Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study.

BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.

[Myositis-specific antibodies associated with juvenile dermatomyositis]. / Myositisspezifische Antikörper bei juveniler Dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune disease associated with typical skin changes and muscle weakness. Within the framework of the diagnostics, myositis-associated (MAA) and myositis-specific antibodies (MSA) can be detected. These are important for the assessment of the course of the disease and the prognosis. METHOD: In this study we searched for MAA and MSA by means of a line immunoassay in 12 currently supervised JDM patients in the Rheumatism Center Sankt Augustin. RESULTS: In 10 of the 12 patients a total of 15 myositis antibodies were detected where 3 patients each had Mi2, SRP or NXP2 antibodies, 2 had TIF-1γ antibodies and Jo1 or Mi2ß antibodies were found in 1 patient each. Of the patients two had additional PM-Scl antibodies. In the 10 patients with detected antibodies, a good phenotype-serotype correlation was found with deviation from the phenotypes described in the literature in only 3 patients. CONCLUSION: The frequent detection of certain antibodies and the good correlation with those phenotypes described in the literature, show that the determination of MSA is an important diagnostic tool to assess the course, complications and outcome and to initiate adequate therapy at an early stage.

Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is presented by a large heterogeneity of clinical phenotypes. Around 50% of patients suffer from typical CIDP and show better therapy response than atypical variants. The goal of our study was to search for cellular immunological differences in typical versus atypical CIDP in comparison to controls. METHODS: We evaluated 26 (9 typical, 17 atypical) patients with mainly active-unstable CIDP using clinical and immunological examinations (enzyme-linked immunospot assay ELISPOT, fluorescence-activated cell sorting FACS) in comparison to 28 healthy, age-matched controls (HC). Typical or atypical CIDP measurements were compared with HC using Kruskal-Wallis test. RESULTS: Atypical CIDP patients showed increased frequencies of T cell subsets, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM) as well as a tendency of higher T cell responses against the peripheral myelin antigens of PMP-22, P2, P0 and MBP peptides compared to typical CIDP. Searching for novel auto-antigens, we found that T cell responses against P0 180-199 as well as MBP 82-100 were significantly elevated in atypical CIDP patients vs. HC. CONCLUSIONS: Our results indicate differences in underlying T cell responses between atypical and typical CIDP characterized by a higher peripheral myelin antigen-specific T cell responses as well as a specific altered CD4+ memory compartment in atypical CIDP. Larger multi-center studies study are warranted in order to characterize T cell auto-reactivity in atypical CIDP subgroups in order to establish immunological markers as a diagnostic tool.

Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).

Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA.

Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta.

Tolerance of monocytes/macrophages to endotoxin (lipopolysaccharide [LPS]) can be induced both in vivo and in vitro by LPS itself. Exposure to LPS, even at a very low dose, induces a downregulation of cytokine response to a second high dose LPS challenge. To learn more about the unknown mechanisms of this phenomenon, we studied the role of antiinflammatory cytokines in this process. Preculture of human peripheral blood monocytes for 24 hours with low concentrations of LPS induced hyporesponsiveness to high-dose LPS rechallenge with respect to tumor necrosis factor (TNF) alpha and interleukin (IL) 10 but not IL-1RA production. These results suggest that LPS tolerance reflects a functional switch of monocytes rather than a general LPS hyporesponsiveness. IL-10 and transforming growth factor (TGF) beta 1 showed additive effects in replacing LPS for induction of LPS hyporesponsiveness in vitro. Additionally, neutralizing anti-IL-10 and anti-TGF-beta monoclonal antibodies prevented induction of LPS tolerance. In vitro induced LPS tolerance looks like the ex vivo LPS hyporesponsiveness of monocytes from septic patients with fatal outcome: downregulation of LPS-induced TNF-alpha and IL-10 production but not of IL-1RA secretion. LPS hyporesponsiveness in septic patients was preceded by expression of IL-10 at both the mRNA and protein level. In summary, our data suggests that IL-10 and TGF-beta mediate the phenomenon of LPS tolerance in vitro and perhaps in vivo (septic patients), too.

Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial.

UNLABELLED: Infections are a leading cause of death in patients with acute CNS injury such as stroke. Recent experimental evidence indicated that stroke leads to suppression of innate and adaptive peripheral immune responses which predisposes to infection. However, less is known on phenotypic and functional immune alterations in correlation with the occurrence of infectious complications in patients with acute stroke. EXPERIMENTAL PROCEDURES: In the recently completed randomized, double blind, placebo-controlled Preventive Antibacterial Therapy in Stroke (PANTHERIS) trial on the efficacy of short-term antibacterial therapy to prevent the development of post-stroke infections, we assessed longitudinal changes in lymphocyte subpopulations and mitogen-induced lymphocytic interferon gamma (IFN)-gamma production using flow cytometry in 80 patients with acute severe stroke at days 1, 3, 8, 90 and 180 after clinical onset. Plasma interleukin (IL)-6 and IL-10 concentration as well as urinary levels of norepinephrine and cortisol was assessed within the first 8 days after stroke. Patients of the placebo and verum (moxifloxacin) treatment groups who did or did not develop infections within 11 days after stroke were compared to identify immunological changes associated with the occurrence of post-stroke infections. RESULTS: Rapid T-lymphopenia and long-lasting suppression of lymphocytic IFN-gamma production were observed in all stroke patients. Patients of the placebo group who developed infections showed a trend toward greater decline of CD4+ Th cell counts and higher urinary levels of norepinephrine early after stroke than patients without infections. Onset of infections was accompanied with higher plasma IL-6 levels in the placebo group but not in the moxifloxacin group. In addition, an early rise in plasma IL-10 was detected in patients who developed infections despite preventive antibacterial treatment. CONCLUSION: A rapid loss and functional deactivation of T cells are common changes in stroke patients consistent with immunodepression after brain ischemia. A stronger decrease in cellular immune responses and an increased sympathetic activity after stroke are associated with a higher risk of infections. Increased plasma levels of the anti-inflammatory cytokine IL-10 early after stroke may identify patients who will not respond to preventive antibacterial therapy with moxifloxacin.

Delayed onset of (severe) combined immunodeficiency (S)CID (T-B+NK+): complete IL-7 receptor deficiency in a 22 months old girl.

BACKGROUND: Usually IL-7 receptor deficiency presents as (T-B+NK+) (Severe) Combined Immunodeficiency (SCID) within the first six months of life. All published IL-7R-deficient patients so far have been diagnosed and received stem cell transplantation within the first year of life. PATIENT AND METHODS: We present a female patient born to non-consanguineous German parents with delayed manifestation. She presented with superinfected dermatitis at 6 months of life and developed a first pneumonia at age 9 months. On admission to our department at 22 months the patient presented with severe T cell lymphopenia. PNEUMOCYSTIS JIROVECI pneumonia was diagnosed from broncho-alveolar lavage fluid. RESULTS: Sequencing of IL7RA in the patient revealed compound heterozygous mutations. FACS analysis showed no expression of IL-7 receptor alpha-chain on the patient's lympho- and monocytes. The patient successfully received haematopoietic stem cell transplantation from a 9/10 matched unrelated donor at age 24 months. CONCLUSION: [corrected] Despite almost absent T cell functions clinical symptoms occurred late compared to previously published patients. Thus even in patients with moderate clinical symptoms and delayed onset a (T-B+NK+) (Severe) Combined Immunodeficiency ((S)CID)) due to missing IL-7 receptor signalling must be considered.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis.

OBJECTIVES: The heritability of RA has been estimated to be approximately 55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. METHODS: Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404-carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. RESULTS: Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. CONCLUSIONS: The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease.

BACKGROUND: The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. AIMS: To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. PATIENTS AND METHODS: Three hundred eighty-eight German IBD patients [244 with Crohn's disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype-phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. RESULTS: Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (chi(2) = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (chi(2) = 16.054, df = 8, p = 0.034 for age at diagnosis >or=25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 - 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (chi(2) = 16.101, df = 6, p = 0.017 for age at diagnosis >or=25). No association of MDR1 genotypes with disease subgroups in CD was observed. CONCLUSIONS: While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.

Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant--463A of the myeloperoxidase gene.

Myeloperoxidase (MPO), an enzyme that is highly expressed in neutrophil leukocytes, transforms precarcinogens such as benzo(a)pyrene and aromatic amines to highly reactive intermediates. A G/A polymorphism located 463 bp upstream of exon 1 in the promoter region strongly reduces MPO mRNA expression. In a matched case-control study, 196 lung cancer, 245 laryngeal cancer, and 255 pharyngeal cancer patients from the Berlin area were investigated for frequency of the G-463A polymorphism by PCR/RFLP, using AciI. They were matched by age and gender to hospital patients without known malignancies. Moreover, 270 healthy volunteers were genotyped, obtaining 61.1% of individuals with MPO genotype -463G/G, 34.8% of individuals with genotype G/A, and 4.1% of individuals with genotype A/A. In lung and laryngeal cancer patients, but not in pharyngeal cancer patients, mutant genotypes were significantly less frequent. Crude odds ratios for carriers of one or two A alleles, compared to wild-type G/G, were 0.58 [95% confidence interval (CI), 0.38-0.88; P = 0.011] for lung cancer patients, 0.63 (95% CI, 0.43-0.92; P = 0.017) for laryngeal cancer patients, and 0.82 (95% CI, 0.57-1.17; P = 0.27) for pharyngeal cancer patients. The relative risks, adjusted for age, gender, and extent of cigarette smoking were 0.47 (95% CI, 0.28-0.79; P = 0.004), 0.66 (95% CI, 0.44-1.01; P = 0.054), and 0.75 (95% CI, 0.51-1.12; P = 0.16) for lung, larynx, and pharyngeal cancer, respectively. Strikingly, relative risk for carriers of -463A among adenocarcinoma of the lung was 0.24 (95% CI, 0.10-0.58; P = 0.002). Two cases with larynx cancer, one case with lung cancer, and one reference subject displayed novel G/A mutations at -297 nucleotide and -296 nucleotide, destroying a constitutive AciI cleavage site. Our data finally suggest that the MPO -463A variant is a protective factor in the etiology of lung and larynx cancer, but possibly not of pharyngeal cancer.

Reduced procedural risk for coronary catheter interventions in carriers of the coagulation factor VII-Gln353 gene.

OBJECTIVES: We have focused on the role of coagulation factor VII (FVII) Arg353Gln polymorphism as a risk predictor of complications following percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA), and stenting. BACKGROUND: The FVII Arg353Gln mutation decreases FVII activity, and presence of the Gln353 allele could be protective against thrombus formation during catheter interventions. METHODS: A total of 666 consecutive patients with coronary artery disease who had undergone PTCA (n = 280), DCA (n = 104), or stenting (n = 282) were followed up for a 30-day composite end point, which included need for target vessel revascularization, myocardial infarction, and death. The Arg353Gln polymorphism of FVII was determined by PCR/RFLP assay. RESULTS: Carriers of the Gln353 allele had significantly lower levels of total FVII activity (FVIIc, -20.7%, p < 0.001) and of activated circulating FVII (FVIIa, -32.7%, p = 0.03) compared with Arg353/Arg353. The composite end point occurred in 43 patients: 4 were heterozygous Arg353/Gln353, and 39 were homozygous Arg353/Arg353. The incidence of the composite end point was 2.5% in carriers of the Gln353 allele and 7.7% in Arg353/Arg353 homozygotes (p = 0.013). This corresponds to a 72% risk reduction in carriers of the Gln353 allele (relative risk: 0.28; 95% confidence interval: 0.09-0.81; p = 0.02). CONCLUSIONS: The Gln353 allele of FVII is associated with substantial risk reduction in adverse events that complicate coronary catheter interventions. With the perspective of active site-blocked activated FVII (FVIIai) as conjunctive medication, the results suggest that the FVII genotype should be taken into due consideration in assessment of FVIIai medication and of its dosage.

Role of Kozak sequence polymorphism of platelet glycoprotein Ibalpha as a risk factor for coronary artery disease and catheter interventions.

OBJECTIVES: We sought to determine the role of the -5T/C polymorphism of the platelet glycoprotein (GP) Ibalpha as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention. BACKGROUND: The platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The -5T/C polymorphism of GP Ibalpha is associated with increased receptor density. METHODS: We genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death. RESULTS: Carriers of the -5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The -5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029). CONCLUSIONS: The -5C allele of the GP Ibalpha Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA.

Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.

BACKGROUND: P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. OBJECTIVE: We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers. METHODS: In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. CONCLUSION: This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.

Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C). The frequencies were *1: 36.4 and 34.4%; *2: 30.8 and 32.3%; and *3: 32.8 and 33.3%, in cases and controls, respectively. Only one patient was heterozygous for 1317C. None of the six resulting genotypes showed significant influence on tHcy levels. Moreover, there was no significant association with CAD risk or with disease severity or early disease manifestation. In the subgroup presenting with acute coronary syndromes, MTHFR genotypes *2/*3 and *3/*3 were surprisingly underrepresented (relative risk of *3/*3, 0.40; 95% confidence interval 0.20-0.79, P=0.009). We conclude from our genotype-based analysis that, in this well-fed Middle-European population, the observed common allelic variants of the MTHFR gene have no significant influence on tHcy levels or on the chronic process of CAD development.

Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment.

The current use and future perspectives of molecular genetic characterisation of cytochrome P450 enzymes (CYP) for drug development and drug treatment are summarised. CYP genes are highly polymorphic and the enzymes play a key role in the elimination of the majority of drugs from the human body. Frequent variants of some enzymes, CYP2A6, 2C9, 2C19 and 2D6, should be analysed in participants of clinical trials whenever these enzymes may play a role. It is suggested that a CYP genotype certificate is handed out to the volunteers or patients to avoid replicate analyses, and to allow that this information is available for future research and also for treatment with eventually needed drugs. Guidelines on what CYP alleles have to be analysed in drug development, as well as on analytical validation and CYP genotype data handling will be required. Treatment with several drugs may be improved by prior genotyping. The concepts and problems of CYP genotype-based clinical dose recommendations are presented and illustrated for selected drugs. The requirement for prospective trials on the medical and economic benefits of routine CYP genotyping is emphasised. Specific operationally defined recommendations dependent on genotype are a prerequisite for such studies and this review presents tentative CYP genotype-based dose recommendations systematically calculated from published data. Because of the multiplicity of factors involved, these doses will not be the optimal doses for each given individual, but should be more adequate than doses generally recommended for an average total population. Those CYP alleles and polymorphically metabolised drugs which are currently most interesting in drug development and drug treatment are reviewed, and more complete information is available from websites cited in this article.

The beta3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease.

There is some evidence that the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) is associated with atherogenic risk factors that include weight gain, insulin resistance, and diabetes. The objective of this cross-sectional study was to investigate the relationship between the Trp64Arg polymorphism and coronary artery disease (CAD). A total of 1,000 consecutive patients with angiographically confirmed CAD and 1,000 controls, carefully matched for age and sex, were genotyped for the Trp64Arg polymorphism by polymerase chain restriction and subsequent restriction fragment length polymorphism analysis. Among cases with CAD, 83.3% were wild-type Trp/Trp, 15.8% were heterozygotes, and 0.9% were homozygous Arg/Arg compared with 82.3%, 17.3%, and 0.4%, respectively, among controls (P = .27). The odds ratios for the presence of Trp/Arg and Arg/Arg in cases and controls were 0.90 (95% confidence interval [CI] 0.7 to 1.2; P = .40) and 2.2 (95% CI 0.7 to 7.2; P = .17), respectively. There was no effect modification by gender and atherogenic risk factors, including diabetes, hypercholesterolemia, hypertension, and smoking. Furthermore, there was no evidence of an association with premature disease onset (< 40 years) or extent of disease. In conclusion, the results of this study in a large sample of clinically well-characterized patients indicate that neither the Trp/Arg nor the Arg/Arg genotype represents a major risk factor for angiographically confirmed coronary artery disease.

Selective neurogenic blockade and perioperative immune reactivity in patients undergoing lung resection.

OBJECTIVE: This double-blind, prospective, randomized, controlled trial examined the effects of thoracic epidural block and intravenous clonidine and opioid treatment on the postoperative Th1/Th2 cytokine ratio after lung surgery. The primary endpoint was the interferon γ (IFN-γ; Th1 cytokine)/interleukin 4 (IL-4; Th2 cytokine) ratio. Secondary endpoints were reductions in pain and incidence of pneumonia. METHODS: Sixty patients were randomized into three groups to receive remifentanil intravenously (remifentanil group, n=20), remifentanil and clonidine intravenously (clonidine group, n=20), or ropivacaine epidurally (ropivacaine group, n=20). Pain was assessed using a numerical rating scale (NRS). Cytokines were measured using a cytometric bead array. RESULTS: Patients in the ropivacaine group (thoracic epidural block) had a significantly lower IFN-γ/IL-4 ratio at the end of surgery than those in the remifentanil group and clonidine group. There were no significant between-group differences in the IFN-γ/IL-4 ratio at other time-points. There were no differences in NRS scores at any time-point. No patient developed pneumonia. CONCLUSION: Intraoperative thoracic epidural block decreased the IFN-γ/IL-4 ratio immediately after lung surgery, indicating less inflammatory stimulation during surgery.