La enfermedad de Alzheimer (EA) es la primera causa de demencia y una de las principales causas de discapacidad y dependencia que afecta la calidad de vida de los adultos mayores y de sus familiares. ...En la actualidad el manejo farmacológico disponible incluye a los fármacos inhibidores de la acetilcolinesterasa (donepezilo, galantamina, rivastigmina) y a la memantina. Sin embargo, se ha reportado que solo un tercio de los pacientes responden al tratamiento. Se ha evidenciado que los factores genéticos pueden explicar parte de la variabilidad en la respuesta a estos fármacos.
En esta revisión se incluyen los estudios farmacogenéticos de fármacos modificadores de EA, los farmacogenes analizados y los fenotipos que fueron evaluados, además de las consideraciones metodológicas que es importante tomar en cuenta en este tipo de estudios. Se encontraron 33 reportes de farmacogenética de EA en los que principalmente se ha estudiado la variabilidad en la respuesta y en el metabolismo de donepezilo. La población más estudiada es la caucásica, aunque también han sido investigados coreanos, indios y brasileños. Los biomarcadores más estudiados son CYP2D6 y APOE. Los resultados de las asociaciones son controversiales.
Se han identificado posibles biomarcadores farmacogenéticos para el tratamiento de EA; sin embargo, se requieren más estudios farmacogenéticos en otras poblaciones que no han sido investigadas, así como profundizar en la identificación de los biomarcadores. Este conocimiento podría ayudar a predecir la respuesta a fármacos modificadores de EA y contribuiría a tomar mejores decisiones en el tratamiento de la enfermedad en un contexto tan complejo como es el envejecimiento.
Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.
We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.
Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.
Zusammenfassung
Pflanzliche Arzneimittel und Pflanzenextrakte (oft gleichgesetzt mit Phytotherapeutika) werden bei Kindern häufig ohne ärztliche Verordnung angewandt. Entgegen der landläufigen ...Meinung, dass es für pflanzliche Präparate keine evidenzbasierten Studien gäbe, zeigt ein Blick in die wissenschaftliche Literatur, dass für einige klinisch relevante Symptome sehr wohl kontrollierte Studien mit Kindern und Jugendlichen existieren. Zu den am besten untersuchten Indikationsgebieten zählen Magen-Darm-Beschwerden, Atemwegsinfektionen und mit Einschränkung psychische Störungen. Die untersuchten pflanzlichen Arzneimittel oder Pflanzenextrakte zeigten teilweise im Vergleich zu Standardtherapien und/oder Placebo statistisch signifikante und klinisch relevante positive Wirkungen auf den Krankheitsverlauf. Schwerwiegende unerwünschte Ereignisse wurden in den zitierten Studien in keiner Behandlungsgruppe beobachtet. Diese Übersichtsarbeit fasst die Ergebnisse der für den ärztlich-praktischen Alltag relevanten kontrollierten Studien, einschließlich Sicherheitsaspekten, zu den genannten Indikationsgebieten zusammen und gibt praktische Empfehlungen für die Umsetzung.
To estimate the potential global economic productivity loss associated with the existing burden of visual impairment from uncorrected refractive error (URE).
Conservative assumptions and national ...population, epidemiological and economic data were used to estimate the purchasing power parity-adjusted gross domestic product (PPP-adjusted GDP) loss for all individuals with impaired vision and blindness, and for individuals with normal sight who provide them with informal care.
An estimated 158.1 million cases of visual impairment resulted from uncorrected or undercorrected refractive error in 2007; of these, 8.7 million were blind. We estimated the global economic productivity loss in international dollars (I$) associated with this burden at I$ 427.7 billion before, and I$ 268.8 billion after, adjustment for country-specific labour force participation and employment rates. With the same adjustment, but assuming no economic productivity for individuals aged > 50 years, we estimated the potential productivity loss at I$ 121.4 billion.
Even under the most conservative assumptions, the total estimated productivity loss, in $I, associated with visual impairment from URE is approximately a thousand times greater than the global number of cases. The cost of scaling up existing refractive services to meet this burden is unknown, but if each affected individual were to be provided with appropriate eyeglasses for less than I$ 1000, a net economic gain may be attainable.
To estimate the global cost of establishing and operating the educational and refractive care facilities required to provide care to all individuals who currently have vision impairment resulting ...from uncorrected refractive error (URE).
The global cost of correcting URE was estimated using data on the population, the prevalence of URE and the number of existing refractive care practitioners in individual countries, the cost of establishing and operating educational programmes for practitioners and the cost of establishing and operating refractive care facilities. The assumptions made ensured that costs were not underestimated and an upper limit to the costs was derived using the most expensive extreme for each assumption.
There were an estimated 158 million cases of distance vision impairment and 544 million cases of near vision impairment caused by URE worldwide in 2007. Approximately 47 000 additional full-time functional clinical refractionists and 18 000 ophthalmic dispensers would be required to provide refractive care services for these individuals. The global cost of educating the additional personnel and of establishing, maintaining and operating the refractive care facilities needed was estimated to be around 20 000 million United States dollars (US$) and the upper-limit cost was US$ 28 000 million. The estimated loss in global gross domestic product due to distance vision impairment caused by URE was US$ 202 000 million annually.
The cost of establishing and operating the educational and refractive care facilities required to deal with vision impairment resulting from URE was a small proportion of the global loss in productivity associated with that vision impairment.
Zusammenfassung
Hintergrund
Tödliche Schussverletzungen stellen einen kleinen, aber hochrelevanten Anteil des rechtsmedizinischen Untersuchungsguts dar.
Material und Methode
Es wird eine ...retrospektive rechtsmedizinische Studie aus dem Sektionsgut der 3 Berliner rechtsmedizinischen Institute des Zeitraums 2000–2009 vorgestellt. Die Auswertung erfolgte im Hinblick auf rechtsmedizinisch sowie demografisch relevante Merkmale und deren Bezüge zueinander. Weiter wurde die Überlebenszeit nach Schussverletzungen analysiert.
Ergebnisse
Es wurden 332 Schusstodesfälle ausgewertet (90 % Männer, Durchschnittsalter 54,3 Jahre). In mehr als drei Vierteln der Fälle wurde Suizid begangen, mehrheitlich mit illegal besessenen Waffen. Die Schusshand des Suizidenten konnte in 59 % der Fälle identifiziert werden. Am Ereignisort bzw. auf dem Weg ins Krankenhaus verstarben 86 % der Opfer (mediane Überlebenszeit 2 h 27 min 30 s). Lag Alkoholkonsum vor, waren die Opfer in 54 % der Fälle stark alkoholisiert Blutalkoholkonzentration (BAK) > 1,5 mg/g. Kurzwaffen (Pistolen 53 %, Revolver 18 %) fanden am häufigsten Verwendung. Nahschüsse waren in 81 % der Fälle zu verzeichnen; Durchschüsse überwogen (62 %). Durchschnittlich wurden 1,39 Schüsse/Todesfall abgegeben. Am häufigsten war der Kopf des Opfers betroffen (66 %; Kopfdurchschüsse 55 %, Kopfsteckschüsse 21 %). Die meisten Schusswaffensuizide ereigneten sich in den Sommermonaten. Tötungen durch Schusswaffen fanden sich in 20 % der Fälle; im Beobachtungszeitraum ereignete sich lediglich ein tödlicher Unfall mit Schusswaffen.
Schlussfolgerung
Schusstodesfälle stellen insbesondere im Hinblick auf Suizid und illegalen Waffenbesitz weiterhin ein relevantes Problem dar. Jeder Schusstodesfall erfordert eine interdisziplinäre Aufarbeitung, da einzelne morphologische Aspekte nicht allein als für Suizid, Homizid oder Unfall beweisend angesehen werden können. Die Zahl der Schussverletzungen bedingt nicht die Überlebenszeit.
The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 Mb region of chromosome 22. It ...constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), which is responsible for loading Ca(2+) into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca(2+) load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8(+/-) mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.
The ability to use magnets external to the body to focus therapy to deep tissue targets has remained an elusive goal in magnetic drug targeting. Researchers have hitherto been able to manipulate ...magnetic nanotherapeutics in vivo with nearby magnets but have remained unable to focus these therapies to targets deep within the body using magnets external to the body. One of the factors that has made focusing of therapy to central targets between magnets challenging is Samuel Earnshaw’s theorem as applied to Maxwell’s equations. These mathematical formulations imply that external static magnets cannot create a stable potential energy well between them. We posited that fast magnetic pulses could act on ferromagnetic rods before they could realign with the magnetic field. Mathematically, this is equivalent to reversing the sign of the potential energy term in Earnshaw’s theorem, thus enabling a quasi-static stable trap between magnets. With in vitro experiments, we demonstrated that quick, shaped magnetic pulses can be successfully used to create inward pointing magnetic forces that, on average, enable external magnets to concentrate ferromagnetic rods to a central location.
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