[Profiling of patients in a specialized geriatric outpatient clinic]. / Profilanalyse ambulanter Patienten einer geriatrischen Spezialsprechstunde.

BACKGROUND: In Germany geriatric outpatient care is predominantly done by family doctors and general practitioners (GP). There are regionally different concepts for additional specialized geriatric outpatient care but they have not yet been validated and established. Still, it remains unclear whether a geriatric patient has to be diagnosed rather in a specialized outpatient or inpatient setting. The aim of the present study is the profiling of geriatric outpatients to find key distinctions from geriatric patients that have to be admitted to hospital. METHODS: Retrospective data analysis of patients sent to a specialized geriatric outpatient clinic by their GP, compared with data of geriatric inpatients sent to hospital by their GP during the same time period. Study parameters comprised elements of the comprehensive geriatric assessment as well as results of routinely applied laboratory tests. RESULTS: Patients sent to the specialized geriatric outpatient clinic showed better results of functional assessments. Regression analysis: improvement of Barthel Index, GFR and total protein increased the chance of outpatient treatment. CONCLUSION: Early identification of geriatric patients who can be treated in a specialized outpatient setting would ease the burden for GPs by interdisciplinary cooperation and prevent cost-intensive readmissions to hospital.

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia.

Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F.

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade.

The family of death domain (DD)-containing proteins are involved in many cellular processes, including apoptosis, inflammation and development. One of these molecules, the adapter protein MyD88, is a key factor in innate and adaptive immunity that integrates signals from the Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily by providing an activation platform for IL-1R-associated kinases (IRAKs). Here we show that the DD-containing protein Unc5CL (also known as ZUD) is involved in a novel MyD88-independent mode of IRAK signaling that culminates in the activation of the transcription factor nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase. Unc5CL required IRAK1, IRAK4 and TNF receptor-associated factor 6 but not MyD88 for its ability to activate these pathways. Interestingly, the protein is constitutively autoproteolytically processed, and is anchored by its N-terminus specifically to the apical face of mucosal epithelial cells. Transcriptional profiling identified mainly chemokines, including IL-8, CXCL1 and CCL20 as Unc5CL target genes. Its prominent expression in mucosal tissues, as well as its ability to induce a pro-inflammatory program in cells, suggests that Unc5CL is a factor in epithelial inflammation and immunity as well as a candidate gene involved in mucosal diseases such as inflammatory bowel disease.

Ultra-fast carotid CT-angiography: low versus standard volume contrast material protocol for a 128-slice CT-system.

OBJECTIVES: Noninvasive imaging is increasingly accepted for the evaluation of atherosclerotic disease of the carotid arteries. We sought to evaluate the feasibility of a low-contrast media volume protocol for carotid computed tomography angiography (CTA) using a 128-slice-spiral-computed tomography scanner with a gantry rotation time of 300 milliseconds. METHODS AND MATERIALS: Thirty consecutive patients underwent CTA for the evaluation of the carotid vessels, with a 128-section scanner. Fifteen patients were examined with a standard volume contrast injection protocol (group A): 80 mL of contrast material (CM) were injected at 5 mL/s using the test bolus method to assess individual transit time. Another 15 patients were examined with a low-volume contrast media protocol (group B): 30 mL CM were injected at 4 mL/s using bolus tracking to trigger the CTA acquisition. In both groups, contrast administration was followed by a saline flush. Image quality and segmental vascular enhancement as well as the presence and degree of arterial stenosis were independently evaluated by 2 radiologists. Venous enhancement and streak artifacts at the thoracic inlet because of highly concentrated CM in the subclavian veins were evaluated in both groups. Kappa statistic and Pearson correlation coefficient were used to quantify interobserver variability. Qualitative data were compared using the Wilcoxon signed rank test and student t test was used to investigate differences in segmental vessel attenuation. RESULTS: All studies were of diagnostic quality in both groups. Interobserver agreement was high (kappa = 0.82, group A; kappa = 0.78, group B). Attenuation measurement showed excellent interobserver correlation in both groups (r > 0.9). Mean enhancement values were slightly higher in group A, but without statistical significance when averaged for all segments (P = 0.06). Streak artifacts impaired evaluation of 13 adjacent arterial segments in 8 patients at the level of the thoracic inlet in group A. In group B, only 1 segment was rated insufficient by both radiologists. Venous enhancement was significantly lower in group B (P = 0.04). The low-contrast protocol proved to be the more robust method with constant high arterial enhancement, less streak artifacts at the thoracic inlet, and less venous overlay. CONCLUSION: Using the latest CT technology, optimal depiction of the craniocervical arteries can be archived with a low-volume (30 mL) CM protocol.

Churg Strauss syndrome during treatment of bronchial asthma with a leucotriene receptor antagonist presenting with polyneuropathy.

Bronchial asthma can be associated with Churg Strauss syndrome (CSS). A peripheral neuropathy may be the initial manifestation of CSS. There is also some evidence that leucotriene receptor antagonists (LTAs) may trigger CSS in asthmatic patients, especially when steroids are tapered previously. However, the pathogenesis is unclear and the association between CSS and LTAs remains a matter of controversy. The aim of this report is to clarify this issue. A 79-year-old male patient with bronchial asthma for twenty years was admitted due to progressing gait disorder developing within the last two weeks. Asthma had been treated with a leucotriene receptor antagonist (Montelukast) for four years, as well as low doses of inhaled steroids and beta-2-agonists. On admission, neurological examination revealed a mild ataxia on both upper limbs and multifocal sensory disturbances without motor deficits. Nerve conduction velocity studies demonstrated normal results for the upper limbs and an axonal sensorimotor neuropathy of the lower limbs. Electromyography exhibited no spontaneous activity in the right tibialis anterior and rectus femoris muscle. Nerve-muscle biopsy revealed an eosinophilic vasculitis in both nerve and muscle. Laboratory examination showed leucocytosis and marked eosinophilia. A diagnosis of CSS was made. This case demonstrates a severe neuropathy in an asthmatic patient, during long lasting treatment with a LTA and continuous low doses of inhaled steroid, as the initial clinical feature of CSS.

Presentación polineuropática de un síndrome de Churg Strauss desarrollado durante el tratamiento con un antagonista del receptor de los leucotrienos / Churg Strauss syndrome during treatment of bronchial asthma with a leucotriene receptor antagonist presenting with polyneuropathy

El asma bronquial suele estar asociada con el síndrome de Churg Strauss (SCS). El SCS puede presentarse con una semiología polineuropática: También evidencia que los antagonistas del receptor de los leucotrienos (ARL) pueden precipitar un SCS en pacientes asmáticos, especialmente tras la supresión de corticoides. La patogenia, sin embargo, es incierta y la asociación de SCS y ARL controvertida. El caso aquí descrito pretende clarificar esta cuestión. Un paciente de 79 años con asma bronquial de 20 años de evolución fue hospitalizado porque desarrolló un trastorno de la marcha de 2 semanas de evolución. El asma había sido tratada con un ARL (Montelukast) durante 4 años, así como con inhalaciones de esteroides y betabloqueantes. Al ser admitido al hospital, la exploración neurológica reveló ligera ataxia de las manos e hipoestesia parcheada sin déficit motor. El estudio electroneurográfico puso de manifiesto signos de neuropatía sensitivomotora axonal en las piernas; en la electromiografía se registraron potenciales espontáneos de denervación en los músculos tibial anterior y recto anterior del muslo. La biopsia de músculo y nervio evidenció una vasculitis eosinofilica. En los estudios hematológicos había leucocitosis con eosinofilia. Se estableció un diagnóstico de SCS. Este caso demuestra la aparición de una acusada polineuropatía en un paciente asmático durante el tratamiento con un ARL y esteroides inhalados como forma de presentación del SCS (AU)

Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists.

We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053.

Reinserción social, capacidad funcional y supervivencia alejada al egreso de áreas críticas / Social reinsertion, functional capacity and survival far from leaving critical areas

Objetivos: 1) Establecer grado de supervivencia alejada (10 meses o más) al egreso de UTI; 2) Relacionar la mortalidad con los niveles de gravedad en la admisión (Score Mapuche) y el desarrollo de fracasos orgánicos (FO); 3) Relacionar las reinternaciones con el nivel de gravedad y la patología de base; 4) Evaluar la calidad de vida y el grado de reinserción laboral y social a través de parámetros objetivos y subjetivos; 5) Evaluar aspectos psíquicos y de relación médico-paciente referidos a la internación en UTI, según patología de base, y relacionarlos con secuelas psicofísicas posteriores y con reinternaciones; 6) Describir las características de la población fallecida al egreso de UTI. Material y métodos: Diseño prospectivo, observacional, transversal. Se incluyeron 105 pacientes asistidos en UTI y egresados vivos en 2 períodos: enero-septiembre 1991 y septiembre 1992-agosto 1993 (muestra azarizada), y pacientes nivel IV de la clasificación Mapuche y con 3 o más FO (en cualquier nivel), en iguales períodos, que egresaron vivos (muestra consecutiva). Se usaron como métodos estadísticos: media, porcentajes, desvío standar, chi cuadrado, T de Student y Test de Wilcoxon. Se registraron datos por revisión de Dbase y por encuesta personal o telefónica, referidos a supervivencia, y a las áreas psicológicas, afectiva, social, laboral, y a la capacidad funcional. Resultados y conclusiones: 1) Muestra con media de edad 60 años, 55 por ciento sexo M, el 67 por ciento internados menos de 6 días... 2) Sobrevivió el 79 por ciento,... 3) Mortalidad 21 por ciento... 4) Se reinternó el 16,8 por ciento... 5) El 31 por ciento presentó amnesia al egreso... 6) El 22 por ciento quienes trabajaban dejó de hacerlo; 7) El deterioro de las actividades cotidianas fue entre 13 y 61,4 por ciento; 8) El 14,4 por ciento presentó deterioro psíquico; 9) El 17 por ciento tuvo molestias en su internación, y el 50 por ciento de las mismas se debió a factores humanos del personal; 10) Se presentó miedo en el 24 por ciento... 11) Se halló relación entre deterioro psíquico y malas experiencias durante la internación... 12) El consumo de fármacos fue más alto al egreso; 13) Se observaron diferencias de mortalidad en pacientes de niveles I y II con menos de 3 FO; 14) El Mapuche mostró diferencias significativas entre fallecidos y sobrevivientes, no así los FO; 15) Hubo distinta mortalidad en ambos períodos, asociada a diferencias en el Mapuche (sin diferencias de edad y FO)

Reinserción social, capacidad funcional y supervivencia alejada al egreso de áreas críticas / Social reinsertion, functional capacity and survival far from leaving critical areas

Objetivos: 1) Establecer grado de supervivencia alejada (10 meses o más) al egreso de UTI; 2) Relacionar la mortalidad con los niveles de gravedad en la admisión (Score Mapuche) y el desarrollo de fracasos orgánicos (FO); 3) Relacionar las reinternaciones con el nivel de gravedad y la patología de base; 4) Evaluar la calidad de vida y el grado de reinserción laboral y social a través de parámetros objetivos y subjetivos; 5) Evaluar aspectos psíquicos y de relación médico-paciente referidos a la internación en UTI, según patología de base, y relacionarlos con secuelas psicofísicas posteriores y con reinternaciones; 6) Describir las características de la población fallecida al egreso de UTI. Material y métodos: Diseño prospectivo, observacional, transversal. Se incluyeron 105 pacientes asistidos en UTI y egresados vivos en 2 períodos: enero-septiembre 1991 y septiembre 1992-agosto 1993 (muestra azarizada), y pacientes nivel IV de la clasificación Mapuche y con 3 o más FO (en cualquier nivel), en iguales períodos, que egresaron vivos (muestra consecutiva). Se usaron como métodos estadísticos: media, porcentajes, desvío standar, chi cuadrado, T de Student y Test de Wilcoxon. Se registraron datos por revisión de Dbase y por encuesta personal o telefónica, referidos a supervivencia, y a las áreas psicológicas, afectiva, social, laboral, y a la capacidad funcional. Resultados y conclusiones: 1) Muestra con media de edad 60 años, 55 por ciento sexo M, el 67 por ciento internados menos de 6 días... 2) Sobrevivió el 79 por ciento,... 3) Mortalidad 21 por ciento... 4) Se reinternó el 16,8 por ciento... 5) El 31 por ciento presentó amnesia al egreso... 6) El 22 por ciento quienes trabajaban dejó de hacerlo; 7) El deterioro de las actividades cotidianas fue entre 13 y 61,4 por ciento; 8) El 14,4 por ciento presentó deterioro psíquico; 9) El 17 por ciento tuvo molestias en su internación, y el 50 por ciento de las mismas se debió a factores humanos del personal; 10) Se presentó miedo en el 24 por ciento... 11) Se halló relación entre deterioro psíquico y malas experiencias durante la internación... 12) El consumo de fármacos fue más alto al egreso; 13) Se observaron diferencias de mortalidad en pacientes de niveles I y II con menos de 3 FO; 14) El Mapuche mostró diferencias significativas entre fallecidos y sobrevivientes, no así los FO; 15) Hubo distinta mortalidad en ambos períodos, asociada a diferencias en el Mapuche (sin diferencias de edad y FO) (AU)

DL-tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy.

At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.

Static and dynamic stresses during valve closure of a bileaflet mechanical heart valve prosthesis.

The effect of contact geometry and component compliance on the magnitude, distribution, and state of various types of stresses on a bileaflet mechanical heart valve prosthesis during valve closure was analyzed using an Edwards-Duromedics mitral valve as example. Static and dynamic stresses developing on both the leaflet and pivot ball during valve closure were modeled using finite element analysis (FEA). Uniform contact between the leaflet and housing as well as between the pivot ball and pivot slot can significantly reduce both static and dynamic stresses around the contact area. The level of the dynamic flexural stresses can be an order of magnitude higher than that of the static stresses. When both the radial and axial compliance of the housing are taken into consideration, peak dynamic stress was more than 40% less than that generated through the impact between a moving leaflet and a non-compliant rigid housing.