Repopulation by endogenous hepatocytes does not reconstitute liver mass in rats treated with retrorsine.

The retrorsine (RS)-based model for massive liver repopulation was laid on the hypothesis that transplanted cells can proliferate in the recipient liver if the growth capacity of endogenous hepatocytes is persistently impaired. In order to directly test this hypothesis, we examined the long-term response to 2/3 partial hepatectomy (PH) in rats pretreated with RS, according to the protocol for liver repopulation. Rats were given RS or saline and 4 weeks later they underwent PH; they were killed up to 16 weeks thereafter. Liver weights, liver DNA, and protein content were significantly lower in the RS group throughout the experimental time considered (e.g., at 16 weeks post-PH relative liver weight was 1.99 ± 0.30% in RS group vs. 3.06 ± 0.5% in controls). Regenerative nodules were present in RS-treated livers; they occupied about 3% of the liver at 2 weeks post-PH and this value increased to nearly 50% at 8 weeks and to >95% at 16 weeks. In conclusion, RS-treated rat liver is unable to recover its original mass for several months following PH, despite the development of regenerative nodules. This long-lasting effect is likely to contribute to the growth of transplanted hepatocytes, leading to massive liver repopulation

Aging is associated with increased clonogenic potential in rat liver in vivo

Summary Cancer increases with age and often arises from the selective clonal growth of altered cells. Thus, any environment favoring clonal growth per se poses a higher risk for cancer development. Using a genetically tagged animal model, we investigated whether aging is associated with increased clonogenic potential. Groups of 4-, 12-, 18-, and 24-month-old Fischer 344 rats were infused (via the portal vein) with 2 × 106 hepatocytes isolated from a normal syngenic 2-month-old donor. Animals deficient in dipeptidyl-peptidase type IV (DPP-IV–) enzyme were used as recipients, allowing for the histochemical detection of injected DPP-IV+ cells. Groups of animals were sacrificed at various times thereafter. No growth of DPP-IV+ transplanted hepatocytes was present after either 2 or 6 months in the liver of rats transplanted at young age, as expected. In striking contrast, significant expansion of donor-derived cells was seen in animals transplanted at the age of 18 months: clusters comprising 7–10 DPP-IV+ hepatocytes/cross-section were present after 2 months and were markedly enlarged after 6 months (mean of 88 ± 35 cells/cluster/cross-section). These results indicate that the microenvironment of the aged liver supports the clonal expansion of transplanted normal hepatocytes. Such clonogenic environments can foster the selective growth of pre-existing altered cells, thereby increasing the overall risk for cancer development associated with aging

Depression in Heart Failure with Reduced Ejection Fraction, an Undervalued Comorbidity: An Up-To-Date Review

Introduction: Depression is a common and severe comorbidity among individuals with heart failure (HF). Up to a third of all HF patients are depressed, and an even higher proportion have symptoms of depression. Aim: In this review, we evaluate the relationship between HF and depression, explain the pathophysiology and epidemiology of both diseases and their relationship, and highlight novel diagnostic and therapeutic options for HF patients with depression. Materials and Methods: This narrative review involved keyword searches of PubMed and Web of Science. Review search terms included ["Depression" OR "Depres*" OR "major depr*"] AND ["Heart Failure" OR "HF" OR "HFrEF" OR "HFmrEF" OR "HFpEF" OR "HFimpEF"] in all fields. Studies included in the review met the following criteria: (A) published in a peer-reviewed journal; (B) described the impact of depression on HF and vice versa; and (C) were opinion papers, guidelines, case studies, descriptive studies, randomized control trials, prospective studies, retrospective studies, narrative reviews, and systematic reviews. Results: Depression is an emergent HF risk factor and strongly relates with worse clinical outcomes. HF and depression share multiple pathways, including platelet dis-reactivity, neuroendocrine malfunction, inappropriate inflammation, tachi-arrhythmias, and frailty in the social and community setting. Existing HF guidelines urge evaluation of depression in all HF patients, and numerous screening tools are available. Depression is ultimately diagnosed based on DSM-5 criteria. There are both non-pharmaceutical and pharmaceutical treatments for depression. Regarding depressed symptoms, non-pharmaceutical treatments, such as cognitive-behavioral therapy and physical exercise, have shown therapeutic results, under medical supervision and with an effort level adapted to the patient's physical resources, together with optimal HF treatment. In randomized clinical studies, selective serotonin reuptake inhibitors, the backbone of antidepressant treatment, did not demonstrate advantage over the placebo in patients with HF. New antidepressant medications are currently being studied and could provide a chance to enhance management, treatment, and control of depression in patients with HF. Conclusions: Despite the substantial link between depression and HF, their combination is underdiagnosed and undertreated. Considering the hopeful yet unclear findings of antidepressant trials, further research is required to identify people who may benefit from antidepressant medication. The goal of future research should be a complete approach to the care of these patients, who are anticipated to become a significant medical burden in the future

Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.

Although sudden cardiac death (SCD) is one of the most important modes of death in Western countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed and the accurate diagnosis of the causes of SCD is now of particular importance. Pathologists are responsible for determining the precise cause and mechanism of sudden death but there is still considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology has developed these guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate investigation of SCD. The present version is an update of our original article, published 10 years ago. This is necessary because of our increased understanding of the genetics of cardiovascular diseases, the availability of new diagnostic methods, and the experience we have gained from the routine use of the original guidelines. The updated guidelines include a detailed protocol for the examination of the heart and recommendations for the selection of histological blocks and appropriate material for toxicology, microbiology, biochemistry, and molecular investigation. Our recommendations apply to university medical centers, regionals hospitals, and all healthcare professionals practicing pathology and forensic medicine. We believe that their adoption throughout Europe will improve the standards of autopsy practice, allow meaningful comparisons between different communities and regions, and permit the identification of emerging patterns of diseases causing SCD. Finally, we recommend the development of regional multidisciplinary networks of cardiologists, geneticists, and pathologists. Their role will be to facilitate the identification of index cases with a genetic basis, to screen appropriate family members, and ensure that appropriate preventive strategies are implemented

Entropy Principle and Galilean Relativity for Dense Gases, the General Solution without Approximations

The many moments model for dense gases and macromolecular fluids is considered here, where the upper order moment is chosen in accordance to the suggestions of the non-relativistic limit of the corresponding relativistic model. The solutions of the restrictions imposed by the entropy principle and that of Galilean relativity were, until now, obtained in the literature by using Taylor expansions around equilibrium and without proving convergence. Here, an exact solution without using expansions is found. The particular case with only 14 moments has already been treated in the literature in a completely different way. Here, it is proven that this particular closure is included in the presently more general one

Effect of a single IV administration of L-propionylcarnitine on myocardial microcirculation assessed by coronary flow velocity reserve measurement in patients with systemic sclerosis: a pilot study

BACKGROUND: Scleroderma-related cardiac involvement primarily affects coronary microvascular structures and function. The microvasculature disorder is responsible for impairment of coronary flow velocity reserve (CFVR), which has been reported in studies of patients with systemic sclerosis (SSc). L-Propionylcarnitine (L-PC) is a metabolic substance that is associated with a beneficial effect on both microcirculation and myocyte function. OBJECTIVE: The objective of this study was to determine whether or not CFVR was acutely improved or restored in patients with SSc after a single administration of IV L-PC. METHODS: In this pilot study, we screened volunteers with SSc who had no clinical evidence of ischemic heart disease. CFVR was determined by a blinded investigator by evaluating the left anterior descending coronary artery (LADCA) by transthoracic echocardiography during adenosine infusion (140 μg/kg • min−1 for 5 minutes), 30 minutes before and 15 minutes after administration of L-PC (300 mg IV in 5-minute bolus). RESULTS: Thirty-three patients were screened for this study. Fourteen patients (mean [SD] age, 54.3 [11.2] years; mean [SD] weight, 63.8 [14.5] kg; mean [SD] height, 156.3 [8.7] cm) with SSc and no evidence of coronary heart disease were included in the study; 13 women and 1 man (4 with the diffuse cutaneous form of SSc and 10 with the limited cutaneous form). After administration of L-PC to patients with SSc, median CFVR was significantly increased from 2.60 to 3.23 (P < 0.001), whereas peak diastolic velocity in the LADCA decreased significantly at the basal evaluation (30.0 vs 26.0, P = 0.009) and significantly increased (80.0 vs 87.5, P = 0.005) during adenosine infusion. No adverse events occurred before, during, or after L-PC infusion. CONCLUSIONS: Acute administration of L-PC was associated with a short-term beneficial effect on CFVR in this pilot study of patients with SSc. These results suggest that further, randomized, controlled, double-blind evaluation of longer-term administration to patients with SSc should be considered