Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats

BACKGROUND/AIMS: The pathophysiological significance of heme oxygenase-1 up-regulation in portal hypertension is not completely understood. In this study, we determined the role of heme oxygenase-1 on oxidative stress, inflammation, angiogenesis, and splanchnic hemodynamics in rats with portal hypertension induced by partial portal vein ligation. METHODS: Rats were treated with the heme oxygenase inhibitor SnMP or vehicle for 7 days. Then, oxidative stress was quantified by superoxide anion production, and inflammatory response was assessed by immunofluorescence. Expression of angiogenesis mediators was determined by western blotting, and the extent of portosystemic collaterals by radioactive microspheres. Hemodynamic studies were performed by flowmetry. RESULTS: Oxidative stress was significantly increased in the mesentery of portal hypertensive rats, as compared with sham-operated controls. In portal hypertensive rats, chronic heme oxygenase inhibition (1) potentiated oxidative stress and inflammation, (2) significantly decreased VEGF expression, without modifying the extent of collaterals or the splanchnic neovascularization, and (3) significantly decreased superior mesenteric artery blood flow and portal pressure. CONCLUSIONS: This study demonstrates that heme oxygenase plays an important (beneficial) role attenuating oxidative stress and inflammation, but it also plays a detrimental role in stimulating VEGF production, and contributing to the development of hyperdynamic splanchnic circulation in rats with portal hypertension.     

The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis

BACKGROUND/AIMS: We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation. METHODS: GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated. RESULTS: IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels. CONCLUSIONS: Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.     

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1^–/– and Taldo1^+/– mice spontaneously developed HCC, and Taldo1^–/– mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1^–/– livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1^–/– livers reflected adaptation to oxidative stress. Taldo1^–/– hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1^–/– mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.     

The microvascular system of the optic nerve in control and enucleated rats

The microvascular system of the optic nerve of the rat was examined morphometrically to determine the effect of enucleation of one eye at birth on the microvascular development in the contralateral optic nerve. For this purpose, two groups of rats were used: three were unilaterally enucleated on the day of birth and studied on postnatal Day 28; three littermates were used as controls. Using plastic embedded semithin sections, we analyzed various parameters and compared the results statistically. The average diameter of microvessels up to 7.5 microns was found to be 4.7 +/- 0.2 micron in controls and 5.3 +/- 0.5 micron in experimental rats. The density of microvessels expressed as the mean number of sectioned capillaries per tissue area was 137 +/- 25/mm2 in the control group and 169 +/- 32/mm2 in the experimental group. The intravascular volume fraction percentage (Vv), which represents the volume fraction of the capillary network per unit of optic nerve volume (mm3/mm3%), was 0.06% in the controls and 0.10% in the enucleated rats. Total length of capillaries per unit of volume (Lv) averaged 1050 +/- 112 and 2235 +/- 195 mm/mm3 in control and experimental groups, respectively. The internal capillary surface area available for metabolic exchange expressed per volume unit (Sv) was 15.5 +/- 2.1 and 37.2 +/- 2.8 mm2/mm3 in control and experimental groups, respectively. These results, together with the lack of ultrastructural modifications in the vascular walls of microvessels, suggest that these rearrangements of the capillary system in the enucleated group could be triggered by an increase in the optic nerve metabolism resulting from monocular vision.     

Revealing tacit knowledge used by experienced health professionals for interprofessional collaboration

ABSTRACT

With the current interest in interprofessional collaboration in health care as a response to ever-increasing complexity of health issues and scarcity of resources, many higher education institutions are developing interprofessional education (IPE) programs. However, there has been little empirical work on what. With the current interest for interprofessional collaboration in health care ever-increasing knowledge and skills are required to work collaboratively between health professions. We have undertaken to describe interprofessional collaboration as a practice largely underpinned by tacit knowledge acquired by experienced clinicians. Clinicians from all health professions in a large francophone university in Eastern Canada were invited to participate in explicitation interviews. Explicitation interviews require participants to freely recall an interprofessional collaboration event (e.g., team meeting or joint care delivery) and describe specific actions they personally enacted. An experienced health professional encounters many interprofessional situations over time; the actions they describe reflect their personal theories about the practice. Hence, it is highly probable that they use them frequently when working with colleagues in clinical settings. Unveiled tacit knowledge was divided into four themes: the importance of a sense of belonging to a team, the imperative to meet face-to-face, the practice of soliciting the working hypotheses of colleagues, and the art of summarizing meeting discussions.     

Quality-of-life trajectory of clients and carers referred to a community palliative care service

Palliative care clients often have a reduced quality of life (QOL). The purpose of this study was to explore the QOL trajectory of clients and carers newly referred to a community palliative care service. A total of 49 clients and 43 carers respectively completed the McGill QOL scale (MQOL) and the caregiver QOL cancer scale (CQOLC) questionnaires. Baseline data relating to demographics, health status, and QOL are presented for the 49 participants and their 43 carers, and these are compared with follow-up data from 22 clients and 13 carers (matched pairs). On average, there were no significant differences between baseline and follow-up QOL scores in any respects for either clients or carers, including measures of burden, disruptiveness, positive adaptation, and financial concerns. Whether this indicates that the care administered succeeded in cancelling out the worsening of the clients' conditions or whether it indicates a shortcoming of the care was not assessed.     

Prevalence of pituitary adenomas: a community‐based,cross‐sectional study in Banbury (Oxfordshire,UK)

Background Pituitary adenomas (PAs) are associated with increased morbidity and mortality. The optimal delivery of services and the provision of care for patients with PAs require distribution of the resources proportionate to the impact of these conditions on the community. Currently, the resource allocation for PAs in the health care system is lacking a reliable and an up‐to‐date epidemiological background that would reflect the recent advances in the diagnostic technologies, leading to the earlier recognition of these tumours. Objectives To determine the prevalence, the diagnostic delay and the characteristics of patients with PA in a well‐defined geographical area of the UK (Banbury, Oxfordshire). Patients and methods Sixteen general practitioner (GP) surgeries covering the area of Banbury and a total population of 89 334 inhabitants were asked to participate in the study (data confirmed on 31 July 2006). Fourteen surgeries with a total of 81,449 inhabitants (91% of the study population) agreed to take part. All cases of PAs were found following an exhaustive computer database search of agreed terms by the staff of each Practice and data on age, gender, presenting manifestations and their duration, imaging features at diagnosis, history of multiple endocrine neoplasia type 1 and family history of PA were collected. Results A total of 63 patients with PA were identified amongst the study population of 81,149, with a prevalence of 77·6 PA cases/100,000 inhabitants (prolactinomas; PRLoma: 44·4, nonfunctioning PAs: 22·2, acromegaly; ACRO: 8·6, corticotroph adenoma: 1·2 and unknown functional status; UFS: 1·2/100,000 inhabitants). The distribution of each PA subtype was for PRLoma 57%, nonfunctioning PAs 28%, ACRO 11%, corticotroph adenoma 2% and UFS 2%. The median age at diagnosis and the duration of symptoms until diagnosis (in years) were for PRLoma 32·0 and 1·5, nonfunctioning PAs 51·5 and 0·8, ACRO 47 and 4·5 and corticotroph adenoma 57 and 7, respectively. PRLoma was the most frequent PA diagnosed up to the age of 60 years (0–20 years: 75% and 20–60 years: 61% of PAs) and nonfunctioning PA after the age of 60 years (60% of PAs). Nonfunctioning PAs dominated in men (57% of all men with PA) and PRLoma in women (76% of all women with PA). Five patients (7·9%) presented with classical pituitary apoplexy, with a prevalence of 6·2 cases/100,000 inhabitants. Conclusions  Based on a well‐defined population in Banbury (Oxfordshire, UK), we have shown that PAs have a fourfold increased prevalence than previously thought; our data confirm that PAs have a higher burden on the Health Care System and optimal resource distribution for both clinical care and research activities aiming to improve the outcome of these patients are needed.     

Macroglobulinémie de Waldenström

Waldenström's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.