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Biomedical subjects

A Noronha

Publications and source records attributed to A Noronha.

At least 19 recordsLinked to original sources
PubMed2002

Central nervous system mechanisms in alcohol relapse.

BACKGROUND: Alcohol relapse is a major problem in the treatment of alcohol abuse and alcoholism. Understanding the long-term neuronal alterations that promote relapse of alcohol drinking is critical for the development of pharmacotherapies to treat alcoholism and alcohol abuse. The major objectives of this workshop were to present recent findings, by using rodent models, on behavioral and neurobiological factors that may underlie alcohol relapse and the results of clinical and pharmacological treatment strategies for preventing relapse. METHODS: Prolonged ethanol drinking and repeated periods of alcohol deprivation were studied in nonselected rats and in rats selectively bred for high alcohol preference (P rat). The expression of a robust alcohol deprivation effect (ADE) was used as a model for alcohol relapse in rodents. Operant techniques were used to examine responding for ethanol after deprivation in both rats and C57BL/6J mice. Environmental cues and stress were used to assess their effects on reinstatement of alcohol responding. Microdialysis and [14C]-2-deoxyglucose techniques were used to examine neuronal alterations associated with alcohol relapse. RESULTS: Prolonged free-choice ethanol drinking followed by deprivation produced an ADE in both stock and P rats. These rats demonstrated loss of control on reinstatement after chronic drinking and after prolonged deprivation. Acamprosate and naltrexone effectively reduced the ADE in stock rats. Stress reinstated operant responding for alcohol, and rats trained to associate a cue with ethanol presentation increased responding on the ethanol-associated lever in the absence of ethanol. After repeated deprivations, P rats shifted their preference toward drinking higher concentrations of ethanol, which increased the magnitude and duration of the ADE. Stock rats also shifted their preference toward solutions with higher ethanol concentrations and demonstrated a loss of control after prolonged ethanol drinking and deprivation. Long-lasting alterations in neuronal activity, serotonin-3 receptor function, and dopamine neurotransmission within the mesolimbic system were evident after chronic drinking that followed a prolonged deprivation period. CONCLUSIONS: The ADE is a useful model for studying alcohol relapse in both rats and mice. The potential validity of this model is supported by the findings that acamprosate and naltrexone are effective in preventing the ADE in rodents, and both compounds have gained recognition for their therapeutic effects in clinical populations. Genetics, stress, and environmental cues are all important factors that influence alcohol relapse. Long-term alterations in neuronal activity within the mesolimbic system, which possibly involve dopamine and serotonin, may underlie alcohol relapse.

Acamprosate↗
PubMed2000

Novel techniques, standardization tools to enhance reliability of acoustic rhinometry measurements.

Acoustic rhinometry measurements are influenced by factors related to subject posture, breathing, inclination and positioning of the wavetube, leaks and distortion at the nostril-nose adapter connection and ambient noise. We present simple techniques to control these errors. Thus, gel on contoured nose adapters, shadow tracing to maintain posture, laser homing for wavetube alignment, are all integrated into a practical scheme that is easy to implement and causes minimum discomfort to subjects. Repeatability improved to below 3% coefficient of variation (CV) in non decongested subjects when trained operators used all the techniques together viz. gel on nose adaptors, shadow tracing, laser homing. In a factorial experiment, repeated measurements were made on subjects over two consecutive days with operator training and standardization tools as variables. An analysis of variance identified the most important factors to be gel on contoured nose adapters, operator training and control of breathing. With gel, the mean CV between readings was 5.8%, measurement time 30.3 seconds. The tools, especially gel and shadow tracing, helped untrained operators achieve performance levels that were more comparable with trained operators. Reproducible curves could be taken rapidly. Thus a significant difference of 31.2 seconds between untrained and trained operators reduced to 12.6 seconds using tools. These techniques significantly improve the reliability, speed and ease of doing repeated acoustic rhinometry measurements and thus the quality of data generated in nasal studies.

Acoustics↗
PubMed2000

Nasal histamine challenge: a reproducible model of induced congestion measured by acoustic rhinometry.

We describe the development of a clinical model of nasal congestion using a fixed dose histamine challenge in normals. The objective was to use histamine to induce a similar degree of nasal congestion as a natural common cold (from unpublished data of 250 cold sufferers) and thus establish a rapid screening system for decongestant drug effects. Sixtynine normal subjects were challenged with histamine diphosphate (300 micrograms/nostril) on 2 visits. Thirtytwo subjects were identified showing reproducible baseline values (< 15%CV (coefficient of variation)) and adequate nasal congestion (minimum 20%) without excessive sneezing. Reproducibility was evaluated in them post challenge using acoustic rhinometry and rhinomanometry. Twentythree subjects showed a variation < 25%CV of nasal volume over multiple visits in a 5 month period. The average reduction in nasal volume and airflow 15 minutes post challenge was 32% and 41% respectively. Acoustic rhinometry values were less variable than rhinomanometry values. Negligible differences (< 2%) in histamine response over visits and similar correlation between measured values at first, second and last visits indicate that 2 visits are adequate to evaluate response reproducibility in a selected population. We conclude that it is feasible to develop a robust clinical model of nasal congestion using histamine.

Acoustics↗
PubMed1998

Recognition of nucleic acid double helices by homopyrimidine 2', 5'-linked RNA.

We have studied the effect of a 2',5'-RNA third strand backbone on the stability of triple helices with a 'pyrimidine motif' targeting the polypurine strand of duplex DNA, duplex RNA and DNA/RNA hybrids. Comparative experiments were run in parallel with DNA and the regioisomeric RNA as third strands adopting the experimental design of Roberts and Crothers. The results reveal that 2',5'-RNA is indeed able to recognize double helical DNA (DD) and DNA (purine):RNA (pyrimidine) hybrids (DR). However, when the duplex purine strand is RNA and the duplex pyrimidine strand is DNA or RNA (i.e. RD or RR), triplex formation is not observed. These results exactly parallel what is observed for DNA third strands. Based on T m data, the affinities of 2',5'-RNA and DNA third strands towards DD and DR duplexes were similar. The RNA third strand formed triplexes with all four hairpins, as previously demonstrated. In analogy to the arabinose and 2'-deoxyribose third strands, the possible C2'- endo pucker of 2',5'-linked riboses together with the lack of an alpha-2'-OH group are believed to be responsible for the selective binding of 2',5'-RNA to DD and DR duplexes, over RR and RD duplexes. These studies indicate that the use of other oligonucleotide analogues will prove extremely useful in dissecting the contributions of backbone and/or sugar puckering to the recognition of nucleic acid duplexes.

Base Sequence↗
PubMed1998

Triple helices containing arabinonucleotides in the third (Hoogsteen) strand: effects of inverted stereochemistry at the 2'-position of the sugar moiety.

Arabinonucleic acid, the 2'-stereoisomer of RNA, was tested for its ability to recognize double-helical DNA, double-helical RNA and RNA-DNA hybrids. A pyrimidine oligoarabinonucleotide (ANA) was shown to form triple-helical complexes only with duplex DNA and hybrid DNA (Pu):RNA (Py) with an affinity that was slightly lower relative to the corresponding pyrimidine oligodeoxynucleotide (DNA) third strand. Neither the ANA nor DNA third strands were able to bind to duplex RNA or hybrid RNA (Pu):DNA (Py). In contrast, an RNA third strand recognized all four possible duplexes (DD, DR, RD and RR), as previously demonstrated. Such an understanding can be applied to the design of sequence-selective oligonucleotides which interact with double-stranded nucleic acids and emphasizes the role of the 2'-OH group as a general recognition and binding determinant of RNA.

Arabinonucleotides↗
PubMed1998

Physicochemical and biochemical properties of 2',5'-linked RNA and 2',5'-RNA:3',5'-RNA "hybrid" duplexes.

In recent publications, oligonucleotides joined by 2',5'-linkages were found to bind to complementary single-stranded RNA but to bind weakly, or not at all, to single-stranded DNA [e.g., P. A. Giannaris and M. J. Damha (1993) Nucleic Acids Res. 21, 4742-4749]. In this work, the biochemical and physicochemical properties of 2',5'-linked oligoribonucleotides containing mixed sequences of the four nucleobases (A, G, C, and U) were evaluated. CD spectra of RNA:2', 5'-RNA duplexes were compared with the spectra of DNA:DNA, RNA:RNA, and DNA:RNA duplexes of the same base sequence. The CD results indicated that the RNA:2',5'-RNA duplex structure more closely resembles the structure of the RNA:DNA hybrid, being more A-form than B-form in character. The melting temperature (Tm) values of the backbone-modified duplexes were compared with the Tm values of the unmodified duplexes. The order of thermal stability was RNA:RNA > DNA:DNA approximately RNA:DNA approximately DNA:RNA > RNA:2',5'-RNA > 2',5'-RNA:2',5'-RNA >> DNA:2',5'-RNA (undetected). RNA:2',5'-RNA duplexes are not substrates of the enzyme RNase H (Escherichia coli, or HIV-1 reverse transcriptase), but they can inhibit the RNase H-mediated cleavage of a natural DNA:RNA substrate. Structural models that are consistent with the selective association properties of 2',5'-linked oligonucleotides are discussed.

Carbohydrate Conformation↗
PubMed1997

Role of interferons in demyelinating diseases.

IFN beta-1b reduces the frequency of major multiple sclerosis attacks by 50 percent. Serial MRI scanning over the course of the clinical trial that led to approval of the agent revealed a significant lessening both in disease activity and in accumulating burden of disease in IFN beta-1b-treated patients compared to placebo-treated controls. The mechanism by which IFN beta-1b exerts its beneficial effect in multiple sclerosis is unknown. T suppressor cell function fails during MS attacks and is persistently subnormal in multiple sclerosis patients with progressive disease. IFN beta-1b partially restores suppressor function in multiple sclerosis patients. IFN beta-1b also inhibits release of lymphotoxin, tumor necrosis factor, and interferon gamma, at least in vitro. All three cytokines are toxic to oligodendrocytes. In contrast; production of transforming growth factor beta-1 (TGF beta 1) is increased by IFN beta-1b. TGF beta 1 is an immunosuppressive cytokine. All of the above listed actions of IFN beta-1b could contribute to its beneficial effect. Perhaps all do.

Demyelinating Diseases↗
PubMed1997

Inhibitory potency of R-region specific antisense oligonucleotides against in vitro DNA polymerization and template-switching reactions catalysed by HIV-1 reverse transcriptase.

Antisense oligonucleotides (AONs) targeted to the R-region near the 5'-LTR of HIV-1 genomic RNA inhibited both the synthesis of (-) strong stop DNA and the first template-switch reaction catalysed by HIV-1 reverse transcriptase (RT) in vitro. The 18 nucleotide (nt) AONs used were identical in sequence but differed in the sugar component of the 3'-terminal nucleotide, with either 2'-deoxy-D-ribose (DNA), 2'-deoxy-L-ribose (L), or arabinose (ARA) in this position. All three AONs hybridized to complementary 18 nt RNA (T(m) approximately 70 degrees C) and specifically interacted with the target RNA HIV-1 sequence at 37 degrees C. L was unable to serve as primer for RT-catalysed DNA polymerization, whereas priming from ARA was about 30% that noted with DNA. Each of the three AONs resulted in similar 85-95% decreases in the amount of full length (-) strong stop DNA and up to 75% decreases in the first template-switch reaction products formed by RT, implying that elongation of the AONs did not enhance the inhibitory activity in vitro. A concomitant increase in a truncated DNA product corresponding to polymerization termination at the 5'-end of the AON was noted, indicating that RT was unable to displace the AON. Interestingly, near maximal inhibition in vitro an AON:target RNA template ratio of 1:1 was noted. Our results confirm the validity of our in vitro system for the analysis of potential antisense oligonucleotide inhibitors, and suggest that antisense oligonucleotides directed to the R-region of HIV-1 RNA may be effective inhibitors of the initial stages of HIV-1 proviral DNA synthesis.

Biopolymers↗
PubMed1996

Global inhibition of IL-2 and IFN-gamma secreting T cells precedes recovery from acute monophasic experimental autoimmune encephalomyelitis.

Actively induced experimental autoimmune encephalomyelitis (EAE) in the PL/J mouse is a monophasic disease. We isolated mononuclear cells (MNC) from the central nervous system (CNS), lymph node (LN), blood, and spleen over the course of EAE and counted the number of cells secreting IL-2, IFN-gamma or IL-4 in response to polyclonal stimulation. IL-2 secreting cells were present in the CNS at disease onset but absent at disease peak and at recovery. A profound transient drop in IL-2 secreting cells also occurred in LN, blood, and spleen at disease peak and during recovery. IFN-gamma secreting cell number decreased in all compartments as disease evolved. In contrast, IL-4 secreting cell number was greatest in the CNS at disease peak, i.e. IL-4 secreting cells rose as IL-2 and IFN-gamma secreting cells fell. IL-4 secreting cell number did not change appreciably in LN, blood, and splenic MNC as disease evolved. CNS MNC at disease peak failed to proliferate in response to anti-CD3 mAb but did so in response to IL-2. LN, blood and splenic MNC did proliferate in response to anti-CD3 mAb at disease peak and this proliferation was augmented by exogenous IL-2. After prolonged culture, proliferative response of CNS MNC to anti-CD3 mAb was restored. These results indicate that during monophasic EAE global suppression of naive T cell and Th1 T cell cytokine synthesis occurs but that T cell proliferative responsiveness is selectively inhibited in the CNS.

Acute Disease↗
PubMed1996

Charles Bonnet syndrome: an early marker for dementia?

OBJECTIVE: To clarify the neuropsychological function in patients with Charles Bonnet Syndrome. DESIGN: Control group comparison study. SETTING: University of Chicago Hospitals. PARTICIPANTS: The neuropsychological function of 15 older adults with presenting complaints of visual hallucinations who met criteria for Charles Bonnet Syndrome (CBS) were compared with 11 demographically matched controls to determine if there was any evidence of functional brain impairment. CBS patients were screened for focal brain lesions and epileptic disturbance via MRI and EEG and also received pattern visual evoked potentials and ophthalmological examinations. MEASUREMENTS: Scores from the Wechsler Adult Intelligence Scale-Revised, Mattis Dementia Rating Scale, Wechsler Memory Scale, and the Auditory Verbal Learning Test were compared. RESULTS: Significant differences were found between the two groups on the neuropsychological measures. Moreover, 14 of 14 subjects had ocular abnormalities and six of eight had abnormal age-corrected pattern visual evoked potentials indicative of dysfunction in the visual system. CONCLUSIONS: The results of the study indicate that patients diagnosed with Charles Bonnet Syndrome evidence neuropsychological changes commonly associated with the early stages of dementia. Therefore, in patients with impaired vision, the appearance of cognitive deficits, albeit subtle, occur with the onset of visual hallucinations. We propose that isolated visual hallucinations in the older adult may be an indication of the early stages of dementia.

Aged↗
PubMed1996

Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b.

We assessed neuropsychological function longitudinally in 30 MS patients who participated in the pivotal trial of interferon beta-1b (IFN-beta-1b). Nine patients received high-dose IFN-beta-1b (8.0 million units), eight low-dose IFN-beta-1b (1.6 MIU), and 13 placebo. There was significant improvement in Wechsler Memory Scale Visual Reproduction-Delayed Recall scores between years 2 and 4 of the trial in MS subjects receiving high-dose IFN-beta-1b. Motoric performance, MRI lesion area, and depression rating scores did not correlate with this finding. Comparison of MRI at baseline and at years 2 and 4 revealed significant changes over time for the total cohort (p < 0.02). Mean lesion area in the high-dose group did not change over time, whereas the low-dose and placebo groups had increases in total lesion area of 28 and 36%, respectively, at year 4. Expanded disability status scale scores did not change significantly between years 2 and 4 of the trial, nor did they correlate with MRI lesion area at any assessment point. We conclude that high-dose IFN-beta-1b improves delayed visual reproduction test performance in MS patients, a finding unlikely to be explained by practice effects or brain lesion area.

Adult↗
PubMed1995

The medullary vascular syndromes revisited.

There are two major vascular syndromes of the medulla oblongata: the medial and the lateral. The medial medullary syndrome is characterized by the triad of ipsilateral hypoglossal nerve palsy with contralateral hemiparesis and loss of deep sensation. Lateral medullary infarction commonly presents with Horner's syndrome, ataxia, alternating thermoanalgesia, nystagmus, vertigo and hoarseness. Combinations of the two major syndromes occur as bilateral medial medullary, hemimedullary and bilateral lateral medullary syndromes. Each of these syndromes frequently manifests with incomplete or atypical findings depending on the extent of the lesion. Magnetic resonance imaging has been useful in the clinical diagnosis of medullary infarctions. The site of the lesion may help predict the arteries involved.

Aged↗
PubMed1993

Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis.

Interferons (IFN) are biological molecules with anti-viral, anti-proliferative and immunomodulatory actions. There is evidence that IFN-gamma increases the frequency of exacerbations of multiple sclerosis (MS) whereas IFN-beta may reduce their frequency. Here we present evidence that IFN-beta significantly decreases concanavalin A (Con A)-induced proliferation of peripheral blood mononuclear cells (PBMC) of MS patients and healthy individuals. Similar results were obtained when PBMC were activated through the T cell receptor (TcR) by anti-CD3 monoclonal antibody or independently of it by phorbol ester and Ca2+ ionophore. These effects of IFN-beta were also noted when IFN-gamma and IFN-beta were added together. Furthermore, IFN-beta decreased proliferation when added to cells that were already pre-activated. Activated CD4+ and CD8+ T cells were downregulated to approximately the same extent. Analysis of cytokine production showed that IFN-gamma production by Con A activated PBMC was increased in MS when compared to controls. IFN-beta significantly decreased IFN-gamma production in MS patients and control individuals. Con A activated cultures treated with IFN-beta showed decreased IL2R expression and accumulation of IL2. These results show that IFN-beta decreases T cell activation and IFN-gamma production in vitro, effects that may be beneficial in MS.

Adult↗
PubMed1992

Contrasting effects of alpha, beta, and gamma interferons on nonspecific suppressor function in multiple sclerosis.

Interferons are biological molecules with antiviral, antiproliferative, and immunomodulatory actions. Interferon alpha (IFN-alpha) and -beta are potentially useful in the treatment of multiple sclerosis (MS). IFN-gamma, in contrast, increases the frequency of exacerbations of MS. In this study, we compared the effect of recombinant human IFN-alpha, -beta, and -gamma on suppressor function in patients with MS. Nonspecific suppressor cell function, measured in a concanavalin A suppressor assay, was significantly decreased in 16 patients with progressive MS (mean percent suppression +/- SEM, 14.4 +/- 5.5 in patients with MS, 33.5 +/- 4.8 in 16 normal subjects; p less than 0.001). Recombinant human IFN-beta augmented suppressor function in MS to 45.4 +/- 5.1% (p less than 0.001) and in control subjects to 56.8 +/- 3.8% (p less than 0.001). Similarly, recombinant human IFN-alpha improved suppression in MS to 43.0 +/- 5.6% (p less than 0.001) and in control subjects to 51.1 +/- 5.9% (p less than 0.001). In contrast, recombinant human IFN-gamma had no effect on suppressor function in patients with MS and in control subjects. This study shows that IFN-alpha and -beta augment deficient suppressor function in MS, whereas IFN-gamma has no effect on suppressor function in the progressive phase of the disease.

Adult↗
PubMed1992

Preferential increase of IL-2R+ CD4+ T cells and CD45RB- CD4+ T cells in the central nervous system in experimental allergic encephalomyelitis.

We examined lymphocytes isolated from the spinal cord (SC), peripheral blood (PB) and lymph nodes (LN) draining the immunization site of Lewis rats with acute experimental allergic encephalomyelitis (EAE). Cells were analysed for T cell subset markers CD4 (mAb W3/25) and CD8 (mAb OX8), for IL-2R (mAb OX39), and for high molecular mass leukocyte common antigen (LCA, CD45RB) expression (mAb OX22). T cells expressing high (CD45RB+) or low (CD45RB-) molecular mass LCA are of different maturational stages and/or separate lineages. CD4+ T cells were more predominant in SC than in PB and LN; CD8+ T cells were scarce in SC but common in PB and LN. Activated CD4+ T cells (IL-2R+) were common in the SC and LN but infrequent in blood. CD4+ T cells that were CD45RB+ were scarce in the SC. In contrast, the majority of CD4+ T cells in the PB and LN were CD45RB+. The preferential accumulation of IL-2R+ CD4+ T cells and of CD45RB- CD4+ T cells in the central nervous system (CNS) indicates that a selective mechanism directs cell egress into CNS lesions in EAE.

Animals↗
PubMed1991

Seasonal distribution of births in Alzheimer's disease.

We obtained season-of-birth data in 727 autopsy-confirmed cases of Alzheimer's Disease (AD) and compared these data with expected general population birth rates. There were no significant differences between quarterly birth rates in the AD group and expected quarterly birth rates. Edward's test for cyclical trends did not establish a peak period of birth in the AD sample. No significant differences between observed and expected quarterly birth rates were found when data were analyzed with regard to either family history of dementia or to gender. Edward's test for peak quarter was significant for AD females, however, with the peak period occurring early in the first quarter. These negative findings between observed and expected quarterly birth rates, based on the large number of autopsy-confirmed AD cases in this study, suggest that a season-of-birth effect in AD is highly unlikely.

Aged↗
PubMed1990

Interferon beta augments suppressor cell function in multiple sclerosis.

Suppressor cell function has been previously reported to be decreased in patients with progressive multiple sclerosis (MS). The abnormality could not be corrected in vitro and was present even after patients were treated with immunosuppressive agents. We now report that interferon beta augments suppressor cell function in vitro in progressive MS. Nonspecific suppressor cell function as measured in a concanavalin A (Con A) suppressor assay was reduced in 24 MS patients (mean percent suppression, 19.6 +/- 2.2) when compared to 19 normal subjects (mean percent suppression, 35.0 +/- 3.3). The data are highly significant (p less than 0.001). When recombinant human interferon beta (10(3) units/ml) was added to lymphocyte cultures with Con A, suppressor activity improved significantly. The mean percent suppression improved from 19.6 +/- 2.2 to 37.8 +/- 2.6 in MS (p less than 0.001) and from 35.0 +/- 3.3 to 46.2 +/- 3.5 (p less than 0.025) in control subjects. This study shows that recombinant interferon beta improves suppressor function in humans, an effect that is particularly significant in progressive MS.

Adult↗