Regulatory dendritic cells for promotion of liver transplant operational tolerance: Rationale for a clinical trial and accompanying mechanistic studies

Dendritic cells (DC) are rare, bone marrow (BM)-derived innate immune cells that critically maintain self-tolerance in the healthy steady-state. Regulatory DC (DCreg) with capacity to suppress allograft rejection and promote transplant tolerance in pre-clinical models can readily be generated from BM precursors or circulating blood monocytes. These DCreg enhance allograft survival via various mechanisms, including promotion of regulatory T cells. In non-human primates receiving minimal immunosuppressive drug therapy (IS), infusion of DCreg of donor origin, one week before transplant, safely prolongs renal allograft survival and selectively attenuates anti-donor CD8⁺ memory T cell responses in the early post-transplant period. Based on these observations, and in view of the critical need to reduce patient dependence on non-specific IS agents that predispose to cardiometabolic side effects and renal insufficiency, we will conduct a first-in-human safety and preliminary efficacy study of donor-derived DCreg infusion to achieve early (18?months post-transplant) complete IS withdrawal in low-risk, living donor liver transplant recipients receiving standard-of-care IS (mycophenolate mofetil, tacrolimus and steroids). We will test the hypothesis that, although donor-derived DCreg are short-lived, they will induce robust donor-specific T cell hyporesponsiveness. We will examine immunological mechanisms by sequential analysis of blood and tissue samples, incorporating cutting-edge technologies.     

Severity of illness and extra pyramidal symptoms as predictors for oral diseases among patients with schizophrenia

Objective: The study explores the association between severity of illness (positive, negative, depressive and cognitive symptoms) and extra pyramidal symptoms (EPS) with dental caries, periodontal disease and prosthetic needs among patients with schizophrenia.

Material and methods: A total of 71 schizophrenic patients diagnosed based on ICD-10 criteria participated in the study. Clinical Global Impression – Schizophrenia (CGI–SCH) scale was used to evaluate positive, negative, depressive, cognitive symptoms and overall severity of schizophrenia. Simpson–Angus Scale (SAS) was used for assessment of EPS. Dental examinations were conducted as per WHO (1997) criterion.

Results: Mean DMFT and CPI scores with periodontal pockets were 5.57?±?2.12 and 2.37?±?0.74; significant differences being noted among those with and without EPS (p?p?p?p?p?Conclusions: Patients with schizophrenia had high dental caries, periodontal disease and unmet dental prosthetic needs. Severity of the schizophrenic and EPS was associated with poor oral health. Efforts need to be focused on strengthening the evidence of its association with oral health indicators through further studies including cohort investigations.     

A microfluidic in-line ELISA for measuring secreted protein under perfusion

Biomedical Microdevices - To assess the visualization and efficacy of a wireless resonant circuit (wRC) catheter system for carotid artery occlusion and embolectomy under real-time MRI guidance in...     

Impaired NLRP3 inflammasome activity during fetal development regulates IL‐1β production in human monocytes

Interleukin‐1β (IL‐1β) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll‐like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16^pos monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro‐IL‐1β precursor protein upon LPS stimulation. In contrast, high levels of pro‐IL‐1β are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL‐1β. The lack of secreted IL‐1β in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase‐1 activity before 29 weeks of gestation, whereas expression of the apoptosis‐associated speck‐like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP‐induced caspase‐1 activity in cord blood monocytes. Lastly, secretion of IL‐1β in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL‐1β responses early in gestation, in part due to a downregulation of TLR‐mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.     

High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery

Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity. DTI, however, has limitations that include its inability to resolve multiple crossing fibers and its susceptibility to partial volume effects. Therefore, recent focus has shifted to more advanced WM imaging techniques such as high-definition fiber tractography (HDFT). In this paper, we illustrate the application of HDFT, which in our preliminary experience has enabled accurate depiction of perilesional tracts in a 3-dimensional manner in multiple anatomical compartments including edematous zones around high-grade gliomas. This has facilitated accurate surgical planning. This is illustrated by using case examples of patients with glioblastoma multiforme. We also discuss future directions in the role of these techniques in surgery for gliomas.     

The impact of functional constipation on quality of life of middle-aged Black Americans: a prospective case–control study

Purpose

To quantify the impact of constipation on health-related quality of life (HRQoL) in Black Americans.

Methods

Case?Ccontrol design. Black subjects referred for colon cancer screening with a Bristol Stool Score of 3?C5 for >75% of bowel movements served as controls. Frequency-matched functional constipation subjects had to fulfill Rome III criteria. Both groups completed demographic and health surveys. Short Form-36 assessed HRQoL.

Results

We recruited 102 constipated patients and 100 controls. The groups were well matched demographically. After adjustment for comorbidities, SF-36 scores for vitality, bodily pain, social functioning, and role-emotional were significantly lower in constipated patients. Unadjusted physical and mental component summary scores (PCS and MCS) were significantly higher in the control group (47.1?±?10.6 vs. 43.3?±?8.6; P?=?0.005 and 50.6?±?12.4 vs. 43.4?±?11.8; P?<?0.001, respectively). After adjustment for comorbidities, PCS differences were no longer significant (P?=?0.54); however, MCS differences were significant (P?=?0.004). Marginal mean scores for the MCS for controls and constipated subjects were 49.9?±?1.2 and 43.6?±?1.2, respectively. The presence of a comorbidity was independently associated with PCS (P?<?0.001) and MCS (P?=?0.026) results.

Conclusions

Functional constipation has a significant impact on HRQoL in middle-aged Black Americans, particularly in regard to mental well-being.     

Glucose, insulin, and acute myocardial infarction: reply

Dr Das comments that the association between the failure ofglucose levels to drop during hospitalization and higher mortalityfollowing acute myocardial     

Detection of new amino acid markers of liver trauma by proton nuclear magnetic resonance spectroscopy.

OBJECTIVE: We examined serum in patients of liver injury to explore the possible clinical application of abnormal micrometabolites as a marker of liver injury and severity in cases of traumatic liver damage. METHODS: Serum were screened by proton nuclear magnetic resonance spectroscopy in 96 patients with varying degree of liver injury and compared with concentrations in healthy control volunteers. RESULTS: Large quantities of phenylalanine and tyrosine were detected by spectroscopic analysis in patients with liver injury but not in those without liver injury (P < 0.001). Proton nuclear magnetic resonance spectroscopy revealed two unique amino acids, phenylalanine and tyrosine, in the sera of the subjects with liver injury, irrespective of the extent and type of injury gauged by radiology or laparotomy. Phenylalanine spectrum was obtained in all 84 patients with liver injury (100% sensitivity) whereas tyrosine spectrum was present in 83 out of 84 patients (98.8% sensitivity) suggesting that these amino acids were specifically released in the patients of liver injury. Significant correlations were observed between phenylalanine and tyrosine concentrations and total bilirubin levels and albumin levels. Serum phenylalanine and tyrosine concentrations correlated well with imaging and laparotomy findings of liver injury. CONCLUSION: Phenylanaline and tyrosine appear to be specific and new markers of liver injury.