Plasma lipids, phospholipid fatty acids and indices of glycaemia in 10-year-old children born as small-for-gestational-age or preterm infants

Low birthweight has been epidemiologically associated with unfavourable plasma lipid profiles and enhanced risk of cardiovascular morbidity in adulthood. Plasma lipids, lipoprotein cholesterols, apolipoproteins, fatty acid composition of plasma phospholipids and basic indices of glycaemia were investigated in 10-y-old children born with similarly low birthweights as small-for-gestational-age (SGA; n = 16) or preterm infants (n = 16). Plasma total cholesterol (4.32 +/- 0.57 vs 4.60 +/- 0.52, mmol l(-1), mean +/- SD, SGA vs preterm subjects), low-density lipoprotein cholesterol (2.54 +/- 0.51 vs 2.65 +/- 0.51) and high-density lipoprotein cholesterol (1.61 +/- 0.25 vs 1.76 +/- 0.18) concentrations did not differ between the 2 groups. There was no difference in plasma triacylglycerol, apolipoprotein A-I and B, insulin and glucose concentrations or phospholipid fatty acid values. There was no correlation between indices of lipid and carbohydrate metabolism. In conclusion, plasma lipid profiles and basic indices of glycaemia are not different in 10-y-old children born with similarly low birthweights as SGA or preterm infants.     

Agouti-related peptide-expressing neurons are mandatory for feeding

Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.     

Germinal center and activated b-cell profiles separate Burkitt lymphoma and diffuse large B-cell lymphoma in AIDS and non-AIDS cases

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap. No single phenotypic marker or molecular abnormality is pathognomonic. We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL. We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization). After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl-6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells. Hierarchical clustering yielded 2 major clusters significantly associated with morphologic diagnosis (P < .001). For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points. This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P < .001). Protein expression of multiple GC and ABC markers can separate BL and DLBCL.     

Tau acts as an independent genetic risk factor in pathologically proven PD

MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.     

The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.     

Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations

The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.     

High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.     

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

CD14 Influences Host Immune Responses and Alternative Activation of Macrophages during Schistosoma mansoni Infection

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14^−/− mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14^−/− mice exhibited increased production of CD4⁺-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4⁺Foxp3⁺IL-10⁺ regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14^−/− mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14^−/− phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14^−/− mice and normalized the M2 and CD4⁺ Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14^−/− mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4Rα-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4⁺ T cell biasing during helminth infection.     

Identification and Quantification of Oligodendrocyte Precursor Cells in Multiple System Atrophy,Progressive Supranuclear Palsy and Parkinson's Disease

Multiple system atrophy is a neurodegenerative disorder characterized pathologically by abnormal accumulations of α‐synuclein in the cytoplasm of oligodendrocytes, which are termed glial cytoplasmic inclusions (GCIs). Oligodendrocytes are responsible for myelinating axons and providing neurotrophic support, but in MSA, myelin loss, axonal loss and gliosis are consistent features suggesting that GCIs play a central role in disease pathogenesis. Oligodendroglial, myelin and axonal degeneration are also features of multiple sclerosis (MS) in which recent studies have highlighted the robust remyelination capacity of the central nervous system (CNS). The cells responsible for remyelination are called oligodendroglial precursor cells (OPCs). In this study, we investigated the role of OPCs in the pathogenesis of MSA and progressive supranuclear palsy (PSP), a neurodegenerative disease in which neuropathological changes include oligodendroglial inclusions composed of microtubule‐associated protein tau. Despite the lability of OPC‐specific antigens, we successfully identified OPCs and demonstrated that tau and α‐synuclein do not accumulate in OPCs. We also showed that the density of OPCs was increased in a white matter region of the MSA brain, which is also severely affected by GCIs and myelin degeneration. These findings raise the possibility that OPCs could be available to repair disease‐associated damage in MSA, consistent with their biological function.