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OBJECTIVES To assess upgrading rates in patients on active surveillance (AS) for prostate cancer (PCa) after serial multiparametric magnetic resonance imaging (mpMRI). METHODS We conducted a retrospective analysis of 558 patients. Five different criteria for mpMRI progression were used: 1) a Prostate Imaging Reporting and Data System (PI-RADS) score increase; 2) a lesion size increase; 3) an extraprostatic extension score increase; 4) overall mpMRI progression; and 5) the number of criteria met for mpMRI progression (0 vs 1 vs 2-3). In addition, two definitions of PCa upgrading were evaluated: 1) International Society of Urological Pathology Grade Group (ISUP GG) ≥2 with >10% of pattern 4 and 2) ISUP GG ≥ 3. Estimated annual percent changes methodology was used to show the temporal trends of mpMRI progression criteria. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of mpMRI progression criteria were also analysed. Multivariable logistic regression models tested PCa upgrading rates. RESULTS Lower rates over time for all mpMRI progression criteria were observed. The NPV of serial mpMRI scans ranged from 90.5% to 93.5% (ISUP GG≥2 with >10% of pattern 4 PCa upgrading) and from 98% to 99% (ISUP GG≥3 PCa upgrading), depending on the criteria used for mpMRI progression. A prostate-specific antigen density (PSAD) threshold of 0.15 ng/mL/mL was used to substratify those patients who would be able to skip a prostate biopsy. In multivariable logistic regression models assessing PCa upgrading rates, all five mpMRI progression criteria achieved independent predictor status. CONCLUSION During AS, approximately 27% of patients experience mpMRI progression at first repeat MRI. However, the rates of mpMRI progression decrease over time at subsequent mpMRI scans. Patients with stable mpMRI findings and with PSAD

Viral respiratory infections are one of the main causes of hospitalization in children. Even if mortality rate is low, 2% to 3% of the hospitalized children need mechanical ventilation. Risk factors for admission to the pediatric intensive care unit (PICU) are well known, while few studies have described risk factors for invasive ventilator support and prolonged hospitalization.A retrospective study including all patients aged between 2 and 18 months with a confirmed viral respiratory infection, requiring admission to PICU from September to March between 2015 and 2019, was conducted at Bambino Gesù Children's Hospital in Rome, Italy.One hundred ninety patients were enrolled, with a median age of 2.7 months; 32.1% had at least one comorbidity, mainly prematurity. The most frequent isolated viruses were RSV-B, rhinovirus, and RSV-A; 38.4% needed mechanical ventilation. This subgroup of patients had lower median birth weight compared with patients not requiring mechanical ventilation (2800 g vs. 3180 g, p = 0.02); moreover, comorbidities were present in 43.8% of intubated patients and in 24.8% of patients treated with non-invasive ventilation (p = 0.006). Viral coinfection did not result to be a risk factor for mechanical support, while virus-bacteria coinfection was significantly associated with mechanical ventilation (p 0.001). Similar risk factors were identified for prolonged hospitalization.Early identification of patients who could have a sudden respiratory deterioration and need of mechanical ventilation is crucial to reduce complications due to orotracheal intubation and prolonged hospitalization in PICU. Further studies are needed to define high-risk group of patients and to design targeted interventions.

Background Thyroid carcinoma occurring as a second primary associated with head and neck squamous cell carcinoma (HNSCC) is unusual. The clinical management of thyroid cancer in such cases has been debated. Methods Between 1975 and 2004, we collected 33 cases. The associated thyroid carcinoma was diagnosed either during or as a consequence of surgery planned as head and neck cancer treatment. Results The associated thyroid carcinoma was never seen to recur. Five-year overall survival was 41%. Disease-free survival after 40 and 66 months was 11.1% and 5.6%, respectively. Conclusions We consider the treatment of thyroid cancer to be complete when the thyroid gland, either with or without lymph nodes, has been included in the specimen obtained during surgery for HNSCC. In the group of cases in which associated thyroid carcinoma was only found within the neck lymph nodes and the thyroid gland has not been treated, we discourage further surgical treatment or radioactive iodine therapy. © 2006 Wiley Periodicals, Inc. Head Neck, 2006

Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory small-diameter nerve fibers, which are affected early in peripheral neuropathies. The aim of this work was to provide normative reference data on the density of intraepidermal nerve fibers (IENFs) and Langerhans cells in the hindpaw footpad of Sprague-Dawley and Wistar rats. We also evaluated the sensibility of IENF density by comparing neuropathologic findings with neurophysiologic examination and the presence of peripheral neuropathy in two well-characterized animal models of neuropathy. IENF density was quantified in 22 Sprague-Dawley rats and 13 Wistar rats and compared with 19 age-matched Sprague-Dawley rats with streptozotocin-induced diabetic neuropathy and 30 age-matched Wistar rats with cisplatin- or paclitaxel-induced neuropathy. Antidromic tail sensory nerve conduction velocity (SNCV) was assessed in all animals. IENF and Langerhans cell densities were constant in healthy Sprague-Dawley rats at any age, and they were similar to those observed in healthy Wistar rats. In neuropathic rats, both SNCV and IENF density were significantly reduced with respect to controls. Quantification of IENF density was significantly correlated with changes in conduction velocity. Diabetic neuropathy rats alone showed a significantly higher density of Langerhans cells compared with controls. Our study demonstrated that IENF density quantification correlates with SNCV changes and suggests that this might represent a useful outcome measurement in experimental neuropathies. © 2005 Peripheral Nerve Society.

Experimental diabetic neuropathy has a number of features in common with the human disease, including a reduction of nerve conduction velocity (NCV) and Na+, K+-ATPase activity in nerve fibers, and alteration of the essential fatty acid metabolism leading to changes in membrane composition. N-3 polyunsaturated fatty acids (PUFA) are beneficial in different pathological conditions including diabetic complications. Since the PUFA composition of cell membranes largely depends on the diet, most studies have supplemented the diet with fish oil (FO), particularly rich in docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, or DHA and EPA ethyl esters. We have prepared a new formulation of n-3 PUFA wax esters (WE) enriched in DHA and EPA that have a bioavailability comparable to oil and esters, are easily digestible and are free from most of the previous drawbacks. The present study was designed to measure Na+, K+-ATPase activity, NCV, and FA content in plasma phospholipids (PL) and to assess the preventive effect of newly formulated n-3 PUFA-WE, and individual EPA and DHA-WE (as compared with standard and FO-supplemented diets) on these abnormalities. Diabetes was induced by streptozotocin (STZ, 60 mg/kg/ip). After STZ injection, diabetic and non-diabetic control rats were fed the standard diet (St) without supplementation or supplemented with either FO or n-3 PUFA-WE or individual EPA and DHA-WE, to reach a daily dose of 0.15 g/kg, the experiment continued for five weeks. Analysis of the FA composition of plasma PL, which better reflects FA intake and content in biological membranes, showed that the sums of n-3 PUFA were double the St diet after n-3 supplement of independent of the dietary regimen, whereas those of FA of the n-6 family were not affected by n-3 supplementation. Thus, the n-6/n-3 ratios were reduced from 15:1 with the St diet to 7:1 for the FO and WE diets. Na+, K+-ATPase activity was significantly lower in diabetic rats (−30–35%), significantly restored in diabetic rats that received FO, n-3 PUFA and EPA-WE supplementation, and partially restored by DHA-WE (9% lower than with non-diabetic controls). These effects were partially associated with a significant beneficial effect on NCV which was reduced by 20% in diabetic rats. FO protected against this decrease (3%), n-3 PUFA-WE were only partially protective (11%), and EPA and DHA-WE had scant effect. This study indicates that, like FO, n-3 PUFA-EPA and DHA-WE have beneficial effects on diabetic-induced alterations in sciatic nerve ATPase+-ATPase activity and, partially, also on NCV. The newly formulated n-3 PUFA WE offer a potential advantage over products in current use, on account of their greater stability.

Erythropoietin (EPO) has neurotrophic and neuroprotective effects and its efficacy and safety has been demonstrated in patients with ischemic stroke. We investigated its efficacy in preventing and reversing established nerve disorders in streptozotocin (STZ) diabetes. After STZ injection (60 mg/kg/ip), EPO (5000 units/kg b.w. i.p. three times a week) was started in a group of rats and continued for five weeks (prevention schedule). In another group of diabetic rats, EPO was started six weeks after STZ, continued for five weeks (therapeutic schedule). Groups of non-diabetic control rats were similarly treated. Antidromic nerve conduction velocity (NCV) in the tail was assessed at five weeks for all groups and at 11 weeks for the therapeutic schedule. Compared to non-diabetic rats, NCV was 21% lower (P

1. 8-epi-prostaglandin (PG) F2 alpha, a major F2 isoprostane, is produced in vivo by free radical-dependent peroxidation of lipid-esterified arachidonic acid. Both cyclo-oxygenase isoforms (COX-1 and COX-2) may also form free 8-epi-PGF2 alpha as a minor product. It has been recently seen in human volunteers that the overall basal formation of 8-epi-PGF2 alpha in vivo is mostly COX-independent and urinary 8-epi-PGF2 alpha is therefore an accurate marker of 'basal' oxidative stress in vivo. 2. To test the validity of this marker in the rat, we evaluated in vivo the effect of COX inhibition on the formation of 8-epi-PGF2 alpha vs prostanoids. Two structurally unrelated COX inhibitors (naproxen: 30 mg kg-1 day-1; indomethacin: 4 mg kg-1 day-1) were given i.p. to rats kept in metabolic cages. In vivo formation of 8-epi-PGF2 alpha was assessed by measuring its urinary excretion. Prostanoid biosynthesis was assessed by measuring urinary excretion of major metabolites of thromboxane (TX) and prostacyclin (2,3-dinor-TXB1 and 2,3-dinor-6-keto-PGF1 alpha). All compounds were selectively measured by immunopurification/gas chromatography-mass spectrometry. 3. Naproxen reduced urinary excretion of 2,3-dinor-TXB1 and 2,3-dinor-6-keto-PGF1 alpha but, unexpectedly, also that of 8-epi-PGF2 alpha (82, 49 and 52% inhibition, respectively). Indomethacin had a similar effect (77, 69 and 55% inhibition). Esterified 8-epi-PGF2 alpha in liver and plasma remained unchanged after indomethacin. 4. These findings prompted us to re-assess the contribution of COX activity to the systemic production of 8-epi-PGF2 alpha in man. We gave naproxen (1 g day-1) to healthy subjects (four nonsmokers and four smokers). Urinary 8-epi-PGF2 alpha remained unchanged in the two groups (9.63 +/- 0.99 before vs 10.24 +/- 1.01 after and 20.14 +/- 3.00 vs 19.03 +/- 2.45 ng h-1 1.73 m-2), whereas there was a marked reduction of major urinary metabolites of thromboxane and prostacyclin (about 90% for both 11-dehydro-TXB2 and 2,3-dinor-TXB2; > 50% for 2,3-dinor-6-keto-PGF1 alpha). 5. To investigate whether rat COX-1 produces 8-epi-PGF2 alpha more efficiently than human COX-1, we measured the ex vivo formation of 8-epi-PGF2 alpha and TXB2 simultaneously in whole clotting blood. Serum levels of 8-epi-PGF2 alpha and TXB2 were similar in rats and man. 6. We conclude that a significant amount of COX-dependent 8-epi-PGF2 alpha is present in rat but not in human urine under normal conditions. This implies that urinary 8-epi-PGF2 alpha cannot be used as an index of near-basal oxidant stress in rats. On the other hand, our data further confirm the validity of this marker in man.

The turnover of phosphoinositides as well as Na,K-ATPase and protein kinase C (PKC) activities and levels of PKCα were examined in the Zucker diabetic fatty rat (ZDF/GMI-fa), a recently described model for non-insulin dependent diabetes mellitus. These animals exhibit serum glucose concentrations greater than 450 mg/dl after 10 weeks of age. As compared to age matched lean controls, the proportion of 32P incorporated into phosphatidylinositol-4,5-bisphosphate (PIP2) increased from 36 to 43 percent. in obese male ZDF rats which had been diabetic for 2–4 months. Other phospholipids showed no change or small decreases. When these data are expressed as quantity of isotope incorporated, only PIP2 showed a consistent increase. Nerve Na,K-ATPase activity was reduced by 32% in animals after diabetes of this duration. These alterations resemble those observed in several other animal models of diabetes. PKC activity was diminished in a detergent extracted membrane fraction from diabetic nerve, but was unchanged in a cytosolic fraction. The expression of PKCα in diabetic nerve was reduced by 47% and underwent a redistribution from a membrane-associated to a soluble form. © 1997 John Wiley & Sons, Ltd.

Po (Mr 30 kDa), the major protein component of peripheral nervous system (PNS) myelin, is known to be phosphorylated by protein kinase C on serine residues at multiple sites. This study was conducted to assess whether other amino acids might be phosphorylated in the protein. Segments of rat sciatic nerve were incubated with 32P in either the presence or absence of phorbol ester. Labeled Po was isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subjected to partial acid hydolysis. Upon separation of the hydrolysis products by either thin-layer electrophoresis or thin-layer chromatography, a radioactive spot was detected which comigrated with authentic phosphotyrosine. In other experiments, nerves were incubated with the tyrosine phosphatase inhibitors vanadate or vanadyl hydro-peroxide (pervanadate). When the nerve homogenate proteins were separated on gels and probed with a monoclonal antibody to phosphotyrosine on Western blots, a positive immune reaction was obtained for a protein species which migrated with the same mobility as Po on Coomassie Blue-stained gels. In the absence of 2-mercaptoethanol, this immunoreactive band displayed increased mobility on gels which is characteristic of the migration pattern of Po. The same immunostaining results were obtained using a purified peripheral myelin fraction prepared from nerve homogenates. Furthermore, the positions of immunoreactive bands produced by anti-Po and anti-phosphotyrosine antibodies coincided on the same immunoblot of myelin proteins and purified Po. These data indicate that one or more tyrosyl residues in Po can be phosphorylated in intact sciatic nerve. © 1996 Wiley-Liss, Inc.

We used cycloleucine (CL) — which prevents methionine conversion to S-adenosyl-methionine (SAMe) by inhibiting ATP-L-methionine-adenosyl-transferase (MAT) — to characterize the lipid and protein changes induced by methyl donors deficit in peripheral nerve and brain myelin in rats during development. We have previously shown that CL (400 mg/kg ip) given to suckling rats at days 7, 8, 12, and 13 after birth reduced brain and sciatic nerve weight gain, brain myelin content, protein, phospholipid (PL), and galactolipid concentration in comparison to control. Among PLs, only sphingomyelin (SPH) significantly increased by 35–50%. SAMe p-toluensulphonate (SAMe-SD4) (100 mg/kg, ip) given daily from day 7, as with exogenous SAMe, partially prevented some lipid alterations induced by CL, particularly galactolipid and SPH. To test the ability of CL to affect PL metabolism we have measured de novo PL biosynthesis, ex vivo in nerve homogenates (in comparison with brain homogenates) from control and CL-treated animals killed at day 18 after birth, starting from labelled substrates ([3H]-choline, specific activity 20 mCi/mmol) in a Tris/HCl buffer, containing 5 mM MgCl2, 0.2 mM EDTA, 0.1 mM ATP, and 0.5 mM of the labelled substrates. After 60 min incubation, lipids were extracted, PL separated by TLC, and corresponding silica gel fractions scraped and counted in a liquid scintillator. Phosphatidylcholine enrichment in labelled choline resulted in slight increases in brain and sciatic nerve of CL-treated rats, suggesting an increased synthesis rate via the Kennedy pathway, possibly due to the reduced availability of methyl donors. Interestingly, choline incorporation into SPH in brain and nerve myelin resulted in significant increases of 30–40%. In agreement with the observed decrease of galactolipid content and the relative increase in SPH, these data suggest an alteration in sphingolipid metabolism after CL. Among proteins, in sciatic nerves of CL-treated pups the relative content of a number of polypeptides, namely the 116, 90, 66, 58, and 56 kDa bands, decreased, whereas others increased; the most abundant PNS protein, protein zero, remained unchanged. The analyses of myelin basic protein isoforms revealed a dramatic increase in the 14.0 and 18.5 forms, indicating early active myelination. SAMe-SD4 treatment counteracted, and in some cases normalized, these changes. In summary, methyl donor deficiency induced by MAT inhibition produces myelin lipid and protein alterations, partly counteracted by SAMe-SD4 administration. The financial support of Telethon-Italy (grant No. D 51) is gratefully acknowledged.

The hypothesis that the existence of a family of isoenzymes is at the basis of the heterogeneity of esterase activity among skeletal muscles from dystrophic Re 129J and control littermate mice was tested using isoelectrofocusing (IEF) in polyacrylamide gel. All muscles considered showed not only quantitative heterogeneity, as previously observed in this laboratory, but also qualitative differences with regard to their esterase isoenzymes. Differences in the number and the relative amounts of isoenzymatic bands were found between different muscles from both control and dystrophic animals. In most dystrophic muscles a new isoenzymatic band appeared at pH 6.6. Another band, identified at pH 5.12, was more pronounced in dystrophic than in control muscles. The specificity of these observations is indirectly supported by the fact that other tissue, such as heart, liver, and kidney, did not show the quantitative or qualitative abnormality present in the dystrophic skeletal muscles.