Mohammad Hossain

Metabolism of crucifer phytoalexins in Sclerotinia sclerotiorum: detoxification of strongly antifungal compounds involves glucosylation

The strongly antifungal phytoalexins brassilexin and sinalexin were metabolized by the stem rot fungus Sclerotinia sclerotiorum to glucosyl derivatives, whereas the phytoalexins brassicanal A, spirobrassinin and 1-methoxyspirobrassinin, displaying lower antifungal activity, were transformed via non-glucosylating pathways. Significantly, these transformations led to metabolites displaying no detectable antifungal activity. The chemical characterization of all new metabolites as well as the chemistry of these processes and a facile chemical synthesis of 1-beta-D-glucopyranosylbrassilexin are reported. Overall, our results indicate that phytoalexins, strongly antifungal against S. sclerotiorum, are detoxified via glucosylation, which in turn suggests that S. sclerotiorum has acquired efficient glucosyltransferase(s) that can disarm some of the most active plant chemical defenses. Consequently, we suggest that these glucosylation reactions are potential metabolic targets to control S. sclerotiorum.

Accuracy to estimate rates of decline in glomerular filtration rate in renal transplant patients

Background. We examined the use of the Cockroft Gault (C-G) test, Modified Diet in Renal Disease 2 (MDRD2) test, and inverse serum creatinine (&Dgr;1/Scr) to estimate rates of decline in renal transplant function using isotope glomerular filtration rate (GFR) as a reference test. Methods. Percent changes in estimated GFR (&Dgr;eGFR) were compared to simultaneous changes in isotope GFR (&Dgr;iGFR) in 72 patients. Results. The number of iGFR was 508 with a mean of 7.15±3.15 scans per patient. There was a decline in iGFR of 16.14±21.37 ml/min over the study duration of 88.9±57.6 months. &Dgr;eGFR and &Dgr;1/Scr correlated significantly with &Dgr;iGFR. Accuracy to predict &Dgr;iGFR from the eGFRs was limited to <65% concordance within 30% range from changes in iGFR. Slope analyses showed a significantly lower percent annual loss in mean iGFR of 6.03% than that of the C-G of 8.62% and MDRD2 of 8.96% (P<0.001). The within patient variability measured from the standard deviation (ml/min) of root mean square of 4.69 for iGFR was significantly higher than that for C-G and MDRD2 of 2.46 and 2.94, respectively. iGFR and eGFR at first observation correlated significantly (P<0.001) with last observation. Conclusions. iGFR is significantly more variable within patient than the other predictors, and the two estimators predict the iGFR with a high sensitivity but low specificity. This is a clinically reasonable combination. Predicted percent of annual loss in iGFR appears to be smaller than that using the two estimators.

Validation of the Virga GFR Equation in a Renal Transplant Population

Background: Virga and colleagues derived a glomerular filtration rate (GFR) equation which demonstrated a superior performance over Cockcroft-Gault (C-G) and modified diet in renal disease-isotope dilution mass spectrometry (MDRD-IDMS) formulas in chronic kidney disease (CKD) patients. Aim: To validate the performance of the Virga equation on 103 renal transplant patients. Methods: We compared the performances of the MDRD-IDMS, C-G and Virga equations using inulin clearance as a reference test. Error, accuracy, relative accuracy, precision, scatter, and coefficient of variance of each equation were tested. Results: The mean absolute percentage error in estimated GFR by the new equation was 39.8 ± 36.34% (mean ± SD). Relative accuracy at 10, 30 and 50% range were 18.44, 48.54 and 73.78%, respectively. It has a bias of 0.09 ± 0.169 and a precision of 19.69. Inulin clearance (GFR) in stages 1–4 were 106.19 ± 14.11, 71.17 ± 7, 42.37 ± 8.40 and 22.92 ± 3.48 ml/min/1.73 m2, respectively. Comparative statistics in the overall population and in patients with transplant CKD stage 3T showed that the MDRD-IDMS equation had better accuracy. The performance of MDRD-IDMS over the Virga equation was clearly superior for males. In patients with CKD stage 2T, the Virga equation showed superiority over MDRD-IDMS. In the overall and subpopulations, the Virga equation performed better than the C-G equation. Conclusion: Among renal transplant patients, the results suggest that the best GFR estimate is probably obtained using the MDRD-IDMS equation in moderate kidney failure whilst the Virga formula was superior to MDRD-IDMS for patients with mild kidney failure. As in untransplanted patients, estimating GFR with the MDRD-IDMS equation is not advisable in the range of normal renal function because of its known underestimation of renal function.

Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones.

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3-7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.

Contrast-induced nephropathy: Pathophysiology, risk factors, and prevention

Contrast-induced acute kidney injury is a common iatrogenic complication associated with increased health resource utilization and adverse outcomes, including short- and long-term mortality and accelerated progression of preexisting renal insufficiency. The incidence of contrast-induced nephropathy (CIN) has been reported to range from 0% to 24%. This wide range reported by the studies is due to differences in definition, background risk factors, type and dose of contrast medium used, and the frequency of other coexisting potential causes of acute renal failure. CIN is usually transient, with serum creatinine levels peaking at 2-3 days after administration of contrast medium and returning to baseline within 7-10 days after administration. Multiple studies have been conducted using variety of therapeutic interventions in an attempt to prevent CIN. Of these, careful selection of patients, using newer radiocontrast agents, maintenance of hydration status, and avoiding nephrotoxic agents pre- and post-procedure are the most effective interventions to protect against CIN. This review focuses on the basic concepts of CIN and summarizes our recent understanding of its pathophysiology. In addition, this article provides practical recommendations with respect to CIN prevention and management.

Atypical hemolytic uremic syndrome: Laboratory characteristics, complement-amplifying conditions, renal biopsy, and genetic mutations

Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and widespread damage to multiple organs including the kidney. The syndrome has a high mortality necessitating the need for an early diagnosis to limit target organ damage. Because thrombotic microangiopathies present with similar clinical picture, accurate diagnosis of aHUS continues to pose a diagnostic challenge. This article focuses on the role of four distinct aspects of aHUS that assist clinicians in making an accurate diagnosis of aHUS. First, because of the lack of a single specific laboratory test for aHUS, other forms of thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS must be excluded to successfully establish the diagnosis of aHUS. Second, application of the knowledge of complement-amplifying conditions is critically important in making an accurate diagnosis. Third, when available, a renal biopsy can reveal changes consistent with thrombotic microangiopathy. Fourth, genetic mutations are increasingly clarifying the underlying complement dysfunction and gaining importance in the diagnosis and management of patients with aHUS. This review concentrates on the four aspects of aHUS and calls for heightened awareness in making an accurate diagnosis of aHUS.

Prevalence of chronic kidney disease among patients undergoing transradial percutaneous coronary interventions

Background: While transradial approach to conduct percutaneous coronary interventions offers multiple advantages, the procedure can cause radial artery damage and occlusion. Because radial artery is the preferred site for the creation of an arteriovenous fistula to provide dialysis, patients with chronic kidney disease are particularly dependent on radial artery for their long-term survival. Methods: In this retrospective study, we investigated the prevalence of chronic kidney disease in patients undergoing coronary interventions via radial artery. Stage of chronic kidney disease was based on estimated glomerular filtration rate and National Kidney Foundation - Kidney Disease Outcomes Quality Initiative guidelines. Results: A total of 497 patients undergoing transradial percutaneous coronary interventions were included. Over 70.4% (350/497) of the patients had chronic kidney disease. Stage II chronic kidney disease was observed in 243 (69%) patients (estimated glomerular filtration rate = 76.0 ± 8.4 mL/min). Stage III was observed in 93 (27%) patients (estimated glomerular filtration rate = 49 ± 7.5 mL/min). Stage IV chronic kidney disease was observed in 5 (1%) patients (estimated glomerular filtration rate = 25.6 ± 4.3 mL/min) and Stage V chronic kidney disease was observed in 9 (3%) patients (estimated glomerular filtration rate = 9.3 ± 3.5 mL/min). Overall, 107 of 350 patients (30%) had advanced chronic kidney disease, that is, stage III–V chronic kidney disease. Importantly, 14 of the 107 (13%) patients had either stage IV or V chronic kidney disease. Conclusion: This study finds that nearly one-third of the patients undergoing transradial percutaneous coronary interventions have advanced chronic kidney disease. Because many of these patients may require dialysis, the use of radial artery to conduct percutaneous coronary interventions must be carefully considered in chronic kidney disease population.

Hemolytic Anemia an Unusual Presentation of Vitamin B12 Deficiency

Vitamin B12, or cobalamin, is a water soluble vitamin which is synthesized by bacteria and archaea. Vitamin B12 is absorbed in the terminal ileum after binding intrinsic factor, a glycoprotein produced by the parietal cells in the stomach. The most common cause of B12 deficiency worldwide is pernicious anemia. Pernicious anemia is a deficiency of vitamin B12 due to lack of intrinsic factor. Usually, this is secondary to production of autoantibodies directed against the intrinsic factor of gastric parietal cells, leading to atrophic gastritis. Common findings in Vitamin B12 deficiency include anemia, leukopenia, and thrombocytopenia, macrocytosis, and hypersegmented neutrophils. Vitamin B12 deficiency is a rare cause of hemolytic anemia (approximately 1.5% of cases). Here, we present a case of a 59-year-old male found to have hemolytic anemia secondary to marked vitamin B12 deficiency and improved after vitamin supplementation and provide a brief review of literature.

An Unusual and Fatal Cause of Miliary Nodules on Chest Radiography

Foreign body granulomatosis has many etiologies, including the injection of oral medications intravenously. The insoluble filler materials that are used in the medications can lodge in pulmonary arterioles and capillaries, which can trigger foreign body giant cell reaction, chronic inflammation, thrombosis, and fibrosis, resulting in pulmonary hypertension, progressive shortness of breath, and, potentially, fatal conditions. On imaging, this may present with multiple miliary mottling’s/nodules. The use of a bronchoscopy with biopsy can be an excellent way to establish a diagnosis in appropriate clinical settings. Here, we present a case of a 37-year-old old male found to have multiple miliary densities on imaging due to intravenous use of oral medication.

C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction

The advances in our understanding of the alternative pathway have emphasized that uncontrolled hyperactivity of this pathway causes 2 distinct disorders that adversely impact the kidney. In the so-called atypical hemolytic uremic syndrome (aHUS), renal dysfunction occurs along with thrombocytopenia, anemia, and target organ injury to multiple organs, most commonly the kidney. On the other hand, in the so-termed C3 glomerulopathy, kidney involvement is not associated with thrombocytopenia, anemia, or other system involvement. In this report, we present 2 cases of alternative pathway dysfunction. The 60-year-old female patient had biopsy-proven C3 glomerulopathy, while the 32-year-old female patient was diagnosed with aHUS based on renal dysfunction, thrombocytopenia, anemia, and normal ADAMTS-13 level. The aHUS patient was successfully treated with the monoclonal antibody (eculizumab) for complement blockade. The patient with C3 glomerulopathy did not receive the monoclonal antibody. In this patient, management focused on blood pressure and proteinuria control with an angiotensin-converting enzyme inhibitor. This article focuses on the clinical differences, pathophysiology, and treatment of aHUS and C3 glomerulopathy.