Biomedical subjects
E Goudsmit
Publications and source records attributed to E Goudsmit.
Functional somatic syndromes.
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Simultaneous detection of tyrosine hydroxylase-immunoreactivity and vasopressin mRNA in neurons of the human paraventricular and supraoptic nucleus.
Our purpose was to investigate the proportion of tyrosine hydroxylase (TH)-immunoreactive (IR) neurons expressing vasopressin (VP) mRNA in the human paraventricular and supraoptic nuclei by combining in situ hybridization with immunohistochemistry on the same tissue section. A variability in the proportion of TH-IR neurons synthesizing VP mRNA was observed in adults which was usually more than 50%. In neonates almost all the TH-IR neurons appeared to contain VP mRNA.
Chronic fatigue syndrome and depression.
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Functional somatic syndromes.
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Treating chronic fatigue with exercise. Exercise, and rest, should be tailored to individual needs.
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Factual errors and the Press Complaints Commission.
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In situ hybridization for vasopressin mRNA in the human supraoptic and paraventricular nucleus; quantitative aspects of formalin-fixed paraffin-embedded tissue sections as compared to cryostat sections.
In order to study the suitability of formalin-fixed paraffin-embedded brain tissue for vasopressin (AVP)-mRNA detection, we used symmetric halves of 5 human hypothalami. In every case, one half was formalin fixed for 10-35 days and paraffin embedded while the other half was frozen rapidly. Following in situ hybridization (ISH) histochemistry on systematically obtained sections of the supraoptic (SON) and paraventricular nucleus (PVN) of both halves, total amounts of AVP-mRNA in these nuclei were estimated using densitometry of film autoradiographs. Total amounts of radioactivity were found to vary considerably between patients and amounted to 1297 +/- 302 arbitrary units (AU) (PVN) (mean +/- SEM) and 2539 +/- 346 (SON) for the cryostat sections and 868 +/- 94 (PVN) and 1259 +/- 126 (SON) for the paraffin tissue. Variations introduced by the method itself yielded a coefficient of variation of only 0.19. Furthermore, a non-significant negative trend with postmortem delay was found in cryostat tissue, but not in paraffin sections. No effect of fixation time was observed in the paraffin tissue. Both ways of tissue treatment have specific advantages and disadvantages that may be different for other probes or other brain areas. For ISH of a highly abundant mRNA like AVP in a very heterogeneous brain area such as the human hypothalamus, formalin-fixed paraffin-embedded tissue sections can be used for quantitative analysis of entire brain nuclei because of the small variation in this tissue, the remarkably good signal recovery (some 75% as compared to cryostat sections) and its practical advantages with regards to anatomical orientation, storage and sampling of the tissue.
In situ hybridization for vasopressin mRNA in the human supraoptic and paraventricular nucleus; quantitative aspects of formalin-fixed paraffin-embedded tissue sections as compared to cryostat sections.
In order to study the suitability of formalin-fixed paraffin-embedded brain tissue for vasopressin (AVP)-mRNA detection, we used symmetric halves of 5 human hypothalami. In every case, one half was formalin fixed for 10-35 days and paraffin embedded while the other half was frozen rapidly. Following in situ hybridization (ISH) histochemistry on systematically obtained sections of the supraoptic (SON) and paraventricular nucleus (PVN) of both halves, total amounts of AVP-mRNA in these nuclei were estimated using densitometry of film autoradiographs. Total amounts of radioactivity were found to vary considerably between patients and amounted to 1297 +/- 302 arbitrary units (AU) (PVN) (mean +/- SEM) and 2539 +/- 346 (SON) for the cryostat sections and 868 +/- 94 (PVN) and 1259 +/- 126 (SON) for the paraffin tissue. Variations introduced by the method itself yielded a coefficient of variation of only 0.19. Furthermore, a non-significant negative trend with postmortem delay was found in cryostat tissue, but not in paraffin sections. No effect of fixation time was observed in the paraffin tissue. Both ways of tissue treatment have specific advantages and disadvantages that may be different for other probes or other brain areas. For ISH of a highly abundant mRNA like AVP in a very heterogeneous brain area such as the human hypothalamus, formalin-fixed paraffin-embedded tissue sections can be used for quantitative analysis of entire brain nuclei because of the small variation in this tissue, the remarkably good signal recovery (some 75% as compared to cryostat sections) and its practical advantages with regards to anatomical orientation, storage and sampling of the tissue.
The human hypothalamus in development, sexual differentiation, aging and Alzheimer's disease.
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In situ hybridization histochemistry in the human hypothalamus.
We have seen that mRNA for several neuropeptides can be visualized at the microscopic level in human post-mortem brain tissues using in situ hybridization histochemistry and oligonucleotides as probes. The specificity of the hybridization signal detected in each case is supported by several criteria such as Northern blot analysis, use of at least two oligonucleotides complementary to different regions of the same target mRNA, cohybridization of labeled and excess unlabeled oligonucleotide probes, and melting curve analysis of the formed hybrids. Furthermore, factors such as age, post-mortem delay or gender did not show a significant effect in the levels of hybridization in the control population studied. Hybridization signals comparable to those found in the control population were obtained in frozen tissues, stored for up to 6 years before analysis. The results obtained for the different neuropeptides examined are, in general, in good agreement with the available information on their distribution and cellular localization as determined by radioimmunoassay or immunohistochemistry. The use of in situ hybridization histochemistry has clearly revealed the location of neurons synthesizing these neuropeptides, adding important information to that provided by radioimmunoassay or immunohistochemistry. A typical example is the identification of peptide synthesizing neuronal cell bodies by immunohistochemistry. This requires, in some cases, the use of treatments such as colchicine, obviously impossible with human brain tissues. The abundance of mRNA could be further related to transcriptional activity and, when compared with peptide levels, can provide some clues on peptide turnover rates. Thus in the hypothalamus, the paraventricular and supraoptic nuclei were found to contain cells expressing arginine-vasopressin and oxytocin mRNAs. Their distribution was in good agreement with that determined by immunohistochemistry (Dierickx and Vandesande, 1977). We have also found that these nuclei contain transcripts for neuropeptide genes such as preproenkephalin A, neuropeptide Y and somatostatin, in agreement with previously reported immunohistochemical data (Agid and Javoy-Agid, 1985; Emson et al., 1986). In the basal ganglia, numerous cells heterogeneously distributed throughout the caudate and putamen nuclei were found to contain preproenkephalin A mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
The human hypothalamo-neurohypophyseal system in relation to development, aging and Alzheimer's disease.
The research reviewed in the present paper indicates that vasopressin and oxytocin cells in the human HNS constitute an extremely stable population of neurons throughout the human life span. Increases in the activity of these cells, which are probably related to maturation of the system were observed during fetal development and probably extend well beyond term. During senescence an increase in the activity of the vasopressin cells in the human HNS was observed which is probably a compensation for age-related changes in kidney function. These data do not support a role of declining vasopressin secretion in age-related memory decline. Although there is some evidence for an impairment of vasopressin synthesis and release in Alzheimer patients, vasopressin cell numbers in Alzheimer's disease do not fall below values observed in young controls. Furthermore, peripheral administration of vasopressin or vasopressin analogues to AD patients have not yielded consistent results.
Testosterone locally increases vasopressin content but fails to restore choline acetyltransferase activity in other regions in the senescent male rat brain.
Age-related decreases have been reported in both vasopressinergic and cholinergic innervation in the rat brain. Since both systems are also sensitive to sex steroids, the effect of testosterone supplementation on vasopressin (AVP) levels and on choline acetyltransferase (ChAT) activity was investigated in the brains of young, middle-aged and aged male rats. Although no age-related changes in AVP levels were observed in the lateral septum or the medial amygdala (MA), peripheral testosterone administration raised AVP levels in the MA in all age groups. ChAT activity decreased with age in the medial preoptic area and was not restored by testosterone.
Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals.
Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.
Central monoamine metabolism in the male Brown-Norway rat in relation to aging and testosterone.
Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.
Morphometric analysis of the supraoptic nucleus in the human brain.
The supraoptic nucleus (SON) in the human hypothalamus is an elongated, densely packed collection of large neurosecretory cells. The size, shape and cellular morphology of the dorsolateral part of the SON was examined in relation to sex and age in adult subjects. In this region, the following parameters were measured: length of the rostrocaudal axis, maximum cross-sectional area, volume, numerical cell density, total cell number and the mean diameter of the cell nuclei. No sexual differences were observed in any of these parameters with the exception that males have a more elongated SON than females. In contrast to absolute size, sex-linked differences were found in the way the morphometric parameters are interrelated. Of the parameters investigated, only the number of cells in the SON showed significant changes with ageing. A striking increase in the total number of cells, by about 30%, was found between 40 and 65 years of age. A further increase in cell number was observed after the age of 65 years, as a result of which the nucleus contained, on average, 1.4 times as many cells in old subjects (65-90 years) as in young individuals (20-40 years). These findings suggest that a substantial proliferation of glial cells takes place in the human supraoptic nucleus with advancing age. Finally, the morphology of the SON was compared with that of other hypothalamic regions--the suprachiasmatic nucleus (SCN) and the paraventricular nucleus (PVN)--using the same material as that used in previous investigations in this series (Hofman et al. 1988; Hofman & Swaab, 1989).
Testosterone treatment restores reduced vasopressin-binding sites in the kidney of the ageing rat.
Young, middle-aged and aged rats received s.c. testosterone implants for 50-52 days in order to investigate whether supplementation of testosterone in aged rats could normalize the reported reduction of kidney arginine vasopressin (AVP)-binding sites and increase the plasma concentration of AVP. Receptor number, which was measured by means of a membrane-binding assay with [3H]AVP as ligand, was below the detection level in the untreated aged rat. Following testosterone treatment, no effects were seen in the youngest groups, but in the aged group AVP receptors became clearly detectable, albeit with a lower affinity. A remarkable observation was the increase in affinity for renal AVP binding in the middle-aged compared with the young rat. Plasma levels of AVP in control aged rats tended to be higher. Such a tendency was completely absent in the testosterone-treated aged rats. Possible mechanisms underlying the restoration of reduced AVP-binding sites in the kidney of the aged rat by testosterone treatment are discussed.
Changes in vasopressin neurons and fibers in aging and Alzheimer's disease: reversibility in the rat.
The neuropeptide vasopressin (VP) is released from the neurohypophysis into the circulation where it acts as antidiuretic hormone on the kidney. In addition, VP is present in nerve cells and fibers in several areas in the rodent and primate brain where it acts as a neurotransmitter or neuromodulator. In the human brain a marked decrease in total cell number and VP cell number was observed in senescence in the suprachiasmatic nucleus, the hypothalamic nucleus regulating circadian rhythms. This degeneration was even more pronounced in Alzheimer's disease (AD) and might be related to the disturbances in sleep-wake cycle and endocrine rhythms which occur in this condition. No degenerative changes were observed with aging or in AD in the human hypothalamo-neurohypophyseal system (HNS); on the contrary, total cell numbers remain unaltered and the VP cells in this system are activated in senescence, probably in compensation for decreased sensitivity of the kidney to VP. It is proposed that this activation may prevent degeneration of the VP cells in the HNS. The extrahypothalamic VP innervation in the male rat brain was shown to be diminished in senescence in a number of areas. This innervation, which was previously shown to depend on plasma levels of sex-steroids, could be restored in a number of brain structures by subcutaneous testosterone administration to senescent male rats for one month. Reversibility of changes in VP innervation in the senescent rat brain through peripheral testosterone supplementation might open new possibilities for the development of therapeutic strategies in age-related disorders of the central nervous system.