Targeting renal purinergic signalling for the treatment of lithium‐induced nephrogenic diabetes insipidus

Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium‐induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP‐activated P2Y₂ receptor in lithium‐induced NDI in rats and showed that P2Y₂ receptor knockout mice are significantly resistant to Li‐induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP‐activated P2Y₁₂ receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix^®) ameliorates Li‐induced NDI in rodents. Parallel in vitro studies showed that P2Y₁₂ receptor blockade by the reversible antagonist PSB‐0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y₂ or P2Y₁₂ receptors to counter AVP resistance in lithium‐induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti‐AVP effects to those that enhance the sensitivity of the kidney to AVP action.     

Juvenile Ossifying Fibroma of the Maxilla: A Case Report

Ossifying fibroma is a benign neoplasm of the bone, usually involving the posterior tooth bearing area of the mandible, predominantly seen in females in 2nd–4th decade of life with 5:1 prediliction. Fibro-osseous lesions other than FD seem to arise from the periodontal membrane. These lesions are usually asymptomatic, well defined clinically and radiologically amenable for enucleation. Fibro-osseous lesions of the jaws, including Juvenile Ossifying Fibroma (JOF), pose diagnostic and therapeutic difficulties due to their clinical, radiological and histological variability. Ossifying fibromas which appear as fast growing mass between 5 and 15 years of age, radiologically well bordered, and consistent with ossifying fibroma histologically, are referred as juvenile (aggressive) ossifying fibroma. We report a case of JOF of left side of the maxilla in an 11 year old girl which is an uncommon site of occurrence.     

Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase

Thioredoxin-related protein of 14 kDa (TRP14, also called TXNDC17 for thioredoxin domain containing 17, or TXNL5 for thioredoxin-like 5) is an evolutionarily well-conserved member of the thioredoxin (Trx)-fold protein family that lacks activity with classical Trx1 substrates. However, we discovered here that human TRP14 has a high enzymatic activity in reduction of l-cystine, where the catalytic efficiency (2,217 min⁻¹⋅µM⁻¹) coupled to Trx reductase 1 (TrxR1) using NADPH was fivefold higher compared with Trx1 (418 min⁻¹⋅µM⁻¹). Moreover, the l-cystine reduction with TRP14 was in contrast to that of Trx1 fully maintained in the presence of a protein disulfide substrate of Trx1 such as insulin, suggesting that TRP14 is a more dedicated l-cystine reductase compared with Trx1. We also found that TRP14 is an efficient S-denitrosylase with similar efficiency as Trx1 in catalyzing TrxR1-dependent denitrosylation of S-nitrosylated glutathione or of HEK293 cell-derived S-nitrosoproteins. Consequently, nitrosylated and thereby inactivated caspase 3 or cathepsin B could be reactivated through either Trx1- or TRP14-catalyzed denitrosylation reactions. TRP14 was also, in contrast to Trx1, completely resistant to inactivation by high concentrations of hydrogen peroxide. The oxidoreductase activities of TRP14 thereby complement those of Trx1 and must therefore be considered for the full understanding of enzymatic control of cellular thiols and nitrosothiols.The redox or nitrosylation state of reactive cysteine (Cys) residues in proteins can affect a multitude of intracellular events, either beneficial or harmful, depending upon biological context (1, 2). Two major cellular systems that control the redox states of Cys residues are the thioredoxin (Trx) and the glutathione (GSH) systems. The Trx system includes isoforms of Trx, Trx reductase (TrxR), and NADPH together with several Trx-dependent enzymes and proteins (3). The GSH/GSH disulfide redox couple is kept reduced by the NADPH-dependent activity of GSH reductase (GR) and donates electrons to isoforms of glutaredoxin (Grx) and other GSH-dependent enzymes (4).In addition to Trx, many proteins have a Trx fold and a Trx-like active-site sequence. One such protein is thioredoxin-related protein of 14 kDa (TRP14, also known as TXNDC17 or TXNL5), which is an evolutionarily well-conserved cytosolic and widely expressed Trx-fold protein that can be reduced by TrxR1 (5). Its crystal structure, compared with Trx1, shows additional structural features in the active site, thereby explaining its lack of activity with most classical Trx1 protein disulfide substrates including ribonucleotide reductase, insulin, peroxiredoxins, or methionine sulfoxide reductase (5–7). TRP14 was suggested to have evolved to exert specific signaling roles in cells and was identified as a modulator of TNFα/NFκB signaling pathways through interactions with the dynein light chain LC8 protein (6, 8). We previously found that treatment of cells with cisplatin triggered the formation of covalent cross-links between TrxR1 and either Trx1 or TRP14, which suggests that TRP14 is tightly linked to TrxR1 within the cellular context (9). Recently, we also found that TRP14 is able to reactivate oxidized phosphotyrosine phosphatase 1B, thereby indeed implicating specific functions in modulation of cellular signaling pathways (10).In addition to having general protein disulfide reductase activities, Trx1 is also a denitrosylase for a broad spectrum of nitrosoproteins and nitrosothiols (11, 12). Substrates include S-nitrosocaspase 3 (13, 14), S-nitrosocaspase 8 (15), S-nitrosoglutathione (GSNO) (16, 17), and S-nitrosocysteine (l-CysSNO) (12). Nitrosylation and denitrosylation reactions provide a regulatory mechanism for protein function and are thereby also involved in a variety of cellular signal transduction pathways. For example, S-nitrosylation of caspases can inhibit their activity and thus regulate apoptosis in resting cells (18, 19). A full understanding of NO homeostasis and its pathways is of medical importance because an aberrant formation of nitrosylated proteins has been implicated in a variety of diseases. However, protein denitrosylation is a hitherto less studied part in NO-mediated signaling (20, 21). In addition to Trx1, another enzyme mediating cellular denitrosylation reactions is GSNO reductase (GSNOR). GSNOR is the same enzyme as class III alcohol dehydrogenase, mainly catalyzing denitrosylation of GSNO using NADH as an electron donor (22, 23). In addition, S-denitrosylation activities are supported by protein disulfide isomerase (PDI) (24), carbonyl reductase 1 (25), and lipoic acid (17).The high intracellular concentrations of GSH are also important in NO metabolism because of facilitated formation of GSNO by reaction of GSH with NO or by denitrosylation of cellular nitrosothiols (20, 26). Because the synthesis of GSH depends upon availability, cellular uptake and reduction of sulfur-containing precursors such as l-cystine, l-cystine homeostasis is also important for GSH functions (27). l-Cystine is taken up into cells using different transport systems, e.g., the oxidative stress-inducible cystine/glutamate antiporter (system ) (28). The mechanism behind the reduction of l-cystine still has not been fully elucidated, but has been implicated to include GSH itself or also TrxR1-dependent systems (29).In the present study, we wanted to further characterize the enzymatic properties of TRP14, which revealed that the protein is at least as efficient as Trx1 in supporting reduction of specific redox substrates, such as l-cystine. In that assay, TRP14 is a fivefold better substrate for TrxR1 than Trx1 itself and, furthermore, more dedicated as its activity is not diminished in the presence of other Trx1 substrates that are not reduced by TRP14. Furthermore, we discovered that TRP14 is yet another cytosolic oxidoreductase that can catalyze S-denitrosylation reactions.     

System for Integrated Neuroimaging Analysis and Processing of Structure

Mapping brain structure in relation to neurological development, function, plasticity, and disease is widely considered to be one of the most essential challenges for opening new lines of neuro-scientific inquiry. Recent developments with MRI analysis of structural connectivity, anatomical brain segmentation, cortical surface parcellation, and functional imaging have yielded fantastic advances in our ability to probe the neurological structure-function relationship in vivo. To date, the image analysis efforts in each of these areas have typically focused on a single modality. Here, we extend the cortical reconstruction using implicit surface evolution (CRUISE) methodology to perform efficient, consistent, and topologically correct analyses in a natively multi-parametric manner. This effort combines and extends state-of-the-art techniques to simultaneously consider and analyze structural and diffusion information alongside quantitative and functional imaging data. Robust and consistent estimates of the cortical surface extraction, cortical labeling, diffusion-inferred contrasts, diffusion tractography, and subcortical parcellation are demonstrated in a scan-rescan paradigm. Accompanying this demonstration, we present a fully automated software system complete with validation data.     

Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration： implications for the pathogenesis of Parkinson＇s disease

While the cause of dopaminergic neuronal cell death in Parkinson＇s disease（PD）is not yet understood,many endogenous molecules have been implicated in its pathogenesis.β-phenethylamine（β-PEA）,a component of various food items including chocolate and wine,is an endogenous molecule produced from phenylalanine in the brain.It has been reported recently that long-term administration ofβ-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins.The toxicity ofβ-PEA has been linked to the production of hydroxyl radical（.OH）and the generation of oxidative stress in dopaminergic areas of the brain,and this may be mediated by inhibition of mitochondrial complex-I.Another significant observation is that administration ofβ-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents.However,no reports are available on the extent of dopaminergic neuronal cell death after administration ofβ-PEA.Based on the literature,we set out to establishβ-PEA as an endogenous molecule that potentially contributes to the progressive development of PD.The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption ofβ-PEA-containing foods is proposed here.Thus,long-term over-consumption of food items containingβ-PEA could be a neurological risk factor having significant pathological consequences.     

A Clinician’s Role in the Management of Soft Tissue Injuries of the Face: A Clinical Paper

Introduction

Injuries of the facial soft tissues may be due to road traffic accidents, industrial injuries, domestic and interpersonal violence, dog bites, human bites, war injuries etc. They may be described depending on the depth of involvement of the soft tissue and/or region since it gives the clinician the method of treatment. The soft tissue injuries must take into the underlying skeletal injury into account since these injuries if carelessly handled they leave deformed scarring in the most precious and beautiful part of the body.

Materials and Methods

Various patients reporting to the department of Oral and Maxillofacial Surgery, Narayana Dental College and hospital, Nellore were included in the study. Injuries in the various aspects of face at various anatomical areas has been presented with the mode of management.

Conclusion

The maxillofacial surgeon while attending these cases should avoid the need for revision by having a thorough knowledge of the anatomy, physiology of the soft tissues and treat them accordingly after following good clinical and radiological examination.     

Lower eyelid suspension using polypropylene suture for the correction of punctal ectropion

ObjectiveTo evaluate the efficacy and complications of lower eyelid suspension with the modified Safdarjung hospital technique using 5:0 polypropylene suture for punctal ectropion.Study designProspective case series.MethodThirty one eyelids in 19 patients with mild and moderate ectropion and all types of laxity including involutional and paralytic were included. All patients underwent lower eyelid suspension with the modified Safdarjung hospital technique. A 5:0 polypropylene suture was passed in the pre-tarsal plane between the attachments of the lateral and medial canthal tendons near their insertion at the orbital rim. Successful outcome was judged by the anatomical restoration of the apposition of the punctum to the globe in the upward gaze and the physiological relief of epiphora. The recurrence of lid laxity, overall lid/globe apposition and complications were also noted.ResultsAt 1 year follow up anatomical success was achieved in 28 (90%) patients and functional success noted in 27 (87%) patients. Recurrence of lid laxity was noted in 2 patients. There was a suture exposure in one case and a suture granuloma in another case. The results did not correlate to the degree of ectropion and type of laxity.ConclusionLower eyelid suspension using 5:0 polypropylene suture is a useful procedure for the treatment of involutional and paralytic punctal ectropion. It is simple and effective with minimal complications. However, the effect on scleral show and the concern related to suture material biodegradation over years needs to be further evaluated.     

Pulmonary embolectomy with use of pediatric bronchoscope for the detection of residual emboli: an innovative surgical technique

Pulmonary embolectomy in the treatment of massive pulmonary embolus has been in doubt since the introduction of thrombolytic therapy. Recent indications for surgical intervention are- contraindication to thrombolysis, failed medical treatment and severe Right Ventricular (RV) dysfunction. A 54-year male came to us with complaints of palpitation, tachypnea and repeated syncope . Transthoracic echocardiography and Computed Tomography pulmonary angiogram demonstrated- Biatrial mass with right atrial mass extending into right ventricle and main pulmonary artery. Pulmonary embolectomy was performed. Residual emboli of bilateral pulmonary arteries were detected with a fiberoptic pediatric bronchoscope and removed. Bronchoscopic evaluation appears to be safe and useful for direct visual detection of emboli.