Investigations on 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-a]pyridazin-1-amines and related compounds: synthesis, chemical behaviour, structure elucidation and iNOS inhibitory activity.

The present work reports on the preparation of the hitherto unknown title compounds 5, with various synthetic routes described. The initially pursued concept of S-N exchange with varioius 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazines 4 by using nitrogen nucleophiles was only marginally successful. The reactions proceeded slowly and the yields were low, mainly because of the pronounced formation of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2- a ]pyridazin-1-imines 7 by oxidation of the heterocyclic amines 5 initially formed. The integration of the synthesis of 3-acylsulfanyl analogues with the more reactive leaving groups also failed. On the other hand, the cyclization of the hydrohalides of hexahydropyridazine-1-carboximidamide with aromatic aldehydes and some low molecular weight ketones gives significantly better results in the synthesis of the title compounds 5. The use of the hydrochloride 6b proved to be advantageous in comparison to the hydroiodide 6a because the yields were significantly better and the imines 7 formed at the same time only to a small extent. In addition, the starting compound 6b can be prepared in a single-step synthesis in very good yield from hexahydropyridazine hydrochloride 1 and cyanamide. The cyclization of N' -phenylhexahydropyridazine-1-carboximidamide hydrochloride 6c with substituted benzaldehydes gives the 3-aryl-substituted 2-phenyl-2,3,5,6,7,8-hexahydro -1H -[1,2,4]triazolo[1,2- a ] pyridazin-1-imines 8. In the context with the study of the reaction of hexahydropyridazine-1-carboximidamide hydroiodide 6a with cyclohexanone, the hexahydropyridazine-1-carboxamide 9 was specifically synthesized. This can be reacted with aromatic aldehydes to give the 5,6,7,8-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazin-1-ones 10 in very good yields. The results of the biological testing of representatives of the synthesized 5,6,7,8-tetrahydro-[1,2,4] triazolo[1,2-a]pyridazine-1-amines 5 show, in comparison to the already examined thions 3 and 3-methylsulfanyl derivatives 4, significantly less inducible nitric oxide synthase (iNOS) inhibitory activity.

Continuation of Geriatric Discharge Medication in Primary Care and its Association with Rehospitalizations - A Cohort Study.

Transition of care in geriatric patients is a complex and high risk process, particularly the continuation of discharge medication in primary care. We aimed to determine how general practitioners' management of geriatric patients' discharge medication is associated with rehospitalizations. A prospective monocentric cohort study was done in an acute geriatric inpatient clinic with six-months follow-up. Acutely hospitalized patients ≥ 70 years old with functional impairment and frailty currently taking medications were followed up after hospital discharge and continuation (n=27) or change (n=44) of discharge medication by the General Practitioner was determined. Outcomes were rehospitalizations, days spent at home and time until recurrent rehospitalizations. 71 patients (mean age 82 years, 46 women [65%]) were followed up for six months after hospital discharge. In a negative binomial regression model, the rehospitalization rate after three months was 3.8 times higher in participants whose discharge medication was changed (p = 0.023). The effect did not persist over six months. Patients who were continued on their discharge medication were rehospitalized significantly later and/or less often during the six months observation period, statistically measured by a recurrent events survival model (HR 0.267, p = 0.003). In conclusion, continuation of discharge medication after an acute hospitalization in a specialized geriatric clinic could prevent early rehospitalizations.

Nanotechnology for catalysis and solar energy conversion.

This roadmap on Nanotechnology for Catalysis and Solar Energy Conversion focuses on the application of nanotechnology in addressing the current challenges of energy conversion: 'high efficiency, stability, safety, and the potential for low-cost/scalable manufacturing' to quote from the contributed article by Nathan Lewis. This roadmap focuses on solar-to-fuel conversion, solar water splitting, solar photovoltaics and bio-catalysis. It includes dye-sensitized solar cells (DSSCs), perovskite solar cells, and organic photovoltaics. Smart engineering of colloidal quantum materials and nanostructured electrodes will improve solar-to-fuel conversion efficiency, as described in the articles by Waiskopf and Banin and Meyer. Semiconductor nanoparticles will also improve solar energy conversion efficiency, as discussed by Boschloo et al in their article on DSSCs. Perovskite solar cells have advanced rapidly in recent years, including new ideas on 2D and 3D hybrid halide perovskites, as described by Spanopoulos et al 'Next generation' solar cells using multiple exciton generation (MEG) from hot carriers, described in the article by Nozik and Beard, could lead to remarkable improvement in photovoltaic efficiency by using quantization effects in semiconductor nanostructures (quantum dots, wires or wells). These challenges will not be met without simultaneous improvement in nanoscale characterization methods. Terahertz spectroscopy, discussed in the article by Milot et al is one example of a method that is overcoming the difficulties associated with nanoscale materials characterization by avoiding electrical contacts to nanoparticles, allowing characterization during device operation, and enabling characterization of a single nanoparticle. Besides experimental advances, computational science is also meeting the challenges of nanomaterials synthesis. The article by Kohlstedt and Schatz discusses the computational frameworks being used to predict structure-property relationships in materials and devices, including machine learning methods, with an emphasis on organic photovoltaics. The contribution by Megarity and Armstrong presents the 'electrochemical leaf' for improvements in electrochemistry and beyond. In addition, biohybrid approaches can take advantage of efficient and specific enzyme catalysts. These articles present the nanoscience and technology at the forefront of renewable energy development that will have significant benefits to society.

[Epistaxis and anticoagulation therapy: an analysis based on health insurance data from Lower Saxony]. / Epistaxis und antithrombotische Medikation: eine Analyse der Daten einer gesetzlichen Krankenversicherung in Niedersachsen.

BACKGROUND: Epistaxis is a common symptom in the medical practice. It is associated with various comorbidities and the use of medications, especially anticoagulants. Despite the high lifetime prevalence, there is limited data on prevalence and possible risk factors. METHODS: The study examines epistaxis care in a large patient population (AOK Lower Saxony) over a ten-year period (2007-2016). Risk factors, age at diagnosis, concomitant medication and comorbidities were analysed and the prevalence in the study period calculated. RESULTS: 162,167 patients visited their doctors between 2007-2016 (308,947 cases). Most patients were treated as outpatients (96.6%) and 54% of patients were men. Over the study period, the prevalence of epistaxis rose by 21% (increase from 8.6 to 9.3 per 1000 insured persons per year) with a comparatively stable prevalence for the inpatient setting (0.2 per 1000 insured persons per year). In 54,105 of all epistaxis cases (17.5%), the use of antithrombotic drugs was recorded (oral anticoagulants: 9.5%). During the study period, increased prescribing of oral anticoagulants (from 7.7% of cases in 2007 to 11.8% in 2016), especially of NOAC was documented (from 0.1% of cases in 2011 to 5.1% in 2016). CONCLUSION: In addition to arterial hypertension, the predominant male sex and the typical age distribution, we found that cases of epistaxis often received anticoagulation therapy. This study showed an increase of epistaxis along with rising prescriptions of NOAC. In contrast, no increase of severe epistaxis cases leading to hospitalization was found.

[Glucose metabolism in older patients]. / Glukosestoffwechsel im fortgeschrittenen Lebensalter.

Current guidelines for specialized treatment of diabetes mellitus in the elderly (>65 years old) are primarily based on epidemiologic studies and geriatric assessment of functional health. Yet, age-dependent alterations of glucose metabolism and homeostasis are highly relevant to the pathophysiology of diabetes in the elderly. In this review, we focus on age-related alterations in metabolic pathways and their relevance for the specialized diabetic care in the elderly. We review the role of increasing insulin resistance, age-related ß­cell dysfunction and incretin secretion. The clinical relevance of these effects will also be discussed in regard to the central geriatric syndrome of sarcopenia and antidiabetic drug therapy.

Rydberg Excitons in the Presence of an Ultralow-Density Electron-Hole Plasma.

We study the Rydberg exciton absorption of Cu_{2}O in the presence of free carriers injected by above-band-gap illumination. Already at plasma densities ρ_{EH} below one hundredth electron-hole pair per µm^{3}, exciton lines are bleached, starting from the highest observed principal quantum number, while their energies remain constant. Simultaneously, the band gap decreases by correlation effects with the plasma. An exciton line loses oscillator strength when the band gap approaches its energy, vanishing completely at the crossing point. Adapting a plasma-physics description, we describe the observations by an effective Bohr radius that increases with rising plasma density, reflecting the Coulomb interaction screening by the plasma.

Synthesis, chemical behavior, structure elucidation and iNOS inhibitory activity of 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines.

Novel slim and shapely sp3-rich nitrogen containing heterocyclic ring systems are sought-after platforms for the expansion of molecular diversity in lead discovery. The present work describes the synthesis and characterization of a series of derivatives of hitherto unknown 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines 2. This approach was guided by a computational study, aiming at an optimization of previously reported [1,2,4]triazolo[1,2-a]pyridazine-1-thiones 1 known to inhibit the inducible nitric oxide synthase (iNOS). The title compounds are accessible by methylation of compounds 1 under mild conditions. The products were biologically evaluated by the same cell-based assay as applied for previous products of type 1 using RINm5F cells, which were stimulated to produce NO on the influence of proinflammatory cytokines IL-1ß and IFN-γ. Compounds 2 did not display the anticipated improved iNOS inhibitory activity in the selected assay but contribute to SAR in the field. In addition, an unprecedented formation of side-products 3 via oxidation has been investigated. The novel scaffolds represent attractive starting points for the construction of diverse molecules which differ considerably from known compounds based on flat and lipophilic aromatic scaffolds.

[Principles and applications of susceptibility weighted imaging]. / Grundlagen und Anwendungen der suszeptibilitätsgewichteten Bildgebung.

BACKGROUND: Susceptibility-weighted imaging (SWI), initially developed to provide an improved method for cerebral magnetic resonance (MR) venography, is now an integral part of neuroradiological diagnostics and is steadily gaining importance in non-cerebral imaging. PRINCIPLES: Tissue-inherent susceptibility differences generate a local magnetic field in which the dephasing of signal-producing protons occurs. This leads to a characteristic phase shift that can be used as a means to enhance contrast in the well-known T2*-weighted imaging. APPLICATION IN CLINICAL ROUTINE: Many medically relevant pathologies induce tissue alterations that also influence the magnetic properties of tissue. Thus, the detection of blood residues and calcifications in SWI is superior to conventional MR sequences. FUTURE PROSPECTS: New techniques, such as quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI) allow improved differentiation between blood residues and calcifications and provide an alternative imaging method for fiber tractography with respect to diffusion tensor imaging.

[Selected clinically established and scientific techniques of diffusion-weighted MRI. In the context of imaging in oncology]. / Ausgewählte klinisch etablierte und wissenschaftliche Techniken der diffusionsgewichteten MRT. Im Kontext der onkologischen Bildgebung.

BACKGROUND: Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that was established in the clinical routine primarily for the detection of brain ischemia. In the past 15 years its clinical use has been extended to oncological radiology, as tumor and metastases can be depicted in DWI due to their hypercellular nature. PRINCIPLES: The basis of DWI is the Stejskal-Tanner experiment. The diffusion properties of tissue can be visualized after acquisition of at least two diffusion-weighted series using echo planar imaging and a specific sequence of gradient pulses. CLINICAL APPLICATIONS: The use of DWI in prostate MRI was reported to be one of the first established applications that found its way into internationally recognized clinical guidelines of the European Society of Urological Radiology (ESUR) and the prostate imaging reporting and data system (PI-RADS) scale. Due to recently reported high specificity and negative predictive values of 94% and 92%, respectively, its regular use for breast MRI is expected in the near future. Furthermore, DWI can also reliably be used for whole-body imaging in patients with multiple myeloma or for measuring the extent of bone metastases. OUTLOOK: New techniques in DWI, such as intravoxel incoherent motion imaging, diffusion kurtosis imaging and histogram-based analyses represent promising approaches to achieve a more quantitative evaluation for tumor detection and therapy response.

Healthcare utilization of people with type 2 diabetes in Germany: an analysis based on health insurance data.

AIMS: This population-based study assesses the healthcare utilization of people with Type 2 diabetes by analysing routine data from Allgemeine Orts-Krankenkasse (AOK), the largest statutory health insurance provider in Germany. METHODS: Anonymized billing data from all AOK-insured persons with at least one day of insurance during the evaluation year 2010 were analysed. Treatment and cost data from all areas of inpatient and outpatient care were available, as was information regarding patient age and sex. International Classification of Diseases (ICD-10) diagnosis and Anatomical Therapeutic Chemical (ATC) classification were used to identify 2.7 million insured persons with diabetes. RESULTS: The age- and sex-standardized prevalence of Type 2 diabetes was 9.8%. Of those patients identified, 33.9% had at least one diabetes-related complication and 83.0% had a diagnosis of hypertension. Almost two-thirds (63.1%) received antihyperglycaemic medication. Metformin and sulfonylurea were prescribed most often; medications without proof of benefit in endpoint studies were prescribed much less frequently. People without diabetes were admitted to hospital only half as often as those with Type 2 diabetes. The projected total expenditure in Germany for all people with Type 2 diabetes amounted to approximately €33.3 billion in 2010. CONCLUSIONS: This study shows an increase in both the prevalence of diabetes and treatment costs. The majority of people with Type 2 diabetes were aged 70 years or older. One third of this group has diabetes-related complications. Antihyperglycaemic medications without proof of benefit in endpoint studies were prescribed much less frequently than drugs with proof of benefit.

Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review.

BACKGROUND AND PURPOSE: Our aim was to evaluate the available evidence for pharmacological treatment of acute Lyme neuroborreliosis as a basis for evidence-based clinical recommendations in a systematic review. METHODS: A systematic literature search of Medline, EMBASE, the Cochrane Library and three trial registries was performed. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools. The primary outcome was 'residual neurological symptoms' whilst the secondary outcomes were disability, quality of life, pain, fatigue, depression, cognition, sleep, adverse events and cerebrospinal fluid pleocytosis. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening 5779 records, eight RCTs and eight NRS were included. Risk of bias was generally high. No statistically significant difference was found between doxycycline and beta-lactam antibiotics in a meta-analysis regarding residual neurological symptoms at 4-12 months [risk ratio (RR) 1.27, 95% confidence interval (CI) 0.98-1.63, P = 0.07] or adverse events (RR 0.82, 95% CI 0.54-1.25, P = 0.35). Significantly fewer neurological symptoms for cefotaxime compared with penicillin were found (RR 1.81, 95% CI 1.10-2.97, P = 0.02). Adverse events were significantly fewer for penicillin (RR 0.56, 95% CI 0.38-0.84, P = 0.005). CONCLUSIONS: Evidence regarding pharmacological treatment of acute Lyme neuroborreliosis is scarce and therefore insufficient to recommend preference of beta-lactam antibiotics over doxycycline or vice versa. However, due to considerable imprecision, relevant differences between treatments cannot be excluded. No evidence suggesting benefits of extended antibiotic treatments could be identified. Further well-designed trials are needed. Individual treatment decisions should address patients' preferences and individual conditions like prior allergic reactions.

Who gets dipyrone (metamizole) in Germany? Prescribing by age, sex and region.

WHAT IS KNOWN AND OBJECTIVE: Metamizole (dipyrone) is an analgesic that has been the focus of considerable controversy regarding its safety. Because of potentially life-threatening blood disorders such as agranulocytosis, it has been withdrawn in many countries but not in Germany, where prescribing even increased over recent years. We aimed to evaluate prescribing of metamizole in Germany with respect to age, sex and regional variations. METHODS: Using data of a statutory health insurance, we analysed a cohort of 1·7 million persons who were insured at least 1 day in each quarter of 2009. Outcome of interest was the outpatient prescription prevalence, for example the proportion of persons receiving at least one prescription of metamizole. RESULTS AND DISCUSSION: A total of 6·8% received metamizole with a higher prescribing prevalence in females (7·8% vs. 6·0%). The prevalence increased with age up to 26·7% in persons ≥85 years (men: 21·1%; and women: 30·4%). We found large regional variations with higher prevalences in the northern part of Germany. Most of the prescriptions were issued by general practitioners (78·9%). 58·3% were liquid oral formulations with considerable regional variations ranging between 32·3% in Mecklenburg-West Pomerania and 67·3% in North Rhine-Westphalia. Overall, liquid oral forms are much more often prescribed in the western than in the eastern part of Germany. WHAT IS NEW AND CONCLUSION: Metamizole - a drug with a relatively narrow indication - is often prescribed in Germany with relevant differences by age, sex and region. Qualitative studies should clarify reasons for this. Further quantitative research should investigate small-area variations, indications and treatment durations.

[Pain medication in nursing home residents with and without cancer. Most frequently with metamizole]. / Schmerzmittelversorgung von Pflegeheimbewohnern mit und ohne Krebserkrankung. Am häufigsten mit Metamizol.

BACKGROUND: Pain is a highly prevalent symptom in nursing home residents. The analgesic pharmacotherapy of older adults is associated with challenges; however, studies from Germany examining the prescription pattern of analgesics in nursing home residents are rare. OBJECTIVES: This study was carried out to examine the prescription of analgesics in nursing home residents with and without the diagnosis of cancer. MATERIAL AND METHODS: Using health insurance claims data persons aged ≥ 65 years who were newly admitted to a nursing home between 2004 and 2009 and who survived at least the first 90 days after admission were included in the study. Cancer was identified by outpatient diagnoses of malignant neoplasms (ICD-10: C00-C97). Prescription drugs within the first 90 days after admission to a nursing home were analyzed which means that aspirin and acetaminophen were not taken into account. RESULTS: A total of 5549 nursing home residents were included, who were on average 81.5 years old (56.8 % females). More than half (53.5 %) were assigned to care level I and 781 (14.1 %) were diagnosed with cancer. The study cohort received on average 7.8 different medications (with vs. without cancer: 8.6 vs. 7.6, respectively) and 43.8 % had prescriptions for analgesics (with vs. without cancer: 52.5 vs. 42.3 %, respectively). A total of 37.1 % were taking WHO step 1 analgesics (step 2: 11.4 % and step 3: 9.2 %). The proportion of persons receiving metamizole (dipyrone) was 28.3 % (with vs. without cancer: 35.6 vs. 27.1 %, respectively). Regarding all prescriptions, metamizole was by far the most frequently prescribed medication in nursing homes followed by melperone and omeprazole. CONCLUSION: Approximately one third of nursing home residents received metamizole and most were long-term prescriptions. Considering that metamizole is associated with potentially life-threatening adverse effects, caution is indicated particularly when prescribed over long periods.

[Application of the International Classification of Functioning, Disability and Health (ICF) in Psychosomatic Rehabilitation and Addiction Rehabilitation in Germany - The Current State]. / Anwendung der Internationalen Klassifikation der Funktionsfähigkeit, Behinderung und Gesundheit (ICF) in der psychosomatischen Rehabilitation und Suchtrehabilitation in Deutschland - eine Bestandsaufnahme.

OBJECTIVE: The aim of this study was to gather information on the current state of the implementation of the International Classification of Functioning, Disability and Health (ICF) in psychosomatic and addiction rehabilitation. METHODS: In the summer of 2013, rehabilitation clinics in Germany were surveyed online on their ICF utilization. The questionnaire covered scope and purpose of ICF use, application of ICF core sets and assessments as well as barriers to the use of ICF. RESULTS: Of 359 clinics invited, 104 (30%) participated in the survey. Of those surveyed, 60 (61.9%) claimed to have taken measures to implement the ICF in their clinic; only 37 (38.5%), however, reported using the ICF in their daily work. The main barriers identified were complexity of the ICF, time management issues and training deficits. CONCLUSION: Approaches to ICF use are not uniform. There is a need for training programs, and guidance from health care insurance providers could help towards uniform implementation of the ICF.

[Use and potential risks of over-the-counter analgesics]. / Gebrauch und potenzielle Risiken durch nicht verschreibungspflichtige Schmerzmittel.

BACKGROUND AND AIM: We investigated the use of prescription and non-prescription (over-the-counter, OTC) analgesics and the associated risks in elderly patients with multiple morbidities. METHODS: Pain medication use was evaluated from the baseline data (2008/2009) of the MultiCare cohort enrolling elderly patients with multiple morbidities who were treated by primary care physicians (trial registration: ISRCTN89818205). We considered opioids (N02A), other analgesics, and antipyretics (N02B) as well as nonsteroidal anti-inflammatory drugs (NSAIDs; M01A). OTC use, duplicate prescription, dosages, and interactions were examined for acetylsalicylic acid, diclofenac, (dex)ibuprofen, naproxen, and acetaminophen. RESULTS: Of 3,189 patients with multiple morbidities aged 65-85 years, 1,170 patients reported to have taken at least one prescription or non-prescription analgesic within the last 3 months (36.7 %). Of these, 289 patients (24.7 % of 1,170) took at least one OTC analgesic. Duplicate prescription was observed in 86 cases; 15 of these cases took the analgesics regularly. In two cases, the maximum daily dose of diclofenac was exceeded due to duplicate prescription. In 235 cases, patients concurrently took a drug with a potentially clinically relevant interaction. In 43 cases (18.3 % of 235) an OTC analgesic, usually ibuprofen, was involved. DISCUSSION: About one third of the elderly patients took analgesics regularly or as needed. Despite the relatively high use of OTC analgesics, the proportions of duplicate prescription, medication overdoses, and adverse interactions due to OTC products was low.

Synthesis and structure elucidation of 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thione, 3,3-disubstituted and 2-substituted derivatives and evaluation of their inhibitory activity against inducible nitric oxide synthase.

The 3-monosubstituted 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 (R1, R3 = H) were recently reported to possess inhibitory activity against inducible nitric oxide synthase in a cell based assay (Schulz et al. 2013). The 3,3-disubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 and 4 (R2,R3 ≠ H) were synthesized by cyclocondensation of the hexahydropyridazine-1-carbothioamides 1 with ketones. In order to access the 3,3-unsubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones, the unsubstituted parent system of these compounds, several synthetic routes were studied. By these methods the desired heterocyclic system 2a as well as new a-anellated and N-substutited hexahydropyridazines were obtained. The biological evaluation of the title compounds confirmed the previously made finding that an aromatic moiety in position 3 of the substance is important for an inducible nitric oxide synthase (iNOS) inhibitory activity.

Two histone deacetylases, FfHda1 and FfHda2, are important for Fusarium fujikuroi secondary metabolism and virulence.

Histone modifications are crucial for the regulation of secondary metabolism in various filamentous fungi. Here we studied the involvement of histone deacetylases (HDACs) in secondary metabolism in the phytopathogenic fungus Fusarium fujikuroi, a known producer of several secondary metabolites, including phytohormones, pigments, and mycotoxins. Deletion of three Zn(2+)-dependent HDAC-encoding genes, ffhda1, ffhda2, and ffhda4, indicated that FfHda1 and FfHda2 regulate secondary metabolism, whereas FfHda4 is involved in developmental processes but is dispensable for secondary-metabolite production in F. fujikuroi. Single deletions of ffhda1 and ffhda2 resulted not only in an increase or decrease but also in derepression of metabolite biosynthesis under normally repressing conditions. Moreover, double deletion of both the ffhda1 and ffhda2 genes showed additive but also distinct phenotypes with regard to secondary-metabolite biosynthesis, and both genes are required for gibberellic acid (GA)-induced bakanae disease on the preferred host plant rice, as Δffhda1 Δffhda2 mutants resemble the uninfected control plant. Microarray analysis with a Δffhda1 mutant that has lost the major HDAC revealed differential expression of secondary-metabolite gene clusters, which was subsequently verified by a combination of chemical and biological approaches. These results indicate that HDACs are involved not only in gene silencing but also in the activation of some genes. Chromatin immunoprecipitation with the Δffhda1 mutant revealed significant alterations in the acetylation state of secondary-metabolite gene clusters compared to the wild type, thereby providing insights into the regulatory mechanism at the chromatin level. Altogether, manipulation of HDAC-encoding genes constitutes a powerful tool to control secondary metabolism in filamentous fungi.