Showing papers by "Sapienza University of Rome published in 2001"

Bone Marrow Stromal Stem Cells: Nature, Biology, and Potential Applications

Abstract: Bone marrow stromal cells are progenitors of skeletal tissue components such as bone, cartilage, the hematopoiesis-supporting stroma, and adipocytes. In addition, they may be experimentally induced to undergo unorthodox differentiation, possibly forming neural and myogenic cells. As such, they represent an important paradigm of post-natal nonhematopoietic stem cells, and an easy source for potential therapeutic use. Along with an overview of the basics of their biology, we discuss here their potential nature as components of the vascular wall, and the prospects for their use in local and systemic transplantation and gene therapy.

Self-Efficacy Beliefs as Shapers of Children's Aspirations and Career Trajectories.

Abstract: This prospective study tested with 272 children a structural model of the network of sociocognitive influences that shape children's career aspirations and trajectories. Familial socioeconomic status is linked to children's career trajectories only indirectly through its effects on parents' perceived efficacy and academic aspirations. The impact of parental self-efficacy and aspirations on their children's perceived career efficacy and choice is, in turn, entirely mediated through the children's perceived efficacy and academic aspirations. Children's perceived academic, social, and self-regulatory efficacy influence the types of occupational activities for which they judge themselves to be efficacious both directly and through their impact on academic aspirations. Perceived occupational self-efficacy gives direction to the kinds of career pursuits children seriously consider for their life's work and those they disfavor. Children's perceived efficacy rather than their actual academic achievement is the key determinant of their perceived occupational self-efficacy and preferred choice of worklife. Analyses of gender differences reveal that perceived occupational self-efficacy predicts traditionality of career choice.

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

Abstract: Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2

Abstract: This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle

Abstract: Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.

Stem cells in tissue engineering.

Abstract: The concept of producing 'spare parts' of the body for replacement of damaged or lost organs lies at the core of the varied biotechnological practices referred to generally as tissue engineering. Use of postnatal stem cells has the potential to significantly alter the perspective of tissue engineering. Successful long-term restoration of continuously self-renewing tissues such as skin, for example, depends on the use of extensively self-renewing stem cells. The identification and isolation of stem cells from a number of tissues provides appropriate targets for prospective gene therapies.

Pathophysiology of bradykinesia in parkinson's disease

Abstract: Bradykinesia means slowness of movement and is one of the cardinal manifestations of Parkinson's disease. Weakness, tremor and rigidity may contribute to but do not fully explain bradykinesia. We argue that bradykinesia results from a failure of basal ganglia output to reinforce the cortical mechanisms that prepare and execute the commands to move. The cortical deficit is most apparent in midline motor areas. This leads to particular difficulty with self-paced movements, prolonged reaction times and abnormal pre-movement EEG activity. Movements are often performed with normally timed EMG bursts but the amount of EMG activity is underscaled relative to the desired movement parameters. There are also abnormalities in sensory scaling and sensorimotor integration. The brain appears to be able to compensate to some degree for the basal ganglia deficit. There is overactivity in the lateral premotor areas during task performance and movements can be speeded by giving sensory cues. Attention to movement is also beneficial. However, we propose that the engagement of compensatory processes may also lead to reduced performance in other tasks. For example, patients' problems in performing more than one task at the same time could result from lack of sufficient resources both to compensate for their basal ganglia deficit and to run two tasks simultaneously. Surgical therapies are unlikely to work solely by normalizing basal ganglia output to that seen in healthy individuals. It seems more plausible that surgery removes an interfering signal that allows more efficient compensation by other structures.

The Bethe lattice spin glass revisited

Abstract: So far the problem of a spin glass on a Bethe lattice has been solved only at the replica symmetric level, which is wrong in the spin glass phase. Because of some technical difficulties, attempts at deriving a replica symmetry breaking solution have been confined to some perturbative regimes, high connectivity lattices or temperature close to the critical temperature. Using the cavity method, we propose a general non perturbative solution of the Bethe lattice spin glass problem at a level of approximation which is equivalent to a one step replica symmetry breaking solution. The results compare well with numerical simulations. The method can be used for many finite connectivity problems appearing in combinatorial optimization.

Circulating Skeletal Stem Cells

Abstract: We report the isolation of adherent, clonogenic, fibroblast-like cells with osteogenic and adipogenic potential from the blood of four mammalian species. These cells phenotypically resemble but are distinguishable from skeletal stem cells found in bone marrow (stromal stem cells, “mesenchymal stem cells”). The osteogenic potential of the blood-borne cells was proven by an in vivo transplantation assay in which either polyclonal or single colony–derived strains were transplanted into the subcutis of immunocompromised mice, and the donor origin of the fully differentiated bone cells was proven using species-specific probes. This is the first definitive proof of the existence of circulating skeletal stem cells in mammals.

Childhood functional gastrointestinal disorders

Abstract: This is the first attempt at defining criteria for functional gastrointestinal disorders (FGIDs) in infancy, childhood, and adolescence. The decision-making process was as for adults and consisted of arriving at consensus, based on clinical experience. This paper is intended to be a quick reference. The classification system selected differs from the one used in the adult population in that it is organized according to main complaints instead of being organ-targeted. Because the child is still developing, some disorders such as toddler’s diarrhea (or functional diarrhea) are linked to certain physiologic stages; others may result from behavioral responses to sphincter function acquisition such as fecal retention; others will only be recognizable after the child is cognitively mature enough to report the symptoms (e.g., dyspepsia). Infant regurgitation, rumination, and cyclic vomiting constitute the vomiting disorders. Abdominal pain disorders are classified as: functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine, and aerophagia. Disorders of defecation include: infant dyschezia, functional constipation, functional fecal retention, and functional non-retentive fecal soiling. Some disorders, such as IBS and dyspepsia and functional abdominal pain, are exact replications of the adult criteria because there are enough data to confirm that they represent specific and similar disorders in pediatrics. Other disorders not included in the pediatric classification, such as functional biliary disorders, do occur in children; however, existing data are insufficient to warrant including them at the present time. For these disorders, it is suggested that, for the time being, clinicians refer to the criteria established for the adult population.

Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study.

Abstract: Context: In patients with hypoxemic acute respiratory failure (ARF), randomized studies have shown noninvasive positive pressure ventilation (NPPV) to be associated with lower rates of endotracheal intubation. In these patients, predictors of NPPV failure are not well characterized. Objective: To investigate variables predictive of NPPV failure in patients with hypoxemic ARF. Design: Prospective, multicenter cohort study. Setting: Eight Intensive Care Units (ICU) in Europe and USA. Patients: Of 5,847 patients admitted between October 1996 and December 1998, 2,770 met criteria for hypoxemic ARF. Of these, 2,416 were already intubated and 354 were eligible for the study. Results: NPPV failed in 30% (108/354) of patients. The highest intubation rate was observed in patients with ARDS (51%) or community-acquired pneumonia (50%). The lowest intubation rate was observed in patients with cardiogenic pulmonary edema (10%) and pulmonary contusion (18%). Multivariate analysis identified age >40 years (OR 1.72, 95% CI 0.92–3.23), a simplified acute physiologic score (SAPS II) ≥35 (OR 1.81, 95% CI 1.07–3.06), the presence of ARDS or community-acquired pneumonia (OR 3.75, 95% CI 2.25–6.24), and a PaO2:FiO2 ≤146 after 1 h of NPPV (OR 2.51, 95% CI 1.45–4.35) as factors independently associated with failure of NPPV. Patients requiring intubation had a longer duration of ICU stay (P<0.001), higher rates of ventilator-associated pneumonia and septic complications (P<0.001), and a higher ICU mortality (P<0.001). Conclusions: In hypoxemic ARF, NPPV can be successful in selected populations. When patients have a higher severity score, an older age, ARDS or pneumonia, or fail to improve after 1 h of treatment, the risk of failure is higher.

FRP-Confined Concrete Model

Abstract: A uniaxial model for concrete confined with fiber-reinforced polymers (FRP), but also with steel jackets or conventional transverse reinforcement, is presented. The model, which is suitable to be i...

Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance

Abstract: The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

Sociocognitive self-regulatory mechanisms governing transgressive behavior.

Abstract: This longitudinal research examined a structural model of the self-regulatory mechanisms governing transgressive conduct Perceived academic and self-regulatory efficacy concurrently and longitudinally deterred transgressiveness both directly and by fostering prosocialness and adherence to moral self-sanctions for harmful conduct The impact of perceived social self-efficacy was mediated through prosocialness Moral disengagement and prosocialness affected transgressiveness through the mediating influence of irascible affectivity and hostile rumination Ruminative affectivity, in turn, both concurrently and longitudinally affected transgressiveness Moral disengagement also contributed independently to variance in transgressiveness over time This pattern of relations was obtained after controlling for prior transgressiveness The structural model was replicated across gender and provided a better fit to the data than did several alternative models

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.

Abstract: Both ionotropic and metabotropic glutamate receptors (mGluRs) are involved in the behavioral effects of pyschostimulants1,2,3; however, the specific contributions of individual mGluR subtypes remain unknown. Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice. These results demonstrate a significant contribution of mGlu5 receptors to the behavioral effects of cocaine, and suggest that they may be involved in cocaine addiction.

Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.

Abstract: Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to a ∼1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.

Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells

Abstract: In mitotic cells, an error in chromosome segregation occurs when a chromosome is left near the spindle equator after anaphase onset (lagging chromosome). In PtK1 cells, we found 1.16% of untreated anaphase cells exhibiting lagging chromosomes at the spindle equator, and this percentage was enhanced to 17.55% after a mitotic block with 2 μM nocodazole. A lagging chromosome seen during anaphase in control or nocodazole-treated cells was found by confocal immunofluorescence microscopy to be a single chromatid with its kinetochore attached to kinetochore microtubule bundles extending toward opposite poles. This merotelic orientation was verified by electron microscopy. The single kinetochores of lagging chromosomes in anaphase were stretched laterally (1.2–5.6-fold) in the directions of their kinetochore microtubules, indicating that they were not able to achieve anaphase poleward movement because of pulling forces toward opposite poles. They also had inactivated mitotic spindle checkpoint activities since they did not label with either Mad2 or 3F3/2 antibodies. Thus, for mammalian cultured cells, kinetochore merotelic orientation is a major mechanism of aneuploidy not detected by the mitotic spindle checkpoint. The expanded and curved crescent morphology exhibited by kinetochores during nocodazole treatment may promote the high incidence of kinetochore merotelic orientation that occurs after nocodazole washout.

Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection.

Abstract: Objectives To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self-reported symptoms or medication side effects are related to adherence. Design Cross-sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods Participants receiving HAART completed a 16-item self-administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV- and HAART-related symptoms experienced during the last 4 weeks. Results From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA Conclusions In addition to patient characteristics, medication-related variables, and reasons for nonadherence, patient-reported symptoms and medication side effects were significantly associated with adherence to HAART.

Cosmology from MAXIMA-1, BOOMERANG, and COBE DMR cosmic microwave background observations.

Abstract: Recent results from BOOMERANG-98 and MAXIMA-1, taken together with COBE DMR, provide consistent and high signal-to-noise measurements of the cosmic microwave background power spectrum at spherical harmonic multipole bands over 2

Intermittent dislocation flow in viscoplastic deformation

Abstract: The viscoplastic deformation (creep) of crystalline materials under constant stress involves the motion of a large number of interacting dislocations. Analytical methods and sophisticated 'dislocation dynamics' simulations have proved very effective in the study of dislocation patterning, and have led to macroscopic constitutive laws of plastic deformation. Yet, a statistical analysis of the dynamics of an assembly of interacting dislocations has not hitherto been performed. Here we report acoustic emission measurements on stressed ice single crystals, the results of which indicate that dislocations move in a scale-free intermittent fashion. This result is confirmed by numerical simulations of a model of interacting dislocations that successfully reproduces the main features of the experiment. We find that dislocations generate a slowly evolving configuration landscape which coexists with rapid collective rearrangements. These rearrangements involve a comparatively small fraction of the dislocations and lead to an intermittent behaviour of the net plastic response. This basic dynamical picture appears to be a generic feature in the deformation of many other materials. Moreover, it should provide a framework for discussing fundamental aspects of plasticity that goes beyond standard mean-field approaches that see plastic deformation as a smooth laminar flow.

The Arabidopsis ATHB-8 HD-Zip Protein Acts as a Differentiation-Promoting Transcription Factor of the Vascular Meristems

Abstract: ATHB-8, -9, -14, -15, and IFL1/REV are members of a small homeodomain-leucine zipper family whose genes are characterized by expression in the vascular tissue. ATHB-8, a gene positively regulated by auxin (Baima et al., 1995), is considered an early marker of the procambial cells and of the cambium during vascular regeneration after wounding. Here, we demonstrate that although the formation of the vascular system is not affected in athb8 mutants, ectopic expression of ATHB-8 in Arabidopsis plants increased the production of xylem tissue. In particular, a careful anatomical analysis of the transgenic plants indicated that the overexpression of ATHB-8 promotes vascular cell differentiation. First, the procambial cells differentiated precociously into primary xylem. In addition, interfascicular cells also differentiated precociously into fibers. Finally, the transition to secondary growth, mainly producing xylem, was anticipated in transgenic inflorescence stems compared with controls. The stimulation of primary and secondary vascular cell differentiation resulted in complex modifications of the growth and development of the ATHB-8 transgenic plants. Taken together, these results are consistent with the hypothesis that ATHB-8 is a positive regulator of proliferation and differentiation, and participates in a positive feedback loop in which auxin signaling induces the expression of ATHB-8, which in turn positively modulates the activity of procambial and cambial cells to differentiate.

Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium regeneration

Abstract: The concept of tissue-restricted differentiation of postnatal stem cells has been challenged by recent evidence showing pluripotency for hematopoietic, mesenchymal, and neural stem cells. Furthermore, rare but well documented examples exist of already differentiated cells in developing mammals that change fate and trans-differentiate into another cell type. Here, we report that endothelial cells, either freshly isolated from embryonic vessels or established as homogenous cells in culture, differentiate into beating cardiomyocytes and express cardiac markers when cocultured with neonatal rat cardiomyocytes or when injected into postischemic adult mouse heart. Human umbilical vein endothelial cells also differentiate into cardiomyocytes under similar experimental conditions and transiently coexpress von Willebrand factor and sarcomeric myosin. In contrast, neural stem cells, which efficiently differentiate into skeletal muscle, differentiate into cardiomyocytes at a low rate. Fibroblast growth factor 2 and bone morphogenetic protein 4, which activate cardiac differentiation in embryonic cells, do not activate cardiogenesis in endothelial cells or stimulate trans-differentiation in coculture, suggesting that different signaling molecules are responsible for cardiac induction during embryogenesis and in successive periods of development. The fact that endothelial cells can generate cardiomyocytes sheds additional light on the plasticity of endothelial cells during development and opens perspectives for cell autologous replacement therapies.

Recommendations for the diagnosis and management of Turner syndrome

Abstract: Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

Planck-scale deformation of Lorentz symmetry as a solution to the ultrahigh energy cosmic ray and the TeV-photon paradoxes

Abstract: One of the most puzzling current experimental physics paradoxes is the arrival on Earth of ultrahigh energy cosmic rays (UHECRs) with energies above the Greisen-Zatsepin-Kuzmin threshold $(5\ifmmode\times\else\texttimes\fi{}{10}^{19} \mathrm{eV}).$ Photopion production by cosmic microwave background radiation photons should reduce the energy of these protons below this level. The recent observation of 20 TeV photons from Mk 501 (a BL Lac object at a distance of 150 Mpc) is another somewhat similar paradox. These high energy photons should have disappeared due to pair production with IR background photons. A common feature of these two paradoxes is that they can both be seen as ``threshold anomalies'': energies corresponding to an expected threshold (pion production or pair creation) are reached but the threshold is not observed. Several (relatively speculative) models have been proposed for the UHECR paradox. No solution has yet been proposed for the $\mathrm{TeV}\ensuremath{-}\ensuremath{\gamma}$ paradox. Remarkably, the single drastic assumption of the violation of ordinary Lorentz invariance would resolve both paradoxes. We present here a formalism for the systematic description of the type of Lorentz-invariance deformation (LID) that could be induced by the nontrivial short-distance structure of space-time, and we show that this formalism is well suited for comparison of experimental data with LID predictions. We use the UHECR and $\mathrm{TeV}\ensuremath{-}\ensuremath{\gamma}$ data, as well as upper bounds on time-of-flight differences between photons of different energies, to constrain the parameter space of the LID. A model with only two free parameters, an energy scale and a dimensionless parameter characterizing the functional dependence on the energy scale, is shown to be sufficient to solve both the UHECR and the $\mathrm{TeV}\ensuremath{-}\ensuremath{\gamma}$ threshold anomalies while satisfying the time-of-flight bounds. The allowed region of the two-parameter space is relatively small, but, remarkably, it fits perfectly the expectations of the quantum-gravity-motivated space-time models known to support such deformations of Lorentz invariance: an integer value of the dimensionless parameter and a characteristic energy scale constrained to a narrow interval in the neighborhood of the Planck scale.

The role of polygalacturonase-inhibiting proteins (pgips) in defense against pathogenic fungi

Abstract: ▪ Abstract Polygalacturonase-inhibiting proteins (PGIPs) are extracellular plant proteins capable of inhibiting fungal endopolygalacturonases (PGs). Plants have evolved different PGIPs with specific recognition abilities against the many PGs produced by fungi. The genes encoding PGIPs are organized into families, and different members of each family may encode proteins with nearly identical characteristics but different specificities and regulation. PGIPs are typically induced by pathogen infection and stress-related signals. The recognition ability of PGIPs resides in their LRR (leucine-rich repeat) structure, where solvent-exposed residues in the β-strand/β-turn motifs of the LRRs are determinants of specificity. Manipulation of the primary structure of PGIPs is expected to generate more efficient PGIPs with novel recognition specificities to protect crop plants against pathogens.