Sex Differences in Characteristics Associated with Potentially Inappropriate Medication Use and Associations with Functional Capacity in Older Participants of the Berlin Aging Study II.

INTRODUCTION: Medication safety is a vital aim in older adults' pharmacotherapy. Increased morbidity and vulnerability require particularly careful prescribing. Beneath avoiding unnecessary polypharmacy and prescribing omissions, physicians have to be aware of potentially inappropriate medications (PIMs) and related outcomes to optimize older adults' drug therapy, and to reduce adverse drug events. OBJECTIVE: The aim of this study was to identify participants characteristics associated with PIM use and associations of PIM use with functional capacity with a focus on sex differences. METHODS: Multivariable logistic regression analyses of cross-sectional Berlin Aging Study II (BASE-II) data (N = 1,382, median age 69 years, interquartile range 67-71, 51.3% women) were performed with PIM classification according to the EU(7)-PIM list. RESULTS: In the overall study population, higher education was associated with lower odds of PIM use (odds ratio [OR] 0.93, confidence interval [CI] 95% 0.87-0.99, p = 0.017). Falls (OR 1.53, CI 95% 1.08-2.17, p = 0.016), frailty/prefrailty (OR 1.68, 1.17-2.41, p = 0.005), and depression (OR 2.12, CI 95% 1.32-3.41, p = 0.002) were associated with increased odds of PIM use. A better nutritional status was associated with lower odds of PIM use (OR 0.88, CI 95% 0.81-0.97, p = 0.008). In the sex-stratified analysis, higher education was associated with lower odds of PIM use in men (OR 0.90, CI 95% 0.82-0.99, p = 0.032). Frailty/prefrailty was associated with increased odds of PIM use in men (OR 2.04, CI 95% 1.18-3.54, p = 0.011) and a better nutritional status was associated with lower odds of PIM use in men (OR 0.83, CI 95% 0.72-0.96, p = 0.011). Falls in the past 12 months were related to an increased prevalence of PIM use in women (OR 1.74, CI 95% 1.10-2.75, p = 0.019). Depression was associated with a higher prevalence of PIM use in both men (OR 2.74, CI 95% 1.20-6.24, p = 0.016) and women (OR 2.06, CI 95% 1.14-3.71, p = 0.017). We did not detect sex differences regarding the overall use of drugs with anticholinergic effects, but more men than women used PIMs referring to the cardiovascular system (p = 0.036), while more women than men used PIMs referring to the genitourinary system and sex hormones (p < 0.001). CONCLUSION: We found similarities, but also differences between men and women as to the associations between PIM use and participants' characteristics and functional capacity assessments. The association of lower education with PIM use may suggest that physicians' prescribing behavior is modified by patient education, a relationship that could evolve from more critical attitudes of educated patients towards medication use. We conclude that sex differences in associations of PIM use with functional capacities might be partly attributable to sex differences in drug classes used, but not with regard to anticholinergics, as these are used to a similar extent in men and women in the cohort studied here.

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. RESULTS: Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events. CONCLUSIONS: Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy.

BACKGROUND: Tissue factor (TF) is an evolutionary conserved glycoprotein that plays an important role in the pathogenesis of cancer. TF is expressed in 2 naturally occurring protein isoforms, membrane-bound full-length (fl)TF and soluble alternatively spliced (as)TF. Both isoforms have been shown to affect a variety of pathophysiologically relevant functions, such as tumor-associated angiogenesis, thrombogenicity, tumor growth, and metastasis. Therefore, targeting TF either by direct inhibition or indirectly, i.e., on a posttranscriptional level, offers a novel therapeutic option for cancer treatment. CONTENT: In this review we summarize the latest findings regarding the role of TF and its isoforms in cancer biology. Moreover, we briefly depict and discuss the therapeutic potential of direct and/or indirect inhibition of TF activity and expression for the treatment of cancer. SUMMARY: asTF and flTF play important and often distinct roles in cancer biology, i.e., in thrombogenicity and angiogenesis, which is mediated by isoform-specific signal transduction pathways. Therefore, both TF isoforms and downstream signaling are promising novel therapeutic targets in malignant diseases.

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study.

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

[Diclofenac up2date - Part 1: Pharmacology and comparison with other drugs]. / Diclofenac up2date - Teil 1: Die Pharmakologie und der Vergleich mit anderen Medikamenten.

The non-opioid analgesic diclofenac is used worldwide for musculoskeletal and perioperative pain therapy. Despite its frequent use and easy access as an "over the counter" drug, gastrointestinal, cardiovascular, and renal adverse drug effects have to be considered. Availability of diverse formulations (e.g. tablets, suppository, gel-formulations) with different indications, dosage recommendations and contraindications may easily lead to confusion, thus accounting for inadequate use on the one hand or withholding of an effective analgesic. This review may provide physicians in perioperative medicine, intensive care and pain therapy with important and suitable information about the pharmacology and appropriate use of this drug.

[Diclofenac up2date - Part 2: The use in specific groups of patients]. / Diclofenac up2date - Teil 2: Einsatz bei speziellen Patientengruppen.

The non-opioid analgesic diclofenac is used worldwide for musculoskeletal and perioperative pain therapy. Despite its frequent use and easy access as an "over the counter" drug, gastrointestinal, cardiovascular, and renal adverse drug effects have to be considered. Availability of diverse formulations (e.g. tablets, suppository, gel-formulations) with different indications, dosage recommendations and contraindications may easily lead to confusion, thus accounting for inadequate use on the one hand or withholding of an effective analgesic. This review may provide physicians in perioperative medicine, intensive care and pain therapy with important and suitable information about the pharmacology and appropriate use of this drug.

Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer.

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Olaparib in an ovarian cancer patient with end-stage renal disease and hemodialysis.

PURPOSE: For patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis. METHODS: Blood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state. RESULTS: Maximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples. CONCLUSION: A total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.

Tissue lipidomic profiling supports a mechanistic role of the prostaglandin E2 pathway for albuminuria development in glomerular hyperfiltration.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH. Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively. Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.

Longitudinal effects of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in older women and men.

Genetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood pressure (BP), cognitive and physical function parameters in older participants in the BASE-II after long-term follow-up as part of the GendAge study. Overall, 1010 older participants (mean age 75.7 ± 3.7 years, 51.6% women) were analyzed after follow-up (mean 7.4 years) both in cross-sectional analysis and in longitudinal analysis as compared to baseline. In cross-sectional analysis, heterozygous G-allele carriers exhibited significantly higher eGFR values (AA, 71.3 ml/min/1.73 m2, 95% CI, 70.3-72.3 vs. AG, 73.5 ml/min/1.73 m2, 95% CI, 72.1-74.9, P = 0.033). Male heterozygous G-allele carriers had lower odds of eGFR < 60 mL/min/1.73 m2 (OR 0.51, 95% CI, 0.28-0.95, P = 0.032) and in Timed Up and Go-Test ≥ 10 s (OR 0.50, 95% CI, 0.29-0.85, P = 0.011) whereas women were less likely to have hypertension (OR 0.58, CI, 0.37-0.91, P = 0.018). UMOD genotypes were not significantly associated with longitudinal changes in any investigated phenotype. Thus, while the impact of UMOD rs4293393 on kidney function is maintained in aging individuals, this variant has overall no impact on longitudinal changes in BP, kidney, cognitive or functional phenotypes. However, our results suggest a possible sex-specific modifying effect of UMOD on eGFR and physical function in men and hypertension prevalence in women.

Studies in Zebrafish and Rat Models Support Dual Blockade of EP2 and EP4 (Prostaglandin E2 Receptors Type 2 and 4) for Renoprotection in Glomerular Hyperfiltration and Albuminuria.

BACKGROUND: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E2 (PGE2) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE2 receptor type 2) and EP4 (PGE2 receptor type 4) in GH. METHODS: We conducted in vivo studies in a transgenic zebrafish model (Tg[fabp10a:gc-EGFP]) suitable for analysis of glomerular filtration barrier function and a genetic rat model with GH, albuminuria, and upregulation of PGE2. Similar pharmacological interventions and primary outcome analysis on albuminuria phenotype development were conducted in both model systems. RESULTS: Stimulation of zebrafish embryos with PGE2 induced an albuminuria-like phenotype, thus mimicking the suggested PGE2 effects on glomerular filtration barrier dysfunction. Both separate and combined blockade of EP2 and EP4 reduced albuminuria phenotypes in zebrafish and rat models. A significant correlation between albuminuria and podocyte damage in electron microscopy imaging was identified in the rat model. Dual blockade of both receptors showed a pronounced synergistic suppression of albuminuria. Importantly, this occurred without changes in arterial blood pressure, glomerular filtration rate, or tissue oxygenation in magnetic resonance imaging, while RNA sequencing analysis implicated a potential role of circadian clock genes. CONCLUSIONS: Our findings confirm a role of PGE2 in the development of albuminuria in GH and support the renoprotective potential of combined pharmacological blockade of EP2 and EP4 receptors. These data support further translational research to explore this therapeutic option and a possible role of circadian clock genes.

CYP3A5 genotype-phenotype analysis in the human kidney reveals a strong site-specific expression of CYP3A5 in the proximal tubule in carriers of the CYP3A5*1 allele.

Interindividual variability in the drug-metabolizing activity of the CYP3A5 enzyme is mainly due to a single nucleotide polymorphism in CYP3A5, leading to low expression in homozygous CYP3A5*3/*3 individuals compared with CYP3A5*1 allele carriers. In the human kidney, expression of CYP3A5 has been implicated in blood pressure regulation and calcineurin inhibitor-associated nephrotoxicity. The effect of the CYP3A5*1/*3 polymorphism on the expression level and protein distribution within the human kidney is not well characterized. Therefore, we performed a genotype-phenotype analysis of CYP3A5 mRNA and protein expression in the human kidney. To this end, we analyzed sections of normal kidney tissue obtained from 93 white individuals undergoing nephrectomy by quantitative mRNA expression analysis. Qualitative protein expression analysis of CYP3A5 was performed by immunohistochemistry. Mean renal mRNA expression of carriers of the CYP3A5*1 (n = 12) allele was more than 18-fold higher than that of CYP3A5*3/*3 carriers (n = 81, p < 0.001). Immunohistochemical analysis demonstrated CYP3A5 protein in all epithelia of the nephron in kidney sections with the CYP3A5*3/*3 genotype. In carriers of the CYP3A5*1 allele, a strong increase in protein expression of CYP3A5 was detected, and this was confined to the proximal tubule. This study confirms a significant effect of the CYP3A5*1/*3 polymorphism on CYP3A5 expression in the normal human kidney and reveals a strong nephron segment-specific difference in the CYP3A5 protein expression limited to the proximal tubule.

15-keto-Prostaglandin E2 exhibits bioactive role by modulating glomerular cytoarchitecture through EP2/EP4 receptors.

AIMS: Prostaglandins are important signaling lipids with prostaglandin E2 (PGE2) known to be the most abundant prostaglandin across tissues. In kidney, PGE2 plays an important role in the regulation of kidney homeostasis through its EP receptor signaling. Catabolism of PGE2 yields the metabolic products that are widely considered biologically inactive. Although recent in vitro evidence suggested the ability of 15-keto-PGE2 (a downstream metabolite of PGE2) to activate EP receptors, the question whether 15-keto-PGE2 exhibits physiological roles remains unresolved. MATERIALS AND METHODS: Pharmacological treatment was performed in transgenic zebrafish embryos using 500 µM 15-keto-PGE2 and 20 µM EP receptors antagonists' solutions during zebrafish embryonic development. After the exposure period, the embryos were fixed for confocal microscopy imaging and glomerular morphology analysis. KEY FINDINGS: Here, we show that 15-keto-PGE2 can bind and stabilize EP2 and EP4 receptors on the plasma membrane in the yeast model. Using lipidomic analysis, we demonstrate both PGE2 and 15-keto-PGE2 are present at considerable levels in zebrafish embryos. Our high-resolution image analysis reveals the exogenous treatment with 15-keto-PGE2 perturbs glomerular vascularization during zebrafish development. Specifically, we show that the increased levels of 15-keto-PGE2 cause intercalation defects between podocytes and endothelial cells of glomerular capillaries effectively reducing the surface area of glomerular filtration barrier. Importantly, 15-keto-PGE2-dependent defects can be fully reversed by combined blockade of the EP2 and EP4 receptors. SIGNIFICANCE: Altogether, our results reveal 15-keto-PGE2 to be a biologically active metabolite that modulates the EP receptor signaling in vivo, thus playing a potential role in kidney biology.

Effect of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in a community-based cohort of older adults.

In genome-wide association studies, genetic variants in the UMOD gene associate with kidney function, blood pressure (BP), and hypertension. Elevated BP is linked to kidney function and impaired cognitive as well as physical performance in later life. We investigated the association between UMOD rs4293393-A > G and kidney function, BP, cognitive and physical function in the Berlin Aging Study II (BASE-II). Data of 1556 older BASE-II participants (mean age 68.2 ± 3.7 years) were analyzed. BP was determined by standardized automated measurements, estimated glomerular filtration rate (eGFR) by CKD Epidemiology Collaboration creatinine equation. Cognitive function was assessed by Mini-Mental State Examination and Digit Symbol Substitution Test, while physical function by Handgrip Strength and Timed Up and Go-Test. Association analyses were performed by covariance and logistic regression models adjusting for sex. G-allele carriers at UMOD rs4293393 exhibited significantly higher eGFR values compared to non-carriers (AA, 76.4 ml/min/1.73 m², CI: 75.7-77.2 vs. AG, 78.4 ml/min/1.73 m², CI: 77.3-79.5 vs. GG, 78.5 ml/min/1.73 m², CI: 75.4-81.7; P = 0.010), and a lower risk of eGFR < 60 mL/min/1.73 m2 (AG, OR: 0.63, CI: 0.41-0.97, P = 0.033). However, UMOD rs4293393 genotypes were not associated with BP, diagnosis of hypertension or cognitive and physical function parameters. Our data corroborate previous findings on the association of UMOD rs4293393-G with better kidney function in older adults. However, no association between UMOD and BP or physical and cognitive parameters in these community-dwelling older adults was detected.

Prescribing of inappropriate medication in nursing home residents in Germany according to a French consensus list: a cross-sectional cohort study.

PURPOSE: The current use of inappropriate medication in elderly nursing home residents (NHRs) in Germany is unclear. We therefore set out to analyse the frequency and patterns of potentially inappropriate drug prescriptions in elderly NHRs in Germany. METHODS: We utilised prescription data for NHRs 65 years or older from a large German health insurance company during a period of 3 months. Inappropriate drugs were identified from a recently reported French consensus list. RESULTS: Data for 7271 (83.7%) females and 1414 (16.3%) males were available for analysis. The average age was 83.6 ± 7.3 years. Overall 48 inappropriate drugs were prescribed resulting in a total of 3825 inappropriate drug prescriptions which accounted for 4.3% of all documented prescriptions (n = 88,695). One thousand nine hundred and three (21.9%) residents received at least one inappropriate drug prescription. Using logistic regression we detected no significant influence of gender or level of care on frequency of inappropriate prescriptions. However, age had a significant influence; with increasing age the frequency of residents receiving inappropriate medications decreased steadily (r = -0.92, p = 0.003) and ranged from a maximum of 32.8% in the group between 65 and 69 years to a minimum of 15.2% in residents older than 94 years. This observation was paralleled by a significant and continuous decrease of drug prescription rates with increasing age (r = -0.88, p = 0.009). CONCLUSION: The present analysis demonstrates that about one out of five elderly NHRs received at least one inappropriate drug prescription. Additional studies may aim to establish a list of frequently prescribed inappropriate drugs for Germany.

[Potentially inappropriate medication for the elderly: adaptation and evaluation of a French consensus list]. / Unangemessene Arzneistoffe für geriatrische Patienten. Anpassung und Bewertung einer französischen Konsensusliste.

BACKGROUND: Appropriate pharmacotherapy is one of the most important topics due to demographic development in many industrialised countries. The purpose of our work was to evaluate and adjust a French consensus list for Germany. MATERIALS AND METHODS: We conducted a thorough literature review with regard to the safety of drugs for the elderly. RESULTS: Originally, 34 criteria containing drugs or drug classes were classified as inappropriate. From these, we evaluated 12 criteria as appropriate, and all others as potentially inappropriate, too. Frequently, drugs affecting the central nervous system, for example anticholinergics and benzodiazepines, were evaluated as potentially inappropriate medication. CONCLUSION: Our adapted list may be used as recommendation for appropriate drug prescribing in the elderly in Germany.

Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E2 Activation in Human Podocytes.

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman's space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.

Role of the H1 haplotype of microtubule-associated protein tau (MAPT) gene in Greek patients with Parkinson's disease.

BACKGROUND: The extended tau haplotype (H1) that covers the entire human microtubule-associated protein tau (MAPT) gene has been implicated in Parkinson's disease (PD). Nevertheless, controversial results, such as two studies in Greek populations with opposite effects, have been reported. Therefore, we set out to determine whether the H1 haplotype and additional single nucleotide polymorphisms (SNPs) included in H1 are associated with PD in a sample of Greek patients. METHODS: We analysed MAPT haplotypes in cohorts of 122 patients and 123 controls of Greek origin, respectively. SNP genotyping was performed with Taqman assays and genotyping results were confirmed by sequencing. RESULTS: The presence of the H1 haplotype was significantly associated with PD (odds ratio for H1H1 vs. H1H2 and H2H2: 1.566; 95% CI: 1.137-2.157; P = 0.006) and remained so after adjustment for sex. Further analysis of H1 sub-haplotypes with three single nucleotide polymorphisms (rs242562, rs2435207 and rs3785883) demonstrated no significant association with PD. CONCLUSION: Our data support the overall genetic role of MAPT and the H1 haplotype for PD susceptibility in Greek patients. However, the previously supported association of H1 sub-haplotypes with PD could not be confirmed in our study.

Potentially inappropriate medication in older participants of the Berlin Aging Study II (BASE-II) - Sex differences and associations with morbidity and medication use.

INTRODUCTION: Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE: The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS: Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS: Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p<0.001). CONCLUSION: PIM use occurred more frequently in women than in men, while it was associated with higher morbidity in males. As expected, EU(7)-PIM identifies more subjects as PIM users than the PRISCUS list but further studies are needed to investigate the differential impact of both lists on ADEs and outcome. KEY POINTS: We found PIM use to be associated with a higher number of regular medications and with increased morbidity. Additionally, we detected a higher prevalence of PIM use in females compared to males, suggesting that women and people needing intensive drug treatment are patient groups, who are particularly affected by PIM use.

Moderation of alcohol consumption as a recommendation in European hypertension management guidelines: a survey on awareness, screening and implementation among European physicians.

OBJECTIVES: Moderation of alcohol consumption is included as a class I, level of evidence A recommendation in the current European guidelines for the management of hypertension. We investigated its awareness and self-reported implementation among European physicians across different specialties and workplaces. DESIGN AND SETTING: A cross-sectional survey study conducted in two annual German meetings (German Society of Cardiology and the German Society of Internal Medicine) and two annual European meetings (European Society of Hypertension and European Society Cardiology) in 2015. PARTICIPANTS: 1064 physicians attending the European meetings were interviewed including 52.1% cardiologists, 29.2% internists and 8.8% general practitioners. MAIN OUTCOME MEASURES: Physician screening of alcohol consumption, awareness and self-implementation of the recommendation of the current European guidelines about moderation of alcohol consumption for the management of hypertension. RESULTS: Overall, 81.9% of physicians reported to generally quantify alcohol consumption in patients with hypertension. However, only 28.6% and 14.5% of participants reported screening alcohol consumption in their patients with newly detected or treatment-resistant hypertension. Physicians recommended a maximum alcohol intake of 13.1±11.7 g/day for women (95% CI 12.3 to 13.8) and 19.9±15.6 g/day for men (95% CI 18.8 to 20.9). In case of moderate to high alcohol consumption, 10.3% would manage only hypertension without addressing alcohol consumption, while 3.7% of the physicians would do so in case of alcohol dependence (p<0.001). CONCLUSIONS: The average amount of alcohol intake per day recommended by European physicians in this survey was in agreement with the guidelines. The low number of physicians that screen for alcohol consumption in patients with newly detected and with treatment-resistant hypertension indicates an important deficit in the management of hypertension.