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Biomedical subjects

R A Philibert

Publications and source records attributed to R A Philibert.

At least 19 recordsLinked to original sources
PubMed2006

Lower TSH and higher T4 levels are associated with current depressive syndrome in young adults.

OBJECTIVE: The relationship of individual thyroid function indices to depression in those without a history of prior thyroid dysfunction is uncertain. METHOD: We examined the relationship between thyroid-stimulating hormone (TSH) and thyroxine (T4) levels and current or lifetime history of depressive symptoms using information from 6869 participants, aged 17-39 years, in the Third National Health and Nutrition Examination Survey without history of thyroid-related illness. RESULTS: We found that lower TSH and higher T4 levels were associated with current depressive syndrome in men, but only higher T4 levels correlated with current depressive syndrome in women. Lifetime depressive syndrome was associated with neither TSH level nor T4 levels in men or women. CONCLUSION: These findings suggest that transient or 'state dependent' changes are associated with depression in those without a history of thyroid illness. Further studies to discern whether these depression-associated changes represent distinct endophenotypes of depression should be encouraged.

Adolescent↗
PubMed2001

Absence of a significant linkage between Na(+),K(+)-ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old-order Amish.

Previous studies provide evidence for a genetic component for susceptibility to bipolar affective disorder (BPAD) in the old-order Amish population. El-Mallakh and Wyatt [1995: Biol Psychiatry 37:235-244] have suggested that the Na(+),K(+)-ATPase may be a candidate gene for BPAD. This study examines the relationship between BPAD in the old-order Amish cohort and the Na(+),K(+)-ATPase alpha1 and beta3 subunit genes (ATP1A3, ATP1B3). A total of 166 sibling pairs were analyzed for linkage via nonparametric methods. Suggestive levels of statistical significance were not reached in any stratification model for affective illness. Overall, the results do not support linkage of bipolar disorder to the Na(+),K(+)-ATPase alpha subunit gene (ATP1A3) and beta subunit gene (ATP1B3) in these old-order Amish families and they show that these Na(+),K(+)-ATPase subunit genes are not major effect genes (>or=fourfold increased genetic risk of disease) for BPAD in the old-order Amish pedigrees. We cannot exclude other genetic variants of the Na(+),K(+)-ATPase hypothesis for BPAD, whereby other loci may modifying Na(+),K(+)-ATPase activity.

Bipolar Disorder↗
PubMed2001

Population-based association analyses of the HOPA12bp polymorphism for schizophrenia and hypothyroidism.

HOPA is an Xq13 chromosome gene that codes for a RXR nuclear receptor co-activator. In a prior study of the genetic basis of schizophrenia, we showed that exonic polymorphisms in HOPA were associated with increased risk of schizophrenia and hypothyroidism in a large cohort of probands from New York. In an attempt to replicate these findings, we examined this relationship in a cohort of 173 schizophrenic probands (128 males and 45 females providing 218 alleles) from Iowa. Consistent with the prior findings, we found an increased rate of the HOPA12bP exonic polymorphism in schizophrenic probands compared with random newborn controls (9 of 218 alleles vs. 33 of 2,049 alleles, P < 0.02). Furthermore, retrospective review of the medical records showed that two of the nine probands possessing the HOPA12bp allele in whom thyroid function was assessed were hypothyroid compared with 6 of 164 probands possessing the normal HOPAwild allele(s) (P < 0.06). We conclude that the HOPA12bp polymorphism shows a nominally significant association with schizophrenia and a nominal trend for association with hypothyroidism in our study and that further studies are required to define the features of this syndrome and the molecular mechanisms of disease pathogenesis.

Amino Acid Sequence↗
PubMed2000

Investigation of a candidate gene for schizophrenia on Xq13 previously associated with mental retardation and hypothyroidism.

Weak support for linkage of schizophrenia to proximal Xq has previously been reported. In addition, an increased prevalence of thyroid disorder has been noted in families of individuals with schizophrenia. Recently, a gene mapped to Xq13 termed HOPA has been found to be associated with mental retardation, hypothyroidism, and depression and to function as a coactivator for the thyroid receptor. We therefore examined the HOPA gene in a group of 111 probands from a larger cohort of multiplex families with schizophrenia, several of whom (n = 53) also had a family history of hypothyroidism. Four males and two females were found with an alteration in exon 42 of the HOPA gene compared with 8/492 males and 18/471 females (942 X chromosomes) compared with consecutively screened newborns (chi(2) = 3.92, P < 0.05). However, when available family members of each of the probands with an exon 42 variation were subsequently screened, the mutation did not segregate with schizophrenia in three of five families, although all 6 probands with an exon 42 variation did have hypothyroidism in either themselves (n = 3) or their mothers (n = 3) (P < 0.008). These findings replicate prior findings demonstrating an association between HOPA polymorphisms and hypothyroidism. In addition, the increased frequency of HOPA variants in this population may also provide a genetic basis for the familial association of thyroid disease and schizophrenia.

Amino Acid Sequence↗
PubMed2000

The structure and expression of the human neuroligin-3 gene.

The neuroligins are a family of proteins that are thought to mediate cell to cell interactions between neurons. During the sequencing at an Xq13 locus associated with a mental retardation syndrome in some studies, we discovered a portion of the human orthologue of the rat neuroligin-3 gene. We now report the structure and the expression of that gene. The gene spans approximately 30kb and contains eight exons. Unlike the rat gene, it codes for at least two mRNAs and at least one of which is expressed outside the CNS. Interestingly, the putative promoter for the gene overlaps the last exon of the neighboring HOPA gene and is located less than 1kb from an OPA element in which a polymorphism associated with mental retardation is found. These findings suggest a possible role for the neuroligin gene in mental retardation and that the role of the gene in humans may differ from its role in rats.

Alternative Splicing↗
PubMed1998

A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

Adult↗
PubMed1998

The characterization and sequence analysis of thirty CTG-repeat containing genomic cosmid clones.

We have systematically isolated and characterized DNA containing large CTG (n > 7) repeats from a human cosmid genomic DNA library. Using a CTG10 probe, more than 100 cosmid clones were identified, and 30 of these have been extensively characterized. The sequenced cosmids contain repeats that are between three and 19 perfect units (average 10 perfect repeats). The cosmids map to at least 12 different chromosomes. Sequence analysis of flanking regions suggests that more than one third of the repeats occur in exons, and many share strong sequence identity with databank sequences, including the gene involved in dentatorubral pallidoluysian atrophy (DRPLA). Genotyping of human DNA samples demonstrates that more than half of the repeats are polymorphic. This and similar collections of clones containing trinucleotide repeats should aid in the identification of genes that may contain expansions of trinucleotide repeats involved in human disease.

Animals↗
PubMed1998

Association of an X-chromosome dodecamer insertional variant allele with mental retardation.

Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.

Alleles↗
PubMed1997

The effect of gender and age at onset of depression on mortality.

BACKGROUND: Depression has a marked negative impact on geriatric patient mortality and morbidity. The risk factors and exact reasons for these effects are not well understood. METHOD: Seeking to better define the factors, we retrospectively analyzed the effects of gender and age at onset of affective disorder in a naturalistic study of 192 geriatric patients consecutively admitted to a large midwestern tertiary care center between 1980 and 1987 for the treatment of unipolar depression. RESULTS: After controlling for age at index admission, patients with an onset of depression before age 40 suffered significantly (p < .05) less mortality in follow-up than those with onset after age 40. When effects of gender are examined, the effects of age at onset are most profound in women, with a threefold increase in the rate of death in the cohort with age at onset of depression after 70 years when compared to those with onset before age 40. CONCLUSION: These results and those of others suggest that depressed elderly women with no previous history of affective disorder are at a markedly increased risk compared with elderly women with a history of affective illness for morbidity and mortality and that a significant proportion of elderly depressed patients are admitted to a psychiatric hospital for a depression that is secondary to serious medical illness.

Age Factors↗
PubMed1995

Effect of ECT on mortality and clinical outcome in geriatric unipolar depression.

BACKGROUND: Recent reports have called into question the safety and effectiveness of electroconvulsive therapy (ECT). METHOD: To investigate these claims, the effects of ECT on clinical outcomes were examined as part of a retrospective, naturalistic study of 192 geriatric patients consecutively admitted between 1980 and 1987 to a large midwestern tertiary care center for the treatment of depression. Data were analyzed by a variety of parametric and nonparametric methods including ANOVA and survival analysis. RESULTS: Patients who received ECT (N = 108) were more likely to exhibit psychomotor retardation and to have had prior courses of ECT than those who did not receive ECT (N = 84). Furthermore, despite the absence of differences in the overall rate or severity of medical comorbidity, patients receiving ECT were more likely to be alive at follow-up and to demonstrate greater clinical improvement than those treated only with pharmacotherapy. CONCLUSION: These results confirm previous studies demonstrating the superior efficacy of ECT as compared with conventional pharmacotherapy treatment in patients hospitalized with depression and document its safety in long-term follow-up.

Age Factors↗
PubMed1991

K(+)-stimulated amino acid release from cultured cerebellar neurons: comparison of static and dynamic stimulation paradigms.

The release of several endogenous amino acids and adenosine from rat cerebellar neuronal cultures following elevated K+ exposure in the presence and absence of added Ca2+ was studied. The amino acids aspartate (ASP), glutamate (GLU) and GABA were released from the cultures in a dose- and Ca(2+)-dependent manner. Taurine (TAU) and the nucleoside adenosine (ADN) efflux rates were dose-dependent but Ca(2+)-independent, and basal levels increased in the absence of Ca2+. The K+ depolarization induced release of serine (SER), alanine (ALA) and proline (PRO), was not dose-dependent and in the absence of extracellular Ca2+ (with added Mg2+) higher basal release of SER and ALA, but not PRO, was noted. These findings demonstrate that in addition to known cerebellar neurotransmitters, other neuroactive and neutral amino acids are released from cultured cerebellar neurons in response to K+ depolarization. Their observed efflux suggests they may have as yet unidentified roles in neuronal function with different classes of efflux corresponding to: neurotransmitter-type release (ASP, GLU, GABA), an osmoregulatory, possibly neuromodulatory-type release (TAU), a Ca(2+)-insensitive, possibly neuromodulatory-type release (ADN), and a depolarization-sensitive release (SER, ALA, PRO) of which SER and ALA are partially Ca(2+)-sensitive.

Amino Acids↗
PubMed1991

Astrocyte taurine.

The evidence presented, together with the lack of solid evidence for a specific receptor site, strongly suggests that taurine does not act as a traditional neurotransmitter in the CNS. In fact, the properties seen to be governing its efflux from both glial cells and neurons argue strongly in favor of a primary role in volume regulation. However, subsequent to its release into the extracellular space, it is possible that the inherent neuroactive properties (e.g., inhibitory neuromodulation and Ca(2+)-level modulation) may be important at the synapse, at the cell plasma membrane, and intracellularly in further directing the level of neuronal activity. Whether or not the levels of released taurine are great enough to sustain these effects has still to be determined.

Animals↗
PubMed1990

K(+)- and temperature-evoked taurine efflux from hypothalamic astrocytes.

Hypothalamic astrocytes in culture released taurine, a suspected inhibitory amino acid neurotransmitter/neuromodulator/osmoregulator, in response to isoosmotically increasing extracellular K+ in a dose-dependent fashion. In the absence of added Ca2+, basal release levels rose to approach those obtained after exposure to 60 mM K+ in the presence of 2.5 mM Ca2+, and were only partially lowered by the addition of 10 mM Mg2+. Stimulation with K+ (60 mM) did not further increase taurine efflux above the high basal levels seen in the absence of Ca2+. Under standard conditions complete replacement of Na+ with choline Cl had little effect on basal taurine release, but reduced K(+)-evoked (60 mM) efflux by 60%. The temperature dependence of the basal levels of taurine released from hypothalamic astrocytes was similar to that seen for cultured cerebellar astrocytes and neurons over the range 5-50 degrees C. Taurine release increased from 5 to 15 degrees C, remained constant between 15 and 33 degrees C, decreased between 33 and 37 degrees C and increased thereafter. The infection point of increased basal taurine release seen around 37 degrees C (most prominent in astrocytes), may be of physiological significance. Results presented also show that the ion (Na+, Ca2+ and K+) sensitivities of taurine efflux for cultured hypothalamic astrocytes are similar to those previously reported for cultured astrocytes from the cerebellum.

Animals↗
PubMed1990

Glutamate receptor agonists cause efflux of endogenous neuroactive amino acids from cerebellar neurons in culture.

Cultured neurons from rat cerebellum were used to examine the effects of glutamate receptor agonists on the release of endogenous amino acids and adenosine. Kainic acid exposure resulted in the release of glutamate, taurine, GABA and alanine in a dose- and calcium-dependent manner. Stimulation with quisqualic acid resulted in the dose- and calcium-dependent release of GABA. N-Methyl aspartic acid did not elicit the release of any neuroactive amino acids. These findings suggest that N-methyl aspartate receptors are not coupled to transmitter release in these cultures, and that kainate and quisqualate receptors may have different neuronal distributions.

Amino Acids↗
PubMed1989

Dihydropyridines modulate K+-evoked amino acid and adenosine release from cerebellar neuronal cultures.

Partial depolarization of primary cerebellar neuronal cultures with K+ evoked the release of aspartate, glutamate, adenosine, serine, taurine, gamma-aminobutyric acid (GABA), alanine and proline. The dihydropyridine calcium channel agonist, BAY K 8644, significantly augmented the K+-induced release of adenosine, aspartate, glutamate and GABA, but not that of serine, taurine, alanine or proline. However, in all cases the dihydropyridine antagonist nifedipine decreased this BAY K 8644-enhanced, K+-evoked efflux to below control levels. Neither BAY K 8644 nor nifedipine alone affected basal efflux levels. The phenylalkylamine calcium channel antagonist, verapamil, was ineffective in antagonizing K+-evoked amino acid release except at very high concentration (100 microM). These findings suggest that L-type Ca2+ channels are present in both excitatory (glutamatergic granule cells) and inhibitory (GABAergic stellate and basket cells) neurons in these cultures, and that they appear to be involved in regulating the release of not only neuroactive amino acids, but also some neutral amino acids and adenosine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗