[The application of real-world evidence in drug regulatory decision-making]. / Die Anwendung von Real-world-Evidenz in Entscheidungsprozessen der Arzneimittelregulation.

Drug regulation is a system to support and protect public health. Drugs with market access must be effective, safe and of high quality. Therefore, drug regulatory decision-making by the competent authorities is made on a scientific basis. Real-world evidence (RWE) from real-world data (RWD) has so far predominantly been taken into account in a supportive manner in drug regulatory decision-making with regard to drug safety after marketing authorisation. The extensive potential of RWE for regulatory decision-making processes along the entire product life cycle has been increasingly used and further examined in recent years.This article provides an overview of current applications of RWE in drug regulatory decision-making processes. The potentials of RWE along with the hurdles to be addressed are described and examples of current projects on RWE research for drug regulation are given. The work is based on current international literature as well as examples from international and European initiatives and regulatory practice, which aim to support an increased use of RWD/RWE in regulatory decision-making processes. In order to be able to utilise the potential of RWE even more in the future, it is important to make relevant RWD sources more readily available through research projects and initiatives, to further develop evaluative methods and to establish the significance of RWE.

Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes.

The impact of genetic variability of pharmacogenes as a possible risk factor for adverse drug reactions is elucidated in the EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/English: influence of metabolic profiles on the safety of drug therapy in routine care) study. EMPAR evaluates possible associations of pharmacogenetically predicted metabolic profiles relevant for the metabolism of frequently prescribed cardiovascular drugs. Based on a German study population of 10,748 participants providing access to healthcare claims data and DNA samples for pharmacogenetic assessment, first analyses were performed and evaluated. The aim of this first evaluation was the characterization of the study population with regard to general parameters such as age, gender, comorbidity, and polypharmacy at baseline (baseline year) as well as important combinations of cardiovascular drugs with relevant genetic variants and predicted metabolic phenotypes. The study was registered in the German Clinical Trials Register (DRKS) on July 6, 2018 (DRKS00013909).

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance.

Voltage-gated Ca2+ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca2+ channels were shown to be involved in theta genesis, learning, and memory processes. In particular, HVA Cav2.3 R-type and LVA Cav3 T-type Ca2+ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Cav3 Ca2+ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca2+ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca2+ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer's disease (AD). The age-related downregulation of T-type Ca2+ channels in humans goes together with increased Aß levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca2+ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.

Enrichment designs using placebo nonresponders.

Enrichment designs that select placebo nonresponders have gained much attention during the last years in areas with high placebo response rates, eg, in depression. Proposals were made that re-randomize patients who did not respond to placebo during a first study phase as the sequential parallel design (SPD). This design uses in a second phase an enriched patient population where the treatment effect is expected to be more pronounced. This may be problematic if an effect in the overall population is claimed. Proposals were made to combine the treatment effects in the overall population from study phase 1 and the enriched population from study phase 2, alleviating but not solving the issue of a potential selection bias. This paper shows how this bias corresponding to the effect difference between the overall population and the enriched population depends on the variability of a potential subject-by-treatment interaction. Sample sizes are given, which lead to a significant result in the combining test with a given probability if actually the average effect in the overall population is zero. If, on the other hand, no subject-by-treatment interaction is given, the enrichment is shown to be inefficient. We conclude that enrichment designs using placebo nonresponders are not able to claim a positive average effect in the overall population if a subject-by-treatment interaction cannot be excluded. It cannot be used to demonstrate positive efficacy in the overall population in a pivotal phase III trial but may be used in early phases to demonstrate varying treatment effects between patients.

Hyperuricemia and dementia - a case-control study.

BACKGROUND: There is evidence that uric acid may have antioxidant and neuroprotective effects and might therefore alter the risk for neurodegenerative diseases such as dementia. So far, the relation between serum uric acid (SUA) levels or hyperuricemia and dementia remains elusive. Most studies focused on the disease or SUA levels. Effects of anti-hyperuricemic treatment have not been considered yet. This study investigated the association between hyperuricemia and dementia taking into account anti-hyperuricemic treatment. METHODS: We used longitudinal German public health insurance data and analyzed the association between hyperuricemia with and without different treatment options and dementia in a case-control design. Applying logistic regression the analysis was adjusted for several potential confounders including various comorbidities and polypharmacy. RESULTS: We identified 27,528 cases and 110,112 matched controls of which 22% had a diagnosis of hyperuricemia or gout and 17% received anti-hyperuricemic drugs. For patients with a diagnosis of hyperuricemia we found a slightly reduced risk for dementia (adjusted odds ratio [OR] 0.94, 95% confidence interval [CI] 0.89 to 0.98). The risk reduction was more pronounced for patients treated with anti-hyperuricemic drugs (adjusted OR 0.89, 95% CI 0.85 to 0.94, for regular treatment). CONCLUSIONS: Our results showed a slight reduction for dementia risk in patients with hyperuricemia, both with and without anti-hyperuricemic treatment.

Association of joint replacement surgery with incident dementia diagnosis in German claims data.

ABSTRACTBackground:Cognitive decline is an important complication of joint replacement surgeries in senior people. METHODS: We determined incidence rates of dementia diagnosis following endoprosthetic joint replacement surgery (upper and lower extremities). The observation period covered up to 28 quarters using German claims data comprising 154,604 cases 65 years and older. Effects were controlled for cerebrovascular and vascular risk factors, age, sex, the presence of a diagnosis of delirium, and regular prescription of sedative or analgesic drugs (SAD). RESULTS: The rate of incident dementia diagnoses in people without joint replacement surgery was 21.34 per 1,000 person years, compared with 80.76 incident cases when joint replacement surgery was conducted during the quarter of the incident dementia diagnosis; rates declined to 21.77 incident cases 7 and more quarters after joint replacement surgery had taken place. This pattern was maintained when controlling for delirium diagnosis and regular prescription of SAD. Among 10,563 patients with at least one joint replacement surgery, patients with a diagnosis of delirium in the quarter of the surgery were at increased risk of a dementia diagnosis compared to patients without such a diagnosis (HR=2.00, p < 0.001). CONCLUSION: In people surviving the high-risk phase for dementia immediately after surgery, long-term risk of dementia may reach the level of those without surgery. These findings encourage consequent perioperative management to reduce the risk of dementia as well as prospective studies of potentially beneficial effects of joint replacement surgery on mid- to long-term recovery of mobility and cognition in geriatric patients.

Informal caregivers' perspectives on health of and (potentially inappropriate) medication for (relatively) independent oldest-old people - a qualitative interview study.

BACKGROUND: Oldest-old persons frequently receive potentially inappropriate medication. Medication use takes place under the patients' informal caregivers' influence. We explored informal caregivers' perspectives on medication of (relatively) independent oldest-old persons to identify starting points for safer medication prescription/handling. METHODS: In this exploratory qualitative interview study we interviewed 45 informal caregivers of 45 oldest-old persons (23 with potentially inappropriate medication/22 without potentially inappropriate medication). Interviews were recorded, transcribed and content analyzed (deductive/inductive coding). RESULTS: Interviewees had little knowledge about/influence on oldest-old persons' medication, but declared to monitor oldest-old persons' needs for assistance. They were unaware of the concept of potentially inappropriate medication but sometimes sensitive to substance dependency. Most informal caregivers were satisfied with the oldest-old persons' medication and viewed medication as increasing the patients' quality of life. Inadequate communication was found between informal caregivers and general practitioners. CONCLUSIONS: Influence of informal caregivers on (relatively) independent oldest-old persons' medication seems low. Stakeholders need to be aware that there is a transitional period where independency of oldest-old persons decreases and support needs increase which may be missed by (in-)formal caregivers or concealed by oldest-old persons. Monitoring patients' medication competencies; measures supporting communication between informal caregivers and health care professionals; provision of educational and support resources for informal caregivers and the acceptance of oldest-old persons' increasing assistance needs may increase medication safety.

Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next-generation sequencing.

Mast cell activation syndrome (MCAS) and systemic mastocytosis (SM) are two clinical systemic mast cell activation disease variants. Few studies to date have investigated the genetic basis of MCAS. The present study had two aims. First, to investigate whether peripheral blood leukocytes from MCAS patients also harbor somatic mutations in genes implicated in SM using next-generation sequencing (NGS) technology and a relatively large MCAS cohort. We also addressed the question, whether some of the previously as somatic reported mutations are indeed germline mutations. Second, to identify germline mutations of relevance to MCAS pathogenesis. Here, mutation frequency in the present MCAS cohort was compared to that in public- and in-house databases in the case of frequent variants, and co-segregation was investigated in multiply affected families in the case of rare variants (allele frequency < 1%). MCAS diagnoses were assigned according to current criteria. Twenty five candidate genes were selected on the basis of published findings for SM. NGS was performed using a 76kbp custom designed Agilent SureSelect Target Enrichment and an Illumina Hiseq2000 2x100bp sequencing run. NGS revealed 67 germline mutations. No somatic mutations were detected. None of the germline mutations showed unequivocal association with MCAS. Failure to detect somatic mutations was probably attributable to the dilution of mutated mast cell DNA in normal leukocyte DNA. The present exploratory association findings suggest that some of the detected germline mutations may be functionally relevant and explain familial aggregation. Independent replication studies are therefore warranted.

General practitioners' views on (long-term) prescription and use of problematic and potentially inappropriate medication for oldest-old patients-A qualitative interview study with GPs (CIM-TRIAD study).

BACKGROUND: Potentially inappropriate medication (PIM) is defined as medication with uncertain therapeutic effects and/or potential adverse drug reactions outweighing the clinical benefits. The prescription rate of PIM for oldest-old patients is high despite the existence of lists of PIM (e.g. the PRISCUS list) and efforts to raise awareness. This study aims at identifying general practitioners' views on PIM and aspects affecting the (long-term) use of PIM. METHODS: As part of the CIM-TRIAD study, we conducted semi-structured, qualitative interviews with 47 general practitioners, discussing 25 patients with and 22 without PIM (according to the PRISCUS list). The interview guideline included generic and patient-specific questions. Interviews were digitally recorded and transcribed verbatim. We content analyzed the interviews using deductive and inductive category development. RESULTS: The majority of the general practitioners were not aware of the PRISCUS list. Agents deemed potentially inappropriate from the general practitioners' point of view and the PRISCUS list are not completely superimposable. General practitioners named their criteria to identify appropriate medication for elderly patients (e.g. renal function, cognitive state) and emphasized the importance of monitoring. We identified prescription- (e.g. benzodiazepines on alternative private prescription), medication- (e.g. subjective perception that PIM has no alternative), general practitioner- (e.g. general practitioner relies on specialists), patient- (e.g. "demanding high-user", positive subjective benefit-risk-ratio) and system-related aspects (e.g. specialists lacking holistic view, interface problems) related to the (long term) use of PIM. CONCLUSIONS: While the PRISCUS list does not seem to play a decisive role in general practice, general practitioners are well aware of risks associated with PIM. Our study identifies some starting points for a safer handling of PIM, e.g. stronger dissemination of the PRISCUS list, better compensation of medication reviews, "positive lists", adequate patient information, multifaceted interventions and improved communication between general practitioners and specialists.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study an APPswePS1dE9 AD mouse model has been analyzed using implantable video-EEG radiotelemetry to perform long-term EEG recordings from the primary motor cortex M1 and the hippocampal CA1 region in both genders. Besides motor activity, EEG recordings were analyzed for electroencephalographic seizure activity and frequency characteristics using a Fast Fourier Transformation (FFT) based approach. Automatic seizure detection revealed severe electroencephalographic seizure activity in both M1 and CA1 deflection in APPswePS1dE9 mice with gender-specific characteristics. Frequency analysis of both surface and deep EEG recordings elicited complex age, gender, and activity dependent alterations in the theta and gamma range. Females displayed an antithetic decrease in theta (θ) and increase in gamma (γ) power at 18-19 weeks of age whereas related changes in males occurred earlier at 14 weeks of age. In females, theta (θ) and gamma (γ) power alterations predominated in the inactive state suggesting a reduction in atropine-sensitive type II theta in APPswePS1dE9 animals. Gender-specific central dysrhythmia and network alterations in APPswePS1dE9 point to a functional role in behavioral and cognitive deficits and might serve as early biomarkers for AD in the future.

Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases.

Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic themes--including very wide arrays of central and peripheral NPS. Significantly helpful treatment--including for neuropsychiatric issues--usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy.

Risk of dementia in elderly patients with the use of proton pump inhibitors.

Drugs that modify the risk of dementia in the elderly are of potential interest for dementia prevention. Proton pump inhibitors (PPIs) are widely used to reduce gastric acid production, but information on the risk of dementia is lacking. We assessed association between the use of PPIs and the risk of dementia in elderly people. Data were derived from a longitudinal, multicenter cohort study in elderly primary care patients, the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), including 3,327 community-dwelling persons aged ≥ 75 years. From follow-up 1 to follow-up 4 (follow-up interval 18 months), we identified a total of 431 patients with incident any dementia, including 260 patients with Alzheimer's disease. We used time-dependent Cox regression to estimate hazard ratios of incident any dementia and Alzheimer's disease. Potential confounders included in the analysis comprised age, sex, education, the Apolipoprotein E4 (ApoE4) allele status, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease, and stroke. Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04-1.83] and Alzheimer's disease (HR 1.44, 95% CI 1.01-2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this finding is of high interest to research on dementia and provides indication for dementia prevention.

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease.

Recently, evidence was provided for common familial occurrence of systemic mast cell activation disease (MCAD), i.e., mast cell disorders characterized by aberrant release of mast cell mediators and/or accumulation of pathological mast cells in potentially any tissue. Since there is accumulating evidence that epigenetic processes may have transgenerational consequences, the aim of the present study was to investigate by two different experimental approaches whether epigenetic effects may contribute to the familial occurrence of MCAD. (1) High throughput profiling of the methylation status of the genomic DNA in leukocytes from MCAD patients in comparison to healthy subjects revealed for the first time an association of MCAD with alterations in DNA methylation comprising genes encoding proteins crucially involved in DNA/RNA repair and processing, apoptosis, cell activity, and exocytosis/cell communication. A set of 195 differentially methylated CpG sites could be regarded as candidates for a MCAD signature at the methylation level of the DNA. (2) In a cohort of MCAD patients, a correlation between age at symptom onset and year of birth (reflecting different generations) was observed suggesting the presence of the phenomenon of anticipation. In conclusion, the present findings suggest that epigenetic processes could substantially contribute to the transgenerational transmission of MCAD.

Sex-specific cortical, hippocampal and thalamic whole genome transcriptome data from controls and a G72 schizophrenia mouse model.

OBJECTIVES: The G72 mouse model of schizophrenia represents a well-known model that was generated to meet the main translational criteria of isomorphism, homology and predictability of schizophrenia to a maximum extent. In order to get a more detailed view of the complex etiopathogenesis of schizophrenia, whole genome transcriptome studies turn out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cortex, hippocampus and thalamus of G72 transgenic and wild-type control mice. Experimental animals were age-matched and importantly, both sexes were considered separately. DATA DESCRIPTION: The isolated RNA from all three brain regions was purified, quantified und quality controlled before initiation of the hybridization procedure with SurePrint G3 Mouse Gene Expression v2 8  ×  60 K microarrays. Following immunofluorescent measurement und preprocessing of image data, raw transcriptome data from G72 mice and control animals were extracted and uploaded in a public database. Our data allow insight into significant alterations in gene transcript levels in G72 mice and enable the reader/user to perform further complex analyses to identify potential age-, sex- and brain-region-specific alterations in transcription profiles and related pathways. The latter could facilitate biomarker identification and drug research and development in schizophrenia research.

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer's disease mice.

A variety of Alzheimer's disease (AD) mouse models has been established and characterized within the last decades. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome studies turned out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cortex and hippocampus of age-matched, eight months old male and female APP/PS1 AD mice and control animals to perform sex- and brain region specific analysis of transcriptome profiles. The results of our studies reveal novel, detailed insight into differentially expressed signature genes and related fold changes in the individual APP/PS1 subgroups. Gene ontology and Venn analysis unmasked that intersectional, upregulated genes were predominantly involved in, e.g., activation of microglial, astrocytic and neutrophilic cells, innate immune response/immune effector response, neuroinflammation, phagosome/proteasome activation, and synaptic transmission. The number of (intersectional) downregulated genes was substantially less in the different subgroups and related GO categories included, e.g., the synaptic vesicle docking/fusion machinery, synaptic transmission, rRNA processing, ubiquitination, proteasome degradation, histone modification and cellular senescence. Importantly, this is the first study to systematically unravel sex- and brain region-specific transcriptome fingerprints/signature genes in APP/PS1 mice. The latter will be of central relevance in future preclinical and clinical AD related studies, biomarker characterization and personalized medicinal approaches.

Whole genome transcriptome data from the WT cortex and hippocampus of female and male control and APP/PS1 Alzheimer's disease mice.

A variety of Alzheimer disease (AD) mouse models has been established and characterized within the last decades. These models are generated to meet the principal criteria of AD isomorphism, homology and predictability to a maximum extent. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome data analysis turns out to be indispensable. Here, we present a microarray-based transcriptome data collection based on RNA extracted from the retrosplenial (RS) cortex and the hippocampus of APP/PS1 AD mice and control animals. Experimental animals were age matched and importantly, both sexes were considered separately. Isolated RNA was purified, quantified und quality controlled prior to the hybridization procedure with SurePrint G3 Mouse Gene Expression v2 8 × 60K microarrays. Following immunofluorescent measurement und preprocessing/extraction of image data, raw transcriptome data were uploaded including differentially expressed gene candidates and related fold changes in APP/PS1 AD mice and controls. Our data allow further insight into alterations in gene transcript levels in APP/PS1 AD mice compared to controls and enable the reader/user to carry out complex transcriptome analysis to characterize potential age-, sex- and brain-region-specific alterations in e.g., neuroinflammatory, immunological, neurodegenerative and ion channel pathways.

Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics.

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.

Pharmacological characterization of tegaserod at the wild type and 124Cys variant of the human 5-HT1B receptor.

Sumatriptan, an antimigraine drug, causes contraction of human coronary arteries through activation of 5-HT1B receptors which couple to Gi/Go inducing inhibition of adenylate cyclase. At a rare, naturally occurring human receptor variant (124Cys-h5-HT1B), sumatriptan has previously been shown to act as a more potent agonist than at wild-type receptor. Tegaserod, a 5-HT4-receptor agonist, developed for the treatment of functional gastrointestinal disorders, has been suspected to be involved in very rare cardiac ischemic events in patients with cardiovascular risk factors. In this study, we examined the potential agonist-like effects of tegaserod in comparison with sumatriptan at heterologously expressed human wild type and 124Cys-variant 5-HT1B receptors, using assays addressing G-protein coupling and inhibition of forskolin-stimulated cyclic AMP accumulation. Sumatriptan exhibited agonist effects as previously reported, whereas tegaserod acted as partial agonist at both wild type and 124Cys-variant h5-HT1B receptors (expressed in rat C6 glioma cells). Sumatriptan and tegaserod were more potent at the 124Cys-variant h5-HT1B receptor. It remains to be shown whether the very rare cardiovascular side effects reported with these drugs are predominantly observed in patients homozygously expressing the variant receptor.