Evaluation of plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) as an early diagnostic marker of acute kidney injury (AKI) in critically ill trauma patients.

Background and Aims: Acute kidney injury (AKI) is a frequent complication of severe trauma associated with high mortality. The aim of this study was to evaluate the diagnostic ability of plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of AKI assessed by RIFLE criteria as reference in trauma patients in intensive care unit (ICU). Material and Methods: This was a prospective observational study. Four hundred and eighteen patients admitted in the trauma ICU with age ≥18 years without known renal diseases were followed-up (serum creatinine, urine output, and estimated glomerular filtration rate) for 5 consecutive days. As per RIFLE criteria, 70 patients were broadly classified as AKI and rest of the patients (n = 348) as non-AKI. Plasma and urine samples of AKI (n = 70) and non-AKI (n = 70) patients were further assessed for 3 consecutive days following admission. Results: Mean plasma NGAL (pNGAL) was significantly elevated in AKI patients as compared with non-AKI patients; on admission: 204.08 versus 93.74 ng/mL (P = 0.01); at 24 h: 216.73 versus 94.63 ng/mL (P = 0.01); and 48 h: 212.77 versus 86.32 ng/mL (P = 0.01). Mean urine NGAL (uNGAL) at 48 h was also significantly elevated: 15.45 ng/mL in AKI patients as compared with 13.48 ng/mL in non-AKI patients (P = 0.01). Plasma and urine NGAL levels were significantly associated with increased mortality. Conclusion: pNGAL had good predictive value on admission (area under the receiver operative characteristic [AUROC] 0.84), at 24 h (AUROC 0.88) and 48 h (AUROC 0.87), while uNGAL had moderate performance at 24 h (AUROC 0.61) and 48 h (AUROC 0.71). pNGAL can be used as an early and potent diagnostic and predictive marker of AKI and mortality in critically ill trauma patients.

Outcomes of Participants With Diabetes in the ISCHEMIA Trials.

BACKGROUND: Among patients with diabetes and chronic coronary disease, it is unclear if invasive management improves outcomes when added to medical therapy. METHODS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trials (ie, ISCHEMIA and ISCHEMIA-Chronic Kidney Disease) randomized chronic coronary disease patients to an invasive (medical therapy + angiography and revascularization if feasible) or a conservative approach (medical therapy alone with revascularization if medical therapy failed). Cohorts were combined after no trial-specific effects were observed. Diabetes was defined by history, hemoglobin A1c ≥6.5%, or use of glucose-lowering medication. The primary outcome was all-cause death or myocardial infarction (MI). Heterogeneity of effect of invasive management on death or MI was evaluated using a Bayesian approach to protect against random high or low estimates of treatment effect for patients with versus without diabetes and for diabetes subgroups of clinical (female sex and insulin use) and anatomic features (coronary artery disease severity or left ventricular function). RESULTS: Of 5900 participants with complete baseline data, the median age was 64 years (interquartile range, 57-70), 24% were female, and the median estimated glomerular filtration was 80 mL·min-1·1.73-2 (interquartile range, 64-95). Among the 2553 (43%) of participants with diabetes, the median percent hemoglobin A1c was 7% (interquartile range, 7-8), and 30% were insulin-treated. Participants with diabetes had a 49% increased hazard of death or MI (hazard ratio, 1.49 [95% CI, 1.31-1.70]; P<0.001). At median 3.1-year follow-up the adjusted event-free survival was 0.54 (95% bootstrapped CI, 0.48-0.60) and 0.66 (95% bootstrapped CI, 0.61-0.71) for patients with diabetes versus without diabetes, respectively, with a 12% (95% bootstrapped CI, 4%-20%) absolute decrease in event-free survival among participants with diabetes. Female and male patients with insulin-treated diabetes had an adjusted event-free survival of 0.52 (95% bootstrapped CI, 0.42-0.56) and 0.49 (95% bootstrapped CI, 0.42-0.56), respectively. There was no difference in death or MI between strategies for patients with diabetes versus without diabetes, or for clinical (female sex or insulin use) or anatomic features (coronary artery disease severity or left ventricular function) of patients with diabetes. CONCLUSIONS: Despite higher risk for death or MI, chronic coronary disease patients with diabetes did not derive incremental benefit from routine invasive management compared with initial medical therapy alone. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Metabolic acidosis in the initial 6 months after renal transplantation: A prospective study.

BACKGROUND: There is limited information about the incidence of metabolic acidosis (MA) after renal transplantation. This single centre prospective study aimed to delineate the incidence and risk factors of MA in the first 6 months after renal transplantation (RTX). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Patients who underwent RTX between November 2018 and July 2020 were monitored with weekly measurement of serum bicarbonate level for 6 months and those who were diagnosed with MA were evaluated further to characterize the type of MA. RESULTS: One hundred and twenty-five patients were included in the study, 89 (71.2%) of whom developed MA. Seventy-two patients developed MA in the first month, 11 during the 2-3 months and 6 between 4 and 6 months after transplantation. Of the 89 patients, 55(61.8%) had type 1 renal tubular acidosis (T1RTA), 27 (30.3%) had type 2 RTA (T2RTA) and 7 (7.9%) type 4 RTA (T4RTA). Two patient who had T1RTA, subsequently developed high anion gap MA following severe graft rejection. On stepwise multivariate regression analysis, serum creatinine at time of diagnosis of MA [OR (95% CI): 12.02 (1.79 to 80.59), p = .01] and high tacrolimus C0 levels [OR (95% CI): 2.43 (1.0 to 5.90), p = .049], were independent risk factors for MA. CONCLUSION: There is a high incidence of MA in the initial 6 months post-transplant with serum creatinine and high tacrolimus C0 levels being independent risk factors.

Timing of intraoperative crystalloid infusion may decrease total volume of infusate without affecting early graft function in live related renal transplant surgery: A randomized, surgeon-blinded clinical study.

INTRODUCTION: Early graft function is crucial for successful kidney transplantation. Intravascular volume maintenance is paramount in ensuring reperfusion of transplanted kidney. This study was planned to compare whether the timing of fluid infusion can help to decrease amount of fluid given without altering early graft function during renal transplantation. MATERIALS AND METHODS: The present study included forty recipients, randomized into standard (Group-S) or targeted fluid therapy (Group-T). Group S received fluid according to conventional fasting deficit while Group T received at 1 ml/kg/h from the start of surgery till start of vascular anastomosis after which fluid infusion rate in both group was increased to maintain a central venous pressure of 13-15 mm of Hg till reperfusion. Primary outcome measured was serum creatinine level on first postoperative day while secondary outcomes were IV fluid given, perioperative hemodynamics, onset of diuresis, graft turgidity, urine output, and renal function during first 6 postoperative days. RESULTS: The study showed Group T postoperatively had early fall in serum creatinine (day 3) than S (day 6) although this difference was not statistically significant. Group T had received significantly less fluid per kg of dry weight (T-42.7 ± 9.7 ml/kg, S-61.1 ± 11.1 ml/kg, P < 0.001), had early diuresis, better graft turgidity and urine output than Group S. CONCLUSION: Targeted hydration significantly decreases the total amount of fluid infused during the intraoperative period without altering early graft function. Targeted hydration during vascular anastomosis produced stable hemodynamics and early diuresis without any side-effects pertaining to hypo or hyper-volemia.Clinical trial identifier number-CTRI/2016/07/007111.

Spectrum of biopsy-proven renal disease in northern India: A single-centre study.

AIM: Pattern of kidney diseases varies across geographies due to multiple factors. There is a paucity of information from South Asia due to the absence of nationwide/regional biopsy registries. This study aimed to delineate the spectrum of renal parenchymal diseases in our region. METHODS: Records of kidney biopsies done in our nephrology department between 2006 and 2016 were analysed. Clinico-pathological correlation was done from the available records. RESULTS: Of the 3275 biopsy evaluated, 61.9% were males, and mean age was 33.2 ± 14.2 years. 6.2% patients were elderly (age ≥ 60 years). Nephrotic syndrome (60.3%) was the commonest indication for biopsy. On histology, 73.0% patients had primary glomerulonephritis (GN), 15.5% secondary GN, 5.3% tubulo-interstitial and 3.7% vascular disease. Focal segmental glomerulosclerosis (FSGS) was the commonest primary GN accounting for 18.2% of all GNs, followed by minimal change disease (16.8%), membranous nephropathy (MN) (16.0%) and IgA nephropathy (10.4%). Lupus nephritis (10.6%) and amyloidosis (3.7%) were the commonest secondary GN. The commonest cause of nephrotic syndrome was minimal change disease (22.9%), acute nephritic syndrome was lupus nephritis (30.6%), rapidly progressive renal failure was pauci-immune crescentic GN (24.5%). IgA nephropathy was the commonest etiology of asymptomatic urinary abnormalities (26.3%) and gross haematuria (50%). About 60.9% patients of undetermined chronic kidney disease had glomerular diseases, and 13.6% had chronic tubulointerstitial nephritis. Lupus nephritis and acute cortical necrosis were significantly more common in females compared with males. CONCLUSION: This is one of the largest cohorts of kidney biopsies from India, and it delineates the unique features and differences in the pattern of kidney disease in our population.

Infection is the chief cause of mortality and non-death censored graft loss in the first year after renal transplantation in a resource limited population: A single centre study.

AIM: Few studies have assessed the impact of infections after renal transplantation (RTX) in low and middle income countries. This single centre study aimed to delineate the profile and impact of infections requiring hospitalization (IRH) occurring in the first year after RTX in India. METHOD: Patients who underwent RTX between July 2012 and June 2015 were followed up for 12 months after transplantation. RESULTS: 60.2% of the 387 patients studied had at least one IRH and total 492 infections were diagnosed. The most common were urinary tract (30.3%), gastrointestinal (17.1%) and pulmonary (11.2%) infections. Viral aetiology (33.3%) was most frequent, followed by bacterial (23.6%), parasitic (5.1%), tuberculosis (4.5%), and fungal infections (3.9%). 86.4% deaths were due to infections. One year patient and graft survival were inferior among recipients with IRH compared to those with no IRH: 91.8% vs. 98.1% (log rank = 0.010) and 90.1% vs. 97.4% (log rank = 0.006) respectively. Average monthly income per family member <5000 Rupees (75 USD), NODAT, and acute rejection were independent risk factors for IRH. CONCLUSION: The profile of IRH is unique involving opportunistic, community-acquired and endemic infections seen in this country. It is the predominant cause of mortality and graft loss in the first year after RTX. Poor economic status is an important determinant of IRH in our population.

Dengue fever in renal allograft recipients: Clinical course and outcome.

BACKGROUND: There are annual outbreaks of dengue infection in tropical and subtropical countries. This retrospective study aimed to assess the clinical manifestation of dengue and outcome in renal transplant recipients. METHODS: Renal transplant recipients diagnosed with dengue in the nephrology department during the outbreak from August 2015 to December 2015 were included in the study. RESULTS: Twenty patients developed dengue presenting during the outbreak. Mean age was 31.9 ± 8.8 years and all were males. Two patients had severe dengue (dengue hemorrhagic fever, dengue shock syndrome). Clinical presentation included febrile illness (95%), myalgia (65%), headache (30%), retro-orbital pain (10%), and mucocutaneous bleeding manifestations (10%). Three (15%) had third space fluid accumulation and 2 (10%) had hypotension. Ninety percent patients had thrombocytopenia, with 4 requiring platelet transfusion. Leucopenia (WBC < 4000/mm3 ) developed in 50% patients. About 60% had transient transaminitis. One patient with severed dengue expired and 1 recovered with IV immunoglobulin therapy. About 40% patients had rise in serum creatinine, with complete recovery in all patients. CONCLUSION: Clinical manifestations of dengue infection in renal transplant recipients were similar to that in general population. However, leucopenia necessitating temporary withdrawal of immunosuppression was common. Renal dysfunction was frequent but completely reversible.

Clinical and Laboratory Features Associated with Acute Kidney Injury in Severe Malaria.

INTRODUCTION: Critically ill severe malaria constitutes one of the major hospital admissions in Indian setting. Clinical studies identifying the factors associated with acute kidney injury (AKI) in malaria are lacking. This study aimed to identify these factors. METHODS: This prospective observational study was conducted in a tertiary care center of North India. All adult patients with severe malaria were studied during 2012-2014. RESULTS: The study included 79 patients and AKI was observed in 36 patients. Of these 79 patients, 52.7% were Plasmodium falciparum positive and 47.2% were Plasmodium vivax positive. In AKI patients, thrombocytopenia and jaundice were the most common other complications seen. Among P. vivax malarial patients, 17 (36%) patients had AKI. Features associated with AKI among patients admitted with P. vivax malaria were as follows: tachycardia (adjusted relative risk [RR]: 3.9; 95% confidence interval [CI]: 1.1-13.7), direct hyperbilirubinemia (adjusted RR: 4.7; 95% CI: 1.4-15.2), anemia (adjusted RR: 6; 95% CI: 1.7-22.4), and sepsis (adjusted RR: 3.3; 95% CI: 1.1-13.7). The presence of tachycardia, acidosis, cerebral malaria, acute respiratory distress syndrome/acute lung injury, hypotensive shock, and poor Glasgow Coma Scale were associated with higher mortality in patients with AKI. Patients who required mechanical ventilation and/or vasopressor support had higher mortality. CONCLUSION: P. vivax is an important cause of severe malaria with AKI in our setting. Various other clinical features are associated with AKI and related mortality.

Impact of type of calcineurin inhibitor on post-transplant tuberculosis: Single-center study from India.

INTRODUCTION: Tuberculosis (TB) is an important cause of morbidity and mortality in renal transplant recipients. Immunosuppressive drugs are one of the most important risk factor for post-transplant tuberculosis (PTTB). A paucity of data exists about the impact of the type of calcineurin inhibitor on PTTB. METHODS: In this retrospective study, all adult patients on calcineurin inhibitor-based immunosuppression were included. Patients receiving TB chemoprophylaxis were excluded. Diabetes, duration of dialysis, hepatitis B and C, past treated TB, induction therapy, type of antimetabolite, acute rejection, new onset of diabetes after renal transplantation (RT) (NODAT) and cytomegalovirus (CMV) were analyzed in tacrolimus (Tac) and cyclosporine (CsA) groups. Primary outcome was incidence of TB and secondary outcomes were timeline of development of TB after RT and pattern of TB in the two groups. RESULTS: Of the 1664 patients included, 582 patients received CsA-based immunosuppression while 1082 received Tac-based immunosuppression. Duration of dialysis, positive tuberculin skin test, use of induction, mycophenolate mofetil use, CMV infection, and NODAT were significantly more, and hepatitis B infection, past treated TB, and acute rejection episodes were significantly less in the Tac group. At the end of follow-up, incidence of TB in the Tac group was significantly less than in the CsA group (6.1% vs 19.9%, P<.001). Mean time for development of TB after RT was similar in both the groups and nodal and disseminated TB were more common in the Tac group. CONCLUSION: In conclusion, our study shows that use of Tac as compared to CsA significantly decreases incidence of PTTB. Time of infection since transplant was similar in both the groups. However, nodal and disseminated TB were more common in the Tac group.

BK polyomavirus infection after renal transplantation: Surveillance in a resource-challenged setting.

BACKGROUND: There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India. METHODS: We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12 months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (≥10 000 copies/mL) detected ≥2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction. RESULTS: All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12 months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6 months. Nine (14.5%) patients had SSBKV. There was no biopsy-proven BKVAN. At the end of 1 year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV. CONCLUSION: Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6 months. Most clear their viremia by 12 months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients.

Clinical and histopathologic profile of patients with primary IgA nephropathy seen in a tertiary hospital in India.

BACKGROUND: IgA nephropathy (IgAN) is known to have an aggressive course in Asians. There is a paucity of data regarding the Oxford classification pattern of Indian patients with IgAN. This study aims to characterize the clinical and histopathologic profile of these patients. METHODS: All patients diagnosed to have primary IgAN by kidney biopsy in the nephrology department from July 2009 to July 2014 were included in this study. All kidney biopsies were reviewed and the MEST score was assigned as per the Oxford classification. The clinical features and Oxford classification score of patients were characterized. RESULTS: Nephrotic range proteinuria (NRP) (65/103, 63.1%) with or without edema was the commonest presentation. 67.0% patients had eGFR ≥ 60 mL/min and 16.5% patients had eGFR < 30 mL/min. Of the 103 patients, 80 (77.7%) had M1, 10 (9.7%) had E1, 45 (43.7%) had S1 and 41 (39.8%) had T1/T2 lesions by the Oxford criteria and 11 (10.7%) patients had crescents. 62 patients had eGFR ≥ 30 mL/min and follow up for at least 6 months (median -17.7 (6-65.1) months) of whom 52(83.9%) had received ACEi/ARBs and 38 (61.3%) had received immunosuppression. 11/62 (17.7%) patients developed renal worsening in this period of which 7 (11.3%) developed end stage kidney disease (ESKD). CONCLUSION: Indian patients with primary IgA nephropathy have a unique profile. They commonly present with nephrotic range proteinuria. A significant proportion of these patients have normal renal function despite heavy proteinuria. Mesangial proliferative lesions are predominant with a paucity of endocapillary proliferation and crescents compared to other Asian populations. Immunosuppressive use is more common in Indian patients.

Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells.

The genes and pathways that govern the functions and expansion of hematopoietic stem cells (HSC) are not completely understood. In this study, we investigated the roles of serine/threonine Pim kinases in hematopoiesis in mice. We generated PIM1 transgenic mice (Pim1-Tx) overexpressing human PIM1 driven by vav hematopoietic promoter/regulatory elements. Compared to wild-type littermates, Pim1-Tx mice showed enhanced hematopoiesis as demonstrated by increased numbers of Lin(-) Sca-1 (+) c-Kit (+) (LSK) hematopoietic stem/progenitor cells and cobblestone area forming cells, higher BrdU incorporation in long-term HSC population, and a better ability to reconstitute lethally irradiated mice. We then extended our study using Pim1(-/-), Pim2(-/-), Pim3(-/-) single knockout (KO) mice. HSCs from Pim1(-/-) KO mice showed impaired long-term hematopoietic repopulating capacity in secondary and competitive transplantations. Interestingly, these defects were not observed in HSCs from Pim2(-/-) or Pim3(-/-) KO mice. Limiting dilution competitive transplantation assay estimated that the frequency of LSKCD34(-) HSCs was reduced by approximately 28-fold in Pim1(-/-) KO mice compared to wild-type littermates. Mechanistic studies demonstrated an important role of Pim1 kinase in regulating HSC cell proliferation and survival. Finally, our polymerase chain reaction (PCR) array and confirmatory real-time PCR (RT-PCR) studies identified several genes including Lef-1, Pax5, and Gata1 in HSCs that were affected by Pim1 deletion. Our data provide the first direct evidence for the important role of Pim1 kinase in the regulation of HSCs. Our study also dissects out the relative role of individual Pim kinase in HSC functions and regulation.

The Pim protein kinases regulate energy metabolism and cell growth.

The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies and promote cell growth and survival. Here, we find that a novel Pim kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked the rapamycin-sensitive mammalian target of rapamycin (mTORC1) activity by stimulating the phosphorylation and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three Pim kinases [triple knockout (TKO) MEFs] demonstrated activated AMPK driven by elevated ratios of AMPATP relative to wild-type MEFs. Consistent with these findings, TKO MEFs were found to grow slowly in culture and have decreased rates of protein synthesis secondary to a diminished amount of 5'-cap-dependent translation. Pim-3 expression alone in TKO MEFs was sufficient to reverse AMPK activation, increase protein synthesis, and drive MEF growth similar to wild type. Pim-3 expression was found to markedly increase the protein levels of both c-Myc and the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. Overexpression of PGC-1α in TKO MEFs elevated ATP levels and inhibited the activation of AMPK. These results demonstrate the Pim kinase-mediated control of energy metabolism and thus regulation of AMPK activity. We identify an important role for Pim-3 in modulating c-Myc and PGC-1α protein levels and cell growth.

Scleral imbrication with vitreoretinal surgery as a primary procedure for retinal detachment in pathological myopia.

ABSTRACT: A 45-year-old male presented with diminution of vision in the right eye (RE) for the past 2 weeks. He underwent sequential bilateral cataract surgery 25 years ago, with an intraocular lens in RE, which was his better eye. The left eye was aphakic with a thick fibrous membrane at the pupillary plane. Visual acuity was hand movement in the RE with the iris claw lens and total bullous retinal detachment (RD). The axial length with RD was 28.6 mm in RE and 29 mm in the left eye (LE). We did a vitrectomy with scleral imbrication, endolaser, fluid gas exchange, and tamponade in the RE. The LE developed RD subsequently, and he underwent similar surgical procedures in his LE. The best corrected visual acuity in his RE was 20/80, and that in the LE was 20/120 on follow-up. RD with staphyloma is a surgical challenge as the thin atrophic retina at the posterior pole fails to conform to the concavity of staphyloma. Vitrectomy with tamponade alone does not take care of staphyloma and has more chances of recurrent detachment or persistent fluid at the posterior pole. Scleral imbrication shallows the staphyloma cavity and shortens the axial length, thereby giving a good surgical outcome.

MRI Insights in Chiari Malformation Type 1 and Variations With Hydrosyringomyelia.

Chiari malformation (CM) type 1 is a complex neurological disorder characterized by the displacement of the cerebellar tonsils into the upper spinal canal. Hydrosyringomyelia (HSM), which frequently coexists with this condition, presents diagnostic and treatment problems due to its broad spectrum of symptoms. There are various forms of CMs, with CM type 1 (CM1) being the most common type. Magnetic resonance imaging (MRI) is the best imaging technique to properly identify and diagnose CM1 and HSM. Important imaging findings include downward displacement of the cerebellar tonsils across the foramen magnum, the appearance of the syrinx in the spinal cord, and the alteration of the flow dynamics of the cerebrospinal fluid. This study was conducted at Datta Meghe Medical College, Nagpur, and Government Medical College & Super Speciality Hospital, Nagpur, India. It focuses on the diagnostic use of MRI in CM1 and its variations associated with HSM. Individuals who are asymptomatic may not need any treatment; however, those who are symptomatic or have HSM may require surgical decompression and restoration of the flow. We discuss the findings of MRI of six cases of CM1 and its variants with HSM and search for possible underlying causes. We conclude that magnetic resonance imaging is an imaging modality for the identification and evaluation of CM1 in cases of HSM.

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A.

The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1(-/-) MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34(+) mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance.

Clinical Profile of Nonproteinuric Kidney Disease in Type 2 Diabetic Patients in India.

Background: Diabetic kidney disease (DKD) is the commonest cause of end-stage renal disease (ESRD) across the world. Development of microalbuminuria is the earliest marker of DKD and predicts progressive decline in estimated glomerular filtration rate (eGFR). However, recent evidence has suggested that a significant proportion of type 2 diabetic patients have chronic kidney disease (CKD) without proteinuria. Methods: In this single-center, prospective observational study, 400 consecutive type 2 diabetic patients with either overt proteinuria (>500 mg/day) and/or renal dysfunction eGFR <60 ml/min/1.73 m2) were recruited. Baseline demographic and clinical data were recorded. eGFR and proteinuria were recorded at 6 months and 1 year. Patients with proteinuric (proteinuria >0.5 g/day) and nonproteinuric phenotypes were compared for progression of renal dysfunction in terms of doubling of serum creatinine and need for dialysis. Results: In our study cohort, 106 (26.5%) were nonproteinuric. Both the groups were similar in terms of gender, duration of diabetes, comorbidities, body mass index (BMI), blood pressure control, and glycemic control. The nonproteinuric group was older (56.5 ± 2.1 vs. 54.7 ± 11.6 years, P = 0.012), had lesser prevalence of diabetic retinopathy (49 [46.2%] vs. 218 [74.1%], P < 0.001), higher hemoglobin levels (11.3 ± 1.7 vs. 10.5 ± 2.0 g/dl, P < 0.001), and higher cholesterol levels (169.3 ± 43.3 vs 157.1 ± 58.1 mg/dl, P = 0.025). The nonproteinuric phenotype had higher eGFR at baseline, 6 months, and 1 year. However, doubling of serum creatinine (10 [9.4%] vs. 48 [16.3%]) and progression to ESRD (5 [4.7%] vs. 19 [6.5%], P = 0.159) were not different between the two phenotypes. Conclusion: Nonproteinuric DKD is common. Patients with nonproteinuric DKD tend to be older with a slower decline in eGFR.

Depression and marital dissatisfaction among Indian hemodialysis patients and their spouses: a cross-sectional Study.

AIM: Interaction of patient in marital dyad may have bearing on long-term patient outcome. Depression, subjective stress, and marital discord have been reported in healthy spouses of patients with end-stage renal disease (ESRD). Depressed patients on dialysis along with their spouses can function as depressed dyad. We looked at the incidence and factors associated with depression and marital stress among Indian hemodialysis patients and their spouses. METHODS: A total of 49 (32 males, 17 females) patients on maintenance hemodialysis and their spouses were independently administered Beck Depression Inventory (BDI), Revised Dyadic Adjustment Scale, and self-rated subjective quality-of-life scale. Their demographic parameters, socioeconomic status, and type of family (nuclear or joint) were also noted. RESULTS: About 57.1% of patients were depressed compared with 42.8% of spouses (p = 0.133). In both patients and spouses, BDI correlated with quality of life and perceived marital stress. About 36.7% of patients and 24.4% of spouses reported marital stress (p = 0.69). Male spouses had more marital stress compared with female spouses (p < 0.0001). Depression and marital stress in patients and spouses was not associated with socioeconomic status, literacy levels, and employment. Depression in patients had direct correlation with depression in spouse (r = 0.572, p < 0.0001) and degree of marital dissatisfaction in spouse (r = 0.623, p < 0.0001). Patients living in nuclear family were more depressed and had more marital stress. CONCLUSION: Married ESRD patients and their spouses function as a complex psychosocial dyad with significant two-way interactions. Social support, as is seen in joint families, leads to significantly lesser depression and better marital understanding.

In vitro evaluation of the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth.

OBJECTIVES: The aim of this study was to evaluate the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth. MATERIAL AND METHOD: Seventy-five extracted human incisors were endodontically treated, out of which 60 were decoronated 2 mm above the cementoenamel junction and divided into two experimental groups based on the type of post system to be used: glass fiber post (GFP) and Ribbond fiber post groups (RFP). Endodontically treated human anterior teeth in which no post was placed served as control group. Each group was divided into two subgroups according to the length of post space: 5 and 10 mm and all the samples were restored with metal crowns. The fracture resistance was measured by applying loads at an angle of 130° to the long axis of teeth in an Instron universal testing machine. RESULTS: The results revealed that GFP group at 10-mm post space length showed the significantly highest fracture resistance (740.2133 N) among all groups and subgroups. Decrease in post length resulted in the decrease in fracture resistance in GFP group (425.1867 N), whereas in group RFP 5-mm subgroup (299.6200 N) showed significantly higher fracture resistance than 10-mm subgroup (216.9300 N) but lesser than the control (437.8733 N) in both the subgroups. CONCLUSION: Glass fiber posts efficiently increase the fracture resistance of an endodontically treated tooth but the determination of optimal post length is also essential. CLINICAL RELEVANCE: The present investigation highlights the significance of using glass fiber posts in the restoration of endodontically treated teeth. Endodontically treated teeth restored with glass fiber posts showed increased fracture strength and favorable mode of fracture, and are therefore highly recommended to achieve better clinical outcomes.

A study of incidence of AKI in critically ill patients.

BACKGROUND: There have been many studies to estimate the incidence of acute kidney injury (AKI) in critically ill patients. However, results were variable due to the non-usage of uniform criteria and retrospective design of most studies. There are no new studies from the developing countries looking at AKI in these patients since adoption of uniform Acute Kidney Injury Network (AKIN) criteria. METHODS: In this prospective observational study from a tertiary care hospital in India, we enrolled 100 consecutively admitted critically ill patients and followed them during hospital stay. AKI was defined by AKIN criteria. Both the groups of patients, those who developed AKI and those who did not develop AKI, were then followed during the course of their hospital stay. RESULTS: AKI occurred in 33 patients with an incidence rate of 17.3 per person year. Thirty-one out of 33 (93.9%) patients died in the AKI group, whereas 31 out of 67 (53.7%) patients died in the non-AKI group. Independent risk factors for AKI were older age (adjusted relative risk (RR) = 4.42, 95% CI = 2.57-5.23), septic shock (adjusted RR = 2.82, 95% CI = 1.43-3.80), prolonged duration of mechanical ventilation (adjusted RR = 2.35, 95% CI = 1.09-3.6), higher acute physiology and chronic health evaluation II (APACHE II) score (adjusted RR = 2.74, 95% CI = 1.28-4.13), and higher sequential organ failure assessment (SOFA) score (adjusted RR = 2.53, 95% CI = 1.04-4.08). Development of AKI was an independent risk factor for mortality (adjusted RR = 1.76, 95% CI = 1.25-1.84). CONCLUSION: Older patients, those with septic shock, and those requiring prolonged mechanical ventilation had increased risk for AKI. AKI was an independent predictor of mortality.