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Background: One of the side effects of anti-estrogen treatments in breast cancer survivors (BCSs), especially with aromatase inhibitor (AI) treatment, is the frequent appearance of vulvo-vaginal atrophy (VVA). We aim to evaluate the efficacy, safety and feasibility of a new type of non-ablative Solid-State Vaginal Laser (SSVL) treatment in BCSs with VVA., Methods: A total of 30 BCSs with a history of AI use and symptoms of VVA were treated with a non-ablative SSVL (LASEmaR 1500™-EUFOTON)in this non-randomized pilot study. The effects of the laser have been evaluated at baseline, 10 wk and 24 wk using a visual analogue scale (VAS), the Vaginal Health Index (VHI), the Vulvar Health Index (VuHI), the Female Sexual Function Index (FSFI), the EORTC QLQ-BR23, the Vaginal Maturation Index (VMI) and vaginal pH., Results: At 10-week follow-up vs. baseline there were no statistically significant differences in FSFI, lubrication and EORTC QLQ-BR23. In all the subjective (dyspareunia, VHI, VuHI, FSFI, QLQ) and objective parameters (VMI and pH) there was a statistically significant improvement at the 6-month follow-up. Satisfaction was very high (4.7 out of 5), with 95.7% of patients being satisfied, more than or very satisfied., Conclusions: Preliminary results of SSVL treatment of VVA and dyspareunia in BCSs after AI treatment suggest clinical improvement, without relevant side effects and with a high degree of satisfaction.

Symptomatic uncomplicated diverticular colon disease (SUDCD) is a highly prevalent disease in our setting, which significantly affects the quality of life of patients. Recent changes in understanding the natural history of this disease and technological and pharmacological advances have increased the available options for both diagnosis and treatment. However, consensus regarding the use of these options is scarce and sometimes lacks scientific evidence. The objective of this systematic review is to clarify the existing scientific evidence and analyse the use of the different diagnostic and therapeutic options for SUDCD, comparing their advantages and disadvantages, to finally suggest a diagnostic-therapeutic algorithm for this pathology and, at the same time, propose new research questions., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Mercury (Hg), particularly as methylmercury (MeHg), is a nonessential, persistent, and bioaccumulative toxic element with high biomagnification capacity and is considered a threat to marine environments. We evaluated total Hg concentrations in liver, kidney, and brain in 62 individuals of 9 bird species linked to marine ecosystems from western Mediterranean admitted in a Wildlife Rehabilitation Center (WRC) (Alicante, Spain, 2005-2020). Age- and sex-related differences in Hg levels, as well as the cause of admission to the WRC, were also evaluated in certain species. The species studied were: northern gannet (Morus bassanus), European shag (Phalacrocorax aristotelis), great cormorant (Phalacrocorax carbo), osprey (Pandion haliaetus), Balearic shearwater (Puffinus mauretanicus), yellow-legged gull (Larus michahellis), razorbill (Alca torda), common tern (Sterna hirundo), and black-headed gull (Chroicocephalus ridibundus). Concentrations in feathers of 27 individuals, and concentrations in internal tissues in 7 other individuals of 7 different species were also reported but not statistically evaluated due to the limited number of samples. Results suggest that individuals were chronically exposed to Hg through diet. The differences in Hg concentrations among species may be explained by their diet habits. Mercury concentrations strongly correlated between tissues (r = 0.78-0.94, p < 0.001, n = 61-62). Some individuals of certain species (i.e., European shag, northern gannet, and great cormorant) showed Hg concentrations close to or above those described in the literature as causing reproductive alterations in other avian species. Consequently, certain individuals inhabiting western Mediterranean could be at risk of suffering long-term, Hg-related effects. Some of the species evaluated are listed within different categories of threat according to the International Union for Conservation of Nature (IUCN) and are endangered at a national level, so this study will provide valuable information for assessors and authorities in charge of the management of the environment and pollution.

Background & Aims: Acute kidney injury (AKI) is common in cirrhosis and is associated with poor prognosis. In patients who survive after AKI, it is not known whether the acute injury leads to chronic impairment of kidney function (chronic kidney disease [CKD]). The aim of the study was to determine the frequency of CKD at 3 months after an AKI episode and its effects on patient outcomes., Methods: Patients admitted for complications of cirrhosis during a 6.5-year period were evaluated using the same protocol, with assessment of kidney function at regular intervals during and after hospitalization. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m 2 at 3 months after AKI., Results: A total of 409 patients (168 with AKI and 241 without AKI) were included. After 3 months, 97 patients with AKI and 188 patients without AKI had survived. Of the 97 patients with AKI, 24 had developed CKD at 3 months compared to only 2 of the 188 patients without AKI (25% vs. 1%, odds ratio 31; p <0.0001). Risk factors independently associated with CKD were nosocomial AKI and severity of AKI (stage ≥1B). At diagnosis of CKD, all patients had stage 3A CKD and one-quarter of them progressed to stages 3B and 4 after 1 year. The transition from AKI to CKD was associated with an increased rate of 3-month hospital readmission, increased frequency of AKI, bacterial infections, ascites, and refractory ascites and a trend towards a higher need for liver transplantation. Transplant-free survival was not impaired., Conclusions: CKD frequently develops in patients with cirrhosis who survive AKI and has a negative impact on relevant clinical outcomes. The transition from AKI to CKD is common and should be considered a high-risk condition in patients with cirrhosis., Lay Summary: Episodes of acute impairment of kidney function are common in patients with cirrhosis. This study shows that the development of chronic impairment of kidney function is frequent in patients surviving these acute episodes and that it is associated with a higher risk of developing other complications of cirrhosis and to a higher rate of 3-month hospital readmissions., Competing Interests: Conflicts of interest PG reports Investigator Research grant and Advisory Board work from Grífols, Investigator Research grant and Advisory Board from Gilead, Investigator Research grant from Mallinckrodt, Advisory Board for Promethera, Advisory Board for Martin-Pharmaceuticals, grants from Ferring Pharmaceuticals, grants and Advisory Board Work from Sequana, outside the submitted work. The other authors have declared no conflict of interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Kidney biomarkers appear to be useful in differential diagnosis between acute tubular necrosis (ATN) and other types of acute kidney injury (AKI) in cirrhosis, particularly hepatorenal syndrome (HRS-AKI). Distinction is important because treatment is different. However, kidney biomarkers are still not used in clinical practice. The aim of the current study was to investigate the accuracy of several biomarkers in differential diagnosis of AKI and in predicting kidney outcome and patient survival. This was a prospective study of 320 consecutive cases of AKI in patients hospitalized for decompensated cirrhosis. Evaluation of AKI was made with a diagnostic algorithm that included identification and removal/treatment of precipitating factors and albumin administration (1 g/kg for 2 days) to patients with AKI stage 1B or greater. Urinary neutrophil gelatinase-associated lipocalin (NGAL), monomeric NGAL (mNGAL), interleukin-18, and standard biomarkers were measured at diagnosis and on days 3, 7, and 14. Of the 320 cases, 153 were hypovolemia-induced AKI (48%), 93 were HRS-AKI (29%), 39 were ATN (12%), and 35 were due to miscellaneous causes (11%). Among all biomarkers, urinary NGAL measured at day 3 had the greatest accuracy for differential diagnosis between ATN and other types of AKI (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.78-0.95). The cutoff with the best predictive accuracy for ATN diagnosis was 220 µg/g creatinine. Progression of AKI during hospitalization was associated with persistently high NGAL levels, and NGAL was an independent predictive factor of AKI progression. Likewise, NGAL was also an independent predictive factor of 28-day mortality together with Model for End-Stage Liver Disease score. Conclusion: These results support the use of NGAL in clinical practice within the context of a diagnostic algorithm for differential diagnosis of AKI and outcome prediction in cirrhosis., (© 2019 by the American Association for the Study of Liver Diseases.)

Unlabelled: MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis., Aim: To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis., Methods: Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed., Results: 69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27-2.1) and 2003 (705-4586) ug/g creat vs 0.47 (0.2-1.1) and 1188 (512-2958) ug/g creat, in patients with and without readmission, respectively; p<0.05; median (IQR)). Furthermore, urine levels of MCP-1 were significantly associated with mortality (1.01 (1-3.6) vs 0.5 (0.2-1.1) μg/g creat, in dead and alive patients at 3 months; p<0.05). Patients with higher levels of urine MCP-1 (above percentile 75th) had higher probability of development of hepatic encephalopathy, bacterial infections or AKI. Urine MCP-1 was an independent predictive factor of hospital readmission and combined end-point of readmission or dead at 3 months. Plasma levels of MCP-1 did not correlated with outcomes., Conclusion: Urine, but not plasma, MCP-1 levels are associated with hospital readmission, development of complications of cirrhosis, and mortality. These results suggest that in cirrhosis there is an inflammatory response that is associated with poor outcomes.

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Liver disease of unknown cause in HIV-infected persons is rare but increasingly being reported. Noncirrhotic portal hypertension is the main feature in a subset of these patients, in whom gastrointestinal bleeding is the most frequent and potentially life-threatening clinical presentation., Methods: We describe the epidemiological, clinical and histological features of 12 HIV-positive individuals presenting with noncirrhotic portal hypertension., Results: An interpretable liver biopsy was available in 11, and cirrhosis was absent in all patients. Three patients had nodular regenerative hyperplasia of the liver, whereas eight showed morphological features previously described as 'hepatoportal sclerosis'. In four of the later group, a distinctive lesion was noted characterized by massive absence of portal veins along with focal fibrous obliteration of small portal veins. All patients had been treated with didanosine for long periods and inflammatory and thrombotic processes hypothetically triggered by this purine analogue in the hepatic microvasculature might result in this form of obliterative portal venopathy., Conclusion: Noncirrhotic portal hypertension is a rare but unique entity presenting in HIV-positive individuals generally with prior prolonged exposure to didanosine, which shows an obliteration of portal veins as the most distinctive histological finding in the liver.

Background: Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddl) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddl removal., Methods: From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified., Results: Thirty-two individuals (prevalence approximately 1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddl for a median of 44 months; removal of ddl in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan., Conclusions: Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddl seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.

Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45alpha, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45alpha mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45alpha also exhibit the same pattern of differential expression. Our findings suggest that GADD45alpha might play a major role in the regulation of brain tumour invasive potential.

Scaling techniques were used to analyze the fractal nature of colonies of 15 cell lines growing in vitro as well as of 16 types of tumor developing in vivo. All cell colonies were found to exhibit exactly the same growth dynamics-which correspond to the molecular beam epitaxy (MBE) universality class. MBE dynamics are characterized by 1), a linear growth rate, 2), the constraint of cell proliferation to the colony/tumor border, and 3), surface diffusion of cells at the growing edge. These characteristics were experimentally verified in the studied colonies. That these should show MBE dynamics is in strong contrast with the currently established concept of tumor growth: the kinetics of this type of proliferation rules out exponential or Gompertzian growth. Rather, a clear linear growth regime is followed. The importance of new cell movements-cell diffusion at the tumor border-lies in the fact that tumor growth must be conceived as a competition for space between the tumor and the host, and not for nutrients or other factors. Strong experimental evidence is presented for 16 types of tumor, the growth of which cell surface diffusion may be the main mechanism responsible in vivo. These results explain most of the clinical and biological features of colonies and tumors, offer new theoretical frameworks, and challenge the wisdom of some current clinical strategies.

The Spanish data collection was consistent with the overall study design and drew from three groups: laboring women, children and elderly patients. The Valencia data was amongst the most detailed, specific and complete in this international study. This is most likely due to the experienced nature of the Spanish research team. The study results revealed more commonalities than differences in all age groups with regard to pain identification and pain alleviation. Across age groups, pain was identified by study participants through observation and listening.