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Rocco Barazzoni,
Michela Zanetti,
Carlo Nagliati,
Maria Rosa Cattin,
Clara Ferreira,
Michela Giuricin,
Silvia Palmisano,
Elisabetta Edalucci, Franca Dore,
Gianfranco Guarnieri,
Nicolò de Manzini
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ABSTRACT: Gastric bypass (GBP) lowers food intake, body weight, and insulin resistance in severe obesity (SO). Ghrelin is a gastric orexigenic and adipogenic hormone contributing to modulate energy balance and insulin action. Total plasma ghrelin (T-Ghr) level is low and inversely related to body weight and insulin resistance in moderately obese patients, but these observations may not extend to the orexigenic acylated form (A-Ghr) whose plasma concentration increase in moderate obesity. We investigated the impact of GBP on plasma T-, A-, and A/T-Ghr in SO patients (n = 28, 20 women), with measurements at baseline and 1, 3, 6, and 12 months after surgery. Additional cross-sectional comparison was performed between nonobese, moderately obese, and SO individuals before GBP and at the end of the follow-up period. Before GBP, SO had lowest T-Ghr and highest A/T-Ghr profile compared with both nonobese and moderately obese individuals. Lack of early (0-3 months from GBP) T-Ghr changes masked a sharp increase in A-Ghr and A/T-Ghr profile (P < 0.05) that remained elevated following later increments (6-12 months) of both T- and A-Ghr (P < 0.05). Levels of A-Ghr and A/T-Ghr at 12 months of follow-up remained higher than in matched moderately obese individuals not treated with surgery (P < 0.05). The data show that following GBP, early T-Ghr stability masks elevation of A/T-Ghr, that is stabilized after later increments of both T- and A-hormones. GBP does not normalize the obesity-associated elevated A/T-Ghr ratio, instead resulting in enhanced A-Ghr excess. Excess A-Ghr is unlikely to contribute to, and might limit, the common GBP-induced declines of appetite, body weight, and insulin resistance.
Obesity 06/2012; · 4.28 Impact Factor
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ABSTRACT: Altered glucose metabolism negatively modulates outcome in acute coronary syndromes (ACS). Insulin resistance is commonly associated with increasing BMI in the general population and these associations may involve obesity-related changes in circulating ghrelin and adipokines. We aimed at investigating interactions between BMI, insulin resistance and ACS and their associations with plasma ghrelin and adipokine concentrations. Homeostasis model assessment of insulin resistance (HOMA(IR))-insulin resistance index, plasma adiponectin, leptin, total (T-Ghrelin), acylated (Acyl-Ghrelin), and desacylated ghrelin (Desacyl-Ghrelin) were measured in 60 nondiabetic ACS patients and 44 subjects without ACS matched for age, sex, and BMI. Compared with non-ACS, ACS patients had similar HOMA(IR) and plasma adipokines, but lower T- and Desacyl-Ghrelin and higher Acyl-Ghrelin. Obesity (BMI > 30) was associated with higher HOMA(IR), lower adiponectin, and higher leptin (P < 0.05) similarly in ACS and non-ACS subjects. In ACS (n = 60) HOMA(IR) remained associated negatively with adiponectin and positively with leptin independently of BMI and c-reactive protein (CRP) (P < 0.05). On the other hand, low T- and Desacyl-Ghrelin with high Acyl-Ghrelin characterized both obese and non-obese ACS patients and were not associated with HOMA(IR). In conclusion, in ACS patients, obesity and obesity-related changes in plasma leptin and adiponectin are associated with and likely contribute to negatively modulate insulin resistance. ACS per se does not however enhance the negative impact of obesity on insulin sensitivity. High acylated and low desacylated ghrelin characterize ACS patients independently of obesity, but are not associated with insulin sensitivity.
Obesity 05/2012; · 4.28 Impact Factor
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Matteo Biasotto,
Silvia Chiandussi,
Serena Zacchigna,
Silvia Moimas, Franca Dore,
Gabriele Pozzato,
Fabio Cavalli,
Fabrizio Zanconati,
Luca Contardo,
Mauro Giacca,
Roberto Di Lenarda
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ABSTRACT: The aim of this study was to evaluate a novel animal model of bisphosphonates-associated osteonecrosis, which realistically recapitulates the same pathological human condition. Five Wistar rats were given intravenous zoledronic acid 0.04 mg once a week for 5 weeks. After 2 weeks, the animals underwent the extraction of an upper molar, producing a 4 mm-diameter bone defect on the same site. After 7 weeks from the extraction, the animals were clinically examined and a bone scintigraphy was carried out. After an additional week, the rats were killed and both Computerized Tomography and histological analysis were performed. Five rats, not treated with zoledronic acid and exposed to the same surgical treatment, were used as controls. At 7 weeks after the extraction, all the rats treated with zoledronic acid showed expansion of the defect and bone exposure. These features were confirmed by bone scintigraphy. The rats of the control group demonstrated epithelialization of the bone defect and a normal uptake of the contrast medium during the scan. The Computerized Tomography scan disclosed irregularity of the cortical margin and bone destruction, which were not evident in the control group. On microscopy, the samples showed necrotic bone, loss of osteocytes and peripheral resorption without inflammatory infiltrate, while the controls showed normal bone healing. The rat treated with zoledronic acid can be considered a novel, reliable and reproducible animal model to understand better the pathophysiology of osteonecrosis of the jaw and to develop a therapeutic approach.
Journal of Oral Pathology and Medicine 02/2010; 39(5):390-6. · 1.63 Impact Factor
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Journal of Nuclear Medicine 08/2009; · 6.38 Impact Factor
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ABSTRACT: Members of the vascular endothelial growth factor (VEGF) family are among the most promising cytokines to induce neovascularization of ischaemic tissues; however, their unregulated expression often results in major undesired effects. Here, we describe the properties of inducible vectors based on the adeno-associated virus (AAV), allowing precise control of VEGF expression, and exploit these vectors to define the kinetics of the angiogenic response elicited by the factor.
Based on a tetracycline-inducible transactivator, we designed an AAV vector system allowing the pharmacological regulation of VEGF production in vivo and tested its efficacy in inducing functional neoangiogenesis in both normoperfused and ischaemic skeletal muscle in mice by a combination of histological, immunofluorescent, and molecular imaging techniques. We observed that a prolonged expression of VEGF was required to determine the formation of stable vessels, able to persist upon withdrawal of the angiogenic stimulus. However, the vessels formed in the presence of continuous VEGF expression consisted mainly of dilated and leaky capillaries. As determined after pinhole scintigraphy, this abnormal vasculature accounted for a significant drop in functional tissue perfusion. In contrast, transient VEGF expression, followed by a period of VEGF withdrawal, allowed maintenance of functional perfusion under resting conditions and during exercise. This VEGF-inducible system was highly effective in improving vascularization and function in a hind-limb ischaemia model.
Together, these results clearly indicate that the fine tuning of VEGF expression is required to achieve the formation of a stable vasculature able to sustain functional neovascularization.
Cardiovascular research 06/2009; 83(4):663-71. · 5.80 Impact Factor
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ABSTRACT: An increasing number of cases of osteonecrosis of the jaws (ONJ) in patients treated with bisphosphonates has been reported in the literature. ONJ significantly affects the patients' quality of life and its management is still extremely difficult.
A woman with ONJ secondary to therapy with zoledronic acid came to our attention for recurrent oral infections and orocutaneous fistula unresponsive to antibiotic therapy combined with minor surgical debridements. The patient underwent major surgery to remove the fistula and clean the necrotic bone and soft tissues; a lobed skin platysma flap was used to close the defect. The treatment outcome was good.
When ONJ fails to respond to antibiotic therapy and surgical debridements, a more invasive surgical approach may be necessary to guarantee a better quality of life for the patient.
Head & Neck 04/2009; 31(9):1249-54. · 2.40 Impact Factor
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ABSTRACT: Endovenous bisphosphonate therapy seems associated with osteonecrosis of the jaw. The aim of this study was to evaluate the additional diagnostic value of hybrid SPECT/CT in 99mTc-methylene diphosphonate 3-phase bone scintigraphy of osteonecrosis of the jaw in bisphosphonate-treated patients.
We studied 15 patients (12 women and 3 men) with extraoral tumors affected by lytic bone metastases and multiple myeloma. All patients were previously treated with intravenous bisphosphonates (zoledronic acid) for 1-3 y, were negative for dental disease at clinical examination, and had suspected osteonecrosis of the jaw. All 15 patients underwent panoramic x-ray orthopantomography, CT or MRI (or both), microbiologic examination, 3-phase bone scintigraphy, and SPECT/CT of the maxillary region.
Three-phase bone-scintigraphy showed increased perfusion and an increased blood pool in 9 of 12 and 10 of 12 patients, respectively; at the metabolic phase, SPECT was positive in all patients and showed abnormal hyperactivity in the maxilla of 2 patients, in the mandible of 9 patients, and in both the mandible and the maxilla of 4 patients. Hybrid SPECT/CT was of particular value in 8 of 15 patients, allowing discrimination of the osteonecrotic core from nearby hyperactivity due to viable bone. Whole-body scintigraphy showed remote and multiple metastases in all patients. Orthopantomography showed nonspecific bone rarefaction in all patients but was not able to aid diagnosis of osteonecrosis of the jaw. CT and MRI showed anomalies in all symptomatic patients: CT was helpful in evaluating both cortical and trabecular bone aspects, and MRI was able to detect soft-tissue involvement but not cortical bone destruction.
In appropriately selected oncology patients treated with bisphosphonates, an increased uptake of 99mTc-methylene diphosphonate in maxillary bones may suggest probable osteonecrosis of the jaw. In such cases, SPECT/CT may be of value in increasing the diagnostic accuracy of bone scanning, providing a precise functional anatomic correlation for the definition of the extent of disease.
Journal of Nuclear Medicine 01/2009; 50(1):30-5. · 6.38 Impact Factor
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ABSTRACT: Insulin resistance is common in maintenance hemodialysis (MHD) and it can contribute to exceedingly high mortality in MHD patients. Ghrelin is a gastric hormone whose total plasma concentration is increased in MHD. Emerging data suggest a potential role of ghrelin to modulate intermediate metabolism but the metabolic impact of ghrelin in chronic kidney disease is unknown. The current study aimed at assessing the potential relationships between ghrelin and insulin sensitivity in MHD.
Total (T-Ghr) and acylated (A-Ghr) ghrelin as well as insulin-mediated glucose disposal [(M): hyperinsulinemic-euglycemic clamp] were measured in non-diabetic non-obese ambulatory MHD patients (n=19, 16 Males). C-reactive protein (CRP) was also measured since systemic inflammation is associated with insulin resistance in non-renal patients and inflammation is negatively modulated by ghrelin in experimental models.
Compared to control subjects (C: n=9, 7 Males), MHD had similar body fat and resting energy expenditure but reduced M and increased CRP (P<0.05). MHD also had higher T-(P<0.05) but not A-Ghr. M was associated positively with T-Ghr and negatively with CRP in linear regression analysis in MHD. In stepwise multiple regression analysis only T-Ghr remained associated with M (P<0.05) in a model including A-Ghr and CRP.
Insulin sensitivity is associated negatively with systemic inflammation and positively with total plasma ghrelin in non-diabetic MHD patients. Based on available knowledge these results suggest a potential novel role of ghrelin in preserving insulin sensitivity in MHD.
Clinical nutrition (Edinburgh, Scotland) 03/2008; 27(1):142-9. · 3.27 Impact Factor
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Rocco Barazzoni,
Michela Zanetti,
Clara Ferreira,
Pierandrea Vinci,
Alessia Pirulli,
Mariapia Mucci, Franca Dore,
Maurizio Fonda,
Beniamino Ciocchi,
Luigi Cattin,
Gianfranco Guarnieri
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ABSTRACT: Metabolic syndrome shows clustered metabolic abnormalities with major roles for insulin resistance and obesity. Ghrelin is a gastric hormone whose total plasma concentration (T-Ghr) is associated positively with insulin sensitivity and is reduced in obesity. Ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms, but their potential differential associations with insulin resistance and whether they are differentially altered in obesity remain undefined.
Our objective was to determine potential differential associations of ghrelin forms with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and the impact of obesity on their plasma concentrations in metabolic syndrome.
This is a cross-sectional study.
The study was performed in a metabolic outpatient unit.
Patients with metabolic syndrome (National Cholesterol Education Program-Adult Treatment Panel III; n = 45, 23 males/22 females) were included in the study.
The main study outcomes were metabolic syndrome criteria, HOMA-IR, and ghrelin forms.
Plasma insulin and HOMA-IR were associated negatively with T-Ghr and D-Ghr but positively with A-Ghr and acylated to desacylated ghrelin (A/D-Ghr) ratio (n = 45; P < 0.05). Compared with nonobese [body mass index (BMI) < 27.5 kg/m(2); n = 12, six males/six females], obese metabolic syndrome patients (BMI > 27.5 kg/m(2); n = 33) had lower T-Ghr and D-Ghr but comparable A-Ghr and higher A/D-Ghr ratio (P < 0.05). BMI and waist circumference (WC) were positively related with HOMA-IR (n = 45; P < 0.05). However, opposite associations between A/D-Ghr ratio and HOMA-IR remained significant after adjustment for sex and BMI (or WC). Additional obese individuals without metabolic syndrome (n = 10: age-, sex-, BMI-, and WC-matched to obese metabolic syndrome patients) had lower T-Ghr but higher A-Ghr (P < 0.05) compared with age-, sex-matched healthy nonobese counterparts (n = 15). T-Ghr and A-Ghr were comparable in obese with or without metabolic syndrome.
Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome.
Journal of Clinical Endocrinology & Metabolism 11/2007; 92(10):3935-40. · 6.50 Impact Factor
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ABSTRACT: In spite of association between high plasma adiponectin and high metabolic and cardiovascular (CV) risk, highest adiponectin increments retain CV and metabolic protective effects in advanced chronic kidney disease (CKD). Passive accumulation can favor CKD-associated hyperadiponectinemia but potential additional regulation by adipose tissue remains undefined. Oxidative stress (OS) is associated with metabolic and CV disease and with CKD [increasing from conservative treatment (CT) to maintenance hemodialysis (MHD)], and OS can reduce adiponectin expression in experimental models. OS (in the form of plasma thiobarbituric acid-reactive substances: TBARS), subcutaneous adipose adiponectin mRNA, and plasma adiponectin were studied in CKD patients (stages 4 and 5) on CT (n = 7) or MHD (n = 11). Compared with CT and controls (C: n = 6) MHD had highest TBARS and lowest adiponectin mRNA (P < 0.05) with lower adipose adiponectin protein (P < 0.05 vs. CT). MHD also had lower plasma adiponectin than CT, although both had higher adiponectin than C (P < 0.05). In renal transplant recipients (RT: CKD stage 3; n = 5) normal TBARS were, in turn, associated with normal adiponectin mRNA (P < 0.05 vs. MHD). In all CKD (n = 23), adiponectin mRNA was associated positively with adiponectin plasma concentration (P < 0.01). In all subjects (n = 29), adiponectin mRNA was related (P < 0.05) negatively with TBARS after adjusting for plasma C-reactive protein (CRP) or CRP and creatinine. Thus altered OS, adiponectin expression, and plasma concentration represent a novel cluster of metabolic and CV risk factors in MHD that are normalized in RT. The data suggest novel roles of 1) MHD-associated OS in modulating adiponectin expression and 2) adipose tissue in contributing to circulating adiponectin in advanced CKD.
AJP Regulatory Integrative and Comparative Physiology 08/2007; 293(1):R47-54. · 3.34 Impact Factor
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ABSTRACT: An increasing incidence of osteonecrosis of the jaws (ONJ) in patients treated with intravenous bisphosphonates has been reported in the literature. The aim of this study was to evaluate the clinical aspects, diagnostic investigations, and management of ONJ associated with bisphosphonates in a series of 12 patients.
Our patients included 1 asymptomatic and 11 symptomatic subjects. For the symptomatic patients, the osteonecrosis was diagnosed through histological investigations of exposed bone that showed avascular and necrotic tissue with inflammatory infiltrate. The patients were complaining of swelling, fever, and bone exposure involving the jaws. The asymptomatic patient presented as an occasional finding during a routine dental examination and the necrosis was confirmed on the basis of imaging investigations. Radiographic, scintigraphic, and microbiological examinations were carried out for all patients. Treatment included antibiotics, minor surgical interventions, and hyperbaric oxygen therapy.
The radiological investigations revealed osteolytic areas and the scintigraphy demonstrated increased bone metabolism. The microbiological analysis showed pathogenic micro-organisms in the majority of patients. Therapy was useful in obtaining short-term symptomatic relief.
Histological, radiological, nuclear medicine, and microbiological investigations are important diagnostic tools for patients with bisphosphonates-associated osteonecrosis of the jaws. However, a long-term follow-up is necessary if we are to better understand the treatment outcome.
Acta Odontologica Scandinavica 12/2006; 64(6):348-54. · 1.07 Impact Factor
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ABSTRACT: Patients with cancer are characterized by decreased muscle protein synthesis and glutamine availability that contribute to an impaired immune response. These abnormalities worsen after surgical stress. We tested the hypothesis that pharmacologic doses of branched-chain amino acids would improve the early metabolic response after major cancer surgery.
By using a crossover experimental design, we compared the metabolic effects of isonitrogenous solutions of balanced and branched-chain-enriched amino acid mixtures infused at the rate of 82 mg x h(-1) x kg(-1) for 3 h in patients with colorectal or cervical cancer on the first and second days after radical surgery combined with intraoperative radiation therapy. The ratios of leucine to total amino acid (grams) in the two mixtures were 0.09 and 0.22, respectively. Muscle protein and glutamine kinetics were determined by using stable isotope of amino acids and the leg arteriovenous balance technique. Glucose and insulin were continuously infused throughout the 2-d study to maintain near euglycemia.
Rates of muscle protein synthesis and degradation were not significantly affected by the balanced amino acid infusion. In contrast, the isonitrogenous, branched-chain-enriched amino acid mixture accelerated muscle protein turnover by stimulating (P <or= 0.05) protein synthesis. The rate of muscle glutamine de novo synthesis did not significantly change after infusion of the balanced amino acid mixture but increased (P <or= 0.05) by 263 +/- 69% during infusion of the branched-chain-enriched amino acid mixture.
An excess of branched-chain amino acids in the presence of an optimal profile of other essential amino acids acutely increased muscle protein synthesis and glutamine flux from skeletal muscle in cancer patients after surgery.
Nutrition 05/2006; 22(5):475-82. · 3.03 Impact Factor
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ABSTRACT: The aim of this study was to determine factors that predict non-sentinel axillary lymph nodes (NSLNs) metastases in breast cancer patients with positive sentinel node biopsy (SLNB).
We reviewed the records of a consecutive series of 176 breast cancer patients who underwent SLNB at our institution. From the database we analysed those cases with one or more positive sentinel lymph nodes (SLNs) in order to determine factors predicting NSLN metastases.
From a series of 176 consecutive patients, we evaluated 41 cases (23.3%) with positive SLNB. Subsequent completion axillary lymph node dissection (CALND) revealed NSLN metastases in 15 cases (36.6%). The significant variables predictive of NSLN involvement were the presence of macrometastases with extranodal extension (p = 0.048), the presence of more than one positive SLN (p = 0.08) and a ratio between positive SLN and SLNs globally dissected higher than 0.5 (p = 0.05).
CALND is the gold standard for patients with positive SLNB, but results, in almost 40-70% of cases, in no additional positive nodes and its therapeutic benefit remains controversial. Clinicopathologic factors predictive of NSLN metastases may be useful in identifying a subset of patients with lower risk of further axillary involvement.
In patients with early breast carcinoma and a positive SLNB, the size of SLN metastases, the presence of extranodal extension, more than one positive SLN and a nodal ratio higher than 0.5 are the factors that significantly increase the frequency of additional axillary positive lymph nodes.
Annali italiani di chirurgia 81(5):335-41. · 0.23 Impact Factor
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ABSTRACT: Completion axillary lymph node dissection (CALND) performed as a standard procedure after a positive sentinel node biopsy (SLNB) in breast cancer patients results, in almost 40-70% of cases, in no additional positive nodes. A nomogram has been developed at Memorial Sloan Kettering Cancer Center (MSKCC) to predict the likelihood of nonsentinel node metastases (NSLNM) after a positive SLNB. Aim of study was to assess the accuracy of MSKCC nomogram in our community breast cancer population.
From a retrospective database of 276 breast cancer patients we evaluated 62 consecutive cases who underwent CALND after a positive SLNB. Patient and tumor characteristics were collected and the nomogram was used to calculate the probability of NSLNM. The accuracy of MSKCC nomogram was tested by the Receiver Operating Characteristic (ROC) curve. The Area Under the Curve (AUC), sensitivity and specificity were calculated for a 10% cut-off value.
Presence of macrometastases (p=0.03) and its extranodal extension (p=0.013) in sentinel node were associated with NSLNM, while other tumor and patient characteristics were not. The accuracy of MSKCC nomogram as measured by AUC was 0.67. The nomogram showed 95% sensitivity and 14% specificity. We revised the nomogram by incorporating the presence of extranodal extension and we obtained a new test with improved specificity (84%).
The modified predictive model is a useful tool in predicting the likelihood of NSLNM in our cohort of patients and may help decision regarding the need of completion axillary lymph node dissection.
Annali italiani di chirurgia 83(6):461-8. · 0.23 Impact Factor
