Impact of a Modified Early Warning Score on Rapid Response and Cardiopulmonary Arrest Calls in Telemetry and Medical-Surgical Units.

To reduce the number of cardiac arrests in telemetry and medical- surgical units, a 70-bed community hospital integrated a weighted, aggregate, electronic modified early warning score into the elec- tronic medical record. Impact was evaluated via a quality improvement initiative.

Treatment of Epiphyseal Metastasis to the Proximal Humerus Secondary to Breast Carcinoma: A Case Report.

Metastasis to the bone is a known risk of breast cancer, with the humerus being the most common upper extremity site of metastases, with most lesions located at the humeral diaphysis. We present a unique case of proximal humeral metastasis involving the epiphysis secondary to primary invasive ductal carcinoma in a middle-aged Caucasian female. It is important to have a high degree of suspicion for metastasis when musculoskeletal pain occurs in breast cancer patients, as it may be masked by common, degenerative conditions about the shoulder girdle. When humeral metastases involve the epiphysis, treatment options are complicated by its location, which jeopardizes the integrity of articular cartilage and the function of the shoulder girdle. External beam irradiation provides pain control in a non-invasive manner, sans surgical risks. Surgical intervention will vary depending on the characteristics of the bony lesion, but the use of endoprosthetics has emerged as the most effective option for restoring range of motion and pain control with acceptable rates of implant survival.

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.

The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit alpha7, a mechanism termed "the cholinergic antiinflammatory pathway." Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of alpha7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiac-superior mesenteric plexus, and projecting in the splenic nerve.

Trapezial Acrometastasis as the First Presentation of Occult Lung Cancer: A Case Report.

CASE: Acrometastasis is extremely rare, accounting for 0.1% of all skeletal metastases. Metastases to the carpus are rarer still. This condition can be the first manifestation of an occult malignancy and generally indicates advanced disease. We present the case of a 53-year-old woman with acrometastasis of squamous cell lung cancer to the trapezium as the initial presentation of her malignancy. CONCLUSION: The presentation of acrometastasis can mimic infectious or inflammatory processes, leading to an erroneous diagnosis. Although exceptionally uncommon, it is important to consider as a differential diagnosis for a destructive hand lesion.

Intra-articular Hyaluronic Acid for Osteoarthritis of the Knee in the United States: A Systematic Review of Economic Evaluations.

BACKGROUND: The economic impact of intra-articular hyaluronic acid (IAHA) for the treatment of knee pain associated with osteoarthritis (OA) has been evaluated in the United States, but not systematically summarized. OBJECTIVE: We reviewed the literature to determine the economic impact of IAHA for pain associated with knee OA in the United States. METHODS: A literature review was performed in PubMed (including MEDLINE and MEDLINE In-Process), Embase, the Cochrane Database of Systematic Reviews, and National Health Service Economic Evaluation Database and was limited to English language human studies published from January 2000 to October 2020. RESULTS: The literature search identified 215 unique abstracts; of these, 47 were selected for full-text review and 21 studies met the inclusion criteria. Intra-articular hyaluronic acid injections delayed progression to total knee arthroplasty (TKA), and repeated courses of treatment successfully delayed TKA by more than 5 years. Intra-articular hyaluronic acid was found to reduce the use of pain medications overall and reduce the number of patients receiving opioid prescriptions by 6% (P < .001). Several studies showed that IAHA is more cost-effective in treating pain associated with knee OA compared with conventional care with nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids, and several authors concluded that IAHA should be the dominant treatment strategy. CONCLUSIONS: Current studies suggest that IAHA may reduce the use of pain medications, such as NSAIDs and opioids, and impact time to TKA procedures, thus potentially decreasing overall treatment costs of knee OA over time. Furthermore, IAHA was determined to be cost-effective against NSAIDs, corticosteroids, analgesics, and conservative treatment. As the safety and efficacy of IAHA for knee OA have been well established, the findings from our literature review may be used to inform future economic evaluations.

Safety of Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Trials Involving More than 8,000 Patients.

OBJECTIVE: The objective of this systematic review and meta-analysis was to report the safety of intra-articular hyaluronic acid (IAHA) in patients with symptomatic knee osteoarthritis (OA). METHODS: We identified randomized controlled trials reporting the safety of IAHA versus IA saline in adults with symptomatic knee OA. Main safety outcomes were adverse events (AEs), local AEs, serious adverse events (SAEs), study withdrawals, and AE-related study withdrawals. RESULTS: A total of 35 randomized controlled trials with 38 group comparisons comprising 8,078 unique patients (IAHA: 4,295, IA saline: 3,783) were included in the meta-analysis. Comparing IAHA with IA saline over a median of 6 months follow-up, there were no differences in the risk of AEs (42.4% vs. 39.7%, risk ratio [RR] = 1.01, 95% CI = 0.96-1.07, P = 0.61), SAEs (1.8% vs. 1.2%, RR = 1.44, 95% CI = 0.91-2.26, P=0.12), study withdrawals (12.3% vs. 12.7%, RR = 0.99, 95% CI = 0.87-1.12, P = 0.83), or AE-related study withdrawals (2.7% vs. 2.1%, RR = 1.37, 95% CI = 0.97-1.93, P = 0.08). Local AEs, all of which were nonserious, were more common with IAHA vs. IA saline (14.5% vs. 11.7%, RR = 1.21, 95% CI = 1.07-1.36, P = 0.003) and typically resolved within days. CONCLUSION: IAHA was shown to be safe for use in patients with symptomatic knee OA. Compared with IA saline, IAHA is associated with an increased risk of nonserious, transient local reactions. There was no evidence to suggest any additional safety risks of IAHA.

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the "cholinergic anti-inflammatory pathway," defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to alpha7nAChR knockout mice failed to suppress TNF levels, indicating that the alpha7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and alpha7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.

Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling.

The alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural alpha7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the alpha7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-kappaB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in alpha7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from alpha7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires alpha7nAChR-mediated signaling.

Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

High-mobility group box-1 isoforms as potential therapeutic targets in sepsis.

High-mobility group box-1 (HMGB1) protein was originally described as a nuclear DNA-binding protein that functions as a structural cofactor critical for proper transcriptional regulation and gene expression. Recent studies indicate that damaged, necrotic cells liberate HMGB1 into the extracellular milieu where it functions as a proinflammatory cytokine. Indeed, HMGB1 represents a novel family of inflammatory cytokines composed of intracellular proteins that can be recognized by the innate immune system as a signal of tissue damage. Posttranslational modifications of HMGB 1 determine its interactions with other proteins and modulate its biological activity. However, very little is known about how these posttranslational modifications of HMGB1 affect its extracellular inflammatory activity and pathological potential. These studies can provide more efficient therapeutic strategies directed against specific HMGB1 isoforms. Therapeutic strategies against these specific HMGB1 isoforms can serve as models for more efficient therapeutic strategies against rheumatoid arthritis or sepsis. This article reviews the recent studies on HMGB1 regulation and their impact on the inflammatory activity and pathological contribution of HMGB 1 to infectious and inflammatory disorders.

Comparison of the vastus-splitting and median parapatellar approaches for primary total knee arthroplasty: a prospective, randomized study. Surgical technique.

BACKGROUND: A vastus-splitting approach for total knee arthroplasty has been advocated to preserve function of the extensor mechanism and to decrease the prevalence of lateral release. Critics have claimed that there is greater blood loss and compromised exposure in large patients who are managed with this approach. The purpose of the present study was to compare vastus-splitting and median parapatellar approaches for primary total knee arthroplasty. METHODS: Forty-two consecutive patients (fifty-one knees) undergoing primary total knee arthroplasty were randomized to treatment with a median parapatellar or vastus-splitting approach. The interval of the vastus muscle split was marked with radiopaque vascular clips. Surgical data, functional parameters, and preoperative and postoperative electromyograms were assessed. RESULTS: Early (six-month) and intermediateterm (five-year) follow-up showed no differences in functional parameters, tourniquet time, or the frequency of patellar resurfacing. Significantly more lateral releases (p < 0.01) and greater blood loss (p = 0.03) occurred in the median parapatellar group. Nine (43%) of twenty-one knees in the vastus-splitting group had abnormal electromyographic findings at six months postoperatively, whereas all patients in the median parapatellar group had normal findings. Seven knees with abnormal electromyographic findings at six months had normal findings when restudied at five years; in each of these knees, the vastus split had been developed bluntly. The other two knees with abnormal findings at six months had had sharp dissection for the muscle split. Both of these knees had chronic changes, one with changes indicative of reinnervation and the other with ongoing denervation, but neither demonstrated functional compromise. CONCLUSIONS: The vastus-splitting approach offers a viable alternative to the median parapatellar approach for primary total knee arthroplasty that reduces the need for lateral retinacular release without impairment of quadriceps function. Electromyographic abnormalities in the quadriceps muscle have no functional consequence and most likely represent reversible neurapraxic injury that may be avoided by blunt dissection in the vastus medialis muscle.

Essential role for the myotubularin-related phosphatase Ymr1p and the synaptojanin-like phosphatases Sjl2p and Sjl3p in regulation of phosphatidylinositol 3-phosphate in yeast.

The requirement of Vps34p, the sole phosphatidylinositol (PI) 3-kinase in Saccharomyces cerevisiae, for protein sorting to the vacuole in yeast has exemplified the essential role for phosphoinositides, phosphorylated derivatives of PI, in membrane trafficking. To better understand mechanisms that regulate PI 3-phosphate [PI(3)P]-mediated signaling, the role of the yeast myotubularin-related PI(3)P phosphatase Ymr1p was investigated. We found that Ymr1p and the synaptojanin-like phosphatase Sjl3p function as key regulators of the localization and levels of PI(3)P. Our data indicated that the ymr1Delta sjl3Delta double mutant aberrantly accumulated PI(3)P and demonstrated a steady-state redistribution of this lipid that leads to enrichment on the vacuolar membrane. This resulted in vacuole protein sorting defects, vacuolar fragmentation, and the misregulation of PI(3)P-specific effectors. Triple deletion of YMR1, SJL2, and SJL3 was lethal, suggesting an essential requirement for phosphatase-mediated PI(3)P regulation. Consistent with this, growth was restored to a ymr1Delta sjl2Delta sjl3Delta triple mutant by a PI(3)P-targeted Sac1p domain chimera (GFP-Sac1DeltaC-FYVE(EEA1)) that returned PI(3)P to levels comparable with wild-type cells. Together, this study demonstrated that Ymr1p, a myotubularin phosphatase family member, functions in the control of PI(3)P-dependent signaling and the maintenance of endosomal system integrity. In addition, this work defined an essential overlapping role for lipid phosphatases in the regulation of 3' phosphoinositides in yeast.

Efficacy of platelet-rich plasma injections for symptomatic tendinopathy: systematic review and meta-analysis of randomised injection-controlled trials.

AIM: To determine the efficacy of platelet-rich plasma (PRP) injections for symptomatic tendinopathy. DESIGN: Systematic review of randomised, injection-controlled trials with meta-analysis. DATA SOURCES: Systematic searches of MEDLINE and EMBASE, supplemented by manual searches. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials with 3 months minimum follow-up that evaluated pain reduction with PRP versus control (saline, local anaesthetic, corticosteroid) injections in patients with symptomatic tendinopathy. RESULTS: A total of 16 randomised controlled trials (18 groups) of PRP versus control were included. Median sample size was 35 patients, a study size that would require an effect size ≥1.0 to achieve statistical significance. PRP was more efficacious than control in reducing tendinopathy pain, with an effect size of 0.47 (95% CI 0.22 to 0.72, p<0.001), signifying a moderate treatment effect. Heterogeneity among studies was moderate (I2=67%, p<0.001). In subgroup analysis and meta-regression, studies with a higher proportion of female patients were associated with greater treatment benefits with PRP. CONCLUSIONS: Injection of PRP is more efficacious than control injections in patients with symptomatic tendinopathy.

Hmgb-1 as a therapeutic target for infectious and inflammatory disorders.

High-mobility group box (HMGB)-1 was recently identified as a lethal mediator of severe sepsis and represents a novel group of intracellular proteins that function as inflammatory cytokines when released into the extracellular milieu. From a clinical perspective, extracellular HMGB-1 can cause multiple organ failure and contribute to the pathogenesis of diverse disorders including sepsis, cardiovascular shock, rheumatoid arthritis, diabetes, and cancer. HMGB-1 has been proven to be a successful therapeutic target in experimental models of diverse infectious and inflammatory diseases, and these findings have renewed the clinical interest of specific cytokine inhibitors. However, little is known about the molecular mechanisms underlying the cytokine activity of HMGB-1 and its contribution to infection and inflammation. This article analyzes the value of HMGB-1 as a therapeutic target for the treatment of diverse infectious and inflammatory disorders and its interest for human clinical trials.

Comparison of the vastus-splitting and median parapatellar approaches for primary total knee arthroplasty: a prospective, randomized study.

BACKGROUND: A vastus-splitting approach for total knee arthroplasty has been advocated to preserve function of the extensor mechanism and to decrease the prevalence of lateral release. Critics have claimed that there is greater blood loss and compromised exposure in large patients who are managed with this approach. The purpose of the present study was to compare vastus-splitting and median parapatellar approaches for primary total knee arthroplasty. METHODS: Forty-two consecutive patients (fifty-one knees) undergoing primary total knee arthroplasty were randomized to treatment with a median parapatellar or vastus-splitting approach. The interval of the vastus muscle split was marked with radiopaque vascular clips. Surgical data, functional parameters, and preoperative and postoperative electromyograms were assessed. RESULTS: Early (six-month) and intermediate-term (five-year) follow-up showed no differences in functional parameters, tourniquet time, or the frequency of patellar resurfacing. Significantly more lateral releases (p < 0.01) and greater blood loss (p = 0.03) occurred in the median parapatellar group. Nine (43%) of twenty-one knees in the vastus-splitting group had abnormal electromyographic findings at six months postoperatively, whereas all patients in the median parapatellar group had normal findings. Seven knees with abnormal electromyographic findings at six months had normal findings when restudied at five years; in each of these knees, the vastus split had been developed bluntly. The other two knees with abnormal findings at six months had had sharp dissection for the muscle split. Both of these knees had chronic changes, one with changes indicative of reinnervation and the other with ongoing denervation, but neither demonstrated functional compromise. CONCLUSIONS: The vastus-splitting approach offers a viable alternative to the median parapatellar approach for primary total knee arthroplasty that reduces the need for lateral retinacular release without impairment of quadriceps function. Electromyographic abnormalities in the quadriceps muscle have no functional consequence and most likely represent reversible neurapraxic injury that may be avoided by blunt dissection in the vastus medialis muscle.

Normal platelet function in platelet concentrates requires non-platelet cells: a comparative in vitro evaluation of leucocyte-rich (type 1a) and leucocyte-poor (type 3b) platelet concentrates.

BACKGROUND: Therapeutic success of platelet-rich plasma (PRP) may vary based on the composition and preparation method. The objective of this study was to evaluate the cellular components of platelet concentrates produced by a leucocyte-rich (LR-PRP) and a leucocyte-poor PRP systems (LP-PRP). METHODS: Parameters evaluated included platelet recovery, platelet concentration, red blood cell (RBC) and white blood cell (WBC) composition, platelet growth factor release and stimulation of human tendon cell proliferation in vitro. RESULTS: Platelet recoveries were 52% for LP-PRP and 89% for LR-PRP. LR-PRP demonstrated greater reproducibility with a 4.2% coefficient of variation (CV) compared with 19.4% for LP-PRP (p<0.001). LR-PRP demonstrated a greater increase in platelet concentration (7.9-fold) than LP-PRP (2.2-fold; p<0.001). LP-PRP showed 5.0-fold reductions in WBCs, while LR-PRP showed a 4.0-fold increase (p<0.001). LP-PRP reduced RBCs to a haematocrit of 0.25, while LR-PRP reduced haematocrit to 11.8. LP-PRP did not coagulate robustly on reactivation with CaCl2, and released significantly lower levels of epidermal growth factor (EGF) and transforming growth factor ß1 (TGF-ß1) than whole blood (p<0.03). LP-PRP also did not stimulate tendon cell proliferation greater than whole blood. In contrast, LR-PRP showed increases in each growth factor on activation with CaCl2 (p<0.01) and stimulated greater proliferation (p<0.05) compared with whole blood. Forced activation of LP-PRP with exogenous thrombin rescued the coagulation deficiency and induced greater growth factor release than comparable whole blood (p<0.03). CONCLUSIONS: These data suggest that non-platelet cellular components in platelet concentrates are important for proper platelet function, including thrombin generation, growth factor release and clot retraction.

The cytoplasmic end of transmembrane domain 3 regulates the activity of the Saccharomyces cerevisiae G-protein-coupled alpha-factor receptor.

The binding of alpha-factor to its receptor (Ste2p) activates a G-protein-signaling pathway leading to conjugation of MATa cells of the budding yeast S. cerevisiae. We conducted a genetic screen to identify constitutively activating mutations in the N-terminal region of the alpha-factor receptor that includes transmembrane domains 1-5. This approach identified 12 unique constitutively activating mutations, the strongest of which affected polar residues at the cytoplasmic ends of transmembrane domains 2 and 3 (Asn84 and Gln149, respectively) that are conserved in the alpha-factor receptors of divergent yeast species. Targeted mutagenesis, in combination with molecular modeling studies, suggested that Gln149 is oriented toward the core of the transmembrane helix bundle where it may be involved in mediating an interaction with Asn84. These residues appear to play specific roles in maintaining the inactive conformation of the protein since a variety of mutations at either position cause constitutive receptor signaling. Interestingly, the activity of many mammalian G-protein-coupled receptors is also regulated by conserved polar residues (the E/DRY motif) at the cytoplasmic end of transmembrane domain 3. Altogether, the results of this study suggest a conserved role for the cytoplasmic end of transmembrane domain 3 in regulating the activity of divergent G-protein-coupled receptors.

Calcaneal tumors and tumor-like conditions.

Approximately 3% of osseous tumors occur in the foot and ankle. Solitary bone cysts, chondroblastoma, intraosseous lipoma, osteoid osteoma, chondrosarcoma, and Ewing's sarcoma seem to have a predilection for the calcaneus. Biopsy is often a crucial step in management. Tumor-like conditions, such as cysts, reactive lesions, and osteomyelitis, must be considered during evaluation. Treatment is often observation or curettage of benign lesions and resection or amputation for malignancies.