Changes in autonomic modulation to the heart and intracellular catecholamines. A longitudinal study in differentiated thyroid carcinoma during short-term hypothyroidism and thyroid hormone replacement.

BACKGROUND: The effects of thyroid deprivation on the autonomic modulation to the heart remain controversial. METHODS: In this study in patients followed for thyroid carcinoma, we investigated (1) heart rate variability parameters and the baroreflex gain and (2) intracellular catecholamine levels in circulating lymphocytes during short-term hypothyroidism (phase 1) and after reinstitution of TSH-suppressive thyroid hormone replacement (phase 2). RESULTS: The RR interval value (p < 0.01) and systolic blood pressure (p < 0.05) were higher in phase 1 than in phase 2. The low-frequency/high-frequency (LF/HF) ratio was significantly lower in the hypothyroid state (p < 0.05), with a higher HF component (p < 0.05). After adjusting for mean RR interval in the regression model, the difference between the power of RR interval oscillations calculated in the two states was greater for the LF band (p = 0.005) and it was borderline significant for the HF band (p = 0.052). The baroreflex gain alpha(LF) index was similar in the two phases. The stimulus-induced cellular production of norepinephrine and epinephrine in peripheral blood mononuclear cells was significantly higher in phase 2. CONCLUSION: The neurally-mediated influences on the sinus node and the study of intracellular catecholamine production suggest a reduced sympathoexcitation in hypothyroidism compared with the treatment phase. The early increase in blood pressure observed after thyroid hormone withdrawal is not due to impaired sensitivity of the baroreflex arc.

Glutamate receptors of the AMPA type modulate neurotransmitter release and peristalsis in the guinea-pig isolated colon.

To assess the role of AMPA and kainate receptors in modulating neurotransmitter release from the myenteric plexus, the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainic acid on endogenous acetylcholine (ACh) and noradrenaline (NA) overflow from the guinea-pig isolated colon was studied. AMPA inhibited spontaneous ACh overflow and increased electrically-evoked NA overflow. Kainic acid did not influence both ACh and NA overflow. AMPA-mediated effects on ACh and NA overflow were significantly reduced by the AMPA/kainate antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, CNQX. The inhibitory effect of AMPA on ACh overflow could be due, at least in part, to the AMPA-induced NA overflow as it was greatly reduced after adrenoceptor blockade and virtually abolished in sympathetically-denervated animals. The possible functional significance of these findings was studied by measuring the efficiency of the peristaltic reflex in the presence of the different agonists. The efficiency of peristalsis was enhanced by AMPA, whereas it was not modified by kainic acid. In conclusion, AMPA receptors, but not kainate receptors, may play a role in the modulation of ACh and NA release and of peristalsis in the guinea-pig colon.

HPLC-ED measurement of endogenous catecholamines in human immune cells and hematopoietic cell lines.

A rapid and simple HPLC-ED method is described to identify and measure catecholamines (CTs) and their major metabolites in immune cells. Using this method, intracellular CTs were quantified in human peripheral blood mononuclear cells (PBMCs), T and B lymphocytes, monocytes and granulocytes. Immune cell subsets were separated by density gradient centrifugation and immunomagnetic cell sorting. CTs were also found in the human hematopoietic cell lines NALM-6 (pre-B) and (in smaller amounts) in Jurkat (T lymphoblastoid) and U937 (promonocytic). In cultured PBMCs, intracellular CTs were reduced by both the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine and the chromaffin granule depletant reserpine. In NALM-6 cells, both alpha-methyl-p-tyrosine and the dopamine-beta-hydroxylase inhibitor disulfiram reduced intracellular CTs, supporting the presence of active synthetic pathways in these cells. Since sympathoadrenergic mechanisms play a key role in the interactions between the immune system and the nervous system, these findings may be relevant for a better understanding of the neuro-immune network.

Endogenous catecholamine synthesis, metabolism, storage and uptake in human neutrophils.

Evidence is presented that human neutrophils contain catecholamines and several of their metabolites. In vitro, incubation with alpha-methyl-p-tyrosine or pargyline affects intracellular dopamine, norepinephrine and their metabolites, suggesting catecholamine synthesis and degradation by these cells. Reserpine reduces intracellular dopamine and norepinephrine and desipramine reduces intracellular norepinephrine, suggesting the presence of storage and uptake mechanism. In view of the ability of catecholamines to affect neutrophil function, the present results support the hypothesis that autoregulatory adrenergic mechanisms may exist in these cells.

Endogenous catecholamine synthesis, metabolism storage, and uptake in human peripheral blood mononuclear cells.

Evidence has been obtained that peripheral blood mononuclear cells contain dopamine, norepinephrine, epinephrine, and their metabolites. Pharmacologic inhibition of tyrosine hydroxylase or monoamine oxidase profoundly affected intracellular catecholamines (CTs) and their metabolites, indicating that these cells are able to synthesize and breakdown CTs. The sensitivity of intracellular CTs to reserpine and the presence of CTs in the extracellular medium suggest that CTs are stored and released. Moreover, the increase of extracellular CTs in the presence of monoamine uptake blockers point to the presence of functional uptake mechanisms. Altogether, these results indicate the existence of a CT lifecycle in human mononuclear cells and warrant further studies to investigate the role of adrenergic autoregulatory mechanisms in modulation of the immune response and in the pathogenesis of diseases involving the immune system.

Measurement of catecholamines in mouse bone marrow by means of HPLC with electrochemical detection.

BACKGROUND AND OBJECTIVE: Noradrenergic innervation is present in the bone marrow and adrenergic agents can modulate hematopoiesis. However, since no data are available concerning endogenous catecholamines at this level, we investigated their presence and origin. METHODS: Using a high performance liquid chromatographic method, we have and measured endogenous catecholamines in bone marrow from normal, 6-OHDA-treated and pargyline-treated mice. RESULTS: Noradrenaline, adrenaline and dopamine levels were, respectively, 2806.74 +/- 408.85, 803.37 +/- 87.66 and 274.47 +/- 51.54 pg/g of tissue. Noradrenaline levels were lower after 6-OHDA (1130.47 +/- 142.73 pg/g of tissue, p < 0.01 vs. control values) and higher after pargyline (4122.62 +/- 509.54 pg/g of tissue, p < 0.05). None of these treatments significantly affected adrenaline or dopamine content. INTERPRETATION AND CONCLUSIONS: Noradrenaline in the bone marrow originates mainly from sympathetic nerve endings and is metabolized through specific enzymatic pathways. Adrenaline and dopamine may originate from other sources, such as the systemic circulation.

The biomechanics of the normal and dysplastic hip.

The author describes a simple method to highlight forces, by extrapolating on x-rays of normal and dysplastic hips the direction of the skeletal lamellae of the pelvis and that of the proximal femoral metaepiphysis. In the pelvis is described a tridimensional structure, made of two basic lamellar systems: one that begins from the "lamina quadrilatera" and one from the lateral border of the "sourcil." They move in the opposite direction: the first towards the Waldayer tuberosity, the anterosuperior and inferior iliac spine; the second towards the sacroiliac joint. They form a structure similar in shape to an hourglass, the inferior cone of which underlines the "sourcil" and looks like a Gothic arch. In the normal hip the "sourcil" is slightly oblique (3-4 degrees) in bipodalic support. It becomes horizontal in monopodalic support. From the direction of the lamellae of the Gothic arch the author obtains the direction of the forces acting in the static and dynamic phase of the normal hip. In the dysplastic hip the "sourcil" may be oblique in an anterocraniolateral or posterocraniomedial direction. Consequently, the lamellae of the hour-glass and of the Gothic arch undergo a different orientation. From these altered orientations the author visualizes the direction of the pathologic forces. Based on the shape of the Gothic arch and of the angle of inclination of the femoral neck the author describes the forces acting on the pelvis and on the femoral head when there is either valgus or varus in the neck; according to the degrees of inclination of the femoral neck he describes the variation of magnitude of loading on the support surfaces.

Modulation of neurotransmitter release by opioid mu- and kappa-receptors from adrenergic terminals in the myenteric plexus of the guinea-pig colon: effect of alpha 2-autoreceptor blockade.

We have studied the effect of [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO, opioid mu-receptor agonist) and ICI-204,448 (kappa-receptor agonist) on endogenous noradrenaline release in the guinea-pig isolated distal colon. DAMGO enhances noradrenaline over-flow and this effect is antagonized by naloxone (pIC50 = 10.27) and nor-binaltorphimine (pIC50 = 7.97), and concentration-dependently turned into inhibition by yohimbine. ICI-204,448 inhibits noradrenaline overflow and is antagonized by naloxone (pIC50 = 9.38) and nor-binaltorphimine (pIC50 = 10.48), but is not affected by yohimbine. Evidence is thus given that mu- and kappa-opioid receptors modulate noradrenaline release in the guinea-pig colon. Modifications by yohimbine of the effect of DAMGO indicate the existence of a functional relationship between mu-receptors and alpha(2)-autoreceptors in this model.

Muscarinic modulation of endogenous noradrenaline release from adrenergic terminals in the guinea-pig colon.

1 The present study examined the role of muscarinic receptors in the modulation of noradrenaline (NA) release in the guinea-pig isolated distal colon. The spontaneous endogenous NA overflow assayed by HPLC-ED was taken as an index of NA release from enteric noradrenergic nerve terminals. 2 Physostigmine (10 microM) significantly enhanced spontaneous endogenous NA overflow. Hyoscine (muscarinic antagonist), (R)-(-)-trihexyphenidyl and telenzepine (M1-selective antagonists), and 11[[2-[(diethylamino)methyl]-1-piperydil]acetyl]-5,11 -dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116, M2-selective antagonist) inhibited NA overflow in a concentration dependent manner, with the following EC50 values: 131.74 (18.19-953.96), 101.62 (58.83-175.60), 150 (60-330), 30 (5-170) nM, respectively. 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M1- and M3-selective antagonist) had no significant effect up to 100 microM. 3 The muscarinic agonist oxotremorine inhibited NA overflow in a concentration dependent manner, with an EC50 value of 0.67 (0.30-1.51) microM. The response to oxotremorine was inhibited by muscarinic antagonists with the following order of potency: hyoscine = (R)-(-)-trihexyphenidyl = telenzepine > 4-DAMP >> AF-DX 116. 4 In the presence of 3 microM tetrodotoxin (TTX), the effect of oxotremorine and 4-DAMP was unchanged, while hyoscine, (R)-(-)-trihexyphenidyl, telenzepine and AF-DX 116, instead of inhibiting, significantly enhanced NA overflow. 5 The present results indicate that, in the guinea-pig colon, endogenous acetylcholine sustains spontaneous NA release by activating muscarinic receptors possibly located on interneurones. In addition, inhibitory muscarinic receptors may exist on adrenergic terminals.

Valgus-extension osteotomy for osteoarthritis of the hip. Indications and long-term results.

We reviewed the results of 277 intertrochanteric valgus-extension osteotomies performed between 1973 and 1975 for primary or secondary osteoarthritis. The average age of the patients was 51 years and follow-up varied from 11 to 15 years. At the latest evaluation 67% of the hips were good or excellent on the Merle D'Aubigné scale. Better results were obtained in patients under 40 years of age with unilateral involvement and a mechanical (secondary) aetiology. An elliptical femoral head, minimal subluxation and an adequate pre-operative range of motion were also favourable. There was radiographic evidence of regression of the arthritic changes in 39% of the hips at final review. Valgus-extension osteotomy is effective for secondary osteoarthritis of the hip in selected younger patients, but not for those with primary hip disease or a poor range of movement.

Osteonecrosis of the hip treated by intertrochanteric osteotomy. A four- to 15-year follow-up.

We have reviewed the results of 106 intertrochanteric osteotomies performed for osteonecrosis of the femoral head. The average age at operation was 47.5 years. At two years from operation 71% of the hips had a clinically satisfactory result and at final follow-up, an average of 8.2 years after operation, 58% continued to have excellent or good rating. Twenty-four hips had needed total replacement or arthrodesis because of pain. Patients aged less than 55 did better than those operated on after that age, and hips with an idiopathic or post-traumatic aetiology did considerably better than alcohol-induced or steroid-induced cases. In view of these findings we believe that in the younger adult, in the absence of metabolic bone disease or advanced joint destruction, intertrochanteric osteotomy should be considered for the treatment of osteonecrosis.

The isoelastic, noncemented total hip arthroplasty. Preliminary experience with 400 cases.

The first 400 patients having cementless isoelastic total hip arthroplasties with a polyacetyl femoral component stem were assessed by independent observers with a minimum review time of two years. Six percent of the patients had died at the time of review; these were mainly elderly patients with subcapital fractures. Ninety-seven percent of the surviving patients appeared for a complete clinical and radiological review. Ninety-two percent of these patients considered that they had a good result following surgery. Six patients (1.6%) developed infection, and three patients (0.8%) required revision procedures, two for femoral loosening and one for recurrent dislocation. Two (0.5%) acetabular components were loose, one of which was associated with infection. In the initial part of the series with narrow-diameter, second-generation femoral components, some had subsided and tilted into varus, but with improved instrumentation and availability of wider diameter femoral components, this problem has been overcome. In order to obtain a more secure mechanical fixation of the femoral component in the medullary canal and to increase implant-bone interface, the third-generation femoral components were used in the latter 48 cases of the series, and clinical and radiological results were excellent with corresponding reduction in the recommended period of gait support. No component had broken. Femoral fractures incurred during surgery by dislocation or impaction had all healed with routine management. These early results are encouraging, but the effectiveness of this prosthesis must be determined by longer follow-up data.

The inclination of the weight bearing surface in the hip joint. The clinical significance of abnormal force.

The mechanical basis responsible for the development of secondary osteoarthritis in adults and slipped capital femoral epiphysis in adolescents is discussed, with the role of the oblique weight-bearing surface in generating abnormal shearing forces in these two conditions emphasized. The same biomechanical principles have been found to apply to the acetabular component in total hip implants. A vertical cup position will lead to abnormal stress concentration in the outer edge of the bone implant interface with an increase in shearing forces. The form of the subchondral bone sclerosis on the radiograph has been studied and found to correlate well with the distribution of stresses in the bone implant interface.

Mechanics of the normal and osteoarthritic hip. A new perspective.

The mechanism of force transmission in normal and osteoarthritic human hips is interpreted with the aid of the following hypothesis: the essential anatomic requisite for the maintenance of mechanical equilibrium about the hip is a horizontal acetabular weight-bearing surface. Anatomic deviations from this norm result in a disequilibrium of opposing vector forces and may be contributory to the eventual onset of osteoarthritis (OA). The radiographic anatomy of the hip is the temporal record of the biologic response of bone to load transmission. From the analysis of radiographs the magnitude and direction of mechanical forces about the hip can be inferred. Deviations from normal, as in OA, can be understood by such radiographic analyses.

Cementless isoelastic RM total hip prosthesis.

Some surgeons are beginning to doubt the reliability of bone cement in joint replacements. In 1967 Robert Mathys conceived the idea of an isoelastic prosthesis made of plastic, which would anchor into the bone without cement. He developed the idea by extensive tests in animals and, in 1973, the first human RM cementless hip prosthesis was inserted by E Morscher. In this paper the concept of the cementless isoelastic prosthesis is developed by Robery Mathys, and Professor Bombelli records his experience with the prosthesis between 1977 and 1981.