Symptomatic burden as an endpoint to evaluate interventions in patients with atrial fibrillation.

Management of patients with atrial fibrillation (AF) is clinically challenging and has led to the development of new pharmacologic and nonpharmacologic therapies. However, no clear consensus on optimal endpoints for defining responses to therapy exists. This paradox arises largely because symptoms, often used to gauge efficacy of interventions, have not been well correlated with long-term "hard" endpoints such as stroke and death. One widely used symptom-based metric is "time to first symptomatic AF episode," but this correlates poorly with frequency of symptomatic episodes. Similarly, although quality-of-life (QOL) measures have been used, the precise and unbiased assessment of QOL is difficult to define and measure. The availability of implantable devices capable of monitoring and recording all AF episodes has made the accurate determination of total time in AF ("burden") possible. However, QOL tools and formal measures of AF burden do not correlate well, suggesting that measures of subjective well-being are important adjunct measures to conventional measures of disease severity when evaluating the therapeutic efficacy of treatments for AF. Although measurement of total AF burden requires invasive monitoring, symptomatic AF burden (defined by frequency, duration and severity of symptoms) can be determined in all patients with symptomatic AF and may serve as a valid endpoint, as elimination of symptoms is a common and realistic therapeutic goal. Therefore, we propose an algorithm to quantify symptomatic AF burden as an endpoint in clinical trials.     

Functional comparison of serine protease autotransporters of enterobacteriaceae

The plasmid-encoded toxin (Pet) of enteroaggregative Escherichia coli (EAEC) belongs to a family of high-molecular-weight serine protease autotransporters of Enterobacteriaceae (SPATEs) which also includes Pic from EAEC and Shigella flexneri, EspC from enteropathogenic E. coli, EspP from enterohemorrhagic E. coli, Sat from uropathogenic E. coli, Tsh from avian pathogenic E. coli, and SepA from S. flexneri. Phylogenetic analysis shows the SPATE proteins to represent a distinct subfamily of autotransporters with amino acid identities ranging from 35 to 55%, providing a powerful resource to direct structure-function studies. In this study, we show that these related proteins are proteases with divergent substrate specificities, suggesting different functions. The cleavage profile of oligopeptides was found to be unique for each SPATE protein. The SPATEs showed proteolytic activity for several substrates, namely mucin, pepsin, human coagulation factor V, and erythroid spectrin. The cleavage of spectrin has been hypothesized as the mechanism through which Pet induces cytopathic effects. However, whereas Pet, Sat, and EspC cleaved spectrin, only Pet and Sat elicited cytopathic effects; the remaining SPATEs did not cause any morphological changes to HEp-2 cell monolayers. EspC and Pet exhibited acid-dissociable binding to HEp-2 cells. However, Pet was more efficient at entering HEp-2 cells, suggesting a basis for the different abilities of these two proteases to damage cells. Our data suggest that, despite the homologies observed among these proteins, the SPATEs have different pathogenetic functions only partly dependent on their substrate specificities.     

Sympathetic activation enhances QT prolongation by quinidine

INTRODUCTION: Salt restriction results in endogenous sympathetic activation, and we previously showed that plasma concentrations of quinidine measured after oral drug administration are increased during a low-salt diet. However, it is not known whether, independent of effects on plasma concentration, the extent to which quinidine prolongs the QT interval also is modulated by changes in endogenous sympathetic activity. METHODS AND RESULTS: In these studies, we evaluated quinidine concentration-QT relations during low-salt (10 mEq/day for 8 days) and high-salt (400 mEq/day for 8 days) diets, with or without beta blockade in normal volunteers. In the absence of beta blockade, the concentration producing a fixed (15%) increase in QTc was significantly lower with salt restriction: 1.2 +/- 0.4 microg/mL (low salt) versus 2.2 +/- 0.4 microg/mL (high salt) (P < 0.01). With beta blockade, this difference was abolished: 1.9 +/- 0.3 microg/mL (low salt + beta blockade) versus 2.1 +/- 0.3 microg/mL (high salt + beta blockade). QT morphologic abnormalities including bifid T waves and U waves were abolished with beta-adrenergic blockade. CONCLUSION: Sympathetic activation by a low-salt diet not only modulates drug disposition but also increases sensitivity to drug-induced QT prolongation.     

Bilateral eventration of the diaphragm with malrotation and unilateral renal agenesis

Bilateral eventration of the diaphragm associated with malrotation of gut and unilateral renal agenesis is a very rare entity. The authors treated a seven mth old male child who presented to them with respiratory distress and gastrointestinal problem. The child was anemic and was in type II respiratory failure. His X-ray chest showed bilateral eventration of diaphragm and ultrasonography abdomen was consistent with left renal agenesis which was confirmed by radionuclide scan. Bilateral plication of the diaphragm done with correction of malrotation which was diagnosed peroperatively. The association of these three anomalies are rare and to be kept in mind whenever treating a patient with bilateral eventration of the diaphragm.     

Changing Scenario in Aetiological Profile of Short Stature in India-Growing Importance of Celiac Disease: A Study from Tertiary Care Centre

Objective  

To compare the etiological profile of short stature at a tertiary care hospital of North India over a decade from 1995–2007.     

Facial infiltrating lipomatosis: A case report and review of literature

Infiltrating lipomatosis of the face has been described as a congenital disorder in which mature lipocytes invade adjacent tissues in the facial region. The presentation is always unilateral with hypertrophy of hard and soft structures on the affected side of the face. We present a case of a 27-year-old female who reported with a complaint of recurrent unilateral facial swelling with history of two previous resections, the histopathology or details of these surgeries were not available. The patient underwent resection of tumour and the histopathology confirmed it to be infiltrating lipomatosis. The surgery resulted in a definite improvement in the facial asymmetry and the patient is being closely followed up with no evidence of recurrence. The pathogenesis of the condition is unclear, though it has been postulated that the condition is at one end of a spectrum of overgrowth syndromes with classic Proteus syndrome on the other extreme. Management of this condition involves resection of the tumour which in most cases is subtotal to reduce the risk of damage to facial nerve. There is a controversy regarding both timing and extent of resection in the literature and we think the subtotal resection of tumour in an adolescent or older patient can give good aesthetic outcome without compromising facial nerve function. However, the patients should be informed about high rate of recurrence and increase risk of complications with any subsequent surgery.