Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM.

OBJECTIVE: ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism. The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension. Prospectively defined cardiovascular events were assessed as secondary outcomes. RESEARCH DESIGN AND METHODS: Inclusion criteria included a diagnosis of NIDDM and hypertension (systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg). Exclusion criteria included a history of coronary heart disease or stroke, serum creatinine > 1.5 mg/dl, albuminuria > 40 micrograms/min, and use of lipid-lowering drugs, aspirin, or antihypertensive agents other than beta-blockers or diuretics. A total of 380 hypertensive diabetics were randomly assigned to open-label fosinopril (20 mg/day) or amlodipine (10 mg/day) and followed for up to 3.5 years. If blood pressure was not controlled, the other study drug was added. RESULTS: Both treatments were effective in lowering blood pressure. At the end of follow-up, between the two groups there was no significant difference in total serum cholesterol, HDL cholesterol, HbA1c, fasting serum glucose, or plasma insulin. The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infarction, stroke, or hospitalized angina than those receiving amlodipine (14/189 vs. 27/191; hazards ratio = 0.49, 95% CI = 0.26-0.95). CONCLUSIONS: Fosinopril and amlodipine had similar effects on biochemical measures, but the patients randomized to fosinopril had a significantly lower risk of major vascular events, compared with the patients randomized to amlodipine.

Thyrotropin-releasing hormone enhances event-related brain potentials and growth hormone release in man.

Changes in contingent negative variation (CNV), a brain-evoked potential related in arousal, as well as in serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) levels were recorded in 12 male volunteers receiving either thyrotropin-releasing hormone (TRH) or saline infusion. Only during TRH administration an increase in CNV (P less than 0.02) and, 30 min later, in GH (P less than 0.05) occurred; thyroid hormones and PRL increased as well, in the absence of any correlation with CNV areas. Cortisol was not affected by TRH. As dopamine (DA) agonistic drugs notoriously increase both CNV areas and GH levels and experimental evidence for prodopaminergic properties of TRH has accumulated in animal models, a possible explanation of the results here presented might be the activation of DA pathways by TRH also in the human.

[The incidence and clinical significance of the echocardiographic finding of false chordae tendineae]. / Frequenza e significato clinico del rilievo ecocardiografico di false corde tendinee.

The presence of false tendons (FT) with M-mode and 2-D echocardiography in a consecutive series of 916 patients (520 men--396 women) with a wide age range (9-83 y) was investigated, and a possible correlation with heart systolic murmurs and/or heart arrhythmias evaluated. The problems that FT cause in differential diagnosis with other intraventricular structures were also considered. FT were observed in 53 subjects (5.8%), 30 men--23 women, and in an additional 51 cases (96%) in the left ventricular cavity. A clear prevalence of FT was observed during childhood and adolescence (26.1%), with the preferential location at the top of the ventricular chamber. No relevant correlation between FT and heart systolic murmurs and/or cardiac rhythm disorders was found. Although our results show that FT constitute an occasional finding, with no anatomic or functional relevance, they should always be held in due consideration in case of diagnostic uncertainty with other pathological structures, in particular intracavitary thrombi.

The effect of microgravity on testicular androgen secretion.

BACKGROUND: Spaceflight causes a number of physiological changes in the human body. Most would consider space travel to be a stressful event even for well-trained astronauts. Should this be true, pituitary gonadotrophins (mainly LH) and testicular androgens, like testosterone (T), should decrease inflight in male astronauts. We therefore hypothesized that lowered testicular androgen levels might occur in men during spaceflight, due to stress-dependent lowered LH concentrations. METHODS: In order to test this hypothesis, on different day pre-, in- and postflight we assayed wake-time salivary and urinary T in four astronauts, as well as wake-time plasma levels of adrenocorticotropin (ACTH), cortisol (CS), LH, T and its peripherally active metabolite 3-alpha-diol glucuronide (3ADG). In order to compare clinical to subjective data, all 7 male crewmembers anonymously answered a daily questionnaire from pre- to postflight asking them to self-rate sexual drive and potency, muscle strength and mood. RESULTS: Salivary, urinary and plasma T, as well as 3ADG, decreased during flight, while LH unexpectedly increased inflight (p < 0.05). A parallel decrease in sexual drive was observed (p < 0.05). A dramatic recovery of salivary T was found on R + 1. CONCLUSIONS: This was the first time that spaceflight was demonstrated to cause temporary, still dramatic hypoandrogenism which was not due to blunted pituitary gonadotrophin secretion. The cause for hypoandrogenism is unknown but it may depend on fluid shift affecting testicular function or androgen distribution in various body compartments.

Indirect evidence of CNS adrenergic pathways activation during spaceflight.

BACKGROUND: Microgravity causes cephalad fluid shift and compensatory mechanisms. Hormonal changes suggestive of peripheral sympathetic (catecholaminergic) nervous system activation have been recently found in astronauts during flight. Simulation studies showed increased perivascular sympathetic fiber density in the rat brain. HYPOTHESIS: Intracranial microcirculatory adaptations might also occur in astronauts, involving an increase in the turnover rate of catecholamines, i.e., norepinephrine (NE) and its precursor, Dopamine (DA). DA is known to inhibit prolactin (PRL) release and to enhance growth hormone (GH) secretion by the pituitary. Therefore, increased brain dopaminergic activity would result into lower circulating PRL concentrations. At the same time, plasma levels of GH and of its effector insulin-like growth factor-1 (IGF-1) would increase during flight. METHODS: Circulating cortisol (CS), PRL, GH and IGF-1 levels were measured 2 d preflight, inflight (4-5 d after launch) and on different days postflight in four astronauts involved in the Spacelab D-2 mission. RESULTS: No significant changes were found in CS concentrations. PRL decreased while GH and IGF-1 increased inflight (p < 0.05). After flight no statistically relevant hormonal changes were found with respect to preflight. CONCLUSION: The observed hormonal changes were consistent with the original hypothesis that spaceflight might activate CNS adrenergic pathways. They occurred in the absence of two typical markers of stress, namely CS and PRL increase, thus ruling out any non-specific effect of acute stress on the results. In agreement with the most recent results of real and simulated microgravity studies performed in both the experimental animal and in man, these data lend support to the hypothesis that the CNS adrenergic pathways are also activated in the human during spaceflight.

Free Triiodothyronine and Cholesterol Levels in Euthyroid Elderly T2DM Patients.

Thyroid function regulates lipid metabolism. Despite the fact that T2DM is more prevalent in the elderly, often associates with thyroid dysfunction and increases cardiovascular risk both per se and via high TC and LDL-C levels, the association of the latter with FT(3) and FT(4) levels has not yet been fully investigated in T2DM. While trying to fill this gap in 296 elderly outpatients with T2DM, we found that TC and LDL-C correlated negatively with FT(4) and positively with FT(3). When divided according to treatment by oral hypoglycaemic agents (OHA) and insulin (IT), they reacted differently with respect to investigated associations: in the OHA's TC and LDL-C correlated negatively with FT(4) and showed no association with FT(3), whereas, in the IT's TC and LDL-C correlated positively with FT(3) and negatively with FT(4). When controlled for possible confounding factors, these associations did not change in the IT's but were missing in the OHA's. Recent literature reports upon complex hypothalamic and peripheral interactions between T2DM and thyroid, and suggests T(3) to enhance cholesterol synthesis and to have a role in insulin resistance states. Further investigations are needed to understand the intimate mechanisms of lipid metabolism in T2DM with respect to thyroid function.

The pituitary-testicular axis in microgravity: analogies with the aging male syndrome.

Extraterrestrial exploration has gone on for decades before reversible testicular failure was shown to be a consequence of space flight in humans and animals at the end of the XXth century. This phenomenon was initially thought to depend on the psycho-physical stress expected to derive from a decidedly unusual environment, but the lack of consistent data concerning cortisol increase and/or gonadotrophin suppression pointed to the possibility of a primary defect. This was indirectly confirmed by the observation that a continuum of testicular androgen secretion potential exists from microgravity to centrifuge-derived hypergravity. Further experiments using tissue slices and suspended cells confirmed a direct inhibitory effect of microgravity upon testicular androgen production. A parallel deterioration of major physiological parameters, such as bone density, muscle mass/force, red blood cell mass, hydration and cardiopulmonary performance, has been repeatedly described during space missions, which, luckily enough, fully recover within days to weeks after landing, the time lag depending on single organ/system adaptation rates. According to the Authors of the present review, when taking together all reported changes occurring in space, a picture emerges closely resembling the so-called aging male syndrome, which is currently the object of daily screening and clinical care in their endocrine unit, so that microgravity may become a tool for better understanding subtle mechanisms of testicular senescence.

[Verification of 2 fundamental types of kalemic curves during glucose tolerance tests]. / Riconoscimento di due tipi fondamentali di curve kaliemiche in corso di OGTT.

The authors have carried out statistical analysis of serum K+ decrease during OGTT test. Two kinds of K+ curves were distinguished: "one way" and "undulating". The latter are characterized by: faster starting K+ decrease (p less than 0.05), faster speed slowing down (p less than 0,005), lower starting serum K+ (p less than 0,02), precocious sign-inversion of decrease-speed value, serum K+ level before rebound lower than final K+ level in the "one way" curves. Clinical significance of this is due to the fact that in "one way" curves, low K+ levels are kept longer, presumably causing diffuse tissue damage.

[Ocular electrophysiologic study of patients with a family history of diabetes]. / Etude électrophysiologique oculaire chez des malades avec antécédent familial diabétique.

The electrofunctional alterations in a group of non diabetic patients with diabetic familiarity are considered. A high percentage of electrofunctional abnormalities was found in these patients as compared with fundus eye changes and blood glucose metabolic imbalances.

[Effect of acute intravenous administration of thyroliberin on circulating reverse-T3]. / Effetto del carico endovenoso acuto di tiroliberina (TRH) sulla reverse-T3 (rT3) circolante.

Some of the Authors previously demonstrated a significant precocious serum T3 increase after 200 micrograms TRH acute intravenous administration (TRH test). Reverse-T3 (rT3) is now known to interfere with T4 conversion to T3. We therefore compared spontaneously occurring to TRH test-induced changes in T3 and rT3 serum levels within a group of four healthy women in fertile age. Maximum rT3 increase during TRH test did not differ significantly from the maximum spontaneous variation at the same time of the day. Maximum T3 increase, on the contrary, was significantly higher than observed maximum spontaneous variation (0,81 ng/ml versus 0,39 ng/ml increase, p less than 0,01). Possible implications are discussed in the text.

[Comparison between spontaneous changes in circulating triiodothyronine (T3 and reverse-T3) and those induced by acute intravenous administration of thyroliberin]. / Confronto tra le variazioni spontanee delle triiodotironine circolanti (T3 e rT3) e quelle indotte da carico endovenoso acuto di tiroliberina (TRH).

Some of the Authors had previously observed a slight-non significant decrease in T3 serum levels 10 minutes after TRH intravenous administration. On the other hand, it is now well known that reverse T3 (rT3) inhibits T4 conversion to T3. We therefore investigated the changes in T3 and rT3 serum levels within the first ten minutes of a 200 micrograms TRH test in a group of 10 healthy women in fertile age. No significant change in T3 was demonstrated. On the other hand, rT3 showed a significant-yet slight-decrease 6 minutes after TRH injection (from 0,27 to 0,21 ng/ml, p less than 0,05). Some feasible explanations for this phenomenon are given in the text.

[Influence of blood potassium variations on changes in electrocardiographic patterns during oral glucose tolerance test]. / Influenza delle variazioni kaliemiche sulle modificazioni eletrocardiografiche rilevate in corso di "test" di tolleranza al glucosio per via orale.

In 45 apparently healthy subjects an OGTT was performed and glucose, insulin, potassium and sodium were measured at fixed intervals. A standard EKG was recorded at the beginning and at the end of the trial. K+ levels steadily decreased reaching their lowest value 60 to 120 min after insulin peak. Na+ levels did not change. In those subjects whose final EKG showed some worsening, the ratio final to initial K+ levels, unlike glucose levels, significantly decreased (p less than 0,01). The hypothesis is given that many clinical pictures of coronary heart disease, so often encountered during OGTTs, may depend on K+, rather than glucose, unbalance.

[Relation between the blood potassium and blood glucose responses and electrocardiographic changes, specifically the T wave, during the oral glucose tolerance test]. / Rapporto fra tipo di risposta kaliemica e glicemica e modificazioni elettrocardiografiche, interessanti l'onda T, in corso di "test" di tolleranza al glucosio per via orale.

As previously showed by the Authors, serum K+ levels significantly decrease during OGTT. Moreover, two possible patterns were separated: a) monophasic decrease ("M" type curve) causing a mild but continuous down-slope, possibly physiologically more relevant, and b) polyphasic decrease ("O" type curve) causing a sharp down-slope followed by a rebound to normal K+ levels. In 10 of 12 M type subjects (83%) electrocardiographic changes were shown after OGTT, comparative to only 9 out of 16 O type subjects. The Authors believe this to be suggestive of a heavier impact of kaliemic changes on to myocardial function in M type curves. The hypothesis needs further analysis.

Changes in human adrenal and gonadal function onboard Spacelab.

Astronauts have to face chronic stress during the mission period. This might cause: (i) increased adrenocortico-trophin (ACTH) and cortisol (Cort) secretion; (ii) impaired luteinizing hormone (LH) output with consequent testosterone (T) hyposecretion in men. Moreover, should the subjects prove not to synchronize their inner clocks to the time shift protocols defined by NASA, most results would be questionable. The aim of this study was to verify if plasma testicular androgens were lower than baseline and Cort biorhythm was preserved in male astronauts during a short duration flight.

[Correlation between blood insulin response and blood potassium changes during oral glucose load (preliminary note)]. / Correlazioni tra riosposta insulinemica e modificazioni della kaliemia in corso di carico orale di glucosio (nota preliminare).

Glucose, insulin, K+ and Na+ serum levels were measured at fixed intervals during OGTT. Na+ showed no significant changes, while K+ progressively decreased from 0 to 240 min. A good correlation was found between kaliaemic lowest levels and insulin peak (p less than 0,01): the former followed the latter by 60-120 min. No correlation seemed to exist between nadir K+/basal K+ ratio and insulin peak. The results and their clinical implications are discussed.

Hormonal adaptation to real and simulated microgravity.

NASA: The authors provide an overview of relevant results from endocrine studies in astronauts before, during, and after space flight. The hormonal systems examined are the water-electrolyte regulation, the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary gonadal axis, the growth hormone-insulin like growth factor 1-prolactin system, hormones which affect bone turnover, the hypothalamic-pituitary-thyroid axis, and the endocrine pancreas. Hormones studied include renin, aldosterone, vasopressin, atrial natriuretic factor, cortisol, testosterone, lutenizing hormone, prolactin, growth hormone, insulin-like growth factor-1, insulin, glucose, T4, thyroid stimulating hormone, calcitonin, active D3, and parathyroid hormone.^ieng

Gender affects the pattern of neuroendocrine response to head-up tilt.

One of the major concerns in space medicine is post-mission postural hypotension. Since the beginning, most of the studies have been aimed at the identification of mechanical and neuroautonomic mechanisms within the cardiovascular system potentially involved in this phenomenon. Some gender differences in the cardiovascular reactivity to changing posture have been described so far, which still need better clarification. Moreover, the neuroendocrine contribution to postflight readaptation deserves more indepth studies. Sudden passive head-up tilting is considered to be a good simulation method for hemodynamic changes occurring during transition from 0xg to 1xg. The aim of this study was to verify whether cardiovascular or neuroendocrine changes occurring after sudden passive +70 degrees head-up tilt (HUT) became already evident within 10 min and were similar in healthy young-adult men and women.