Iron Support in Erythropoietin Treatment in Myelodysplastic Syndrome Patients Affected by Low-Risk Refractory Anaemia: Real-Life Evidence from an Italian Setting.

Refractory anaemia (RA) among myelodysplastic syndrome (MDS) is associated with a partial functional iron deficit and may require transfusions. In low-risk lymphoma and solid tumour patients, iron support improves erythropoietin (EPO) cost-effectiveness in treating anaemia. The aim of this study is to see if oral sucrosomial iron support improves the cost-effectiveness of EPO treatment in MDS patients affected by low-risk RA. We treated patients with EPO only or with EPO plus oral sucrosomial iron or intravenous (i.v.) iron. The need for transfusions was lowest in the group taking oral iron (p = 0.016) or not receiving supplementation at all (p = 0.022). We compared costs of EPO with i.v. ferric gluconate or oral sucrosomial iron supplementation or no iron supplementation. The oral iron group had fewer side effects, fewer patient medical visits in the out-patient setting, and fewer transfusions; this led to higher savings on direct hospital costs and indirect patient costs (lost days at work) and translated into a 50% abatement of overall expenditures. EPO treatment-related expenditures in MDS-RA patients were lowest with oral sucrosomial iron supplementation (Sideral®), with a longer interval between EPO administration in maintenance treatment, quicker hemoglobin recovery, lower ferritin increase and fewer blood transfusions.

Prediabetes Increases the Risk of Frailty in Prefrail Older Adults With Hypertension: Beneficial Effects of Metformin.

BACKGROUND: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals. METHODS: We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months. RESULTS: We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P<0.0001). Similarly, we analyzed the association between the triglyceride-to-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P<0.0001). Prediabetes was found to significantly (P<0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (P<0.0001). CONCLUSIONS: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty.

Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019).

CONTEXT: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking. OBJECTIVE: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program. METHODS: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism. RESULTS: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 µg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%. CONCLUSION: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy.

Effect of cabergoline on metabolism in prolactinomas.

INTRODUCTION: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. PATIENTS AND METHODS: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. RESULTS: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 µg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). CONCLUSIONS: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Image-guided robotic radiosurgery (CyberKnife) for pancreatic insulinoma: is laparoscopy becoming old?

Insulinomas constitute about 25% of endocrine pancreatic tumors. Laparoscopic surgery is the treatment of choice. However, pancreas-related complications rate is very high, even in experienced hands, ranging up to 37%. Alternative procedures such as embolization with trisacryl have not been accepted by the surgical community. Image-guided robotic radiosurgery or stereotactic radiosurgery (CyberKnife) is a minimally invasive procedure delivering large doses of ionizing radiation to a well-defined target. CyberKnife radiosurgery is successfully used in brain cancer, lung cancer, prostate cancer, liver metastases, kidney cancer, and pancreatic cancer. The authors present the first case to their knowledge of a benign functioning insulinoma successfully treated by a CyberKnife technique with a 3-year follow-up.

Lactobacilli Infection Case Reports in the Last Three Years and Safety Implications.

Lactobacilli constitute the dominant microbiota in many fermented foods and comprise widely used probiotics. However, these bacteria cause rare infections mostly in diabetic and immunocompromised subjects in presence of risk factors such as prosthetic hearth valves and dental procedures or caries. The scope of this survey was re-assessing the pathogenic potential of lactobacilli based on the infection case reports published in the last three years. In 2019, 2020, and 2021, total of 17, 15, and 16 cases, respectively, including endocarditis, bacteremia, and other infections, were reported. These annual numbers are higher than those observed previously. Lacticaseibacillus rhamnosus (13 cases), comprising strain GG (ATCC 53103) with established applications in healthcare, L. paracasei (7 cases), Lactobacillus acidophilus (5 cases), L. jensenii (5 cases), Lactiplantibacillus plantarum (3 cases), L. paraplantarum, L. delbrueckii subsp. delbrueckii, L. gasseri, L. paragasseri, Limosilactobacillus fermentum, and L. reuteri (1 case each) were involved. Virulence characterization of two strains that caused infections, a derivative of L. rhamnosus GG and L. paracasei LP10266, indicated that increased biofilm-forming capacity favors pathogenicity and it is determined by variable genetic traits. This survey highlights that the strains of lactobacilli that cause infections are little characterized genetically. Instead, to avoid that these bacteria become a hazard, genetic stability should be periodically re-evaluated by whole genome sequencing (WGS) to ensure that only non-pathogenic variants are administered to vulnerable individuals.

A versatile approach to evaluate the occurrence of microfibers in mussels Mytilus galloprovincialis.

Microplastics of fibrous shape are esteemed to be the most abundant micro-debris form present in the environment. Despite the occurrence of microfibers in fish may pose a risk to human health, the literature is scarce regarding studies on the contamination in commercial marine fish mostly due to methodological issues. In this study, a versatile approach, able to discriminate among natural and synthetic microfibers according to the evaluation of specific morphological features, is proposed in farmed mussels (Mytilus galloprovincialis). The approach was useful to determine that microfibers were present in 74% of mussel samples, with a mean number of 14.57 microfibers/individual, corresponding to 3.13 microfibers/g w.w. A negative correlation between the size of analysed mussels and the amount of microfibers/g w.w. was detected, showing that smaller specimens contained more microfibers than the larger ones. This work paves the way to further studies aimed to adequately assess the risk that microfibers may pose to marine biota, also considering the commercial value as seafood items of many species of the Mytilus genus and the potential implication for human exposure.

Extraction and identification of microplastics from mussels: Method development and preliminary results.

Microplastics (MPs) are an emerging threat to marine ecosystems. One of the primary environmental risks is their bioavailability for aquatic organisms. Some fish and bivalves are of particular interest because their feeding strategies expose them to particles present in the water column. The aim of the study was to assess an extraction method in order to isolate and quantify MPs from fish gastrointestinal tract (n.8) and muscle (n.4), and bivalves (n.8) samples. The accuracy of the method was assessed through the calculation of the recovery percentage in samples spiked with a known number of MPs using microscopic observation. Successively, the extraction was preliminarily applied on n.20 mussels collected from mariculture plants of the Tyrrhenian and the Adriatic Sea. The results of the digestion protocol showed an average extraction yield of 80% in fish gastrointestinal tracts, 90% in fish muscle samples, and 95% in mussels. Preliminary analysis carried out on farmed mussels showed an average abundance of 3.8 items/individual, and 0.5 items/g of tissue, among those black, was the most represented color.

FDG/PET uptake in asymptomatic multilobar Chlamydia pneumoniae pneumonia.

BACKGROUND: FDG-PET is a diagnostic imaging procedure effective in staging primary and recurrent cancer. False-positive uptake already has been described in both inflammatory and infectious respiratory diseases, although no reports associate Chlamydia pneumoniae infection to FDG uptake. CASE REPORT: An incidental diagnosis of asymptomatic multilobar pneumonia during screening for thyroid malignancy is reported. Three areas of pulmonary consolidation strongly positive on PET/CT scan, mimicking pulmonary malignancy were identified. Both radiologic features and serum IgM antibodies for Chlamydia pneumoniae suggested the diagnosis of an unusual presentation of a Chlamydia pneumoniae respiratory infection. Specific antibiotic therapy induced a complete resolution of the areas of pulmonary consolidation. CONCLUSIONS: This case suggests that positive PET is not an absolute indicator for malignancy. Chlamydia pneumoniae respiratory infections can exhibit positive uptake on FDG-PET.

Transgenic mice overexpressing growth hormone (GH) have reduced or increased cardiac apoptosis through activation of multiple GH-dependent or -independent cell death pathways.

GH has antiapoptotic effects in cardiac or noncardiac cell lines; however, increased apoptosis has been found in myocardial samples of patients with acromegaly. The aim of this study was to investigate cardiac apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH [acromegalic mice (Acro)] aged 3 or 9 months. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase assay and annexin V; expression of pro- or antiapoptotic proteins was assessed by Western blot. Specificity of GH action was confirmed using a selective GH receptor antagonist. Apoptosis was lower in 3-month-old Acro than in controls; reduction was abolished by a GH receptor antagonist. The effects of GH were consistent with an antiapoptotic phenotype (increased Bcl2 and Bcl-XL and reduced Bad and cytochrome c levels, leading to lower activation of caspase-9 and caspase-3). In contrast, apoptosis was higher in 9-month-old Acro than in littermate controls; in addition, a GH receptor antagonist was without effect; the proapoptotic phenotype consisted in increased Bad, cytochrome c, caspase-9, and caspase-3. GH reduced apoptosis through p38 and p44/42 kinase pathways at young ages, whereas phosphatidylinositol-3-kinase was silent; on the contrary, the effects of GH on p38 and p44/42 kinase pathways were overcome by GH-independent stimuli in 9-month-old Acro. In addition, the antiapoptotic effect of GH was still present at this age as shown by phosphatidylinositol-3-kinase/Akt pathway activation. In conclusion, chronic GH excess reduced apoptosis at a young age, whereas its antiapoptotic action was overwhelmed in older animals by GH-independent mechanisms, leading to increased cell death.

Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH.

Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-kappaB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47+/-5% OD vs 33+/-4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-kappaB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.

Identification of acromegalic patients at risk of developing colonic adenomas.

BACKGROUND: Acromegaly seems to be associated with an increased prevalence of colonic adenomas, although factors affecting their development and recurrence of the latter are not fully known. SUBJECTS AND METHODS: Seventy-nine patients with active acromegaly were prospectively followed up for 5 yr. Two hundred eighty healthy subjects served as controls. Colonoscopy and assessment of acromegaly activity were performed at 1-yr intervals. Acromegaly was defined as controlled if serum IGF-I levels were within the normal age-adjusted range. RESULTS: Colonic adenomas were found in 26 of 79 acromegalic patients (32.9%) and 60 of 280 controls (21.4%) at baseline (P = 0.035, adjusted for age and sex, odds ratio 1.82, 95% confidence interval, 1.02-3.25). Seven patients had hyperplastic polyps; the remaining 46 acromegalic patients had no detectable lesions at baseline and did not develop adenomas during the study period. Of the 26 patients with colonic adenomas at baseline, 16 (61.5%) had at least one recurrence of colonic adenomas (P < 0.0001 vs. patients without colonic lesions at baseline), and multiple recurrences were more frequent in patients with uncontrolled acromegaly (66.7% vs. 17.6% in patients with controlled acromegaly, P = 0.028). CONCLUSIONS: The first colonoscopy helps to identify acromegalic patients at high risk of developing colonic adenomas. If colonic adenomas are not present initially, it is unlikely that they develop thereafter, independently of metabolic control of acromegaly. Conversely, new lesions are frequent (and often multiple) in patients who already have colonic adenomas at baseline, particularly if acromegalic disease is poorly controlled by treatment.

The reduction of bone mineral density in postmenopausal women with primary hyperparathyroidism is higher in the presence of concomitant GH secretion impairment.

OBJECTIVE: To investigate, in a large group of postmenopausal primary hyperparathyroidism (PHP) women, whether the concomitance of GH deficiency (GHD) may contribute to the development of changes in bone mineral density (BMD). DESIGN: GH secretion, bone status and metabolism were investigated in 50 postmenopausal women with PHP and in a control group of 60 women with no evidence of PHP, matched for age, age at menopause and body mass index (BMI). METHODS: GH response to growth hormone-releasing hormone (GHRH)+arginine (Arg), femoral neck BMD (g/cm2) by dual energy X-ray absorptiometry, BMI, serum-ionized calcium, parathyroid hormone (PTH) and markers of bone remodelling were evaluated in all patients and controls. RESULTS: Among PHP patients, GH secretion was reduced (8.8 +/- 4.2 microg/l, range 1.1-16.5 microg/l) in 34 patients and normal (28.7 +/- 11.8 microg/l, range 17.9-55.7 microg/l) in the remaining 16 (P < 0.05), no women in the control group had GHD (peak GH 33.8 +/- 10.9 microg/l, range 21.7 +/- 63.2 microg/l). Osteoporosis (T-score < - 2.5) and osteopenia (T-score > -2.5 and < -1) were found in 73.5 and 17.6% of GHD patients, in 37.5 and 43.7% of patients with normal GH secretion and 3.1 and 27% of controls. T-score and BMD were not correlated with ionized calcium, age, age at menopause, BMI, GH peak and IGF-I but were correlated with serum PTH levels in both groups. T-score was correlated with serum levels of markers of bone remodelling only in PHP patients with GHD. CONCLUSIONS: Concomitant impairment of GH secretion may play a pathogenetic role in the occurrence of changes in bone mass observed in PHP and contribute to make them more severe.

Colonoscopic screening and follow-up in patients with acromegaly: a multicenter study in Italy.

Acromegaly is an infrequent disease attributable to endogenous excess of GH and IGF-I. Human studies have associated the GH-IGF-I axis with the development of colorectal cancer; however, the question of whether colorectal cancer is a problem in acromegaly is currently unresolved. We performed a cross-sectional study to assess the risk of colonic neoplasia in patients with acromegaly. Colonoscopic screening was performed in 235 patients with acromegaly at five tertiary care hospitals in Italy between January 1, 1996, and December 31, 2001. A repeat colonoscopy was performed in 121 patients after a mean interval of 32.1 months. Colonoscopic findings in patients with acromegaly were compared with those of 233 patients with nonspecific abdominal complaints who were referred for endoscopy during the study period. A total of 65 patients (27.7%) and 36 controls (15.5%) had colonic neoplasia. In 55 patients (23.4%) and 34 control subjects (14.6%), the most important findings were adenomas (odds ratio, 1.7; range, 1.1-2.5), whereas 10 patients (4.3%) and two control subjects (0.9%) had carcinoma (odds ratio, 4.9; range, 1.1-22.4). The risk of colonic neoplasia was higher for younger patients with acromegaly compared with age-matched controls. Patients with acromegaly with or without colonic neoplasia did not differ significantly for IGF-I levels or duration of disease. A neoplastic recurrence was found in 16.5% of patients who underwent follow-up; 90% of them had had a neoplasm removed at the first colonoscopy. Acromegaly carries with it a moderate, but definitive, increase in the risk of colonic neoplasia that occurs at a younger age than in the general population. Patients who are found to harbor a colonic neoplasia are at risk for recurrence.

Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study.

CONTEXT: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism. OBJECTIVE: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury. DESIGN AND PATIENTS: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32). RESULTS: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency. CONCLUSION: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

Growth hormone inhibits apoptosis in human colonic cancer cell lines: antagonistic effects of peroxisome proliferator activated receptor-gamma ligands.

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor-gamma (PPARgamma) activation enhances apoptosis, and a link between GH and PPARgamma in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPARgamma ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05-50 nm GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55-85% reduction of PPARgamma expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1-50 microm ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPARgamma expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPARgamma. The reduced GH-dependent apoptosis can be overcome by PPARgamma ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.

Peroxisome proliferator activated receptor gamma expression is reduced in the colonic mucosa of acromegalic patients.

UNLABELLED: Acromegalic patients have an increased prevalence of colonic polyps, due to the elevated serum insulin like growth factor (IGF)-I levels. The mechanisms underlying this process are poorly understood. Peroxisome proliferator activated receptor (PPAR)gamma, a nuclear receptor that regulates adipocyte differentiation, is highly expressed in the human colonic mucosa, where it induces growth inhibition and cell differentiation. In the present study we evaluated the expression of PPARgamma in the bioptic samples of colonic mucosa from 22 patients with acromegaly (Acro) and 13 normal subjects (CONTROLS) matched for age and sex. Among Acro patients, 10 had active, untreated disease (AcroUntr), 6 were in remission after surgery (AcroRem), and 6 had active disease under treatment with somatostatin analogs (AcroSMSa). Serum GH and IGF-I (mean +/- SD) levels were as follows: AcroUntr: GH, 36 +/- 40 microg/l; IGF-I, 769 +/- 298 microg/l; AcroRem: GH, 1.0 +/- 1.3 microg/l; IGF-I, 248 +/- 96 microg/l; AcroSMSa: GH, 7.8 +/- 12 microg/l; IGF-I, 429 +/- 221 microg/l; CONTROLS: GH, 0.8 +/- 0.7 microg/l; IGF-I, 203 +/- 67 microg/l. In the CONTROLS the level of expression of PPARgamma mRNA was 15230 +/- 891 transcripts. Patients with AcroUntr had 2750 +/- 688 transcripts of PPARgamma. (p < 0.0001) vs. CONTROLS); patients AcroSMSa had 4629 +/- 1286 transcripts of PPARgamma. (p = NS vs AcroUntr, p = 0.0002 vs. CONTROLS); patients with AcroRem had 8261 +/- 2481 transcripts of PPARgamma (p = 0.008 vs. AcroUntr, p = NS vs. AcroSMSa, p = 0.007 vs. CONTROLS). A significant inverse correlation was found between serum IGF-I concentrations and the level of expression of PPARgamma (r = 0.43, p = 0.03). In conclusion, patients with active Acro have a reduced expression of PPARgamma in the colonic mucosa, which appears be related to the increased serum IGF-I levels and might lead to an increased prevalence of colonic polyps.

Improvement of growth hormone deficiency in patients with primary hyperparathyroidism after parathyroidectomy: results of a prospective study.

GH secretion is impaired in most patients with primary hyperparathyroidism (PHP), although the secretion of the other anterior pituitary hormones is unaffected. However, whether restoration of euparathyroidism is associated with reversal of GH deficiency in PHP patients is not known. To address this issue, we studied 30 consecutive patients with PHP due to a single parathyroid adenoma before and after parathyroidectomy. GH secretion was evaluated by peak serum GH after the maximal GHRH + arginine (Arg) stimulation test. A group of 35 age- and sex-matched normal subjects served as controls. Serum IGF-I concentration was below the normal age- corrected values in six of 30 patients before surgery and in four of 30 patients after parathyroidectomy (P = not significant). Mean serum peak GH values after the GHRH + Arg test were 17.5 +/- 2.8 micro g/liter before surgery and 23.8 +/- 2.5 micro g /liter after surgery (P = 0.0008). The GH response to the GHRH + Arg test was reduced in 20 (67%) and normal in 10 (33%) of 30 PHP patients at baseline; after surgery, 22 of 30 (73%) PHP patients had a normal GH response to the GHRH + Arg test, and only eight (27%) had an impaired GH secretion (P < 0.02). In conclusion, this study confirms that GH secretion is impaired in PHP patients and indicates that it is reversed in many patients after parathyroidectomy. Accordingly, GH deficiency in PHP patients must be considered a functional phenomenon for which GH therapy is not recommended.

Changes in the expression of the peroxisome proliferator-activated receptor gamma gene in the colonic polyps and colonic mucosa of acromegalic patients.

Acromegalic patients have an increased prevalence of colonic neoplasms and lower peroxisome proliferator-activated receptor gamma (PPARgamma) levels, the latter acting as a tumor suppressor gene. In this study we evaluated the expression of PPARgamma in the biopsy samples of the polyps and outside polyps colonic mucosa from seven patients with active, untreated acromegaly, 11 with cured disease, and 15 controls. Serum GH and IGF-I levels were higher in patients with untreated acromegaly than in those with acromegaly in remission or controls (P = 0.003 and P = 0.002, respectively) The expression of PPARgamma mRNA (mean +/- SE) was 1) mucosa outside polyps, 24,188 +/- 3,254 transcripts in the controls, 22,432 +/- 2,006 transcripts in acromegaly in remission, and 1,952 +/- 342 transcripts in untreated acromegaly (P < 0.0001 vs. controls and acromegaly in remission); and 2) polyps mucosa, 1,554 +/- 236 transcripts in the controls, 1,112 +/- 143 in acromegaly in remission, and 1,570 +/- 251 in untreated acromegaly (P = NS among polyps groups and mucosa outside polyps of untreated acromegaly; P < 0.0001 vs. mucosa outside polyps of controls and acromegaly in remission). Eighty-five percent of the cells in the mucosa outside polyps from controls or acromegaly in remission were positive at immunohistochemistry, at variance with 45% of the cells from polyps mucosa from each group and from those of mucosa outside polyps of untreated acromegaly (P = 0.0002). In conclusion, patients with untreated acromegaly have reduced expression of PPARgamma in the mucosa outside polyps, which might be reversed by curing the disease; conversely, patients with acromegaly in remission have the same low levels of expression of PPARgamma in the polyps mucosa as untreated acromegaly or controls, supporting the concept that reduced expression of PPARgamma might be an early event in colonic tumorigenesis.

PPARgamma inhibits GH synthesis and secretion and increases apoptosis of pituitary GH-secreting adenomas.

OBJECTIVE: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma in pituitary adenomas from 14 consecutive acromegalic patients and to establish its role in apoptosis. SUBJECTS AND METHODS: Fourteen consecutive acromegalic patients were enrolled in the study. Wistar-Furth rats were used for in vivo studies. Expression of PPARgamma was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARgamma ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. RESULTS: PPARgamma was expressed in all human GH-secreting adenoma (GH-oma), in normal pituitary tissue samples (39+/-24% and 78+/-5% of immunostained nuclei respectively; P<0.0002; ANOVA), and in rat GH-secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3 cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P=0.0003) and arrested cell proliferation, reducing the number of cells in the S-phase (P<0.0001 vs untreated cells). TZDs increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs reduced GH concentrations in the culture media from 43.7+/-5.4 ng/ml to 2.1+/-0.3 ng/ml (P<0.0001) and in cell extracts (P<0.004). PPARgamma-RXRalpha heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x 10(6) vs 5.7 x 10(6) transcripts respectively vs untreated cells; P<0.002). Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth increased in placebo-treated rats and to a lesser extent in TZDs-treated animals (24.1+/-2.0 g, and 14.8+/-4.2 g respectively, P<0.03). Serum GH concentrations were lower in TZDs-treated rats than in controls (871+/-67 ng/ml vs 1.309+/-238 ng/ml; P<0.05). CONCLUSIONS: The results of this study indicate that PPARgamma controls GH transcription and secretion as well as apoptosis and growth of GH-oma; thus, TZDs have the potential of a useful tool in the complex therapeutic management of acromegalic patients.