Regulation by Interleukin-1β of Formation of a Line of Delimiting Astrocytes Following Prenatal Trauma to the Brain of the Mouse

The regulation of perinatal glia limitans (GL) reformation by interleukin-1β (IL-1β) following prenatal neural trauma in the mouse was studied in lesioned fetal mice by immunocytochemistry and computer-assisted image analysis for presence and distribution of astrocytes and IL-1β immunoreactivity (ir). Astrocytes stained with anti-glial fibrillary acidic protein (GFAP) were observed as a line of delimiting astrocytes (LDA) near the lesion edge on Postnatal Day 0 (P0, 2 days postlesion). At P6, a new and complete GL composed of GFAP-positive astrocytes was continuous with that of adjacent undamaged tissue. The new GL was located in the same area at P6 as was the LDA at P0, suggesting that the LDA is the precursor structure to a reformed GL. Astrocytes comprising the new GL were positive for anti-IL-1β. The IL-1 receptor antagonist (IL-1ra), administered acutely into the lesion, produced a significantly decreased optical density of IL-1β-ir at the LDA at P0 compared to animals that received injections of vehicle, human recombinant IL-1β, or a combination injection of IL-1ra + IL-1β. Furthermore, although GFAP-stained cells appeared at the lesion site, an organized LDA was not visible at P0 in IL-1ra-treated animals. Vehicle-, IL-1β-, and combination-injected animals showed a robust LDA at the lesion site at P0. These data suggest that upregulation of IL-1β in astrocytes and interaction of IL-1β with the neural IL-1 receptor are important for reconstruction of the GL following prenatal lesion in the murine brain.     

Metabolic syndrome after a liver transplantation in an Asian population

BackgroundWith improvements in patient survival after a liver transplantation (LT), long-term sequelae such as metabolic syndrome (MS) have become increasingly common. This study aims to characterize the prevalence, associations and long-term outcomes of post-LTMS and its components in an Asian population.MethodsA retrospective review of all adult patients who underwent LT at the National University Health System Singapore between December 1996 and May 2012 was performed. MS was defined using the Adult Treatment Panel (ATP) III criteria modified for an Asian population.ResultsThe median age of this cohort of 90 patients was 50.0 (16.0–67.0) years, with a median follow-up duration of 60.0 (7.0–192.0) months. The prevalence of post-LTMS was 35.6%, diabetes mellitus (DM) 51.1%, hypertension 60.0%, obesity 26.7% and dyslipidaemia 46.7%. On univariate analysis, factors significantly associated with post-LT MS include female gender (P = 0.066), pre-LT respiratory comorbidities (P= 0.038), pre-LT obesity (P= 0.014), pre-LTDM (P < 0.001), pre-LT hypertension (P = 0.039), pre-LTMS (P < 0.001), prednisolone use ≥24 months (P = 0.005) and mycophenolate mofetil use ≥24 months (P = 0.035). On multivariate analysis, independent associations of post-LT MS were pre-LTDM (P = 0.011) and pre-LTMS (P = 0.024). There was no difference in long-term survival of patients with and without post-LTMS (P = 0.425).ConclusionIn conclusion, pre-LT components of the MS and the use of certain immunosuppressants are related to developing post-LTMS.     

Pancreaticoduodenectomy with vascular reconstruction for adenocarcinoma of the pancreas with borderline resectability

AIM: To analyze whether pancreaticoduodenectomy with simultaneous resection of tumor-involved vessels is a safe approach with acceptable patient survival.METHODS: Between January 2001 and March 2012, 136 patients received pancreaticoduodenectomy for adenocarcinoma at our hospital. Seventy-eight patients diagnosed with pancreatic head carcinoma were included in this study. Among them, 46 patients received standard pancreaticoduodenectomy (group 1) and 32 patients received pancreaticoduodenectomy with simultaneous resection of the portal vein or the superior mesenteric vein or artery (group 2) followed by reconstruction. The immediate surgical outcomes and survivals were compared between the groups. Fifty-five patients with unresectable adenocarcinoma of the pancreas without liver metastasis who received only bypass operations (group 3) were selected for additional survival comparison.RESULTS: The median ages of patients were 67 years (range: 37-82 years) in group 1, and 63 years (range: 35-86 years) in group 2. All group 2 patients had resection of the portal vein or the superior mesenteric vein and three patients had resection of the superior mesenteric artery. The pancreatic fistula formation rate was 21.7% (10/46) in group 1 and 15.6% (5/32) in group 2 (P = 0.662). Two hospital deaths (4.3%) occurred in group 1 and one hospital death (3.1%) occurred in group 2 (P = 0.641). The one-year, three-year and five-year overall survival rates in group 1 were 71.1%, 23.6% and 13.5%, respectively. The corresponding rates in group 2 were 70.6%, 33.3% and 22.2% (P = 0.815). The one-year survival rate in group 3 was 13.8%. Pancreaticoduodenectomy with simultaneous vascular resection was safe for pancreatic head adenocarcinoma.CONCLUSION: The short-term and survival outcomes with simultaneous resection were not compromised when compared with that of standard pancreaticoduodenectomy.     

Electrophysiological actions of oxytocin on hypothalamic neurons in vitro: neuropharmacological characterization and effects of ovarian steroids.

Oxytocin (OT) neurotransmission in the brain has a facilitatory effect on sexual receptivity in rats. This effect of OT is dependent on priming by ovarian steroids, estrogen and progesterone. These steroids modulate OT binding in specific brain nuclei, including the ventrolateral portion of the ventromedial hypothalamic nucleus (vlVMN). In the present study, single-unit activity was recorded from the vlVMN in hypothalamic slices to characterize the electrophysiological actions of OT. To examine the effects of ovarian steroids on OT actions, we used brain slices prepared from ovariectomized rats either treated with estrogen or not, and some slices were treated with progesterone in vitro. OT had little modulatory action on neuronal responses to other agents, but affected the activity of large numbers of vlVMN units. Of those neurons affected, 94% responded with excitation. This predominant stimulatory action of OT is consistent with its lordosis-facilitating effect, because increases in the activity of VMN neurons are generally associated with the facilitation of lordosis. Pharmacological analyses with selective OT agonists and antagonists as well as structurally related peptides showed that the excitatory action of OT is mediated by OT receptors. Estradiol modulated several aspects of OT transmission. First, it increased neuronal responsiveness to OT, especially at the lowest concentration used (0.2 nM). In addition, it caused neuronal responses to OT to correlate significantly with responses to acetylcholine and norepinephrine, which also can act on the ventromedial hypothalamus to facilitate lordosis. Finally, estradiol enhanced the excitability of laterally projecting neurons, which have been implicated in lordosis. In estrogen-pretreated slices, addition of progesterone in vitro caused little further effect on responses of individual neurons to exogenous OT. Altogether, the present electrophysiological findings are consistent with the hypothesis that estrogen potentiates OT action by increasing functional OT receptors preferentially in lordosis-relevant neurons, thereby enabling OT to efficiently facilitate female reproductive behavior.     

Metformin therapy in COVID-19: inhibition of NETosis

Journal of Thrombosis and Thrombolysis -     

Single-unit activity of hypothalamic arcuate neurons in brain tissue slices. Effects of anterior pituitary hormones, cholecystokinin-octapeptide, and neurotransmitters

Extracellular single-unit activity was recorded from hypothalamic arcuate nucleus (ARC) in brain tissue slices. Adult female Sprague-Dawley rats, ovariectomized or ovariectomized plus estrogen treated for at least 1 week, were used. Resting activity and responses of ARC neurons to six anterior pituitary hormones, or (as a positive control) cholecystokinin-octapeptide sulfate (CCK-8S), and a battery of four neurotransmitters including norepinephrine, serotonin, dopamine, and glutamate were recorded. A total of 263 neurons were recorded. Estrogen treatment did not cause any significant changes in the firing patterns nor in responses to most agents tested except for CCK-8S. A large percentage of the ARC neurons were either silent (40%) or slow-firing units (43% fired less than twice/s). Only a small percentage of ARC neurons (20-30%) responded to the anterior pituitary hormones, and these responses were small, delayed increases in firing despite the fact that CCK-8S stimulated more than half of the neurons with large responses. Glutamate was also excitatory, but not quite as effective as CCK-8S. Norepinephrine and serotonin were equally effective in eliciting a neuronal response (over 70% of units responded with an excitation or inhibition). Dopamine acted like norepinephrine, but was less potent. Since anterior pituitary hormones only weakly affected ARC neurons, these electrophysiological data give scant support to the notion that short-loop feedback is accompanied by electrical changes. In the ARC, however, CCK-8S may play some functional roles that are influenced by estrogen.     

Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2

Linkage analysis was performed on a large pedigree with an autosomal dominant platelet disorder and a striking propensity in affected family members to develop hematologic malignancy, predominantly acute myelogenous leukemia. We report the linkage of the autosomal dominant platelet disorder to markers on chromosome 21q22. Four genetic markers completely cosegregate with the trait and yield maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001). Two flanking markers, D21S1265 and D21S167, define a critical region for the disease locus of 15.2 centimorgan. Further analysis of this locus may identify a gene product that affects platelet production and function and contributes to the molecular evolution of hematologic malignancy.     

Elimination of myeloma cells from bone marrow by using monoclonal antibodies and magnetic immunobeads

The efficacy of immunomagnetic beads to purge human myeloma cells from bone marrow ex vivo was evaluated. The optimal conditions for purging were studied first by using three myeloma cell lines: RPMI-8226, SKO- 007, and SKMM-2. Myeloma cells labeled with the vital fluorescent dye Hoechst 33342 were admixed with normal bone marrow cells, and two monoclonal antibodies reactive with the myeloma cells (PCA-1 and BL-3) were added alone or in combination with the cells. Magnetic beads coated with goat antimouse immunoglobulin G were then added, and the tumor cells to which beads were attached were separated from the mixture with a magnet. The efficacy of tumor cell removal was dependent on the bead-to-tumor ratio; a ratio of more than 500 was optimal in the presence of excess normal marrow cells. The combination of monoclonal antibodies PCA-1 and BL-3 increased the tumor cell removal as compared with either antibody alone. Two cycles of treatment were more effective than one cycle was. Under optimal conditions, 2.3 to 4 logs of tumor cells could be removed from the mixture containing 10% myeloma cells without a significant loss of normal hematopoietic progenitors as measured by CFU-GM, CFU-GEM, and BFU-E. When the efficacy of this procedure was tested on fresh bone marrow from patients with multiple myeloma (MM) by using the combination of PCA-1, BL-3, and J-5, 1.6 to 2.5 logs of tumor cells could be removed by one cycle of treatment, even from marrows containing less than 10% myeloma cells. These observations support the use of monoclonal antibody combinations and immunobeads as a reliable and nontoxic method to eliminate contaminating myeloma cells ex vivo in preparation for autologous bone marrow transplantation in patients with MM.