Rafts for antigen presentation?
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Animals↗
Biomedical subjects
G Lombardi
Publications and source records attributed to G Lombardi.
Characterization of ionotropic glutamate receptors in human lymphocytes.
The effect of L-glutamate (Glu) on human lymphocyte function was studied by measuring anti-CD(3) monoclonal antibody (mAb) or phytohaemagglutinin (PHA)-induced intracellular Ca(2+) ([Ca(2+)](i)) rise (Fura-2 method), and cell proliferation (MTT assay). Glu (0.001 - 100 microM) did not modify basal lymphocyte [Ca(2+)](i), but significantly potentiated the effects of anti-CD(3) mAb or PHA. Maximal [Ca(2+)](i) rises over resting cells were: 165+/-8 and 247+/-10 nM at 3.0x10(-2) mg ml(-1) anti-CD(3) mAb; 201+/-4 and 266+/-9 nM at 5.0x10(-2) mg ml(-1) PHA, in the absence or presence of 1 microM Glu, respectively. The Glu effect showed a bell-shape concentration-dependent relationship, with a maximum (+90+/-3% for anti-CD(3) mAb and +57+/-2% for PHA over Glu-untreated cells) at 1 microM. Non-NMDA receptor agonists (1 microM) showed a greater efficacy (+76+/-2% for (S)-AMPA; +78+/-4% for KA), if compared to NMDA (+46+/-2%), or Glu itself. Ionotropic Glu receptor antagonists completely inhibited the effects of the corresponding specific receptor agonists (1 microM). The IC(50) values calculated were: 0.9 microM for D-AP5; 0.6 microM for (+)-MK801; 0.3 microM for NBQX. Both NBQX and KYNA were able to abolish Glu effect. The IC(50s) calculated were: 3.4 microM for NBQX; 0.4 microM for KYNA. Glu (0.1 - 1 mM) did not change the resting cell proliferation, whereas Glu (1 mM) significant inhibited (-27+/-4%) PHA (1.0x10(-2) mg ml(-1))-induced lymphocyte proliferation at 72 h. In conclusion, human lymphocytes express ionotropic Glu receptors functionally operating as modulators of cell activation.
2-Amino-5-phosphonovalerate↗
Minor H antigens: genes and peptides.
In this review, we describe the evidence from which the existence of non-MHC histocompatibility (H) antigens was deduced, the clinical setting of bone marrow transplantation in which they are important targets for T-cell responses, and the current understanding of their molecular identity. We list the peptide epitopes of the human and murine minor H antigens now identified at the molecular level, their MHC restriction molecules and the genes encoding them. Identification of the peptide epitopes allows T-cell responses to these antigens following transplantation of MHC-matched, minor H-mismatched tissues to be enumerated using tetramers and elispot assays. This will facilitate analysis of correlations with host-versus-graft (HVG), graft-versus-host (GVH) and graft-versus-leukaemia (GVL) reactions in vivo. The potential to use minor H peptides to modulate in vivo responses to minor H antigens is discussed. Factors controlling immunodominance of T-cell responses to one or a few of many potential minor H antigens remain to be elucidated but are important for making predictions of in vivo HVG, GVH and GVL responses and tailoring therapy after HLA-matched bone marrow transplantation and donor lymphocyte infusion.
Alleles↗
In vivo and in vitro effects of octreotide, quinagolide and cabergoline in four hyperprolactinaemic acromegalics: correlation with somatostatin and dopamine D2 receptor scintigraphy.
OBJECTIVE: GH and PRL cosecretion frequently occurs in acromegaly and the sensitivity of both hormones to somatostatin analogs (SA) and dopamine agonists (DA) alone or in combination, is still debated. This study was designed to evaluate the in vivo and in vitro sensitivity to SA and/or DA and correlate the response in terms of hormone suppression to the results of in vivo somatostatin and dopamine receptor scintigraphy and to the immunohistochemical findings. DESIGN AND PATIENTS: Scintigraphy using 111In-DTPA-D-Phe(1)-OCT (111In-OCT) and 123I-methoxybenzamide (123I-IBZM) was performed in four patients with acromegaly and high circulating GH, PRL and IGF-I levels. The results were correlated with the response to long-term treatment with octreotide (OCT), quinagolide (QN) and/or cabergoline (CAB), to the in vitro hormone suppression by OCT and DA in primary cultures from the pituitary tumors and to the immunohistochemical findings. RESULTS: The first patient showed high tumour uptake of 111In-OCT and 123I-IBZM, the second high uptake of only 111In-OCT, while the third one showed faint tumour uptake of only 123I-IBZM, and the fourth a faint uptake of 111In-OCT. In the first and in the fourth patients OCT or CAB administered alone failed to normalize hormone levels while the combined treatment induced circulating GH, IGF-I and PRL normalization. In the second patient OCT administered alone normalized hormone levels while QN reduced PRL levels only. In the third patient both OCT and QN, alone or in combination, failed to normalize hormone levels. However, in this patient GH and PRL suppression was significantly greater after QN than OCT treatment. After medical therapy, all the patients were operated on. Immunohistochemistry showed diffuse GH and focal PRL staining in the first patient, while diffuse GH and PRL staining in the remaining three. In vitro, OCT significantly suppressed GH secretion in the four primary pituitary tumor cultures, while PRL secretion was significantly suppressed only in the second and the fourth cases. Dopamine agonists (DA) significantly suppressed PRL release in all the cultures, while GH secretion was significantly suppressed in three out of four. CONCLUSIONS: These four acromegalics, presenting similar clinical findings and comparable peripheral hormone levels, showed different responsiveness to SA and DA. Moreover, during the in vitro study on primary tumor cell cultures, OCT and DA displayed an inhibiting activity on GH and PRL secretion positively correlated with the response observed in vivo. This evidence together with the in vivo receptor imaging study suggest the existence of somatostatin and/or dopamine D2 receptor heterogeneity in this class of pituitary tumors. The new potent DA might be primarily considered in the medical treatment of hyperprolactinemic acromegalics, while SA alone or in combination with DA in case of ineffective hormone suppression.
Acromegaly↗
Central diabetes insipidus and heart: effect of acute arginine vasopressin deficiency and replacement treatment with desmopressin on cardiac performance.
Besides its effects on water balance, arginine vasopressin (AVP) increases peripheral vascular resistance and decreases cardiac output, mainly by decreasing heart rate. The current study was designed to evaluate cardiac performance in patients with central diabetes insipidus (CDI), focusing on the acute effects of desmopressin replacement withdrawal and its subsequent reinstatement in patients with CDI. Twelve patients with CDI and 12 sex- and age-matched healthy subjects entered the study. All patients were receiving treatment with intranasal desmopressin at standard doses. All patients and controls were assessed for water balance, by measuring plasma osmolality and total body water, anterior pituitary function, heart rate, systolic and diastolic blood pressure. Left ventricular (LV), end-diastolic and end-systolic diameters (LVEDD, LVESD) and volumes (LVEDV, LVESD), end-diastolic and end-systolic interventricular septum thickness (EDIVST, ESIVST) and posterior wall thickness (LVEDPWT, LVESPWT), and mass (LVM) were measured by echocardiography. Moreover, LV systolic function was assessed by measuring the ejection fraction (EF), the fractional shortening (FS), the Suga index, the stroke volume and the cardiac output, while LV diastolic function was assessed by measuring early (M1) and late (M2) maximal transmitral blood flow velocities, the ratio between M1 and M2, the mitral deceleration time (MDT) and the isovolumetric relaxation time. All parameters were assessed in the patient group 24 h after discontinuing treatment with nasal desmopressin (baseline study) and 1 week after re-starting replacement treatment, while in the control group before (baseline study) and after 1-week of a nasally administered placebo. At baseline, compared to controls, patients with CDI had increased plasma osmolality (P < 0.01), plasma ACTH (P < 0.01), serum (P < 0.01) and urinary cortisol (P < 0.01) levels, and heart rate (P < 0.05), and decreased total body water (P < 0.05). Systolic and diastolic blood pressure and the other anterior pituitary hormones were similar in patients and controls. At echo-cardiography, EDIVST (P < 0.05), ESIVST (P < 0.01), LVEDPWT (P < 0.05) and LVESPWT (P < 0.01), EF (P < 0.01), Suga index (P < 0.05), FS (P < 0.05), M2 (P < 0.01) and IRT (P < 0.05) were significantly higher while LVESD (P < 0.01), LVESV (P < 0.01), LVEDD (P < 0.05), LVEDV (P < 0.05), M1 (P < 0.05), and M1/M2 (P < 0.01) were significantly lower in patients than in controls. LVM, stroke volume and cardiac output, were similar in patients and controls. In the patient group, after 1 week of replacement treatment with desmopressin, all echocardiographic parameters were normalized, except IVT, LVPWT and the diastolic parameters that were still abnormal compared to controls. No difference was found in any of the parameters in the control group one week after placebo administration. Patients with central diabetes insipidus have increased heart rate and left ventricular contractility, and impaired diastolic function. The altered heart rate and left ventricular contractility, reversible after desmopressin replacement, is likely to be due to stimulation of sympathetic nervous activity, induced by the hypovolemia associated with arginine vasopressin deficiency. Conversely, the impairment of diastolic function, persistent after desmopressin replacement, probably relates to a stable impairment of the left ventricular compliance.
Administration, Intranasal↗
Growth hormone and the heart.
Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in GH deficiency and excess. Experimental and clinical studies have supported the evidence that GH and IGF-I are implicated in cardiac development. In most patients with acromegaly a specific cardiomyopathy, characterized by myocardial hypertrophy with interstitial fibrosis, lympho-mononuclear infiltration and areas of monocyte necrosis, results in biventricular concentric hypertrophy. In contrast, patients with childhood or adulthood-onset GH deficiency (GHD) may suffer both from structural cardiac abnormalities, such as narrowing of cardiac walls, and functional impairment, that combine to reduce diastolic filling and impair left ventricular response to peak exercise. In addition, GHD patients may have an increase in vascular intima-media thickness and a higher occurrence of atheromatous plaques, that can further aggravate the haemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. However, several lines of evidence have suggested that the cardiovascular abnormalities can be partially reversed by suppressing GH and IGF-I levels in acromegaly or after GH replacement therapy in GHD patients. Recently, much attention has been focussed on the ability of GH to increase cardiac mass suggesting its possible use in the treatment of chronic nonendocrine heart failure. In fact, GH administration can induce an improvement in haemodynamic and clinical status in some patients. Although these data need to be confirmed in more extensive studies, such promising results seem to open new perspectives for GH treatment in humans.
Acromegaly↗
Increased arterial intima-media thickness by B-M mode echodoppler ultrasonography in acromegaly.
BACKGROUND: Patients with acromegaly have an increased morbidity and mortality for cardiovascular diseases. Despite the increasing evidence for the existence of a specific cardiomyopathy in acromegaly, the presence of vascular abnormalities has been never investigated. OBJECTIVE: To evaluate the cardiovascular risk and premature atherosclerosis in acromegaly. SUBJECTS: Forty-five patients with acromegaly and 30 sex- and age-matched healthy subjects were included in this study: 30 patients were studied at the diagnosis of acromegaly and were in active disease (GH 59.3 +/- 10.2 mU/l, IGF-I 733 +/- 57.6 microg/l) while 15 patients were studied after surgery and/or radiotherapy and were cured from the disease (GH 4.5 +/- 0.7 mU/l, IGF-I 172.4 +/- 16.9 microg/l). METHODS: Body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), serum total, LDL- and HDL-cholesterol, triglycerides, and fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), glucose and insulin levels (fasting and after glucose load) were measured in all patients and controls. By echodoppler ultrasonography, blood systolic (SPV) and diastolic (DPV) peak velocity, and resistance index (RI) were measured at both common and internal carotid arteries where presence, size and location of atherosclerotic plaques were evaluated by B-Mode ultrasonography. Intima-media thickness (IMT) of both common carotids was measured by M-Mode ultrasonography. RESULTS: SBP, but not DBP, was significantly higher in patients with active disease than in cured patients and controls (P = 0.003). Hypertension was found in nine (30%) patients with active disease, in two (13.3%) of those cured from acromegaly and in none of controls (chi2 = 10.81, P < 0.004). Fasting blood glucose levels were significantly higher both in patients with active disease and in those cured from the disease than in controls (P < 0.001). Circulating insulin levels were significantly higher in patients with active disease than in cured patients and controls (P < 0.001) and in cured patients than in controls (P < 0.001). Glucose tolerance abnormalities were found in 13 (43.3%) patients with active disease, in four (26.6%) patients with inactive disease and in four controls (13.3%) (chi2 = 6.71, P = 0.03). Total blood cholesterol levels were similar in the three groups, LDL-cholesterol and triglycerides levels were significantly higher, whereas HDL-cholesterol levels were significantly lower both in patients with active disease and in those cured from the disease than in controls (P < 0.001). Serum fibrinogen levels were significantly higher both in patients with active disease and in those cured from the disease than in controls (P < 0.001). No difference was found in PT and APTT levels among the three groups. At the level of right and left common carotid arteries, IMT was significantly higher both in patients with active disease and in those cured from the disease than in controls (P < 0.001). Both right and left SPV, but not DPV, were significantly higher in patients with active disease than in those cured from the disease and in controls (P < 0.01). Well defined carotid wall plaques were detected in two patients (6.6%) with active disease, in one patient cured from the disease (6.6%) and in two controls (6.6%). At the level of right and left internal carotid arteries, SPV, DPV and RI were similar among the three groups. Well defined carotid wall plaques were detected in three patients with active disease (10%), two patients cured from the disease (13.3%) and in one control (3.3%). CONCLUSIONS: A significant increase of IMT of both common carotid arteries was observed in patients with active acromegaly, this was also found in those cured from acromegaly. However, the prevalence of well defined carotid plaques was not increased in both groups of patients with acromegaly as compared to controls. On this basis, heart more than vessels seems to be affected by chronic GH and IGF-I excess in acromegaly.
Acromegaly↗
The contributions of T-cell anergy to peripheral T-cell tolerance.
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Abatacept↗
Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn's disease and ulcerative colitis: a GISC study.
OBJECTIVES: Recent studies in familial Crohn's disease (CD) have suggested that anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) may represent a new specific marker of genetic susceptibility. In this study we aimed to assess the importance of ASCAs by comparing their presence in a large number of patients with sporadic and familial occurrence of CD or ulcerative colitis (UC) and their unaffected relatives. METHODS: Serum samples from 96 patients with sporadic CD, 97 patients with sporadic UC, and 50 unrelated healthy controls were tested for ASCAs by a standard ELISA method. Moreover, 73 families with two or more members affected by CD and/or UC were recruited. From these families 58 CD patients, 84 UC patients, and 216 unaffected first degree relatives were investigated. RESULTS: ASCAs were detected in 34 of 96 patients with sporadic CD (35%, p < 0.01 vs controls), 11 of 97 patients with sporadic UC (12%), and two of 50 controls (4%). ASCAs were significantly (p < 0.04) more frequent in patients with familial CD (55%) and familial UC (25%) than in sporadic cases. Moreover, ASCAs were found in 25% of unaffected relatives, and this rate did not significantly differ in CD, UC, and mixed families (28%, 26%, and 22%, respectively). CONCLUSIONS: In this study we confirm that ASCAs occur particularly frequently in CD patients, especially with the presence of a positive family history. However, they are also significantly increased in UC patients with a family history and in a considerable number of unaffected relatives of inflammatory bowel disease families, irrespective of the characteristics of their families (UC, CD, mixed, ASCA positive, and ASCA negative). The presence of ASCAs in unaffected relatives might point toward a genetic predisposition to either CD or UC.
Adolescent↗
Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum.
OBJECTIVE: Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS: In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (< 1 yr or > or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS: A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS: Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.
Adolescent↗
Dynamics of a nosocomial outbreak of multidrug-resistant Pseudomonas aeruginosa producing the PER-1 extended-spectrum beta-lactamase.
From November 1998 to August 1999, a large outbreak occurred in the general intensive care unit of the Ospedale di Circolo in Varese (Italy), caused by Pseudomonas aeruginosa producing the PER-1 extended-spectrum beta-lactamase. A total of 108 clinical isolates of P. aeruginosa resistant to broad-spectrum cephalosporins were recovered from 18 patients. Epidemic isolates were characterized by synergy between clavulanic acid and ceftazidime, cefepime, and aztreonam. Isoelectric focusing of crude bacterial extracts detected two nitrocefin-positive bands with pI values of 8.0 and 5.3. PCR amplification and characterization of the amplicons by restriction analysis and direct sequencing indicated that the epidemic isolates carried a bla(PER-1) determinant. The outbreak was of clonal origin as shown by pulsed-field gel electrophoresis analysis. This technique also indicated that the epidemic strain was not related to three other PER-1-positive isolates obtained at the same hospital in 1997. Typing by enterobacterial repetitive intergenic consensus-PCR showed that minor genetic variations occurred during the outbreak. The epidemic strain was characterized by a multiple-drug-resistance phenotype that remained unchanged over the outbreak, including extended-spectrum cephalosporins, monobactams, aminoglycosides, and fluoroquinolones. Isolation of infected patients and appropriate carbapenem therapy were successful in ending the outbreak. Our report indicates that the bla(PER-1) resistance determinant may become an emerging therapeutic problem in Europe.
Cephalosporins↗
Growth hormone secretion after baclofen administration in different phases of the menstrual cycle in healthy women.
AIM: The aim of this study was to investigate the effect of baclofen administration on growth hormone (GH) secretion during different phases of the menstrual cycle. METHODS: Twelve healthy women (33.6 +/- (SD) 2.8 years; range 23-40 years) with regular menstrual cycles were enrolled. The phases of the menstrual cycle were determined using transvaginal ultrasonography (TV-US) and detecting hormonal serum levels. Plasma GH levels were evaluated during the early follicular, periovulatory and luteal phases of the cycle before and after the baclofen challenge test. RESULTS: After acute baclofen administration, GH levels increased significantly (p < 0.001) compared to basal values during the periovulatory and luteal phases, while no significant variation was detected during the early follicular phase. In addition, plasma GH levels resulted significantly (p < 0.001) higher during the luteal phase than during the periovulatory phase. CONCLUSION: Acute baclofen administration induces a significant increase in plasma GH levels in healthy females during the periovulatory and luteal phases, but not during the early follicular phase. These data suggest a modulator role of plasma sex steroids levels on GH release induced by baclofen.
Administration, Oral↗
Diffusion of knowledge about Helicobacter pylori as assessed in an open-access endoscopy system: a prospective observational study based on the Maastricht guidelines.
BACKGROUND/AIM: Aim of the present study is to assess, according to the guidelines of the Maastricht Consensus Conference, the appropriateness and diagnostic yield of upper gastrointestinal endoscopy in an open-access endoscopy system, in order to evaluate the diffusion of knowledge about Helicobacter pylori among different types of physicians. METHODS: Patients undergoing endoscopy because of dyspeptic symptoms were prospectively considered in 21 endoscopy services of Campania during two different 1-week periods in 1998 and 2001. The following data were recorded: age, sex, symptoms, history of peptic ulcer with regard to previous endoscopic or radiographic examinations and treatment, endoscopic diagnosis, and H. pylori status. The indication for endoscopy was evaluated according to Maastricht guidelines and current medical knowledge. RESULTS: In the two periods, 1998 and 2001, 706 and 520 patients were, respectively, considered. The two series were matched for demographic characteristics, symptoms, and endoscopic diagnosis. Endoscopy was considered not indicated in 398 patients (56.4%) in 1998 and in 265 patients (50.9%) in 2001 (p = NS). The majority of them, 288/398 (72.3%) in 1998 and 162/265 (61.1%) in 2001 (p = 0.001), had recently undergone endoscopy or radiology and empiric antisecretory treatment or eradication. They had been referred to endoscopy because of recurrence of symptoms or to assess healing. In 110 cases in 1998 (27.6%) and in 103 cases in 2001 (38.9%; p = 0.001) endoscopy was performed in dyspeptic patients younger than 45 years without alarm symptoms. CONCLUSIONS: 4 years after the Maastricht Conference, a large number of endoscopic examinations are not indicated and could be avoided following the Maastricht guidelines. In 2001, in comparison to 1998, a larger number of physicians are likely to investigate and treat correctly the H.-pylori-related diseases, but there are still some problems with the application of the 'test-and-treat policy'.
Adolescent↗
The influence of intense ballet training on trabecular bone mass, hormone status, and gonadotropin structure in young women.
A cross-sectional study on young dancers and exdancers was performed to evaluate the effects of intense weight-bearing exercise and dietary restriction, started during puberty, on bone mineral density (BMD), menarche age, menstrual function, and gonadotropin structure. Twenty current dancers (group 1) and 9 exdancers (group 2) were compared with a control group of 30 age-matched, regularly cycling women. Body weight, body mass index, total daily caloric intake, and nutritional markers were significantly lower (P < 0.05) in groups 1 and 2 than in controls. Using Quantitative Computed Tomography for the BMD evaluation, 12 dancers and 5 exdancers had Z-scores less than 2.5 SD below the mean of the controls; whereas, in 6 dancers and in 2 exdancers, BMD was between 1 and 2.5 SD. Groups 1 and 2 had a delay of menarche, which correlated positively with years of dance before menarche (r = 0.8; P < 0.001). Dancers had low levels and altered structure of circulating gonadotropins, which improved after GnRH stimulation. In conclusion, ballet training performed by dancers during puberty, dietary restriction, and low body mass index can all be associated with reduction in BMD and altered gonadotropin isoforms, with subsequent delay of menarche, menstrual dysfunctions, and insufficient peak bone mass. A longitudinal study must be conducted to confirm the persistence of low lumbar spine bone density in adult age.
Adult↗
Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy.
To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point). After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P < 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5-7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15-20 mg/d. In these resistant macro- and microprolactinomas, the maximal tumor diameter was reduced by 43.7 +/- 3.6% and 22.1 +/- 3.7% and by 59.3 +/- 7.1% and 4.3 +/- 2.1% after CAB and BRC, respectively (P < 0.001). In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion.
Adenoma↗
Guidelines for diagnosis and therapy of MEN type 1 and type 2.
This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.
Humans↗
Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance.
Acromegalic patients are considered to be exposed to a doubled mortality rate, mostly for cardiovascular diseases. This open prospective study was designed to evaluate whether the impairment of cardiac performance could be reversed by the long-term suppression of GH and insulin-like growth factor I (IGF-I) levels. Eighteen patients with active acromegaly were studied before and 5 yr after surgery, followed by sc octreotide in 11 patients. Disease control (GH levels < or =1 microg/L after glucose load or < or =2.5 microg/L after fasting, respectively, together with normalized IGF-I levels for age) was achieved in seven patients after surgery and in six patients after 0.3--0.6 mg/day sc octreotide. Five patients were not controlled during the 5-yr follow-up. Cardiac performance at rest and at peak exercise was assessed by equilibrium radionuclide angiography at study entry and 5 yr after surgery alone or plus octreotide. Thirty-six sex- and age-matched healthy subjects served as controls. At study entry, patients had a lower left ventricular ejection fraction (LVEF) at peak exercise and LVEF exercise-induced changes, exercise duration, and capacity than controls (P < 0.001). After 5 yr of treatment, a significant decrease of resting heart rate (P = 0.03) and a significant increase of LVEF at peak exercise (P = 0.003) was found in patients achieving disease control. LVEF response at peak exercise worsened in none of the patients with controlled disease and in three patients with uncontrolled disease (60%) (chi(2) = 5.5; P = 0.02). Diastolic filling, exercise duration, and workload did not significantly change during the 5-yr follow-up. No difference was found between patients controlled by surgery alone or by surgery plus octreotide. This 5-yr prospective study demonstrated that the LVEF response at peak exercise improved in all patients achieving disease control, while it was worsened in 60% of uncontrolled ones. These results strengthen the need of a stable suppression of GH and IGF-I hypersecretion to restore a normal cardiac performance in acromegaly.
Acromegaly↗
Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency.
Adult GH deficiency (GHD) is associated with increased cardiovascular morbidity and mortality due to unfavorable lipid profile, hyperfibrinogenemia, and impairment of cardiac performance. This prospective controlled cohort study evaluated the effects of 12-month GH replacement on lipid profile, fibrinogen levels, cardiac mass by echocardiography, and performance by equilibrium radionuclide angiography. To this end we studied 20 patients (11 men and 9 women, aged 19-40 yr), 10 with childhood-onset (co-) and 10 with adult-onset (ao-) disease, and 20 sex- and age-matched healthy subjects. At study entry, insulin-like growth factor I (IGF-I; P < 0.0001) and high density lipoprotein (HDL) cholesterol (P < 0.0001) levels, left ventricular mass index (LVMi; P < 0.0001), ejection fraction (LVEF) at rest (P = 0.001) and at peak exercise (P < 0.0001), peak ejection rate (P = 0.005), and exercise duration (P < 0.0001) and capacity (P = 0.002) were lower, whereas total cholesterol (P = 0.02), triglycerides (P = 0.003), and fibrinogen (P = 0.005) levels were higher in patients than in controls. After 12 months, increases in IGF-I (P < 0.0001) and HDL cholesterol levels (P = 0.04), LVMi (P < 0.0001), LVEF at peak exercise (P < 0.0001), and exercise duration (P = 0.009) and capacity (P = 0.003) and decreases in total cholesterol (P < 0.0001), low density lipoprotein cholesterol (P < 0.0001), triglycerides (P < 0.0001), and fibrinogen (P = 0.01) levels were found in all patients, without any difference between co- and ao-GHD. At the end of treatment, however, total cholesterol, triglycerides, and fibrinogen levels were still higher, and HDL cholesterol levels, IGF-I levels, and LVEF at rest and at peak exercise were lower in patients than in controls. In conclusion, GH replacement for 12 months significantly improved lipid profile, decreased fibrinogen levels, and increased LVMi and LVEF in young adults with co- or ao-GHD. However, lipid profile, fibrinogen levels, and systolic function remained abnormal compared with those in age- and sex-matched controls, suggesting that a longer period of GH replacement is necessary to normalize cardiovascular parameters and reverse the cardiovascular risk of these patients.
Adolescent↗