Genetics/genomics and drug effects.

Differences in response to medications both in terms of clinical activity and side-effects have long been recognised by physicians. Genetics has been recently considered as a potential factor to explain part of this variability. Pharmacogenetics focuses on the variants within one or more candidate genes while pharmacogenomics evaluates the entire genome for associations with pharmacologic phenotypes. Genetic variants can effect drug metabolism, drug transport or drug targets. Drug metabolism is responsible 1. for the conversion of prodrugs into active compounds or conversion of drug to toxic or inactive metabolites mostly through reactions mostly catalysed by cytochromes (CYP) P450 (phase reactions) and 2. for transforming drugs to compounds that are more water soluble and more easily excreted (phase type II reactions). Genetic polymorphisms can modify the activity of several CYPs such as CYPs, 2D6, 2C9, 2C19 with altered responses to codeine, tamoxifen, clopidogrel, warfarin, ... or of enzymes of the phase II reactions with abnormal responses to drugs like irinotecan, 5-fluorouracil, azathioprine, ... Proteins involved in the transport of drugs in or out the cells such as chemiotherapeutic agenrs, simvastatin, ... can also be affected by genetics. Genetics can also modify drug targets by mutations affecting tumour cells rending these later more or less responsive to drugs. Genetic tests have been launched for screening polymorphisms before giving drugs such as warfarin and several biomarkers are available in oncology. However, many challenges exist. For example, we need more prospective studies to have a better knowledge of the clinical impact and the cost-effectiveness of these tests. It remains that in the future pharmacogenetics/genomics will probably help to personalise medicine by conferring to the clinician the possibility of giving the right drug to the right patients and by this way improving efficacy and safety of medications.

Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury.

BACKGROUND: Urinary calprotectin has recently been identified as a promising biomarker for the differentiation of pre-renal and intrinsic acute kidney injury (AKI). This study compares the diagnostic performance of calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) in this differential diagnosis. METHODS: Urinary calprotectin and NGAL concentrations were assessed in a study population of 87 subjects including 38 cases of intrinsic AKI, 24 cases of pre-renal AKI and 25 healthy controls. Urinary tract obstruction, renal transplantation and metastatic cancer were defined as exclusion criteria. RESULTS: Mean calprotectin concentrations were significantly lower in pre-renal (190.2 ± 205.7 ng mL(-1) ) than in intrinsic AKI (6250.1 ± 7167.2 ng mL(-1) , P < 0.001). Receiver-operating characteristic (ROC) analysis provided an AUC of 0.99. Mean NGAL concentrations were significantly higher in intrinsic than in pre-renal AKI as well (458.1 ± 695.3 vs. 64.8 ± 62.1 ng mL(-1) , P = 0.001) providing an AUC of 0.82. A combination of the present study population with the cohort of the proof of concept study led to a population of 188 subjects (58 pre-renal AKI, 90 intrinsic AKI, 40 healthy controls). ROC analyses provided an AUC of 0.97 for calprotectin and 0.76 for NGAL yielding sensitivity and specificity values of 93.3 and 94.8% (calprotectin) vs. 75.3 and 72.4% (NGAL). Optimal cut-off values were 440 ng mL(-1) (calprotectin) and 52 ng mL(-1) (NGAL). Pyuria increased calprotectin concentrations independent of renal failure. CONCLUSION: This study shows that both calprotectin and NGAL are able to differentiate between pre-renal and intrinsic AKI after exclusion of pyuria. In the present population, calprotectin presents a higher sensitivity and specificity than NGAL.

Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization.

UNLABELLED: Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) levelabove 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). CONCLUSION: The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.

Country of origin predicts nutrition risk among community living older people.

OBJECTIVES: To assess the nutrition risk status of community living older people and to identify associated risk factors. DESIGN: A cross-sectional study using convenience sampling. SETTING: North Shore City, Auckland, New Zealand. Data collection was carried out by a research nutritionist using computer assisted personal interviewing in the participant's own home. PARTICIPANTS: Fifty-one independently living people aged between 80 and 85 years. MEASUREMENT: A survey using three validated questionnaires: Practitioner Assessment of Network Type (PANT) to evaluate social networks; Elderly Assessment System (EASY-Care) to evaluate physical and mental wellbeing and Seniors in the Community: Risk Evaluation for Eating and Nutrition Version II (SCREEN II) to assess nutrition risk. RESULTS: A third of the participants (31%) were at high risk of malnutrition (SCREEN II score <50; range 29-58 out of maximum score of 64). The majority of participants (82%) lived alone and nearly half (47%) had supportive social networks including close relationships with local family, friends and neighbours. Low self-rated health, disability and social factors (being born outside of New Zealand, losing a spouse and loneliness) were key underlying factors associated with being at nutrition risk. CONCLUSION: Nutrition risk is common among aged individuals living in the community. Health and social factors that shape eating behaviours place older people at increased nutrition risk. Strategies are needed for the early identification of risk factors to prevent nutrition problems. Engaging older people at risk to share meal preparation and dining experiences may foster better outcomes.

Influencia de la diabetes mellitus tipo 2 en el deterioro cognitivo en un grupo de adultos mayores / Cognitive decline in diabetic and non-diabetic older subjects

Background: Type 2 diabetes mellitus may be associated with cognitive decline (CD) in older subjects. Aim: To determine if CD is more common among diabetic subjects that their non-diabetic counterparts. Material and Methods: Using a case-control design, 17 diabetic patients with a median age of 73 years (nine females) and 21 non diabetic subjects with a median age of 72 years (17 females), with a similar educational background, were studied. Cognitive status was assessed using the Mini mental State Examination (MMSE), using a cutoff point of 23, and the Frontal Assessment Battery (FAB), that evaluated conceptualization, mental flexibility, motor initiative, sensibility to interference, inhibitory control, and environmental autonomy. The presence of any mental or organic cerebral disease, sensorial impairment or illiteracy were considered exclusion criteria. Results: Fifty nine percent of diabetic subjects and 24 percent of their non-diabetic counterparts, had a MMSE below the cutoff point (p = 0.03). An abnormal FAB was found in 29 and 14 percent of diabetic and non-diabetic subjects, respectively (p = NS). Both tests were abnormal in 29 and 5 percent of diabetic and non-diabetic subjects, respectively (p = 0.05). Conclusions: In this group of subjects, CD was more common among diabetics than their non-diabetic counterparts.

Are ACE-inhibitors or ARB's still needed for cardiovascular prevention in high risk patients? Insights from profess and transcend.

The HOPE and EUROPA clinical studies have shown that treatment with the angiotensin-converting enzyme (ACE) inhibitors, ramipril and perindopril, may reduce the occurrence of major cardiovascular events in patients with proven atherosclerotic disease. The recently published results of the PRoFESS and TRANSCEND trials completed the much needed information concerning the use of an angiotensin receptor blocker for patients at high risk of cardiovascular events. PROFESS compared a therapy of telmisartan 80 mg daily with placebo in patients with a recent ischemic stroke. The difference in the primary outcome of first recurrent stroke was not statistically significant between telmisartan and placebo. The secondary outcome of major cardiovascular events showed a relative risk reduction (RRR) of 7% in favour of telmisartan. This tended to be significant (p = 0.06) despite a rather short follow-up period of only 28 months. In TRANSCEND 5926 patients at high risk for cardiovascular events were randomized to a treatment with telmisartan 80 mg daily or placebo for a mean duration of follow-up of 56 months. The primary composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure showed a non-significant 8% RRR in favour of the telmisartan treated patients. The main secondary outcome of cardiovascular death and myocardial infarction or stroke as used in the HOPE trial showed a non-significant RRR of 13% in favour of telmisartan treated patients (p = 0.068 adjusted for multiplicity of comparisons). In comparing the Kaplan-Meier curves for the endpoint of major cardiovascular events used in HOPE, EUROPA, TRANSCEND and PRoFESS, the trends are similar. Results of most of the recently published trials have been neutral.This could partly be explained by major improvements in the optimal background therapy of the patients included. Nevertheless, the results of PRoFESS and TRANSCEND do not contradict the results from previous studies with theACE inhibitors ramipril and perindopril and the ARB telmisartan.

Diagnostic value of confocal endomicroscopy in celiac disease.

BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.

Generics and cost-effective prescribing in Belgium: does bioequivalence always translate in therapeutic equivalence?

As many other countries, Belgium has a policy to promote the use of generic pharmaceutical products. In order to protect consumers, these generic products must be demonstrated to be essentially similar to the previously approved product, typically an innovator product. The therapeutic equivalence of a generic and an innovator product is most commonly based on the demonstration of bioequivalence, i.e. clinically insignificant differences in the rate and extent of drug absorption usually assessed from pharmacokinetic measurements, in a normal and healthy population. This article reviews the bioequivalence requirements for generic products and examines whether bioequivalence always adequately substantiates therapeutic equivalence and interchangeability. Clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence. There are fears that use of this measure may be inappropriate in the case of a drug with a narrow therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. Bioequivalence issues are discussed together more general concerns about generic drug substitution, such as differences in product and packaging appearance and differences in excipients.

Generics: need for clinical concern?

The market of generic drugs is in continuous development in all countries, including Belgium. Their low cost explains their success in western and developed countries. However, clinical concerns have been raised when generics are used. Indeed, various studies suggest that generic substitution can be associated with reduced efficacy or (and) increased side-effects, particularly with drugs used in severe diseases or pathological states such as epilepsy, cardiac arrhythmia, prevention of graft-rejection, ... The generic drugs must have systemic bioavailability similar to that of the original drug. Thus, they have supposed similar therapeutic bioequivalence. However, similar pharmacokinetics does not imply identical therapeutic activity, particularly with drugs having narrow therapeutic indices such as anti-epileptics, anti-arrythmics ... In this case, switchability rather than prescribability may cause problems. Low pharmaceutical quality is more frequent when drugs are produced in certain countries, in some cases causing a real concern when activity and safety are considered.

In vivo diagnosis of acute intestinal graft-versus-host disease by confocal endomicroscopy.

BACKGROUND AND STUDY AIMS: Conventional histology with hematoxylin and eosin (H&E) staining is the accepted standard for diagnosing acute intestinal graft-versus-host disease (GvHD). Confocal endomicroscopy (CEM) is a noninvasive method that allows in vivo histology to be performed during endoscopy. The aim of this study was to evaluate CEM for the diagnosis of acute intestinal GvHD. PATIENTS AND METHODS: This observational pilot study conducted between September 2006 and August 2008 included patients with acute diarrhea after stem cell transplantation, infectious diarrhea, or active ulcerative colitis. CEM (EC-3870CIFK, Pentax, Tokyo, Japan) was performed after intravenous injection of fluorescein 10% and topical application of acriflavine 0.05%. RESULTS: A total of 35 patients with acute diarrhea after stem cell transplantation were examined. In 16 patients, CEM and histology showed no evidence of GvHD. In 14/19 patients with histologically confirmed GvHD, the diagnosis could already be established by CEM during ongoing endoscopy. In GvHD grade IV, near complete destruction of the colonic crypts ("flat mucosa") was visible. Control patients with infectious colitis (N = 15) or ulcerative colitis (N = 15) displayed inflammatory changes but no evidence of GvHD. Altogether, sensitivity of CEM was 74% and specificity was 100 %. CONCLUSIONS: CEM improves rapid diagnosis of acute intestinal GvHD with high accuracy while performing endoscopy. Platelet transfusions and unnecessary biopsy acquisition can be avoided once acute intestinal GvHD has been diagnosed in vivo.

Adenosis poliquística esclerosante de la glándula parótida / Sclerosing polycystic adenosis of the parotid gland

La adenosis poliquística esclerosante de la parótida (APEP) es una enfermedad infrecuente, caracterizada por elementos histológicos inflamatorios reactivos de las glándulas salivales, pero la presencia de displasia y atiplas hace también posible pensar se trate de un pseudotumor o una neoplasia. La APEP posee además semejanzas histopatológicas con la enfermedad fibroquística de la mama y comparten receptores de progesterona y estrógenos en las células ductales. La edad promedio de ocurrencia de esta patología es de 44,5 años y generalmente afecta las glándulas salivares mayores. Presentamos aquí el caso clínico de una mujer de 25 años de edad que el año 2002 consultó por un aumento de volumen de la parótida derecha, de larga data. Después de estudios diagnósticos y tratamientos fue intervenida quirúrgicamente y el análisis histopatológico sugirió el diagnóstico APEP.

Sclerosing polycystic adenosis (SPA) of the parotid gland is a rare disease characterized histologically by a reactive inflammation of the salivary glands, although the presence of displasia and atypia raise the possibility that SPA might represent a neoplastic lesion. SPA bears histopathological resemblance to fibrocystic disease of the breast, and both glands show progesterone and oestrogen receptors in the ductal cells. The mean age of occurrence is 44.5 year-old, and it mostly affects major salivary glands. We report the case of a 25-years-old woman, who in 2002 presented with increased volume in the right parotid gland. After medical studies and several surgical treatments, the histopathological study revealed it to be SPA.

Epithelial apoptosis is a prominent feature of the epithelial barrier disturbance in intestinal inflammation: effect of pro-inflammatory interleukin-13 on epithelial cell function.

In ulcerative colitis, the T helper type 2 proinflammatory cytokine Interleukin-13 (IL-13) contributes as effector cytokine to the epithelial changes associated with disturbed epithelial barrier function. This study aimed to investigate the underlying mechanisms in a colonic epithelial cell culture model. For studying these epithelial features in response to proinflammatory cytokines epithelial apoptosis was investigated by TdT-mediated X-dUTP nick end labeling (TUNEL) staining in HT-29/B6 cell monolayers. In contrast to interferon-gamma, IL-13 significantly upregulated the apoptotic rate of cells, which was intensified by simultaneous exposure to tumor necrosis factor-alpha. That this has a direct functional influence on epithelial barrier was shown by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp, which inhibited IL-13 induced apoptosis induction and concomitantly reversed the decrease in epithelial resistance by approximately 50%. Direct evidence for apoptotic rosettes at corresponding sites of barrier defects in the epithelium was obtained by conductance scanning. In addition, the pore-forming tight junction protein claudin-2 was found to be upregulated at protein and mRNA level. In conclusion, IL-13 disturbs intestinal barrier function through mechanisms including apoptosis induction and alteration of tight junction protein composition.

Lessons from ONTARGET.

The recently published results of the ONTARGET trial shed a new light on the cardiovascular protection of patients at high risk of a cardiovascular event. Despite a number of trials looking at the efficacy of Angiotensin Converting Enzyme inhibitors (ACEis) or Angiotensin Receptor Blockers (ARBs) in the prevention of cardiovascular events in patients with specific high risk profiles, the question of the equivalence of ACEis and ARBs remained unanswered. The ONTARGET trial has shown that telmisartan 80 mg administered for a median duration of 4.5 years to patients at high risk of developing a major cardiovascular event, is equally effective to ramipril 10 mg. In addition, telmisartan was slightly better tolerated. The comparator ramipril has been chosen as it is currently the gold standard ACEi since the results of the HOPE study, in terms of the composite outcome of cardiovascular death, myocardial infarction and stroke. Moreover, ONTARGET is the first trial to test the hypothesis of superiority of adding an ARB (telmisartan 80 mg) to an ACEi (ramipril 10 mg) over the ACEi ramipril monotherapy in cardiovascular protection of the same broad range of high-risk patients. Surprisingly, despite a more pronounced blood pressure lowering, the combination of the two agents did not lead to an additional decrease in the number of events, but had significantly more side-effects compared to ramipril monotherapy. ONTARGET is a landmark study, performed according to the highest statistical and clinical standards, providing compelling evidence and clear answers to two important clinical questions.

Compartment specific expression of dendritic cell markers in human glomerulonephritis.

Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases.

Restriction of duty hours for residents in internal medicine: a question of quality of life but what about education and patient safety?

Like in other medical specialities, training in internal medicine is confronted with the duty hours regulation. A reduction to a maximum of 48 duty hours has been introduced in Belgium in 1999 for all residents and is still under debate in the European Communities. A reduction of duty hours to a maximum of 80 hours per week was recently adopted in the USA. Several surveys were conducted in this country before and after the introduction of the new system to evaluate its impact on training and patient care. A reduction of duty hours appears to improve the mental health and the security and the quality of life of the trainees. On the other hand, it is suspected that reducing training hours can have a negative effect not only on education but also on patient safety and satisfaction giving the fragmentation of care. This appears to be a key problem, particularly in internal medicine, as it implies more frequent transfers of medical information, a source of medical errors and a loss of responsibility.

[Measuring the contrast-enhancement in the skin and subcutaneous fatty tissue with the NMR-MOUSE: a feasibility study]. / Messung der Kontrastmittelanreicherung in der Haut und im subkutanen Fettgewebe mit der NMR-MOUSE -- eine Machbarkeitsstudie.

PURPOSE: The NMR-MOUSE is an open and mobile sensor for measuring NMR relaxation parameters in organic matters. T1-measurements of the subcutaneous fatty tissue and the skin are reported. MATERIAL AND METHOD: For the first time, the NMR-MOUSE was employed to measure the signal recovery following saturation of the skin and the subcutaneous fatty tissue of three patients, before and after administering a contrast agent. RESULTS: Despite a low signal-to-noise ratio, changes in the relaxation behaviour of the skin could be detected. Malignant tissue exhibits faster signal recovery than scar tissue and healthy tissue, which only show a small difference. CONCLUSIONS: Changes in the relaxation behavior can be monitored with the NMR-MOUSE. Before the clinical use of the NMR-MOUSE, sensitivity, sensor mounting device, and sensor tuning must be improved. Further investigations need to be performed on a statistically relevant number of patients.