Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Among vascular-enriched receptor tyrosine kinases, Tie2 is unusual in at least two functional aspects. First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1–6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.Based largely on Angpt-1 overexpression studies, Tie2 has been implicated in vascular barrier defense (8, 9). However, adult-specific deletion of Angpt-1 does not appear to trigger vascular leakage (10). Moreover, Angpt-1 has repeatedly been ascribed functions that are independent of Tie2 (11–13). Finally, observational studies in humans suffering clinical manifestations of vascular leakage have consistently shown a marked imbalance in Tie2 ligands tilting in favor of Angpt-2 (reviewed in 14). Although decreased Tie2 activity has been inferred from these reports, the role of TIE2 gene expression has not been directly queried experimentally or in clinical settings.This question is important not only for understanding control mechanisms of the circulatory system but also to guide the development of strategies to predict, stratify, and treat patients affected by acute vascular leakage. If tonic Tie2 signaling is indeed necessary for vascular barrier maintenance, then reducing the pool of receptors could constitute a ligand-independent means to attenuate barrier-protective signaling in the endothelium. We therefore hypothesized that the level of Tie2 expression modulates the sensitivity of blood vessels, and thereby the entire organism, to noxious stimuli. Cellular, rodent, and human genetics studies were undertaken to test this concept.     

Dermatomyositis and the Nephrogenic Hepatic Dysfunction Syndrome

Abstract: Dermatomyositis and the nephrogenic hepatic dysfunction syndrome. R. G. Reiner, W. D. Parry, R. Bowey, E. Chandra and A. Kerr Grant, Aust. N.Z. J. Med ., 1981, 11, pp. 52–55.
Two uncommon associations of a renal malignancy occurring in an elderly male are described. A localized dermatomyositis and non-meta static abnormal liver functions were features of this otherwise occult neoplasm     

Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 10⁴ cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.     

A Study of Promethazine Hydrochloride and Pentazocine Intramuscular Sedation Along with 2?% Lidocaine Hydrochloride and Adrenaline and Comparison to Placebo Along with 2?% Lidocaine Hydrochloride and Adrenaline for Surgical Extraction of Mandibular Third Molar

Background and Objectives

The main objective is to study and compare the sedative and analgesic effects of intramuscular injection fortwin–phenergan along with local anesthetic and normal saline placebo along with local anesthetics in mandibular third molar surgery. We also assessed and compared the postoperative experience of the patient in relation to the pain intensity, time to first analgesic taken and total number of analgesics consumed over a period of 48 h in the two groups.

Materials and Methods

Patients who came to the Department of Oral and Maxillofacial Surgery, The Regional Dental College; with complaints regarding mandibular third molar were chosen for the treatment. Patients were evaluated using Corah Dental Anxiety Scale (CDAS) and those patients having a score of CDAS 13 and above were selected. Sixty patients were selected out of which 30 patients formed group 1 and another 30 patients group 2. The patients were randomly divided with flip method into group 1 (study group) and or group 2 (controlled group).

Results

Our study results showed that the operating conditions for both the groups at the end of surgery were similar without significant difference. Most of the surgical procedures were graded as excellent and good in both the groups except that difficulty was encountered in two patients from group 1 and one from group 2.

Conclusion

It could be concluded that particular drugs do not have much influence on the surgical procedure in our study, but it was found that patients from group 1 were more cooperative as compared to group 2 when difficulty was encountered during the surgical procedure.     

“Vanishing Bone Disease” in Maxillofacial Region: A Review and Our Experience

Vanishing bone disease (VBD) is a rare disease of unknown etiology which is characterised by progressive replacement of bony framework by proliferation of endothelial lined lymphatic vessels. It has been given numerous names like massive osteolysis, Gorham’s disease, phantom bone disease, and progressive osteolysis. It has no age, sex or race predilection. It may involve single or multiple bones and spread of the disease does not respect the relevant joint as boundary. The first report of the disease was published around two decades back but the mysterious nature of its etiology and ideal management strategy has still not been completely unfolded. The disease may functionally or aesthetically effect the patient and also has the potential to be life threatening. The first case of VBD in maxillofacial region was reported by Romer in 1924, Handbuch der speziellen pathologischen Anatomie and histology, Springer, Berlin. Since then, there have been few case reports of the same in maxillofacial region. We present a review of cases of VBD in maxillofacial region reported in literature along with our experience of a case.