Urinary excretion of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate in malignancy.

The urinary excretion of cyclic adenosine 3',5'-monophosphate (cAMP), corrected for urinary creatinine, was determined in 177 patients with primary or metastatic tumours and in 149 normal subjects. In 26 patients with malignancy and in 10 control subjects the excretion of cyclic guanosine 3',5'-monophosphate (cGMP) was also evaluated. The urinary cAMP/Cr ratio in human neoplasms of epithelial origin was often significantly lower than normal, irrespective of the extension of malignancy. Surgical resection of the tumour, radiotherapy, or theophylline treatment increased urinary excretion of the nucleotide. In patients with malignancy, intravenous infusion of glucagon failed to produce the degree of elevation of plasma cAMP seen in normal subjects. Urines from patients with malignant neoplasms had low values of cAMP/Cr ratio with increased values of cGMP/Cr ratio. These findings could be the result of systemic alteration in synthesis or breakdown of the nucleotides.

Long-term treatment with calcitriol in postmenopausal osteoporosis.

In order to assess the long-term effects of calcitriol treatment in postmenopausal osteoporotic patients, 1.0 micrograms/d of calcitriol was administered in two divided doses for 1 to 8 years to 270 women with symptomatic, histologically proven postmenopausal osteoporosis. No calcium supplementation was given. Clinically, the treatment resulted in substantial relief from pain, with improvement of ambulancy. Intestinal calcium absorption, which was lower than normal at baseline, increased significantly and remained higher than the baseline value as long as calcitriol was administered. Urinary calcium absorption also increased, but hypercalcemia occurred, exceptionally and transiently, in only a few patients. Urinary hydroxyproline excretion did not increase, indicating that hypercalciuria was not of resorptive origin. Total-body density, determined by dual-photon total-body absorptiometry in 56 patients, showed an increase after 18 to 24 months of therapy in most cases. The occurrence of nontraumatic, clinically relevant fractures decreased noticeably as compared with the period preceding calcitriol treatment. No change occurred in renal function, and no renal stones developed. Calcitriol was an effective and safe treatment of postmenopausal osteoporosis.

Effects of pravastatin treatment on vitamin D metabolites.

Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.

Early synthesis and correlation of serum anti-thyroid antibodies with clinical parameters in multiple sclerosis.

A high frequency of anti-thyroid antibodies has been demonstrated in multiple sclerosis (MS), but there is a lack of data on the possible association of thyroid autoimmunity with disease activity. To assess whether anti-thyroid antibodies are synthesized early in MS or are induced over the course of the disease and whether or not they are correlated with clinical findings, we assayed serum anti-peroxidase and anti-thyroglobulin antibodies in 129 relapsing-remitting MS patients at the time of diagnosis and prior to any immunosuppressive or immunomodulatory treatment. Anti-peroxidase antibodies were detected in 28/129 (21.7%) MS patients, compared to 12/130 (9.2%) neurological controls (P=0.006) and 8/152 (5.3%) normal healthy subjects (P<0.0001). High titres of anti-thyroglobulin antibodies were detected in 11/129 (8.5%) MS patients compared to 6/130 (4.6%) patients with other neurological diseases (P=0.22) and 5/152 (3.3%) normal healthy subjects (P=0.07). Anti-peroxidase antibodies were associated with initial relapse in 14 of 28 (50%) of the patients compared to 18/101 (18%) without antibodies (P=0.001). Similarly, anti-thyroglobulin antibodies were associated with first relapse in 8/11 (73%) of the patients compared to 11/118 (9.3%) of those without (P<0.0001). However, there was no correlation between anti-thyroid antibody titres and disease duration or CSF IgG index values. By contrast, a significant inverse correlation was found between anti-thyroglobulin antibody titres and EDSS score (r(s)=-0. 75; P=0.008). Our findings demonstrate that anti-peroxidase and anti-thyroglobulin antibodies are synthesized early in relapsing-remitting MS and are associated with early clinical disease activity. Furthermore, high titres of anti-thyroglobulin antibodies are associated with low disability scores, suggesting a possible protective role of these antibodies that deserves further investigation.

Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism.

A condition of osteopenia in some cerebrotendinous xanthomatosis (CTX) patients led us to investigate bone metabolism in 8 patients belonging to 5 families. Serum calcium, phosphate and vitamin D metabolites were in the normal range; a reduction in total body density and impairment of intestinal radiocalcium absorption were found in the majority of our patients.

Calcitonin levels in normal subjects according to age and sex.

To evaluate the effect of age and sex on plasma calcitonin in human beings, the concentrations of the hormone were measured in 63 normal subjects aged 13-87 years of both sexes. In another study 30 healthy women were studied, 14 of them were pre-menopausal, 16 were post-menopausal. Plasma calcitonin was determined by means of a radioimmunoassay, using delayed tracer addition for increasing sensitivity. The antibody was produced in rabbits against pure synthetic human calcitonin and was specific for the aminoacid sequence 17 to 32 in the calcitonin molecule. A second antibody was used as a precipitating agent. A mean plasma calcitonin level of 71.3 +/- 37.0 SD pg/ml was observed. Women were found to have lower levels than men, the mean values being 63.4 +/- 34.7 pg/ml and 92.6 +/- 35.4 pg/ml respectively. The difference was statistically significant (P less than 0.005). No significant correlation was found between calcitonin levels and age of subjects. Premenopausal women, however, showed higher levels of plasma calcitonin than post-menopausal women, the mean values being 88.5 +/- 38.4 pg/ml and 54.0 +/- 33.6 pg/ml, respectively. This difference was also significant (P less than 0.01). Possible implications of these data are discussed.

Pathophysiological aspects of calcium metabolism in spasmophilia.

In order to clarify the pathophysiological mechanisms of spasmophilia, 34 subjects (31 females and 3 males) with spasmophilia were studied. The diagnosis of spasmophilia was based on a specific clinical protocol and electromyographic criteria. In the study, markedly reduced plasma ionized calcium and serum magnesium concentrations were observed together with slightly and non-significantly reduced plasma calcium and phosphate levels. An impairment of intestinal radiocalcium absorption was also noticed. Parathyroid secretion did not show any significant disturbance, but circulating calcitonin levels were found to be significantly lower than in normal subjects. The mean value of serum 25OHD was within the normal range, while a slight reduction in bone Gla protein, an index of osteoblastic activity, was detected. No difference between patients with spasmophilia and normal subjects was observed concerning 47Ca kinetics in red blood cells. The studies indicated that an impaired intestinal calcium transport together with low levels of circulating calcitonin represent the most important pathophysiological determinants of spasmophilia.

The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.

UNLABELLED: H. pylori infection is putatively associated with extra-digestive disorders and may also play a role in the development of autoimmune thyroid diseases (ATD). It was recently found that monoclonal antibodies to an H. pylori strain with cagA-positivity reacted with follicular cells of the thyroid gland, and that an H. pylori organism possessing the cag pathogenicity island carried a gene encoding for an endogenous peroxidase. The aims of this study was (1); To ascertain whether the infection by strains endowed with an increased inflammatory potential (those expressing CagA) could further enhance the risk of developing ATD (2); To verify the possible existence of an immune cross-reactivity between autoantibodies to peroxidase and thyroglobulin and H. pylori antigens (3). To establish whether thyroid colloid antigens could cross-react with an anti-H. pylori serum. The study was partly designed retrospectively. We examined 41 consecutive women with ATD, and, as a control, 33 consecutive age- and socio-economic class-matched women without autoimmune thyroid disorders, living in the same area as patients, occurred at the same institution in the same period (six months). Both patients and controls were examined serologically for H. pylori infection and CagA status by Western blotting. Some serum samples were absorbed with H. pylori to determine whether the antibody levels decreased. Colloid proteins were resolved electrophoretically and matched with a hyperimmune serum raised in rabbits against a CagA-positive H. pylori. Thirty-two patients (78.0%) tested seropositive for H. pylori infection, vs. 16 controls (48.4%) (P = 0.008, OR = 3.78, RR = 1.61). The prevalence of anti-CagA antibodies was 71.8% in infected patients, and 50% in infected controls (P = 0.161, n.s.). The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31). The other tests gave negative or inexplicable results. IN CONCLUSION: CagA-positive H. pylori infection increases the risk of ATD development.

[Gas chromatographic determination of urinary 17-ketosteroids in normal adults of various ages]. / Dosaggio gascromatografico dei 17-chetosteroidi urinari nell'adulto sano di diverse età.

The excretion of individual urinary 17-ketosteroids, pregnanediol and pregnanetriol, as measured in 98 healthy adults subdivided into groups according to age and sex, by means of a gas chromatographic analysis method based on enzymatic hydrolysis, extraction with ethyl ether, and conversion of the extracted steroids into trimethylsilyl ethers. The results showed that age and sex substantially influence the steroid pattern. Metabolites with 5-alpha configuration are predominant in young subjects; those with 5-beta configuration are pre-eminent in the more advanced ages, particularly in women. Metabolites with definite androgenous significance (C19O2-17KS) decline rapidly with advancing age, while the C19O3-17KS undergo a lesser decrease.

Adrenal function and essential hypertension.

A study of the adrenal function in patients with essential hypertension was performed using gas-liquid chromatography to separate and measure the daily urinary excretion of individual 17-ketosteroids, pregnanediol and pregnanetriol in basal conditions and after a dexamethasone suppression test. The purpose of the study was to detect alterations of adrenal function possibly indicative of some role of the adrenal cortex in the pathogenesis of hypertension. The results showed normal urinary levels of 17-ketosteroids, pregnanediol and pregnanetriol in most patients. Higher values were observed in the remaining cases. Dexamethasone suppression tests confirmed that steroid excess in these patients was of adrenal origin.

Technical problems in the assay of serum 25-hydroxyvitamin D.

Various methods to enhance the solubility of 25-hydroxyvitamin D in the aqueous buffer used for competitive protein binding assay are compared. The problem of non-specific binding caused by the addition of various substances to the buffer to prevent loss of 25-hydroxyvitamin D from the reaction mixture is also evaluated. Bovine albumin at the concentration of 0.2-0.4 g % seems to represent the best solution of the above problems, since it exerts a good solubilizing effect on 25-hydroxyvitamin D with low non-specific binding counts.

Studies on the hydroxylation of vitamin D in man.

The authors have studied some of the factors influencing vitamin D hydroxylases in man, using two indirect experimental approaches. In the first study they have considered the effect of a long-term treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the serum levels of 25-hydroxyvitamin D (25-OHD) in postmenopausal osteoporosis, a condition in which high serum levels of 25-OHD and low mean levels of 1,25(OH)2D have been observed. In the second study the effects of the infusion of physiological doses of human parathyroid hormone (PTH) on the serum levels of 1,25(OH)2D and 24,25(OH)2D have been investigated. In the first study a decrease in the circulating levels of 25-OHD was observed during 1,25(OH)2D3 treatment. This could be considered as an indirect evidence of an inhibitory action of 1,25(OH)2D3 on 25-hydroxylase: in this view 1,25(OH)2D3 treatment decreases 25-hydroxylase activity, which is higher than normal in postmenopausal osteoporosis due to the low levels of 1,25(OH)2D. In the second study PTH infusion was followed by a remarkable increase in 1,25(OH)2D serum levels as a result of 1 alpha-hydroxylase stimulation, which was much higher in patients with hypoparathyroidism. The determination of 24,25(OH)2D levels during PTH infusion indicated an inhibitory effect on 24-hydroxylase.