Intracellular trafficking of fluorescently tagged proteins associated with pathogenesis in Candida albicans.

Proteins that enter the secretory pathway play important roles in virulence and pathogenesis in Candida albicans, but our understanding of the trafficking of these proteins is in its early stages. In Saccharomyces cerevisiae, dominant negative alleles of YPT1 and SEC4 interrupt secretory traffic at pre- and post-Golgi steps, respectively. We therefore used a dominant negative genetic approach to examine the intracellular trafficking of several proteins associated with virulence or azole resistance. When the dominant negative ypt1(N121I) allele of C. albicans was overexpressed, yellow-fluorescent protein (YFP) tagged forms of two plasma membrane transporters (Cdrlp and Ftrlp) and the vacuolar membrane ABC transporter Mltlp accumulated in intracellular structures that appeared related to the ER, but localization of Cdc10p and Int1p was unaffected. When the dominant negative sec4(S28N) allele of C. albicans was overexpressed, Cdrlp and Ftrlp accumulated intracellularly, and localization of Mltlp, Cdc10p and Int1p was unaffected. These results imply that (i) Cdrlp and Ftrlp are transported to the plasma membrane by the general secretory pathway, (ii) Mlt1p enters the secretory pathway but is diverted to the vacuole at an early post-Golgi step, and (iii) like Cdc10p, Int1p does not enter the general secretory pathway.     

Kidney progression project (KiPP): Protocol for a longitudinal cohort study of progression in chronic kidney disease of unknown etiology in Sri Lanka

Over the last two decades, a global epidemic of chronic kidney disease of unknown etiology (CKDu) has emerged in rural, arid, agricultural, lowland areas. Endemic regions have reported 15 to 20% prevalence among residents aged 30–60 years. CKDu is a progressive and irreversible disease resulting in renal failure and death in the absence of dialysis or a kidney transplant. While much of the research has focused on identifying etiology, this project seeks to ascertain factors associated with the rapidity of kidney disease progression in one of Sri Lanka’s CKDu endemic areas. A sample of 296 male and female residents aged 21 to 65 with moderate CKD, as measured by their serum creatinine level, and a clinical diagnosis of CKDu are followed using quarterly serum testing to track the rate of progression. A baseline survey administered to the entire sample addresses potential risk factors, supplemented by a short survey focusing on changes through time. Concurrently water, soil and air are tested at the local and household levels. The study is the first to foster a multi-disciplinary approach that focuses on disease progression, identifying behavioural and exposure risk factors for rapid kidney function decline, in this progressively fatal disease.     

Cardiac computed tomography in the contemporary evaluation of infective endocarditis

Increasing data have accumulated on the role of Cardiac Computed Tomography (CCT) in infective endocarditis (IE) with high accuracy for large vegetations, perivalvular complications and for exclusion of coronary artery disease to avoid invasive angiography. CCT can further help to clarify the etiology of infective prosthetic valve dysfunction (e.g. malposition, abscess, leak, vegetation or mass). Structural interventions have increased the relevance of CCT in valvular heart disease and have amplified its use. CCT may be ideally integrated into a multimodality approach that incorporates a central role of transesophageal echocardiography (TEE) with 18-FDG PET and/or cardiac magnetic resonance in individually selected cases, guided by the Heart Team. The coronavirus-19 (COVID-19) pandemic has resulted in renewed attention to CCT as a safe alternative or adjunct to TEE in selected patients. This review article provides a comprehensive, contemporary review on CCT in IE to include scan optimization, characteristics of common IE findings on CCT, published data on the diagnostic accuracy of CCT, multimodality imaging comparison, limitations and future technical advancements.     

Transcatheter aortic valve replacement: The year in review 2017

This article is a continuation of our previously published annual reviews of transcatheter aortic valve replacement (TAVR). In 2017, TAVR further established a foothold in the management of intermediate risk patients with the publication of SURTAVI trial. Randomized trials also addressed the use of cerebral protection during TAVR and single versus dual antiplatelet therapy after TAVR. Newer generation valve systems continued to be studied for their efficacy and safety. This paper summarizes the major studies published in 2017.

     

Research letters

Patients with transfusion-dependent thalassemia are expected to have an unfavorable quality of life due to multiple factors. We studied the quality of life in 72 patients (age 5-39 y) with transfusion-dependent thalassemia in the era of improved care, and assessed different parameters affecting it.     

Surgical management of contiguous multilevel thoracolumbar tuberculous spondylitis

Introduction

Tuberculous spondylitis (TBS) is the most common form of extra-pulmonary tuberculosis. The mainstay of TBS management is anti-tuberculous chemotherapy. Most of the patients with TBS are treated conservatively; however in some patients surgery is indicated. Most common indications for surgery include neurological deficit, deformity, instability, large abscesses and necrotic tissue mass or inadequate response to anti-tuberculous chemotherapy. The most common form of TBS involves a single motion segment of spine (two adjoining vertebrae and their intervening disc). Sometimes TBS involves more than two adjoining vertebrae, when it is called multilevel TBS. Indications for correct surgical management of multilevel TBS is not clear from literature.

Materials and methods

We have retrospectively reviewed 87 patients operated in 10 years for multilevel TBS involving the thoracolumbar spine at our spine unit. Two types of surgeries were performed on these patients. In 57 patients, modified Hong Kong operation was performed with radical debridement, strut grafting and anterior instrumentation. In 30 patients this operation was combined with pedicle screw fixation with or without correction of kyphosis by osteotomy. Patients were followed up for correction of kyphosis, improvement in neurological deficit, pain and function. Complications were noted. On long-term follow-up (average 64 months), there was 9.34 % improvement in kyphosis angle in the modified Hong Kong group and 47.58 % improvement in the group with pedicle screw fixation and osteotomy in addition to anterior surgery (p < 0.001). Seven patients had implant failures and revision surgeries in the modified Hong Kong group. Neurological improvement, pain relief and functional outcome were the same in both groups.

Conclusion

We conclude that pedicle screw fixation with or without a correcting osteotomy should be added in all patients with multilevel thoracolumbar tuberculous spondylitis undergoing radical debridement and anterior column reconstruction.

     

Ischemia-Mediated Dysfunction in Subpapillary Myocardium as a Marker of Functional Mitral Regurgitation

ObjectivesThe goal of this study was to test whether ischemia-mediated contractile dysfunction underlying the mitral valve affects functional mitral regurgitation (FMR) and the prognostic impact of FMR.BackgroundFMR results from left ventricular (LV) remodeling, which can stem from myocardial tissue alterations. Stress cardiac magnetic resonance can assess ischemia and infarction in the left ventricle and papillary muscles; relative impact on FMR is uncertain.MethodsVasodilator stress cardiac magnetic resonance was performed in patients with known or suspected coronary artery disease at 7 sites. Images were centrally analyzed for MR etiology/severity, mitral apparatus remodeling, and papillary ischemia.ResultsA total of 8,631 patients (mean age 60.0 ± 14.1 years; 55% male) were studied. FMR was present in 27%, among whom 16% (n = 372) had advanced (moderate or severe) FMR. Patients with ischemia localized to subpapillary regions were more likely to have advanced FMR (p = 0.003); those with ischemia localized to other areas were not (p = 0.17). Ischemic/dysfunctional subpapillary myocardium (odds ratio: 1.24/10% subpapillary myocardium; confidence interval: 1.17 to 1.31; p < 0.001) was associated with advanced FMR controlling for infarction. Among a subgroup with (n = 372) and without (n = 744) advanced FMR matched (1:2) on infarct size/distribution, patients with advanced FMR had increased adverse mitral apparatus remodeling, paralleled by greater ischemic/dysfunctional subpapillary myocardium (p < 0.001). Although posteromedial papillary ischemia was more common with advanced FMR (p = 0.006), subpapillary ischemia with dysfunction remained associated (p < 0.001), adjusting for posteromedial papillary ischemia (p = 0.074). During follow-up (median 5.1 years), 1,473 deaths occurred in the overall cohort; advanced FMR conferred increased mortality risk (hazard ratio: 1.52; 95% confidence interval: 1.25 to 1.86; p < 0.001) controlling for left ventricular ejection fraction, infarction, and ischemia.ConclusionsIschemic and dysfunctional subpapillary myocardium provides a substrate for FMR, which predicts mortality independent of key mechanistic substrates.