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.     

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.     

Identification of the site on IgG Fc for interaction with streptococci of groups A, C and G.

The interaction between living groups A, C and G streptococci and IgG Fc was studied using human IgG, IgG Fc and IgG Fc-intermediate (Fci) fragments, chemically modified human IgG and fragment D of staphylococcal protein A (SPA). Diethylpyrocarbonate modification of His or N-acetylimidazole modification of Tyr of human IgG resulted in the loss of its capacity to inhibit the binding of radiolabelled human IgG Fc to the group A streptococci types M1 and M55, and to the group C strain SC-1, indicating that the amino acids His and Tyr are involved in the binding. Lys seems not to participate in the binding of IgG to these bacteria, however, since reductive methylation of Lys did not reduce its inhibitory capacity. Fragment D of SPA also inhibited the binding of radiolabelled human IgG Fc to strains M1, M55 and SC-1. We have previously shown that these bacteria do not bind to IgG fragments consisting of only the C gamma 2 or C gamma 3 domains. On the basis of these results, and the known relative positions in space of the His and Tyr residues on IgG Fc, it is speculated whether streptococci with IgG Fc receptors, like SPA and rheumatoid factors, interact with IgG in the interface between the C gamma 2 and C gamma 3 domains and involve His 435 and one or more of Tyr 436, His 433 and His 310. The similarities in binding sites on IgG for RFs and these bacterial Fc binding proteins suggest structural similarities between them that may be relevant to the production of rheumatoid factors in rheumatoid arthritis.     

Fusimotor reflexes to antagonistic muscles simultaneously assessed by multi-afferent recordings from muscle spindle afferents

Several single agonist/antagonist primary muscle spindle afferents were simultaneously recorded in chloralose anaesthetized cats. It was shown that their dynamic and static sensitivity to sinusoidal muscle stretches could be increased or decreased via the fusimotor system by extension and flexion of the contralateral hind limb as well as by stretch of ipsilateral muscles and stimulation of ipsilateral skin nerves. The results seem to support the hypothesis that the primary muscle spindle afferents convey complex multisensory messages to the central nervous system (CNS).     

Dimensional alterations of the gingiva related to changes of facial/lingual tooth position in permanent anterior teeth of children

Abstract Maxillary and mandibular anterior permanent teeth in 38 children aged 7–12 years were examined 2 × with an interval of 2 years to determine whether spontaneous facial/lingual tooth position changes were related to alterations of the widths of keratinized and attached gingiva and the clinical crown height. Measurements included dental plaque, gingival inflammation, probing depth, and width of keratinized and attached gingiva. In addition, study casts from the baseline and 2-year examinations were used to measure clinical crown height and tooth position. The results showed that significant alterations in the widths of the keratinized and attached gingiva took place when the teeth changed positions in facial or lingual directions. The changes in gingival widths could to some extent be coupled to changes in clinical crown height. In teeth moving lingually, the gingival widths increased and the clinical crown height decreased. In teeth moving facially, the gingival widths decreased, and the facial gingiva sometimes receded. These gingival alterations call for examination of the facial gingiva as part of the monitoring of the development of the permanent dentition.     

Stricture and perforation of the esophagus: Overlooked threats in the Zollinger-Ellison syndrome

This study was undertaken to assess the frequency of significant esophageal involvement in the Zollinger-Ellison syndrome (ZES). In a consecutive series of 24 patients with this disease, 9 (37%) showed endoscopic evidence of acid-induced esophageal lesions ranging from erosive inflammation to ulceration with massive bleeding, severe stricture formation, and perforation. In 3 cases, pronounced esophagitis was known 1–5 years before the underlying disease was diagnosed. Severe esophageal complications developed despite treatment with antisecretory drugs. It is emphasized that the best way to limit such complications is by excision of the underlying gastrin-secreting tumor(s) when possible.

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Resumen El presente estudio fue emprendido con el propósito de determinar la frecuencia de afección ácido péptica significativa del esófago en pacientes con síndrome de Zollinger-Ellison. En una serie de 24 pacientes consecutivos con esta enfermedad, 9 (37%) exhibieron evidencia endoscópica de lesiones esofágicas inducidas por ácido, las cuales variaron entre inflamación erosiva y ulceración con sangrado masivo, estrechez severa, y perforación. En 3 pacientes se conocía la existencia de esofagitis severa entre 1 y 5 años antes del diagnóstico de la enfermedad de base. Se desarrollaron graves complicaciones esofágicas a pesar del tratamiento con drogas antisecretorias en 3 pacientes. Se hace enfasis en que la mejor manera de disminuir tales complicaciones es mediante la resección del tumor(es) secretor de gastrina, cuando ello sea posible.

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Résumé Nous avons entrepris cette étude pour établir la fréquence de participation oesophagienne dans le syndrome de Zollinger-Ellison. Pour une série de 24 patients présentant cette maladie, 9 (37%) avaient à l'endoscopie des lésions oesophagiennes dues à l'acidité allant de l'érosion inflammatoire à l'ulcération avec saignement important, sténose sévère, et perforation. Dans 3 cas, une oesophagite importante était connue 1–5 ans avant que la maladie sous-jacente soit diagnostiquée. Des complications oesophagiennes sévères se sont produites malgré le traitement antisécrétoire. Nous insistons sur le fait que le meilleur moyen de limiter ces complications est d'exciser chaque fois que possible la ou les tumeurs sous-jacentes sécrétant la gastrine.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.

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Supported by grants from the Swedish Medical Research Council, the Swedish Society of Medicine, the Anders Otto Swärd Foundation, and the Surgery Foundation of Skövde Central Hospital.