Enhanced GABAergic Immunoreactivity in Hippocampal Neurons and Astroglia of Multiple Sclerosis Patients.

Cognitive dysfunction occurs frequently in multiple sclerosis (MS). Research suggests that hippocampal lesions and GABAergic neurotransmitter changes contribute to cognitive dysfunction. In the present study, we aim to determine the cellular changes in GABAergic expression in MS hippocampus related to inflammation and demyelination. To this end, the presence and inflammatory activity of demyelinating lesions was determined by immunohistochemistry in human postmortem hippocampal tissue of 15 MS patients and 9 control subjects. Subsequently, GABAergic cells were visualized using parvalbumin (PV) and glutamate acid decarboxylase 67 (GAD67) markers. Fluorescent colabeling was performed of GAD67 with neuronal nuclei, PV, astrocytic glial fibrillary acidic protein, or vesicular GABA transporter. We observed increased GAD67-positive (GAD67+) neuron and synapse numbers in the CA1 of MS patients with active hippocampal lesions, not due to neurogenesis. The number and size of PV-positive neurons remained unchanged. GAD67+ astrocytes were more numerous in hippocampal white matter than grey matter lesions. Additionally, in MS patients with active hippocampal lesions GAD67+ astrocyte surface area was increased. Disturbed cognition was most prevalent in MS patients with active hippocampal lesions. Summarizing, increased GAD67 immunoreactivity occurs in neurons and astrocytes and relates to hippocampal inflammation and possibly disturbed cognition in MS.

Novel Approach to Treat Uncomplicated Sigmoid Volvulus Combining Minimally Invasive Surgery with Enhanced Recovery, in a Rural Hospital in Zambia.

AIM: In sub-Saharan Africa, sigmoid volvulus is a frequent cause of bowel obstruction. The aim of this study was to evaluate the results of acute sigmoid resection and anastomosis via a mini-laparotomy in patients with uncomplicated sigmoid volvulus, following the principles of "Enhanced Recovery After Surgery (ERAS)", in a low-resource setting. MATERIALS AND METHODS: Patients with uncomplicated sigmoid volvulus were operated acutely, via a mini-laparotomy, according to the principles of ERAS. Intraoperative complications, duration of operation, morbidity, mortality and length of hospital stay were evaluated, retrospectively. RESULTS: From 1 March 2012 to 1 September 2017, 31 consecutive patients were treated with acute sigmoid resection and anastomosis, via a mini-laparotomy. There were 29 men and 2 women, median age 57 (range 17-92) years. Patients were operated after a median period of 4 (range 1.5-18) hours. The median duration of the operative procedure was 50 (range 30-105) minutes. Two patients died (6.3%). One patient died during an uncomplicated operation. The cause of death is unknown. One patient with a newly diagnosed HIV infection had an anastomotic dehiscence. After Hartmann's procedure, he died on the 17th post-operative day as a result of a HIV-related double-sided pneumonia, without signs of abdominal sepsis. One patient had an urinary retention and 1 patient haematuria after bladder catheter insertion. CONCLUSION: Acute sigmoid resection and primary anastomosis via a mini-laparotomy for uncomplicated sigmoid volvulus, without preoperative endoscopic decompression is a safe procedure with a low morbidity and mortality.

Pathological differences between white and grey matter multiple sclerosis lesions.

Multiple sclerosis (MS) is a debilitating disease characterized by demyelination of the central nervous system (CNS), resulting in widespread formation of white matter lesions (WMLs) and grey matter lesions (GMLs). WMLs are pathologically characterized by the presence of immune cells that infiltrate the CNS, whereas these immune cells are barely present in GMLs. This striking pathological difference between WMLs and GMLs raises questions about the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WMLs; however, since GMLs show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WMLs and GMLs, and suggest some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics of WM and GM, and local differences within WMLs and GMLs (in particular, in glial cell populations and the molecules they express), determine the pathway to demyelination. Further understanding of GML pathogenesis, considered to contribute to chronic MS, may have a direct impact on the development of novel therapeutic targets to counteract this progressive neurological disorder.

Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients.

A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML,of post-mortem MS patients, and of control subjects. CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate. We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.

Interleukin-1ß and interleukin-1 receptor antagonist appear in grey matter additionally to white matter lesions during experimental multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has been mainly attributed to white matter (WM) pathology. However, recent evidence indicated the presence of grey matter (GM) lesions. One of the principal mediators of inflammatory processes is interleukin-1ß (IL-1ß), which is known to play a role in MS pathogenesis. It is unknown whether IL-1ß is solely present in WM or also in GM lesions. Using an experimental MS model, we questioned whether IL-1ß and the IL-1 receptor antagonist (IL-1ra) are present in GM in addition to affected WM regions. METHODS: The expression of IL-1ß and IL-1ra in chronic-relapsing EAE (cr-EAE) rats was examined using in situ hybridization, immunohistochemistry and real-time PCR. Rats were sacrificed at the peak of the first disease phase, the trough of the remission phase, and at the peak of the relapse. Histopathological characteristics of CNS lesions were studied using immunohistochemistry for PLP, CD68 and CD3 and Oil-Red O histochemistry. RESULTS: IL-1ß and IL-ra expression appears to a similar extent in affected GM and WM regions in the brain and spinal cord of cr-EAE rats, particularly in perivascular and periventricular locations. IL-1ß and IL-1ra expression was dedicated to macrophages and/or activated microglial cells, at sites of starting demyelination. The time-dependent expression of IL-1ß and IL-1ra revealed that within the spinal cord IL-1ß and IL-1ra mRNA remained present throughout the disease, whereas in the brain their expression disappeared during the relapse. CONCLUSIONS: The appearance of IL-1ß expressing cells in GM within the CNS during cr-EAE may explain the occurrence of several clinical deficits present in EAE and MS which cannot be attributed solely to the presence of IL-1ß in WM. Endogenously produced IL-1ra seems not capable to counteract IL-1ß-induced effects. We put forward that IL-1ß may behold promise as a target to address GM, in addition to WM, related pathology in MS.

[An ulcerating wound of both breasts]. / Een vrouw met een grote ulcererende wond van beide mammae.

A 44-year old woman came with an ulcerating wound, covering both mammas and axillas. Because of an extreme fear for doctors, the woman hid this for more than a year. The diagnoses was an inoperable T4N3M1 mamma carcinoma. Patient was treated with palliative hormonal therapy with good effects.

Emerging roles of microglial activation and non-motor symptoms in Parkinson's disease.

Recent data has indicated that the traditional view of Parkinson's disease (PD) as an isolated disorder of the nigrostriatal dopaminergic system alone is an oversimplification of its complex symptomatology. Aside from classical motor deficits, various non-motor symptoms including autonomic dysfunction, sensory and cognitive impairments as well as neuropsychiatric alterations and sleep disturbances are common in PD. Some of these non-motor symptoms can even antedate the motor problems. Many of them are associated with extranigral neuropathological changes, such as extensive α-synuclein pathology and also neuroinflammatory responses in specific brain regions, i.e. microglial activation, which has been implicated in several aspects of PD pathogenesis and progression. However, microglia do not represent a uniform population, but comprise a diverse group of cells with brain region-specific phenotypes that can exert beneficial or detrimental effects, depending on the local phenotype and context. Understanding how microglia can be neuroprotective in one brain region, while promoting neurotoxicity in another, will improve our understanding of the role of microglia in neurodegeneration in general, and of their role in PD pathology in particular. Since neuroinflammatory responses are in principle modifiable, such approaches could help to identify new targets or adjunctive therapies for the full spectrum of PD-related symptoms.

The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression.

Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [(11)C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.

Cholinergic imbalance in the multiple sclerosis hippocampus.

Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this disease.