Cotransduction of the HOX cofactor MEIS1 with TLX3 or HOXA13 did not alter this outcome. However, in a myeloid clonogenic assay HOXA13 and TLX3 extended the proliferation of progenitors similarly to what was observed for TLX1. Altogether, our results strongly suggest the absolute requirement for cooperative events in association with homeobox gene up-regulation to induce T-cell leukemogenesis., ((c) 2006 Wiley-Liss, Inc.)

Starting from the four DNA bases order in the Boolean lattice, a novel Lie Algebra of the genetic code is proposed. Here, the main partitions of the genetic code table were obtained as equivalent classes of quotient spaces of the genetic code vector space over the Galois field of the four DNA bases. The new algebraic structure shows strong connections among algebraic relationships, codon assignments and physicochemical properties of amino acids. Moreover, a distance defined between codons expresses a physicochemical meaning. It was also noticed that the distance between wild type and mutant codons tends to be small in mutational variants of four genes: human phenylalanine hydroxylase, human beta-globin, HIV-1 protease and HIV-1 reverse transcriptase. These results strongly suggest that deterministic rules in genetic code origin must be involved.

The energetic metabolism and its relationship with body weight generated a vivid controversy, since the Rubner's surface law was introduced into biology. Recently, the multifactor theory (Darveau et al) has caused again a revival of this polemic topic. Moreover, the investigations concerning metabolism and body weight include all terrestrial mammals, from the shrew (3 grams) to the elephant (three tons). The corresponding allometric exponent for standard metabolic rate, both theoretical and empirical, fluctuates around an average value of 0.75, in contrast with the surface law, which postulated a value of 0.67. The "metabolic range" (rest vs maximal exercise) does vary from 1 to 10, due to the prevalent influence of the skeletal muscle activity. Recent investigations have emphasized the fact that the allometric exponent is not unique (0.75), but it should be subjected to statistical variability, both in standard and in maximal exercise.

Despite the fact that the concept of sheet-flow in the pulmonary microcirculation of mammals was introduced more than three decades ago, the capillary circulatory model still prevails in the physiological literature. Since cardiac output is identical in the systemic and in pulmonary circulations, it is noteworthy that in the former, the resulting arterial pressure is five times higher than that of the latter, which means that the corresponding microcirculations must be radically different. The present study addresses this problem from both morphological and physiological perspectives.

A wide spectrum of cyclic functions in terrestrial mammals of different size, from the 3-gram shrew to the 3-ton elephant, yields an allometric exponent around 0.25, which is correlated--as a kind of common denominator--with the specific metabolic rate. Furthermore, the applicability of these empirical findings could be extrapolated to chronological events in the sub-cellular realm. On the other hand, the succession of growth periods (T98%) until sexual maturity is reached also follows the 1/4 power rule. By means of Verhulst's logistic equation, it has been possible to simulate three different biological conditions, which means that by modifying the numerical value of only one parameter, revertible physiological and pathological states can be obtained, as for instance isostasis, homeostasis and heterostasis.

This paper proposes a genetic code Boolean structure derived from hydrogen bond numbers and chemical types of bases, purines and pyrimidines. It shows that in such Boolean structure, deductions comprise physico-chemical meaning. In particular, codons with adenine as a second base coding to hydrophilic amino acids are not deductible from codons with uracil in the same position, which code to hydrophobic amino acids. Boolean deductions could help us describe the gene evolution process. For instance, most of the reported mutations that confer drug resistance to the HIV protease gene correspond to deductions. What is more, in the human beta-globin gene a similar situation appears where most of the single codon mutations correspond to Boolean deductions from the respective wild-type codon.

In contrast with classical physics, particularly with Sir Isaac Newton, where time is a continuous function, generally valid, eternally and evenly flowing as an absolute time dimension, in the biological sciences, time is in essence of cyclical nature (physiological periodicities), where future passes to past through an infinitely thin boundary, the present. In addition, the duration of the present (DP) leads to the so-called 'granulation of time' in living beings, so that by the fusion of two successive pictures of the world, which are not entirely similar, they attain the perception of 'movement,' both in the real world as well as in the sham-movement in the mass media (TV).

The purpose of this study was to characterize time-frequency behavior using the Continuous Wavelet Transform (CWT) and Fast Fourier Transform (FFT) to analyze ventricular and arterial pressure signals from anesthetized mongrel dogs. Both ventricular and arterial pressure pulsations were recorded using catheter-tip manometers and the CWT was applied to these signals to obtain module coefficients, associated contours, and the 3-D representation of these modules. FFT was applied to obtain the Fourier spectrum. The mathematical analysis of the cardiovascular pressure pulsations permitted the identification of the evolution of the frequency components for the aortic and pulmonary valve functions as well as the intra-ventricular and respiratory influences on the cardiovascular dynamics. The CWT is a very sensitive and reliable procedure for determining the three-dimensional (time-frequency-amplitude) of the oscillatory phenomena during each cardiac cycle, providing more, although complementary, information than the spectral analysis obtained with the FFT. Thanks to the FFT, exact values in Hz could be found for the different events produced in each cycle, and thus the information provided by CWT could be related to the information provided by FFT. The combination of both mathematical methodologies permitted identification of each component of the analyzed signals. The 3D representation allowed an easy comparison of the relative importance of the complex magnitudes in frequency for the different components of the pulsatile waves.

In Saccharomyces cerevisiae MATa haploid cells, the a-specific genes are expressed, whereas in the MATalpha haploid and MATa/alpha diploid cell types their transcription is repressed. It is shown in this report that Itc1p, a component of the ATP-dependent Isw2p-Itc1p chromatin remodelling complex, is required for the repression of a-specific genes. It has previously been reported that disruption of the ITC1 gene leads, in MATalpha cells, to an aberrant cell morphology resembling the polarized mating projection of cells responding to pheromone. The activation of the pheromone signalling pathway in itc1 mutants of both mating types was examined and found to be constitutively active in MATalpha itc1 but not in MATa itc1 cells. Furthermore, unlike the wild-type, MATalpha itc1 and MATa/alpha itc1/itc1 cells secrete a-factor and express significant levels of other a-specific genes. The results indicate that the inappropriate a-factor production in a MATalpha context, due to the derepression of the a-specific genes, produces an autocrine signalling loop that leads to the aberrant morphology displayed by MATalpha itc1 cells. It is suggested that the Isw2p-Itc1p complex contributes to maintain the repressive chromatin structure described for the asg operator present in the promoters of a-specific genes.

The applicability of dimensional analysis (DA) is discussed in relation to the metabolic scaling laws. The evolution of different theories of biological similarity has shown that the calculated reduced exponents (b) of Huxley's allometric equation are closely correlated with the numerical values obtained from the statistical analysis of empirical data. Body mass and body weight are not equivalent as biological reference systems, since in accordance to Newton's second law, the former has a dimension of a mass, while the latter should be dimensionally considered as a force (W = MLT-2). This distinction affects the coefficients of the mass exponent (alpha). This difference is of paramount importance in microgravity conditions (spaceflight) and of buoyancy during the fetal life in mammals. Furthermore, the coefficients (beta) of the length dimension, and (gamma) of the time dimension do not vary when mass or weight are utilized as reference systems. Consequently, the "specific metabolic time," that results from the ratio of basal oxygen consumption and body mass or body weight yields the "biological meaning" of the time dimension, which is of fractal nature.

In the present paper we have examined the applicability of dimensionless and invariant numbers (DN & IN) to the analysis of the cardiovascular system of mammals, whose functions were measured at standard metabolic conditions. The calculated IN did not change when we compared these figures with those obtained in dogs while they were submitted to graded exercise on a treadmill. In both instances, rest and exercise, the constancy of the IN prevailed, in accordance with Cannon's principle of "homeostasis" (1929). On the contrary, when dogs were examined during a standardized hypovolemic shock, we observed a breakdown of the IN, and the resulting DN evolved as a reliable index of the condition of "heterostasis" as defined by H. Selye. The robustness of the homeostatic regulations is based on high-gain integral feedback mechanisms, while "heterostasis" could be associated with low-gain integral feedback processes, when organisms are submitted to unitary step disturbances or to changes of the set-point at the entrance of the feedback loop.

From four empirical allometric equations concerning the dynamics of the respiratory functions of mammals, it has been possible to obtain an invariant and dimensionless number after applying Buckingham's pi-theorem. In the present study, this invariant number (IN(R)), whose origin was interspecies comparisons in mammals of different sizes, was assayed with the aim to compare in a quantitative manner the possible difference between newborn and adult mammals. The results were compared with the predicted values from two theories of biological similarity, one mass-dependent, valid for newborns, and the other, weight-dependent, valid for adult mammals. Finally, we utilized Stahl's residual mass exponents (RME) to test the validity of the empirical and theoretical approaches.

Background: The prediction of the length of stay at the moment of hospital admission is of utmost importance. Many studies have used lineal models to predict this variable, but there are inherent limitations to these models. The use of non lineal models has been scarce., Aim: To develop a non lineal model to predict length of stay in intensive care units., Material and Methods: Retrospective analysis of 294 patients admitted to two intensive care units in Santiago, Chile. The severity of the disease motivating the admission was nominally quantified. This and other physiological variables were included in the model. The length of stay was modeled using Artificial Neural Networks., Results: The model yielded an error of 8.7% (3.6 +/- 0.4 days, CI 95%) and a correlation coefficient of 0.9 (p < 0.001) for the prediction of length of stay. Using net sensitivity analysis, the model determined that gastrointestinal diseases, infections and respiratory problems were the main causes of prolongation of intensive care unit stay., Conclusions: Intensive care units should have, in the future, computer systems that gather vital information to predict length of stay.

Purpose: To describe an easily home-made diathermy probe for the performance of retrograde endopyelotomies using a small-caliber rigid ureteroscope., Methods: The diathermy probe is easily built by putting a rigid guidewire through a 5F ureteral catheter, the distal tip being naked and slightly bent. The other end is linked to the electric generator. Among a total of 24 retrograde endopyelotomies performed to treat ureteropelvic junction obstruction in the last 7 years, five were done using this device., Results: Surgery with the probe took an average of 30 minutes. There were no complications, and, as of today, all cases are successes., Conclusion: This device allows the performance of retrograde endopyelotomy using a small-caliber ureteroscope. Long-term results will presumably match the good results obtained using the larger-caliber ureteroscopes with the classic cold knife.

This study consisted of an analysis of the occurrence of bioindicator polychaete species of organic pollution along beaches of the north coast of São Paulo State, southeastern Brazil, taking into account the importance of benthic species as indicators of organically enriched environments. A comparison was established between the frequence and abundance of these species in areas qualified as impacted and improper for bathing. The study area comprehends 17 beaches of the Caraguatatuba Bay and the Channel of São Sebastião. The data about the macrobenthos were collected from March, 1988 to March, 1991 and the data on bathing conditions came from reports published by CETESB. The biological samples were obtained with an iron core of 0.025 m2 surface area. The results show markedly the presence of species considered as indicators of organically enriched places, such as Capitella capitata, Heteromastus filiformis, Laeonereis acuta, and Scolelepis squamata. The high density of Capitella and Heteromastus in beaches considered improper for bathing consist in a strong indication of the degree of damage to these areas.

The present allometric study deals with the duration of three electrocardiographic intervals (PQ, QRS, QT) and their relationships with the corresponding cardiac cycle length (R-R interval) in mammals across a wide body mass range. The numerical values of the different ECG intervals were obtained from Grauwiler's (1965) monograph on the subject. Because the corresponding body masses were not given by this author, Heusner's (1991) data on basal metabolic rate as function of body mass were used to establish the most likely body mass figure for each case, based on the taxonomic identity between the corresponding specimens. On the other hand, in a recent study we established the "duality" of physiological times (Günther & Morgado, 1996) and, therefore, we adopted this novel approach to investigate the ECG intervals and their relationships with the R-R interval (heart rate reciprocal). Considering that the anatomy and physiology of auricles and ventricles are different (spheroids versus quasi-cylinders), and that excitation (sino-atrial node and His-Purkinje's system) and contraction processes can be described either by Euclidean or fractal geometries, only a quantitative analysis of the different ECG waves could resolve the dilemma. From the present preliminary study we can conclude that fractal geometry is prevalent with regard to ECG intervals.

The aim of the present study was to differentiate two modalities of intrinsic time scales: i- the geometric or Euclidean modality, which is based on the constant speed of mass transport or of wave transmission in cylindrical structures (arteries, veins, nerves), whose allometric exponent (TE = aMb) is b = 0.33, where M is body mass (kg) and a the mass coefficient; ii- the fractal time scale (TF), which is characteristic of organs with self-similar branching structures and with volume-specific flows, whose allometric exponent is b = 0.25. The proposed dichotomy could be confirmed by means of the statistical analysis of empirical allometric exponents (b). Our findings demonstrate the need to separate the chronology of bulk transport at long distances (inter-organic) which follows an Euclidean geometry (cylinders), from the fractal time scale, which operates at short distances (intra-organic) and is represented by a self-similar branching system which determines both the morphometric and physiometric characteristics within each organ.

The aim of the present study is to emphasize the applicability and versatility of the allometric equation in the biological sciences. This equation (Y = a x Mb) was introduced by Huxley (1932) for intra- and interspecific comparisons of morphological, physiological and ecological variables (Y), when they are expressed as functions of body mass (M). The regression analysis of the experimental data, plotted in a double logarithmic scale, yields a straight line, which is equivalent to the logarithmic form of the above mentioned allometric equation [log Y = log(a) + (b) x log(M)]. Only the exponent (b) can be calculated a priori for a given function, based firstly on the corresponding dimensional analysis in accordance with the MLT-system of physics, and secondly on one of the theories of biological similarity, while parameter (a) is of empirical nature. A relevant feature of the allometric equations is that they can be treated algebraically to obtain allometric ratios, mass independent numbers (MIN), and even dimensionless numbers (M0L0T0), which are valid for all organisms pertaining to the same taxonomic classification.