Necroptotic cell death in failing heart: relevance and proposed mechanisms

As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1–RIP3–MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.     

Unusual presentation of mandibular extraoral sinus in a fourteen year old girl: a case report

A case of fourteen year old healthy girl with complaint of a discharging sinus on the lower right side of face is reported. All teeth were vital and there was no evidence of periodontitis. There was no history of extraction of a tooth. Total leucocyte count, differential leucocyte count, fasting blood sugar, chest x-ray and routine urine examination were within normal limits. Actinomycosis and scrofuloderma which simulate such a condition were ruled out by culture study. The intraoral periapical x-ray of mandibular molar showed questionable periapical changes at the time of presentation. But definite osteolysis was observed in the repeat radiograph after three months. It was decided to extract the second molar and curette the sinus tract. The extraction proved to be difficult. On examination of the extracted tooth, it was found that the mandibular second molar and second premolar were fused together. The radiograph of the tooth taken after extraction showed confluence of the premolar pulp with the periodontal membrane. On follow up, the lesion was found to heal satisfactorily.     

Pharmacology and therapeutic applications of A1 adenosine receptor ligands

Adenosine's diverse physiological functions are mediated by four subtypes of receptors (A(1), A(2A), A(2B) and A(3)). The A(1) adenosine receptor pharmacology and therapeutic application of ligands for this receptor are the subjects of this review. A(1) receptors are present on the surface of cells in organs throughout the body. Actions mediated by A(1) receptors include slowing of heart rate and AV nodal conduction, reduction of atrial contractility, attenuation of the stimulatory actions of catecholamines on beta-adrenergic receptors, reduction of lipolysis in adipose tissue, reduction of urine formation, and inhibition of neuronal activity. Although adenosine analogs with high efficacy, affinity, and selectivity for the A(1) receptor are available, the ubiquitous distribution and wide range of physiological actions mediated by A(1) receptors are obstacles to development of therapeutic agents that activate these receptors. However, it may be possible to exploit the high A(1) "receptor reserve" for some actions of adenosine by use of weak (partial) agonists to target these actions while avoiding others for which receptor reserve is low. The presence of high receptor reserves for the anti-arrhythmic and anti-lipolytic actions of adenosine suggests that partial A(1) agonists could be used as anti-arrhythmic and anti-lipolytic agents. In addition, allosteric enhancers of the binding of adenosine to A(1) receptors could be used therapeutically to potentiate desirable effects of endogenous adenosine. Antagonists of the A(1) receptor can increase urine formation, and because they do not decrease renal blood flow, are particularly useful to maintain glomerular filtration in patients having edema secondary to reduced cardiac function.