Three phases of cerebral arteriopathy in meningitis: vasospasm and vasodilatation followed by organic stenosis

A systematic radiological and pathological study of the cerebral arteries was made in an autopsy case of meningitis associated with three phases of cerebral arteriopathy. The latter consisted of vasospasm, vasodilatation, and organic stenosis. A marked change in the caliber of the cerebral arteries was demonstrated 3 times. Vasospasm, the stimulus phenomenon, was produced by the surrounding purulent material. Vasodilatation, the paralytic phenomenon, was presumably due to decreased contractile energy in association with myonecrosis. Organic stenosis, the repair process, was due to the organization of subendothelial edema with resultant intimal thickening. Evidence of increased endothelial permeability, subendothelial proliferation of smooth muscle cells, and necrosis of the latter in the media is presented in both light and electron micrographs.     

Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys

The G-protein coupled receptor 40 (GRP40) is a transmembrane receptor for free fatty acids, and is known for its relation to insulin secretion in the pancreas. Recent studies demonstrated that spatial memory and hippocampal long-term potentiation of rodents and cognitive function of humans are improved by a dietary supplementation with arachidonic and/or docosahexaenoic acids, which are possible ligands for GPR40. While free fatty acid effects on the brain might be related to GPR40 activation, the role of GPR40 in the central nervous system (CNS) is at present not known. Here, we studied expression and distribution of GPR40 in CNS of adult monkeys by immunoblotting and immunohistochemistry. Immunoblotting analysis showed a band of approximately 31 kDa consistent with the size of GPR40 protein. GPR40 immunoreactivity of was observed in the nuclei and/or perikarya of a wide variety of neurons including neurons in the cerebral cortex, hippocampus, amygdala, hypothalamus, cerebellum, spinal cord. In addition, astrocytes of the cerebral white matter, the molecular layer and multiform layer of the cerebral cortex, the subventricular zone along the anterior horn of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus showed GPR40 immunoreactivity. The present data first provide a morphological basis for clarifying the role of GPR40 in the primate CNS.     

Does Routine Follow-Up after Patients Have Completed Adjuvant Therapy for Early-Stage Breast Cancer at a Cancer Center Improve Prognosis?

IntroductionThis study aimed to assess whether follow-up of patients with operative breast cancer at cancer centres (CCs) improved prognosis compared with follow-up by family physicians (FPs).MethodsThe study included 254 patients who relapsed within 7 years from the first postoperative period. The patients were divided into two groups according to the follow-up facility: the CC and FP groups (the follow-up of patients was structured in the same way between FPs and CCs). There are 146 and 108 cases of recurrence in the CC and FP groups, respectively. The analysis targets of the two groups were determined using the propensity matching method based on the following 7 factors: oestrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, St. Gallen category, menopausal status, surgical procedure, and receipt of postoperative chemotherapy at the time of surgery. Overall survival (OS) in both groups was analysed using the Kaplan-Meier method and compared using the log-rank test.ResultsOverall, 97 patients each in the CC and FP groups who relapsed were analysed using the propensity matching method. The median recurrence-free survival periods were 1,676 and 994 days in the FP and CC groups, respectively, and were significantly longer in the FP group. However, the median OS starting from the day of surgery was 3,424 and 2,794 days in the FP and CC groups, respectively, with no significant difference.ConclusionThis study revealed that regular follow-up at CCs did not improve survival compared with regular follow-up by FPs.     

Adult hippocampal neurogenesis in rodents and primates: endogenous, enhanced, and engrafted

Since the studies of Ramon y Cajal, a central postulate in neuroscience has been the view that the adult brain lacks the ability to regenerate its neurons. This dogma has been challenged in the last few decades, and mounting evidence has accumulated showing the existence of a phenomenon designated 'adult neurogenesis'. De novo generation of neurons by neural progenitor cells in the adult brain is thought to be preserved only in restricted brain areas, such as the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. Data in the last decade coming mostly from rodent models have clearly documented that precursor cells residing in the anterior portion of SVZ and the subgranular zone of DG are responsible for adding new neurons in the olfactory bulb and DG, respectively. This raised significant interest in the clinical potential of neural progenitor cells, and recent studies have documented that brain injury is capable of activating an endogenous program of neurogenesis resulting in neuronal replacement in various cerebral regions of rodents and primates. If the newly generated neurons in the adult brain prove to be functional, it could have a tremendous impact for cell replacement therapies. Here, we summarize current knowledge of the mechanisms affecting adult hippocampal neurogenesis in both rodents and primates, and discuss its implications in developing novel strategies for the treatment of human neurological diseases.     

Cellular localization of epidermal‐type and brain‐type fatty acid‐binding proteins in adult hippocampus and their response to cerebral ischemia

This study aimed at an analysis of expression of epidermal‐type and brain‐type fatty acid‐binding proteins (E‐FABP and B‐FABP, also called FABP5 and FABP7, respectively) in adult hippocampus and their potential value as neuroprotective factors after ischemic brain damage in monkey model. The immunostaining and Western blotting results show that FABP5 was mainly expressed in neurons, whereas FABP7 was primarily expressed in astrocytes and progenitors of the subgranular zone (SGZ). Interestingly, FABP5 expression in neurons increased in cornu Ammonis 1 (CA1) and remains stable within dentate gyrus (DG) after ischemia; FABP7 expression increased within both CA1 and SGZ. This indicates a potential role for FABP5 and FABP7 in intracellular fatty acid transport within different neural cells. The change in FABP5–7 expression within CA1 and DG of the adult postischemic hippocampus was compatible with previous findings of downregulation in CA1 neurons and upregulation in SGZ progenitor cells after ischemia. Altogether, the present data suggest that polyunsaturated fatty acids, such as docosahexaenoic acid, may act via FABP5 or 7 to regulate adult postischemic hippocampal neuronal antiapoptosis or neurogenesis in primates. © 2009 Wiley‐Liss, Inc.     

Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma

Disialoganglioside (GD2)-specific chimeric antigen receptor (CAR)-T cells (GD2-CAR-T cells) have been developed and tested in early clinical trials in patients with relapsed/refractory neuroblastoma. However, the effectiveness of immunotherapy using these cells is limited, and requires improvement. Combined therapy with CAR-T cells and molecular targeted drugs could be a promising strategy to enhance the antitumor efficacy of CAR T cell immunotherapy. Here, we generated GD2-CAR-T cells through piggyBac transposon (PB)-based gene transfer (PB-GD2-CAR-T cells), and analyzed the combined effect of these cells and a MEK inhibitor in vitro and in vivo on neuroblastoma. Trametinib, a MEK inhibitor, ameliorated the killing efficacy of PB-GD2-CAR-T cells in vitro, whereas a combined treatment of the two showed superior antitumor efficacy in a murine xenograft model compared to that of PB-GD2-CAR-T cell monotherapy, regardless of the mutation status of the MAPK pathway in tumor cells. The results presented here provide new insights into the feasibility of combined treatment with CAR-T cells and MEK inhibitors in patients with neuroblastoma.     

A light and electron microscopic and immunohistochemical study of human arachnoid villi

The structure of human arachnoid villi was investigated by light and electron microscopy with the aid of immunohistochemical techniques. The human arachnoid villi examined were basically composed of four portions: a fibrous capsule, an arachnoid cell layer, a cap cell cluster, and a central core. The arachnoid cell layer encompassing the central core was mostly covered by the thin fibrous capsule with an endothelial investment. However, the fibrous capsule was often absent at the apical portion of the villus and a factor VIII-related antigen stain failed to confirm the investment of endothelial cells. Instead, the arachnoid cell layer abutted directly upon the lumen of a lateral lacuna or the sinus. The arachnoid cell layer was thickened in places, forming cap cell clusters; it usually consisted of outer and inner zones. On vimentin staining, the former was slightly positive while the latter was strongly positive. The central core contained a network of arachnoid cells intermingled with connective tissue fibers and was in continuity with the cranial subarachnoid space. Electron microscopy showed that the arachnoid cells contained a larger number of intermediate filaments in the inner zone than the outer zone. Ultrastructural immunohistochemical localization showed that vimentin was localized at the intermediate filaments and desmosomal plaques of the arachnoid cells. The arachnoid cells showed a marked variety in both the cell forms and the number of intermediate filaments or desmosomes, depending on their location.