Intravenous thrombolysis and endovascular thrombectomy for acute ischaemic stroke in patients with Moyamoya disease - a systematic review and meta-summary of case reports

Journal of Thrombosis and Thrombolysis - Patients with Moyamoya disease (MMD) can present with ischaemic or haemorrhagic stroke. There is no good evidence for treatment strategies in MMD-associated...     

Agonist-specific differential changes of cellular signal transduction pathways in senescent human diploid fibroblasts

Changes in the signal transduction efficiency of senescent cells led us to compare the signaling events induced by two mitogenic agonists, platelet-derived growth factor (PDGF) and lysophosphatidic acid (LPA) in presenescent and senescent or near-senescent human diploid fibroblasts. When the changes in intracellular [Ca(2+)](i) were analyzed, both PDGF and LPA generated a rhythmic increase in [Ca(2+)](i) in presenescent cells. The frequency of calcium response was reduced and desensitized in PDGF-stimulated senescent cells, while response to a LPA-induced calcium signal was also reduced in frequency, though its magnitude was unaltered. PDGF treatment increased the fibrous actin (F-actin) level in presenescent cells but not in senescent cells in contrast to a reduced but visible increase in F-actin in LPA-treated senescent cells. The effect of PDGF on phospholipase D (PLD) activation was also reduced significantly, as a ca. 60-80% reduction of PLD activity was observed in PDGF-stimulated cells but only a little reduction in LPA-induced cells. Agonist-specific differential changes of cellular signaling events caused a differential effect on DNA synthesis after growth factor stimulation. We observed a dramatic (80-90%) reduction of [3H]thymidine incorporation into DNA in the PDGF-stimulated near-senescent cells. LPA resulted in a 2-3-fold increase in thymidine incorporation even in the near-senescent cells. These differences in the responses of senescent or near-senescent cells to PDGF- and LPA-stimulation raised questions about the differential changes of the respective signaling apparatuses induced by aging. Since PDGF signaling event was affected greatly by aging, we further examined the protein contents involved in PDGF signal transduction pathway. PDGF receptor (PDGFR), protein kinase C-alpha (PKC-alpha), phospholipase C-gamma1 (PLC-gamma1), and PLD1 were examined by Western blot analysis. The protein levels of PKC-alpha and PLC-gamma1 were unchanged, but those of PLD1 and PDGFR were reduced with age. The reduced content of PDGFR protein may be one of the important contributors to the failure of PDGF-stimulated signal transduction in human senescent fibroblasts. Our results strongly suggest that age-dependent agonist-specific changes in signaling events might be in charge of the functional deterioration of senescent cells through imbalance of signal responses.     

The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.     

Influence of meal composition on canine jejunal water and electrolyte absorption.

The absorption of water and electrolytes from the proximal jejunal lumen increases immediately after a meal. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. This study was designed to characterize the jejunal absorptive response to a series of isovolumetric gavage-delivered stimuli. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and jejunal absorption studies (n = 66) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing 14C-labeled polyethylene glycol. Each study consisted of a 1-hour basal period, followed by a 3-hour experimental period. Nine groups were studied, each receiving one of the following isovolumetric stimuli delivered via the gavage route: water, 0.9% saline, mixed meal, protein, lipid, carbohydrate, and mannitol (150 mmol/L, 300 mmol/L, and 600 mmol/L). The water and 0.9% saline gavage groups showed no significant changes in integrated postprandial water and electrolyte absorption above basal. The isocaloric mixed meal, protein, lipid, carbohydrate, and mannitol groups all had significantly increased integrated postprandial jejunal water and electrolyte absorption above basal (P less than 0.05). These results indicate that a proabsorptive signal for meal-induced jejunal absorption originates from or distal to the stomach. Meal-induced jejunal absorption occurs in response to nutrients of diverse composition and is also responsive to nonnutritive solutes such as mannitol. These findings support a new role for gastric or intestinal chemo- or osmo-receptors in stimulating the neurohumoral mechanisms that mediate meal-induced jejunal absorption.     

ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.     

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.     

Precommissural Fornix in the Human Brain: A Diffusion Tensor Tractography Study

Purpose

Other than a single case report, no diffusion tensor tractography (DTT) studies of the precommissural fornix in the human brain have been conducted. In the current study, we attempted to visualize the precommissural fornix in the human brain using DTT.

Materials and Methods

We recruited 36 healthy volunteers for this study. Diffusion tensor images were scanned using a 1.5-T scanner, and the precommissural fornix was analyzed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) software. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the precommissural fornix were measured.

Results

The precommissural fornix originated from the hippocampal formation on each hemisphere as a crus; both crura were then joined to the body of the fornix. The body of the fornix continued anteriorly to the level just superior to the anterior commissure, where it divided into each column of the precommissural fornix. Each column descended anteriorly to the anterior commissure and terminated in the septal nuclei. Values of FA, MD, and tract volumes of the precommissural fornix did not differ between the right and left hemispheres (p>0.05).

Conclusion

We believe that the methodology and results of this study would be helpful to future research on the precommissural fornix and in the elucidation of the pathology of diseases involving the precommissural fornix.     

Dipeptidyl Peptidase 10, a Novel Prognostic Marker in Colorectal Cancer

Purpose

The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood.

Materials and Methods

The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes.

Results

DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008).

Conclusion

DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes.