Suppression of immunoglobulin E-mediated allergic responses by regulator of G protein signaling 13.

Mast cells elicit allergic responses through degranulation and release of proinflammatory mediators after antigen crosslinking of the immunoglobulin E receptor FcepsilonRI. Proteins of the 'regulator of G protein signaling' (RGS) family negatively control signaling mediated by G protein-coupled receptors through GTPase-accelerating protein activity. Here we show that RGS13 inhibited allergic responses by physically interacting with the regulatory p85alpha subunit of phosphatidylinositol-3-OH kinase in mast cells and disrupting its association with an FcepsilonRI-activated scaffolding complex. Rgs13-/- mice had enhanced immunoglobulin E-mediated mast cell degranulation and anaphylaxis. Thus, RGS13 inhibits the assembly of immune receptor-induced signalosomes in mast cells. Abnormal RGS13 expression or function may contribute to disorders of amplified mast cell activity, such as idiopathic anaphylaxis.

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.

gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.

Efficacy of Intravenous Clonidine Premedication in the Prevention of Adverse Hemodynamic Changes During Intubation in Patients Undergoing Laparoscopic Surgery in Comparison with Placebo.

Context: Laparoscopic surgeries involve the creation of pneumoperitoneum, which produces significant hemodynamic changes. Alpha-2 adrenergic receptor agonists like clonidine are used as adjuvants during aesthesia for analgesic, sedative, sympatholytic and cardiovascular stabilizing effects. Aims: This study aims to assess the efficacy of intravenous (i.v.) clonidine premedication in the prevention of adverse hemodynamic changes during intubation in a patient undergoing laparoscopic surgery in comparison with (normal saline) placebo. Settings and Design: Eighty patients undergoing elective laparoscopic surgery were randomly assigned into two groups to receive either clonidine 3 µg.kg-1 diluted in normal saline or an equivalent quantity of normal saline administered intravenously 20 min before surgery. Materials and Methods: The primary outcome was to compare the efficacy of clonidine premedication in the prevention of adverse hemodynamic changes during intubation in patients undergoing laparoscopic surgery. Other outcome parameters observed were requirements of induction agents and intraoperative analgesia and postoperative adverse effects. Statistical Analysis Used: Analysis of variance has been used to find the significance of study parameters between three or more groups of patients; Chi-square/Fisher exact test has been used to find the significance of study parameters on a categorical scale between two or more groups. Results: Heart rate reduced significantly after 10 min 3 µg.kg-1 clonidine administration and the decrease persisted throughout induction and intubation. The fluctuations of systolic, diastolic, and mean arterial pressures were high in the control group when compared with the clonidine group, throughout induction and intubation. Conclusions: Premedication with i.v. clonidine is a relatively safe and effective method that provides stable hemodynamics and protection against stress responses induced during laryngoscopy and intubation in patients undergoing laparoscopic surgery.

The Ratio of Height to Thyromental Distance (RHTMD) and Height to Sternomental Distance (RHSMD) as the Predictive Tests for Difficult Tracheal Intubation.

BACKGROUND: Pre-operative evaluation is a cornerstone in identifying patients with a risk of difficulty in intubation. Thyromental distance (TMD) is the most commonly used predictor of difficult intubation. However, it's not a reliable indicator of difficulty during intubation because it differs with patients' body & size proportion. The present study was done for the evaluation of the ratio of height to thyromental distance (RHTMD) and ratio of height to sternomental distance (RHSMD) as difficult airway predictors.  Methods: Data was taken from 400 consecutive patients posted for the need for anesthesia with intubation during surgery. Preoperatively examination of RHTMD and RHSMD was done. Difficulty during intubation has been explained in this current study with Cormack and Lehane grade 3 or 4. The positive and negative predictive values, as well as sensitivity and specificity of individual tests, were calculated as per the recognized formula. RESULTS: The study enrolled 400 patients, which include a maximum number of participants (138 [34.5%]) from the 41-50 year age group. On analyzing RHTMD and RHSMD, the former was found to have a better predictive value than RHSMD (p=0.001). RHTMD & RHSMD was found to have 62.5% & 37.50% sensitivity, respectively. RHTMD was found to have better specificity, positive & negative predictive values, and accuracy than RHSMD. CONCLUSION: RHTMD was observed to have superior precision in anticipating difficulty in intubation compared to RHSMD.

Angioleiomyoma of the knee: case series and an unusual cause of knee pain.

We present a consecutive series of five patients with angioleiomyoma, a rare benign soft tissue tumor around the knee. Between 2005 and 2010, five patients with histopathologically confirmed diagnosis of angioleiomyoma of the knee underwent surgical excision. All five patients were Afro-caribbean in origin. The presenting feature was burning medial knee pain localized to a tender hyperesthetic swelling around the knee. The mean age of presentation was 45 years (range, 42 to 51 years), and the mean duration of symptom was 34 months (range, 12 to 96 months). Although magnetic resonance imaging (MRI) scans were helpful in locating and delineating the tumors, true diagnosis was established only by histopathology. All patients underwent surgical excision with complete resolution of symptoms. No recurrences were seen at an average follow-up of 16 months (range, 3 to 24 months). The treatment of these tumors, especially around the knee, is frequently delayed due to their late presentation and lack of awareness of this clinical condition. We recommend a high index of suspicion in patients, especially of Afro-caribbean origin, presenting with painful hyperesthetic subcutaneous swelling around the knee. Early investigation by MRI expedites the diagnosis, and surgical excision results in complete resolution of symptoms.

Unusual mid-shaft fractures during long-term bisphosphonate therapy.

BACKGROUND: Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of nonvertebral fractures. OBJECTIVE: The objective of this study was to report the clinical presentation, selected bone histomorphometry and X-ray images of patients who developed mid-shaft long bone fractures during bisphosphonate therapy, six of whom had bone biopsy for histomorphometery. RESULTS: Of the 13 patients who sustained atraumatic mid-shaft fractures, 10 were on alendronate and three were on risedronate therapy before the fractures. In addition to bisphosphonates, three patients were on oestrogen and two on tamoxifen concomitantly. Four patients with glucocorticoid-induced osteoporosis were on alendronate for 3-11 years along with glucocorticoid therapy. Bone histomorphometry showed severe suppression of bone turnover in five patients and low bone turnover in one patient. CONCLUSION: Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is probably due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy remains unknown, but appears to be small.

RGS13 controls g protein-coupled receptor-evoked responses of human mast cells.

IgE-mediated mast cell degranulation and release of vasoactive mediators induced by allergens elicits allergic responses. Although G protein-coupled receptor (GPCR)-induced signals may amplify IgE-dependent degranulation, how GPCR signaling in mast cells is regulated remains incompletely defined. We investigated the role of regulator of G protein signaling (RGS) proteins in the modulation of these pathways in human mast cells. Several RGS proteins were expressed in mast cells including RGS13, which we previously showed inhibited IgE-mediated mast cell degranulation and anaphylaxis in mice. To characterize how RGS13 affects GPCR-mediated functions of human mast cells, we analyzed human mast cell lines (HMC-1 and LAD2) depleted of RGS13 by specific small interfering RNA or short hairpin RNA and HMC-1 cells overexpressing RGS13. Transient RGS13 knockdown in LAD2 cells lead to increased degranulation to sphingosine-1-phosphate but not to IgE-Ag or C3a. Relative to control cells, HMC-1 cells stably expressing RGS13-targeted short hairpin RNA had greater Ca(2+) mobilization in response to several natural GPCR ligands such as adenosine, C5a, sphingosine-1-phosphate, and CXCL12 than wild-type cells. Akt phosphorylation, chemotaxis, and cytokine (IL-8) secretion induced by CXCL12 were also greater in short hairpin RGS13-HMC-1 cells compared with control. RGS13 overexpression inhibited CXCL12-evoked Ca(2+) mobilization, Akt phosphorylation and chemotaxis. These results suggest that RGS13 restricts certain GPCR-mediated biological responses of human mast cells.

Arthrodesis of the thumb metacarpophalangeal joint with plate fixation.

This is a surgical technique for arthrodesis of the thumb metacarpophalangeal joint using a low-profile plate. Using the principles of tension band fixation and interfragmentary compression, a high rate of fusion is achieved with a low incidence of complications. The technique is versatile allowing fixation at any desired position. It can be used in porotic bone and avoids the need for postoperative immobilization.

Treating stiffness after total knee arthroplasty: a technical note and preliminary results.

Total Knee Replacement is used to treat pain, stiffness and reduced range of movement. It has been estimated that a minimum of 90 degrees of range of motion in the knee is required for normal activities of daily living. In this article we demonstrate a technical note with a small patient series about the methods of treating knee stiffness after Total Knee Replacement.

Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation.

Atypical tibial tuberosity fracture in an adolescent.

Avulsion fractures of the tibial tuberosity are typically sustained by adolescent males during sporting activities. Tibial tuberosity avulsions with simultaneous proximal tibial epiphyseal fractures are rare injuries. We present an unusual case of Ogden type IIIA avulsion fracture of tibial tuberosity with a Salter Harris type IV posterior fracture of proximal tibial epiphysis in a 13-year-old boy. We believe that the patient sustained the tibial tuberosity avulsion during the take-off phase of a jump while playing basketball due to sudden violent contraction of the quadriceps as the knee was extending. This was then followed by the posterior Salter Harris type IV fracture of proximal tibial physis as he landed on his leg with enormous forces passing through the knee. Although standard radiographs were helpful in diagnosing the complex fracture pattern, precise configuration was only established by computed tomography (CT) scan. The scan also excluded well-recognized concomitant injuries including ligament and meniscal injuries. Unlike other reported cases, our patient did not have compartment syndrome. Anatomic reduction and stabilization with a partially threaded transepiphyseal cannulated screw and a metaphyseal screw followed by early mobilization ensured an excellent recovery by the patient.Our case highlights the importance of vigilance and a high index of suspicion for coexisting fractures or soft tissue injuries when treating avulsion fractures of tibial tuberosity. A CT scan is justified in such patients to recognize complex fracture configurations, and surgical treatment should be directed appropriately to both the fractures followed by early rehabilitation. Patients with such injuries warrant close monitoring for compartment syndrome during the perioperative period.

A rare case of angioleiomyoma of the knee: a case report.

We report a case of an angioleiomyoma occurring in a 40-year-old Kenyan female. The patient presented with recurrent pain and a soft tissue swelling at the posteromedial aspect of her right knee. Angioleiomyomas are benign soft tissue tumours, which occur most commonly in the skin of the lower extremities in middle-aged females. They very rarely occur in the knee and are treated curatively with resection. A brief literature review is included.

Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells.

NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19(INK4d)) and CDKN1B (p27(Kip1)), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL.

Wireless transmission of neuronal recordings using a portable real-time discrimination/compression algorithm.

A design challenge of portable wireless neural recording systems is the tradeoff between bandwidth and power consumption. This paper investigates the compression of neuronal recordings in real-time using a novel discriminating Linde-Buzo-Gray algorithm (DLBG) that preserves spike shapes while filtering background noise. The technique is implemented in a low power digital signal processor (DSP) which is capable of wirelessly transmitting raw neuronal recordings. Depending on the signal to noise ratio of the recording, the compression ratio can be tailored to the data to maximally preserve power and bandwidth. The approach was tested in real and synthetic data and achieved compression ratios between 184:1 and 10:1.

Cutting edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling.

Reactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10-1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.