Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs.

The endogenous cannabinoid anandamide (AEA) plays important roles in modulating pain. Head pain is an almost universal human experience, yet primary headache disorders, such as migraine without aura (MoA) or episodic tension-type headache (ETTH), can represent a serious threat to well-being when frequent and disabling. We assessed the discriminating role of endocannabinoids among patients with ETTH or MoA, and control subjects. We measured the activity of AEA hydrolase and AEA transporter, and the level of cannabinoid receptors in peripheral platelets from MoA, ETTH and healthy controls. Sixty-nine headache patients and 36 controls were selected. Diagnosis of headache type was made according to the International Headache Society criteria. We observed significant sex differences concerning AEA membrane transporter and fatty acid amide hydrolase activity in all groups. An increase in the activity of AEA hydrolase and AEA transporter was found in female but not male migraineurs. Cannabinoid receptors were the same in all groups. Here we show that the endocannabinoid system in human platelets is altered in female but not male migraneurs. Our results suggest that in migraineur women an increased AEA degradation by platelets, and hence a reduced concentration of AEA in blood, might reduce the pain threshold and possibly explain the prevalence of migraine in women. The involvement of the endocannabinoid system in migraine is new and broadens our knowledge of this widespread and multifactorial disease.

Does the antimigraine action of flunarizine involve the dopaminergic system? A clinical-neuroendocrinological study.

We have investigated the prolactin response to bromocriptine (BRC), a D2 dopamine receptor agonist in migrainous women before and after treatment with flunarizine. We evaluated whether this test was predictive of therapeutic efficacy of flunarizine treatment and whether the therapeutic response to flunarizine treatment was related to its effect on dopaminergic system at tuberoinfundibular level. Ten migrainous women underwent a BRC test in the late follicular phase before and after 1 and 3 months of treatment with flunarizine 10 mg at bedtime. Blood samples of prolactin (PRL), growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone were taken at basal condition. PRL was also evaluated 1 and 2 h after BRC (2.5 mg) administration. Each patient kept a daily headache diary for 1 month prior to the test and throughout the study. The level of PRL inhibition after BRC administration, observed before flunarizine treatment, was not predictive of the therapeutic response observed after 1 and 3 months of treatment. The effect of flunarizine on PRL level was not related to the therapeutic efficacy of the drug. These data suggest that flunarizine does not attenuate the activity of dopaminergic neurons in migrainous patients, and that the antimigraine effect of flunarizine does not seem related to its action on dopaminergic system at least at tuberoinfundibular level.

Intrauterine growth retardation: evidence for the activation of the insulin-like growth factor (IGF)-related growth-promoting machinery and the presence of a cation-independent IGF binding protein-3 proteolytic activity by two months of life.

Thirty-seven children with intrauterine growth retardation (IUGR) were enrolled in a 3-mo longitudinal study. Weight, length, and knee-heel length (by knemometry) were measured at birth and at 7, 14, 30, 60, and 90 d. GH, IGF-I, IGF binding protein (BP)-3, IGFBP-1, and C-peptide were measured at birth and at 2 mo. IGFBP-3 Western immunoblotting and proteolytic activity assay were also performed. Twenty-five newborns with birth weight appropriate for gestational age were chosen as controls. At birth IUGR newborns showed levels of GH and IGFBP-1 significantly higher, and IGF-I, IGFBP-3, and C-peptide significantly lower than control subjects. At 2 mo GH and IGFBP-1 levels decreased, whereas IGF-I, IGFBP-3, and C-peptide rose, attaining the concentrations found in control subjects at birth. Baseline peptide levels as well as their 2-mo variations did not correlate with the gain in weight, supine length, and knee-heel length recorded at 3 mo. Fourteen of nineteen IUGR cord blood samples showed the presence of the intact approximately 42-39-kD IGFBP-3 doublet and the major approximately 29-kD fragment. At 2 mo the IGFBP-3 band pattern was characterized by the predominance of a approximately 18-kD fragment in 6 of 19 tested IUGR infants. The incubation of 2-mo IUGR samples with normal adult serum induced the appearance of the approximately 18-kD band, which was not modified by the addition of EDTA. These results suggest that: 1) the IGF-related growth-promoting mechanism is impaired in IUGR children at birth but is fully restored at 2 mo; 2) the cord blood levels of GH, IGF-I, IGFBP-3, IGFBP-1, and C-peptide are not predictive of the weight and length gain during the first 3 mo of life; 3) IUGR children have at least two different IGFBP-3 proteases, one cation-dependent protease that is present at birth and able to yield the major approximately 29-kD IGFBP-3 fragment and a second one, with a different activation timing, which exhibits cation independence and induces the formation of a approximately 18-kD IGFBP-3 form.

IGF-I and IGF-binding protein-1 are related to cortisol in human cord blood.

OBJECTIVE: To assess cortisol concentrations in cord blood and investigate their relationships with the IGF system. STUDY DESIGN: Fifteen newborns with birth weight appropriate for gestational age (AGA) and 30 children with intrauterine growth retardation (IUGR) were studied. Serum samples were collected from umbilical cord blood and cortisol, IGF-I and IGF-binding proteins (IGFBPs)-1 and -3 were measured. IUGR infants were followed up for 3 months with repeated measurements of weight, supine length and knee-heel length (by knemometry). RESULTS: IUGR newborns showed significantly greater concentrations of IGFBP-1 (P<0.0001) and lower concentrations of IGF-I (P< 0.0001) and IGFBP-3 (P< 0.0001) than did controls. In AGA children, cortisol correlated inversely with IGF-I (r=-0.75, P< 0.002) and directly with IGFBP-1 (r=0.52, P <0.05), whereas no correlation between cortisol and IGF system-related variables was observed in IUGR. Finally, in IUGR children an inverse correlation was found between length gain in the first trimester of life and cortisol concentrations at birth (r=-0.54, P < 0.005). CONCLUSIONS: Cortisol might be a physiological regulator of fetal growth, at least in the last part of pregnancy, by modulating IGF-I and IGFBP-1 release under conditions of fetal stress. In IUGR children, a rearrangement of this growth control mechanism seems to occur. The close inverse relationship of cortisol with linear growth, if confirmed by large-scale studies, suggests cord blood cortisol to be potentially predictive of early postnatal catch-up growth in IUGR infants.

A process for the recovery of strontium from the urine of patients injected with 89Sr.

89Sr is a beta emitter used for palliation of pain in patients with metastatic bone cancer. After each intravenous administration, up to 80% of the isotope is eliminated in the urine. A simple chemical process is described, which permits the recovery and purification of the 89Sr from the urine.

Tall cell variant of papillary thyroid cancer.

Papillary histologic type is the most common form of thyroid carcinoma amounting to 85% cases. This pathology presents a rather good prognosis, but a few years ago, new subtypes have been described. Some of these variants show a fairly good prognosis i.e follicular, macropapillary, encapsulated while others appear to have a decidedly worse one, columnar cells, diffused sclerosing, or even to be clearly malignant as in the case of the tall cell variant. The authors report a case treated by a combined surgical and radiometabolic therapy and evidence the main characteristics of this rare and underestimated neoplasia.

Prolactin response to bromocriptine in flunarizine-treated migrainous women.

Flunarizine, a calcium channel blocker, is widely used in migraine prophylaxis. Although an antidopaminergic effect has been suggested for this drug, it is unclear whether the antimigraine action of flunarizine involves the dopaminergic system. We studied the inhibitory response of prolactin to acute administration of bromocriptine, a D2 dopamine receptor agonist, before and after 1 month of treatment with flunarizine in migrainous women. Flunarizine treatment increased basal prolactin levels, but it did not reduce the inhibitory response of prolactin to acute bromocriptine administration. These findings do not support the hypothesis that flunarizine acts as a direct antagonist at the D2 dopamine receptor.

Renal cell carcinoma detection and systemic therapy with tumour-affine gallium-67 and with yttrium-90 citrate solutions.

BACKGROUND: There have been no major advances in the systemic detection of renal cell carcinoma (RCC) and its unpredictable metastases. Surgery, thus, remains the mainstay of the curative treatment for the localized disease. The propose of the present study has been to systemically detect and treat advanced RCC respectively with Ga-67 and Y-90 radiopharmaceuticals containing tumour-affine species. PATIENTS AND METHODS: Thirty-three RCC patients were imaged with Tc-99m-MDP and then with Ga-67 citrate solution in order to detect RCC and its metastases. Yttrium-90 citrate solution, containing the radionuclide species chromatographically and electrophoretically identical to those in RCC-affine Ga-67 solution, was administered i.v. for systemic therapy of advanced RCC. Total-body distribution of Y-90 was studied with a gamma-camera equipped with an ultra-high-sensitivity collimator. The efficacy of the therapy was studied by the clinical condition of the patient and by the total-body scintigraphic imaging with Tc-99m-MDP and with Ga-67 citrate solution. RESULTS: Ga-67 detects RCC bone metastases better than Tc-99m-MDP. Systemic therapy of RCC metastasized to bones, lung and brain was obtained with RCC-affine Y-90 citrate solution. CONCLUSIONS: Third group metal radionuclides, Ga-67 and Y-90, detect and treat advanced RCC.

Advanced prostate cancer diagnosis and therapy with gallium-67 and yttrium-90, respectively.

BACKGROUND: Androgen deprivation therapy remains so far the mainstay of advanced prostate cancer treatment. Although it improves the quality of life of the patient for some time, the disease progresses and soon it becomes hormonally unresponsive. The object of our research has been to find a systemic therapy for prostate cancer patients whose disease no longer responds to hormone therapy, radiation therapy, chemotherapy and immunotherapy. PATIENTS AND METHODS: Thirty-one advanced prostate cancer patients with intense bone metastasis pain, bed ridden, and with permanent urinary catheter were first examined with Ga-67 and then treated with Y-90 solutions which were chromatographically and electrophoretically analysed for the presence of both cationic and anionic species of the radionuclide. The quality of life and prostate specific antigen (PSA values) values were followed for testing the success of the therapy. RESULTS: Prostate cancer-affine Y-90 cured the advanced prostate cancer patients who regained their normal life. The uptake of the radionuclide in the primary cancer and its metastases responsible for the treatment has been confirmed by scintigraphy. CONCLUSIONS: Prostate cancer-affine Y-90 solution, containing stable cationic and anionic species of the radionuclide, is effective in the cure of advanced prostate cancer patients.

Gamma camera imaging of osseous metastatic lesions by strontium-89 bremsstrahlung.

The aim of this study was to optimise the parameters affecting the Bremsstrahlung scintigraphy of patients injected with strontium-89 chloride. The parameters considered were : (1) instrumental detection efficiency, and (2) tissue attenuation factor for 89Sr calibrated sources, which permit quantitative evaluation of the activity in a given bone lesion. Some typical examples of in vivo 89Sr imaging are presented to illustrate the clinical utility of the imaging procedure developed by us, which is implemented in our department for all patients treated with 89Sr chloride.

Urinary pyridinium collagen cross-links predict growth performance in children with idiopathic short stature and with growth hormone (GH) deficiency treated with GH. Skeletal metabolism during GH treatment.

GH is able to promote longitudinal growth in children with GH-deficiency (GHD) and in some children with idiopathic short stature (ISS). The objectives of this study were to evaluate the predictive value of bone and collagen markers on the growth response to GH therapy in children with ISS and with GHD, and to characterize the effects of GH treatment on bone and collagen turnover in children with ISS and with GHD. Twenty prepubertal short, slowly growing, children treated with GH, 15 IU/m2 per week, were studied; of them 13 (10 males) had ISS and 7 (5 males) had GHD. An overnight 12-h urinary collection and a fasting morning blood sample were obtained at baseline, 1, 3, 6, and 12 months of treatment. Urinary levels of collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), and circulating levels of osteocalcin, intact PTH, calcitonin, procollagen type III aminoterminal propeptide (PIIINP), insulin-like growth factor-I, and alkaline phosphatase were determined. Urinary collection was also obtained from 127 healthy children (51 males) aged 6-13 yr. In children with ISS, the changes in Dpd over 1 month of GH therapy were related to the changes in height velocity (HV) over 1 yr of therapy (r = 0.67; P < 0.05); the changes in Pyd after 1 month of GH treatment were related to the changes in HV at 6 months of GH treatment (r = 0.57; P < 0.05). All the other markers evaluated were not related to the HV changes in children with ISS. In children with GHD, the changes in Pyd and in Dpd after 1 month of GH treatment were positively related to the changes in HV after 12 months of therapy (r = 0.82; P < 0.05, and r = 0.82; P < 0.05, respectively). The changes in Pyd after 1 month were also related to the HV changes after 6 months of GH (r = 0.77; P < 0.05). Positive relationships between the HV after 6 months of GH and the increases of PIIINP (r = 0.80; P < 0.05) and osteocalcin (r = 0.77; P < 0.05) after 3 months of GH therapy were observed. All patients showed urinary Dpd and Pyd excretions in the normal range. In patients with ISS, Pyd (P < 0.05), Dpd (P < 0.05), osteocalcin (P < 0.01), PIIINP (P < 0.01), and alkaline phosphatase (P < 0.01) increased longitudinally during the GH treatment and the increments reached a maximum after 3-6 months of therapy. Patients with GHD showed an increase of the same markers but the increases occurred earlier, after 1 month of GH therapy. The collagen cross-links, Pyd and Dpd, could be helpful early markers in predicting the responsiveness to GH therapy in children with ISS and with GHD. GH treatment stimulates bone and collagen metabolism.

Timing and course of leucocyte aggregation in myocardial infarction.

In order to evaluate the pathophysiological relevance and clinical implications of leukocyte rheology in myocardial ischaemia we measured the percentage of aggregated leukocytes in 43 subjects with acute substernal pain before diagnosis. The percentage of aggregated leukocytes was significantly higher in 16 patients with subsequent diagnosis of myocardial infarction with respect to 11 with angina and 16 with non ischaemic chest pain (4.75 +/- 0.88, 3.43 +/- 0.65 and 1.52 +/- 0.32 respectively p < 0.01). The percentage of aggregated leukocytes was also evaluated in another group of 46 patients hospitalized for myocardial infarction. Among these, aggregated leukocytes were significantly higher in those with residual ischaemia, with respect to those without residual ischaemia (7.4 +/- 1.1 vs 3.5 +/- 0.6, p < 0.01). In conclusion, leukocyte aggregation is precociously increased after myocardial ischaemia. It may be a marker of residual ischaemia in patients with myocardial infarction.

Is IGF binding protein-3 assessment helpful for the diagnosis of GH deficiency?

OBJECTIVE: The measurement of serum immunoreactive IGFBP-3 levels has been proposed as a screening test to identify children with growth hormone deficiency (GHD). We tested the sensitivity and specificity of the IGFBP-3 assessment in comparison with the measurement of IGF-I. DESIGN: We assessed the IGFBP-3 and IGF-I circulating levels in normal subjects and patients with GHD or idiopathic short stature (ISS). PATIENTS: Eighty-two normal subjects, 16 GHD, and 10 children with ISS were studied. Controls were divided into three age groups: group A, 1-4 years (n = 16); group B, 5-9 years (n = 35), and group C, 10-14 years (n = 31). MEASUREMENTS: All subjects underwent standard anthropometry. In short patients, GH secretory status was assessed by clonidine and arginine stimulation tests. IGFBP-3 and IGF-I circulating levels were measured by radioimmunoassay. RESULTS: IGFBP-3 and IGF-I levels were closely related (r = 0.51, P < 0.0001) and IGFBP-3 was less age dependent than IGF-I (r = 0.57, P < 0.02 vs r = 0.64, P = 0.0001). Sensitivity (true positive ratio) and specificity (true negative ratio) of IGFBP-3 measurement were 50 and 92% respectively, whereas sensitivity and specificity of IGF-I assessment were 75 and 90% respectively. Below the age of 5 years, sensitivity was 20% for IGFBP-3 and 40% for IGF-I; specificity was 94% for IGFBP-3 and 88% for IGF-I. CONCLUSIONS: IGFBP-3 measurement had poor sensitivity in detecting growth hormone deficient patients, offering no diagnostic advantage over IGF-I, even in the first years of life, although, due to the high specificity, the finding of subnormal levels of IGFBP-3 was strongly suggestive of growth hormone deficiency. The presence of low IGFBP-3 and IGF-I levels in a short child with normal GH response to provocative tests should prompt further investigations, such as the determination of spontaneous GH secretion or assessment of the GH binding proteins together with an IGF-I and/or IGFBP-3 generation test, in order to identify neurosecretory dysfunction or GH receptor deficiency. Finally, we believe that there is no definitive test for diagnosing or excluding growth hormone deficiency and detailed analysis of the results of endocrine tests, clinical findings and other laboratory and radiological information is necessary to maximize diagnostic accuracy.

l-deprenyl test in migraine: neuroendocrinological aspects.

We evaluated the effect of l-deprenyl, a drug that increases the availability of endogenous dopamine, on the plasma levels of prolactin and growth hormone in 10 female patients with migraine and in 10 control subjects matched for age and menstrual phase. The patients showed a significant decrease in prolactin levels at 30, 60 and 120 min after the oral administration of 5 mg of l-deprenyl when compared with the values obtained in controls (p < 0.001). The effects of l-deprenyl on growth hormone plasma levels were not significantly different between patients and controls. These data suggest that l-deprenyl inhibits prolactin release in migraine patients, but not in control subjects. This differential sensitivity could be explained by dopamine receptor supersensitivity in migraine patients.

Use of the thyroid 99Tcm scintiscan with lead-shield on the hot nodule in the diagnosis of autonomous adenoma.

Eighteen patients bearing a hot nodule, imaged by basal 99Tcm scintiscan and toxic in eight of them, were studied. All patients underwent 99Tcm thyroid scintiscan in basal conditions and after placing a lead-shield on the hot thyroid nodule, without other radioisotope administration. In eight cases the thyroid scintiscan after lead-shield overlapping the hot nodule, was compared to a second 99Tcm thyroid scintiscan after thyrotrophic hormone stimulation, TSH. This technique of nodule shielding was able to show the extranodular tissue in 15 patients; in the remaining three cases neither this approach nor the scintiscan after exogenous TSH were able to demonstrate any remainder thyroid parenchyma. Thus, this scintigraphic method can be considered excellent in the diagnosis of autonomous adenoma: it needs, in fact, a single radioisotope administration and does not present the adverse effects frequently induced by exogenous TSH.

A study of esophageal reflux following total gastrectomy with hepatobiliary sequential scintigraphy using TC-99m DISIDA.

A new technique to study esophageal reflux by means of hepatobiliary photoscintigraphy using TC-99m DISIDA was examined. The study was undertaken on 19 patients undergoing total gastrectomy without esophageal recurrence or hepatic or pulmonary metastases. The results of hepatobiliary photoscintigraphy were compared with the clinical, endoscopic and radiologic data. From this comparison it was demonstrated that photoscintigraphy is a non-invasive procedure which permits the study of the intestinal loops excluded from the transit of food but not of bile. Hepatobiliary scintigraphy was shown to be a reliable examination and the only one which demonstrates the reflux under physiological conditions, since the 24h. pH test in the absence of the stomach does not clearly prove the presence of alkaline reflux (bile) in an alkaline environment (esophagus). The disadvantages of photoscintigraphy are that the reflux is demonstrated only during the period of examination and in the patients undergoing total gastrectomy it is difficult to identify with accuracy the esophageal anastomosis. In these cases however, the radioactive bolus was used to localize the anastomosis and therefore to assess the esophageal reflux.