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Within the past three years there has been a spate of historical discoveries by our research team on various different facets of the historical foundations of cancer risk assessment. This series of discoveries was stimulated by the creation of a 22-episode documentary of the historical foundations of cancer risk assessment by the US Health Physics Society and the need to provide documentation. This process yielded nearly two dozen distinct historical findings which have been published in numerous papers in the peer-reviewed literature. These discoveries are itemized and summarized in the present paper, along with the significance of each discovery within the historical context of ionizing radiation research and cancer risk assessment., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Transition is a crucial process in the care of IBD patients, although it remains largely heterogeneous., Aims: To provide an overview of the transition process in Italy and to investigate the perspective of the paediatric and adult physicians., Methods: An online survey was developed by the Italian Group for Inflammatory Bowel Diseases (IG-IBD) and the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition (SIGENP)., Results: 104 physicians (62 paediatric and 42 adult gastroenterologists) participated to the survey. The disease status was ranked with the highest priority among the key elements of the transition process. The age of the patient was perceived with a higher priority by paediatric gastroenterologists than by adult ones (p < 0.01). In most cases, the transition was organized through one or more joint meetings. Only less than 25 % of responders reported to involve other professions during transition. The struggle in leaving paediatric setting was perceived as the main obstacle to an effective transition process. Paediatric IBD gastroenterologists ranked the struggle in leaving the paediatric setting and the attending physician as higher critical point than adult gastroenterologists., Conclusions: The current survey provided a snapshot of the IBD transition process in Italy. The present findings highlight the need to embed transitional care in healthcare policy., Competing Interests: Conflict of interest None., (Copyright © 2023. Published by Elsevier Ltd.)

The diverse biological effects of polyamines (putrescine, spermidine and spermine) were reviewed in the context of hormesis in an integrative manner for the first time. The findings illustrate that each of these polyamines commonly induces hormetic dose responses in a wide range of biological models and types of cells for multiple endpoints in numerous plant species and animal models. Plant research emphasized preconditioning experimental studies in which the respective polyamines conferred some protection against the damaging effects of a broad range of environmental stressors such as drought, salinity, cold/heat, heavy metals and UV-damage in an hormetic manner. Polyamine-based animal hormesis studies emphasized biomedical endpoints such as longevity and neuroprotection. These findings have important biological and biomedical implications and should guide experimental designs of low dose investigations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Intestinal ultrasonography (US) allows for the characterization of the intestinal lesions and provides information on transmural inflammation. The aim of the study was to assess the clinical relevance of echopattern and correlation with Crohn's disease (CD) behavior and activity., Methods: We performed a prospective study including CD patients assessed by intestinal US. The echopattern was classified as hypoechoic, hyperechoic and stratified. Color-doppler US was also performed in the thickest segment., Results: One hundred CD patients were enrolled. The hypoechoic echopattern was significantly correlated with penetrating behavior (r = 0.44, p<0.0001), active disease (r = 0.21, p = 0.034), C-reactive protein/Fecal Calprotectin (r = 0.31, p = 0.004; r = 0.34, p = 0.031, respectively) and steroids (r = 0.33, p = 0.0008). Hypoechoic echopattern was associated with younger age than stratified (p = 0.046) and hyperechoic (p = 0.018) echopatterns. Bowel wall thickness was greater in the hypoechoic group than in the hyperechoic/stratified groups (p = 0.011 and p<0.0001, respectively). Hypoechoic echopattern was associated with fistulas (r = 0.52, p<0.0001) and increased vascularization (r = 0.32, p = 0.001). The hyperechoic echopattern showed a significant correlation with stricturing disease and an inverse correlation with fistulas. During a follow up period of 6 months, patients with hypoechoic echopattern had an increased risk of biological therapy need or surgery., Conclusions: The characterization of bowel wall echopattern allows for the identification of different CD behaviors., Competing Interests: Conflict of Interest EDC: None to declare LM: None to declare EL: None to declare LB: None to declare GM: served as a consultant for First Wave BioPharma and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides. EC: Served as a speaker for AbbVie, Takeda, MSD and Janssen FZ: Served as a speaker for Janssen, Takeda, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Boron is shown in the present review to induce hormetic dose responses in a broad range of biological models, organ systems and endpoints. Of particular importance is that numerous hormetic findings have been reported with whole animal studies, with extensive dose response evaluations with the optimal dosing being similar across multiple organ systems. These findings appear to be underappreciated and suggest that boron may have clinically significant systemic effects beyond that of its putative and more subtle essentiality functions. The re-exploration of boron's bioactivity as seen through hormetic mechanisms may also underscore the value of this approach to the assessment of micronutrient effects in human health and disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. G. Dhawan is employed by Stantec (ChemRisk), a consulting firm that provides scientific support to the government, corporations, law firms, and various scientific/professional organizations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Association between Hidradenitis Suppurativa (HS) and Inflammatory Bowel Disease (IBD) has been suggested., Aims: To assess characteristics of HS and IBD in patients with or without concomitant IBD., Methods: In a prospective, nested case-control study, each IBD patient with concomitant HS (Case) was retrospectively matched with 4 patients with HS and no IBD (Controls) for gender and age (±5 years).HS was classified according to the Hurley score and the International Hidradenitis Suppurativa Severity Score System (IHS4). Data were expressed as mean (Standard Deviation). Statistical analysis included Student-t Test or Mann-Whitney Test, χ2 test, univariate and multivariate logistic regression., Results: The study population included 125 patients with HS: 25 with IBD, 100 matched Controls with no IBD. IBD group included 19 (76%) Crohn's disease and 6 (24%) Ulcerative Colitis patients. Obesity, familial HS and perianal HS were less frequent in Cases than in Controls (1[4%] vs 25(25%];p = 0.02; 1[4%] vs 21(21%];p = 0.04; 1[4%] vs 31(31%];p = 0.005, respectively).HS was less severe in Cases when assessed by the IHS4 (5.9 ± 4 vs 9 ± 6.7;p = 0.04).Complete drug-induced response for HS was more frequent in IBD (13[53%] vs28 (28%]; p = 0.04)., Conclusion: Clinical characteristics of HS and of patients differed between Cases and Controls. Present findings suggest the need to appropriately search and assess skin lesions compatible with HS in IBD., Competing Interests: Conflict of interest All authors declare no disclosures specifically related to the study. Biancone L: speaker fee from Takeda, Janssen, ViforPharma, Celltrion; Monteleone G: consultant for First Wave BioPharma and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides; Calabrese E: speaker fee from Takeda, Janssen, MSD; Bianchi L: speaker or board member for Abbvie, Amgen, Novartis, Almirall, Sunpharma, Sanofi Genzyme, Biogen, Eli Lilly, Janssen, Leo Pharma; Campione E: advisory boards, lectures lee and research grants from Amgen, Almirall, Leo Pharma, UCB., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of Competing Interest None

Objective: Differentiate high- versus low-volume radiologists who interpret neurological (Neuro) MRI or musculoskeletal (MSK) MRI and measure the proportion of Neuro and MSK MRIs read by low-volume radiologists., Methods: We queried the 2015 Medicare Physician and Other Supplier Public Use File for radiologists who submitted claims for Neuro or MSK MRIs. Radiologists were classified as high-volume versus low-volume based on their work relative value units (wRVUs) focus or volume of studies interpreted using three different methodologies: Method 1, percentage of wRVUs in Neuro or MSK MRI; Method 2, absolute number of Neuro or MSK MRIs interpreted; and Method 3, both percentage and absolute number. Multiple thresholds with each methodology were tested, and the percentage of Neuro or MSK MRIs interpreted by low-volume radiologists was calculated for each threshold., Results: With Method 1, 33% of Neuro MRI and 50% of MSK MRI studies were interpreted by a radiologist whose wRVUs in Neuro or MSK MRI were less than 20% (Method 1). With Method 2, 22% of Neuro MRIs and 37% of MSK MRIs were interpreted by radiologists who read fewer than the mean number of Neuro or MSK MRIs interpreted by an "average full-time radiologist" whose wRVUs in Neuro or MSK MRI were approximately 20%. With Method 3, 38% of Neuro MRIs and 57% of MSK MRIs were interpreted by "low-volume" radiologists. If instead a 50% wRVU threshold is used for Methods One, Two, and Three, then 70%, 58%, and 77% of Neuro MRIs and 86%, 80%, and 90% of MSK MRIs are read by low-volume radiologists., Discussion: A large number of radiologists read a low volume of Neuro or MSK MRIs; these low-volume Neuro or MSK MRI radiologists read a substantial portion of Neuro or MSK MRIs. It is unknown which of the methods for distinguishing low-volume radiologists, combined with which threshold, may best correlate with high-performing or low-performing radiologists., (Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Technological improvements and growing sonographers' expertise boost the role of intestinal ultrasound (IUS) in assessing patients with inflammatory bowel diseases (IBD). Non-invasiveness, low cost and good reproducibility make IUS attractive. Leveraging on the Authors' long-term field experience, this review focuses on the IUS role in IBD patients' clinical management. For detecting IBD, particularly Crohn's disease, the IUS parameters - above all the evidence of a thickened bowel wall (BWT) - show very good diagnostic accuracy similar to that of MRI or CT scan. The standard IUS parameters are not accurate enough to detect inflammatory activity, but intravenous contrast-enhanced US (CEUS) is highly accurate in ruling active inflammation out. However, its routinely use remains limited in clinical practice and its parameters need standardization. IUS is accurate in detecting IBD main complications: in particular, fistulae and abscesses. As to stenosis the recent introduction of IUS-based elastographic techniques allows to differentiate prevalently inflammatory from highly fibrotic strictures. IUS proves valid also for monitoring IBD patients. In particular, the evidence of transmural healing, defined as BWT normalization, has got an important prognostic meaning, as associated with better long-term clinical outcomes. Post-surgery CD recurrence can be suggested by early IUS assessment., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Little is known about the unmet needs of physicians caring for patients with inflammatory bowel disease (IBD)., Aims: This study explored the practical difficulties and needs for professional updating of Italian IBD physicians., Methods: A questionnaire was distributed to 600 physicians attending IG-IBD meetings., Results: 280 physicians completed the questionnaire (46.7%). On a 5-point Likert scale (from 1, strongly disagree to 5, strongly agree), they identified the most problematic issues in managing IBD patients as increasing bureaucracy (3.9), lack of extra-gastroenterological IBD expertise (3.4), lack of diagnostic techniques (3.1) and budget limitations (2.9). The most lacking techniques, ranked from 1 (greatest need) to 9 (lowest need), were: anti-drug antibody and trough level assays (2.7), device-assisted enteroscopy (3.1), exploration under anaesthesia (3.2), MR enterography (3.2), and bowel ultrasonography (3.3). About professional updating, respondents indicated (on a 5-point Likert scale) that helpful topics were practical medicine (4.3), managing difficult patients (4.1), and guidelines (4.0). The most desired modality for updating was residential courses on clinical practice (4.3)., Conclusion: Several factors potentially limit the best management of IBD patients in Italy. Satisfying these unmet needs could improve care for IBD patients., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: Radiation therapy (RT) after prostatectomy is an important curative treatment option for patients with prostate cancer. It can be delivered immediately after surgery as adjuvant treatment, or after biochemical PSA failure as salvage treatment. There is currently a lack of consensus regarding whether salvage RT in the event of biochemical failure or immediate adjuvant RT is the optimal postprostatectomy RT treatment. Although both types of postprostatectomy RT are generally well tolerated, patients may develop some toxicity that can impact their quality of life and the duration and frequency of treatments can be challenging for patients. It is imperative that patients be provided with evidence-based information so that they are able to make a treatment decision most aligned with their values., Methods: To help address patients' informational needs, an online education resource was created for patients with prostate cancer considering postoperative RT. Patients and their families were asked to evaluate the effectiveness of this resource using a validated purpose-based information assessment., Results: Nineteen patients were approached and 14 participated, but only five patients returned their evaluations (35%). Sixty percent found the information to be important with regards to each of the six commonly identified purposes in the purpose-based information assessment: organizing, understanding, decision-making, planning, emotional support, and discussing. Only one participant found the information hard to understand and had difficulty finding specific information., Discussion: Patients should be encouraged to actively participate in their treatment decision-making process involving postprostatectomy RT. For patients to make well-informed decisions, patients must be provided with clear and accessible information so that they may understand their disease and the treatment options., Conclusion: An online education resource has been developed that most study respondents found clear and helpful for a variety of identified purposes. Overall, this online education resource has the potential to reach a large number of patients and their caregivers who desire specific information and involvement in future treatment decisions., (Copyright © 2018. Published by Elsevier Inc.)

The human spinal cord is a central nervous system structure that plays an important role in normal motor and sensory function, and can be affected by many debilitating neurologic diseases. Due to its clinical importance, the spinal cord is frequently the subject of imaging research. Common methods for visualizing spinal cord anatomy and pathology include histology and magnetic resonance imaging (MRI), both of which have unique benefits and drawbacks. Postmortem microscopic resolution MRI of fixed specimens, sometimes referred to as magnetic resonance microscopy (MRM), combines many of the benefits inherent to both techniques. However, the elongated shape of the human spinal cord, along with hardware and scan time limitations, have restricted previous microscopic resolution MRI studies (both in vivo and ex vivo ) to small sections of the cord. Here we present the first MRM dataset of the entire postmortem human spinal cord. These data include 50 μm isotropic resolution anatomic image data and 100 μm isotropic resolution diffusion data, made possible by a 280 h long multi-segment acquisition and automated image segment composition. We demonstrate the use of these data for spinal cord lesion detection, automated volumetric gray matter segmentation, and quantitative spinal cord morphometry including estimates of cross sectional dimensions and gray matter fraction throughout the length of the cord.

A history of mild traumatic brain injury (mTBI), particularly repeated mTBI (rmTBI), has been identified as a risk factor for late-onset neurodegenerative conditions. The mild and transient nature of early symptoms often impedes diagnosis in young adults who are disproportionately affected by mTBIs. A proportion of the affected population will incur long-term behavioral and cognitive consequences but the underlying pathomechanism is currently unknown. Diffusion tensor imaging (DTI) provides sensitive and quantitative assessment of TBI-induced structural changes, including white matter injury, and may be used to predict long-term outcome. We used DTI in an animal model of blast rmTBI (rmbTBI) to quantify blast-induced structural changes at 7 and 90 days post-injury, and their evolution between the two time points. Young adult male rats (~P65 at injury) were exposed to repeated mild blast overpressure, or anesthetized as shams, and their fixed brains were imaged using high-field (7 T) MRI. We found that whole brain volumes similarly increased in injured and sham rats from 7 to 90 days. However, we detected localized volume increases in blast-exposed animals 7 days post-injury, mainly ipsilateral to incident blast waves. Affected regions included gray matter of the frontal association, cingulate, and motor cortex, thalamus, substantia nigra, and raphe nuclei (median and dorsal), as well as white matter of the internal capsule and cerebral peduncle. Conversely, we measured volume reductions in these and other regions, including the hippocampus and cerebellum, at 90 days post-injury. DTI also detected both transient and persistent microstructural changes following injury, with some changes showing distinct ipsilateral versus contralateral side differences relative to blast impact. Early changes in fractional anisotropy (FA) were subtle, becoming more prominent at 90 days in the cerebral and inferior cerebellar peduncles, and cerebellar white matter. Widespread increases in radial diffusivity (RD) and axial diffusivity (primary eigenvalue or E1) at 7 days post-injury largely subsided by 90 days, although RD was more sensitive than E1 at detecting white matter changes. E1 effects in gray and white matter, which paralleled increases in apparent diffusion, were likely more indicative of dysregulated water homeostasis than pathologic structural changes. Importantly, we found evidence for a different developmental trajectory following rmbTBI, as indicated by significant injury x age interactions on volume. Our findings demonstrate that rmbTBI initiates dynamic pathobiological processes that may negatively alter the course of late-stage neurodevelopment and adversely affect long-term cognitive and behavioral outcomes.

The hypothesis that brain pathways form 2D sheet-like structures layered in 3D as "pages of a book" has been a topic of debate in the recent literature. This hypothesis was mainly supported by a qualitative evaluation of "path neighborhoods" reconstructed with diffusion MRI (dMRI) tractography. Notwithstanding the potentially important implications of the sheet structure hypothesis for our understanding of brain structure and development, it is still considered controversial by many for lack of quantitative analysis. A means to quantify sheet structure is therefore necessary to reliably investigate its occurrence in the brain. Previous work has proposed the Lie bracket as a quantitative indicator of sheet structure, which could be computed by reconstructing path neighborhoods from the peak orientations of dMRI orientation density functions. Robust estimation of the Lie bracket, however, is challenging due to high noise levels and missing peak orientations. We propose a novel method to estimate the Lie bracket that does not involve the reconstruction of path neighborhoods with tractography. This method requires the computation of derivatives of the fiber peak orientations, for which we adopt an approach called normalized convolution. With simulations and experimental data we show that the new approach is more robust with respect to missing peaks and noise. We also demonstrate that the method is able to quantify to what extent sheet structure is supported for dMRI data of different species, acquired with different scanners, diffusion weightings, dMRI sampling schemes, and spatial resolutions. The proposed method can also be used with directional data derived from other techniques than dMRI, which will facilitate further validation of the existence of sheet structure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (p corr <0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: We aimed to prospectively assess whether endoscopic recurrence severity at 1 year in Crohn's disease is predictive of clinical recurrence within 5 years., Methods: Clinical recurrence (Crohn's Disease Activity Index>150) was assessed yearly for 5 years in Crohn's disease patients undergoing ileo-colonic resection. At 1 year, recurrence was assessed by colonoscopy (Rutgeerts' score ≥i1 or ≥2i) and small intestine contrast ultrasonography., Results: 40 patients were included (23 males, median age 39 [16-69] years). Clinical recurrence occurred within 5 years in 16 (40%) patients (years 1, 2, 3, 4, 5: 2 [5%]; 10 [25%]; 4 [10%]; 2 [5%]; 4 [10%], respectively). At 1 year, endoscopic recurrence (score≥i1) occurred in 39 (97.5%) patients (score≥i2: 33 [82.5%]). Ultrasound detected lesions compatible with recurrence in 39/40 (97.5%) patients. Endoscopic score at 1 year was correlated with clinical score at 2 years (p=0.007; r=0.41). Endoscopic score at 1 year was higher in patients with (n=10) vs without (n=30) clinical recurrence at 2 years (3 [2-4] vs 2 [0-4]; p=0.003). Higher endoscopic score (>i2) at 1 year was a risk factor for clinical recurrence within 5 years (OR=0.18; 95% CI 0.04-0.71; p=0.008)., Conclusions: In Crohn's disease, severity of endoscopic recurrence at 1 year remains a predictive marker of clinical recurrence within 5 years. Small intestine contrast ultrasonography is useful for assessing 1-year recurrence., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Spondyloarthritis (SpA) and inflammatory bowel disease (IBD) are chronic autoinflammatory diseases that partially share the genetic predisposition and the unchecked inflammatory response linking the gut to the joints. The coexistence of both conditions in patients and the increased cross-risk ratios between SpA and IBD strongly suggest a shared pathophysiology. The prevalence of Enteropathic-related Spondyloarthritis (ESpA) in IBD patients shows a wide variation and may be underestimated. It is well accepted that the management of joint pain requires rheumatological expertise in conjunction with gastroenterologist assessment. In this view, we aimed at assessing, in a prospective study performed in a combined Gastro-Intestinal and Rheumatologic "GI-Rhe" clinic: (1) the prevalence of ESpA and other rheumatologic diseases in IBD patients with joint pain; (2) the features of the ESpA population; and (3) the diagnostic delay and the potential impact of the combined assessment. From November 2012 to December 2014, IBD patients with joint pain referring to a dedicated rheumatologist by the IBD-dedicated gastroenterologist were enrolled. Clinical and biochemical evaluations, joint involvement and disease activity assessment, diagnostic delay, and treatment were recorded. IBD patients (n=269) with joint pain were jointly assessed in the "GI-Rhe" Unit. A diagnosis of ESpA was made in 50.5% of IBD patients with joint pain. ESpA patients showed a peripheral involvement in 53% of cases, axial in 20.6% and peripheral and axial in 26.4% of cases. ESpA patients had a higher prevalence of other autoimmune extra-intestinal manifestations and received more anti-TNF treatment compared with IBD patients. A mean diagnostic delay of 5.2 years was revealed in ESpA patients. Patients with joint disease onset in the 2002-2012 decade had reduced diagnostic delay compared with those with onset in the 1980-1990 and 1991-2001 decades. Diagnostic delay was further reduced for patients with joint onset in the last two years in conjunction with the establishment of the GI-Rhe clinic. Multidisciplinary approach improved management of rheumatic disorders in IBD patients allowing a more comprehensive care., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Discrepancies between severity of lesions and symptoms may be observed in Crohn's disease. We prospectively assessed whether Crohn's disease may be diagnosed among asymptomatic relatives of patients, using Small Bowel Contrast Ultrasonography., Methods: Diagnosis of asymptomatic Crohn's disease relatives was defined ultrasonographically as: bowel wall thickness >3mm, bowel dilation/stricture, lumen diameter >2.5 cm. Diagnosis was confirmed by ileocolonoscopy. Subjects were also screened for the Leu3020insC mutation., Results: Consent was given by 35 asymptomatic first-degree relatives of 18 Crohn's disease patients. Ultrasonography indicated increased bowel wall thickness (5mm) compatible with ileal Crohn's disease in 1 relative (2.8%), a 42 year-old male. Ileocolonoscopy, histology, and radiology confirmed the diagnosis of stricturing ileal Crohn's disease. Gallbladder stones were detected in 7/35 (20%) relatives and Leu3020insC mutation in 3/35 (8.5%)., Conclusions: Small Bowel Contrast Ultrasonography may be a useful tool to diagnose asymptomatic small bowel Crohn's disease among first-degree relatives of patients., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Aim of our prospective study was to investigate accuracy of bowel ultrasonography in detecting gastrointestinal acute graft versus host disease (GVHD), when using clinical assessment as gold standard. In a subgroup of patients, bowel ultrasonography was compared with colonoscopy and histology in diagnosing of gastrointestinal acute GVHD., Methods: Fifty-two patients underwent allogeneic hematopoietic stem cell transplantation and developed gastrointestinal symptoms., Results: Clinical assessment lead to a diagnosis of gastrointestinal acute GVHD in 17/52 patients, no gastrointestinal acute GVHD was detected in 20/52 patients, while 15 patients were not able to complete the study. Bowel ultrasonography detected either bowel wall thickness of the ileum and the colon or dilation in 16/17 patients and showed 94% sensitivity (95% CI 0.69-0.99), 95% specificity (95% CI 0.73-0.99), and 94.5% accuracy. Colonoscopy was performed in 13/52 patients, showing gastrointestinal acute GVHD in 11/13. In these 11 patients, histology confirmed the diagnosis of gastrointestinal acute GVHD, and bowel ultrasonography detected findings compatible with gastrointestinal acute GVHD in all 11 patients, and was negative in the 2 patients with no gastrointestinal acute GVHD., Conclusion: Bowel ultrasonography can be considered a valuable tool to add to clinical assessment for patients with suspected gastrointestinal acute GVHD for addressing a prompt and appropriate treatment., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The development of symptomatic strictures in Crohn's Disease after anti-Tumour Necrosis Factor-α antibodies is undefined., Aim: To assess, in a prospective longitudinal study, the frequency of sub/obstructions in Crohn's Disease patients after treatment with Infliximab or Adalimumab. Changes of small bowel lesions after these biological therapies were searched by ultrasonography., Materials and Methods: From January 2007 to October 2008, 36 Crohn's Disease patients with no previous sub/obstructions were treated with either Infliximab (n=13) or Adalimumab (n=23) for ≥12months (mean follow-up duration after the first treatment 23.2±6.8months). Small Intestine Contrast Ultrasonography was performed before and after treatment in 19/36 patients. Sonographic parameters included: bowel wall thickness, lumen diameter, bowel dilation and lesion extent., Results: Sub/obstructions developed in 3/36 patients treated with Infliximab (n=1) or Adalimumab (n=2), all with fibrostricturing Crohn's Disease. Sonographic parameters did not significantly change after treatment., Conclusions: Sub/obstructive symptoms may develop in one tenth of Crohn's Disease patients treated with anti-Tumour Necrosis Factor-α antibodies, with no significant sonographic changes of the small bowel lesions., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The interaction between PD1 on T lymphocytes and PD-L1 on antigen presenting cells (APC) modulates the balance between inflammation and tolerance by inducing IL-10 production and apoptosis of antigen-specific cells. We analyzed the PD1/PD-L1 pathway, annexin V (AV)-expression, and proliferation in amyloid-beta (Aβ)-stimulated PBMC of patients with Alzheimer's disease (AD) (N = 35) or mild cognitive impairment (MCI) (N = 30) and of age-matched healthy controls (HC; N = 30). Results showed that PD1-expressing CD4(+) T cells, density of PD-L1 on CD14(+) APC, IL-10 production, and PD-L1-expressing/IL-10-producing CD14(+) APC were significantly reduced in AD and MCI patients compared to HC. Aβ-stimulated PD1/AV-expressing (apoptotic) CD4(+) T cells were also diminished, whereas proliferation was augmented in AD and MCI patients compared to controls. Finally, incubation of cells with PD-L1-neutralizing antibodies significantly decreased apoptosis of Aβ-specific CD4(+) T lymphocytes. An impairment of the PD-L1/PD1 pathway is present in AD and MCI. Such alteration results in reduced IL-10 production and diminished apoptosis of Aβ-specific CD4(+) T lymphocytes; these phenomena could play a role in the neuroinflammation accompanying AD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Inflammatory mediators are responsible for the neuroinflammation observed in Alzheimer's disease (AD), a phenomenon that might be the culprit of disease or, possibly, a reaction to pathology. To better investigate inflammation in AD we performed an extensive immunophenotypic and functional analysis of amyloid-beta (Aβ) stimulated T lymphocytes in patients with a diagnosis of AD comparing data to those obtained in individuals with mild cognitive impairment (MCI) or aged-matched healthy individuals (HC). Results showed that IL-21- and IL-9-producing Aβ stimulated CD4(+) T cells, as well as IL-23- and IL-6-producing monocytes and CD4(+) T cells expressing the RORγ and NFATc1 transcriptional factors (TF), were significantly increased, whereas IL-10-producing monocytes were decreased in AD. Notably, GATA-3 TF-expressing CD4(+) T lymphocytes were significantly increased in MCI alone. Analysis of the post-thymic differentiation pathway indicated that Aβ specific naïve and central memory CD4(+) T lymphocytes were diminished whereas effector memory and terminally differentiated CD4(+) T lymphocytes were increased in AD and MCI compared to HC. Data herein indicate that cytokines (IL-21, IL-6, IL-23) and TF (RORγ) involved in the differentiation of Th-17 cells), as well as cytokines (IL-21, IL-22) generated by such cells, and IL-9, produced by Th-9 cells, are significantly increased in AD. This is accompanied by a shift of post-thymic differentiation pathways favoring the accumulation of differentiated, effector T lymphocytes. These data shed light on the nature of AD-associated neuroinflammation. A better understanding of the complexity of this phenomenon could facilitate the search for novel therapeutic strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.

Association of the A2 allele of the human leukocyte antigen (HLA) with Alzheimer disease (AD) is still controversial. The authors evaluated HLA-A2 association with AD in 173 Italian AD patients, considering also the possible interaction with APOE pattern, age of onset and gender. No evidence of any association was found.

Postoperative recurrence after ileo-colonic resection is a feature of Crohn's Disease (CD), almost 73% of patients show endoscopic recurrence at 1 year and 90% at 3 years. After surgical resection for CD, symptoms may be related to the surgical resection itself. Moreover, the development of an early severe endoscopic recurrence within 1 year represents a risk factor for early clinical recurrence. On the basis of these observations, the early detection and assessment of asymptomatic endoscopic recurrence may allow a timely and appropriate treatment of CD patients after ileo-colonic resection. At this purpose, conventional colonoscopy with ileoscopy currently represents the gold standard for assessing CD recurrence, graded according to the Rutgeerts' score. Lesions compatible with CD recurrence can be also detected by conventional radiology, including small bowel follow through and enema, both associated with a high radiation exposure. Due to the ineluctable course of CD after resection, and to the need of a proper follow up for assessing CD recurrence, several alternative, non invasive techniques have been searched in order to assess the post-operative recurrence, including: faecal alpha 1-antitrypsin clearance, faecal calprotectin, 99Tc-HMPAO scintigraphy, virtual colonoscopy, ultrasonography and, more recently, wireless capsule endoscopy (WCE) and Small Intestine Contrast Ultrasonography (SICUS). Among these, current evidences suggest that in experienced hands, ultrasound examination by SICUS represents a non-invasive technique useful for assessing recurrence in CD patients under regular follow up after surgery. The same findings are suggested for WCE, although the impact risk related to the recurrence or to the surgical anastomosis itself limits the use of this non-invasive technique for assessing CD recurrence after surgery.

Poultry has commonly been considered highly susceptible to aflatoxins. However, among domestic fowl there is wide variability in specific species sensitivity to these mycotoxins. Comparative toxicological studies in avian species have shown that ducklings and turkey poults are the most sensitive species to aflatoxins, quails show intermediate sensitivity, whereas chickens are the most resistant. Hormesis is a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition. The low-dose stimulation is typically maximal at only about 30 to 60% greater than controls. Hormesis has been noted in regards to changes in body weight in numerous studies, including those performed for the US National Toxicology Program, with over 50 chemicals. The present paper assesses how relatively low levels of aflatoxin consumption in feed may affect the growth rate of chickens. In general, multiple independent investigations have shown that such aflatoxin consumption affects growth in a hormetic-like biphasic manner with a low dose stimulation and a high dose inhibition. Such observations were then generalized to other toxic agents and animal models, suggesting that low doses of stressor agents induce adaptive responses as reflected in accelerated growth rates. The implications of such hormetic dose responses are briefly discussed.

Researchers from Europe and the USA met at the Joint Research Center (JRC) of the European Commission to discuss how to integrate gene and protein expression analyses with bioinformatic tools in the field of ecotoxicology and how this new approach could be translated in improved risk assessment procedures. The measurements of gene and/or protein expression levels, upon exposure to a chemical or a stressor, can be used to develop robust molecular biomarkers that will allow the early detection of environmental stress, study long-term exposure and infer the mechanism of action. These molecular biomarkers should be linked to phenotypic end points of exposure such as adverse effects in growth and reproduction in single organisms and populations. At environmentally realistic exposure levels there could be "non-linear" dose-response curves, which should be accounted for in the experimental design and in the analyses of microarray and proteomic data. The application of gene and protein expression profiling in ecotoxicology will have a significant impact on the ecotoxicology field in the near future and international collaborations will play an important role in accelerating the application of those techniques.

To investigate the signs of inflammatory processes in Alzheimer's disease (AD), we examined peripheral blood mononuclear cells (PBMC) from 51 AD patients (29 with mild and 22 with moderately severe dementia) and 51 age-matched healthy controls (HC), using flow cytometry to analyse the absolute number and the percentage of T, B and NK cells. We also studied the surface expression of CD25, CD28, CD57, CD71, CD45RA and CD45RO markers on cells CD4+ and CD8+. In 30 AD patients and 20 HC the production of IL-2, IFN-gamma, IL-10 and TNF-alpha by PBMC after stimulation with [25-35], [1-40] and [1-16] beta-amyloid (betaA) fragments was also evaluated. A significant decrease in circulating B and CD8+CD28- cells, as well as an increase in CD8+ cells expressing CD71+ and CD28+, was observed in AD patients. A significant decrease in IL-10 production was also found after stimulation of PMBC with betaA [1-40]. The decreased IL-10 production was not related to disease severity. The observed imbalance of immune peripheral cell subpopulations and decreased IL-10 production point to a reduction of suppressor cell function in AD patients.

Background: Topical beclomethasone diproprionate has shown efficacy in ulcerative colitis., Aim: To assess, in a multicenter, randomized, double-blind study, the tolerability and safety of topical beclomethasone diproprionate (3mg) enema and foam versus mesalazine (2g) enema and foam in mild-moderate distal ulcerative colitis., Patients: In 15 referral gastrointestinal units, 99 patients with distal ulcerative colitis were enrolled. This number was lower than planned according to the statistical analysis, due to a low recruitment rate., Methods: Patients were randomly assigned to random preparations (beclomethasone diproprionate enema, beclomethasone diproprionate foam, mesalazine enema, mesalazine foam) once nightly for 8 weeks, with clinical and endoscopical assessment (Disease Activity Index score) at baseline (T0), 4 (T4) and 8 weeks (T8). Results were expressed as median and range (95% confidence interval). The efficacy was assessed by comparing the Disease Activity Index value at T4 and T8 by using the Student's t-test or the Wilcoxon-Mann-Whitney test., Results: Efficacy was comparable in the beclomethasone diproprionate or mesalazine groups at both T4 and T8 (response at T4: beclomethasone diproprionate 78% [95% confidence interval 0.6-0.8] versus mesalazine 79% [95% confidence interval 0.6-0.8]; T8: beclomethasone diproprionate 84% [95% confidence interval 0.7-0.9] versus mesalazine 90% [95% confidence interval 0.7-1.0]; p=n.s.; remission at T4: beclomethasone diproprionate 24% [95% confidence interval 0.1-0.3] versus mesalazine 28% [95% confidence interval 0.1-0.3]; remission at T8: beclomethasone diproprionate 36% [95% confidence interval 0.2-0.5] versus mesalazine 52% [95% confidence interval 0.3-0.6]; p=n.s.). The Disease Activity Index lowered at T4 and T8 versus T0 in the four groups (T4 versus T0: beclomethasone diproprionate foam Disease Activity Index 2 versus 6 p<0.0001; beclomethasone diproprionate enema 4 versus 6, mesalazine enema 3 versus 6, mesalazine foam 3.5 versus 7, p<0.001 for all three groups; T8 versus T0: p<0.01). The Disease Activity Index lowered at T8 versus T4 in the beclomethasone diproprionate enema and foam (Disease Activity Index: 2 versus 4 and 1 versus 4, respectively; p<0.05) and in the mesalazine enema (Disease Activity Index: 1.5, range 0-4 versus 3, range 0-12; p<0.01), but not in the mesalazine foam group (Disease Activity Index: 1, range 0-9 versus 3.5, range 0-8; p=n.s.). The safety profile was favourable for all groups., Conclusions: Beclomethasone diproprionate and mesalazine enema and foam show a comparable tolerability and efficacy in mild active distal ulcerative colitis.

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

Interleukin-1alpha (IL-1alpha) and IL-1beta are two pro-inflammatory cytokines involved in the pathogenesis of Alzheimer's disease (AD). The genes coding for IL-1alpha (IL-1A) and for IL-1beta (IL-1B) are clustered in chromosome 2q14-2q14.2. In a previous work, we investigated the role of IL-1A promoter polymorphism (-889 position) in AD pathogenesis: IL-1A -889 TT genotype was associated with sporadic early onset AD. We now report the study on polymorphism of exon 5 IL-1B in position +3953, the nearest polymorphism to -889 IL-1A. We found that the genotype distribution of IL-1B +3953 varied significantly between patients with early and late onset of AD (P<0.0001). Patients carrying IL-1B +3953 CT or TT genotypes had 4 or 5 years anticipation of AD onset (P=0.0034; odds ratio for early onset, 3.01) and 7 years anticipation if they also carried the IL-1A -889 TT genotype (P<0.0001; odds ratio for early onset, 7.4). These data further support a role for inflammation-related genes in AD or indicate linkage disequilibrium with an unknown chromosome 2 locus.

Unlabelled: A history of physical and/or sexual abuse is a frequent occurrence in patients referred for chronic gastrointestinal disorders and it may predispose to the development of functional gastrointestinal disorders, and multiple medical complaints. This study was aimed to determine: (a) prevalence of abuse history in Italian patients with chronic gastrointestinal disturbances, and (b) relationship between abuse history and clinical manifestations., Subjects and Methods: Consecutive gastrointestinal out-patients filled in a self-administered standardised questionnaire, made up of two separate sections: (1) a medical section enquiring on gastrointestinal and extra-gastrointestinal symptoms, and (2) a section on abuse enquiring on the presence and type of abuse suffered during their lifetime. Associations between number of symptoms and abuse history were evaluated using univariate and multivariate logistic models., Results: Questionnaires were handed out to 260 patients; 13% of whom did not fill in the questionnaires. Functional gastrointestinal disorders were diagnosed in 72.5% of patients and organic gastrointestinal diseases in 27.5%. A total of 31% of patients with organic gastrointestinal diseases and 32% of those with functional gastrointestinal disorders referred to a history of sexual or physical abuse. Histories of physical plus sexual abuse, sexual abuse, childhood abuse and female gender, were statistically associated with an increased number of gastrointestinal and extra-gastrointestinal symptoms irrespective of functional or organic disorders, whereas there was no statistical association with physical abuse only. Furthermore, diagnosis of functional gastrointestinal disorders was associated with a significantly (p<0.001) greater number of gastrointestinal symptoms than the diagnosis of organic gastrointestinal diagnosis. A total of 10 patients met the diagnostic criteria of somatization disorder. Of these, eight reported a history of severe physical and sexual abuse that had occurred, in all but one, during childhood., Conclusions: A history of physical and/or sexual abuse has a high prevalence in Italian patients with chronic gastrointestinal disorders, irrespective of organic or functional diagnosis. Abuse history has no relevant role in the pathogenesis of either functional or organic chronic gastrointestinal disorders but it can affect their clinical expression irrespective of functional or organic diagnosis. Severe physical and sexual abuse and childhood abuse were found in patients who met diagnostic criteria for somatization disorder, suggesting a role of abuse history in this subset of patients.

The effect of lead (Pb) ingestion on hematological parameters in male and female Swiss mice was assessed. Eight different doses of Pb were administered through preparation of different feeds. The levels of Pb in the diet were designed to provide exposure below (0.6 to <2.0 microg/dl) and above (>2.0-13 microg/dl) normal background. One litter of mice was exposed to each Pb dose, with the mother given the feed 1 day after mating, and the mother and offspring continuing to receive the feed until the litter was 90 days old. Male and female mice receiving below normal background levels of dietary Pb displayed enhanced red blood cell (RBC) production as measured by increased numbers of RBC and increased hemoglobin and hematocrit values. However, as the blood Pb levels approached 10 microg/dl there was a marked decrease in RBC production. These findings are significant since Pb was biologically active in a stimulating manner below typical background levels (2.0 microg/dl) while adversely effecting red cell synthesis at above background levels (7.0-13 microg/dl) encountered in the environment by humans.

The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimer's disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinson's disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding., (Copyright 2002 Elsevier Science Inc.)

Previously published studies indicate that hepatotoxicity is associated with high blood lead (Pb) levels in animal models and humans. The present investigation evaluated the effects of in vivo Pb exposure via drinking water on mouse hepatocyte survival in vitro when blood Pb concentrations reflected those seen in children in urban and rural settings (2-15 microg/dl). The findings indicated a biphasic dose-response with low concentrations associated with a modest decrease in hepatocyte survival, while at the highest concentration, survival was significantly enhanced (60%). Since these responses were associated with concentrations normally encountered by children, follow-up investigations are warranted.

The nephrotoxic effect of a single intraperitoneal dose of mercuric chloride (HgCl(2); 6 mg/kg) on adult CD-1 female mice was reduced at 24 and 48 h after injection, by a 48-h pretreatment nontoxic dose of lead acetate (Pb; 5 mg/kg) delivered by intravenous tail-vein injection (intravenous). While protection is temporally associated with lead-induced mitosis, occurring about 39 h after intracardiac lead injection (D. D Choie and G. W. Richter, 1974, Lab. Invest. 30, 447-451), the mechanism of the observed protection remains to be established., (Copyright 2001 Academic Press.)

The presence of estrogen receptors or binding proteins was demonstrated in the free-living nematode species Panagrellus redivivus and Caenorhabditis elegans by radioimmunoassay. Twenty-five nanomolar concentrations of toxaphene, dieldrin, and dieldrin plus nonylphenol significantly inhibited estrogen binding to the receptor in P. redivivus. Binding was inhibited but not significantly by 25 nM nonylphenol, toxaphene plus dieldrin, or toxaphene plus nonylphenol. The current research supports the hypothesis that dieldrin, nonylphenol, and toxaphene may mimic estrogen, altering the normal pathways of estrogen metabolism. Based on observations of secondary sex structures, estrogenic chemicals had no effect on sex ratios or growth in Panagrellus redivivus, but caused a reduction of fecundity in this nematode., (Copyright 2000 Academic Press.)

The concept of hormesis (i.e., low-dose stimulation/high-dose inhibition) has been shown to be widely generalizable with respect to chemical class, animal model, gender, and biological end point. The public health implication of this lack of linearity in the low-dose area of the dose-response curve raises the question of whether low doses of carcinogens will reduce cancer risk. Articles relating to the process of carcinogenesis (i.e., initiation, promotion, tumor development, and progression) were obtained from a recently developed chemical hormesis database and evaluated for their evidence of hormesis. Numerous examples in well-designed studies indicate that U- or J-shaped dose-response relationships exist with respect to various biomarkers of carcinogenesis in different animal models of both sexes. Examples of such J-shaped dose-response relationships in each stage of the process of carcinogenesis were selected for detailed toxicological examination. These results have important implications for both the hazard assessment of carcinogens and cancer risk assessment procedures., (Copyright 1998 Academic Press.)

Cellular regeneration and tissue repair greatly influence the outcome of acute carbon tetrachloride (CCl4) hepatotoxicity. This study examined the temporal kinetics of cellular regeneration and tissue repair processes in male and female Sprague Dawley (SD) rats following an acute CCl4 exposure (0.8 ml/kg, i.p.). In female rats, hepatic damage peaked at 24 h following the treatment and was approximately 2.5-fold (AST 2.7-fold, ALT 2.3 fold) greater than the damage observed in male rats. The hepatic damage in male rats appeared to peak by 3 h post-exposure and did not significantly change through the 36-h time-point. The activity of cytochrome P 4502E1 was 20% greater in male rats and did not correlate with the magnitude of hepatic damage. Morphometric analysis of cell cycle indices revealed that cellular regeneration was significantly greater in female rats as compared to male rats at 48 h and corresponded proportionally to the extent of liver damage. This study demonstrated that female SD rats respond more severely to acute CCl4 hepatotoxicity than male SD rats and the extent of tissue repair and cellular regeneration was greater in female rats. Furthermore, our results suggest that tissue repair is unlikely to result in accounting for the different responses exhibited by male and female SD rats to CCl4 hepatotoxicity.

A toxicologically based predictive scheme is presented for quantitatively ranking chemical agents with respect to their capacity to ensure endocrine disruption in target species based on short-term bioassays. Criteria providing the predictive framework include: (1) endocrine disruption as a multistage process, (2) phylogenetic considerations, (3) model system, and (4) estrogenic potency. Relative rankings were calculated for 15 environmentally relevant agents reported to have endocrine-disrupting effects. The relative ranking process offers a procedure for assessing the potential of endocrine disruption and for identifying data gaps for specific chemical agents. Although the current scheme is limited to "estrogenic" agents, it is anticipated that future refinements (e.g., incorporation of antiestrogenic potency data) will improve the system.

Soil ingestion was evaluated in 10 adults as part of a larger study to evaluate soil ingestion in children. Each adult was followed for 4 weeks in a mass-balance study that was designed to evaluate the detection limit for soil ingestion in a similarly designed, concurrent children's study. After a baseline week, during Weeks 2 through 4, adults received daily soil capsules containing 20, 100, and 500 mg of soil, respectively. A 1-week period separated each study week. Based on the first 3 weeks of observation after subtracting the capsule ingestion amounts, the median, 75th percentile, and 95th percentile soil ingestion estimates were 1, 49, and 331 mg/day, with estimates calculated as the median of the three trace elements Al, Si, and Y. The average estimate of soil ingestion was 10 mg/day (SD = 94 mg/day). These findings augment sparse empirical data on adult soil ingestion, and suggest lower levels of soil ingestion in adults than previous studies.