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Biomedical subjects

A Zaia

Publications and source records attributed to A Zaia.

16 recordsLinked to original sources
PubMed2001

Use of mathematical models of survivorship in the study of biomarkers of aging: the role of heterogeneity.

An ever increasing number of people have been engaging in aging research using various interventions aimed to modify aging processes, and/or life span, of experimental animals. Since this type of studies needs outcome parameters for assessing the efficacy of such interventions, research on biomarkers of aging (ABs) has received new stimuli. In the present paper, the problem of the occurrence of a vicious circle any time we study ABs and determinants of aging is addressed. In fact, while ABs would represent the standard reference to be used in the study of the main causes of processes of aging, these very determinants should already be known in order to get reliable ABs. A feasible way to overcome this impasse is proposed, using mathematical models of survivorship or mortality based on biological hypotheses and accounting for inter-individual heterogeneity, a necessary ingredient for a correct interpretation of survival results. Specific kinetics of experimental parameters that are candidates as ABs can be compared to the kinetics hypothesized for general biological functions entering the model. We have built a model of this type that can also be used to perform a reliable overall gross estimate of the rate of aging, R(a), in the population, a parameter useful when judging the success of interventions aimed to act on determinants of aging. The perspective that theory of complex systems can be of help in the search for ABs is also discussed.

Aging↗
PubMed2001

Long-live euthymic BALB/c-nu mice. I. Survival study suggests body weight as a life span predictor.

This paper is the first of a series aimed to show the main physiological and pathological characteristics of male euthymic BALB/c-nu mice, a long-live strain of BALB/c mice bred in our own Institute. In particular, the first two paired papers are respectively devoted to general survival information and disease characteristics, also taking into account very old animals that are of high interest for studies on successful aging. In this paper we report the analysis of survival kinetics, the time course of body weight and the correlation between body weight and time-at-death. The longitudinal study has been performed on 88 male mice, checking individually their body weight and date of death and analyzing survival data by a model built by our own. Survival analysis shows quite higher longevity (median age: about 29 months) in this population when compared with other BALB/c strains. The most relevant finding on body weight is its correlation with longevity until the age of 22 months: thinner subjects live longer and lose weight at a lower rate than their heavier mates. Results have formed the basis on which to plan the cross-sectional experiment to study pathologies and biological parameters at different ages, including a group of mice at very advanced ages (34 months).

Animals↗
PubMed2001

Long-live euthymic BALB/c-nu mice. II: spontaneous tumors and other pathologies.

This paper is the second of a series aimed to show the main physiological and pathological characteristics of male euthymic BALB/c-nu mice, a long-live strain of BALB/c mice bred in our own Institute. The previous paired paper Piantanelli (Mech. Ageing Dev. (2001)) has been devoted to a survival study up to advanced ages highly interesting for studies on successful aging. In the present paper we report first data of a cross-sectional study on 4,15,22,28 and 34 months-old mice, dealing with tumors and other relevant pathologies. Results have shown that tumors or other pathologies can hardly be detected up to the age of 22 months. At 34 months of age about 40% of mice revealed a variety of neoplasia and other diseases are clearly detectable. These results suggest that a significant increase in longevity could be a factor increasing the risk of tumor development; thus, caution has to be paid in studies on mice utilized for long term carcinogenicity assay, where animals are sacrificed at the age of 18 months, according to the International Program. Finally, animals of the same chronological age have been subdivided in clusters according to their presumptive longevity, estimated taking advantage of the relationship between body weight and age-at-death found in the paired longitudinal study. This subdivision will be helpful in interpreting inter-individual variability of the biological parameters checked in these animals.

Aging↗
PubMed2001

An outbreak of serogroup C meningococcal disease associated with a secondary school.

An outbreak of 3 cases of invasive meningococcal disease occurred in a secondary school on 2 campuses in Victoria. Despite having only one isolate (a C.2a:nst strain), meningococcal DNA was identified by polymerase chain reaction (PCR) in early culture-negative blood specimens of the other 2 cases. Both were subsequently shown by PCR to be capsule serogroup C by PCR. An committee was formed to manage the response to the outbreak. Chemoprophylaxis was offered to family and children who had been in close contact with the cases. As one strain had been confirmed as being of a vaccine-preventable group, vaccination was offered to the whole school community as well as the families of cases. The direct costs of the outbreak to public health, which would have been identical whatever the causative serogroup, was $8,178. Vaccine charges accounted for most of the additional $56,941 cost of vaccinating the target group of 1600 students, staff, and families. No further cases have been associated with this outbreak.

Child↗
PubMed2001

Gut neuroendocrine cells: relationship to the proliferative activity and apoptosis of mucous epitheliocytes in aging.

OBJECTIVES: Diffuse neuroendocrine system (DNES) cells regulate homeostasis via neurocrine, endocrine and paracrine mechanisms. Extensive effects of peptide hormones and biogenic amines necessitate studying of DNES cell biology in aging. In this connection, the functional morphology of gut neuroendocrine cells (NEC), proliferative activity and apoptosis of mucous epithelial cells in aging have been studied. MATERIAL AND METHODS: The study was performed on BALB/c-nu mice of 4, 21 and 34 months of age. NEC, proliferative activity and apoptosis of mucous epitheliocytes in stomach and duodenum have been studied by histochemical, immunohistochemical and morphometrical methods. RESULTS: The total number of NEC shows an increasing trend with advancing age. However, the different types of NEC elicit differential patterns. The total number of epithelial cell nuclei does not show any statistically significant difference during aging. The proliferative activity of mucous epitheliocytes also shows no difference among the three animal groups studied. On the contrary, the apoptotic index increases with advancing age. CONCLUSIONS: The results demonstrate that various gut NEC show differential behavior with age and their time-courses are dependent on the site of location (stomach or duodenum). The picture seems quite complex to allow a comprehensive interpretation, nonetheless it gives us some useful indications for further investigation. In fact, since the gut does not show evident gross age-related physiological changes, modifications with age in specific biological parameters can suggest the key mechanisms of compensative regulatory processes possibly acting during aging.

Aging↗
PubMed2000

Insulin receptors in the brain cortex of aging mice.

The aim of the present study was to analyze whether aging also affects central insulin receptors in brain cortex as it does in whole brain of BALB/c-nu mice. Results showed statistically significant decrease of number and increase of affinity of insulin high affinity binding sites in old animals. As a consequence, central insulin actions, among which neuromodulation of monoaminergic system, can result altered during aging.

Aging↗
PubMed1999

Group II nucleopolyhedrovirus subgroups revealed by phylogenetic analysis of polyhedrin and DNA polymerase gene sequences.

Two major clades, designated Groups I and II, of nucleopolyhedroviruses (NPVs) from lepidopteran hosts have been previously identified. To reveal more detailed relationships, a series of DNA polymerase nucleotide sequences from the taxa MbMNPV, SeMNPV, HzSNPV, HearNPV, SpltNPV, BusuNPV, and OranNPV have been determined using a polymerase chain reaction (PCR)-based approach. This technique enabled gene sequence determination using microliter samples of NPV-infected insect cadavers. Polyhedrin genes from HearNPV, OranNPV, SeMNPV, and SpltNPV were also isolated and sequenced using a similar approach. These sequences, together with other database entries, were aligned for positional homology of peptide sequences. Phylogenetic analysis of DNA polymerase molecular sequence alignments supports LdMNPV as a taxon of Group II and three Group II subclades, designated A, B, and C. Comparison of DNA polymerase trees with those estimated from occlusion protein molecular sequences enabled identification of three subclades of Group II. These are Subgroup II-A [MbMNPV, LeseNPV, MacoNPV, PaflNPV, SeMNPV, SpltNPV (India isolate), SfMNPV]; Subgroup II-B [SpliNPV, SpltNPV (Japan isolate), SpltNPV (Queensland isolate), and possibly HzSNPV, HearNPV, and ManeNPV], and Subgroup II-C [OpSNPV, OranNPV (S-type), BusuNPV (S-type), and possibly EcobNPV (S-type)]. Notably, all Subgroup II-A taxa are from noctuid hosts. Correlations of virus and host evolution within Group II taxa are discussed. The methods and data developed in this study will allow rapid sequencing of NPV DNA polymerase genes.

Amino Acid Sequence↗
PubMed1997

Insulin receptors in mouse brain: age-related modifications are corrected by thymus graft.

Recently, we have shown that insulin receptors (InsRs) in the brain undergo impairment with aging, as happens for other receptors such as alpha- and beta-adrenoceptors. Age-related alterations of adrenoceptors, which are modulated by brain InsRs, are not definitive as they can be recovered by a thymus graft. In this study we verified the possibility that the thymus graft can also recover the age-dependent modifications of brain InsRs. InsR characteristics were assayed in a group of 27 months old Balb/c-nu mice grafted with a neonatal thymus, under renal capsule, one month before the animals were killed. Another two groups of young (3 months) and old (27 months) mice were used as controls. A two-sites model analysis of receptor data confirmed the age-dependent decrease of InsR density previously observed in the high affinity population. Furthermore, a statistically significant recovery of this impairment was shown in thymus grafted animals. The low affinity receptor subset also showed some differences among the three animal models; however, they were not statistically significant. Thymus graft induced recovery of the age-related changes found in brain InsRs, together with the similar one observed on the adrenergic system, calls for deeper studies of their interaction and the role they can play on aging processes.

Aging↗
PubMed1991

Thymus-induced recovery of age-related decrease of brain cortex alpha- and beta-adrenoceptors.

It has previously been demonstrated that thymus exerts a regulatory influence on beta-adrenergic system during aging. In particular, it has been shown that thymus can correct the beta-adrenoceptor density decrease in old mice. In the present paper results of experiments are reported dealing with the influence of the thymus on alpha-adrenoceptors of mouse brain cortex. Both subtypes of alpha-adrenoceptors are studied separately, using different labelled ligands. Results show that alpha 1-adrenoceptor density decreases in old animals, while alpha 2-adrenoceptor density does not change significantly. A neonatal thymus grafted into old recipients is capable of correcting the alteration observed in old mice. The differential impairment of alpha-adrenoceptors resembles that one previously observed on beta-adrenoceptors, where beta 1-type decreases in number during aging with a parallel decrease of adenylyl-cyclase activity, while beta 2-type remains unchanged.

Adenylyl Cyclases↗
PubMedDate not supplied

Functional interrelationships in aging processes: alterations and reversibility.

The problem of assessing the relevance of the reversibility of age-related functional alterations for aging studies has been presented. Transduction mechanisms of adrenergic stimulation have been chosen as the target of age-related changes and thymus as the effector of some corrective interventions performed at advanced age. Both alterations of adrenoceptor characteristics and their reversibility have been reviewed. beta-adrenoceptors have been studied in organs bearing only one subtype of receptors or both, revealing an age-related decrease in density only in the beta1-subtype. It has been shown that a similar age-related decrease is present in alpha1-adrenoceptor density. Such alterations are corrected by grafting a neonatal thymus into old mice. On the contrary, thymus fails to correct the alteration of T4-induced upregulation of beta-adrenoceptors indicating some limits to its corrective effect when the net of functional interrelationships becomes relatively complex. Both failures and successes of thymic grafts and thymic extracts in reversing age-related changes are discussed taking into account the effects induced on the life span of the animals. Different unsolved problems stemming from the previous considerations are also presented. Among them the controversial question about linearity and non-linearity of biological parameters presumed to be good indices of aging is discussed, with the aid of a simple model as a schematic example.

Journal Article↗
PubMedDate not supplied

Alterations of brain insulin receptor characteristics in aging mice.

An interesting role of insulin and insulin receptors (InsRs) in the brain is neuromodulation of monoaminergic systems. Since our previous studies showed age-dependent alterations of alpha- and beta-adrenoceptors in mouse brain cortex, the intriguing role of brain InsRs per se and their involvement in adrenergic modulation prompted us to check their eventual changes with aging. Thus, brain InsR characteristics were studied in young (3 months) and old (27 months) Balb/c-nu mice by direct binding with (125)I-insulin. A two-sites model analysis of data shows a statistically significant age-related decrease of receptor density (39%) and k(d) (57%) in the high affinity population. The low affinity receptor subset also shows a decreasing trend of its characteristics; however, differences are not statistically significant and show a high degree of interindividual variability in both groups of mice.

Journal Article↗
PubMedDate not supplied

Transcriptional regulation of the androgen signaling pathway by the Wilms' tumor suppressor gene WT1.

The androgen-signaling pathway plays a critical role in prostate cancer development and progression. We have recently demonstrated that the Wilms' tumor suppressor gene product, WT1, binds to multiple sites in the androgen receptor (AR) promoter and transcriptionally represses the AR gene promoter in vitro. We asked whether WT1 repression of the endogenous AR gene interferes in the androgen signal transduction cascade and modifies AR target gene expression. We analyzed the effect of WT1 (-/-) overexpression on an AR target gene reporter construct that contains the luciferase gene, the ElB TATA box, and two copies of the androgen-response element (ARE), the dimeric AR binding site. Luciferase activity was determined in 293 kidney and TM4 Sertoli cells, two nontumorigenic cell lines that express both AR and WT1. Cells were cotransfected by lipofectamine in the presence or absence of the synthetic androgen R1881. Results showed that overexpression of WT1 downregulates ARE-reporter gene transcription in both cell lines tested. The inhibitory effect of WT1 on the AR target gene construct was dose-dependent and androgen-independent in 293 cells, whereas in TM4 cells it was androgen-dependent. Additionally, a zinc-finger mutant WT1 (-/-) expression construct, R394W, failed to decrease luciferase activity, suggesting that WT1 downregulates the ARE-reporter gene construct activity by directly repressing the endogenous AR gene promoter. Furthermore, we analyzed the expression of WT1 and AR mRNA in several prostate cancer cell lines in order to understand the role WT1 may play in prostate cancer development and progression. Gel analysis of cDNA amplified by RT-PCR of AR and WT1 RNA from prostate cancer and non-prostatic cell lines showed that LNCaP and MDAPCa2b, two metastatic prostate cancer cell lines which are androgen-sensitive, expressed AR but not WT1. Du145 and PC3, two cell lines from advanced metastatic prostate cancer, which are characterized as androgen-independent and -insensitive, did not express AR but expressed a high level of WT1. Two non-prostatic cell lines, T47D and 293, weakly co-expressed AR and WT1. This inverse relationship between AR and WT1 expression in prostate cancer cell lines, together with WT1 repression of the AR promoter, suggest a role for WT1 in the androgen signaling pathway and in prostate cancer development and progression.

Androgens↗
PubMedDate not supplied

Assay of estrogen and progesterone receptors in small samples of breast cancer: II. The conventional procedure compared to the mathematical one.

Parallel assays of ER and PR receptors have been performed in the same tissue samples using both the conventional method employing two sets of test tubes and a mathematical method which does not need the second set of tubes containing excess cold ligand concentrations. Determinations have been performed in calf uterus and human breast cancer samples. Findings show that the two methods give quite similar results. In particular, they are very close in human BC tissues where receptor density values show a very wide range. The mathematical method seems quite useful when the samples are poor of receptors, a case where the precision of the method may influence both prognosis and therapy.

Animals↗
PubMedDate not supplied

Assay of insulin receptors in mouse brain.

We previously demonstrated that mouse adrenergic system undergoes age-related impairments which can be reversed by grafting thymus into old animals. Recently, our attention is devoted to brain insulin receptors (InsRs), because of their possible involvement in neuromodulation of monoaminergic systems. The paucity of information on brain InsRs in general, and on mouse in particular, prompted us to look for methods by which brain InsR characteristics can be determined accurately, before beginning a study on possible age-dependent modifications of this receptor system and their eventual recovery by thymus graft. Brain insulin receptor characteristics were studied in a group of young Balb/c-nu mice by binding competition experiments, set up incubating fresh brain membranes with a constant amount of 125I-insulin in presence of increasing concentrations of cold insulin. Experimental data were analysed using both one-site and two-site models. Comparison of results demonstrates that curvilinear Scatchard plot of brain InsRs is indicative of the presence of two binding sites with high and low affinity, respectively. Data also shows that density and affinity of the high affinity receptor subset can be determined accurately, while the low affinity receptor subpopulation presents a high degree of interindividual variability for both density and affinity. It can be concluded that this method of determination of InsR characteristics can be safely used to deepen the study of thymus graft-induced recovery of age-related modifications of brain InsR system.

Animals↗