Integration of woodchuck hepatitis and N-myc rearrangement determine size and histologic grade of hepatic tumors

Integrations of woodchuck hepatitis virus (WHV) DNA and rearrangements of the N-myc 2 gene have been detected frequently in hepatocellular carcinoma (HCC) of Eastern woodchucks (Marmota monax) chronically infected with WHV. Fifty-five hepatocellular neoplasms and matched nontumor hepatic tissue specimens obtained postmortem from 13 chronic WHV carriers were analyzed and the frequency of WHV DNA integrations and of N-myc rearrangements compared in tumors of different size and histologic grade. Four small tumor nodules were classified histologically as adenomas and integrated sequences of WHV DNA were detected in two of the four tumor nodules. In one of the two nodules, there was evidence of N-myc rearrangement. Fifty-one neoplasms were classified as HCC. Seven were grade 1 HCCs. WHV DNA integrations were demonstrated in 43% but none had N-myc rearrangements. Twenty grade 2 HCCs had WHV DNA integrations in 80% and in 38% N-myc rearrangements were present. Twenty-four grade 3 HCCs had integrations of WHV DNA in 79% and N-myc rearrangements in 74%. In two other grade 3 HCCs, rearrangements of N-myc were detected in the absence of WHV DNA integrations. The 12 largest tumors in the series all were grade 2 or 3 HCCs, and in 83%, both WHV DNA integrations and N-myc rearrangements were demonstrated. In conclusion, molecular changes observed in this study suggest a progression of genetic alterations providing either a significant proliferative stimulation and/or a growth advantage in hepatocarcinogenesis of woodchucks with chronic WHV infection.     

Resistin expression and plasma concentration peak at different times during pregnancy in rats

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5-15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin - which peaks in early pregnancy - to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.     

Authorship: From credit to accountability. Reflections from the Editors’ Network

The Editors’ Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Continuous Glucose Monitoring Versus Capillary Point-of-Care Testing for Inpatient Glycemic Control in Type 2 Diabetes Patients Hospitalized in the General Ward and Treated With a Basal Bolus Insulin Regimen

Background:

Continuous glucose monitoring (CGM) may improve the management of patients with type 2 diabetes hospitalized in the general ward by facilitating the detection of hyper- and hypoglycemic episodes. However, the lack of data on the accuracy and safety of CGM have limited its application.

Methods:

A prospective pilot study was conducted including 38 patients hospitalized in the general ward with a known diagnosis of type 2 diabetes mellitus (DM) and hyperglycemic individuals without a history of DM with a blood sugar of 140-400 mg on admission treated with a basal bolus insulin regimen. Inpatient glycemic control and the incidence of hypoglycemic episodes were compared between detection by CGM of interstitial fluid for up to 6 days and point-of-care (POC) capillary blood glucose monitoring performed pre- and postprandially, before bedtime and at 3 am.

Results:

No differences in average daily glucose levels were observed between CGM and POC (176.2 ± 33.9 vs 176.6 ± 33.7 mg/dl, P = .828). However, CGM detected a higher number of hypoglycemic episodes than POC (55 vs 12, P < .01). Glucose measurements were clinically valid, with 91.9% of patients falling within the Clarke error grid A and B zones.

Conclusions:

Our preliminary results indicate that the use of CGM in type 2 patients hospitalized in the general ward provides accurate estimation of blood sugar levels and is more effective than POC for the detection of hypoglycemic episodes and asymptomatic hypoglycemia.     

Contaminación del aire y síntomas recientes de asma,rinitis alérgica y eccema atópico en escolares de 6 y 7 años

Objective

The objective of the study was to analyze the relationship between air pollutants and the prevalence of recent symptoms of asthma, allergic rhinitis, and atopic eczema in schoolchildren aged between 6 and 7 years.

Patients and Methods

The prevalence of recent (previous 12 months) symptoms of allergic diseases was obtained by means of the questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC), Spain, with the participation of 7 centers (Asturias, Barcelona, Bilbao, Cartagena, La Coruña, Madrid, and Valencia) and 20 455 schoolchildren aged between 6 and 7 years, from 2002 to 2003. The pollutant detection systems of the aforementioned centers provided the mean annual concentrations of sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and total suspended particulate matter.

Results

The annual average concentration of SO₂ showed a significant association with a higher prevalence of recent severe asthma (adjusted odds ratio [aOR] between level-1 and level-3 pollution, 1.32; 95% confidence interval [CI], 1.01–1.73), rhinitis (aOR, 1.56; 95% CI, 1.39–1.75), and rhinoconjunctivitis (aOR, 1.70; 95% CI, 1.45–2.00). The annual average concentration of CO was associated with a higher prevalence of rhinitis (aOR, 1.65; 95% CI, 1.34–2.04), rhinoconjunctivitis (aOR, 1.76; 95% CI, 1.31–2.37), and eczema (aOR, 1.55; 95% CI, 1.17–2.04). The annual average concentration for NO₂ and total suspended particulate matter showed inverse associations with the prevalence of nocturnal dry cough.

Conclusions

Findings suggest that air pollutants such as SO₂ and CO increase the risk of recent symptoms of asthma and allergic rhinitis in schoolchildren aged between 6 and 7 years in Spain.     

Rectal advancement flap for the treatment of complex cryptoglandular anal fistulas: a systematic review and meta-analysis

Purpose

Rectal advancement flap is an accepted approach for treating complex fistula-in-ano. However, a diversity of technical modifications have been described. The aim of this study was to evaluate recurrence and fecal continence rates after performing rectal advancement flaps depending upon flap thickness (full-thickness, partial-thickness, or mucosal flaps) and treatment of the fistulous tract (core-out or curettage).

Methods

Medline (PubMed, Ovid), the Cochrane Library database, and ClinicalTrials.gov were searched. Studies that involved patients with complex cryptoglandular fistulas who had been treated with rectal advancement flaps were included. The outcomes measured were recurrence and fecal continence. All of the statistical analyses were performed using Comprehensive Meta-Analysis software. A fixed model was used if there was no evidence of heterogeneity; otherwise, a random effects model was used.

Results

Twenty-six studies were included (1655 patients). The pooled rate of recurrence was 21%. Full-thickness flaps showed the best results concerning recurrence (7.4%), partial flaps revealed 19% and mucosal flaps 30.1%. Core-out and curettage had a similar recurrence (19 vs 21%). Regarding anal incontinence, the pooled rate was 13.3%. Mucosal- and partial-thickness flaps showed similar rates (9.3 vs 10.2%), while full-thickness flaps disturbed it in 20.4%. Most of these alterations were minor symptoms. Otherwise, core-out and curettage showed similar rates (14.3 vs 12%).

Conclusions

1. Full-thickness rectal advancement flaps offer better results regarding the recurrence than mucosal or partial flaps. 2. All flaps cause some incontinence, which increases with the thickness of the flap. 3. The results did not suggest differences in recurrence and incontinence between core-out and curettage.

     

Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas

Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice.     

Infectious agents and cancer: criteria for a causal relation

Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas); hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias); and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor (Burkitt's lymphoma-EBV; mesothelioma - SV(40)). For others the association is inconsistent (Hodgkin's Disease, gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious agents will continue to illuminate molecular oncogenic processes.