Digital dermoscopy monitoring of melanocytic lesions: Two novel calculators combining static and dynamic features to identify melanoma.

BACKGROUND: Early diagnosis is the most effective intervention to improve the prognosis of cutaneous melanoma. Even though the introduction of dermoscopy has improved the diagnostic accuracy, it can still be difficult to distinguish some melanomas from benign melanocytic lesions. Digital dermoscopy monitoring can identify dynamic changes of melanocytic lesions: To date, some algorithms were proposed, but a universally accepted one is still lacking. OBJECTIVES: To identify independent predictive variables associated with the diagnosis of cutaneous melanoma and develop a multivariable dermoscopic prediction model able to discriminate benign from malignant melanocytic lesions undergoing digital dermoscopy monitoring. METHODS: We collected dermoscopic images of melanocytic lesions excised after dermoscopy monitoring and carried out static and dynamic evaluations of dermoscopic features. We built two multivariable predictive models based on logistic regression and random forest. RESULTS: We evaluated 173 lesions (65 cutaneous melanomas and 108 nevi). Forty-two melanomas were in situ, and the median thickness of invasive melanomas was 0.35 mm. The median follow-up time was 9.8 months for melanomas and 9.1 for nevi. The logistic regression and random forest models performed with AUC values of 0.87 and 0.89, respectively, were substantially higher than those of the static evaluation models (ABCD TDS score, 0.57; 7-point checklist, 0.59). Finally, we built two risk calculators, which translate the proposed models into user-friendly applications, to assist clinicians in the decision-making process. CONCLUSIONS: The present study demonstrates that the integration of dynamic and static evaluations of melanocytic lesions is a safe approach that can significantly boost the diagnostic accuracy for cutaneous melanoma. We propose two diagnostic tools that significantly increase the accuracy in discriminating melanoma from nevi during digital dermoscopy monitoring.

Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

Tracing sources of Listeria contamination in traditional Italian cheese associated with a US outbreak: investigations in Italy.

In 2012 a US multistate outbreak of listeriosis was linked to ricotta salata imported from Italy, made from pasteurized sheep's milk. Sampling activities were conducted in Italy to trace the source of Listeria monocytogenes contamination. The cheese that caused the outbreak was produced in a plant in Apulia that processed semi-finished cheeses supplied by five plants in Sardinia. During an 'emergency sampling', 179 (23·6%) out of 758 end-products tested positive for L. monocytogenes, with concentrations from <10 c.f.u./g to 1·1 × 106 c.f.u./g. Positive processing environment samples were found in two out of four processing plants. A 'follow-up sampling' was conducted 8 months later, when environmental samples from three out of six plants tested positive for L. monocytogenes and for Listeria spp. PFGE subtyping showed 100% similarity between US clinical strains and isolates from ricotta salata, confirming the origin of the outbreak. The persistence of strains in environmental niches of processing plants was demonstrated, and is probably the cause of product contamination. Two PFGE profiles from clinical cases of listeriosis in Italy in 2011, stored in the MSS-TESSy database, were found to have 100% similarity to one PFGE profile from a US clinical case associated with the consumption of ricotta salata, according to the US epidemiological investigation (sample C, pulsotype 17). However, they had 87% similarity to the only PFGE profile found both in the US clinical case and in 14 ricotta cheese samples collected during the emergency sampling (sample B, pulsotype 1). Sharing of molecular data and availability of common characterization protocols were key elements that connected the detection of the US outbreak to the investigation of the food source in Italy. Simultaneous surveillance systems at both food and human levels are a necessity for the efficient rapid discovery of the source of an outbreak of L. monocytogenes.

Does the metabolic syndrome predict subclinical atherosclerotic damage in an asymptomatic population at intermediate cardiovascular risk?

BACKGROUND AND AIMS: It is not clear whether the metabolic syndrome (MetS) is a distinct entity or a combination of risk factors. Several studies showed the association between MetS and cardiovascular disease (CVD). Subclinical target organ damage (TOD) is a recognized marker of atherosclerosis and predictor of cardiovascular events. Increased burden of subclinical atherosclerosis was detected in individuals with MetS. We thus aimed to examine the association between MetS and cumulative or specific TOD and to assess whether MetS predicts TOD better than the risk factors included in current definitions. METHODS AND RESULTS: We recorded TOD in 979 patients at intermediate cardiovascular risk with and without MetS according to IDF and NCEP criteria. We measured common carotid intima-media thickness, left ventricular mass index (LVMI), urine albumin to creatinine ratio (UACR), and ankle-brachial index. We found no correlation between having at least one TOD and being positive for MetS. A high UACR was associated with MetS using both IDF and NCEP criteria, while only NCEP identified individuals with increased LVMI. Using a multivariate logistic regression model including MetS, age, sex, waist circumference, triglycerides, HDL cholesterol, blood pressure and blood glucose levels we found no correlations between the presence of MetS and at least one TOD. The associations with high UACR and LVMI disappeared when age, blood pressure and glycemia were counted in. CONCLUSION: Although MetS showed some relation with subclinical renal and cardiac damage, it does not predict TOD any better than the risk factors specified in the definitions.

Itch: a HECT-type E3 ligase regulating immunity, skin and cancer.

The HECT-type E3 ubiquitin ligase (E3) Itch is absent in the non-agouti-lethal 18H or Itchy mice, which develop a severe immunological disease, including lung and stomach inflammation and hyperplasia of lymphoid and hematopoietic cells. The involvement of Itch in multiple signaling pathways and pathological conditions is presently an area of extensive scientific interest. This review aims to bring together a growing body of work exploring Itch-regulated biological processes, and to highlight recent discoveries on the regulatory mechanisms modulating its catalytic activity and substrate recognition capability. Our contribution is also an endeavor to correlate Itch substrate specificity with the pathological defects manifested by the mutant Itchy mice.

Physiology and pathophysiology of pleural fluid turnover.

Tight control of the volume and composition of the pleural liquid is necessary to ensure an efficient mechanical coupling between lung and chest wall. Liquid enters the pleural space through the parietal pleura down a net filtering pressure gradient. Liquid removal is provided by an absorptive pressure gradient through the visceral pleura, by lymphatic drainage through the stomas of the parietal pleura, and by cellular mechanisms. Indeed, contrary to what was believed in the past, pleural mesothelial cells are metabolically active, and possess the cellular features for active transport of solutes, including vesicular transport of protein. Furthermore, the mesothelium was shown, on the basis of recent experimental evidence, both in vivo and in vitro, to be a less permeable barrier than previously believed, being provided with permeability characteristics similar to those of the microvascular endothelium. Direct assessment of the relative contribution of the different mechanisms of pleural fluid removal is difficult, due to the difficulty in measuring the relevant parameters in the appropriate areas, and to the fragility of the mesothelium. The role of the visceral pleura in pleural fluid removal under physiological conditions is supported by a number of findings and considerations. Further evidence indicates that direct lymphatic drainage through the stomas of the parietal pleura is crucial in removing particles and cells, and important in removing protein from the pleural space, but should not be the main effector of fluid removal. Its importance, however, increases markedly in the presence of increased intrapleural liquid loads. Removal of protein and liquid by transcytosis, although likely on the basis of morphological findings and suggested by recent indirect experimental evidence, still needs to be directly proven to occur in the pleura. When pleural liquid volume increases, an imbalance occurs in the forces involved in turnover, which favours fluid removal. In case of a primary abnormality of one ore more of the mechanisms of pleural liquid turnover, a pleural effusion ensues. The factors responsible for pleural effusion may be subdivided into three main categories: those changing transpleural pressure balance, those impairing lymphatic drainage, and those producing increases in mesothelial and capillary endothelial permeability. Except in the first case, pleural fluid protein concentration increases above normal: this feature underlies the classification of pleural effusions into transudative and exudative.

Electrical resistance and ion diffusion through mesothelium.

(1) Since phospholipids (PHL) added on the luminal side of specimens of parietal pericardium of rabbits decrease diffusional permeability (P) to Na+, but not to Cl-, P to Rb+, a cation with hydrated radius similar to that of Cl- was measured. P(Rb+) was 13.1 (+/-1.1, S.E.)x10(-5) cm/sec and it was not decreased by PHL. This suggests that PHL decrease size of intercellular "pores" of mesothelium, and restrict diffusion of solutes with radius>0.2 nm. (2) Electrical resistance (Re) of pericardium specimens was measured without PHL, with PHL, and after mesothelium was scraped away, to obtain Re of connective tissue and, thus, to compute Re of mesothelium. Re of connective tissue was 1.0+/-0.2 Omega cm(2); Re of mesothelium was 10.1+/-0.6 and 12.3+/-0.9 Omega cm(2) without and with PHL, respectively. The fraction of electrical current carried by Na+ indicates that Na+ diffusion through mesothelium without PHL is nearly free. (3) Re of cultured mesothelial cell monolayers of rat visceral pleura was 6.1+/-0.2 Omega cm(2), i.e. smaller than that of specimen mesothelium; it did not increase with PHL. P(Na+) of cultured mesothelial cell monolayers was 20.0x10(-5) cm/sec, i.e. greater than that of specimen mesothelium.

Macromolecule transfer through mesothelium and connective tissue.

Diffusional permeability (P) to inulin (P(in)), albumin (P(alb)), and dextrans [70 (P(dx 70)), 150 (P(dx 150)), 550 (P(dx 550)), and 2, 000 (P(dx 2,000))] was determined in specimens of parietal pericardium of rabbits, which may be obtained with less damage than pleura. P(in), P(alb), P(dx 70), P(dx 150), P(dx 550), and P(dx 2, 000) were 0.51 +/- 0.06 (SE), 0.18 +/- 0.03, 0.097 +/- 0.021, 0. 047 +/- 0.011, 0.025 +/- 0.004, and 0.021 +/- 0.005 x 10(-5) cm/s, respectively. P(in), P(alb), and P(dx 70) of connective tissue, obtained after removal of mesothelium from specimens, were 10.3 +/- 1.42, 2.97 +/- 0.38, and 2.31 +/- 0.16 x 10(-5) cm/s, respectively. Hence, P(in), P(alb), and P(dx 70) of mesothelium were 0.54, 0.20, and 0.10 x 10(-5) cm/s, respectively. Inulin (like small solutes) fitted the relationship P-solute radius for restricted diffusion with a 6-nm "pore" radius, whereas macromolecules were much above it. Hence, macromolecule transfer mainly occurs through "large pores" and/or transcytosis. In line with this, the addition of phospholipids on the luminal side (which decreases pore radius to approximately 1.5 nm) halved P(in) but did not change P(alb) and P(dx 70). P(in) is roughly similar in mesothelium and capillary endothelium, whereas P to macromolecules is greater in mesothelium. The albumin diffusion coefficient through connective tissue was 17% of that in water. Mesothelium provides 92% of resistance to albumin diffusion through the pericardium.

Equivalent radius of paracellular "pores" of the mesothelium.

Diffusional permeability (P) to water (P(w)), Cl(-) (P(Cl(-))), and mannitol (P(man)) was determined in specimens of rabbit parietal pericardium without and with phospholipids added on the luminal side, as previously done with sucrose and Na(+). P to the above-mentioned molecules and to Na(+) (P(Na(+))) was also determined after mesothelium was scraped away from specimens. P(w), P(Cl(-)), P(Na(+)), and P(man) of connective tissue were the following (x10(-5) cm/s): 73.1 +/- 7.3 (SE), 59.5 +/- 4.5, 41.7 +/- 3.4, and 23.4 +/- 2.4, respectively. From these and corresponding data on integer pericardium, P(w), P(Cl(-)), P(Na(+)), and P(man) of mesothelium were computed. They were the following: 206, 17.9, 9.52, and 3.93, and 90.2, 14.4, 4.34, and 1.75 x 10(-5) cm/s without and with phospholipids, respectively. As previously found for P to sucrose, P to solutes is smaller in mesothelium than in connective tissue, although the latter is approximately 35-fold thicker; instead, P(w) is higher in mesothelium, suggesting marked water diffusion through cell membrane. Equivalent radius of paracellular "pores" of mesothelium was computed with two approaches, disregarding P(w). The former, a graphical analysis on a P-molecular radius diagram, yielded 6.0 and 1.7 nm without and with phospholipids, respectively. The latter, on the basis of P(man), P to sucrose, and function for restricted diffusion, yielded 7.8 and 1. 1 nm, respectively.

Diffusional permeability of rabbit mesothelium.

Diffusional permeability (P) to sucrose (Psuc) and Na+ (PNa+) was determined in specimens of rabbit sternal parietal pericardium, which may be obtained without stripping. Specimens were mounted in an Ussing apparatus with 3H-labeled sucrose and 22Na+ in a luminal (L) or interstitial (I) chamber. Psuc was 2.16 +/- 0.44 for L-->I and 2.63 +/- 0.45 (SE) x 10(-5) cm/s for I-->L, i.e., approximately 10 times smaller than that previously obtained in stripped specimens of pleura despite the similarity of intercellular junctions in pericardium and pleural mesothelium of various species. These findings suggest that previous Psuc was overestimated because stripping damages the mesothelium. PNa+ (x10(-5) cm/s) was 7.07 +/- 0.71 for L-->I and 7.37 +/- 0.69 x 10(-5) cm/s for I-->L. Measurements were also done with phospholipids, which are adsorbed on the luminal side of mesothelium in vivo. With phospholipids in L, Psuc was 0.75 +/- 0.10 and 0.65 +/- 0.08 and PNa+ was 3.80 +/- 0.32 and 3.76 +/- 0.15 x 10(-5) cm/s for L-->I and I-->L, respectively, i. e., smaller than without phospholipids. With phospholipids in I (where they are not adsorbed), Psuc (2.33 +/- 0.42 x 10(-5) cm/s) and PNa+ (7.01 +/- 0.45 x 10(-5) cm/s) were similar to those values without phospholipids. Hence, adsorbed phospholipids decrease P of mesothelium. If the mesothelium were scraped away from the specimen, Psuc of the connective tissue would be 13.2 +/- 0.76 x 10(-5) cm/s. Psuc of the mesothelium, computed from Psuc of the unscraped and scraped specimens, corrected for the effect of unstirred layers (2. 54 and 19.4 x 10(-5) cm/s, respectively), was 2.92 and 0.74 x 10(-5) cm/s without and with phospholipids, respectively. Hence, most of the resistance to diffusion of the pericardium is provided by the mesothelium.

Mechanical coupling and liquid exchanges in the pleural space.

The pleural space provides the mechanical coupling between lung and chest wall: two views about this coupling are reported and discussed. Information on volume, composition, thickness, and pressure of the pleural liquid under physiologic conditions in a few species is provided. The Starling pressures of the parietal pleura filtering liquid into pleural space, and those of the visceral pleura absorbing liquid from the space are considered along with the permeability of the mesothelium. Information on the lymphatic drainage through the parietal pleura and on the solute-coupled liquid absorption from the pleural space under physiologic conditions and with various kinds of hydrothorax are provided.

Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P < 0.01). This displacement did not occur with lower adrenaline concentrations or after pretreatment with the beta-blocker propranolol. Hence, this increase in Jnet is mediated by stimulation of beta-receptors. It seems to be caused by an increase in solute-coupled liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P < 0.01), while its origin did not change. This increase in slope did not occur with a lower clonidine concentration or after pretreatment with the alpha-blocker phentolamine. Hence, it is caused by stimulation of alpha 2-receptors, which probably lead to an increase in lymphatic drainage related to liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was simlar to control values.

[Intravascular surgery in the treatment of peripheral arteriopathies: our experience]. / La chirurgia endovascolare nel trattamento delle arteriopatie periferiche: la nostra esperienza.

The Authors, through a review of their vascular surgery experience in the treatment of PAOD at the III General Surgery Institute directed by Prof. G. Di Matteo (University, of Rome), focus their attention on endovascular surgery. Initially considered as an effective complement to "traditional surgery" rapidly its role has grown as an effective alternative for a number of vascular patients.

Effect on phloridzin on net rate of liquid absorption from the pleural space of rabbits.

Previous indirect findings have suggested the occurrence of solute-coupled liquid absorption from the pleural space, consistent with Na(+)-K(+)-ATPase on the interstitial side plus a Na(+)-H+ and CI(-)-HCO3- double exchange on the luminal side of the pleural mesothelium. To assess whether Na(+)-glucose cotransport also operates on the luminal side, the relationship between net rate of liquid absorption from the right pleural space (Jnet) and volume of liquid injected into this space (0.5, 1 or 2 ml) was determined in anaesthetized rabbits during hydrothoraces with phloridzin (10(-3)M) or with phloridzin plus 4-acetamido-4'-isothiocyanatostilbene-2, 2'-disulphonic acid (SITS; 1.5 x 10(-4)M). The relationship obtained during hydrothoraces with phloridzin was displaced downwards by 0.09 ml h-1 relative to that in control hydrothoraces (P < 0.01). The decrease in Jnet was similar in hydrothoraces of various sizes. The relationship obtained in hydrothoraces with phloridzin plus SITS was displaced downwards by 0.16 ml h-1 relative to that in control hydrothoraces (P < 0.01), i.e. the decrease in Jnet was similar to the sum (0.17 ml h-1) of the decreases in Jnet produced individually by phloridzin and by SITS (0.08 ml h-1). The decrease in Jnet was similar in hydrothoraces of differing size. The above findings are consistent with the occurrence of Na(+)-glucose cotransport on the luminal side of the pleural mesothelium, operating simultaneously with the double exchange also under physiological conditions.

Beta-agonist activation of an amiloride-insensitive transport mechanism in rabbit pleura.

The beta-agonist terbutaline increases the net rate of liquid absorption from hydrothoraces with albumin-Ringer solution: since beta-agonists decrease lymphatic drainage, the effect of terbutaline seems due to an increase in solute-coupled liquid absorption, (Zocchi et al. 1994 Respir. Physiol. 97:347-356). In this research we determined in anesthetized rabbits the rate of volume change in albumin-Ringer hydrothoraces of different size with amiloride plus terbutaline, and compared it with that previously obtained in hydrothoraces with amiloride alone. The net rate of liquid absorption was 0.09 ml/h greater (P < 0.01) with amiloride plus terbutaline than with amiloride alone. This indicates that terbutaline activates an amiloride-insensitive mechanism of Na+ transport. The increase in net rate of liquid absorption produced by terbutaline persisted with bumetanide 10(-6) M and SITS 10(-4) M, disappeared almost completely with bumetanide 10(-5) M, and completely with furosemide 10(-3) M. These findings suggest that the mechanism activated by terbutaline, when the amiloride-sensitive mechanisms of the pleura have been blocked, is a Na(+)-K(+)-2 Cl- or Na(+)-Cl- symport little sensitive to bumetanide.

Effects of beta-adrenergic blockade or stimulation on net rate of hydrothorax absorption.

We determined in anesthetised rabbits the net rate of liquid absorption (NRLA) from Ringer or 1% albumin-Ringer hydrothoraces with the beta-blocker propranolol (or nadolol) or the beta-agonist terbutaline. The beta-blocker reduced NRLA by 38% in 2 ml Ringer hydrothoraces, and did not change it in 2 ml albumin-Ringer hydrothoraces; hence, with beta-blocker NRLA became similar in both kinds of hydrothorax (0.31 +/- 0.02 ml/h). Terbutaline decreased NRLA by 25% in 2 ml Ringer hydrothoraces, and increased it by 29% in 2 ml albumin-Ringer hydrothoraces; hence, with terbutaline NRLA became similar in both kinds of hydrothorax (0.40 +/- 0.02 ml/h), and 25% higher than with beta-blocker. Because beta-adrenoreceptor activity inhibits lymphatic smooth muscles and may increase Na+ transport in epithelia, these results suggest that: (1) pleural mesothelium is provided with beta-receptors, which increase Na+ transport and seem activated by protein dilution, (2) beta-receptors of the pleural lymphatics are essentially silent with and without protein dilution, (3) the lymphatic drainage produced by smooth muscle activity is smaller than the increase in solute-coupled liquid absorption caused by mesothelium beta-receptors.

Effect of pressure and timing of contraction on human rib cage muscle fatigue.

Breathing against inspiratory loads can be accomplished with different degrees of coupling between the diaphragm and the other muscles attached to the rib cage (RCM). Thus, the electromyographic signs of fatigue develop separately in each muscle group. While breathing with diaphragm emphasis, the occurrence of diaphragmatic fatigue was found to be related to the tension-time index TTdi (= Pdi/Pdimax x Ti/Ttot). Above the critical range of 0.15 to 0.18, the endurance of the diaphragm is less than 1 h and it is inversely related to the TTdi value. However, in most loaded breathing conditions, the spontaneous pattern of breathing is characterized by predominant activation of RCM. The tension-time conditions at which fatigue develops during breathing with RCM emphasis are not known. We assessed the critical tension-time value in four normal subjects breathing with RCM emphasis against inspiratory threshold loads. RCM predominance was achieved by developing negative abdominal pressure swings during inspiration, and it was characterized by the tension-time index TTrc (Ppl/Pplmax x Tl/Ttot), where Ppl is pleural pressure developed under this condition. Above a critical TTrc value of 0.30, endurance time was inversely related to TTrc, and it resulted from failure of the RCM rather than of the diaphragm. We conclude that the critical threshold, as assessed by TTrc, is higher for breathing patterns with RCM emphasis than previously described by TTdi for diaphragm emphasis. However, when predominantly recruited, as in breathing patterns commonly adopted in loaded conditions, the RCM fatigue earlier than the diaphragm.