Il carcinoma delle paratiroidi: impatto dello status genetico HRPT2 nella pratica clinica

ABSTRACT Background and aim of the study We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, and for its clinical impact in sporadic parathyroid carcinoma and atypical parathyroid adenoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism - hyperparathyroidism-jaw tumor (HPT-JT) syndrome – that carries an increased risk of aggressive parathyroid cancer. Methods We investigated every patient with a diagnosis of parathyroid carcinoma or atypical parathyroid adenoma, who had undergone surgery by one surgeon from 1975 to May 2012 at our Department. Genetic studies were performed from genomic DNA isolated from peripheral blood leukocytes and parathyroid tissue. Preoperative (symptoms, biochemical analysis, imaging), operative (surgery, histological analysis) and post-operative (follow-up) data have been collected in a database and statistically processed. The genetic analysis results have been correlated with the clinical course. Results The study involved 70 patients (group 1: 39 carcinomas, group 2: 31 atypical adenoma). Until now, we investigated 18 patients with parathyroid carcinoma and 8 patients with atypical adenoma. We detected HRPT2 mutation in two patients with carcinoma that died for rapid tumor progression. Conclusions HRPT2 status would be a piece of information to add to the conventional clinical parameters: it correlates with a more aggressive disease. The diagnostic utility of the HRPT2 screening might provide grounds for more aggressive follow-up and family screening. This test will be especially helpful if it directs us to an aggressive surgical approach because that is ultimately the only cure for this devastating disease

A mathematical model of mitochondrial swelling

<p>Abstract</p> <p>Background</p> <p>The <it>permeabilization </it>of mitochondrial membranes is a decisive event in apoptosis or necrosis culminating in cell death. One fundamental mechanism by which such permeabilization events occur is the calcium-induced mitochondrial permeability transition. Upon Ca²⁺-uptake into mitochondria an increase in inner membrane permeability occurs by a yet unclear mechanism. This leads to a net water influx in the mitochondrial matrix, mitochondrial swelling, and finally the rupture of the outer membrane. Although already described more than thirty years ago, many unsolved questions surround this important biological phenomenon. Importantly, theoretical modeling of the mitochondrial permeability transition has only started recently and the existing mathematical models fail to characterize the swelling process throughout the whole time range.</p> <p>Results</p> <p>We propose here a new mathematical approach to the mitochondrial permeability transition introducing a specific delay equation and resulting in an optimized representation of mitochondrial swelling. Our new model is in accordance with the experimentally determined course of volume increase throughout the whole swelling process, including its initial lag phase as well as its termination. From this new model biological consequences can be deduced, such as the confirmation of a positive feedback of mitochondrial swelling which linearly depends on the Ca²⁺-concentration, or a negative exponential dependence of the average swelling time on the Ca²⁺-concentration. Finally, our model can show an initial shrinking phase of mitochondria, which is often observed experimentally before the actual swelling starts.</p> <p>Conclusions</p> <p>We present a model of the mitochondrial swelling kinetics. This model may be adapted and extended to diverse other inducing/inhibiting conditions or to mitochondria from other biological sources and thus may benefit a better understanding of the mitochondrial permeability transition.</p

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Il carcinoma delle paratiroidi: impatto dello status genetico HRPT2 nella pratica clinica

ABSTRACT Background and aim of the study We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, and for its clinical impact in sporadic parathyroid carcinoma and atypical parathyroid adenoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism - hyperparathyroidism-jaw tumor (HPT-JT) syndrome – that carries an increased risk of aggressive parathyroid cancer. Methods We investigated every patient with a diagnosis of parathyroid carcinoma or atypical parathyroid adenoma, who had undergone surgery by one surgeon from 1975 to May 2012 at our Department. Genetic studies were performed from genomic DNA isolated from peripheral blood leukocytes and parathyroid tissue. Preoperative (symptoms, biochemical analysis, imaging), operative (surgery, histological analysis) and post-operative (follow-up) data have been collected in a database and statistically processed. The genetic analysis results have been correlated with the clinical course. Results The study involved 70 patients (group 1: 39 carcinomas, group 2: 31 atypical adenoma). Until now, we investigated 18 patients with parathyroid carcinoma and 8 patients with atypical adenoma. We detected HRPT2 mutation in two patients with carcinoma that died for rapid tumor progression. Conclusions HRPT2 status would be a piece of information to add to the conventional clinical parameters: it correlates with a more aggressive disease. The diagnostic utility of the HRPT2 screening might provide grounds for more aggressive follow-up and family screening. This test will be especially helpful if it directs us to an aggressive surgical approach because that is ultimately the only cure for this devastating disease.RIASSUNTO Presupposti e scopo dello studio La nostra ricerca è finalizzata all’analisi di mutazione del gene HRPT2, che codifica per la proteina Parafibromina, e alla valutazione del suo impatto clinico nelle forme sporadiche di carcinoma delle paratiroidi e negli adenomi paratiroidei atipici, in quanto mutazioni inattivanti il gene HRPT2 sono emerse in una forma famigliare di iperparatiroidismo- la sindrome iperparatiroidismo associato a tumore della mandibola (HPT-JT)- che comporta un aumentato rischio di carcinoma delle paratiroidi clinicamente aggressivo. Materiali e Metodi Lo studio ha arruolato tutti i pazienti affetti da carcinoma o adenoma atipico delle paratiroidi che sono stati sottoposti ad intervento chirurgico presso il nostro reparto dal 1975 a maggio 2012. Lo studio genetico è stato eseguito su DNA isolato dal tessuto patologico e dai leucociti ottenuti da sangue periferico. Sono stati raccolti in un database e analizzati statisticamente i dati clinici preoperatori (sintomi, dati di laboratorio, dati radiologici), operatori (tipo di intervento chirurgico, esame istologico, paratormone rapido intraoperatorio-IOPTH) e postoperatori (dati di laboratorio, follow-up). I risultati dello studio genetico sono stati correlati con i dati clinici. Risultati Lo studio ha compreso 75 pazienti (gruppo 1: 41 carcinomi; gruppo 2: 34 adenomi atipici) di età media 59 anni. I pazienti con adenoma atipico e carcinoma non differivano statisticamente per sintomi, calcemia media preoperatoria (3,2 mMol/L), dimensione della lesione , ma i carcinomi presentavano valori medi di PTH più elevati (477,8 vs 931,8 ng/L). La sopravvivenza è risultata dell’88,13% a cinque anni e del 79,74% a dieci anni. Costituiscono fattori di rischio per lo sviluppo di recidiva: valori elevati di calcemia preoperatoria (3,4 mMol/L), l’esecuzione di paratiroidectomia semplice, la mancata riduzione dello IO-PTH, il reperto istologico di infiltrazione dei tessuti limitrofi. Fattore prognostico negativo è risultata la presenza di mutazione HRPT2, riscontrata in tre pazienti affetti da carcinoma, i quali hanno avuto decorso rapidamente infausto. Nessun adenoma atipico ha presentato mutazione HRPT2. Conclusioni Nei carcinomi delle paratiroidi, la genetica HRPT2 dovrebbe essere considerata parte delle analisi da valutare assieme ai parametri convenzionali in quanto correla con una forma di malattia più aggressiva. L’utilità dello screening genetico HRPT2 dovrebbe presupporre un follow-up più intenso e uno screening famigliare. Lo studio genetico è sicuramente utile nell’indirizzare ad un approccio chirurgico più aggressivo che a tutt’oggi rimane il solo trattamento più efficace

Applicatiom of the LigaSureTm tissue sealing system to intestinal resection. Experimental and clinical trial.

Abstract: Nodular goiter encompasses a spectrum of diseases from the incidental asyntomatic small solitary nodule to the large intrathoracic goiter causing pressure symptoms as well as functional complaints. The mainstay in the diagnostic evaluation is related to functional and morphological characterization with serum thyroid-stimulating hormone (TSH), ultrasound (US) and other imaging procedures and cytology by fine needle aspiration (FNA) on the basis of the different diseases. A clinical classification considering solitary cyst, adenomatous functioning nodule, follicular lesion and multinodular goiter may be proposed to consider the alternative therapies other than surgery as TSH suppressive or thyrostatic treatment, (131)I therapy, percutaneous ethanol injection therapy (PEIT) or the only clinical exam in benignant lesions. Surgery should be advocated for the treatment of thyroid nodules whenever a patient presents with either pressure symptoms, hyperthyroidism or follicular/indeterminate cytology. Surgical approach, intraoperatory strategy and the extension of surgical treatment are correlated to the different clinical categories. At surgery the frozen section analysis in case of hemithyroidectomy is of aid to rule out malignancy and to prevent the reoperation. The surgical treatment of choice in case of uninodular goiter is lobectomy, total thyroidectomy or near total thyroidectomy is the correct treatment of multinodular bilateral goiter. The choice of the treatment must be condivided with the patient

Innovative fabrication of diffractive surfaces on plastic parts via textures micromilled on NiP injection moulds

none5noDiffractive microstructured surfaces are nowadays increasingly applied to polymeric parts for aesthetic, security and optical functionalities. However, both the machining of the mould blaze-grating and its replication on plastic are still representing challenging issues, from both the technical and economical points of view. In this work, an innovative process chain based on carbide tools micromilling of mould gratings was developed for mass production of diffractive patterns on injection moulded parts. A micromilling experimental campaign was conducted on a nickel-phosphorus (NiP) thick coating to machine a blaze-grating on the mould surface, evaluating the influence of the cutting parameters on the diffractive surface quality. Subsequently, the microstructures were replicated on ABS, PC and PMMA by injection moulding. The roughness parameters Sk, Spk and Svk were added with the idea that their sum is representative of the polymer replication of regular diffraction grating pattern. Moreover, the effect of the moulded grating surface quality on the optical performance was preliminarily assessed. The obtained results show that the proposed process chain is suitable for low-cost mass production of polymeric parts with diffractive microstructures.openMilan N.; Parenti P.; Annoni M.; Sorgato M.; Lucchetta G.Milan, N.; Parenti, P.; Annoni, M.; Sorgato, M.; Lucchetta, G

Effects of micromilled NiP mold surface topography on the optical characteristics of injection molded prismatic retroreflectors

Automotive lighting applications require mold micro-features with increasingly better surface finishing, especially for optical lenses and retroreflectors. In this work innovative micromilling experiments were conducted on electroless-plated nickel phosphorous (NiP) surfaces to fabricate a mold for prismatic retroreflectors. Cutting parameters effects on surface topography of mold micro-features were experimentally characterized and optimized, monitoring moreover the cutting forces generated by NiP micromilling. Furthermore, the mold surface topography was replicated on polycarbonate injection molded retroreflectors and its effects on their optical performance was characterized by means of a dedicated spectrophotometric technique. The obtained results show that micromilling of electroless-plated NiP can substitute polishing in the fabrication of high surface finish mold micro-features