Evidence-Based Mechanical Ventilatory Strategies in ARDS.

Acute respiratory distress syndrome (ARDS) remains one of the leading causes of morbidity and mortality in critically ill patients despite advancements in the field. Mechanical ventilatory strategies are a vital component of ARDS management to prevent secondary lung injury and improve patient outcomes. Multiple strategies including utilization of low tidal volumes, targeting low plateau pressures to minimize barotrauma, using low FiO2 (fraction of inspired oxygen) to prevent injury related to oxygen free radicals, optimization of positive end expiratory pressure (PEEP) to maintain or improve lung recruitment, and utilization of prone ventilation have been shown to decrease morbidity and mortality. The role of other mechanical ventilatory strategies like non-invasive ventilation, recruitment maneuvers, esophageal pressure monitoring, determination of optimal PEEP, and appropriate patient selection for extracorporeal support is not clear. In this article, we review evidence-based mechanical ventilatory strategies and ventilatory adjuncts for ARDS.

A Prospective, Randomized Trial of Splinting After Minicarpal Tunnel Release.

PURPOSE: To determine if any significant differences exist in patient-reported or clinical outcomes among 3 different postoperative orthotic regimens: no orthosis, removable orthosis, and plaster nonremovable orthosis-following miniopen carpal tunnel release (CTR) surgery for symptomatic isolated carpal tunnel syndrome. METHODS: A total of 249 patients received a miniopen CTR and were subsequently randomized into 1 of 3 orthotic regimens: 80, no orthosis; 83, removable orthosis; and 86, nonremovable orthosis-to be removed at the first postoperative visit 10 to 14 days later. Patient-reported outcomes included the quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) surveys, Levine-Katz Symptom Severity and Functional Status Scales, and Pain at Rest and in Action using the Numerical Pain Rating Scale. Clinical outcomes included wrist range of motion, grip, and lateral pinch strengths. All outcomes were evaluated bilaterally at 10 to 14 days, 6 weeks, and 3, 6, and 12 months after surgery by evaluators blinded to the assigned regimen. Demographic information was obtained before surgery, and complications were recorded throughout the study. RESULTS: There were no statistically significant differences in any patient-reported or clinical outcomes at any follow-up period except at 6 and 12 months: the lateral pinch strength of the nonremovable orthosis group with CTR in the dominant hand was weaker than both of the other groups. Patient demographic characteristics did not significantly influence the outcomes at any time. Scar tenderness was the most commonly observed complication followed by stiffness. There were 2 cases each of complex regional pain syndrome and superficial wound dehiscence and 1 case of wound infection that resolved with oral antibiotics. CONCLUSIONS: The postoperative orthotic regimen does not change any patient-reported outcome up to at least 12 months following miniopen CTR. Lateral pinch strength was weaker in the nonremovable orthosis group at 6 and 12 months. Our data do not support the use of any postoperative orthosis following routine miniopen CTR. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

Intrafocal pin plate fixation of distal ulna fractures associated with distal radius fractures.

Subcapital ulnar fractures in association with distal radius fractures in elderly patients increase instability and pose a treatment challenge. Fixation of the ulnar fracture with traditional implants is difficult due to the subcutaneous location, comminution, and osteoporosis. We describe an intrafocal pin plate that provides fixation by a locking plate on the distal ulna and intramedullary fixation within the shaft. The low profile and percutaneous technique make this device a useful alternative for treatment of subcapital ulna fractures in the elderly.

Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway.

Nrf2 regulates the expression of numerous cytoprotective genes in mammalian cells. The activity of Nrf2 is regulated by the Cul3 adaptor Keap1, yet little is known regarding mechanisms of regulation of Keap1 itself. Here, we have used immunopurification of Keap1 and mass spectrometry, in addition to immunoblotting, to identify sequestosome 1 (SQSTM1) as a cellular binding partner of Keap1. SQSTM1 serves as a scaffold in various signaling pathways and shuttles polyubiquitinated proteins to the proteasomal and lysosomal degradation machineries. Ectopic expression of SQSTM1 led to a decrease in the basal protein level of Keap1 in a panel of cells. Furthermore, RNA interference (RNAi) depletion of SQSTM1 resulted in an increase in the protein level of Keap1 and a concomitant decrease in the protein level of Nrf2 in the absence of changes in Keap1 or Nrf2 mRNA levels. The increased protein level of Keap1 in cells depleted of SQSTM1 by RNAi was linked to a decrease in its rate of degradation; the half-life of Keap1 was almost doubled by RNAi depletion of SQSTM1. The decreased level of Nrf2 in cells depleted of SQSTM1 by RNAi was associated with decreases in the mRNA levels, protein levels, and function of several Nrf2-regulated cell defense genes. SQSTM1 was dispensable for the induction of the Keap1-Nrf2 pathway, as Nrf2 activation by tert-butylhydroquinone or iodoacetamide was not affected by RNAi depletion of SQSTM1. These findings demonstrate a physical and functional interaction between Keap1 and SQSTM1 and reveal an additional layer of regulation in the Keap1-Nrf2 pathway.

Management of proximal interphalangeal joint dislocations in athletes.

Proximal interphalangeal joint dislocations are common athletic injuries. In dislocations and fracture dislocations, the most important treatment principle is congruent joint reduction and maintenance of stability. This article reviews the relevant anatomy, injury characteristics, and treatment options for proximal interphalangeal joint dislocations and fracture dislocations. Treatment methods discussed include closed reduction, percutaneous fixation, and open reduction.

Cell shape-dependent Control of Ca2+ influx and cell cycle progression in Swiss 3T3 fibroblasts.

The ability of adherent cells such as fibroblasts to enter the cell cycle and progress to S phase is strictly dependent on the extent to which individual cells can attach to and spread on a substratum. Here we have used microengineered adhesive islands of 22 and 45 mum diameter surrounded by a nonadhesive substratum of polyhydroxyl methacrylate to accurately control the extent to which individual Swiss 3T3 fibroblasts may spread. The effect of cell shape on mitogen-evoked Ca2+ signaling events that accompany entry into the cell cycle was investigated. In unrestricted cells, the mitogens bombesin and fetal calf serum evoked a typical biphasic change in the cytoplasmic free Ca2+ concentration. However, when the spreading of individual cells was restricted, such that progression to S phase was substantially reduced, both bombesin and fetal calf serum caused a rapid transient rise in the cytoplasmic free Ca2+ concentration but failed to elicit the normal sustained influx of Ca2+ that follows Ca2+ release. As expected, restricting cell spreading led to the loss of actin stress fibers and the formation of a ring of cortical actin. Restricting cell shape did not appear to influence mitogen-receptor interactions, nor did it influence the presence of focal adhesions. Because Ca2+ signaling is an essential component of mitogen responses, these findings implicate Ca2+ influx as a necessary component of cell shape-dependent control of the cell cycle.

Human keratinocytes release ATP and utilize three mechanisms for nucleotide interconversion at the cell surface.

Nucleotide activation of P2 receptors is important in autocrine and paracrine regulation in many tissues. In the epidermis, nucleotides are involved in proliferation, differentiation, and apoptosis. In this study, we have used a combination of luciferin-luciferase luminometry, pharmacological inhibitors, and confocal microscopy to demonstrate that HaCaT keratinocytes release ATP into the culture medium, and that there are three mechanisms for nucleotide interconversion, resulting in ATP generation at the cell surface. Addition of ADP, GTP, or UTP to culture medium elevated the ATP concentration. ADP to ATP conversion was inhibited by diadenosine pentaphosphate, oligomycin, and UDP, suggesting the involvement of cell surface adenylate kinase, F(1)F(0) ATP synthase, and nucleoside diphosphokinase (NDPK), respectively, which was supported by immunohistochemistry. Simultaneous addition of ADP and GTP elevated ATP above that for each nucleotide alone indicating that GTP acts as a phosphate donor. However, the activity of NDPK, F(1)F(0) ATP synthase or the forward reaction of adenylate kinase could not fully account for the culture medium ATP content. We postulate that this discrepancy is due to the reverse reaction of adenylate kinase utilizing AMP. In normal human skin, F(1)F(0) ATP synthase and NDPK were differentially localized, with mitochondrial expression in the basal layer, and cell surface expression in the differentiated layers. We and others have previously demonstrated that keratinocytes express multiple P2 receptors. In this study we now identify the potential sources of extracellular ATP required to activate these receptors and provide better understanding of the role of nucleotides in normal epidermal homeostasis and wound healing.

Membrane topology of CLN3, the protein underlying Batten disease.

Juvenile neuronal ceroid lipofuscinosis, or Batten disease, is an autosomal recessive disorder characterized by progressive loss of motor and cognitive functions, loss of vision, progressively severe seizures, and death. The disease is associated with mutations in the gene CLN3, which encodes a novel 438 amino acid protein, the function of which is currently unknown. Protein secondary structure prediction programs suggest that the CLN3 protein has five to seven membrane-spanning domains (MSDs). To distinguish among a number of hypothetical models for the membrane topology of CLN3 we used in vitro translation of native, Flag epitope-labeled and glycosylation site-mutated CLN3 protein in the presence or absence of canine pancreatic microsomes. These were immunoprecipitated using antibodies specific for Flag or peptide sequences within CLN3 or left untreated. The results indicate that CLN3 contains five MSDs, an extracellular/intraluminal amino-terminus, and a cytoplasmic carboxy-terminus.