[Three-year follow-up of infraclinical hypothyroidism: course in a cohort of 97 women aged 45 to 70 years attending healthcare screening centers]. / Evolution à trois ans de 97 cas d'hypothyroïdie fruste. Suivi d'une cohorte de femmes de 45 á 70 ans examinées dans les Centres d'Examens de Santé.

Infraclinical hypothyroidism is a recognized entity defined in terms of laboratory results which occurs more readily in women. The appropriateness of thyroid hormone multicentric prospective study initiated in 1997 has established that infraclinical hypothyroidism occurred in about 3% of women over 45 years of age undergoing routine check-ups at eleven health screening centers. Associated clinical signs and laboratory findings were reported. The purpose of the present study was to describe findings in a 3-year follow-up of these women with infraclinical hypothyroidism in order to assess natural history and appropriate care. Ninety-seven women of the 151 women with a TSH level between 4 and 12 mU/l in the 1997 survey were reviewed during the last three months of 2000. Forty-three of them had taken thyroid hormone replacement drugs since 1997. About 44% of the women examined still had infraclinical hypothyroidism or developing hypothyroidism. There was not significant difference between treated (33%) and non-treated (55%) patients. Clinical and biological signs associated with infraclinical hypothyroidism at the initial examination (elevated serum cholesterol, abnormal ECG, eyelid edema, recent weight gain) were unchanged at the second examination, both in treated and not treated women. A logistic model including all these factors demonstrated that the probability of prescription of thyroid hormone replacement therapy increased 5.4-fold when the starting TSH level was above 6 mU/l and 3.2-fold if ECG abnormalities were present. Using a statistical model with anti TPO antibodies, a level above 64 U/l increased the probability of treatment 7-fold, with ECG findings being related to probability of treatment. Age, cholesterol level, use to lipid lowering drugs, presence of eyelid edema or weight gain were not associated with replacement therapy in this model. No consistent conclusion concerning the appropriateness of screening for infraclinical hypothyroidism can be drawn from these three-year follow-up findings. Another examination scheduled for 2003 should provide further precision concerning the natural history of infraclinical hypothyroidism as well as long-term medical practices and therapeutic impact.

Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo.

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg. d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E(2) (PGE(2)) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LPS-mediated increase in PGE(2) was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.

Evidence of functional myocardial ischemia associated with myocardial dysfunction in brain-dead pigs.

BACKGROUND: Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs. METHODS AND RESULTS: Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10+/-3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt(max), rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt(max), RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt(max), RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism. CONCLUSIONS: Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.

Lipopolysaccharide-induced increase of prostaglandin E(2) is mediated by inducible nitric oxide synthase activation of the constitutive cyclooxygenase and induction of membrane-associated prostaglandin E synthase.

NO produced by the inducible NO synthase (NOS2) and prostanoids generated by the cyclooxygenase (COX) isoforms and terminal prostanoid synthases are major components of the host innate immune and inflammatory response. Evidence exists that pharmacological manipulation of one pathway could result in cross-modulation of the other, but the sense, amplitude, and relevance of these interactions are controversial, especially in vivo. Administration of 6 mg/kg LPS to rats i.p. resulted 6 h later in induction of NOS2 and the membrane-associated PGE synthase (mPGES) expression, and decreased constitutive COX (COX-1) expression. Low level inducible COX (COX-2) mRNA with absent COX-2 protein expression was observed. The NOS2 inhibitor aminoguanidine (50 and 100 mg/kg i.p.) dose dependently decreased both NO and prostanoid production. The LPS-induced increase in PGE(2) concentration was mediated by NOS2-derived NO-dependent activation of COX-1 pathway and by induction of mPGES. Despite absent COX-2 protein, SC-236, a putative COX-2-specific inhibitor, decreased mPGES RNA expression and PGE(2) concentration. Ketoprofen, a nonspecific COX inhibitor, and SC-236 had no effect on the NOS2 pathway. Our results suggest that in a model of systemic inflammation characterized by the absence of COX-2 protein expression, NOS2-derived NO activates COX-1 pathway, and inhibitors of COX isoforms have no effect on NOS2 or NOS3 (endothelial NOS) pathways. These results could explain, at least in part, the deleterious effects of NOS2 inhibitors in some experimental and clinical settings, and could imply that there is a major conceptual limitation to the use of NOS2 inhibitors during systemic inflammation.

Effect on osteoarthritis of spa therapy at Bourbonne-les-Bains.

OBJECTIVES: Several studies suggest a beneficial overall effect of spa therapy in chronic musculoskeletal diseases. The present open controlled study investigated the effects of spa therapy at Bourbonne-Les-Bains, France, in patients with hip or knee osteoarthritis or low back pain. PATIENTS AND METHODS: In 1998, 102 men and women older than 50 years were included in the study. All had low back pain or lower limb osteoarthritis, and none had contraindications to spa therapy. Quality of life was assessed three times at intervals of 4 weeks, twice before and once immediately after 3 weeks of spa therapy, using the Duke Health Profile (five dimensions and five dysfunctions). RESULTS: Mean age was 66.4 years, and 67% of the patients were women. Quality of life was markedly decreased as compared to the population at large (1996, CFES). The two pretreatment evaluations produced similar quality-of-life scores. Spa therapy was associated with significant improvements in overall quality of life (P=0.004), self-esteem (P=0.009), and pain (P=0.01). CONCLUSION: These findings support those of other studies conducted in France and in other European countries. They indicate that patients report meaningful improvements in their quality of life after spa therapy.

Retinoic acid and host-pathogen interactions: effects on inducible nitric oxide synthase in vivo.

Vitamin A and its metabolite retinoic acid modulate the host response to pathogens through poorly characterized mechanisms. In vitro studies have suggested that retinoic acid decreases inducible NO synthase (NOS2, or iNOS) expression, a component of innate immunity, in several cell types stimulated with lipopolysaccharide (LPS) or cytokines. This study investigated the effect of retinoic acid on LPS-stimulated NOS2 expression in vivo. Wistar-Kyoto rats received all-trans retinoic acid (RA, 10 mg/kg) or vehicle intraperitoneally daily for 5 days followed by LPS (4 mg/kg) or saline intraperitoneally and were killed 6 h later. NOS2 activation was estimated by mRNA (RT-PCR) and protein (Western-blot) expression and plasma nitrate/nitrite accumulation. In sharp contrast to previous in vitro study reports, RA significantly enhanced NOS2 mRNA, protein expression, and plasma nitrate/nitrite concentration in LPS-injected rats but not in saline-injected rats. This was associated with increased expression of interleukin-2, interferon (IFN)-gamma and IFN regulatory factor-1 mRNAs in several organs and increased IFN-gamma plasma concentration. RA significantly increased mortality in LPS-injected rats. The NOS inhibitor aminoguanidine (50 mg/kg before LPS injection) significantly attenuated the RA-mediated increase in mortality. These results demonstrate for the first time that RA supplementation in vivo enhances activation of the LPS-triggered NOS2 pathway.

Serum parathormone profile during surgical treatment of hyperfunctioning parathyroid adenoma: a multicompartmental model.

Patterns of intact parathyroid hormone (iPTH) elimination and subsequent recovery of parathyroid function were studied in seven patients undergoing surgical removal of solitary hyperfunctioning parathyroid adenoma. Using a sensitive two-site immunoradiometric assay, iPTH levels were measured pre, peri-, and postoperatively. Blood samples were taken at very early and at late stages, including 3, 6, 9, and 15 minutes and 48, 72, and 96 h after adenomectomy. A biexponential formula was calculated to fit the decreasing values of iPTH in all patients. The PTH half-life in the early phase was 1.4 +/- 1.1 minutes (95% confidence limits). The PTH half-life in the second phase was 64.45 +/- 32.19 minutes (95% confidence limits). A third phase is represented by a slow, linear increase in plasma iPTH values as a result of the recovery of healthy suppressed parathyroid glands. The extrapolation to baseline of the later phase shows that the recovery of normal parathyroid function begins as soon as 240 minutes after adenomectomy and is independent of the decrease in PTH of adenomatous origin. All individual results were consistent with this model. Five patients had iPTH values below 5 pg/ml, one had 15 pg/ml, and the last had 27 pg/ml 5 h after parathyroid adenomectomy. The recovery of the hormonal activity of the remaining glands occurred rapidly. By the postoperative hour 24 the mean serum iPTH concentration was 12.28 +/- 8.07 pg/ml. The intraoperative serum iPTH concentration offers a model to assess both recovery of hormonal secretion from functionally suppressed parathyroid glands and disappearance of parathyroid hormone.

Endocrine response to plasma volume expansion during the early postoperative period in heart transplant recipients.

The purpose of this study was to investigate the changes in endocrine control of blood pressure and electrolyte homeostasis during the early postoperative period after heart transplantation. Dynamic testing using volume-expansion to increase cardiac filling pressures was performed to determine changes in alpha atrial natriuretic peptide, renin, aldosterone, and vasopressin secretion in response to a physiologic stimulus. Volume expansion was performed on five heart transplant patients each day from postoperative day 1 to postoperative day 5. Alpha atrial natriuretic peptide, renin, aldosterone, and vasopressin plasma levels were assessed by radioimmunoassay before and during the 6 hours after the beginning of infusion. No significant changes in the secretion of any of the various hormones studied were found after volume expansion. Moreover, we found that heart transplant recipients were unable to increase water and sodium renal excretion after volume expansion. The physiologic decrease in vasopressin release after volume expansion appears to be altered by graft denervation. Furthermore, persistently elevated alpha atrial natriuretic peptide plasma levels at rest despite improved patient hemodynamic status and the absence of enhanced hormone secretion after a physiologic stimulus are in favor of an intrinsic hypersecretion of this hormone. Moreover, the absence of an appropriate renal response could be a major consequence of both the lack of further increased alpha atrial natriuretic peptide secretion and the heart denervation resulting from transplantation. This blunted renal response should be taken into account when managing patients in the early period after transplantation.

Changes in endocrine control of electrolyte homeostasis and blood pressure following heart and heart-lung transplantation. A comparative study.

The purpose of this study was to compare the early postoperative effects of heart and heart-lung transplantation on the secretion of atrial natriuretic peptide (alpha-ANP), renin, aldosterone, and vasopressin. This was carried out from the first to the eighth postoperative day in ten heart and five heart-lung recipients. The changes in the release of these hormones were similar in both groups. Vasopressin release remained stable while that of the renin-angiotensin-aldosterone system progressively returned to more normal levels. Grafted heart tissue was capable of high alpha-ANP release early on in both heart and in heart-lung recipients. This sustained alpha-ANP release was not a function of the resulting overall atrial tissue mass. Our findings suggest that it might be the consequence of an intrinsic hypersecretion of alpha-ANP resulting from the loss of normal heart innervation occurring in both heart and heart-lung transplantation.

[Contribution of intra-operative measurement of intact parathormone in surgery for primary hyperparathyroidism]. / Apport du dosage per-opératoire de la parathormone intacte dans la chirurgie de l'hyperparathyroidie primaire.

Using a sensitive two-site immunoradiometric assay which detects intact parathormone (iPTH), we studied the decrease in peripheric and jugular plasmatic iPTH during surgical removal of abnormal parathyroid (s). In the next future, results of intact parathormone (iPTH) assay will be given in 45 minutes. In a prospective study of 33 patients operated on for hyperparathyroidism or for cold thyroid nodule, the serum levels of intact PTH was measured intraoperatively in peripheric and in jugular blood. The preoperative mean serum iPTH concentration was 119.23 +/- 172.48 pg/ml and fell to 34.5 +/- 32.21 pg/ml after surgery in 14 cases of primary hyperparathyroidism (p < 0.001). Thirteen out of 14 patients had serum iPTH values less than 65 pg/ml within 15 minutes after parathyroidectomy. The preoperative mean serum iPTH concentration in the 5 secondary hyperparathyroidism was 781.2 +/- 403.19 pg/ml. This value fell to 124 +/- 66.91 pg/ml after parathyroidectomy (p < 0.04). No significant decrease was observed in the mean serum concentration of the 14 patients operated on for cold thyroid nodule. Patients suffering from single parathyroid adenoma presented a significant gradient in jugular plasmatic PTH concentration between the adenoma side and the contralateral one. This gradient decreased during effective parathyroid adenomectomy (309.7 +/- 313.3 pg/ml to 3.7 +/- 35.1 pg/ml). Intraoperative serum iPTH concentration will provide a valuable tool to appreciate the effectiveness of surgical removal of parathyroid glands and to detect the location of parathyroid adenoma when the surgical research is negative.

[Atrial natriuretic factor after heart-lung transplantation. Consequences of cardiac denervation]. / Facteur atrial natriurétique après transplantation cardio-pulmonaire. Conséquences de la dénervation cardiaque.

Due to the discovery and elaboration of alpha ANP, the heart can be considered a veritable endocrine gland involved in fluid and electrolyte homeostasis as well as blood pressure regulation. Nevertheless, the mechanisms regulating the synthesis and release of this new hormone are far from being understood. Heart-lung transplantation provides an interesting research model for evaluating the consequences of allograft denervation on alpha ANP synthesis and release, without the disadvantage of significantly increasing the overall atrial tissue mass, as observed in orthotopic heart transplantation. To appreciate better these consequences, we studied the changes in alpha ANP release following heart-lung transplantation. Five patients were included in the study. It began during the immediate postoperative period and went on to the 8th postoperative day. Alpha ANP levels were determined using radioimmunoassay. The postoperative course was characterized by a rapid significant increase in hormone levels as of the 6th postoperative day (45.6 +/- 5.5 fmol/ml). These findings were comparable to those found in a previous study involving orthotopic heart transplantation alone. Thus, the heart-lung group was also capable of high levels of alpha ANP release from the onset. However, this rapidly increasing release was not found to be correlated with the changes in hemodynamic parameters observed postoperatively (blood and cardiac filling pressures). Moreover, we observed no episodes of rejection which might explain the increased release of this hormone. Finally, the fact that increased alpha ANP release occurs despite a smaller increase in the overall tissue mass is more than noteworthy. In conclusion, as we found in our initial study involving heart transplant recipients, the sustained high levels of alpha ANP observed following heart-lung transplantation are in favour of a possible modulating role played by cardiac innervation on the release of this hormone.

Short-term effects of human orthotopic heart transplantation on hormones regulating fluid and electrolyte balance.

Hormonal regulation of fluid and electrolyte homeostasis and blood pressure is under the auspices of three organs: the heart, the brain, and the kidneys. Their regulatory roles are fulfilled by the actions of atrial natriuretic peptide (ANP), vasopressin, and the renin-angiotensin-aldosterone system (RAAS), respectively. The aim of this study was to appreciate the short-term effects of orthotopic human heart transplantation on the release of these hormones. Alpha-ANP, renin, aldosterone, and vasopressin serum levels were assessed by radioimmunoassay before and during the 10 days after grafting in a series of 10 patients. On day 1, alpha-ANP levels dropped from 42.4 +/- 6.5 to 25.1 +/- 2.2 fmol/ml before returning to levels comparable with those found before transplantation. This decrease in alpha-ANP levels was associated with a peak in vasopressin and aldosterone levels. With the exception of the peak in vasopressin levels seen on day 1, preoperative and postoperative levels of this hormone were near normal. Increased preoperative renin levels dropped significantly as of day 5 (from 268 +/- 99 to 122 +/- 66 ng/L). This decrease was related to improved patient hemodynamic status. No significant correlation was found between the changes in alpha-ANP levels, RAAS or vasopressin levels, patient hemodynamic status, or administered drugs. In conclusion, grafted heart tissue was capable of high alpha-ANP release early on. The drop in alpha-ANP serum levels, compared with the peaks in vasopressin and aldosterone on day 1, might have been caused by the ability of the graft to play a role in the hormonal regulation of fluid and electrolyte balance.(ABSTRACT TRUNCATED AT 250 WORDS)

[1 alpha 25-dihydroxyvitamin D3 (calcitriol) and malignant hemopathies. Decreased serum levels in acute leukemia: preliminary results]. / 1 alpha 25-dihydroxyvitamine D3 (calcitriol) et hémopathies malignes. Taux sériques diminués dans les leucémies aiguës: résultats préliminaires.

We used the Amersham radioimmunological method to measure plasma 1 alpha 25-dihydroxyvitamin D3 (calcitriol) levels in patients presenting with one of the following diseases: (i) non-acute myelodysplastic syndrome (39 cases); (ii) acute myeloid leukaemia in blastic phase (43 cases) or in complete remission (15 cases) and (iii) acute lymphoid leukaemia in blastic phase (11 cases). All patients had normal metabolic functions. Compared with our standard laboratory values (15-35 pg/ml), the results of these assays were related to the type of pathology or, in patients with acute myeloid leukaemia, to the stage of the disease (p less than 0.001). Moreover, the mean plasma calcitriol values differed according to the type of pathology (p less than 0.003). Patients with acute myeloid leukaemia in blastic phase had a low level of calcitriol as compared with controls (p less than 0.05) and with patients with acute myeloid leukaemia in complete remission (p less than 0.001) whose calcitriol levels were never low. In contrast, there was no significant difference between controls and patients with myelodysplastic syndrome or acute lymphoid leukaemia in blastic phase. This study demonstrates the usefulness of plasma calcitriol assays in malignant blood diseases where low values in certain types of leukaemia would incite to include calcitriol in therapeutic regimens.

Haematological and hormonal responses to dynamic exercise in patients with chronic airway obstruction.

The influence of exercise on hormonal and total white blood cells (WBC), lymphocytes (L). Granulocytes (GR), and platelet (P) count responses was studied in: twenty-five patients with chronic airway obstruction (CAO, 47 +/- 1.8 years, mean +/- SEM) and thirteen normal subjects (N, 36 +/- 2.6 years). They performed a submaximal (40 W) and a maximal exercise (VO2max). Arterial blood samples were taken at rest, 40 W, and VO2max. [H+], PaCO2, PaO2 haematocrit (Hct), [Hb], P, total platelet volume (TPV), WBC, GR, L, and total red blood cells (RBC) were measured. At rest, WBC, GR, P and TPV were higher in CAO patients, whilst PaO2 and cortisol were lower. At 40 W, when compared to values obtained at rest, WBC, GR, L, P and TPV were increased in both groups; WBC, GR, P and TPV were higher in CAO patients. VO2max of CAO patients represented 54% of that of controls. At VO2max, Hct, [Hb] and RBC were approximately 10% higher than at rest in both groups, whilst changes were more significant in normals for WBC (CAO = 55%, N = 76%), lymphocytes (CAO = 83%, N = 105%), GR, (CAO = 37%; N = 51%), platelets (CAO = 23%, N = 29%), TPV (CAO = 25.4%, N = 35%), [H+] (CAO = 43%, N = 38%) and ACTH (CAO = 82%, N = 139%). PaO2 and cortisol did not differ between groups. PaCO2 and platelets however, were higher in the CAO group.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukocyte, lymphocyte and platelet response to dynamic exercise. Duration or intensity effect?

The influence of work intensity and duration on the white blood cell (WBC), lymphocyte (L) and platelet (P) count response to exercise was studied in 16 trained subjects (22 +/- 5.4 years, means +/- SD). They performed three cyclo-ergospirometric protocols: A) 10 min at 150 W followed by a progressive test (30 W/3 min) till exhaustion; B) constant maximal work (VO2max); C) a 45 min Square-Wave Endurance Exercise Test (SWEET), (n = 5). Arterial blood samples were taken: at rest, submaximal and maximal exercise in A; maximal exercise in B; 15th, 30th and 45th min in the SWEET. Lactate, [H+], PaCO2, PaO2, [Hct], Hb, cortisol, ACTH, total platelet volume (TPV), total blood red cell (RBC), WBC, L and P were measured. At 150 W, WBC, L, P, and TPV increased. VO2max did not differ between A and B, but a difference was found in total exercise time (A = 25 +/- 3 min; B = 7 +/- 2 min, p less than 0.001). In A, at VO2max, the increase was very small for Hct, [Hb], and RBC (10%), in contrast with large changes for WBC (+93%), L (+137%), P (+32%), TPV (+35%), [H+] (+39%), lactate (+715%), and ACTH (+95%). At VO2max there were no differences in these variables between A and B. During the SWEET: WBC, L, P, TPV and ACTH increased at the 15th min as much as in VO2max, but no difference was observed between the 15th, 30th and 45th min, except for ACTH which continued to rise; the lactate increase during the SWEET was about half (+341%) the value observed at VO2max, and [H+] did not vary with respect to values at rest.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acid labile aldosteronuria. Comparison of radio-immunoassay and colorimetry (author's transl)]. / L'adostéronurie acido-labile. Comparaison des méthodes radio-immunologique et colorimétrique.

The daily excretion of aldosteronuria was studied in 87 normal or pathological subjects by 3 methods : one, classical, by thin layer chromatography (TLC), based on a modification of Neher's technic, the others, by radio-immunoassay with or without prior extraction of urinary aldosterone (RIA). The normal subjects receiving a daily sodium intake of 150 nmol excrete 24,9 +/- 3,4 nmol/24 hours of aldosterone (TLC) and 23,0 +/- 4,2, 26,3 +/- 3,7 nmol/24 hours (RIA) respectively. These values are not statistically different, RIA of aldosteronuria appears to be a reliable and simple technic and permits one to carry out a large number of examinations within a short period of time with only one technician.