SULM – Schweizerische Union für Labormedizin | Union Suisse de Médecine de Laboratoire | Swiss Union of Laboratory Medicine

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Elizabeta Topic

1University Department of Clinical Chemistry, Sisters of Mercy University Hospital, Zagreb, Croatia

Variation in drug metabolism and drug response among individuals of the same body weight and on the same drug dose can be due temporary causes such as transient enzyme inhibition and induction, or permanent causes such as genetic mutation, gene deletion or amplification. A genetic mutation frequency exceeding 1% of a population is considered as a genetic polymorphism. Pharmacogenetic polymorphisms can manifest at the pharmacokinetic and pharmacodynamic levels. The pharmacokinetic level deals with gene polymorphisms that modify the concentrations of drug and its metabolites at the sites of their molecular action (polymorphisms of drug metabolism enzymes, drug transporters), whereas the pharmacodynamic level deals with polymorphisms of the genes associated with drug effect and mechanism of action not related to its concentration (receptors, ion channels). Pharmacogenetics explores the connection between genetic predisposition and drug efficacy, thus allowing for the specific phenotypes to identify. According to drug metabolizing ability, genetic polymorphism is related to three phenotype classes. The extensive drug metabolizer phenotype is characteristic of the normal population; the poor drug metabolizer phenotype is a consequence of mutation and/or deletion of both alleles and is associated with accumulation of specific drug substrates; the ultraextensive drug metabolizer phenotype is a consequence of gene amplification and results in enhanced drug metabolism. Genetic polymorphism of a drug transporter and receptor results in a phenotype characterized by slow and fast drug absorption, and by poor or efficient interaction with receptors.
Examples of specific genes that modify drug response and can presently be used in clinical practice are those encoding for metabolic enzymes of the cytochrome P-450 family: CYP2D6, 2C19 and 2C9; the enzymes N-acetyltransferase 2 (NAT2) and thiopurine methyltransferase (TPMT); and ⓶-adrenoceptors (B2-AR) among receptors.
The pharmacogenetic screening approach in phenotype prediction is based on the identification of alleles showing diagnostic sensitivity greater than 95%, and is performed by PCR amplification, usually followed by restriction endonuclease digestion, or some other identification method, of single nucleotide polymorphism (SNP). The result of this pharmacogenetic study can be used to identify those from a group of patients with the same diagnosis who require higher or lower drug doses, or those who need another drug of the same action which is not the polymorphic gene substrate. The ultimate goal of the pharmacogenetic polymorphism research is development of a pharmacogenetic identity card which, however, requires indepth understanding of the mechanisms of genetic predisposition to undesired reactions, sophisticated SNP mapping technologies, less expensive genotyping methods, and elaboration of appropriate ethics criteria.

N Troillet

1Central Institute of the Valais Hospitals, Sion, Switzerland

Surgical site infection (SSI, formerly surgical wound infection) still represents one of the most common nosocomial infection. It is associated with significant costs, morbidity and mortality. Many means, are used to prevent this feared complication of any surgical procedure. Surveillance, including gathering data, analyzing them, and feeding rates back to the concerned persons while allowing benchmarking with others, constitutes a cornerstone in the fight against nosocomial infections, particularly SSI.
In 1998, a multicentric surveillance program for SSI was initiated in western Switzerland, according to the principles of the U.S. National Nosocomial Infection Surveillance (NNIS) system. As of December 2003 it had included 12’000 interventions from 9 hospitals. The global rate of SSI was 7.4% (colon surgery 20.8%, surgery of the liver and pancreas 13.8%, gastric surgery 10.4%, appendectomy 7.2%, thoracic surgery 3.5%, cholecystectomy 2.6%, herniorraphy 2.1%, and orthopaedic prostheses 1.1%). Forty-two percent of the SSIs necessitated an invasive procedure for drainage. The mean delay from the intervention to the diagnosis of SSI was 11.5 days. Thirty-seven percent of them were diagnosed after discharge, of which 35% had to be re-admitted. The mean length of hospital stay was 24 days for those with SSI (post-discharge diagnoses not included) vs. 6 days for those without SSI (P < .0001). Hospital hygiene committees and surgeons were periodically informed on their own rates and relative risks by intervention, including adjusted comparisons with the others by using multivariate statistical models using the NNIS index, thus allowing to control for factors linked to the patient (score of the American Society of Anaesthesiology, ASA) or the intervention (contamination class, duration). This surveillance program was appreciated, allowed interventions aiming at a better prevention of SSI, and was associated in most of the participating hospitals with a decrease of SSI rates.

H. van Pelt1

1Departmentsof Clinical Chemistry, Leiden University Medical Center, the Netherlands and AZ St Jan, Brugge, Belgium

Point of Care Testing (POCT) has found its place in a lot of different situations. Besides very common selftesting by patients in case of diabetes or pregnancy and decentralized testing in smaller settings by general physicians and in small hospitals, POC apparatus are used more and more within large hospitals e.g. in Intensive Care units, Emergency Rooms or Operation Theatres.
The major advantage of POCT is of course a small turnaround time ( TAT) which offers the possibility to act directly on the laboratory results. A disadvantage is the impossibility to save the results in a proper or efficient way. In most cases the data are lost after some time and not saved in the patients files. Recent developments in ICT make it possible to profit from the advantages of POCT without the major disadvantages. With modern Laboratory Information Systems (LIS) POCT data can be saved and integrated in the patients files with the date and time of analysis. For this purpose bi-directional software connections are necessary with all decentralized apparatus e.g. Bloodgas apparatus. Obviously this needs positive patient identification which can be reached by unique numbers in barcodes suitable for barcode readers. The coupling offers also possibilities for on-distance quality control; the central laboratory can control the working of the decentralized apparatus. In case of real near patient testing e.g. with blood glucose analyzers or handheld bloodgas- and electrolyte-measurement devices the results are transferred to the LIS or HIS after placing the devices in a docking station which is connected to the LIS. A data management system transfers the results to the LIS/HIS and then presentation of the data is possible on paper or on screen.
In conclusion: ICT offers possibilities to shorten the turn-around time and to expand decentralized laboratory analysis without losing data or lack of quality control. Due to appropriate and user-friendly software and apparatus analyses can be carried out by others than lab-technicians.

D.A. Tsakiris1

1Hemostasis Laboratory DCL, University Hospital Basel, Switzerland

Disseminated intravascular coagulation (DIC) is an acquired syndrome of generalized activation of coagulation. It arises in the context of various disorders, sepsis being one of them. Main biological feature of DIC is systemic thrombin generation and fibrin deposition in the microvascular bed leading, when severe, to organ damage and/or multi-organ failure. In sepsis, DIC is triggered by release of tissue factor from various sources, such as monocytes and neutrophils in response to endotoxins. Direct activation of coagulation through bacteria has also been reported. Diagnosis of DIC includes recognition of DIC status as well as risk assessment. The International Society for Thrombosis and Hemostasis (ISTH) has proposed a score (DIC score) for initial diagnosis, based on global coagulation tests. These include platelet count, fibrin degradation products, fibrinogen and prothrombin time. DIC score can distinguish between overt and nonovert DIC. Specific tests can further help assess severity of the syndrome, such as determination of antithrombin III, factor V and protein C levels. New findings have linked coagulation with inflammatory reactions. For example, infusion of activated factor VIIa to humans has been found to increase levels of interleukin –6 and -8, both being inflammatory mediators. In vitro experiments have shown that activated protein C, a natural coagulation inhibitor, can inhibit endotoxin-induced production of tumor necrosis factor-alpha, as well as of interleukin-6 and –8, thus ameliorating inflammatory reactions. D-dimer and protein C levels have been shown to be good prognostic markers in the risk assessment of DIC. Regular laboratory monitoring with a combination of global and specific parameters is crucial in the assessment of severity and prognosis of DIC.

H.F.A. Vasen 1

1 Netherlands Foundation Detection Hereditary Tumours, Leiden, The Netherlands

During the last decade, great progress has been made in molecular genetics. The genes for most of the inherited forms of cancer of the colorectum, breast and prostate have been identified (or localized), and DNA-testing has been implemented in clinical practice on a large scale. The advantage of testing is that people predisposed to cancer can be identified, and may be offered preventative measures. At present, more than 1000 families with hereditary breast cancer (HBC), hereditary colorectal cancer (hereditary nonpolyposis colorectal cancer)(HNPCC), familial adenomatous polyposis (FAP)) and hereditary prostate cancer (HPC) are registered at the national hereditary cancer registry in the Netherlands. Most studies show that the lifetime risk of developing cancer in the various groups is >50%.
An important question is whether the available surveillance programs are effective and will reduce the mortality. Studies in HBC families show that mammography is less effective compared to the national breast screening program. The first results of studies that compare mammography and MRI indicate that the latter is more sensitive. However, currently, the most efficacious way to reduce the cancer risk in HBC is prophylactic surgery. On the other hand, in families with HNPCC regular colonoscopy (1-2 yearly) appears to be effective in reducing the mortality associated with colorectal cancer. Whether surveillance for prostate cancer in HPC leads to an improved survival is subject of an ongoing Dutch surveillance program coordinated by the NFDHT.
The above-mentioned cancer syndromes are only responsible for 5% of the total cancer burden. However, in a larger proportion of cases (10-20%) various genetic factors play a role, as do lifestyle, dietary and other environmental factors. In recent years, an increasing number of polymorphisms have been identified which are more common in the general population and are associated with a slightly (twofold) increased risk of developing cancer. These findings will lead to a better definition of risk groups. It is probable that the current population screening programs ultimately will be replaced by more tailored programs in which the protocol will depend of the cancer risks taking into account the influence of lifestyle and genetic factors.

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