Subchronic infusion of the product of inflammation prostaglandin J2 models sporadic Parkinson\u27s disease in mice

Background Chronic neuroinflammation is implicated in Parkinson\u27s disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated under in vivo conditions. Methods We addressed the neurodegenerative and behavioral effects of the administration of prostaglandin J2 (PGJ2) simultaneously into the substantia nigra/striatum of adult male FVB mice by subchronic microinjections. One group received unilateral injections of DMSO (vehicle, n = 6) and three groups received PGJ2 [3.4 μg or 6.7 μg (n = 6 per group) or 16.7 μg (n = 5)] per injection. Immunohistochemical and behavioral analyses were applied to assess the effects of the subchronic PGJ2 microinfusions. Results Immunohistochemical analysis demonstrated a PGJ2 dose-dependent significant and selective loss of dopaminergic neurons in the substantia nigra while the GABAergic neurons were spared. PGJ2 also triggered formation of aggregates immunoreactive for ubiquitin and α-synuclein in the spared dopaminergic neurons. Moreover, PGJ2 infusion caused a massive microglia and astrocyte activation that could initiate a deleterious cascade leading to self-sustained progressive neurodegeneration. The PGJ2-treated mice also exhibited locomotor and posture impairment. Conclusion Our studies establish the first model of inflammation in which administration of an endogenous highly reactive product of inflammation, PGJ2, recapitulates key aspects of PD. Our novel PGJ2-induced PD model strongly supports the view that localized and chronic production of highly reactive and neurotoxic prostaglandins, such as PGJ2, in the CNS could be an integral component of inflammation triggered by insults evoked by physical, chemical or microbial stimuli and thus establishes a link between neuroinflammation and PD neurodegeneration

Cyclic GMP in the pig vitreous and retina after experimental retinal detachment

Purpose: Earlier studies have revealed a decreased level of cGMP in vitreous fluid obtained from patients with a retinal detachment. To further investigate this phenomenon, we developed an experimental retinal detachment model in pigs. Methods: Experimental unilateral retinal detachments were induced in pig eyes by subretinal injection of 0.25% sodium hyaluronate. Fourteen days later the vitreous and retinas were analyzed for cGMP expression. Following enucleation, the retinas were incubated in the presence of a nonselective phosphodiesterase inhibitor (IBMX), and the particulate guanylyl cyclase stimulator atrial natriuretic peptide (ANP) or the soluble guanylyl cyclase stimulator sodium nitroprusside (SNP). cGMP was visualized in retinal wholemounts by immunochemistry combined with a computer based stereology system. cGMP levels in vitreous were determined by ELISA. Results: The mean vitreous cGMP level in pig eyes with a retinal detachment (1.45 pmol/ml) was significantly lower compared to the mean level of cGMP in healthy pig eyes (4.61 pmol/ml; p= 0.028 was considered significant). In the inner retina, ANP as well as SNP induced cGMP immunoreactivity in both detached and healthy retinas. After incubation with ANP, cGMP could also be detected in the outer nuclear layer of the detached retina, whereas this was not the case in the normal retina. Conclusions: Experimental retinal detachment in the pig eye leads to a decrease of cGMP levels in vitreous similar to that observed in clinical studies. This model may be helpful to analyze the mechanisms involved in cGMP dynamics following retinal detachment

Специфика организации транспортной службы предприятия

В данной статье были рассмотрены проблемы организации транспортной службы предприятия. Актуальность темы исследования обусловлена, тем, что любую готовую продукцию необходимо транспортировать, в связи с этим были рассмотрены общие характеристики транспортной службы предприятия, сделаны выводы, позволяющие повысить эффективность работы транспортного цеха предприятия за счет повышения качества надежности внешних и внутрипроизводственных перевозок, что обеспечит повышение конкурентоспособности предприятия в целом

Detection of amyloid beta aggregates in the brain of BALB/c mice after Chlamydia pneumoniae infection

Neuroinflammation, initiated by cerebral infection, is increasingly postulated as an aetiological factor in neurodegenerative diseases such as Alzheimer’s disease (AD). We investigated whether Chlamydia pneumoniae (Cpn) infection results in extracellular aggregation of amyloid beta (Aβ) in BALB/c mice. At 1 week post intranasal infection (p.i.), Cpn DNA was detected predominantly in the olfactory bulbs by PCR, whereas brains at 1 and 3 months p.i. were Cpn negative. At 1 and 3 months p.i., extracellular Aβ immunoreactivity was detected in the brain of Cpn-infected mice but also in the brain of mock-infected mice and mice that were neither Cpn infected nor mock infected. However, these extracellular Aβ aggregates showed morphological differences compared to extracellular Aβ aggregates detected in the brain of transgenic APP751SL/PS1M146L mice. These data do not unequivocally support the hypothesis that Cpn infection induces the formation of AD-like Aβ plaques in the brain of BALB/c mice, as suggested before. However, future studies are required to resolve these differences and to investigate whether Cpn is indeed an etiological factor in AD pathogenesis

Increased Number of Cerebellar Granule Cells and Astrocytes in the Internal Granule Layer in Sheep Following Prenatal Intra-amniotic Injection of Lipopolysaccharide

Chorioamnionitis is an important problem in perinatology today, leading to brain injury and neurological handicaps. However, there are almost no data available regarding chorioamnionitis and a specific damage of the cerebellum. Therefore, this study aimed at determining if chorioamnionitis causes cerebellar morphological alterations. Chorioamnionitis was induced in sheep by the intra-amniotic injection of lipopolysaccharide (LPS) at a gestational age (GA) of 110 days. At a GA of 140 days, we assessed the mean total and layer-specific volume and the mean total granule cell (GCs) and Purkinje cell (PC) number in the cerebelli of LPS-exposed and control animals using high-precision design-based stereology. Astrogliosis was assessed in the gray and white matter (WM) using a glial fibrillary acidic protein staining combined with gray value image analysis. The present study showed an unchanged volume of the total cerebellum as well as the molecular layer, outer and inner granular cell layers (OGL and IGL, respectively), and WM. Interestingly, compared with controls, the LPS-exposed brains showed a statistically significant increase (+20.4%) in the mean total number of GCs, whereas the number of PCs did not show any difference between the two groups. In addition, LPS-exposed animals showed signs of astrogliosis specifically affecting the IGL. Intra-amniotic injection of LPS causes morphological changes in the cerebellum of fetal sheep still detectable at full-term birth. In this study, changes were restricted to the inner granule layer. These cerebellar changes might correspond to some of the motor or non-motor deficits seen in neonates from compromised pregnancies

From flailing to gaining app workers: shedding light on the job characteristics in app work and how app workers can craft them.

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Unknown makes unloved-A case study on improving integrated health and social care in the Netherlands using a participatory approach.

Many initiatives integrating health and social care have been implemented in order to provide adequate care and support to older people living at home. Further development of existing initiatives requires iterative processes of developing, implementing and evaluating improvements to current practice. This case study provides insight into the process of improving an existing integrated care initiative in the Netherlands. Using a participatory approach, researchers and local stakeholders collaborated to develop and implement activities to further improve collaboration between health and social care professionals. Improvement activities included interprofessional meetings focussing on reflection and mutual learning and workplace visits. Researchers evaluated the improvement process, using data triangulation of multiple qualitative and quantitative data sources. According to participating professionals, the improvement activities improved their communication and collaboration by establishing mutual understanding and trust. Enabling factors included the safe and informal setting in which the meetings took place and the personal relationships they developed during the project. Different organisational cultures and interests and a lack of ownership and accountability among managers hindered the improvement process, whereas issues such as staff shortages, time constraints and privacy regulations made it difficult to implement improvements on a larger scale. Still, the participatory approach encouraged the development of partnerships and shared goals on the level of both managers and professionals. This case study highlights that improving communication between professionals is an important first step in improving integrated care. In addition, it shows that a participatory approach, in which improvements are co-created and tailored to local priorities and needs, can help in the development of shared goals and trust between stakeholders with different perspectives. However, stakeholders' willingness and ability to participate in such an improvement process is challenged by many factors

A genetic answer to a neuropsychiatric challenge

Major depressive disorder and other mood disorders are amongst the most common psychiatric disorders general practtoners and psychiatrists are encountered with. Of these patents, a substantal part is sufering from a therapyresistant depression, inducing the necessity for augmentaton of pharmacological and non-pharmacological treatments. However, when the patent fails to respond to treatment, or other cognitve or motor symptoms occur, the diferental diagnosis should be extended to include neurodegeneratve disorders. In this case report, we present a man sufering from a therapy-resistant depression, who despite in depth pharmacological and non-pharmacological therapy did not improve and developed a catatonia. Genetc analysis revealed a repeat expansion mutaton in the C9orf72 gene. Subsequently the patent developed an extrapyramidal syndrome, frontal dementa syndrome and motor neuron disorder. We present the clinical course of this patent and review the neuropsychiatric symptomatology associated with C9orf72 mutatons. We emphasize the relevance of early gene analysis in the diagnostc workout