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PubMed2002

Genetic factors associated with the absence of atherosclerosis in octogenarians.

BACKGROUND: Atherosclerosis (ATS) is a common age-related disease of large arteries. The prevalence of older subjects with vascular successful aging (VaSA), defined as the absence of clinical symptoms and instrumental signs of ATS, is low in Western countries. The possible contribution of genetics to the VaSA phenomenon is not known. METHODS: We investigated the distribution of four genetic polymorphisms (angiotensin converting enzyme [ACE], methylenetetrahydrofolate reductase [MTHFR], apolipoprotein E [apo E], and paraoxonase [PON] genes) in 30 subjects with VaSA, 30 subjects with moderate carotid atherosclerosis (ATS group), and 161 controls with a negative history for cardiovascular disease. Clinical examination; ultrasonographic examination of carotid, vertebral, abdominal aortic, iliac, and femoral arteries; and electrocardiogram were performed. RESULTS: The frequency of PON 192 B allele was lower in VaSA patients (13%) compared with ATS patients (37%) and controls (46%) ( p =.06 and.006, respectively); B/B homozygotes were 27% in the ATS group, 12% in controls, and 0% in the VaSA group. The frequency of the MTHFR thermolable + allele was higher in VaSA (0.51) compared with ATS (0.39) and controls (0.40) (VaSA vs C, p =.006). No differences in the distribution of ACE I/D and apo E alleles emerged between the three groups. CONCLUSIONS: The low prevalence of the PON 192 B allele in the VaSA subjects suggests that this polymorphism might have an important role in VaSA, probably by hydrolyzing lipid peroxides and thus preventing low-density lipoprotein from undergoing the oxidative modification. This finding further supports the oxidative hypothesis of ATS.

Aged↗
PubMed1995

Regulation of prolactin receptor expression by estradiol in the female rat brain.

Prolactin (PRL) receptors have been identified in many tissues, including the brain, but little is known about their distribution and regulation. In the female rat brain, ovariectomy significantly (p < 0.05) decreased PRL binding capacity, but not the affinity, in the hypothalamus and pons-medulla. Using reverse transcription and polymerase chain reaction (RT-PCR) amplification and Western blot analyses we found both the long and short forms of the PRL receptor mRNAs and proteins in the hypothalamus, pons-medulla and cortex in the female rat. Ovariectomy decreased the expression of short, but not the long form of the PRL receptor in the hypothalamus and pons-medulla, but not the cortex. Administration of estradiol (1.0 mg per 100 g b.w.) restored the PRL binding capacity, protein and mRNA levels of the short form of the receptor back to control levels. These results suggest that the expression and distribution of PRL receptors in the brain are differentially regulated in specific brain regions.

Animals↗
PubMedDate not supplied

Magnetization transfer imaging of the pituitary: further insights into the nature of the posterior "bright spot".

PURPOSE: After more than a decade of investigation, the chemical nature of the posterior pituitary "bright spot" remains elusive. Speculations into the source of this high signal have included relaxation of water by phospholipid vesicles, vasopressin, paramagnetic substances, and membrane-associated proteins. We hypothesized that if the T1 shortening observed in this structure were caused by water/macromolecular interactions, this interaction could be modulated by the use of magnetization transfer (MT) saturation. METHOD: Twenty-five normal subjects were recruited over a 2 month period who were identified on routine T1 sagittal head images to have pituitary bright spots with cross-sectional area of > 2 mm2. Thin section (4 mm), T1-weighted (SE 450/20) sagittal MR images were obtained both with and without the use of an MT suppression pulse (1,000 Hz offset, 200 Hz bandwidth, peak amplitude 7.3 microT). Region-of-interest measurements were made of the posterior pituitary lobe, anterior pituitary lobe, genu of corpus callosum, and pons, with MT ratios (MTRs) calculated for each structure. RESULTS: Relatively low (and similar) MTRs were observed in both parts of the pituitary gland: anterior lobe, 12.3%; posterior lobe 10.8%. Paired t test analysis demonstrated no statistically significant difference between the MTRs of the anterior and posterior pituitary lobes (p = 0.23). Considerable suppression of signal was noted in the genu (MTR = 25.0%) and pons (MTR = 21.9%). The MTRs of both portions of the pituitary differed significantly from those of the genu and pons (p < 0.00001). CONCLUSION: The high signal of the posterior pituitary gland suppresses only slightly on MT images, having a behavior similar to that in the anterior lobe but significantly different from the rest of the brain. These findings suggest that direct water/macromolecule, water/membrane, or water/phospholipid interactions are not likely to be responsible for the appearance of the bright spot. The experimental results are more consistent with water interacting with a paramagnetic substance or low molecular weight molecule (e.g., vasopressin, neurophysins).

Adolescent↗
PubMed1988

Synthesis of catecholamines in the hypothalamus and brainstem in one-kidney, one clip and two-kidney, one clip hypertension in rabbits.

In order to examine the role of central catecholaminergic neurons in hypertension, the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, was studied in the hypothalamus, midbrain, pons-upper medulla, mid-medulla and lower medulla of one-kidney, one clip (1-K,1C) and two-kidney, one clip (2-K,1C) hypertensive rabbits and their respective operated controls (1-K,1 Cc and 2-K,1 Cc). Comparing the 1-K,1 C group to the 1-K, 1 Cc group, the activity of TH was increased by 79% in the hypothalamus (P less than 0.02), 37% in the mid-medulla region (P less than 0.02) and was unchanged in the midbrain, pons-upper medulla and the lower medulla. Comparing the 2-K,1 C group to the 2-K,1 Cc group, the activity of TH was increased by 89% in the mid-medulla (P less than 0.01), decreased by 36% in the pons-upper medulla (P less than 0.01) and unchanged in the hypothalamus, midbrain and lower medulla. These results indicate that similarities and differences exist in the contribution of central catecholaminergic neurons to the pathophysiology of 1-K,1 C and 2-K,1 C hypertension in rabbits.

Animals↗
PubMed2002

Cervical kyphosis: predictive factors for progression of kyphosis and myelopathy.

STUDY DESIGN: A retrospective study of 13 patients with cervical kyphosis. The authors propose new methods of measuring spinal cord compression and predicting the progression of kyphosis. OBJECTIVES: To ascertain predictive factors for progression of cervical kyphosis and myelopathy. SUMMARY OF BACKGROUND DATA: Cervical kyphosis may be congenital, result from decompression surgery, or occur as a posttraumatic deformity. Although there is the potential for progressive deformity and the development of myelopathy in all these situations, there are few previous reports of predictive factors for progression of cervical kyphosis and myelopathy in patients with cervical kyphosis. METHODS: The authors studied radiographs and magnetic resonance imaging scans of 13 patients with cervical kyphosis, including 9 who had been operated on and had postsurgical secondary kyphosis, and 4 with idiopathic kyphosis without any of the above causes. Compression of the spinal cord at the apex of the cervical kyphosis was evaluated by magnetic resonance imaging of the ratio between the anteroposterior diameter of the medulla-pons junction and the spinal cord at the apex. RESULTS: The mean ratio between the anteroposterior diameter of the medulla-pons junction and the spinal cord at the apex in five patients in whom myelopathy did not develop was 0.37, and was 0.21 in the patients in whom myelopathy developed. Progression of cervical kyphosis was associated with osteophyte formation at the anterior aspect of the vertebral body. CONCLUSION: A ratio below 0.3 between the anteroposterior diameter of the medulla-pons junction and the spinal cord at the apex was a risk factor for cervical myelopathy. One of the most predictable risk factors of progression of the cervical kyphosis was osteophyte formation at the anterior aspect of the vertebral body.

Adolescent↗
PubMed2002

Association of lipids, lipoproteins, apolipoproteins and paraoxonase enzyme activity with premature coronary artery disease.

BACKGROUND AND DESIGN: The association of serum apolipoprotein (apo) A-I and apo B concentrations and paraoxonase (PON) enzyme activity with angiographically determined coronary artery disease (CAD) was investigated in Iranian non-diabetic patients with premature CAD and control participants in a sex- and age-matched case-control study. METHODS: The study population consisted of 59 non-diabetic patients with premature CAD and 55 CAD control participants. Premature CAD was defined as the presence of angiographically proven coronary stenosis (> or =50% involvement) in men and women younger than 55 and 65 years, respectively. Apolipoprotein concentrations were measured by immunoturbidometric assay and paraoxonase/arylesterase activities by spectrophotometric assay of p-nitrophenol/phenol production following addition of paraoxon/phenylacetate to serum. RESULTS: In CAD patients, increased concentrations of total cholesterol (215 +/- 43 compared with 193 +/- 43, P < 0.001), low-density lipoprotein cholesterol (137 +/- 46 compared with 116 +/- 39, P < 0.05) and apo B (102 +/- 24 compared with 84 +/- 17, P < 0.001) and a decreased ratio of apo A-I/apo B (1.7 +/- 0.4 compared with 2.0 +/- 0.6, P < 0.001) were observed compared to the control group. Other study variables were not significantly different between the two groups. On multiple logistic regression analysis, the only marker for discrimination between the CAD+ group and the CAD- control group was apo B level. CONCLUSIONS: In Iranian non-diabetic patients with premature CAD, the concentration of apo B is a better marker than traditional lipids in discriminating between CAD+ and CAD- patients. The lack of significant difference in PON activity between CAD patients and control participants supports the concept of interethnic variability in PON activity and gene polymorphism observed in other studies.

Adult↗
PubMed2006

Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy.

A 77-year-old woman presenting with progressive visual loss in both eyes was found to have small cell lung cancer. Assay for collapsin response-mediating protein (CRMP) -5 was positive suggesting a paraneoplastic optic neuropathy (PON). During treatment of the small cell lung cancer, the patient died of pneumonia and autopsy disclosed neuropathologic abnormalities consistent with PON. This is only the second case of CRMP-5-confirmed PON to report neuropathologic findings.

Aged↗
PubMed2004

Association of serum paraoxonase activity with insulin sensitivity and oxidative stress in hyperthyroid and TSH-suppressed nodular goitre patients.

OBJECTIVE: Low serum paraoxonase (PON) activity is thought to be a risk factor for the development of atherosclerosis. The present study was designed to evaluate PON1 activity and its relationship with preatherosclerotic markers such as lipid peroxidation and insulin resistance in hyperthyroid patients before and after propylthiouracil (PTU) treatment and in subjects with iatrogenic subclinical hyperthyroidism. PATIENTS AND DESIGN: Twenty patients with hyperthyroidism, 20 patients with euthyroid multinodular goiter (MNG) and 20 age- and sex-matched healthy controls were enrolled in the study. Insulin sensitivity index, PON activity and lipid peroxidation were measured at baseline and 2 months after achieving euthyroidism or subclinical hyperthyroidism. Levothyroxine was given as a part of TSH suppression therapy in multinodular goitre patients. MEASUREMENTS: Insulin sensitivity was determined by an oral glucose tolerance test (OGTT) based on the insulin sensitivity index (ISI) formula, serum paraoxonase activity was determined with a spectrophotometric method. Lipid peroxidation was measured by the formation of thiobarbituric acid reactive substances (TBARs). RESULTS: ISI was significantly lower in the hyperthyroid group than baseline levels in MNG patients and controls (P < 0.001). While ISI increased after treatment in the hyperthyroid group (P < 0.01), it significantly decreased with L-T4 treatment in the MNG group (P < 0.01). Serum paraoxonase activity was significantly lower in the hyperthyroid group before treatment than baseline and final measurements of other groups (P < 0.05). While PON activity increased after restoration of the euthyroid state in the hyperthyroid group (P < 0.05), it decreased with L-T4 treatment in the MNG group (P < 0.05). Lipid peroxidation was significantly higher in hyperthyroid group compared to baseline levels of other groups (P < 0.05). It decreased after treatment in the hyperthyroid group (P < 0.05) but a significant increase was observed following L-T4 treatment in the MNG group (P < 0.05). Serum paraoxonase activity was found to be negatively correlated with serum TT4 (r = -0.32, P = 0.003), TT3 levels (r = -0.31, P = 0.004), TBARs levels (r = 0.32, P = 0.003) and positively correlated with ISI (r = 0.35, P = 0.001) and high-density lipoprotein (HDL) cholesterol levels (r = 0.35, P = 0.0011) in the hyperthyroid and MNG groups. CONCLUSIONS: Iatrogenic thyroid hormone excess seems to mimic the effects of endogenous thyroid hormone excess on paraoxonase activity, insulin sensitivity and oxidative stress. These findings suggest that TSH suppression with levothyroxine may increase oxidative stress and LDL oxidation and thereby promote atherogenesis.

Adult↗
PubMed1986

Linkage between the loci for cystic fibrosis and paraoxonase.

In a material of 22 Danish, 26 Canadian, 10 Australian, 5 English and 5 American families with at least 2 children affected with cystic fibrosis (CF) a combined positive LOD score of 3.46 was found for the relationship cystic fibrosis-paraoxonase (PON) at recombination fraction theta = 0.07 in males and theta = 0.13 in females. Assuming a three allele model for PON the LOD score was 4.50 at the same recombination fractions. This confirms our earlier finding of an indication of CF-PON synteny.

Alleles↗
PubMed1991

Neuroanatomical correlates of skin conductance orienting in normal humans: a magnetic resonance imaging study.

Although little is known about the neuroanatomical basis of skin conductance orienting in intact normal humans, the limited literature on animals and humans with neurological and clinical disorders implicate prefrontal, temporal/amygdala, and pons brain areas in mediating skin conductance orienting. This study relates area of these structures using magnetic resonance imaging techniques to skin conductance orienting responses in 17 normal humans in order to test hypotheses that larger area of these excitatory structures will be associated with more orienting responses. Left and right hand skin conductance orienting was significantly associated with left and right prefrontal area (r = .44-.60), area of the pons (r = .43-.54), and left but not right temporal/amygdala area (r = .47-.53). No relationships were observed with areas thought to be unrelated to skin conductance activity (cerebellum, nonfrontal cortical area), medial prefrontal cortex, or the third ventricle. This appears to be the first study relating brain structure to skin conductance orienting in intact normal humans. Although preliminary at the present time, these results implicate prefrontal, pons, and temporal/amygdala areas in the mediation of skin conductance orienting in normal humans.

Adult↗
PubMed1984

Regional development of glutamate dehydrogenase in the rat brain.

The development of glutamate dehydrogenase enzyme activity in rat brain regions has been followed from the late foetal stage to the adult and through to the aged (greater than 2 years) adult. In the adult brain the enzyme activity was greatest in the medulla oblongata and pons greater than midbrain = hypothalamus greater than cerebellum = striatum = cortex. In the aged adult brain, glutamate dehydrogenase activity was significantly lower in the medulla oblongata and pons when compared to the 90-day-old adult value, but not in other regions. The enzyme-specific activity of nonsynaptic (free) mitochondria purified from the medulla oblongata and pons of 90-day-old animals was about twice that of mitochondria purified from the striatum and the cortex. The specific activity of the enzyme in synaptic mitochondria purified from the above three brain regions, however, remained almost constant.

Age Factors↗
PubMed1987

High-affinity transport of gamma-aminobutyric acid, glycine, taurine, L-aspartic acid, and L-glutamic acid in synaptosomal (P2) tissue: a kinetic and substrate specificity analysis.

In a cortical P2 fraction, [14C]gamma-aminobutyric acid ([14C]GABA), [14C]glycine, [14C]taurine, and [14C]glutamic and [14C]aspartic acids are transported by four separate high-affinity transport systems with L-glutamic acid and L-aspartic acid transported by a common system. GABA transport in cortical synaptosomal tissue occurs by one high-affinity system, with no second, low-affinity, transport system detectable. Only one high-affinity system is observed for the transport of aspartic/glutamic acids; as with GABA transport, no low-affinity transport is detectable. In the uptake of taurine and glycine (cerebral cortex and pons-medulla-spinal cord) both high- and low-affinity transport processes could be detected. The high-affinity GABA and high-affinity taurine transport classes exhibit some overlap, with the GABA transport system being more specific and having a much higher Vmax value. High-affinity GABA transport exhibits no overlap with either the high-affinity glycine or the high-affinity aspartic/glutamic acid transport class, and in fact they demonstrate somewhat negative correlations in inhibition profiles. The inhibition profiles of high-affinity cortical glycine transport and those of high-affinity cortical taurine and aspartic/glutamic acid transport also show no significant positive relationship. The inhibition profiles of high-affinity glycine transport in the cerebral cortex and in the pons-medulla-spinal cord show a significant positive correlation with each other; however, high-affinity glycine uptake in the pons-medulla-spinal cord is more specific than that in the cerebral cortex. The inhibition profile of high-affinity taurine transport exhibits a nonsignificant negative correlation with that of the aspartic/glutamic acid transport class.

Amino Acids↗
PubMed1989

Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes.

Pyrithiamine-induced thiamine-deficiency encephalopathy in the rat shows many neuropathological and biochemical similarities to Wernicke's encephalopathy in humans. Treatment of rats with pyrithiamine resulted in moderate reductions of glutamate in thalamus and pons and in generalized severe reductions of aspartate in pons (by 89%, p less than 0.01), thalamus (by 83%, p less than 0.01), cerebellum (by 53%, p less than 0.01), and cerebral cortex (by 33%, p less than 0.05). Alanine concentrations were concomitantly increased. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were decreased in parallel with the aspartate decreases; pyruvate dehydrogenase complex activities were unchanged in all brain regions. Following thiamine administration to symptomatic pyrithiamine-treated rats, neurological symptoms were reversed and concentrations of glutamate, aspartate, and alanine, as well as alpha KGDH activities, were restored to normal in cerebral cortex and pons. Aspartate levels and alpha KGDH activities remained below normal values, however, in thalamus. Thus, pyrithiamine treatment leads to reductions of cerebral alpha KGDH and (1) decreased glucose (pyruvate) oxidation resulting in accumulation of alanine and (2) decreased brain content of glutamate and aspartate. Such changes may be of key significance in the pathophysiology of the reversible and irreversible signs of Wernicke's encephalopathy in humans.

Alanine↗
PubMed1996

Atrophy of the corpus callosum in Alzheimer's disease versus healthy aging.

OBJECTIVE: To investigate the specificity of atrophic changes in the corpus callosum (CC) compared with the cerebellum and pons in patients with Alzheimer Disease (AD), healthy elderly subjects (HE), and a sample of prospectively studied subjects who have developed cognitive decline or "incipient dementia" (ID). DESIGN: Cross-sectional comparison by age using quantitative MRI. SETTING: Ambulatory research unit. PARTICIPANTS: Sixty HE subjects (mean age 78.2 years; range 66-95), 20 ID subjects (mean age 88.1 years; range 78-98) and 39 AD subjects (mean age 72.2 years; range 52-91) were enrolled in longitudinal studies of healthy aging or AD. The population was selected for optimal health; all were examined to exclude medical, neurological and psychiatric illness. MEASUREMENTS: Brain atrophy by quantitative MRI. RESULTS: AD subjects had smaller CC than HE or ID subjects, who did not differ from each other. All three sectors of the CC were smaller in AD than in HE or ID subjects. The cross sectional area of the cerebellum and pons did not differ between groups. HE and ID subjects showed a significant decline in CC size with age. No age-related decline was found for AD subjects. The regional atrophy of the CC in AD subjects was significantly related to cognitive function but not to disease duration. CONCLUSIONS: Atrophy of the CC differentiates HE and ID from AD subjects and tracks the cognitive decline of this disease. In addition, optimally healthy subjects show an age-related decline in callosum size. The atrophy is specific to the CC, a cortical projection system, and does not occur in cerebellum or pons.

Aged↗
PubMed1985

Effects of prolonged supratentorial mass expansion on regional blood flow and cardiovascular parameters during the Cushing response.

To clarify the central nervous and the cardiovascular mechanisms mediating the Cushing response (CR) during intracranial hypertension, the effects of continuous and prolonged expansion of an epidural supratentorial balloon was studied in six dogs. Regional cerebral blood flow, cardiac output, extracerebral tissue blood flow and regional vascular resistance were measured with radioactive microspheres before and during the CR while heart rate, arterial blood pressure and ECG were continuously recorded. The results showed that balloon expansion led progressively to cerebrospinal ischemia beginning in the cerebrum and progressing to the pons, medulla oblongata and spinal cord in an orderly rostro-caudal fashion. This progressing ischemia was closely associated with patterned and stereotyped changes in cardiovascular indices. Thus, respiration ceased, heart rate decreased, blood pressure increased and cardiac output fell when the ischemia appeared in the lower pons. Further advancement of the ischemic front to the lower medulla oblongata led to an abrupt switch-over from bradycardia to tachycardia, which persisted until the experiment was terminated. Since bradycardia disappeared when ischemia reached the vagal cardiomotor nucleus, the initial bradycardia appeared to be the result of increased vagal discharge. When ischemia reached the pons, the mean arterial pressure rose to a maximum of 245 mm Hg (+/- 45) but then fell progressively when the ischemia reached the spinal cord. The decrease in cardiac output persisted throughout the CR and was associated with decreased flow in most extracerebral organs. Exceptions were the heart muscle and the adrenal medulla in which blood flow increased considerably. Changes in regional vascular resistance reciprocated the changes in flow. These results suggest that the vasomotor component of the CR is brought about entirely by peripheral vasoconstriction.

Animals↗
PubMed1989

Effect of isopropanol on rat brain monoamine levels.

Changes in monoamines were studied in discrete areas of brain with varying dose of isopropanol. Acute administration of isopropanol (0.463 g/kg, 0.925 g/kg and 1.85 g/kg) decreased dopamine level in hypothalamus, pons medulla and cerebral cortex and whereas it was increased in striatum and cerebellum. Noradrenaline level was reduced in all the brain areas studied. Adrenaline level was increased in hypothalamus, striatum, midbrain and pons medulla, and decreased in hippocampus and cerebral cortex. Serotonin level was increased in hypothalamus, midbrain, pons-medulla and cerebral cortex, and decreased in striatum and hippocampus. These changes were dose-dependent. It is concluded that isopropanol causes changes in brain monoamine content that this effect is not the same in all the regions of the brain.

1-Propanol↗
PubMed1992

The first breaths of air stimulate noradrenaline turnover in the brain of the newborn rat.

The aim of this study was to analyse the noradrenaline (NA)-turnover in the brain around birth and its significance for neonatal adaptation. NA and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) have been measured by high-pressure liquid chromatography (HPLC) in the pons-medulla and cortex in rat foetuses and pups. The MHPG/NA ratio was used as an index of NA-turnover. Catecholamines were also determined in the adrenals for comparison. The MHPG/NA ratios were found to increase 2.7-fold in the pons-medulla and 2-fold in the cortex during the first day after birth. The surge of NA-turnover occurred after the pups had been breathing air for two hours. The increase of NA-turnover was significantly lower in the cortex of rat pups breathing a hypoxic gas mixture or when they were kept in a cooler environment. The differences were less marked in the pons-medulla. We conclude that breathing air stimulates NA-turnover in the brain of the newborn rat and this stimulatory effect is modulated by environmental factors.

Animals↗
PubMed2003

Characterization of hypoxia-induced ventilatory depression in newborn piglets.

We evaluated the hypothesis that a 'central oxygen detector' in the brainstem is necessary for depressions of ventilatory activity to be manifested in the newborn. Decerebrate piglets, ventilated with 100 % O(2), were studied following neuromuscular blockade. The vagi and carotid sinus nerves were sectioned bilaterally in order to remove the influence of the peripheral chemoreceptors. Activity of the phrenic nerve was recorded as the index of the central respiratory rhythm. This activity declined and, in some preparations, ceased upon ventilation with air or a hypoxic gas, at either normocapnia or hypercapnia. The degree of depression in hypercapnic hypoxia was greatest in the youngest piglets. Following a medial section of the brainstem, extending to the caudal pons, the depression was reduced. In some preparations, a similar reduction followed the placement of radiofrequency lesions in the caudal ventromedial pons. We conclude that a region of the caudal mesencephalon or pons is necessary for the manifestation of depressions of ventilatory activity in the newborn pig.

Animals↗