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Biomedical subjects

S Vanhatalo

Publications and source records attributed to S Vanhatalo.

At least 37 records · Page 2Linked to original sources
PubMed2000

Markedly elevated nitrate/nitrite levels in the cerebrospinal fluid of children with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome).

PURPOSE: To compare the levels of brain nitric oxide production in patients with PEHO or PEHO-like syndrome and in controls with other neurologic disease. METHODS: Nitric oxide metabolites, nitrates, and nitrites (NNx), were measured in the cerebrospinal fluid (CSF) of children with PEHO syndrome or PEHO-like syndrome, and in controls with other neurologic diseases. RESULTS: The NNx levels were markedly higher in both PEHO (mean, 48 microM; p < 0.001) and PEHO-like (22 microM; p < 0.003) patients as compared with the controls (6 microM), but did not correlate with age or with brain atrophy or CSF levels of insulin-like growth factor-1 (IGF-1). CONCLUSIONS: Our findings suggest that in PEHO syndrome, production of nitric oxide is markedly increased, suggesting that nitric oxide is involved in the pathologic phenomena (i.e., seizures and neurodegeneration) of the disease.

Adolescent↗
PubMed1999

Age-related augmentation of the dehydration-induced increase in the supraoptic nitric oxide synthase activity in rats.

Hypothalamic supraoptic nucleus (SON) neurons express nitric oxide synthase (NOS) in an activity-dependent manner. In the present study, the effect of aging on the NOS expression of the SON neurons, as detected by nicotinamide adenine dinucleotide phosphate-diaphorase activity, was studied under normal conditions and under dehydration stress induced by salt loading. In the control rats, the number of stained neurons did not differ between the two age groups. Dehydration resulted in an increase in both the number of staining neurons and in the staining intensity in both 2- and 14-16-month-old rats. Furthermore, dehydration-induced NOS expression was significantly higher in the older animals. The results suggest that the response to dehydration, as indicated by increased NOS activity in the supraoptic nucleus, is enhanced in the aging rat.

Age Factors↗
PubMed1999

Inducible expression of tryptophan hydroxylase without serotonin synthesis in hypothalamic dopaminergic neurons.

In the present study we have further studied the previous findings that rat hypothalamic dopaminergic neuronal cell groups may express tryptophan hydroxylase (TpH), the serotonin synthesizing enzyme, without a detectable serotonin synthesis. Chemical and mechanical neuronal injuries, namely colchicine treatment and axonal transection, respectively, were performed, and distributions of neurons exhibiting immunoreactivity for TpH and/or tyrosine hydroxylase (TH), the dopamine synthesizing enzyme, were analyzed throughout the hypothalamic periventricular and arcuate nuclei. After colchicine treatment there was a statistically significant 87% (P = 0,01) increase in the number of TpH expressing neurons, while TH expression remained essentially similar. Axonal transection resulted also in a statistically significant 131% (P < 0,01) increase in the number of TpH expressing neurons, while TH expression was not significantly altered. All TpH expression coexisted with TH expression, and the induction of TpH expression by neuronal injuries occurred evenly throughout the rostrocaudal length of the territory studied. A possible serotonin synthesis by TpH was examined by giving drugs that increase brain serotonin synthesis, but no immunohistochemically detectable serotonin synthesis could be found in any of the TpH expressing neurons. Finally the possibility was studied that the relative shortage of the cofactor tetrahydrobiopterin would limit serotonin synthesis. However, an administration of tetrahydrobiopterin did not result in detectable serotonin synthesis in these neurons. Taken together these results suggest that dopaminergic neurons in the hypothalamic periventricular and arcuate nuclei are able to express TpH, this expression is induced after neuronal injury, and this induction occurs similarly throughout the territories studied. TpH expression occurs independently of TH expression, and the newly expressed TpH appears not to synthesize serotonin, regardless of pharmacological pretreatments. Thus, our findings (i) support the idea that neurons may possess inducible expression of nonfunctional transmitter-synthesizing enzymes, in this case TpH, and (ii) suggest that expression of an enzyme synthesizing a certain transmitter may not necessarily imply the corresponding transmitter phenotype.

Animals↗
PubMed1998

Colchicine differentially induces the expressions of nitric oxide synthases in central and peripheral catecholaminergic neurons.

This study was aimed at elucidating differences in nerve injury induced expression of nitric oxide synthases (NOS) between the peripheral and central catecholaminergic neurons. Colchicine was used to disrupt chemically the neuronal cytoskeletal integrity. A marked increase in the expression of neuronal NOS-IR and NADPH-diaphorase activity, a marker of neuronal NOS (nNOS), was seen in distinct populations of post-ganglionic sympathetic neurons of the superior cervical ganglion after intraganglionic colchicine injection. Similarly, immunoreactivity for the inducible form of NOS (iNOS) was induced in some sympathetic neuron somata. However, this immunoreactivity did not coincide with nNOS-IR. In contrast to the sympathetic neurons, hypothalamic arcuate and periventricular dopaminergic neurons did not show NOS-IR or NADPH-DA either in intact animals or in animals treated with an intracerebroventricular injection of colchicine. Immunoreactivity for the inducible form of NOS revealed no neuronal staining in the hypothalamic neurons in either group, while a large number of glia-resembling cells around the third ventricle showed slight expression of iNOS-IR. The present results show that expression of both neuronal and inducible forms of NOS may be induced by colchicine in some catecholaminergic neurons. It is suggested that these inductions are specific to certain catecholaminergic neuronal systems, like the sympathetic neurons, rather than a general property of catecholaminergic neurons.

Animals↗
PubMed1998

The ontogenic appearance of tyrosine hydroxylase-, serotonin-, gamma-aminobutyric acid-, calcitonin gene-related peptide-, substance P-, and synaptophysin-immunoreactivity in rat pituitary gland.

The initial appearance of tyrosine hydroxylase (TH)-, serotonin (5-HT)-, gamma-aminobutyric acid (GABA)-, calcitonin gene-related peptide- (CGRP), substance P-, and synaptophysin-immunoreactivity in the rat pituitary gland, and in the related brain regions was investigated. Several groups of TH-immunoreactive neurons were first detected in the brain stem on day E17, and in the hypothalamus on day E18, followed by TH-immunoreactivity in the median eminence and infundibulum on E19-E20. TH-positive fibers appeared in the posterior lobe on day E20 and in the intermediate lobe on day P0. 5-HT-immunoreactivity was first detected on day E17 in neurons and nerve fibers in the brain stem and in the median eminence, respectively. On day E18, a few 5-HT-immunoreactive fibers were detected in the posterior lobe of the pituitary, although they were consistently seen in the infundibulum from day E19. In newborn rats, some 5-HT-immunoreactive fibers, but no neurons, were seen in the hypothalamus. GABA immunoreactivity appeared on day E17 in several nerve fibers of the infundibulum and the posterior lobe. Some neurons in the cortex and ventral hypothalamus transiently expressed GABA-immunoreactivity on day E17. In newborn rats, a plexus of GABA-immunoreactive fibers was detected for the first time in the intermediate lobe. No CGRP-immunoreactive fibers could be detected in the prenatal pituitary. On day P10, CGRP-immunoreactive fibers were first observed in the anterior lobe. Later their number considerably increased, while only sporadic fibers could be found in the intermediate or posterior lobes. No substance P-immunoreactivity could be detected in any of the lobes in the embryonic or developing postnatal rat pituitary, instead the adult anterior lobe occasionally showed some substance P-immunoreactive fibers. Synaptophysin-immunoreactivity was first detected in the posterior lobe on day E20, followed shortly by its expression in the intermediate lobe in newborn rats. The time course of GABA and 5-HT expression revealed in the present study suggests that these transmitters, which are initially expressed in the developing pituitary clearly before synaptic maturation, may act as trophic molecules during the prenatal period.

Animals↗
PubMed1998

Serotonin is not synthesized, but specifically transported in the neurons of the hypothalamic dorsomedial nucleus.

A small group of neurons in the hypothalamic dorsomedial nucleus (DMN) have been reported to contain serotonin after pharmacological treatments enhancing brain serotonin levels. This study aimed at elucidating whether these neurons are able to synthesize serotonin de novo, and whether they possess a specific serotonin transport mechanism. Serotonin content in these neurons was raised by administration of L-tryptophan and pargyline. Double immunostaining for serotonin and tryptophan hydroxylase (TpOH), the serotonin synthesizing enzyme, revealed that none of the serotonin-containing neuronal somata expressed TpOH. Intracerebroventricular colchicine treatment did not result in TpOH-IR in these neurons. Fluoxetine, a specific serotonin transport inhibitor, prevented the accumulation of serotonin in these neurons. The present results thus indicate that the serotonin-containing DMN neurons are not able to synthesize serotonin. Instead, they take up exogenous serotonin via a specific serotonin transport mechanism. As serotonin and DMN are associated with various physiological functions, such as regulation of food intake and modulation of fear and anxiety, the mechanisms revealed in the present study may participate in these clinically important brain functions.

Animals↗
PubMed1998

The concept of chemical neurotransmission--variations on the theme.

The present concept of chemical neurotransmission occurring purely through synaptic transmission has dominated neurobiological thinking for about the last 40 years. According to this conventional view neurotransmitters are substances that are synthesized within the neurones, liberated into the synaptic cleft after stimulation of the nerve, and that finally elicit a biologically plausible response in the postsynaptic target cell or the nerve terminal itself. This concept undoubtedly comprises the main body of interneuronal chemical signalling. However, a large amount of evidence, obtained during the last two decades, suggests that there are a number of parallel mechanisms, which may essentially participate in neuronal signalling, or at least modulate it. Thus, the recent progress of research has provided the following compelling evidence: 1) a large variety of substances, some of them synthesized in non-neuronal cells, actually participate actively in neuronal signalling; 2) functional connections in brain are not determined by the synaptic connections only; 3) glial cells have an active and fundamental role in signal transmission; and 4) the signalling properties and mechanisms of each neurone are constantly under functional and structural regulation. The aim of this review is to present shortly some of the central concepts and/or mechanisms that have risen during the last two decades. Also the functional and/or clinical relevance of these mechanisms is addressed briefly.

Animals↗
PubMed1998

Long-term treatment with GM-CSF in patients with chronic lymphocytic leukemia and recurrent neutropenic infections.

In this prospective study we evaluated the multiple effects of long-term GM-CSF therapy on blood counts, granulocyte functions and disease progression in patients with chronic lymphocytic leukemia (CLL) with chronic neutropenia and recurrent bacterial infections. The treatment duration varied from 2 to 12 weeks. The neutrophil count was raised in all patients, by the median of 6.6-fold. The neutrophil level of 1.0 x 10(9)/l was usually reached after two weeks. The initial dose of GM-CSF was 5 microg/kg/day, and 1-7 microg/kg/day was required to maintain the neutrophil level above 1.0 x 10(9)/l. Granulocyte functions, i.e. chemiluminescence (CL), random migration, and fMLP-stimulated chemotaxis were initially depressed in all patients when compared to healthy controls. GM-CSF enhanced significantly CL even when given at small doses (less than 1 microg/kg/day), even lower than the dose required to promote granulopoiesis. We conclude that GM-CSF is effective in improving CLL associated chronic neutropenia and also enhances impaired granulocyte chemiluminescence. Thus, GM-CSF could be helpful for giving chemotherapy without neutropenic delays and for prophylaxis of infectious complications in CLL patients.

Aged↗
PubMed1997

Expression of nitric oxide synthase in hypothalamic nuclei following axonal injury or colchicine treatment.

Nitric oxide (NO) has recently gained much attention due to its apparently double-edged role in neuronal injury. This study was aimed at elucidating neuronal nitric oxide synthase (nNOS) expression in the brain after two types of injury, namely axonal transection and colchicine treatment. The neurosecretory hypothalamo-pituitary pathway served as a model for the reaction of central neurons to these two types of injury. Axonal transection, i.e., pituitary stalk section, resulted in a qualitative increase in NOS content in the supraoptic and paraventricular nuclei. In these nuclei, there was also an increase in the number of NOS-expressing neurons after the operation. Surprisingly, in the periventricular nucleus, a strong decrease in the number of NOS-positive magnocellular neurons was observed in the anterior part of the nucleus. Intracerebroventricular injection of colchicine resulted in an increase in the cell count in the paraventricular nucleus, while the other nuclei remained unchanged. Our results suggest that axonal injury results in an increase in nNOS expression in the major neurosecretory nuclei, while the periventricular nucleus shows the opposite reaction. Colchicine treatment has an effect similar to that of axotomy in the major neurosecretory nuclei, suggesting that an increase in NOS expression may be induced by interrupted axonal transport. In the periventricular nucleus, the decrease in the number of NOS-containing neurons suggests differences among hypothalamic NOS-containing neuron groups in response to neuronal injury.

Animals↗
PubMed1997

Peptide GEGLSS-like immunoreactivity in the rat central nervous system.

A rabbit antiserum was raised against the N-terminal fragment peptide, GEGLSS (Gly-Glu-Gly-Leu-Ser-Ser) of bovine neuropeptide AF (NPAF, A18Famide). NPAF is an octadecapeptide isolated from the bovine brain together with neuropeptide FF (NPFF). GEGLSS-like immunoreactivity was localized with immunofluorescence technique in colchicine-treated rats in neuronal cell bodies of the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. A few neurons were also observed in the retrochiasmatic part of the SON. GEGLSS-like immunoreactivity was also localized to nerve terminals of the posterior pituitary. No GEGLSS-ir neuronal cell bodies were observed in the medial hypothalamus, in an area that contains NPFF-ir neurons. GEGLSS immunoreactivity was also seen in the fibers and terminals of nucleus of the solitary tract. We injected a retrograde tracer, fluorogold, to the posterior pituitary gland and visualized GEGLSS-ir neuronal cell bodies double-labeled with the tracer in SON, PVN, and SOR. The pituitary stalk transsection totally abolished the GEGLSS-ir structures from the posterior pituitary. Our results suggest that GEGLSS immunoreactivity in the rat brain has a more limited distribution than NPFF immunoreactivity. GEGLSS immunoreactivity was partially colocalized with arginine-vasopressin and oxytocin in neuronal cell bodies in the SON and PVN. Considering the fact that the known rat NPFF-NPAF precursor does not contain GEGLSS structure, the detected GEGLSS immunoreactivity may be derived from a previously unknown precursor.

Animals↗
PubMed1997

Effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on chemotherapy-induced myelosuppression in patients with chronic lymphocytic leukemia: a crossover study.

Patients with advanced, refractory chronic lymphocytic leukemia (CLL) have an high morbidity and mortality from infections following chemotherapy-induced myelosuppression. A crossover study on the prophylactic effect of GM-CSF therapy on neutropenia was carried out in 12 patients with advanced CLL. The patients received GM-CSF in association with every second cycle of COP (cyclophosphamide, vincristine, prednisone) chemotherapy. A total of 40 COP cycles were analyzed. Blood neutrophil levels were significantly higher two to three weeks after the first COP cycle followed by GM-CSF (medians 2.24 and 5.47 x 10(9)/l) when compared to the first cycle without GM-CSF support (0.59 and 0.75 x 10(9)/l; p < 0.0195 and <0.002, respectively). In the next two cycles the same tendency persisted, although the difference was not statistically significant. There were no significant differences in the number of febrile days, days on intravenous antibiotics, hospitalization days, or the number of red blood cell transfusions. Mortality during COP treatment was 8%. In conclusion, GM-CSF efficiently ameliorates chemotherapy-induced neutropenia in CLL patients with a poor bone marrow reserve due to advanced disease.

Adult↗
PubMed1996

Anoxic terminal negative DC-shift in human neocortical slices in vitro.

In animal models, the hallmark of a hypoxic condition is a strong negative shift of the DC potential (anoxic terminal negativity, ATN). This DC-shift is interpreted to be primarily due to a breakdown of the membrane potential of neurons. Such massive neuronal depolarizations have not been reported for all human neocortical neurons in vitro even during prolonged hypoxic periods. This poses the question whether ATN develop also in human neocortical slices made hypoxic. ATN could be observed when human brain slice preparations (n = 15, 13 patients) were subjected to periods of hypoxia (10 to 120 min). These ATN were usually monophasic and appeared with a latency of 16 +/- 4 min (mean +/- S.E.M.). Separating the ATN according to their slopes of rise, steep (> 10 mV/min) and flat (< 10 mV/min) ATN could be distinguished. Steep and flat ATN may be regarded as two different entities of reactions since steep ATN had also greater amplitudes and slopes of decay as compared a flat ATN. With repetitive hypoxias, the latency of both the steep and flat ATN was reduced for the following hypoxic episodes. During hypoxic DC-shifts, evoked potentials were suppressed. With the 1st through 4th hypoxia, they recovered fully within 30 min after reoxygenation when hypoxia was terminated at the plateau of ATN; with extension of hypoxia, recovery was only partial. From the 5th hypoxia onwards, recovery usually did not take place or was not complete.

Adolescent↗
PubMed1996

Superfluous expression of tryptophan hydroxylase in the zona incerta dopaminergic neurones.

We studied by double labelling the relationship between tryptophan hydroxylase-immunoreactive (TpOH-IR) neurones and A13 dopaminergic neurones in the zona incerta (ZI). TpOH-IR in the ZI was dramatically increased after colchicine treatment. While all of the TpOH-IR neurones exhibited also tyrosine hydroxylase-immunoreactivity (TH-IR), a marker of dopaminergic neurones, less than half (46%; n = 794) of the A13 TH-IR neurones in the ZI showed TpOH-IR. None of these neurones were immunoreactive, however, for serotonin either in intact animals or in animals pretreated with serotonin precursor L-tryptophan and the monoamine oxidase inhibitor pargyline. Thus, the neurones of the A13 dopaminergic group in the ZI expressing TpOH are unable to synthesize serotonin. These findings support the idea that neurones may superfluously express non-functional transmitter synthesizing enzymes, in this case TpOH, and suggest that expression of an enzyme synthesizing a certain transmitter does not necessarily confirm the corresponding transmitter phenotype.

Animals↗
PubMed1996

Pituitary gland receives both central and peripheral neuropeptide Y innervation.

Neuropeptide Y (NPY)-containing neural projections to the rat pituitary gland were studied by combining NPY immunohistochemistry with retrograde tracing with Fluorogold as well as central and peripheral denervations. Numerous pituitary-projecting, i.e. Fluorogold-labelled, neurons in the superior cervical ganglion, as well as in the hypothalamic magnocellular nuclei were NPY-immunoreactive (NPY-IR). In contrast, no other hypothalamic NPY-IR neurons, e.g. in the arcuate nucleus or the preoptic area, were observed to be projecting into the pituitary. Within the posterior lobe of the pituitary gland two morphologically distinct NPY-IR fiber populations were discovered, namely thinner parenchymal terminals, distinct from the neurosecretory terminals, and thicker, perivascular fibers. Neurosecretory nerve terminals, in contrast, were devoid of NPY-IR, being consistent with the previous reports on their sensitivity to osmotic stimulation. On the other hand, the anterior and intermediate lobes contained no NPY-IR fibers. Bilateral extirpation of the superior cervical ganglion resulted in disappearance of the perivascular NPY-IR fibers leaving the parenchymal NPY-IR fibers unaffected, while transection of the pituitary stalk abolished all of the parenchymal NPY-IR neurons, leaving the perivascular fibers unaffected. These findings together with the observed colocalization of tyrosine hydroxylase and NPY in the posterior lobe perivascular fibers indicated that they are sympathetic nerve endings. The thin parenchymal terminals, instead, are suggested to stem from central sources other than hypothalamus. Our findings indicate that the pituitary gland receives NPY-containing innervation from at least three distinct sources, and NPY may thus affect pituitary functions in various ways, such as blood flow and vasopressin release.

Animals↗
PubMed1996

Nitric oxide synthase in the autonomic and sensory ganglia innervating the submandibular salivary gland.

This article reviews the neuroanatomical studies on the distribution of nitric oxide synthase (NOS) in neurons and nerve fibers innervating the submandibular gland. Specificity of NADPH-diaphorase activity as a histochemical marker of neuronal NOS is discussed in light of corresponding NOS immunoreactivity. Anatomical data suggest that nitric oxide may affect neural regulation of the submandibular gland through both sympathetic, parasympathetic and sensory divisions of the autonomic nervous system. NOS-containing nerve terminals in the gland parenchyme are mainly vascular and either parasympathetic and/or sensory in nature, while sympathetic terminals lack NOS. Most postganglionic parasympathetic neurons are intensely NOS-immunoreactive. Some of the preganglionic parasympathetic neurons show vague reactivity, while their terminals in the submandibular ganglia stain heavily. The postganglionic sympathetic neurons normally show only barely visible reactivity, while manipulations interrupting axonal continuity increase neuronal NOS content. A subpopulation of the preganglionic sympathetic neurons and their terminals are intensely reactive. The observations summarized here suggest that nitric oxide participates in the control of blood flow through the gland, while direct effect on secretion is unlikely.

Animals↗