Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP_wt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ₄₂) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ₄₂ were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.     

Chronic thromboembolic pulmonary hypertension: surgical treatment with thromboendarterectomy

Background and objectivesPulmonary thromboendarterectomy (PTE) is considered the potential curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH). We analysed the results of the PTE application in our institution.Patients and methodsFrom February 1996 to December 2007, 30 patients with CTEPH underwent videoassisted PTE. Preoperative hemodynamic data were: systolic pulmonary artery pressure (SPAP) 87±17 mmHg, mean pulmonary artery pressure (MPAP) 51±11 mmHg, pulmonary total resistance 1067±485 dynes·s·cm^?5, pulmonary vascular resistance 873±389 dynes·s·cm^?5 and cardiac index 2.2±0.5 l/min/m². We analysed the influence of several factors on hospital mortality and survival, and we performed partial analysis of mortality since 2004.ResultsPTE resulted in significant improvements in SPAP (P<0.001), MPAP (P=0.001) and cardiac index (P<0.001). Hospital mortality was 17% (5/30) (95% confidence interval, 6%-35%). From 2004, it dropped to 5% (1/20) (95% confidence interval, 0%-25%). Hospital mortality was influenced by preoperative pulmonary total resistance, preoperative pulmonary vascular resistance, postoperative SPAP, reduction of SPAP, reduction of MPAP, reperfusion pulmonary oedema and residual postoperative pulmonary hypertension (P=0.036; P=0.018;P=0.013; P=0.050; P=0.050; P=0.030; P=0.045). Survival after PTE, including hospital mortality, was 76±9% at 10 years. Through long-term follow-up, functional status (P=0.001), 6 min walking distance (P=0.001), end-diastolic right ventricle size (P<0.001), and tricuspid regurgitation (P<0.001) significantly improved.ConclusionsPTE effectively reduces pulmonary hypertension and offers CTEPH patients a substantial improvement in survival and quality of life.     

Hairy cell leukemia and myelomatosis: chance association or clinical manifestations of the same B-cell disease spectrum

We describe three patients who had typical features of hairy cell leukemia (HCL) and multiple myeloma (MM) at the same time. In two, both diagnoses were made within a short period of time, and in the third, HCL had been present for 2 yr before the appearance of a paraprotein, bone lesions, and plasma-cell infiltrates established the diagnosis of MM. Although this association has not been previously reported, cases of HCL with osteolytic lesions or a paraprotein band have been described. The cases described may represent clinical manifestations of closely related disorders arising from divergent differentiation from a common B-cell precursor rather than a chance association.