Targets of antidementive therapy: drugs with a specific pharmacological mechanism of action

Diagnosis and therapy of dementia have made considerable progress in recent years. Drugs have been developed which improve cognitive performance, delay the loss of abilities of daily living and prevent early nursing home placement in a considerable number of patients. With the various pharmacological and non-pharmacological approaches, effective treatment options of AD are available at present and the therapeutic potential will even increase in future. Thus, the treatment of dementia should more focused and explicit in its goals for the doctor, the patient and the relatives. Therapeutic targets must be defined on the basis of the individual needs and deficits and with regard to different levels of the disease process. Ideally, treatment should always aim at an etiological and/or a pathophysiological level. At present, however, aiming at the neurotransmitter level, the core syndrome of cognitive deficits can be approached by treatment options. Further therapeutic targets can be defined on the level of activities of daily living, following a resource focused approach, as well as on the level of behavioral disturbances. Additional therapeutic targets should be seen under a humanitarian or palliative perspective. And finally, family members are also targets for therapy in dementia, even if such therapy is not directed towards the demented patient. All these treatment targets have to be evaluated and adapted under the perspective of time because prominent symptoms in AD change considerably with disease progression. Selection and adaptation of medication becomes easier if such targets are considered and if therapeutic effects are monitored target-specifically.     

Use of brief depression screening tools in primary care: consideration of heterogeneity in performance in different patient groups

Heterogeneity of performance of screening tools in different patient groups has rarely been considered in the literature on depression screening in primary care. The objectives of the present study were to assess and to compare diagnostic accuracy of three screening questionnaires (Brief Patient Health Questionnaire, General Health Questionnaire-12, WHO-5) in identifying depression across various patient subpopulations and to assess the accuracy of the unaided clinical assessment of primary care physicians in the same subgroups. We conducted a cross-sectional validation study in 448 primary care patients. Two-by-two tables as well as receiver operating characteristics were applied. Results indicated that diagnostic accuracy (sensitivity, specificity) of the three screening instruments as well as of the clinical diagnoses differed in the various patient groups. Superiority of one screening tool over the other depends on the subgroup considered. Gender, age, form (subtype), and severity of depression influence the test characteristics of a screening tool. This should be considered if routine depression screening should be widely introduced. Of course, the benefit of routine screening also depends on efforts made for treatment and monitoring of patients in whom depression was diagnosed.     

Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data

BACKGROUND: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. METHODS: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. RESULTS: Enrollment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. CONCLUSION: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.     

Heat shock protein-27 is upregulated in the temporal cortex of patients with epilepsy

PURPOSE: Heat shock protein-27 (HSP-27) belongs to the group of small heat shock proteins that become induced in response to various pathologic conditions. HSP-27 has been shown to protect cells and subcellular structures, particularly mitochondria, and serves as a carrier for estradiol. It is a reliable marker for tissues affected by oxidative stress. Oxidative stress and related cellular defence mechanisms are currently thought to play a major role during experimentally induced epileptic neuropathology. We addressed the question whether HSP-27 becomes induced in the neocortex resected from patients with pharmacoresistant epilepsy. METHODS: Human epileptic temporal neocortex was obtained during neurosurgery, and control tissue was obtained at autopsy from subjects without known neurologic diseases. The tissues were either frozen for Western blot analysis or fixed in Zamboni's fixative for the topographic detection of HSP-27 at the cellular level by means of immunohistochemistry. RESULTS: HSP-27 was highly expressed in all epilepsy specimens and in the cortex of a patient who died in the final stage of multiple sclerosis (positive control), whereas only low amounts of HSP-27 were detectable in control brains. In epilepsy patients, HSP-27 was present in astrocytes and in the walls of blood vessels. The intracortical distribution patterns varied strongly among the epilepsy specimens. CONCLUSIONS: These results demonstrate that HSP-27 becomes induced in response to epileptic pathology. Although the functional aspects of HSP-27 induction during human epilepsy have yet to be elucidated, it can be concluded that HSP-27 is a marker for cortical regions in which a stress response has been caused by seizures.     

Sind plazebokontrollierte Studien zum Wirksamkeitsbeweis von Antidepressiva notwendig?

Ohne Zusammenfassung     

Classification,identification and subtyping of bacteria based on pyrosequencing and signature matching of 16S rDNA fragments

The rapid identification of the etiological agent of microbial infections can bring about both clinical and financial benefits. Thus, fast and generally applicable classification methods are needed that will enable us to rapidly distinguish pathogenic bacteria from commensals or saprophytic bacteria found in the same habitat. We here show that provisional classification of bacterial isolates can be performed on a large scale based on 16S rRNA sequence comparisons using Pyrosequencing, a recently described real-time DNA sequence analysis technique, and the concept of signature matching. The probes we have developed, together with the new technology, will enable early diagnosis of specific pathogens, which is critical for the rational use of antimicrobial therapy in clinical medicine.