Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease.

Microglia contribute to the outcomes of various pathological conditions including Parkinson's disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models. Here, we delved into the diversity of microglia in a preclinical PD model featuring the G2019S mutation in LRRK2, a known pathological mutation associated with PD. Specifically, we investigated the 'dark microglia' (DM) and the 'disease-associated microglia' (DAM) which present a selective enrichment of CLEC7A expression. In the dorsal striatum - a region affected by PD pathology - extensive ultrastructural features of cellular stress as well as reduced direct cellular contacts, were observed for microglia from old LRRK2 G2019S mice versus controls. In addition, DM were more prevalent while CLEC7A-positive microglia had extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Furthermore, our findings revealed a higher proportion of DM in LRRK2 G2019S mice, and an increased number of CLEC7A-positive cells with age, exacerbated by the pathological mutation. These CLEC7A-positive cells exhibited a selective enrichment of ameboid morphology and tended to cluster in the affected animals. In summary, we provide novel insights into the occurrence and features of recently defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions.

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Morphology of and release behavior from porous polyurethane microspheres.

A novel biomaterial application of porous microspheres is for sustained delivery of biologically active agents. Recent studies have pointed out the importance of biomaterial porosity in promoting biocompatibility and controlling release rate of active agents. The objective of this research was to investigate the effect of chain-extending agent on the porosity and release behavior of polyurethane (PU) microspheres prepared using a two-step suspension polycondensation method with methylene diphenyl diisocyanate (MDI) as the isocyanate, polyethylene glycol (PEG400) as the diol, and 1,4-butanediol as the chain-extending agent. Chain-extending agent was used to increase the ratio of hard to soft segments of the PU network, and its effect on microsphere morphology was studied with scanning electron microscopy. According to the results, porosity was significantly affected by the amount of chain-extending agent. The pore size decreased as the concentration of chain-extending agent increased from zero to 50 mole%. With further increase of chain-extending agent to 60 and 67%, PU chains became stiffer and formation of pores was inhibited. Therefore, pore morphology was significantly affected by variations in the amount of chain-extending agent. The release behavior of microspheres was investigated with diazinon as the active agent. After an initial burst, corresponding to 3% of the incorporated amount of active agent, the release rate was zero order.

Epidemics of haemorrhagic cystitis due to influenza A virus.

The present communication describes studies on thirty-three patients with haemorrhagic cystitis. The current epidemic variant of influenza type A virus, A/Tehran/5/75 (H3N2) [antigenically similar to A/Port Chalmers/1/73 (H3N2)], was recovered from the throats of eighteen and the urine of three patients. HI antibody rises to A/Tehran/5/75 virus were detected in over 50% of the cystitis patients tested.

Prevention of hepatitis type B with specific immune serum globulin.

In order to evaluate the preventive value of specific immune serum globulin against hepatitis type B, we have used this immune globulin in required doses in 12 patients (10 with AU antigen negative and 2 with AU antigen positive) with chronic renal failure who required maintenance hemodialysis for a period of 15 months, and we were able to prevent hepatitis type B in our dialysis patients.

Effect of beta adrenergic blocking agents (alprenolol and propranolol) in essential hypertension.

The antihypertensive effect of two adrenergic blocking agents (Alprenolol and Propranolol) have been studied in a group of 107 patients with essential hypertension. A significant reduction of 20 mmHg in the systolic blood pressure was recorded for the group using Alprenolol and 25 mmHg in the group using Propranolol. The corresponding decrease of 7-10 mmHg in the diastolic blood pressure for the entire group was also significant. These two drugs may be of therapeutic value in essential hypertension, independently or in combination with other antihypertensive drugs.

Proved viraemia in Asian influenza (Hong Kong variant) during incubation period.

During an outbreak of influenza specimens were obtained from 21 patients with influenza-like illnesses and from 29 healthy subjects in close contact with the patients. Throat washings from 12 of the patients were positive for influenza virus but virus was not detected from the blood specimens. One healthy contact became ill 12 hours after the specimens were obtained, and the virus was isolated from his blood and throat washings. The remaining contacts showed no clinical illness; but the virus was isolated from the throat washings of four of them, with no viral isolation from the blood specimens.

Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice.

Antibody specific for viral neuraminidase can be demonstrated in mice following (i) pulmonary infection with influenza virus, (ii) immunization with ultraviolet-in-activated influenza virus, (iii) immunization with isolated neuraminidase of influenza A(2) virus, and (iv) passive immunization with sera of rabbits immunized with isolated A(2) neuraminidase. Neuraminidase antibody produced by any of these methods exerts a profound inhibiting effect on virus replication in the lungs of mice challenged with strains of virus having homologous neuraminidase protein, even in the absence of hemagglutinating inhibiting antibody to the challenge virus, and results in markedly decreased pulmonary virus titers and diminished lung lesions. These observations suggest that antineuraminidase immunity may play a significant role in the protection against influenza virus challenge observed in mice after infection or artificial immunization.