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Experimental research has uncovered lipocalin 2 (LCN2) as a novel biomarker implicated in the modulation of intestinal inflammation, metabolic homeostasis, and colon carcinogenesis. However, evidence from human research has been scant. We, therefore, explored the association of pre-diagnostic circulating LCN2 concentrations with incident colorectal cancer (CRC) in a nested case-control study within the in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. LCN2 was measured in 1267 incident CRC cases matched to 1267 controls using incidence density sampling. Conditional logistic regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) according to tumor subsite and sex. Weighted Cox proportional hazard regression was used to explore associations by adiposity status. In multivariable-adjusted analyses, the IRR [95% CI] per doubling in LCN2 concentration was 1.16 [0.98-1.37] for CRC overall, 1.26 [1.00-1.59] for colon cancer, and 1.08 [0.85-1.38] for rectal cancer. The association for colon cancer was more pronounced in women (IRR [95% CI], 1.66 [1.20-2.30]) and for proximal colon cancer (IRR [95% CI], 1.96 [1.15-3.34]), whereas no association was seen in men and distal colon cancer. The association for colon cancer was positive in individuals with high waist circumference (hazard ratio [95% CI], 1.69 [1.52-1.88]) and inverse in individuals with low waist circumference (hazard ratio [95% CI], 0.86 [0.76-0.98], P interaction<0.01). Overall, these data suggest that pre-diagnostic LCN2 concentrations were positively associated with colon cancer, particularly occurring in the proximal colon, in women and among individuals with abdominal adiposity., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: the study of the possible determinants of the rise and fall of infections can be of great relevance, as was experienced during the COVID-19 pandemic. One of the methods to understand whether determinants are simultaneous or develop through contiguity between different areas is the study of the diagnostic replication index RDt among regions., Objectives: to introduce the analysis of RDt variability and the subsequent application of a recently introduced functional clustering method as highly useful procedures for recognizing the presence of clusters with similar trends in epidemic curves., Design: within the considered period, trends in regional RDt are analyzed in detail over four different time intervals., Setting and Participants: to exemplify this methodology, the study of variability in the period from the end of 2021 to the beginning of 2022 may be of interest., Main Outcomes Measures: the variability in the regional RDt indices is assessed by means of the correlation coefficient weighted with respect to the populations of the individual regions. The clustering procedure is applied to the time series of absolute RDt values., Results: it emerges that the periods of increasing variability in the RDt correspond to the initial growth or decrease in the number of infections, while functional clustering identifies macro-areas in which the epidemic curves have had similar trends. What caused contagions to increase seems to relate to a factor that is not specific to certain areas, with the contribution in some cases of a contagion dynamic between adjacent areas., Conclusions: the variability in the trend of regional diagnostic replication indices, which are calculated with only a few days delay, is a further indicator for the early detection of major changes in the trend of epidemic curves. The clustering of epidemic index curves may be useful to determine whether determinants act simultaneously or by contiguity between adjacent areas.

Recent epidemiological studies have suggested a positive association between ultra-processed food consumption and breast cancer risk, although some studies also reported no association. Furthermore, the evidence regarding the associations between intake of food with lower degrees of processing and breast cancer risk is limited. Thus, we investigated the associations between dietary intake by degree of food processing and breast cancer risk, overall and by breast cancer subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intake of EPIC participants was assessed via questionnaires at baseline. More than 11,000 food ingredients were classified into four groups of food processing levels using the NOVA classification system: unprocessed/minimally processed (NOVA 1), culinary ingredients (NOVA 2), processed (NOVA 3) and ultra-processed (NOVA 4). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer per standard deviation increase in daily consumption (grams) of foods from each NOVA group. The current analysis included 14,933 breast cancer cases, diagnosed among the 318,686 EPIC female participants, (median follow-up of 14.9 years). No associations were found between breast cancer risk and the level of dietary intake from NOVA 1 [HR per 1 SD =0.99 (95% CI 0.97 - 1.01)], NOVA 2 [HR per 1 SD =1.01 (95% CI 0.98 - 1.03)] and NOVA 4 [HR per 1 SD =1.01 (95% CI 0.99 - 1.03)] foods. However, a positive association was found between NOVA 3 and breast cancer risk [HR per 1 SD =1.05 (95% CI 1.03 - 1.07)] which became non-significant after adjustment for alcohol intake [HR per 1 SD =1.01 (95% CI 0.98 - 1.05)] or when beer and wine were excluded from this group [HR per 1 SD =0.99 (95% CI 0.97 - 1.01)]. The associations did not differ by breast cancer subtype, menopausal status or body mass index. Findings from this large-scale prospective study suggest that the positive association between processed food intake and breast cancer risk was likely driven by alcoholic beverage consumption., Supplementary Information: The online version contains supplementary material available at 10.1186/s43014-024-00264-2., Competing Interests: Competing interestsThe authors declare no potential conflicts of interest., (© The Author(s) 2024.)

The analysis of circulating tumor cells and tumor-derived materials, such as circulating tumor DNA, circulating miRNAs (cfmiRNAs), and extracellular vehicles provides crucial information in cancer research. CfmiRNAs, a group of short noncoding regulatory RNAs, have gained attention as diagnostic and prognostic biomarkers. This review focuses on the discovery phases of cfmiRNA studies in breast cancer patients, aiming to identify altered cfmiRNA levels compared to healthy controls. A systematic literature search was conducted, resulting in 16 eligible publications. The studies included a total of 585 breast cancer cases and 496 healthy controls, with diverse sample types and different cfmiRNA assay panels. Several cfmiRNAs, including MIR16, MIR191, MIR484, MIR106a, and MIR193b, showed differential expressions between breast cancer cases and healthy controls. However, the studies had a high risk of bias and lacked standardized protocols. The findings highlight the need for robust study designs, standardized procedures, and larger sample sizes in discovery phase studies. Furthermore, the identified cfmiRNAs can serve as potential candidates for further validation studies in different populations. Improving the design and implementation of cfmiRNA research in liquid biopsies may enhance their clinical diagnostic utility in breast cancer patients.

Background: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors., Methods: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM)., Results: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women)., Conclusions: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors., Impact: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population., (©2022 American Association for Cancer Research.)

Background: An accurate measurement of the target volume is of primary importance in theragnostics of hyperthyroidism., Objective: Our purpose was to evaluate the accuracy of a threshold-based isocontour extraction procedure for thyroid tissue volumetry from SPECT-CT., Methods: Cylindrical vials with a fixed volume of 99mTcO4 at different activities were inserted into a neck phantom in two different thickness settings. Images were acquired by orienting the phantom in different positions, i.e., 40 planar images and 40 SPECT-CT. The fixed values of the isocontouring threshold for SPECT and SPECT-CT were calculated by means of linear and spline regression models. Mean, Median, Standard Deviation, Standard Error, Mean Absolute Percentage Error and Root Mean-Square Error were computed. Any difference between the planar method, SPECT and SPECT-CT and the effective volume was evaluated by means of ANOVA and posthoc tests. Moreover, planar and SPECT-CT acquisitions were performed in 8 patients with hyperthyroidism, considering relevant percentage differences greater than > 20% from the CT gold standard., Results: Concerning phantom studies, the planar method shows higher values of each parameter than the other two methods. SPECT-CT shows lower variability. However, no significant differences were observed between SPECT and SPECT-CT measurements. In patients, relevant differences were found in 7 out of 9 lesions with the planar method, in 6 lesions with SPECT, but in only one with SPECT-CT., Conclusion: Our study confirms the superiority of SPECT in volume measurement if compared with the planar method. A more accurate measurement can be obtained from SPECT-CT., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The present work studies the epidemic curve of COVID-19 in Italy between September 2020 and mid-June 2021 in terms of poussées, that is successive waves. There is obviously only one pandemic, although the virus has spread in the form of several variants, but the daily incidence trend can also be read in terms of overlapping of events that are different from each other or, in any case, induced by various phenomena. It can be hypothesized that in this way a succession of various waves was generated, which are modelled here using appropriate adaptation curves used in the study of epidemic data. Each curve corresponds approximately to the situation that would have occurred if no element had intervened to prevent the decrease of infections after the relative peak, while their overlap is considered to describe the subsequent increases. This interpolation has no predictive purpose, being purely descriptive over the time window under consideration. The discrepancies between the superposition of the modelling curves and the real epidemic curve are therefore also highlighted, especially in the transition periods between the various poussées. Finally, the analysis carried out allows to match the trend of the epidemic in the period considered with, on one hand, the series of events and, on the other, with the containment measures adopted which may have determined the succession of increases and decreases in the incidence of infections.

The article compares two of the most followed indices in the monitoring of COVID-19 epidemic cases: the Rt and the RDt indices. The first was disseminated by the Italian National Institute of Health (ISS) and the second, which is more usable due to the lower difficulty of calculation and the availability of data, was adopted by various regional and local institutions.The rationale for the Rt index refers to that for the R0 index, the basic reproduction number, which is used by infectivologists as a measure of contagiousness of a given infectious agent in a completely susceptible population. The RDt index, on the other hand, is borrowed from the techniques of time series analysis for the trend of an event measurement that develops as a function of time. The RDt index does not take into account the time of infection, but the date of the diagnosis of positivity and for this reason it is defined as diagnostic replication index, as it aims to describe the intensity of the development of frequency for cases recognized as positive in the population.The comparison between different possible applications of the methods and the use of different types of monitoring data was limited to four areas for which complete individual data were available in March and April 2020. The main problems in the use of Rt, which is based on the date of symptoms onset, arise from the lack of completeness of this information due both to the difficulty in the recording and to the absence in asymptomatic subjects.The general trend of RDt, at least at an intermediate lag of 6 or 7 days, is very similar to that of Rt, as confirmed by the very high value of the correlation index between the two indices. The maximum correlation between Rt and RDt is reached at lag 7 with a value of R exceeding 0.97 (R2=0.944).The two indices, albeit formally distinct, are both valid; they show specific aspects of the phenomenon, but provide basically similar information to the public health decision-maker. Their distinction lies not so much in the method of calculation, rather in the use of different information, i.e., the beginning of symptoms and the swabs outcome.Therefore, it is not appropriate to make a judgment of preference for one of the two indices, but only to invite people to understand their different potentials so that they can choose the one they consider the most appropriate for the purpose they want to use it for.

Background: The aim of the present study was to assess management strategies for immune thrombocytopenia (ITP) among Italian paediatric haematologists, and to compare these with those of recent international guidelines. Predictors of early remission or disease chronicity were also evaluated., Materials and Methods: During a period of 1 year, 205 children (age: 1 month-18 years) with newly diagnosed ITP were prospectively enrolled by 16 centres belonging to the Italian Association of Paediatric Haematology and Oncology (AIEOP). We collected the subjects demographic data, history, clinical symptoms, platelet count and treatment at presentation and at subsequent visits., Results: Of the 205 patients, 47 (23%) were initially managed with a wait-and-see approach. Compared to these patients, children administered platelet-enhancing therapies were significantly younger (median age: 4.75 vs 7.96 years; p<0.001) and had lower platelet counts. At the 3-month follow-up, 92/202 patients (46%) had persistent ITP. Recovery within 3 months was predicted by younger median age (5.3 vs 7.8 years; p<0.001), and recent viral infection (p<0.001) . At 1 year, 56 patients had chronic ITP, which was associated with older median age (7.54 vs 5.35 years; p<0.001), and a family history of autoimmunity (p<0.05; relative risk: 1.81; 95% confidence interval: 1.09-2.98). In total, 357 pharmacological treatments were recorded (216 intravenous immunoglobulins, 80 steroids). Response to intravenous immunoglobulins did not have an effect on remission rate at 12 months., Discussion: Pediatric hematologists in Italian Centre treat over three-quarters of patients with newly diagnosed ITP, despite recent international guidelines. Almost 80% of patients with mild clinical symptoms received pharmacological treatment at diagnosis, which was significantly associated with younger age. Chronicity at 12 months was not affected by different therapeutic approaches at diagnosis or response to therapy.

The biological mechanisms through which adherence to Mediterranean Diet (MD) protects against colon cancer (CC) are poorly understood. Evidence suggests that chronic inflammation may be implicated in the pathway. Both diet and CC are related to epigenetic regulation. We performed a nested case-control study on 161 pairs from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which we looked for the methylation signals in DNA extracted from leucocytes associated with both CC and MD in 995 CpGs located in 48 inflammation genes. The DNA methylation signals detected in this analysis were validated in a subgroup of 47 case-control pairs and further replicated (where validated) in 95 new pairs by means of pyrosequencing. Among the CpG sites selected a-priori in inflammation-related genes, seven CpG sites were found to be associated with CC status and with MD, in line with its protective effect. Only two CpG sites (cg17968347- SERPINE1 and cg20674490- RUNX3 ) were validated using bisulphite pyrosequencing and, after replication, we found that DNA methylation of cg20674490- RUNX3 may be a potential molecular mediator explaining the protective effect of MD on CC onset. The use of a 'meet-in-the-middle' approach to identify the overlap between exposure and predictive markers of disease is innovative in studies on the relationship between diet and cancer, in which exposure assessment is difficult and the mechanisms through which the nutrients exert their protective effect is largely unknown.

The main aim of mediation analysis is to study the direct and indirect effects of an exposure on an outcome. To date, the literature on mediation analysis with multiple mediators has mainly focused on continuous and dichotomous outcomes. However, the development of methods for multiple mediation analysis of survival outcomes is still limited. Here we extend to survival outcomes a method for multiple mediation analysis based on the computation of appropriate weights. The approach considered has the advantages of not requiring specific models for mediators, allowing nonindependent mediators of any nature, and not relying on the assumption of rare outcomes. Simulation studies show good performance of the proposed estimator in terms of bias and coverage probability. The method is further applied to an example from a published study on prostate cancer mortality aimed at understanding the extent to which the effect of DNA methyltransferase 3b (DNMT3b) genotype on mortality was explained by DNA methylation and tumor aggressiveness. This approach can be used to quantify the marginal time-dependent direct and indirect effects carried by multiple indirect pathways, and software code is provided to facilitate its application., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade., Methods: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure., Results: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only., Conclusions: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

Background: Preterm babies are at high risk of iron deficiency., Methods: We investigated current practices regarding iron prophylaxis in preterm and low birth weight newborns among Local Neonatal Units (LNUs, n = 74) and Neonatal Intensive Care Units (NICUs, n = 20) of three Italian Regions (Piemonte, Marche and Lazio)., Results: Birth weight is considered an indicative parameter in only 64% of LNUs and 71% of NICUs, with a significant difference between LNUs in the three regions (86%, 20% and 62%, respectively; p < 0.001). Iron is recommended to infants with a birth weight between 2000 and 2500 g in only 25% of LNUs and 21% of NICUs, and to late-preterm (gestational age between 34 and 37 weeks) in a minority of Units (26% of LNUs, 7% of NICUs)., Conclusions: Our pilot survey documents a great variability and the urgent need to standardize practices according to literature recommendations., (Copyright © 2018. Published by Elsevier B.V.)

Excessive calorie intake and physical inactivity are considered key determinants of the rapid worldwide increase in obesity prevalence, however the relationship between diet and weight gain is complex. We investigated associations between adherence to a Mediterranean diet and long-term changes in weight and waist circumference in volunteers recruited to the Italian section of the prospective European Prospective Investigation into Cancer and Nutrition (EPIC). We investigated 32,119 cohort members who provided anthropometric measures at recruitment and updated information on recall a mean of 12 years later. Adherence to a Mediterranean diet was assessed using the Italian Mediterranean Index (score range 0-11). Associations between index score and weight and waist changes were assessed by multivariate linear regression models. Risks of developing overweight/obesity and abdominal obesity were investigated by multivariate logistic models. Increasing Italian Mediterranean Index score (indicating better adherence) was associated with lower 5-year weight change in volunteers of normal weight at baseline (β -0.12, 95% CI -0.16 to -0.08 for 1 tertile increase in score), but not in those overweight/obese at baseline (P interaction between Index score and BMI 0.0001). High adherence was also associated with reduced risk of becoming overweight/obese (OR 0.91, 95% CI 0.84-0.99 third vs. first tertile); smaller 5-year change in waist circumference (β -0.09, 95% CI -0.14 to -0.03 for 1 tertile increase in score); and lower risk of abdominal obesity (OR 0.91, 95% CI 0.84-0.99 third vs. first tertile). Adherence to a traditional Italian Mediterranean diet may help prevent weight gain and abdominal obesity.

Objectives: To prospectively evaluate usefulness of the apparent diffusion coefficient (ADC) in differentiating anterior mediastinal lymphoma from nonsuppressing normal thymus on chemical-shift MR, and to look at the relationship between patient age and ADC., Methods: Seventy-three young subjects (25 men, 48 women; age range, 9-29 years), who underwent chemical-shift MR and diffusion-weighted MR were divided into a normal thymus group (group A, 40 subjects), and a lymphoma group (group B, 33 patients). For group A, all subjects had normal thymus with no suppression on opposed-phase chemical-shift MR. Two readers measured the signal intensity index (SII) and ADC. Differences in SII and ADC between groups were tested using t-test. ADC was correlated with age using Pearson correlation coefficient., Results: Mean SII±standard deviation was 2.7±1.8% for group A and 2.2±2.4% for group B, with no significant difference between groups (P=.270). Mean ADC was 2.48±0.38x10 -3 mm 2 /s for group A and 1.24±0.23x10 -3 mm 2 /s for group B. A significant difference between groups was found (P<.001), with no overlap in range. Lastly, significant correlation was found between age and ADC (r=0.935, P<.001) in group A., Conclusions: ADC of diffusion-weighted MR is a noninvasive and accurate parameter for differentiating lymphoma from nonsuppressing thymus on chemical-shift MR in young subjects., Key Points: • SII cannot differentiate mediastinal lymphoma from nonsuppressing normal thymus at visual assessment • ADC is useful for distinguishing nonsuppressing normal thymus from mediastinal lymphoma • ADC is more accurate than transverse-diameter and surface-area in this discrimination • ADC of normal thymus is age dependent and increases with increasing age.

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Endometrial cancer is the fourth most common cancer in European women. The major risk factors for endometrial cancer are related to the exposure of endometrium to estrogens not opposed to progestogens, that can lead to a chronic endometrial inflammation. Diet may play a role in cancer risk by modulating chronic inflammation., Methods: In the framework of a case-control study, we recruited 297 women with newly diagnosed endometrial cancer and 307 controls from Northern Italy. Using logistic regression, we investigated the role of fruit and vegetable intake, adherence to the Mediterranean diet (MD), and the dietary inflammatory index (DII) in endometrial cancer risk., Results: Women in the highest quintile of vegetable intake had a statistically significantly lower endometrial cancer risk (adjusted OR 5th quintile vs 1st quintile: 0.34, 95% CI 0.17-0.68). Women with high adherence to the MD had a risk of endometrial cancer that was about half that of women with low adherence to the MD (adjusted OR: 0.51, 95% CI 0.39-0.86). A protective effect was detected for all the lower quintiles of DII, with the highest protective effect seen for the lowest quintile (adjusted OR 5th quintile vs 1st quintile: 3.28, 95% CI 1.30-8.26)., Conclusions: These results suggest that high vegetable intake, adherence to the MD, and a low DII are related to a lower endometrial cancer risk, with several putative connected biological mechanisms that strengthen the biological plausibility of this association.

Purpose: To assess intra- and interobserver variability in the apparent diffusion coefficient (ADC) measurements of pleural abnormalities., Materials and Methods: Diffusion-weighted magnetic resonance imaging was performed in 34 patients to characterize pleural abnormalities, with a 1.5T unit at b values of 0/150/500/800 sec/mm 2 . In two sessions held 3 months apart, on perfusion-free ADC maps, two independent readers measured the ADC of pleural abnormalities (two readings for each reader in each case) using different methods of region-of-interest (ROI) positioning. In three methods, freehand ROIs were drawn within tumor boundaries to encompass the entire lesion on one or more axial slices (whole tumor volume [WTV], three slices observer-defined [TSOD], single-slice [SS]), while in two methods one or more ROIs were placed on the more restricted areas (multiple small round ROI [MSR], one small round ROI [OSR]). Measurement variability between readings by each reader (intraobserver repeatability) and between readers in first reading (interobserver repeatability) were assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CoV). Analysis of variance (ANOVA) was performed to compare ADC values between the different methods. The measurement time of each case for all methods in first reading was recorded and compared between methods and readers., Results: All methods demonstrated good (MSR, OSR) and excellent (WTV, TSOD, SS) intra- and interreader agreement, with best and worst repeatability in WTV (lower ICC, 0.977; higher CoV, 3.5%) and OSR (lower ICC, 0.625; higher CoV, 22.8%), respectively. The lower 95% confidence interval of ICC resulted in fair to moderate agreement for OSR (up to 0.379) and in excellent agreement for WTV, TSV, and SS (up to 0.918). ADC values of OSR and MSR were significantly lower compared to other methods (P < 0.001). The OSR and SS required less measurement time (10 and 21/22 sec, respectively) compared to the others (P < 0.0001), while the WTV required the longest measurement time (132/134 sec) (P < 0.0001)., Conclusion: ADC measurements of pleural abnormalities are repeatable. The SS method has excellent repeatability, similar to WTV, but requires significantly less measurement time. Thus, its use should be preferred in clinical practice., Level of Evidence: 4 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:769-782., (© 2017 International Society for Magnetic Resonance in Medicine.)

Adherence to the Mediterranean diet (MD) has a preventive effect on colorectal cancer (CRC). Several biological mechanisms have been hypothesized to explain this effect, but the involvement of clinical mediators has not been experimentally proven. We examined the role of abdominal adiposity (i.e., waist-to-hip ratio, WHR) as a potential mediator of the relationship between the MD and CRC in the Italian centres of the European Prospective Investigation into Cancer and Nutrition. We evaluated the effect of the Italian Mediterranean Index (IMI) on WHR and of WHR on CRC risk. We then estimated the natural indirect effect (NIE, mediated by WHR) and the pure direct effect (PDE, unmediated) of IMI on CRC risk using mediation analyses, considering age, sex, education, physical activity, smoking and EPIC centre as confounders. Increased IMI was associated with significantly decreased odds of high WHR (odds ratio [OR] for an IMI of 6-11 vs. 0-1: 0.88, 95% confidence interval [CI]: 0.81-0.97). There was a positive relationship between WHR and CRC (hazard ratio [HR] for high vs. low WHR: 1.34, 95%CI: 1.09-1.66). The total effect of IMI was protective on CRC risk and was mainly explained by the PDE (HR for an IMI of 6-11 vs. 0-1: 0.51, 95%CI: 0.31-0.83), whereas the NIE was 1.00 (95%CI: 0.94-1.10). In this Mediterranean cohort, the protective effect of the MD on the development of CRC was not mediated by abdominal adiposity. Since this is the first study to investigate the mediating effect of abdominal obesity, other studies are needed to replicate this result., (© 2017 UICC.)

Objectives: To investigate inter-reader reproducibility of five different region-of-interest (ROI) protocols for apparent diffusion coefficient (ADC) measurements in the anterior mediastinum., Methods: In eighty-one subjects, on ADC mapping, two readers measured the ADC using five methods of ROI positioning that encompassed the entire tissue (whole tissue volume [WTV], three slices observer-defined [TSOD], single-slice [SS]) or the more restricted areas (one small round ROI [OSR]), multiple small round ROI [MSR]). Inter-observer variability was assessed with interclass correlation coefficient (ICC), coefficient of variation (CoV), and Bland-Altman analysis. Nonparametric tests were performed to compare the ADC between ROI methods. The measurement time was recorded and compared between ROI methods., Results: All methods showed excellent inter-reader agreement with best and worst reproducibility in WTV and OSR, respectively (ICC, 0.937/0.874; CoV, 7.3 %/16.8 %; limits of agreement, ±0.44/±0.77 × 10 -3 mm 2 /s). ADC values of OSR and MSR were significantly lower compared to the other methods in both readers (p < 0.001). The SS and OSR methods required less measurement time (14 ± 2 s) compared to the others (p < 0.0001), while the WTV method required the longest measurement time (90 ± 56 and 77 ± 49 s for each reader) (p < 0.0001)., Conclusions: All methods demonstrate excellent inter-observer reproducibility with the best agreement in WTV, although it requires the longest measurement time., Key Points: • All ROI protocols show excellent inter-observer reproducibility. • WTV measurements provide the most reproducible ADC values. • ROI size and positioning influence ADC measurements in the anterior mediastinum. • ADC values of OSR and MSR are significantly lower than other methods. • OSR and WTV methods require the shortest and longest measurement time, respectively.

Background: A consistent association has been reported between low socioeconomic status (SES) and cardiovascular events (CE), whereas the association between SES and cerebrovascular events (CBVD) is less clear. The aim of this study was to investigate the association between SES (measured using education) and CE/CBVD in a cohort study, as well as to investigate lifestyle and clinical risk factors, to help to clarify the mechanisms by which SES influences CE/CBVD., Material and Methods: We searched for diagnoses of CE and CBVD in the clinical records of 47,749 members of the EPICOR cohort (average follow-up time: 11 years). SES was determined by the relative index of inequality (RII)., Results: A total of 1,156 CE and 468 CBVD were found in the clinical records. An increased risk of CE was observed in the crude Cox model for the third tertile of RII compared to the first tertile (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.21-1.61). The increased risk persisted after adjustment for lifestyle risk factors (HR = 1.19; 95%CI 1.02-1.38), clinical risk factors (HR = 1.35; 95%CI 1.17-1.56), and after full adjustment (HR = 1.17; 95%CI 1.01-1.37). Structural equation model showed that lifestyle rather than clinical risk factors are involved in the mechanisms by which education influences CE. No significant association was found between education and CBVD. A strong relationship was observed between education and diabetes at baseline., Conclusion: The most important burden of inequality in CE incidence in Italy is due to lifestyle risk factors., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To evaluate the usefulness of diffusion-weighted magnetic resonance for distinguishing thymomas according to WHO and Masaoka-Koga classifications and in predicting disease-free survival (DFS) by using the apparent diffusion coefficient (ADC)., Methods: Forty-one patients were grouped based on WHO (low-risk vs. high-risk) and Masaoka-Koga (early vs. advanced) classifications. For prognosis, seven patients with recurrence at follow-up were grouped separately from healthy subjects. Differences on ADC levels between groups were tested using Student-t testing. Logistic regression models and areas under the ROC curve (AUROC) were estimated., Results: Mean ADC values were different between groups of WHO (low-risk = 1.58 ± 0.20 × 10(-3)mm(2)/sec; high-risk = 1.21 ± 0.23 × 10(-3)mm(2)/sec; p < 0.0001) and Masaoka-Koga (early = 1.43 ± 0.26 × 10(-3)mm(2)/sec; advanced = 1.31 ± 0.31 × 10(-3)mm(2)/sec; p = 0.016) classifications. Mean ADC of type-B3 (1.05 ± 0.17 × 10(-3)mm(2)/sec) was lower than type-B2 (1.32 ± 0.20 × 10(-3)mm(2)/sec; p = 0.023). AUROC in discriminating groups was 0.864 for WHO classification (cut-point = 1.309 × 10(-3)mm(2)/sec; accuracy = 78.1 %) and 0.730 for Masaoka-Koga classification (cut-point = 1.243 × 10(-3)mm(2)/sec; accuracy = 73.2 %). Logistic regression models and two-way ANOVA were significant for WHO classification (odds ratio[OR] = 0.93, p = 0.007; p < 0.001), but not for Masaoka-Koga classification (OR = 0.98, p = 0.31; p = 0.38). ADC levels were significantly associated with DFS recurrence rate being higher for patients with ADC ≤ 1.299 × 10(-3)mm(2)/sec (p = 0.001; AUROC, 0.834; accuracy = 78.0 %)., Conclusions: ADC helps to differentiate high-risk from low-risk thymomas and discriminates the more aggressive type-B3. Primary tumour ADC is a prognostic indicator of recurrence., Key Points: • DW-MRI is useful in characterizing thymomas and in predicting disease-free survival. • ADC can differentiate low-risk from high-risk thymomas based on different histological composition • The cutoff-ADC-value of 1.309 × 10 (-3) mm (2) /sec is proposed as optimal cut-point for this differentiation • The ADC ability in predicting Masaoka-Koga stage is uncertain and needs further validations • ADC has prognostic value on disease-free survival and helps in stratification of risk.

Aim: To evaluate the usefulness of computed tomography (CT) and chemical-shift magnetic resonance imaging (MRI) in patients with myasthenia gravis (MG) for differentiating thymoma (THY) from thymic lymphoid hyperplasia (TLH) and normal thymus (NT), and to determine which technique is more accurate., Materials and Methods: Eighty-three patients with generalised MG who underwent surgery were divided into the TLH/NT group (A; 65 patients) and THY group (B; 24 patients). Differences in qualitative characteristics and quantitative data (CT: radiodensity in Hounsfield units; MRI: signal intensity index [SII]) between groups were tested using Fisher's exact test and Student's t-test. Logistic regression models were estimated for both qualitative and quantitative analyses. At quantitative analysis, discrimination abilities were determined according to the area under the receiver operating characteristic (ROC) curve (AUROC) with computation of optimal cut-off points. The diagnostic accuracies of CT and MRI were compared using McNemar's test., Results: At qualitative assessment, MRI had higher accuracy than CT (96.4%, 80/83 and 86.7%, 72/83, respectively). At quantitative analysis, both the radiodensity and SII were significantly different between groups (p<0.0001). For CT, at quantitative assessment, the AUROC of the radiodensity in discriminating between groups was 0.904 (optimal cut-off point, 20 HU) with an accuracy of 77.1% (64/83). For MRI, the AUROC of the SII was 0.989 (optimal cut-off point, 7.766%) with an accuracy of 96.4% (80/83), which was significantly higher than CT (p<0.0001). By using optimal cut-off points for cases with an erroneous diagnosis at qualitative assessment, accuracy improved both for CT (89.2%, 74/83) and MRI (97.6%, 81/83)., Conclusion: Quantitative analysis is useful in evaluating patients with MG and improves the diagnostic accuracy of CT and MRI based on qualitative assessment. Chemical-shift MRI is more reliable than CT in differentiating THYs from non-thymomatous conditions., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The adduction of fumaric acid to the sulfhydryl group of certain cysteine (Cys) residues in proteins via a Michael-like reaction leads to the formation of S-(2-succino)cysteine (2SC) sites. Although its role remains to be fully understood, this post-translational Cys modification (protein succination) has been implicated in the pathogenesis of diabetes/obesity and fumarate hydratase-related diseases. In this study, theoretical approaches to address sequence- and 3D-structure-based features possibly underlying the specificity of protein succination have been applied to perform the first analysis of the available data on the succinate proteome. A total of 182 succinated proteins, 205 modifiable, and 1750 non-modifiable sites have been examined. The rate of 2SC sites per protein ranged from 1 to 3, and the overall relative abundance of modifiable sites was 10.8%. Modifiable and non-modifiable sites were not distinguishable when the hydrophobicity of the Cys-flaking peptides, the acid dissociation constant value of the sulfhydryl groups, and the secondary structure of the Cys-containing segments were compared. By contrast, significant differences were determined when the accessibility of the sulphur atoms and the amino acid composition of the Cys-flaking peptides were analysed. Based on these findings, a sequence-based score function has been evaluated as a descriptor for Cys residues. In conclusion, our results indicate that modifiable and non-modifiable sites form heterogeneous subsets when features often discussed to describe Cys reactivity are examined. However, they also suggest that some differences exist, which may constitute the baseline for further investigations aimed at the development of predictive methods for 2SC sites in proteins., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We report data regarding kinetic of response to oral iron in 34 iron deficiency anemia children. Twenty-four/34 patients (70.5%) reached reference value of hemoglobin (Hb) concentration for age and sex at day + 30 from the beginning of treatment (complete early responders (CERs)), and 4/34 (12%) reached an Hb concentration at least 50% higher than the original (partial early responders (PERs)). CHr at T1 (within 7 days from the beginning of treatment) was significantly different in the different groups (22.95 in CERs versus 18.41 in other patients; p = 0.001; 22.42 in early responders versus 18.07 in NERs; p = 0.001). Relative increase of CHr from T0 to T1 resulted significantly higher in CERs than in other patients (0.21 versus 0.11, p = 0.042) and in early responders than in NERs (0.22 versus 0.004, p = 0.006). Multivariate logistic models revealed a higher probability of being a complete early responder due to relative increase of ARC from T0 to T1 [OR (95% CI) = 44.95 (1.54-1311.98)] and to CHr at T1 [OR (95% CI) =3.18 (1.24-8.17)]. Our preliminary data confirm CHr as early and accurate predictor of hematological response to oral iron.

Objectives: to investigate the impact of socioeconomic status on dietary habits in Italy., Design: large Italian multicentric prospective cohort study., Setting and Participants: more than 45,000 subjects recruited between 1993 and 1998 in five Italian centres (Turin, Varese, Florence, Naples, and Ragusa). Dietary habits, educational level, and other characteristics were collected at baseline using standardised questionnaires., Main Outcome Measures: dietary habits collected for the EPIC study, grouped by food type and summarised by a Mediterranean dietary index., Results: we observed differences in dietary habits and in lifestyle habits by tertile of educational level. Principally, we noticed a positive association between higher education and healthy dietary habits (reduction in intake of processed meat, bread and rice, sweet drinks; increase in intake of fruit and vegetables, yoghurt, fish, olive oil, and tea)., Conclusion: a relationship between educational level and dietary habits is confirmed also in Italy, even if differences due to gender and residence area are present. This study shows an important role of dietary habits in health inequalities of the population with lower socioeconomic status.

Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed-up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen-Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval-CI 18-42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43-2.00), lymphoma (SIR 1.80, 95% CI 1.31-2.40), melanoma (2.12; 1.63-2.70), endometrium (2.18; 1.75-2.70) and kidney cancers (2.40; 1.57-3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post-menopausal status and a history of full-term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full-term pregnancy was inversely associated with the risk of second primary cancer., (© 2015 UICC.)

Objectives: The objective of this study was to prospectively investigate the usefulness of chemical-shift and diffusion-weighted (DW) magnetic resonance imaging (MRI) in patients with myasthenia gravis (MG) for distinguishing thymic lymphoid hyperplasia (TLH), normal thymus (NT), and thymoma (THY) by using the signal intensity index (SII) and the apparent diffusion coefficient (ADC)., Materials and Methods: We examined 87 subjects (44 males, 43 females; range, 15-71 years) with generalized MG and antibodies to the acetylcholine receptor seropositivity who underwent surgery. They were divided into a TLH/NT group (A, 64 patients; TLH, 49; NT, 15) and a THY group (B, 24 patients; nonadvanced THY, 15; advanced THY, 9) on the basis of histological findings. One patient with contemporary findings of TLH and nonadvanced THY at histology was listed in both groups (87 subjects, 88 findings). Chemical-shift MRI (CS-MRI) was performed with dual-echo acquisition, and the SII was measured for each subject. Diffusion-weighted MRI was performed at b values of 0, 150, 500, and 800 s/mm, and the ADC value was obtained on the ADC map after excluding the 0-s/mm b value diffusion weighting. All measures were performed independently by 2 radiologists, and interreader agreement was assessed by calculating the intraclass correlation coefficient. Differences on SII and ADC levels between the groups and subgroups were tested using the Student t test. Logistic regression models were estimated, and discrimination abilities were individuated according to the area under the receiver operating characteristic curve (AUROC). The optimal cut points for the differentiation of the groups and subgroups were obtained by using the Youden index., Results: The interreader agreement was excellent (intraclass correlation coefficient: SII, 0.998; ADC, 0.944). For CS-MRI, the mean (SD) SII value was significantly different between the groups (A, 36.37% [12.60%]; B, -0.06% [3.85%]; P < 0.001). No overlap in indexes was found with sensitivity, specificity, and cut point of 100%, 100%, and 6.37%, respectively. Conversely, the mean SII value was not different between the subgroups of each group (A, P = 0.607; B, P = 0.252). For DW-MRI, the mean (SD) ADC values were significantly different between the groups (A, 1.92 [0.21] × 10·mm/s; B, 1.36 [0.33] × 10 mm/s; P < 0.001) and between the subgroups of group A (TLH, 1.86 [0.17] × 10 mm/s; NT, 2.10 [0.23] × 10 mm/s; P = 0.002), although overlapped values were found. The AUROC of ADC in discriminating TLH/NT from THY was 0.931 (95% confidence interval, 0.863-0.998), and the optimal cut point for this distinction was 1.625 × 10 mm/s (Youden index, J = 0.760) with sensitivity of 96.8% and specificity of 79.2%. For the subgroups of group A, the AUROC of ADC in discriminating NT from TLH was 0.794 (95% confidence interval, 0.666-0.923), and the optimal cut point for this distinction was 2.01 × 10 mm/s (Youden index, J = 0.458) with sensitivity of 66.7% and specificity of 79.2%., Conclusions: CS-MRI and DW-MRI are both useful tools for examining patients with MG. The SII is more accurate than the ADC to differentiate TLH and NT from THY (AUROC, 1.000 and 0.931, respectively). Furthermore, the ADC is a noninvasive parameter that could be used for distinguishing TLH from NT, which is useful in selecting patients for surgery because, for nonthymomatous MG, acceptable rates of complete stable remission after thymectomy are found in TLH but not in NT.

Background: The aim of this study was to investigate the effect of the combined administration of intravenous immunoglobulins and steroids as a second-line therapy in 34 children with primary immune thrombocytopenia and persistent, symptomatic bleeding., Materials and Methods: Combined therapy (intravenous immunoglobulins 0.4 g/kg daily on days 1 and 2, and methylprednisolone 20 mg/kg daily on days 1-3) was administered to 12 patients with newly diagnosed ITP who did not respond to the administration of a single therapy (either intravenous immunoglobulins or steroids) and to 22 children with persistent and chronic disease who required frequent administrations (i.e. more frequently than every 30 days) of either immunoglobulins or steroids (at the same standard dosages) in order to control active bleeding., Results: A response (i.e. platelet count >50×10(9)/L and remission of active bleeding) was observed in 8/12 (67%) patients with newly diagnosed ITP. The clinical presentation of responders and non-responders did not differ apparently. Patients in the chronic/persistent phase of disease had a significantly longer median period of remission from symptoms compared with the previous longest period of remission (p=0.016). The treatment was well tolerated., Discussion: Our data suggest that the combined approach described is a well-tolerated therapeutic option for children with primary immune thrombocytopenia and persistent bleeding symptoms that can be used in both emergency and/or maintenance settings.

Objective: To assess the accuracy of 64-row computed tomography (CT) in the differential diagnosis of acute abdomen in the emergency department., Materials and Methods: Prospective analysis of 181 patients with surgically treated acute abdomen., Results: In 158/181 cases, CT was totally concordant with surgical repertoire. Partial concordance was found in 15 cases. Overall sensitivity was 87.3% when only cases of complete concordance were considered, 95.6% if also partial concordance cases were included., Conclusion: CT showed high reliability in the differential diagnosis of acute abdomen surgically treated, although associated conditions can sometimes be missed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of the present study was to determine the effects of exclusive oral iron supplementation (iron sulphate 2 mg/kg/die) in asymptomatic children with severe iron-deficiency anemia [median hemoglobin (Hb) level before treatment 6.3 g/dL; range 4.5 to 7 g/dL] and to investigate the accuracy of Hb, reticulocyte hemoglobin content (CHr), and absolute reticulocyte count (ARC) as markers for monitoring early response to treatment. The increase in ARC and CHr was statistically significant at day +3. There was a significant association between suitable logarithmic functions of the percentage increase in CHr and ARC at day +3 and the fraction of required Hb increase compared with baseline to reach the mean reference value for age and sex at day +14. If these results are confirmed in a larger population, ARC and CHr could be considered affordable and widely available markers to detect early responders to oral iron therapy, and to switch unresponsive children to parenteral iron supplementation or transfusion.

Neural membrane potential data are necessarily conditional on observation being prior to a firing time. In a stochastic leaky integrate-and-fire model, this corresponds to conditioning the process on not crossing a boundary. In the literature, simulation and estimation have almost always been done using unconditioned processes. In this letter, we determine the stochastic differential equations of a diffusion process conditioned to stay below a level S up to a fixed time t(1) and of a diffusion process conditioned to cross the boundary for the first time at t(1). This allows simulation of sample paths and identification of the corresponding mean process. Differences between the mean of free and conditioned processes are illustrated, as well as the role of noise in increasing these differences.

To relate the noise intensity with a periodically modulated input signal in a single neuron stochastic model we introduce a diffusion model with both time modulated drift and diffusion coefficient. Such a model is the continuous version of a Stein model with time oscillating frequencies for the Poisson processes describing the inputs impinging on the neuron. We focus here on some aspects of the resonance phenomenon for such a model. We compare the corresponding interspike interval distribution with the analogous distribution for a model sharing the same parameter values, but with constant noise intensity. Examples with two different levels for this noise intensity are discussed. The enhancement of the height of the peaks in the interspike interval distribution appearing at the modulation period, the improvement of the phase locking behavior and an enlargement of the noise ranges where a resonance like behavior arises are the main features observed in the considered cases.

The effects of taking into account in a perfect integrate and fire model of neuronal activity the spatial localization of the synapses are studied by superposing to the diffusion a simple discrete jump component. Different criteria are employed to assess the role of excitatory and inhibitory discrete contributions. Comparisons are performed with respect to the case where contributions coming from synapses more distal from the trigger zone are summed up in a continuous model. A systematic study of the output frequency and of the inter spike interval coefficient of variation (CV) is performed by means of examples as the model parameters are varied.

The interspike distribution can be modelled as the first-passage-time distribution of suitable diffusion processes with biologically meaningful boundaries. Since various mathematical difficulties arise when one attempts to obtain closed form solutions for first-passage-time problems, one can resort to simulation methods in order to study the problem. In this paper we pinpoint possible overestimations connected with simulations of first-passage-times for diffusion processes and propose a suitable simulation technique to determine the moments and the distribution of the firing times. After checking the validity of the proposed method in some instances where numerical evaluations for such quantities are available, we apply the simulation algorithm to model the spiking activity by means of a particular diffusion process constrained by a suitable time varying threshold.

Aiming at an improvement of the existing neuronal models, we consider a mixed process ensuing from the superposition of continuous diffusions and of Poisson time-distributed sequence of impulses and focus our attention on the moments of the firing time. In particular, we consider three different instances: the large jumps model in which each jump causes the neuron firing, the reset model characterized by jumps towards the resting potential and a more general model where constant amplitude excitatory and inhibitory jumps are superimposed on diffusion. By resorting to analytical arguments and to numerical computations, the main behavioral differences of the considered models are outlined.

Single-channel properties of a cloned channel activated by cyclic GMP have been analysed. The mRNA encoding for the channel was injected into oocytes of Xenopus laevis and the current flowing through a single ionic channel activated by cGMP was studied in excised patches under voltage-clamp conditions. The ionic channel activated by cGMP had a single-channel conductance of 32 +/- 2 pS at +120 mV and 25 +/- 4 pS at -120 mV, and its conductance was not significantly affected by increasing the cGMP concentration from 20 microM to 200 microM. The single-channel currents in the presence of NH+4, Na+, K+, Li+ and Rb+ in the medium bathing the cytoplasmic side of the membrane at +140 mV were 5.3, 4.7, 3.8, 1.3 and 0.8 pA, respectively. The single-channel current in the presence of Cs+ was less than 0.5 pA. Ca2+ and Mg2+ (both 0.5 mM) in the presence of 100 microM cGMP did not appreciably affect the channel activity at membrane potentials more negative than -80 mV, whereas at +100 mV they reduced the single-channel conductance by about threefold. The ionic selectivity and the blockage by divalent cations of the native channel found in amphibian rods and in the cloned channel from bovine rods are quite similar. However, the cloned channel has well-resolved openings, especially at positive membrane voltages, whereas the native channel is characterized by a continuous flickering between the open and closed state.