Quality Improvement Initiative to Reduce Nighttime Noise in a Transplantation and Cellular Therapy Unit

Sleep is an essential biologic function vital for physiologic rest, healing, and emotional well-being. Sleep disruption is commonly seen in patients and caregivers with lengthy hospital stays such as patients undergoing hematopoietic stem cell transplantation and cellular therapy (TCT). Sleep disruption can lead to increased stress and fatigue, affecting caregivers’ ability to support their loved one. The global aim of our quality improvement initiative was to improve sleep quality in TCT patients and caregivers. The smart aim of our project was to decrease nighttime hallway noise from 47 dB to 43 dB and decrease the number of overnight noise peaks greater than 60 dB from 865 to 432 in 6 months. Through a cross-sectional quantitative and qualitative evaluation of sleep we had previously identified poor sleep quality, and with a cross-sectional focus group analysis of patients, caregivers, and medical staff we identified the factors associated with poor sleep. Hallway noise was a major factor. A simplified failure mode analysis identified 4 main key drivers; unobtrusive nighttime cleaning process, nighttime awareness maintenance system, quiet nighttime nursing system, and reliable nighttime awareness system. Several plan-do-study-act interventions took place and were adopted. From January to June 2018 the overnight mean decibel level decreased from 47 dB to 44 dB (6% reduction). Overnight noise spikes above 60 dB decreased from a mean of 865 spikes to a mean of 463 spikes (46% reduction). With a quality improvement initiative, we identified the causes of hallway nighttime hospital unit noise that negatively impact sleep and through a team-based approach performed interventions that successfully mitigated these factors.     

Haloferax sulfurifontis GUMFAZ2 producing xylanase‐free cellulase retrieved from Haliclona sp. inhabiting rocky shore of Anjuna,Goa‐India

Salt stable cellulases are implicated in detritic food webs of marine invertebrates for their role in the degradation of cellulosic material. A haloarchaeon, Haloferax sulfurifontis GUMFAZ2 producing cellulase was successfully isolated from marine Haliclona sp., a sponge inhabiting the rocky intertidal region of Anjuna, Goa. The culture produced extracellular xylanase‐free cellulase with a maximum activity of 11.7 U/ml, using carboxymethylcellulose‐Na (CMC‐Na), as a sole source of carbon in 3.5 M NaCl containing medium, pH 7 at 40°C and produced cellobiose and glucose, detectable by thin‐layer chromatography. Nondenaturing polyacrylamide gel electrophoresis of the crude enzyme, revealed a single protein band of 19.6 kDa which on zymographic analysis exhibited cellulase activity while corresponding sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed a molecular weight of 46 kDa. Unlike conventional cellulases, this enzyme is active in presence of 5 M NaCl and does not have accompanying xylanase activity, hence can be considered as xylanase‐free cellulase. Such enzymes from haloarchaea offer great potential for biotechnological application because of their stability at high salinity and is therefore worth pursuing.     

Different involvement of the MAPK family in inflammatory regulation in human pulmonary microvascular endothelial cells stimulated with LPS and IFN-γ

Pulmonary endothelial injury is central in the pathogenesis of acute lung injury (ALI). The MAPK signaling cascades are generally thought to be involved in the molecular mechanism underlying the ALI development, but their roles in pulmonary endothelial injury is poorly understood. We thus examined the involvement of the MAPK family member in inflammatory responses of human pulmonary microvascular endothelial cells (HPMVECs) stimulated with LPS and IFN-γ. HPMVECs were found to exhibit the upregulation of expression of Toll-like receptor 4 by IFN-γ, resulting in potentiation of inflammatory cytokine release by LPS stimulation. All MAPKs, ERK1/2, JNK, and p38, were activated by simultaneous stimulation with LPS/IFN-γ. JNK activation in cells stimulated with LPS/IFN-γ was significantly potentiated by the two different p38 inhibitors, SB203580 and RWJ67657, suggesting the negative regulation of JNK activation by p38 in HPMVECs. The mRNA and protein expression levels of ICAM-1 were eliminated by the JNK inhibitor, suggesting that ICAM-1 expression is positively regulated by JNK. The p38 inhibitor significantly enhanced ICAM-1 expression. ERK1/2 activation was not responsible for the LPS/IFN-γ-induced ICAM-1 upregulation in HPMVECs. THP-1 monocyte adhesion to HPMVECs under LPS/IFN-γ stimulation was inhibited by the JNK inhibitor and enhanced by the p38 inhibitor. We conclude that, in HPMVECs stimulated with LPS/IFN-γ, JNK mediates ICAM-1 expression that can facilitate leukocyte adherence and transmigration, while p38 MAPK negatively regulates the upregulation of ICAM-1 through inhibition of JNK activation.     

Pheochromocytoma Management,Outcomes and the Role of Cortical Preservation

Objectives

To evaluate the management and outcome of children with pheochromocytoma and determine the role of cortex preservation in cases of bilateral disease.

Methods

Retrospective review of children, below 12 y of age, with pheochromocytoma managed between November 2003 and December 2012 was done.

Results

Twelve patients, nine boys and three girls with median age 9 y were enroled. Eleven (92 %) had adrenal tumors and in one it was extra-adrenal. Five (42 %) had bilateral disease. Ten presented with hypertension, one with headache and one with abdominal pain and fever. All were stabilized pre-operatively with alpha and beta blockers and volume expansion. Six children with unilateral disease underwent total adrenalectomy. Out of five with bilateral disease, one child underwent bilateral total adrenalectomy and was later started on hormone replacement. Remaining four underwent total adrenalectomy on one side and partial on the other side. Post-operatively all became symptom free and normotensive and were off medications within 1 mo. Two children developed recurrence 1 mo post-operatively, one with an initial unilateral pheochromocytoma and one with paraganglionoma. At the last follow up, 10 out of 12(83 %) were disease free while two with recurrence are still awaiting surgery.

Conclusions

Surgical resection of pheochromocytoma is effective treatment to achieve cure and prolong survival. Cortex preservation should be done in bilateral disease as risk of recurrence in such cases seems to be of lesser significance as compared to the morbidity and mortality of adrenal insufficiency and consequent lifelong hormone replacement.     

Anti-inflammatory Effects of Flavonoids on TNBS-induced Colitis of Rats

It has been shown that the extracts including eupatilin and quercetin-3-β-D-glucuronopyranoside had mucoprotective effects on the esophagus and stomach through their antioxidant activities. This study was designed to investigate the anti-inflammatory effect of these flavonoid compounds in an animal model of inflammatory bowel disease induced by 2,4,6-trinitrobenzene sulfonic acid. Experimental colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid. Extracts including eupatilin or quercetin-3-β-D-glucuronopyranoside were orally administered to animals 48, 24, and 1 h prior to the induction of colitis and then again 24 h later. The animals were sacrificed 48 h after by 2,4,6-trinitrobenzene sulfonic acid treatment and the macroscopic appearance of the colonic lesions was scored in a blinded manner on a scale of 1 to 10. The inflammatory response to colitis induction was assessed by measuring myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, total glutathione levels, and malondialdehyde concentrations in the colon. The results indicated that extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside dose-dependently improved the morphology of the lesions induced by 2,4,6-trinitrobenzene sulfonic acid and reduced the ulcer index accordingly. In addition, rats receiving extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside showed significantly decreased levels of mucosal myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, and malondialdehyde levels, and increased total glutathione levels. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside ameliorated the inflammatory response and colonic injury in acute colitis by decreasing oxidative stress and neutrophil activation. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside may inhibit acute colitis.     

An fMRI investigation of the cognitive reappraisal of negative memories

Episodic memory retrieval can be influenced by individuals' current goals, including those that are emotional in nature. Participants underwent an fMRI scan while reappraising, or changing the way they thought about aversive images they had previously encoded, to down-regulate (i.e., decrease), up-regulate (i.e., increase), or maintain the emotional intensity associated with their recall. A conjunction analysis between down- and up-regulation during the entire 12-s recall period revealed that both commonly activated reappraisal-related regions, particularly in the lateral and medial prefrontal cortex (PFC). However, when we analyzed a reappraisal instruction phase prior to recall and then divided the recall phase into the time when individuals were first searching for their memories and later elaborating on their details, we found that down- and up-regulation engaged greater neural activity at different time points. Up-regulation engaged greater PFC activity than down-regulation or maintenance during the reappraisal instruction phase. In contrast, down-regulation engaged greater lateral PFC activity as images were being searched for and retrieved. Maintaining the emotional intensity associated with the aversive images engaged similar regions to a greater extent than either reappraisal condition as participants elaborated on the details of the images they were holding in mind. Our findings suggest that down- and up-regulation engage similar neural regions during memory retrieval, but differ in the timing of this engagement.     

Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles

α-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT''s antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently reduced by an average of 80%. Treated animals showed knockdown of Z-AAT in liver and serum with concomitant increased serum M-AAT as determined by allele-specific enzyme-linked immunosorbent assays (ELISAs). In addition, decreased globular accumulation of misfolded Z-AAT in hepatocytes and a reduction in inflammatory infiltrates in the liver was observed. Results from microarray studies demonstrate that endogenous miRNAs were minimally affected by this treatment. These data suggests that miRNA mediated knockdown does not saturate the miRNA pathway as has been seen with viral vector expression of short hairpin RNAs (shRNAs). This safe dual-therapy approach can be applied to other disorders such as amyotrophic lateral sclerosis, Huntington disease, cerebral ataxia, and optic atrophies.