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It goes without saying that all people with diabetes should be taught the best injection technique before starting insulin treatment. Nevertheless the extremely high rate of local injection-related skin reactions-i.e., lipodysthrophic lesions-described in literature, proves otherwise. We are hereby presenting a Consensus Document on Injecting Techniques which highlights 18 key points based on a thorough analysis of the available literature and ranked by "Level of evidence" and "Strength of recommendation" according to our National Guideline System. It is meant at providing all professionals involved in diabetes care with a practical guide on how to help patients on insulin perform well.

Diabetes is an independent risk factor for the development of coronary heart disease and has a tremendous impact on mortality. In patients with noninsulin-dependent diabetes mellitus, coronary heart disease is the leading cause of death. Both hyperinsulinemia and hyperglycemia have been suggested as risk factors for accelerated atherogenesis in diabetes. Whichever mechanism is implicated, a beneficial effect of therapy in preventing cardiovascular disease is a major requirement. Until now, it is not clear whether stringent control of blood glucose levels reduces the risk of development of coronary heart disease in patients with noninsulin-dependent diabetes mellitus. This review emphasizes the relative roles of insulin and glucose on coronary heart disease development in noninsulin-dependent diabetes mellitus. The different therapeutic options of pharmacological treatment in hyperglycemia in noninsulin-dependent diabetes mellitus are discussed, as well as their impact on coronary heart disease risk.

We report a case of pilomatrix carcinoma in a 42 year old woman. The patient presented a rapidly growing 4-cm subcutaneous mass in the right preauricular area. She was free of recurrence 24 months after surgery. Immunoreactivity was studied for cytokeratins, epithelial membrane antigen, S-100 protein, blood group antigens, Leu-M1, β-2-microglobulin, vimentin, neuron-specific-enolase and cellular binding for peanut agglutinin. Squamous cells were reactive for cytokeratin AE1/3, epithelial membrane antigen, blood group antigens B and H, and peanut agglutinin. Basaloid cells were focally reactive for cytokeratin AE1/3 and epithelial membrane antigen. Flow cytometry revealed a euploid DNA content and a high proliferative rate of the pilomatrix carcinoma and in benign pilomatrixoma studied for comparison. The pathological diagnosis must be based on histomorphological criteria.

The metabolic and cardiovascular effects of nitrendipine and cilazapril in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM) were compared. After at least 6 weeks of a washout period, 20 NIDDM patients who had diastolic blood pressure in the range of 90-105 mm Hg received a single-blind placebo for 4 weeks and then were randomized to receive 20 mg nitrendipine once daily and 5 mg cilazapril once daily each for 12 weeks according to a crossover, double-blind procedure. Nitrendipine and cilazapril reduced diastolic blood pressure levels 12% and 13%, left ventricular mass index (LVMI) levels 13% and 12%, and raised whole glucose disposal levels 18% and 19.5%, respectively. Only nitrendipine reduced glucose-stimulated insulin levels. Nitrendipine is as effective as cilazapril in lowering diastolic blood pressure and LVMI levels and in increasing glucose disposal levels in these patients.

Background: Diabetic patients are considered less suitable than nondiabetic patients for β-blocker therapy because of the risk for worsened glucose and lipid metabolism and more severe hypoglycemic attacks. Objective: To compare the metabolic and cardiovascular effects of carvedilol with those of atenolol in diabetic patients with hypertension. Design: Randomized, double-blind, 24-week trial. Setting: University hospital clinic. Patients: 45 patients with non-insulin-dependent diabetes mellitus and hypertension. Intervention: After a 4- to 6-week run-in period during which placebo was given in a single-blind manner, patients were randomly assigned to carvedilol or atenolol. Measurements: An oral glucose tolerance test; assessment of insulin sensitivity and hormonal responses to insulin hypoglycemia; and assessment of lipid levels, blood pressure, left ventricular mass, and lipid peroxidation. Results: Changes in systolic and diastolic blood pressure and left ventricular mass index were similar with carvedilol and atenolol (P > 0.2). Fasting plasma glucose and insulin levels decreased with carvedilol and increased with atenolol. Responses to carvedilol were greater than those to atenolol, as follows: increase in total glucose disposal, 9.54 μmol/kg of body weight per minute (95% Cl, 7 to 11.9 μmol/kg per minute); decrease in plasma glucose response to oral glucose, 61 mmol/L x 180 minutes (Cl, -101 to -21 mmol/L x 180 minutes); decrease in insulin response to oral glucose, 6.2 nmol/L x 180 minutes (Cl, -9.8 to -2.6 nmol/L x 180 minutes); decrease in triglyceride level, 0.56 mmol/L (Cl, -0.75 to -0.37 mmol/L; P < 0.001); increase in high-density lipoprotein cholesterol level, 0.13 mmol/L (Cl, 0.09 to 0.17 mmol/L; P< 0.001); and decrease in lipid peroxidation, 0.25 μmol/L (Cl, -0.34 to -0.16 μmol/L). Conclusions: By improving glucose and lipid metabolism and reducing lipid peroxidation, carvedilol may offer advantages in patients with diabetes and hypertension.

Purpose: Cancer-related cognitive impairment (CRCI) has been reported in non-central nervous system neoplasms survivors. The purpose of this study was to evaluate the perception of cognitive decrement in patients undergoing surgical and / or medical therapy for gynecological cancers. Methods: All women diagnosed with primary gynecological cancer and undergoing active medical treatment have been enrolled in a prospective study. Before starting treatment (T1) and 6 months after the end of treatment (T2), patients were interviewed to evaluate the effects of cancer treatment on perceived cognitive function (using FACT-Cog -version 3), on depression (using Beck Depression Inventory-II test) and on quality of life (using EORTC-QLQC-30). Age, education level, marital status, lifestyle, menopausal state at diagnosis, cancer type, cancer FIGO stage, treatment modality was also recorded. The differences between baseline and post-treatment results have been evaluated with Student's t test. The results have been stratified by the menopausal state at diagnosis, type of tumor (endometrial, cervical, ovarian, vulvar) disease stage and type of treatment (chemotherapy or radiotherapy). Results: Seventy-three patients were included. A significant reduction in perceived cognitive impairments was demonstrated at T2 (CogPCI: 61.35 ± 13.83 vs 55.05 ± 16.56; p < 0.05). On the contrary, a significant improvement was shown in depression state (BDII: 21.14 ± 11.23 vs 12.82 ± 12.33, p < 0.005). The menopausal state at surgery, tumor site, stage and treatment modality seem to influence the variables analyzed. Conclusion: CRCI is a true risk also in gynecological cancer survivors. The cognitive impairment does not seem to be dependent on depression state after treatment or to a menopausal condition. Assessing cognitive decline in cancer survivorship is essential for ensuring the optimum quality of life and functioning.

Objective. Evaluate the effects of carboxy-methyl-beta-glucan on cervical epithelialization and on the vaginal microbiota in patients with HPV infection or low-grade cervical preneoplastic lesion (CIN 1). Materials and Methods. Seven-hundred eighty-four women with positive HPV tests or diagnosed with CIN 1 were enrolled in a retrospective case-control study. All the recruited women performed, at baseline and after 6 months, Pap test, HPV test, evaluation of vaginal health according to the Amsel criteria, colposcopy, and punch biopsy. The study population was then divided into 2 groups in relation to the therapy performed during the follow-up period. Group A performed treatment with vaginal gel based on carboxy-methyl-beta-glucan (1 application/day for 20 days per month for 3 months). Group B was the control group. Results. The patients of group A had a significant improvement in the ectopia pattern and a greater number of cases with metaplasia in the maturation phase with a significant increase in Lugol uptake. In the experimental group, a significant improvement in the pH indices, a negative Swift test and a resolution of the leucorrhoea were observed. A negative result of the 37.1% Pap test and the 39.9% HPV test (vs. 15.2% and 16.5%, respectively) were demonstrated in the treatment group with respect to the control group. A negativization of the colposcopic pictures was observed with a reduction in the amount of CIN 1 found higher in the treatment group. Conclusions. Vaginal therapy based on carboxy-methyl-beta-glucan has been able to improve overall vaginal health; this effect seemed to positively impact the risk of persistence and progression of CIN.

Introduction.HPV infection is a highly infectious disease; about 65% of partners of individuals with genital warts will develop genital condylomatosis. Only in 20-30% it regresses spontaneously and relapse rates range deeply (9-80%). Echinacea extracts possess antiviral and immunomodulator activities. The aim of this study was to evaluate the efficacy of the therapy, using a formulation based on HPVADL18® (on dry extracts of 200 mg Echinacea Purpurea (EP) roots plus E. Angustifolia (EA)), on the posttreatment relapse incidence of genital condylomatosis.Materials and Methods.It is a prospective single-arm study. Patients with a satisfactory and positive vulvoscopy, colposcopy, or peniscopy for genital condylomatosis were divided into two random groups and subjected to destructive therapy with Co2 Laser. Group A (N=64) immediately after the laser therapy started a 4-month treatment with oral HPVADL18®; Group B (N=61) did not undergo any additional therapy. Patients were subjected to a follow-up after 1, 6, and 12 months. Differences in relapse incidence between the two groups during follow-up controls were evaluated byχ2-test; the groups were stratified by age, gender, and condylomatosis extension degree.Results and Discussion.Gender, age, and condyloma lesions’ extension degree showed no statistically significant differences between the two trial groups. The relapse incidence differs statistically between the two studied groups and progressively decreases during the 12 months after treatment in both groups. Statistically significant reduction of relapse rates has been shown in Group A in patients over 25 years old. This difference is significant for both men and women. The relapse incidence is superior in case of extended condylomatosis.Conclusions.In conclusion, the presence of a latent infection causes condylomatosis relapse; in order to reduce the relapse risk an induction of a protective immune response seems to be essential to allow rapid viral clearance from genital areas surrounding lesion and treatment zones. Echinacea promotes this process. EP and EA dry root extracts seem to be a valid adjuvant therapy in reducing relapse incidence of lesions in patients treated for genital condylomatosis.

The first step leading to metastasis, or for the acquisition of local invasiveness, involves changes in the phenotype of neoplastic cells in the primary tumor. The epithelial&ndash, mesenchymal transition (EMT) is a process that determines the acquisition of a form and a transcriptional program that are characteristic of mesenchymal cells, in epithelial cells. The factors involved in this process are E-cadherin and N-cadherin adhesion proteins and some transcription factors such as Slug and Twist. EMT is a site-specific mechanism that is also active in embryogenesis&mdash, embryonic cells are affected if invested in certain points, probably due to the signals emanating from the cells or groups of surrounding cells. It is known that neuroendocrine neoplasms have a biological behavior that differs in grading, staging, and site. The aim of our study was to investigate the immunohistochemical expression of EMT factors (Twist, Slug, and E-cadherin) in the neuroendocrine neoplasms of the gastrointestinal tract, the pancreas, and lungs, in 65 cases retrieved from the archives of the Department of Pathology, of three hospitals. The immunoscores were compared in each site and correlated with the clinico-pathological parameters. Statistical evaluation revealed an association between the higher Twist immunoscore and higher grading (p value &lt, 0.0001) and staging (p value = 0.0055). Slug was detected only in pancreatic cases where its reduced expression was associated with a higher grading (p value = 0.0033). This data could be of diagnostic utility in the case of metastases from neuroendocrine neoplasm, to define the site of the primitive tumor when the traditional immunohistochemical panel is not sufficient. In summary, our results indicated, first that the EMT is also an active process in neuroendocrine neoplasms. To the best of our knowledge, this was the first study that evaluated the expression of EMT factors in neuroendocrine neoplasms of different districts.

Introduction: Colposcopy represents the second step of the diagnostic approach of cervical intraepithelial lesions. Limits of colposcopy in studying cervix are essentially related to cervical anatomy. Nowadays, endocervical courettage is the standard technique to examine endocervix. Endocervicoscopy is a new imaging technique for the diagnostic work-up of endocervix in patients with cervical intraepithelial neoplasia (CIN). Objective: To evaluate endocervicoscopy accuracy to identify and grade cervical intraepithelial lesion in comparison to other procedures employed into the diagnostic workup of cervical pathology. Methods: A total of 634 women who performed colposcopy, endocervicoscopy and cytological or histological sampling were included in a retrospective study. The agreement between the endocervicoscopic and the colposcopic impressions, minor and major changes, and between these imaging techniques and histological diagnosis was assessed for the entire cohort. χ2 test and k statistic were used in the statistical analysis. Results: The extension of the lesion resulted significantly greater at endocervicoscopy than at colposcopy. We showed a statistically significant association between colposcopy and endocervicoscopy findings. Overall, the correlation of minor or major findings between colposcopy and endocervicoscopy was statistically significant with a p value for all parameters k value (k = 0.68 [95% CI 0.64–0.73], k = 0.80 [95% CI 0.75–0.85], k = 0.78 [95% CI 0.64–0.90], respectively). The sensitivity (70.1%) and the specificity (77.0%) of endocervicoscopy for all CIN lesions were lower than colposcopy. Conclusion: Endocervicoscopy turned out to be a good method to identify and grade CIN lesions in a subset of patients where colposcopy was not satisfactory. It allowed us to overcome one of the limits of colposcopy in the evaluation of the squamo-columnar junction and to establish the real extension of the lesion into cervical cancer.

Objective. Cesarean scar pregnancy (CSP) is a rare condition that occurs when the pregnancy implants in a cesarean scar. An early diagnosis and a proper management are fundamental to prevent maternal complications. We review and discuss the different treatment employed in our unit to reduce morbidity, preserve fertility, and predict possible complications. Methods. The reported treatment has been expectant management, operative hysteroscopy approach, and intramuscular injection of 50 mg methotrexate (MTX), followed by cervical dilation and manual vacuum aspiration (D&S) with a Karman cannula under ultrasound guidance, uterine artery embolization (UAE), and manual vacuum aspiration under ultrasound guidance and uterine artery embolization before surgical laparotomic resection. Results. Complications were more frequent in women with a history of three or more cesarean section deliveries and with a myometrial thickness thinner than 2 mm. MTX and D&S treatment appear to be most effective and safe at the early age of pregnancy, while UAE and D&S are related to the highest risk of complication in any age of pregnancy. Conclusion. An appropriate preoperative diagnostic evaluation, the identification of cases at higher risk, and those eligible for a conservative treatment are fundamental to reduce complications.

Purpose: The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM). Methods: Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25–75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis ≤ 8.1 kPa and advanced fibrosis ≥ 8.2 Kpa. Results: At baseline, the median value of LSM was 14.1 kPa for advanced fibrosis/cirrhosis and 6.9 kPa for non-advanced fibrosis. LSM was performed at 24 months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5 kPa (p < 0.001) in non-advanced fibrosis and of 6 kPa (p < 0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p = 0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456–5.788; (p = 0.007). Conclusion: Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.

In this report we describe a case of pulmonary epithelioid hemangioendothelioma (PEH) in a young woman. The neoplasm manifested with dry cough, chest pain, finger clubbing, and multiple bilateral pulmonary nodules on chest x-ray and computed tomographic (CT) scan. She underwent thoracoscopy, and the histological features of the lung biopsies were initially interpreted as consistent with a not-well-defined interstitial lung disease. Our patient was clinically and radiologically stable over a period of four years, after which the disease progressed to involve not only the lung but also mediastinal lymph nodes, liver and bone. Fiberoptic bronchoscopy showed subtotal occlusion of the right middle and lower lobe bronchi. The histologic examination of bronchial biopsies revealed a poorly differentiated neoplasm immunohistochemically positive for vimentin and vascular markers CD31, CD34 and Factor VIII. A diagnosis of malignant hemangioendothelioma was made. Positron emission tomography (PET) is more sensitive than CT scan and bone scintigraphy in detecting PEH metastases. Furthermore, 18-fluorodeoxyglucose (FDG) uptake seems to be related to the grade of malignancy of PEH lesions. Therefore, we suggest that FDG-PET should be included in the staging system and follow-up of PEH.

The aim of the study was to determine the impact of etonogestrel (ENG)-implant used for contraceptive purpose on Quality of life (QoL) and on sexual function (FSF) of healthy Italian women. The Female Sexual Function Index (FSFI) questionnaire and the Short Form-36 (SF-36) validated questionnaire were administered at baseline, 3 and 6 months after insertion of Nexplanon. The implant seems to have a positive impact on QoL after the first three months of therapy. Users showed an improved general health status and physical role status. The implant did not show negative effects on libido and on sexual function. In the first three months of treatment, users experienced a temporary reduction of vitality, mental health, social functioning and emotional role functioning, which seem to disappear after six months of therapy.

OBJECTIVE To compare the effects of tolrestat and placebo in patients with subclinical diabetic neuropathy. RESEARCH DESIGN AND METHODS Non-insulin-dependent diabetes mellitus (NIDDM) patients with early involvement of the autonomic nervous system were identified by only one pathological (outside the 99% confidence interval of the normal population) squatting test (vagal or sympathetic). Fifty-seven patients entered a randomized, placebo-controlled, double-blind, parallel 52-week study of tolrestat at a dose of 200 mg/day. Cardiovascular reflex tests (squatting vagal and sympathetic tests, pressure gain, deep breathing, lying-to-standing, Valsalva maneuver, and orthostatic hypertension), vibration thresholds, tendon reflexes, and muscle strength were assessed throughout the study. RESULTS At 12 months, nerve function significantly improved in patients receiving tolrestat and deteriorated in patients taking placebo. At baseline, the squatting vagal test was normal in 16 patients in the tolrestat group and in 15 patients in the placebo group. At 12 months, 25 patients taking tolrestat had a normalized squatting test, but only 6 patients taking placebo did (P = 0.02). Vibration perception threshold improved by a value of 6 ± 3 V in the tolrestat group (P < 0.001) and deteriorated by a value of 3 ± 1.8 V (P < 0.001) in the placebo group. CONCLUSIONS Tolrestat may be useful in the primary prevention of diabetic neuropathy.

To investigate the impact of a 3 months preoperative administration of an oral contraceptive, containing dienogest (DNG) and estradiol valerate (E₂V) on the outcome of office operative hysteroscopy (OOH). One-hundred and forty-two patients diagnosed at office hysteroscopy as having an asynchronous endometrium associated with either a broad-base sessile endometrial polyp (1.5,2.5 cm) or a uterine septum (1/3 uterine cavity) or scheduled for tubal sterilization were enrolled into a prospective case-control study at University "Federico II" of Naples. 86/142 patients accepted the preoperative hormonal treatment (Group A), while 56/142 refused, thus becoming controls (Group B). Group A underwent OOH during the 10th-20th days of the third cycle of treatment. In Group B OOH was performed at enrolment, together with the diagnostic procedure. The study outcomes were: endometrial pattern, success rate, operating time, degree of surgical difficulty and pain score. An overall improvement of the endometrium was reported in 100% of cases in Group A. A statistically significant difference in success rate could not be demonstrated between two groups. Operative procedures were performed significantly quicker and easier in Group A than Group B (p0.001 and p0.05, respectively). The mean Visual Analog Scale (VAS) score was significantly lower in Group A (p0.001). A short pretreatment with combined oral contraceptive (COC) containing E₂V/DNG seems to have a favorable impact on endometrium which in turn may result in an improvement of the overall outcomes of OOH.

Purpose To identify dose–heart-volume constraints that correlate with the risk of developing asymptomatic valvular defects (VD) in Hodgkin's lymphoma (HL) patients treated with three-dimensional radiotherapy (RT). Patients and methods Fifty-six patients undergoing cytotoxic chemotherapy (CHT) and involved-field radiation treatment for HL were retrospectively analyzed. Electro-echocardiography was performed before CHT, after CHT, and after RT. For the entire heart, for right and left ventricle (RV, LV), right and left atrium (RA, LA) percentage of volume exceeding 5–30Gy in increment of 5Gy ( V x ), and dosimetric parameters were calculated using 1.6Gy fraction as reference. To evaluate clinical and dosimetric factors possibly associated with VD, univariate and multivariate logistic regression analyses were performed. Results At a median follow up of 70.5months, 32.1% of patients developed VD (regurgitation and/or stenosis): 25.0% developed mitral, 5.4% developed aortic, and 14.3% tricuspid VD. In particular the percentage of LA exceeding 25Gy (LA- V 25 ) and the percentage of LV exceeding 30Gy (LV- V 30 ) correlated with mitral and aortic VD with an odds ratio (OR) of 5.7 (LA- V 25 >63.0% vs. LA- V 25 ⩽63.0%) and OR of 4.4 (LV- V 30 >25% vs. LV- V 30 ⩽25%), respectively. RV- V 30 correlated with tricuspid VD (OR=7.2, RV- V 30 >65% vs. RV- V 30 ⩽65%). Conclusion LA- V 25 , LV- and RV- V 30 prove to be predictors of asymptomatic alteration of valve functionality.

Aim To evaluate whether the histology and grading of solitary pulmonary nodules (SPNs) correlated with the results of dynamic multiphase multidetector CT (MDCT) and the [ 18 F]fluorodeoxyglucose standardised uptake value (SUV) in 30 patients. Methods Chest x-rays of 270 patients with incidentally detected SPNs were retrospectively evaluated. Thirty patients with histologically proven SPNs were enrolled. On MDCT and positron emission tomography (PET)/CT images, two experts measured the density of nodules in all perfusion phases and the SUV. Net enhancement (NE) was calculated by subtracting peak pre-contrast density from peak post-contrast density. The Pearson test was used to correlate nodule NE, SUV, grading, histology and diameter. Results Of the 30 malignant SPNs, six were classified as G1 (median NE, 31.5 Hounsfield units (HU); median SUV, 4.8 units), 15 were classified as G2 (median NE, 49 HU; median SUV, 6 units), and nine were classified as G3 (median NE, 32 HU; median SUV, 4.5 units). A highly negative correlation was found in G3 SPNs between NE and the corresponding diameters (r=−0.834; p=0.00524). NE increased with the increase in diameter (r=0.982; p=0.284). SUV increased as the SPN diameter increased (r=0.789; p=0.421). NE and SUV were higher in G2 than G1 SPNs, and lower in G2 than G3 SPNs (r=0.97; p=0.137). Conclusions The significant correlation in dedifferentiated (G3) SPNs between NE and diameter (r=−0.834; p=0.00524) supports the theory that stroma and neoangiogenesis are fundamental in SPN growth. The highly negative correlation between NE and diameter demonstrates a net decrease in perfusion despite an increase in dimension. The multidisciplinary approach used herein may result in a more precise prognosis and consequently a better therapeutic outcome, particularly in patients with undifferentiated lung cancer.

OBJECTIVE To determine the effects of metformin on blood pressure, left ventricular mass, and some metabolic and endocrine parameters in nondiabetic, obese, hypertensive women. RESEARCH DESIGN AND METHODS Twelve obese, nondiabetic, hypertensive women received 850 mg metformin 2 times/day for 12 wk and placebo for another 12 wk, according to a double-blind, cross-over, randomized design. All patients were hospitalized 4 times, i.e., before randomization and after each treatment (metformin or placebo), to conduct metabolic and cardiovascular investigations (oral glucose tolerance test, euglycemic clamp associated with indirect calorimetry, and echocardiography). RESULTS Fasting glucose, HbA1c, fasting and glucose-stimulated insulin, blood pressure and left ventricular mass, cholesterol, triglycerides, and fibrinogen decreased significantly after metformin treatment, whereas high-density lipoprotein cholesterol increased. The improvement in glucose metabolism resulted from increased sensitivity to insulin. CONCLUSIONS These findings suggest that metformin treatment in obese, nondiabetic, hypertensive women produces a more favorable cardiovascular risk profile.

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose −4.1 mmol·l−1; glycosylated haemoglobin A1 decrease −1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These postive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile 10 mmol·l−1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (−21.6 U/day). Metformin was well tolerated by all diabetics. Combining metforming with insulin in obese, insulin-treated and poorly controlled diabetics may represent a safe strategy to achieve better glycaemic control with a reduction in certain metabolic risk factors associated with the increased incidence of cardiovascular disease in diabetes mellitus.

Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n = 98; P < 0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).

We report a case of an asymptomatic patient in whom a right atrial mass was fortuitously documented by echocardiography few months after a transcatheter radiofrequency catheter ablation for recurrent AF. No masses were seen in the cardiac chambers before the ablative procedure, raising important diagnostic and decision-making issues. The patient was referred to the surgeon and a diagnosis of right atrial myxoma was made.

An increasing difficulty of couples in achieving pregnancy related to male infertility has been reported. Several factors have been implicated as possible causes of this decrease, including the exposure to the endocrine disruptors and the environmental toxicants, the changes in lifestyle and the exposure to heat. The aim of this study was to evaluate the role of working posture when associated to nitrogen oxides exposure. Three hundred and seven male workers, employed in a motorway company, were enrolled into the study, underwent a complete physical examination and laboratory evaluations, endocrine screening and sperm analysis. Taking into account the exposure to fuel combustion gases and the working posture, sitting or free, the study population was divided in 4 groups. In the subjects occupationally exposed to NO2, a significant lower sperm total motility was observed than in not exposed workers. In the workers with obliged sitting working posture, lower sperm motility was also observed than in the workers with free working posture. Differences in sperm quality were strong when chemical and postural risk factors were associated. The findings of this study confirmed detrimental effects of nitrogen dioxide as a marker of traffic pollutants, showing alterations of sperm quality even if the environmental concentration of gas is very low according to the limits established by the Italian legislation. They suggest, also, the possible interaction between chemical exposure and obliged sitting position.

Background: Histamine plays a central role in the pathogenesis of allergic and inflammatory diseases by modulating vascular and airway responses. Increasing evidence suggests that histamine also regulates the function of inflammatory and immune cells. Macrophages are primarily involved in inflammatory diseases of the lung. We explored the ability of low concentrations of histamine to induce the release of proinflammatory mediators from human lung macrophages. Methods: Macrophages purified (>95%) from lung parenchyma by Percoll density gradients and adherence to polystyrene dishes were incubated (37°C, 2–24 h) with histamine (10–9–10–6M). At the end of incubation, the release of β-glucuronidase and IL-6 was determined. Results: Histamine induced a concentration-dependent release of β-glucuronidase and IL-6 with a maximum release after 2 and 6 h of incubation, respectively. Exocytosis induced by histamine was noncytotoxic and was Ca2+- and temperature-dependent. The effect of histamine was inhibited by the H1 receptor antagonist fexofenadine but not by the H2 antagonist ranitidine. Conclusions: These data indicate that histamine is an effective stimulus for exocytosis and cytokine production from human lung macrophages. These effects are inhibited by pharmacological concentrations of fexofenadine. Our results suggest that histamine may contribute to the long-term evolution of lung inflammation and tissue remodelling in allergic diseases by modulating the production of proinflammatory and immunoregulatory mediators by macrophages.

OBJECTIVE The endothelium plays a pivotal role in the regulation of vascular tone by releasing nitric oxide (NO). Increased availability of L-arginine, the natural precursor of NO, induces vasodilatation and inhibits platelet activity. We studied the effect of metformin on hemodynamic and rheological responses to L-arginine in patients with NIDDM. RESEARCH DESIGN AND METHODS Ten newly diagnosed NIDDM patients with mild fasting hyperglycemia (7.5 ± 0.3 mmol/l) and without evidence of both micro- and macrovascular complications were investigated. They received an intravenous infusion of L-arginine (1 g/min for 30 min) with evaluation of plasma glucose and insulin, systolic (sBP) and diastolic (dBP) blood pressure, heart rate and plasma catecholamines, platelet aggregation, and blood viscosity and filterability. The L-arginine test was repeated after an 8-week treatment with metformin (850 mg b.i.d.). RESULTS Metformin treatment significantly reduced basal fasting plasma glucose, HbA1c, and platelet aggregation to ADP (P < 0.05); the other parameters did not change. During pretreatment test, L-arginine infusion decreased sBP (from 137 ± 4.1 to 129 ± 4.5 mmHg, P < 0.01) and dBP (from 79 ± 1.9 to 75 ± 1.2 mmHg, P < 0.01) without affecting heart rate or plasma catecholamines. Both platelet aggregation and blood viscosity showed significant decrements after L-arginine, while blood filterability did not change. After metformin treatment, the decrease in blood pressure after L-arginine infusion was significantly enhanced, with a maximal decrease of sBP of 12 ± 3.4 mmHg (8 ± 2.5 mmHg pretreatment, P < 0.05) and dBP of 9.5 ± 2.4 mmHg (4.5 ± 1.9 mmHg pretreatment, P < 0.01). Heart rate, plasma norepinephrine levels, and blood filterability also rose significantly (P < 0.05–0.01). The decrease in both platelet aggregation and blood viscosity after L-arginine was significantly amplified after metformin. CONCLUSIONS We conclude that L-arginine infusion in newly diagnosed NIDDM patients without vascular complications produces relevant hemodynamic and theological changes, which are amplified by an 8-week treatment with metformin. Whether these vascular effects of metformin will improve the poor cardiovascular outlook of the diabetic patient is still unknown.

To evaluate whether beta-cell hyperfunction characterizes glucose intolerant states per se independent of fasting glycemia, we conducted a case-control study among 430 subjects who were classified, by NDGG criteria, as having normal glucose tolerance (n=230, 130M/130F), nondiagnostic tolerance (NDT, n=100, 50M/50F) and impaired glucose tolerance (IGT, n=100, 50M/50F). Thirty-four subjects (17M/17F) with normal glucose tolerance were matched by age, sex, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose and HbA1c with 30 NDT (15M/15F) and 30 IGT (15M/15F) subjects. The continuous and significant increase in insulin and C-peptide levels across categories of glucose tolerance (from normal to NDT to IGT) was no longer evident in the case-control study: at a fasting plasma glucose ranging from 5.2–5.5 mmol/L (HbA1c was 5%) the concentration of fasting C-peptide was 0.793±225 nmol/L (mean±SD) in subjects with normal glucose tolerance, 0.805+200 nmol/L in NDT and 0.807±231 nmol/L in IGT subjects (p=NS). Similarly, plasma concentrations of triglycerides and blood pressure values were similar when subjects of different categories were compared at the same level of glycemia. Sixteen normal subjects were rendered mildly hyperglycemic by a 24-h glucose infusion to match the fasting glucose level of NDT (1 mg/kg/min) and IGT (2 mg/kg/min) subjects. At the same fasting glucose level, normal subjects presented elevations of fasting C-peptide significantly (p

Giant cell reparative granuloma (GCRG) is a reactive bone lesion that most often involves the jaws. However, occasional cases of GCRG in the distal extremities have been reported, to which we add five cases. All the patients were young to middle-aged adults and had sharply bordered, lytic lesions. Histologically, all the lesions had areas of osteoclast-like giant cells and osteoblast mantled osteoid. Two of the cases had foci of osteoclast-like giant cells lining vascular spaces. In extragnathic locations, GCRG may simulate other osteolytic giant cells lesions such as giant cell tumour of bone and aneurysmal bone cyst (AnBC). Immunohistochemically, all cases showed positive staining of the stromal spindle cells for vimentin and actin, and of the osteoclast-like giant cells for CD68, vimentin and leucocyte common antigen. GCRG is a benign lesion and conservative therapy is curative. As GCRG may have histological features which resemble AnBC it may be considered to be the solid variant of AnBC.

Peripheral hyperinsulinism is said to be associated and perhaps implicated in the pathogenesis of hypertension. There is however some inconsistency in the evidence of the relationship between insulin and blood pressure. We prospectively investigated glucose metabolism, insulin and C-peptide values and serum lipids in a large sample of hypertensive as compared with age and body habitus-matched normotensive subjects. As a group, the 145 hypertensives (blood pressure: 160/99±8.5/6.5 mmHg, mean±SD) had significantly elevated fasting plasma insulin (p

To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy.Randomized, placebo-controlled, double-blind 52-week trial.University hospital clinic.Forty-five diabetic patients with asymptomatic autonomic neuropathy identified by at least one pathologic cardiovascular reflex test result.All patients were given placebo during a 4-week run-in period (single-blind). Twenty patients were randomly assigned to continue to receive placebo, and 25 were assigned to treatment with tolrestat (200 mg/d given in the morning).At 12 months, improvements in nerve functions occurred in patients receiving tolrestat. Compared with baseline values, postural hypotension decreased by a value of 5.9 mm Hg (95% Cl, 1.6 to 8.7); deep-breathing, maximum/minimum heart rate (expiration/inspiration ratio) increased by a value of 0.026 (Cl, 0.015 to 0.036); and lying-to-standing heart rate ratio (30:15 ratio) increased by a value of 0.032 (Cl, 0.027 to 0.052). In the placebo group, all test results except postural hypotension deteriorated. Vibration perception threshold at the malleolus and great toe of the dominant leg improved in the tolrestat group (-1.4; Cl, -3.69 to -1.09) but tended to worsen in the placebo group during the study period. No important side effects were detected in either group.The progression of mild diabetic autonomic and peripheral neuropathy may be halted or even reversed by pharmacologic intervention with the aldose-reductase inhibitor tolrestat.

An ovarian serous cystic tumor of low malignant potential with solid mural sarcoma-like nodules is reported. This tumor metastasized to the ileal wall. The nodules in the ovary and in the ileal wall were made up of highly malignant cells with admixed osteoclast-like multinucleate giant cells. Immunohistochemical reactions demonstrated the epithelial differentiation of the tumor. We propose that the term "sarcomatoid carcinoma" of the ovary should be adopted for these lesions.

Context: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. Objective: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. Design and Setting: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. Subjects: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. Interventions: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine- free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. Main Outcome Measures: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. Results: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) μmol/L at baseline to 27.1 (6.7) μmol/L at 4 hours (P