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).     

Anabolic and catabolic hormonal response of elite runners to training at high altitude

A 2-week training period 2000 meters above sea level performed by 6 male elite Swedish runners influenced neither basal anabolic (total and non-sex hormone-binding globulin (SHBG)-bound testosterone (NST) and insulin-like growth factor-1 (IGF-1) nor catabolic (cortisol) hormones when comparing serum levels prior to and after the training camp. The anabolic vs catabolic hormone balance, expressed as the NST: cortisol ratio, also remained unchanged as well as SHBG and body mass. Thus, training at 2000 meters above sea level, often practised by elite runners to improve performance in competition at sea level, does not result in a catabolic situation after return to sea level, as measured by peripheral hormones. However, the adaptation to high altitude was associated with a slight (NS) decrease in testosterone as well as in anabolic vs catabolic balance as measured the third day at high altitude. Simultaneously, a decrease in subjective performance was claimed by the runners, but could not be shown by objective measurements. From day 3 to day 9 at high altitude, all runners claimed a subjective recuperation of performance. Total and non-SHBG-bound testosterone increased significantly from day 3 at high altitude to the first post-camp sea-level test. The results reflect the necessity of adaptation when travelling to races at different altitudes. The Swedish runners had significantly higher cortisol, total testosterone and NST levels compared with basal values of a group of 17 elite Kenyan runners living and training at high altitude. Since the NST cortisol and IGF-1 values were not lower, a catabolic state or malnutrition was not likely to be present. The results might reflect an adaptation to altitude or ethnic variations.     

Healing-in of root analogue titanium implants placed in extraction sockets. An experimental study in the beagle dog.

The aim of these animal experiments was to characterize and evaluate the healing-in of root analogue titanium implants fitting with high precision to the alveolar wall. Four beagle dogs were used in the study. The roots of the 3rd and 4th mandibular premolars in both quadrants of 3 dogs and in 1 quadrant of 1 dog (dog 4) were extracted after hemisection. Each root was machine-copied to 1 titanium analogue. In dog 4, however, 2 titanium analogues were fabricated from each of the 4 extracted roots. This enabled insertion of analogues also into the contralateral sockets obtained by extraction of the corresponding roots immediately before implant installation, which was undertaken 2 weeks after the first extractions. Thus, in all, 32 analogues were implanted in their respective (or contralateral) sockets following ridge incision and elevation of mucoperiosteal flaps. The analogues were carefully covered by the repositioned flaps. In dog 4, 2 analogues from the immediate sockets and 2 from the 2-week sockets were surgically exposed and supplied with titanium crowns after a healing period of 2 months. The healing after implantation was evaluated by clinical, radiographic and histological measures after 2, 12 or 36 months. Two analogues (6%) were lost due to early (during the 1st week) exposure to the oral cavity. Another 2 analogues (6%) were, although not exposed, encapsulated by soft tissue and were easily removed with a surgical forceps. Twenty-eight analogues (88%) were healed-in by contact between bone and implant (osseointegration).(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic effects of two nasally administered glucocorticosteroids

Two topical corticosteroids, budesonide (BUD) and beclomethasone dipropionate (BDP), both administered as suspensions in water, were investigated in healthy volunteers regarding influence on cortisol in plasma and urine (U-cortisol) after nasal application. In the first study, single doses of 200, 400, and 800 μg of BDP and BUD were given at 10:00 pm. In the second study, 100, 200, and 400 μg were given mornings and evenings for 4 days. In the single-dose study, none of the drugs or doses showed any significant influence on cortisol in plasma. However, U-cortisol decreased significantly after BUD 400 and 800 μg. In the multidose study, U-cortisol values were significantly reduced after all doses of BUD and the highest dose of BDP. The compounds tested showed different ability to cause measurable systemic effects after nasal application. The clinical implication is that the prescriber, when choosing a compound, should take the application site into consideration and should also be encouraged to find the lowest effective dose.     

Improved long-term bone-implant integration Experiments in transgenic mice overexpressing bovine growth hormone

Several recent studies have investigated the effects of growth hormone (GH) on the healing of fractures and bone ingrowth, but with conflicting results. The negative results may be due to antibody formation against injected GH or because some experimental models are able to prove only positive GH effects. In this study, we wanted to investigate the effect of GH on implant integration in bone. To avoid potential formation of antibodies against injected GH, we used a model with transgenic mice overexpressing bovine GH (bGH).

Titanium implants were inserted in the forehead of the mice. 4 months after insertion, the implants were cut out en bloc with the surrounding bone. The calcified specimens were cut and ground to a thickness of approximately 10m. Histomorphometry demonstrated significantly more direct bone-to-metal contact in the transgenic mice than in the nontransgenic littermates. Our findings indicate that systemic administration of GH in humans may improve implant integration in bone.