Sonomorphologic Changes in Colorectal Deep Endometriosis: The Long-Term Impact of Age and Hormonal Treatment.

PURPOSE: The progression of deep endometriosis (DE) in women of reproductive age is highly variable. This study aimed to analyze the sonomorphological changes of rectal endometriosis over long periods of time and the influence of hormonal treatment. METHODS: This retrospective study included premenopausal women with rectal DE treated conservatively between 2002 and 2021. The lesion length and thickness of the nodule were evaluated at regular intervals over time. We created statistical models with mixed effects to identify potential factors influencing lesion progression and regression. RESULTS: 38 patients were monitored over a mean period of 7.2 (± 4.2) years with a mean of 3.1 (± 2.1) check-ups within the observation period. We detected a significant increase in lesion length until the end of the fourth decade of life. In addition, we found a substantial decrease in the length and thickness of the nodule depending on the length of hormonal treatment. CONCLUSION: In conservatively managed patients with rectal endometriosis, without hormonal therapy, lesion size can exhibit a moderate increase up to the end of the fourth decade of life, after which it appears to stabilize. This increase does not follow a linear pattern. Hormonal therapy is crucial in impeding further progression, resulting in either a cessation or a regression of lesion growth.

Physician-guided, hybrid genetic testing exerts promising effects on health-related behavior without compromising quality of life.

Genetic risk analysis is increasingly in demand by participants. Hybrid genetic testing has the advantage over direct to consumer testing by involving a physician who guides the process and offers counseling after receiving the results. The objective of this study was to determine whether a structured physician moderated primary preventive, hybrid genetic risk assessment enhanced counseling program leads to improvement in lifestyle and does not impair quality of life. Risk genes for malignant, cardiovascular, coagulation, storage diseases and pharmacogenetics (> 100 genes) were tested. Screening, consultation and genetic counseling embedded in a primary/secondary prevention check-up program for executives of surrounding companies took place in a single center in Germany. Follow-up included established questionnaires for quality of life, nutrition and physical activity. Analysis included n = 244 participants. Median age at baseline was 49 years (interquartile range: 44-55), 93% were male, 3% (n = 7 of 136 responses) were smoker. Mean body mass index was 25.2 kg/m2. Follow-up response rate was 74% (n = 180), mean follow-up time was 6.8 months (standard deviation = 2.1). In 91 participants (37.8%, 91/241) at least one pathogenic variant was found, 60 thereof were clinically relevant (24.9%, 60/241). 238 participants (98%, 238/241) had > 1 pharmacogenetic variant, only 2 (0.8%, 2/241) took a correspondingly affected drug (56 participants took ≥ 1 drug/day). The energy expenditure significantly increased by ≈ 35% [median multiple of energy expenditure of 1.34 (confidence interval = 1.15-1.57, p < 0.001)] metabolic equivalents of task (MET)-min/week; participants spent on average 41 min (p < 0.001) less in sedentary activities per day and spent more time for lunch (≈ 2 additional minutes/day; p = 0.031). Indicators of the consumption of red meat and sweet pastries significantly decreased (both adjusted p = 0.049). Neither quality of life in general nor subgroup analysis of participants with at least one conspicuous genetic risk differed significantly over follow-up. Hybrid genetic testing and counseling exerted positive effects on health-related behavior and was not associated with major psychological adverse effects in the short-term follow-up. The approach seems to be feasible for use in preventive health care.

Urinary [TIMP-2]·[IGFBP7]-guided randomized controlled intervention trial to prevent acute kidney injury in the emergency department.

BACKGROUND: Early detection and prevention of acute kidney injury (AKI) is important to reduce morbidity and mortality. Discovery of early-detection biomarkers has enabled early preventive approaches. There are no data on early biomarker-guided intervention with nephrological consultation in emergency departments (EDs). METHODS: In this prospective randomized controlled intervention trial, patients at high risk for AKI were screened with urinary [TIMP-2]·[IGFBP7] in the ED of Robert-Bosch-Hospital (Stuttgart, Germany). We screened 257 eligible patients of whom 100 met the inclusion criteria, with urinary [TIMP-2]·[IGFBP7] >0.3, and were included. The intervention group received immediate one-time nephrological consultation after randomization, implementing Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommendations on AKI. The primary outcome was the incidence of moderate to severe AKI within the first day after admission. Secondary outcomes were AKI occurrence within 3 days after admission, need for renal replacement therapy (RRT), length of hospital stay and death. RESULTS: The primary outcome did not differ significantly (P = 0.9) between the groups, neither within the first day nor within the first 3 days after admission. The intervention group had significantly (P < 0.05) lower serum creatinine (SCr) on Day 2 and lower maximum SCr and tended (P = 0.08) to have higher urine output (UOP) at Day 3 than the non-intervention group. No patient in the intervention group needed RRT (0 versus 3) during the hospital stay (P = 0.09). CONCLUSIONS: One-time routine nephrologist-guided application of the KDIGO bundle in ED patients with a risk for AKI cannot currently be recommended. However, due to the uniform trend of study endpoints in favour of intervention, further trials to investigate larger cohorts of more severely ill patients are warranted. TRIAL REGISTRATION: www.ClinicalTrials.gov, study number NCT02730637.

Impact of an in-Hospital Patient Education Program on Choice of Renal Replacement Modality in Unplanned Dialysis Initiation.

BACKGROUND/AIMS: Up to 50% patients requiring dialysis receive an urgent, unplanned start (UPS) to renal replacement therapy (RRT). Most of these are initiated with an intravenous catheter and commenced and maintained on hemodialysis (HD). Although peritoneal dialysis (PD) could be an equipotent initial modality for RRT, it is used less frequently as long-term RRT in UPS patients. This multicenter-study aimed to evaluate the impact of a structured, in-hospital education program and factors influencing PD rates, especially in UPS patients. METHODS: Three German nephrology departments collaborated to implement an in-hospital education program. Retrospective analysis included 336 subjects and compared the rates of HD and PD in consecutive patients who started RRT 12 months prior (two centers) and for 12 months after (three centers) implementing the education program. RESULTS: PD rates increased significantly (p < 0.05) by 66% in all planned and unplanned dialysis starts after implementation of a structured, patient-centered education program. A highly significant (p < 0.0001) rise in utilization of PD was found, especially in UPS patients. In logistic regression analysis, PD modality choice was significantly influenced by age (p < 0.0001) and gender (p = 0.006). CONCLUSIONS: A structured, patient-centered in-hospital education program increases the frequency of PD in patients needing unplanned RRT. PD modality choice is significantly higher in young (p < 0.0001) and male (p = 0.006) patients.

Renal effects of metallothionein induction by zinc in vitro and in vivo.

BACKGROUND: Metallothionein (MTT) is an endogenous antioxidant that can be induced by both zinc (Zn) and ischemia. In kidneys, increased MTT expression exerts a putative protective role in diabetes and hypoxia. Our goal was to further investigate the behavior of MTT under the influence of Zn and hypoxia in vitro and in vivo. METHODS: MTT expression was measured in vitro in cell cultures of proximal tubular cells (LCC-PK1) by immune-histochemistry and real-time PCR after incubation with increasing concentrations of Zn under hypoxic and non-hypoxic conditions. In addition, in vivo studies were carried out in 54 patients to study MTT induction through Zn. This is a sub-study of a prospective, randomized, double-blind trial on prevention of contrast-media-induced nephropathy using Placebo, Zn and N-Acetylcysteine. Blood samples were obtained before and after 2 days p.o. treatment with or without Zn (60 mg). ELISA-based MTT level measurements were done to evaluate the effects of Zn administration. For in vivo analysis, we considered the ratio of MTT to baseline MTT (MTT1/MTT0) and the ratio of eGFR (eGFR1/eGFR0), correspondingly. RESULTS: In vitro quantitative immuno-histochemical analysis (IHC) and real-time PCR showed that at increasing levels of Zn (5, 10, and 15 µg/ml) led to a progressive increase of MTTs: Median (IQR) expression of IHC also increased progressively from 0.10 (0.09-0.12), 0.15 (0.12-0.18), 0.25 (0.25-0.27), 0.59 (0.48-0.70) (p < 0.0001). Median (IQR) expression of PCR: 0.59 (0.51-1.72), 1.62 (1.38-4.70), 3.58 (3.06-10.42) and 10.81 (9.24-31.47) (p < 0.0001). In contrast, hypoxia did not change MTT-levels in vitro (p > 0.05). In vivo no significant differences (p = 0.96) occurred in MTT-levels after 2 days of Zn administration compared with no Zn intake. Nevertheless, there was a significant correlation between MTT (MTT1/MTT0) and eGFR (eGFR1/eGFR0) in case of Zn administration (rho = -0.49; 95%-CI: -0.78 to -0.03; p = 0.04). CONCLUSIONS: We found that Zn did induce MTTs in vitro, whereas hypoxia had no significant impact. In contrast, no significant increase of MTTs was detected after in vivo administration of Zn. However, there was a significant negative correlation between MTT and eGFR in vivo in case of Zn administration, this could indicate a protective role of MTTs in a setting of reduced kidney function, which is possibly influenced by Zn. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00399256 . Retrospectively registered 11/13/2006.

Smoking Is a Risk Factor for Severe Acute Kidney Injury in Hantavirus-Induced Nephropathia Epidemica.

BACKGROUND/AIMS: Hantaviruses are zoonotic pathogens causing emerging diseases worldwide. Patients typically present with fever, acute kidney injury (AKI) and thrombocytopenia. Puumala virus (PUUV) that causes nephropathia epidemica (NE) is common in Germany. Recently, a study from Finland revealed an association between nicotine consumption and the severity of AKI in NE. Differences between individuals in Finland and Germany might modulate the effect; therefore, the aim of our study was to prove that smoking is a risk factor for a severe course of NE in Germany. METHODS: A cross-sectional prospective survey of 485 patients with hantavirus infections was performed. Clinical and laboratory data during the acute course of the disease were obtained from medical reports and files, while follow-up (including smoking status) data were collected prospectively. RESULTS: Smoking information was available for 298 out of 485 patients (61%). Male was the predominant gender (67%), median age at the time of diagnosis was 50 (interquartile range, IQR 41-60) years and 34% of patients were current smokers during the phase of acute NE. Patients in the smoking group were significantly younger than in the non-smoking group (p < 0.0001). Peak serum creatinine levels were significantly higher in the smoking group than in the non-smoking patients (median 301 (IQR 186-469 µmol/l) vs. median 240 (IQR 137-469 µmol/l), p < 0.05). In addition, severe AKI (stages 2 and 3 using KDIGO criteria) was more common in current smokers (80%) than in the non-smokers (68%, p < 0.05). CONCLUSION: Current smoking is a risk factor for severity of AKI in patients with acute PUUV infection in Germany. Therefore, information about smoking habits needs to be an integral part of the documentation in patients with suspected acute PUUV infection, and increased monitoring of kidney function should be done in NE patients who are current smokers.

C-reactive protein levels in combination with abdominal CT scans is a useful tool to predict the macroscopic appearance in late-stage EPS patients prior to surgery.

BACKGROUND: Diagnosis of encapsulating peritoneal sclerosis (EPS) is based on clinical symptoms, radiologic findings, and macroscopic or histological criteria. Two diagnostic scores for radiologic findings in computed tomography (CT) scans of patients with EPS have been established in the past (by Tarzi et al and Vlijm et al). The macroscopic appearance of EPS has previously been separated into three types. The use of CT scan as a tool to predict different macroscopic phenotypes, leading to specific surgical techniques and different medical treatment, has not yet been investigated. METHODS: We retrospectively analyzed 30 patients with late-stage EPS who underwent major surgery with peritonectomy and enterolysis. The preoperative CT scans were scored according to the two aforementioned established diagnostic CT scores. The macroscopic phenotype, surgical procedure, and laboratory values at the time of surgery were evaluated. CT findings in the different macroscopic phenotypes were analyzed. RESULTS: All patients had highly predictive CT scores for EPS. The macroscopic Type III had significantly higher CT scores compared with the other macroscopic phenotypes. Patients with macroscopic Type I had significantly higher C-reactive protein values compared to EPS Type III. Operation time was significantly longer, and repeated surgery and intraoperative complications were more frequent in EPS Type I compared with EPS Type III (P<0.05). Using the CT score and CRP level, the sensitivities for prediction of EPS I and III were 78% and 87% with corresponding specificities of 67% and 93%. CONCLUSION: Abdominal CT scans might help to identify patients with a higher risk of complications and provide important information for the surgical intervention prior to surgery.

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica.

BACKGROUND: Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS: During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION: This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients.

Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany.

Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.

Polyuria in Hantavirus Infection Reflects Disease Severity and Is Associated with Prolonged Hospital Stay: A Systematic Analysis of 335 Patients from Southern Germany.

Background/Aims: Puumala virus (PUUV) infection leads to nephropathia epidemica (NE), especially in endemic areas in Central Europe. The clinical course of NE is characterized by acute kidney injury (AKI) with thrombocytopenia followed by polyuria to a different degree. The prevalence of polyuria and its associated risk factors have not been reported in a large cohort of NE patients. Methods: Clinical and laboratory data during the acute phase of the disease were obtained from the medical reports and files of 335 patients who received in-hospital treatment during acute hantavirus infection. Comprehensive statistical models were developed to estimate the probability of polyuria. Results: The median age at diagnosis was 47 years (interquartile range, IQR 40-59) and 48% of the patients developed polyuria with a urinary output of 5,100 ml/day (IQR 4,200-7,300). The hospital stay was significantly longer in the polyuric group compared to the nonpolyuric group [8 days (IQR 6-10) vs. 6 days (IQR 5-8); p = 0.04]. Using logistic regression analysis, male gender (odds ratio, OR = 1.6; 95% confidence interval, CI 1.05-2.58; p = 0.03), oliguria/anuria during NE (OR = 2.56; 95% CI 1.65-4.01; p < 0.001), severe AKI (OR = 1.87; 95% CI 1.22-2.9; p < 0.001), and hematuria (OR = 1.78; 95% CI 1.02-3.15; p = 0.04) were significantly associated with the development of polyuria. In a multivariate model, the probability of polyuria was 0.19 (SEM ± 0.05) in female patients presenting with mild/moderate AKI without anuria/oliguria. Conclusions: Almost 50% of hospitalized NE patients developed polyuria, which was associated with a prolonged hospital stay. The probability of the development of polyuria was lowest in female patients with mild/moderate, non-oliguric/anuric AKI. © 2014 S. Karger AG, Basel.

Tubular breast cancer. A retrospective study.

BACKGROUND: The well-characterized tubular-type of breast tumors is classified as low-risk breast cancer. PATIENTS AND METHODS: We report on the results of a retrospective analysis on clinical and biological features of 248 tubular breast tumors including follow-up and treatment data from two German series of 21,065 breast cancer cases. The majority of tumors were stage I or stage II, ER- and PR-positive and c-erbB2-negative with a 5-year survival-rate of 96.3%. 51.3% of patients received hormonal treatment, 75.5% had post-operative radiotherapy and 11.8% were treated with a chemotherapeutical regimen. CONCLUSION: Our retrospective analysis showed no treatment benefit for either anti-hormonal or chemotherapeutical regimens. Post-operative radiotherapy, however, improved the survival rate of patients with tubular carcinoma (log-rank=5, p=0.025). Our data suggest that post-operative radiotherapy is an important treatment to prolong survival for patients suffering from tubular breast cancer.

Analysis of α-klotho, fibroblast growth factor-, vitamin-D and calcium-sensing receptor in 70 patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Secondary hyperparathyroidism (sHPT) is known as a very common complication in patients with chronic kidney disease, and G-protein-coupled calcium-sensing receptor (CaSR), Vitamin D receptor (VDR) and Fibroblast growth factor receptor (FGFR)/Klotho complexes seem to be involved in its development. METHODS: Hyperplastic parathyroid glands from 70 sHPT patients and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional morphological and immunohistochemical analysis of parathyroid glands was performed after dividing each slide in a 3x3 array. RESULTS: The presence of lipocytes in the normal parathyroid gland and tissue architecture (nodal in patients with sHPT) allows for discrimination between normal parathyroid glands and parathyroid glands of patients with sHPT. Protein expression of Klotho, FGFR, CaSR and VDR was higher in the normal parathyroid glands compared to the sHPT group (p<0.001, p=0.07, p =0.01 and p=0.001). The variability of each protein expression within each tissue slide was high. Therefore correlations between the different immunohistochemical variables were analyzed for each of the nine fields and than analyzed for all patients. Using this analysis, a highly significant positive correlation could be found between the expression of FGFR and VDR (p=0.0004). Interestingly, in terms of VDR we found a shift to a more mixed nuclear/cytoplasmic staining in the HPT group compared to normal parathyroid gland cells, which showed solitary nuclear staining for VDR (p>0.05). CONCLUSIONS: CaSR, VDR and an impaired Klotho-FGFR-axis seem to be the major players in the development of sHPT. Whether the detected correlation between FGFR and VDR and the shift to a more mixed nuclear/cytoplasmic staining of VDR will yield new insights into the pathogenesis of the disease has to be evaluated in further studies.

Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism.

The presentation of patients with primary hyperparathyroidism is often atypical and ranges from normocalcemic, primary hyperparathyroidism to severe, symptomatic hypercalcemia. G-protein-coupled, calcium-sensing receptor (CaSR), vitamin D receptor (VDR), and fibroblast growth factor receptor (FGFR)/klotho complexes seem to be involved in the development of pHPT. Parathyroid glands from 53 patients with pHPT and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional detailed morphological and immunohistochemical analyses of parathyroid glands were performed after dividing each slide in a 3 × 3 array. From morphology, the number of lipocytes was significantly lower in parathyroid tissue glands in the pHPT group (p < 0.001). Protein expressions of klotho, CaSR, and VDR were significantly reduced in the pHPT compared with the control group (p = 0.004, p = 0.007, p < 0.001). No differences were seen between the two groups (p = 0.35) regarding expression of FGFR. Correlations between expression showed significant positively correlations between klotho and CaSR and FGFR and VDR. No correlations between klotho expression and serum calcium levels could be detected (R = -0.13, p = 0.66), but there were positive correlations between expressions of CaSR/serum phosphate and klotho/serum phosphate. Impaired protein expression of CaSR and VDR seem to be involved in the development of pHPT. The role of the FGFR/klotho-axis remains still unclear. Correlations between protein expression of CaSR and serum phosphate and klotho and serum phosphate levels could be detected. Whether these findings give new insights into the pathogenesis of the disease is yet unknown and has to be elucidated.

Histological criteria for encapsulating peritoneal sclerosis - a standardized approach.

BACKGROUND: The two most relevant pathologies of long-term peritoneal dialysis (PD) are simple sclerosis and encapsulating peritoneal sclerosis (EPS). The histological differentiation of those two entities is difficult. The Aim of the study was to establish a method to standardize and facilitate the differentiation between simple sclerosis and EPS METHODS: We investigated 58 peritoneal biopsies - 31 EPS patients and 27 PD patients. Two blinded investigators analyzed 20 histological characteristics in EPS and PD patients. RESULTS: THE FOLLOWING FINDINGS WERE SIGNIFICANTLY MORE COMMON IN EPS THAN IN PATIENTS ON PD WITHOUT EPS: fibroblast like cells (FLC) (p<0.0001), mesothelial denudation (p<0.0001), decreased cellularity (p = 0.008), fibrin deposits (p<0.03), Fe deposits (p = 0.05), podoplanin vascular (p<0.0001), podoplanin avascular (p<0.0001). Using all predictor variables we trained the classification method Random Forest to categorize future cases. Podoplanin vascular and avascular were taken together (p<0.0001), FLC (p<0.0001), mesothelial denudation (p = 0.0005), calcification (p = 0.0026), acellular areas (p = 0.0094), and fibrin deposits (p = 0.0336) showed up as significantly important predictor variables. Estimated misclassification error rate when classifying new cases turned out to be 14%. CONCLUSION: The introduced statistical method allows discriminating between simple sclerosis and EPS. The misclassification error will likely improve with every new case added to the database.

Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study.

PURPOSE We started a phase II trial of induction chemotherapy and concurrent hyperfractionated chemoradiotherapy followed by either surgery or boost chemoradiotherapy in patients with advanced, stage III disease. The purpose is to achieve better survival in the surgery group with minimum morbidity and mortality. PATIENTS AND METHODS Patients treated from 1998 to 2002 with neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were analyzed. The treatment consisted of four cycles of induction chemotherapy with carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy. After restaging, operable patients underwent thoracotomy. Inoperable patients received chemoradiotherapy up to 63 Gy. Study end points included resectability, pathologic response, and survival. Results One hundred twenty patients were enrolled; 25% patients had stage IIIA, 73% had stage IIIB, and 2% stage IV. After treatment, 47.5% had downstaging, 29.2% had stable disease, and 23.3% had progressive disease. Thirty patients (25%) were not eligible for operation because of progressive disease, stable disease, and/or functional deterioration with one treatment-related death. The 30-day mortality was 5% in patients who underwent operation. The 5-year survival rate for 120 patients was 21.7%, and it was 43.1% in patients with complete resection. In postoperative patients with stage N0 disease, 5-year survival was 53.3%; if stage N2 or N3 disease was still present, 5-year survival was 33.3%. CONCLUSION Staging and treatment with chemoradiotherapy and complete resection performed in experienced centers achieve acceptable morbidity and mortality.

CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation.

AIMS: To investigate an association of responsiveness to clopidogrel loading dose with genotypes of cytochrome P450 (CYP) 2C19, other CYP isozymes and nongenetic factors in patients with coronary artery disease. MATERIALS & METHODS: Genotyping for CYP2C19 (*2, *3 and *17), CYP3A4*1B and CYP3A5*3 variants was performed in patients (n = 237) who underwent percutaneous coronary intervention. Adenosine diphosphate-induced platelet aggregation was determined after first administration of 600 mg clopidogrel. RESULTS: CYP2C19*2 carriers showed significantly increased residual platelet aggregation (RPA) (OR: 4.6; 95% CI: 2.5-8.7; p < 0.0001) compared with noncarriers. All other polymorphisms had no influence on RPA. For the development of a risk score for better prediction of RPA, CYP2C19*2 genotype and previously identified nongenetic risk factors (age >65 years, Type 2 diabetes mellitus, decreased left ventricular function, renal failure and acute coronary syndrome) were analyzed. Multivariable logistic regression analysis showed a significant correlation of the nongenetic factors (chi (2) = 5.32; p = 0.021) and CYP2C19*2 (chi (2) = 21.31; p < 0.0001) with high RPA, and an even higher association for the combination of both (chi (2) = 25.85; p < 0.0001). CONCLUSIONS: Prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors.

Effects of rifampicin on global gene expression in human small intestine.

OBJECTIVES: The small intestinal wall serves as an important barrier for the entry of foreign substances into the organism. Of particular importance are enzymes and transporters that can inactivate or prevent the uptake of many xenobiotics including drugs. Some of the genes encoding these proteins are transcriptionally activated by xenobiotics, a response well studied in liver but less so in the intestine. The effect of the inducer drug rifampicin on intestinal cells was therefore evaluated both in vivo and in vitro. METHODS: Seven healthy volunteers were treated with rifampicin for 9 days and the global gene expression profile was analysed in RNA from duodenal biopsies taken before and after drug treatment. The gene expression profile was also assessed in LS174T cells derived from a human colon adenocarcinoma after exposure to 10 micromol/l rifampicin for 24 h. RESULTS: We identified 32 genes that were upregulated and two genes that were downregulated by rifampicin treatment in vivo. The list of rifampicin regulated transcripts expectedly included drug metabolizing enzymes and drug transporters, but also genes involved in lipid and amino acid metabolism as well as genes not previously recognized to be part of the adaptation of intestinal cells to xenobiotic exposure. Only a limited number of these rifampicin-regulated transcripts were however also regulated by rifampicin in LS174T cells. CONCLUSION: The similarities and differences of changes in gene expression after rifampicin treatment between duodenal biopsies and cell culture provide a new assessment of the extent and diversity of systems affected by drug exposure.

Presentation, patterns of myocardial damage, and clinical course of viral myocarditis.

BACKGROUND: Enteroviruses and adenoviruses have been considered the most common causes of viral myocarditis, but parvovirus B19 (PVB19) and human herpesvirus 6 (HHV6) are increasingly found in endomyocardial biopsy samples. METHODS AND RESULTS: Consequently, our aim was to evaluate the prevalence and clinical presentation of cardiac PVB19 and/or HHV6 infection in a cohort of myocarditis patients and to follow its clinical course. In addition, we sought to demonstrate patterns of myocardial damage and to determine predictors for chronic heart failure. Our study design consisted of a cardiovascular magnetic resonance protocol as well as endomyocardial biopsies in the myocardial region affected as indicated by cardiovascular magnetic resonance. One hundred twenty-eight patients were enrolled by clinical criteria. In the group of myocarditis patients (n=87), PVB19 (n=49), HHV6 (n=16), and combined PVB19/HHV6 infections (n=15) were detected most frequently. The remaining patients were diagnosed with healing myocarditis (n=15) or did not have myocarditis (n=26). Patients with PVB19 presented in a manner similar to that of myocardial infarction; most had typical subepicardial late gadolinium enhancement in the lateral wall and recovered within months. Conversely, patients with HHV6 and especially with HHV6/PVB19 myocarditis presented with new onset of heart failure, had septal late gadolinium enhancement, and frequently progressed toward chronic heart failure. CONCLUSIONS: Our data indicate that PVB19 and HHV6 are the most important causes for viral myocarditis in Germany and that the clinical presentation is related to the type of virus. Furthermore, clinical presentation, type of virus, and pattern of myocardial damage are related to the clinical course.

Smad4-expression is decreased in breast cancer tissues: a retrospective study.

BACKGROUND: Although transforming growth factor beta (TGF-beta) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits pro-metastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-beta signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer. METHODS: Smad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed. RESULTS: Smad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-beta-receptor I (p < 0.001, n = 197) and TGF-beta-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors. CONCLUSION: According to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-beta signaling in tumor progression.