Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Laser-induced fluorescence studies of the biodistribution of carotenoporphyrins in mice.

The biodistribution of two recently developed tumour markers, trimethylated (CP(Me)3) and trimethoxylated (CP(OMe)3) carotenoporphyrin, was investigated by means of laser-induced fluorescence (LIF) after i.v. injection into 38 tumour-bearing (MS-2 fibrosarcoma) female Balb/c mice. At 3, 24, 48 or 96 h after administration, the carotenoporphyrin fluorescence was measured in tumoral and peritumoral tissue, as well as in the abdominal, thoracic and cranial cavities. The fluorescence was induced by a nitrogen laser-pumped dye laser, emitting light at 425 nm, and analysed by a polychromator equipped with an image-intensified CCD camera. The fluorescence was evaluated at 490, 655 and 720 nm: the second and third wavelengths represent the carotenoporphyrin (CP)-related peaks, whereas the first one is close to the peak of the tissue autofluorescence. The tumour and the liver were the two tissue types showing the strongest carotenoporphyrin-related fluorescence, whereas the cerebral cortex and muscle consistently exhibited weak substance-related fluorescence. In most tissue types, the fluorescence intensities decreased over time. A few exceptions were observed, notably the liver, in which the intensity remained remarkably constant over the time period investigated.     

Fungal endocarditis — a report on seven cases and a brief review

Summary Candida endocarditis is an unusual but severe complication of systemic infection caused byCandida albicans and occasionally by other fungal species. We describe seven cases that occurred during a period of 20 years in western Sweden. In four cases infections were located on prosthetic valves and in three cases native valves were involved. Three patients died of the disease in the acute phase. A definite diagnosis was established in one of four survivors. This patient had an aortic valve endocarditis and a saddle embolisation and was treated with immediate surgery, followed by intensive treatment with liposomal amphotericin B + flucytosine. Fungal endocarditis is still a serious disease with a high mortality and whenever the diagnosis is suspected, antifungal therapy must be started and transesophageal sonography should be performed to visualize vegetations. Immediate surgery should be considered.

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Pilzendokarditis — Bericht über sieben Fälle und kurze Literaturübersicht

Zusammenfassung DieCandida-Endokarditis ist eine seltene, aber schwere Komplikation einer systemischen Infektion durchCandida albicans und gelegentlich auch durch andere Pilzspezies. Wir berichten über sieben Fälle, die in einem Zeitraum von 20 Jahren in Westschweden beobachtet wurden. In vier Fällen waren Klappenprothesen und in drei Fällen natürliche Klappen betroffen. Drei Patienten starben in der akuten Phase an der Krankheit. Bei einem der vier überlebenden Patienten konnte die Diagnose eindeutig gesichert werden. Dieser Patient hatte eine Aortenklappenendokarditis und einen reitenden Embolus. Er wurde sofort operiert und hochdosiert mit liposomalem Amphotericin B und mit Flucytosin behandelt. Die Pilzendokarditis ist nach wie vor eine ernste, mit hoher Letalität belastete Krankheit. Die antimykotische Therapie muß bereits beim ersten Verdacht begonnen werden. Um Vegetationen nachzuweisen, sollte die transösophageale Sonographie durchgeführt werden. Ein sofortiges chirurgisches Eingreifen ist zu erwägen.

     

Discrimination of idiopathic pain syndromes from neurogenic pain syndromes and healthy volunteers by means of clinical rating,personality traits,monoamine metabolites in CSF,serum cortisol,platelet MAO and urinary melatonin

Summary The aim of the present study was to investigate the discriminative power of a series of variables (including determination of depressive symptomatology by means of a visual analogue scale, determination of personality traits by means of the Karolinska Scales of Personality, determination of monoamine metabolites in CSF, platelet MAO activities, serum cortisol before and after dexamethasone suppression and urinary melatonin) in differentiating (a) chronic pain patients from healthy subjects, and (b) patients with idiopathic pain syndromes from patients with neurogenic pain syndromes. Separately each of the measures gave a significant but often low contribution to the discrimination, while a combination of several measures gave a complete discrimination both between healthy subjects and patients with chronic pain syndromes and between patients with idiopathic and neurogenic pain syndromes, respectively.Supported in part by grants from the Swedish Medical Research Council (grants no. 3371, 4145 and 5740) and by a grant from Stiftelsen Söderström-Königska Sjukhemmet     

Precision grip function after free toe transfer in children with hypoplastic digits.

Although toe-to-hand transfer has a defined role in the management of congenital hand deformities, it remains unclear how well children integrate the transferred digits into physiological grasping. We analysed fingertip forces in the precision grip of 13 patients when lifting a test object more than three years after free toe transfer for absent or hypoplastic digits. Clinically, most patients showed normal sensibility of transferred digits, but active motion and pinch strength were limited as compared to the normal hand. For the control of fingertip forces, two key features of the normal two-digit opposition grip were seen in all operated hands: adaptation of grip force to object weight and parallel coordination of lift and grip forces. These physiological grasping strategies developed independently of the patients' age at the time of operation, which ranged from one to 13 years. In four patients, we observed increased tangential load forces with the operated hand due to misalignments in the application of fingertips on the grasp surfaces. Such forces lead to increased grip force requirements on both fingers that may overload transferred digits with limited motor function. The need for optimal alignment of the grip axis during toe-transfer surgery is emphasised.