A multicentre, observational study on demographic and disease characteristics of patients seeking care for chronic hepatitis C in Belgium in 2016.

BACKGROUND AND STUDY AIMS: Direct-acting antivirals provide interferon-free treatments for chronic hepatitis C (CHC) virus infection. In Belgium, in 2016, access to these agents was limited to patients with advanced liver fibrosis stages F3 and F4. This study is the first to describe Belgium's patient population ineligible for interferon-free treatment. PATIENTS AND METHODS: This was an observational, cross-sectional, multicentre study that enrolled adult patients with CHC ineligible for interferon-free treatment. Patient data recorded at a single visit included demographic data, disease characteristics, comorbidities, co-medications, treatment status, and laboratory data. RESULTS: Three hundred and three patients from 16 centres in Belgium were included in the statistical analysis. On average, patients were aged 53.5 years and 50.2% were women ; 94.1% had health insurance and 99.0% resided in Belgium. The current hepatitis C virus (HCV) infection was the first infection for 96.0% of patients and the mean time since infection was 20.0 years. Liver fibrosis stage was F0 for 23.7%, F0/F1 or F1 for 38.3%, F1/F2 or F2 for 25.8%, F3 for 7.1%, and F4 for 5.1% of patients ; 28.4% of patients were CHC treatment-experienced. The main reason for ineligibility for interferon-free treatment was lack of reimbursement (84.8%). Other reasons included no treatment urgency or medical decision to wait (27.1%), waiting for future treatment option (8.3%), and no social insurance coverage (3.6%). CONCLUSIONS: This study provides recent data on the CHC patient population and disease characteristics in Belgium that could help medical communities and government agencies manage CHC disease burden.

Prevalence of occlusal pulpar exposure in 110 equine cheek teeth with apical infections and idiopathic fractures.

Examination of 110 cheek teeth (CT) that were clinically extracted (between 2004 and 2008) because of apical infection (n=79; mean dental age 3.5 years) or idiopathic CT fractures (n=31; median dental age 8.5 years), including examinations of transverse and longitudinal sections, showed the apical infections to be mainly (68%) due to anachoresis, with the residual cases caused by periodontal spread, infundibular caries spread, fissure fractures and dysplasia. The idiopathic fracture patterns were similar to previously described patterns. Occlusal pulpar exposure was found in 32% of apically infected CT, including multiple pulps in 27% and a single pulp in 5%. However, 10% of apically infected CT had changes to the occlusal secondary dentine, termed occlusal pitting, but did not have exposure of the underlying pulp. Multiple pulpar exposures occurred in some CT with apical infections, and the combination of pulp involvement reflects the anatomical relationships of these pulps. A higher proportion (42%) of CT extracted because idiopathic fractures had pulpar exposure (26% multiple, 16% single pulps), especially with midline sagittal maxillary and miscellaneous pattern mandibular CT fractures, but only (3%) had occlusal pitting.

Treatment and blood pressure control in isolated systolic hypertension vs diastolic hypertension in primary care.

Cross-sectional surveys on prevalence, treatment and control of hypertension could not satisfactorily distinguish between diastolic hypertension and isolated systolic hypertension because the definition of hypertension included patients under pharmacological treatment. We assessed the situation in the two types of hypertension in general practice in Belgium, based on current blood pressure (BP) measurements and on BP prior to the initiation of drug therapy. Participating physicians enrolled the first 15 at least 55-year-old men visiting the surgery, measured their BP and recorded data on medical history including pretreatment BP, drug utilization, cardiovascular risk factors and target organ damage. Diastolic hypertension was defined as diastolic BP> or =90 mmHg, irrespective of systolic BP, and isolated systolic hypertension as systolic BP > or =140 mmHg and diastolic BP < 90 mmHg. Among 3761 evaluable patients, 74% were hypertensive. Among the 1533 hypertensive patients in whom blood pressure was known prior to treatment (n=965) or who were untreated at the study visit (n=568), 1164 had diastolic hypertension and 369 isolated systolic hypertension. The prevalence of antihypertensive treatment was, respectively, 75 and 25% (P<0.001) in these two types of hypertension. The odds of being treated were independently determined by type of hypertension, severity of hypertension and level of risk (P<0.001). BP was controlled in 25% of all patients with diastolic hypertension and in 13% of all patients with isolated systolic hypertension (P<0.001). About half of the treated patients with systolic hypertension were on a diuretic and/or a calcium-channel blocker. In conclusion, isolated systolic hypertension is less frequently treated than diastolic hypertension, overall BP control is poor and actual drug therapy diverges from recommendations based on placebo-controlled intervention trials.

Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism. Implications for diabetic retinopathy.

PURPOSE: To assess effects of elevated glucose levels on retinal glycolysis and sorbitol pathway metabolism. METHODS: Freshly isolated retinas from normal male Sprague-Dawley rats were incubated for 2 hours at 37 degrees C, pH 7.45, in Krebs bicarbonate-Hepes buffer containing 5, 10, 20, or 30 mM glucose. Glycolytic metabolites, sorbitol, and fructose were measured in extracts of retina and medium. RESULTS: Elevated glucose levels increased retinal levels of sorbitol and triose phosphates, decreased sn-glycerol-3-phosphate levels, increased lactate and fructose production, and increased the retinal lactate-pyruvate ratio (indicative of an increased cytosolic ratio of free NADH-NAD+ like that induced by hypoxia). An inhibitor of aldose reductase (AL 4114) normalized sorbitol, fructose, triose phosphates, and the lactate-pyruvate ratio without affecting lactate production or sn-glycerol 3-phosphate levels. CONCLUSIONS: Elevation of retinal glucose levels causes a hypoxia-like redox imbalance "pseudohypoxia" that results from increased oxidation of sorbitol to fructose in the second step of the sorbitol pathway. This redox imbalance provides a plausible explanation for impaired regulation of retinal blood flow (in the absence of vascular structural changes) in humans with diabetes and in nondiabetic acutely hyperglycemic animals. These findings, together with other observations, suggest that this redox imbalance precedes, and may contribute to, hypoxic and ischemic retinopathy associated with diabetes.

Inhibition of sorbitol dehydrogenase. Effects on vascular and neural dysfunction in streptozocin-induced diabetic rats.

These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.

Effect of chronic graft-versus-host disease on the intestine in adult BDF1 mice.

This study was performed to characterize the intestinal lesions in chronic graft-versus-host disease (GVHD) in mice and to determine a possible role of intestinal intraepithelial lymphocytes (ilEL) in the development of these lesions. Chronic GVHD was induced by transfer of DBA/2 lymphocytes into non-irradiated (C57BL/10 x DBA/2)F1 (BDF1) recipients. There was mild to moderate mucosal oedema with multifocal mixed inflammatory cell infiltrations in the small intestine. The caecum was more severely affected with severe oedema, progressive loss of crypts and severe distortion of the mucosal architecture. The total number of ilEL did not change during the development of chronic GVHD, but there were alterations in the composition of the ilEL population. An increase of CD3+, Thy-1+ cells was accompanied by an increase of TCR alpha beta + cells and a decrease of TCR gamma delta + cells. There was no evidence of infiltration of donor lymphocytes into the intestinal epithelium as determined by the H2K haplotype of the ilEL. These lesions differ from previously described models of chronic GVHD, induced by DBA/2 donor lymphocytes in BDF1 recipients. We suggest that the haemopoietic organs that are used as the source of donor lymphocytes determine the outcome of the GVHD. Modulation of the composition of the donor lymphocyte population may be useful in the establishment of relevant animal models of human enteropathy.

Hyperglycemic pseudohypoxia and diabetic complications.

Vasodilation and increased blood flow are characteristic early vascular responses to acute hyperglycemia and tissue hypoxia. In hypoxic tissues these vascular changes are linked to metabolic imbalances associated with impaired oxidation of NADH to NAD+ and the resulting increased ratio of NADH/NAD+. In hyperglycemic tissues these vascular changes also are linked to an increased ratio of NADH/NAD+, in this case because of an increased rate of reduction of NAD+ to NADH. Several lines of evidence support the likelihood that the increased cytosolic ratio of free NADH/NAD+ caused by hyperglycemia, referred to as pseudohypoxia because tissue partial pressure oxygen is normal, is a characteristic feature of poorly controlled diabetes that mimics the effects of true hypoxia on vascular and neural function and plays an important role in the pathogenesis of diabetic complications. These effects of hypoxia and hyperglycemia-induced pseudohypoxia on vascular and neural function are mediated by a branching cascade of imbalances in lipid metabolism, increased production of superoxide anion, and possibly increased nitric oxide formation.

Phenotype of intraepithelial lymphocytes in euthymic and athymic mice: implications for differentiation of cells bearing a CD3-associated gamma delta T cell receptor.

This study was carried out to determine the exact phenotype of intraepithelial lymphocytes (IEL) in euthymic and athymic nude mice. The phenotype of IEL in euthymic and athymic mice is mainly CD3+CD8+. However, based on Thy-1- and CD3-associated receptor expression we can subdivide the CD3CD8 population into different subpopulations in euthymic and athymic mice. In euthymic and athymic mice several CD3CD8 populations can be defined. One population expressing Thy-1 and the T cell receptor (TcR) alpha beta is absent in athymic mice. Two other CD3+CD8+ populations can be detected in euthymic and athymic mice. Based on Northern blot and flow cytometric analysis we have to conclude that these populations express the CD3-associated TcR gamma delta. One of the TcR gamma delta-expressing populations also expresses Thy-1 at low surface density. This is in contrast to the CD3CD8 population expressing the TcR alpha beta, which expresses Thy-1 at high surface density. There are also, however, especially in athymic nude mice, significant numbers of CD3-CD8+ cells present with the same localization as IEL. The function of these cells is yet unknown. Using a probe for the delta chain we have shown that IEL preferentially express 2-kb mRNA, while nearly no delta chain 1.7-kb mRNA is expressed by these cells. This is in contrast to delta mRNA in thymocytes. Equal quantities of the 1.7- and 2.0-kb delta chain mRNA species were found in RNA isolated from thymocytes. The results imply that CD3+CD8+ intestinal IEL expressing the CD3-associated TcR gamma delta can differentiate in absence of the thymus and represent a thymus-independent lineage of cells bearing this receptor.

Localization and phenotype of CD3 associated gamma/delta receptor expressing intestinal intraepithelial lymphocytes.

This study was carried out to determine the exact phenotype and localization of intestinal intra epithelial lymphocytes (IEL). IEL reside in the small intestine between or just beneath the epithelial cell layer which covers the lamina propria. These CD3 positive cells were found in equal numbers at this location both in the villi as well as in the crypts. The majority of these cells express a CD3 associated gamma delta receptor. Cell surface marker analysis of isolated IEL reveals high percentages of cells expressing CD8 and/or Thy-1. No CD4 positive cells could be detected in significant numbers. Equal quantities of IEL could be isolated from the intestine of athymic (nude) mice. Although the percentage of CD3 positive cells in the IEL from nude mice was lower than the figures obtained from euthymic mice northern blot analysis revealed a strong expression of gamma delta message in the IEL of nude mice. In the CD3 positive IEL fraction of nude mice the relative contribution of the CD8 positive cells remained unchanged, whereas the percentage of Thy-1 positive cells had decreased. Still significant numbers of such cells could be demonstrated in the IEL of nude mice. Altogether these results show that, at least, a significant part of the gamma delta receptor bearing IEL is independent of the thymus for their differentiation.