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Chronic kidney disease (CKD) and its subset diabetic kidney disease are progressive conditions that affect >850 million people worldwide. Diabetes, hypertension, and glomerulonephritis are the most common causes of CKD, which is associated with significant patient morbidity and an increased risk of cardiovascular events, such as heart failure, ultimately leading to premature death. Despite newly approved drugs, increasing evidence shows that patients respond to treatment differently given the complexity of disease heterogeneity and complicated pathophysiology. This review article presents an integrative approach to understanding and addressing CKD through the lens of precision medicine and therapeutics. Advancements in single-cell omics technologies and artificial intelligence can be leveraged to explore the intricate cellular mechanisms underlying CKD and diabetic kidney disease pathogenesis. Dissecting the cellular heterogeneity and identifying rare cell populations using single-cell approaches will facilitate uncovering novel therapeutic targets and biomarkers for personalized treatment strategies. Finally, we discuss the potential of artificial intelligence-driven analyses in predicting disease progression and treatment response, thereby paving the way for tailored interventions., Competing Interests: Disclosure Statement V.D., S.B., P.A.S., E.T.B.O., and K.S. are employed by Novo Nordisk A/S, and V.D., S.B., P.A.S., and K.S. hold minor stock portions as part of an employee-offering program. The review article and the research were conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Delayed graft function in kidney transplant is associated with an increased risk of rejection and graft loss. Use of rabbit antithymocyte globulin induction in delayed graft function has been correlated with less rejection compared to basiliximab, but optimal dosing remains unknown. Program Evaluation Aims: The purpose of this evaluation was to retrospectively assess the short-term effectiveness and tolerability of a clinical protocol that increased the net state of immunosuppression in delayed graft function kidney transplant recipients using cumulative 6 mg/kg rabbit antithymocyte globulin induction. Design: This retrospective cohort included 88 kidney transplant recipients with delayed graft function, transplanted between January 2017 and March 2021, who either received cumulative 4.5 mg/kg pre-protocol or 6 mg/kg post-protocol rabbit antithymocyte globulin. Outcomes evaluated were biopsy-proven acute rejection and incidence of graft loss, infection, and cytopenia at 6 months. Results: A significant reduction of biopsy-proven acute rejection incidence occurred post-protocol implementation (10/33, 30.3% vs 6/55, 10.9%; P  = .04). Of those with rejection, significantly less post-protocol patients were classified as acute cellular rejection (9/10, 90.0% vs 2/6, 33.3%; P  = .04). No death-censored graft loss was observed in either group. Rates of cytopenia and infection were similar pre- versus post-protocol implementation. Conclusion: Increasing the exposure to rabbit antithymocyte globulin and maintenance immunosuppression in delayed graft function kidney transplant recipients was tolerable and significantly reduced rejection occurrence at 6 months., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: No potential conflicts of interest relevant to this article were reported.

Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS., Competing Interests: Financial interests: W.E.S. is a co-founder of NephKey Therapeutics, Inc. S.B., S.A., and W.E.S. have filed patent # US 20230257817 A1. Non-financial interests: W.E.S. is on the Board of Directors of NephCure Kidney International and receives no compensation as a member of the Board of Directors., (© 2023 The Authors.)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may be effective in reducing body weight and hemoglobin A1c (HbA1c) post-kidney transplantation. Limited literature exists on use of these agents outside of kidney transplant. The purpose of this program evaluation was to evaluate the safety and efficacy of SGLT2i in kidney, liver, and lung transplant recipients. Methods: This was a retrospective program evaluation of adult kidney, liver, and lung transplant recipients between August 31, 2016 and July 31, 2021. Patients initiated on SGLT2i for diabetes for a minimum of 90 days with at least 1 follow-up appointment were screened for inclusion. Outcomes were compared between SGLT2i initiation to nadir values 3-12-months post-initiation. Outcomes included change in hemoglobin A1c, fasting blood glucose, actual body weight, and body mass index. Safety outcomes included adverse effects, cardiovascular events, death-censored graft loss, and all-cause mortality. Results: Forty-nine patients met inclusion criteria, (26 liver, 18 kidney, 4 lung, and 1 simultaneous liver-kidney recipient). The median time from transplant to SGLT2i initiation was 1216 days (IQR 524-2256). Glycemic and weight loss outcomes showed a statistically significant benefit from SGLT2i use. Total safety outcome incidence was minimal at 12 months. No patient experienced myocardial infarctions, graft loss, or mortality at 3-12 months. One incidence of urinary tract infection and stroke occurred each. The most common adverse effects included hypotension and hypoglycemia. Conclusion: This program evaluation demonstrated that SGLT2i can be used safely in solid organ transplant recipients. These agents can provide an additional non-insulin agent for post-transplant diabetes mellitus management in solid organ transplant.

Introduction: Nephrotic syndrome (NS) occurs commonly in children with glomerular disease and glucocorticoids (GCs) are the mainstay treatment. Steroid resistant NS (SRNS) develops in 15% to 20% of children, increasing the risk of chronic kidney disease compared to steroid sensitive NS (SSNS). NS pathogenesis is unclear in most children, and no biomarkers exist that predict the development of pediatric SRNS., Methods: We studied a unique patient cohort with plasma specimens collected before GC treatment, yielding a disease-only sample not confounded by steroid-induced gene expression changes (SSNS n  = 8; SRNS n  = 7). A novel "patient-specific" bioinformatic approach merged paired pretreatment and posttreatment proteomic and metabolomic data and identified candidate SRNS biomarkers and altered molecular pathways in SRNS versus SSNS., Results: Joint pathway analyses revealed perturbations in nicotinate or nicotinamide and butanoate metabolic pathways in patients with SRNS. Patients with SSNS had perturbations of lysine degradation, mucin type O-glycan biosynthesis, and glycolysis or gluconeogenesis pathways. Molecular analyses revealed frequent alteration of molecules within these pathways that had not been observed by separate proteomic and metabolomic studies. We observed upregulation of NAMPT, NMNAT1, and SETMAR in patients with SRNS, in contrast to upregulation of ALDH1B1, ACAT1, AASS, ENPP1, and pyruvate in patients with SSNS . Pyruvate regulation was the change seen in our previous analysis; all other targets were novel. Immunoblotting confirmed increased NAMPT expression in SRNS and increased ALDH1B1 and ACAT1 expression in SSNS, following GC treatment., Conclusion: These studies confirmed that a novel "patient-specific" bioinformatic approach can integrate disparate omics datasets and identify candidate SRNS biomarkers not observed by separate proteomic or metabolomic analysis., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson's disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

Infections caused by multi-drug resistant Klebsiella pneumoniae are a leading cause of mortality and morbidity among hospitalized patients. In neonatal intensive care units (NICU), blood stream infections by K. pneumoniae are one of the most common nosocomial infections leading to poor clinical outcomes and prolonged hospital stays. Here, we describe an outbreak of multi-drug resistant K. pneumoniae among neonates admitted at the NICU of a large tertiary care hospital in India. The outbreak involved 5 out of 7 neonates admitted in the NICU. The antibiotic sensitivity profiles revealed that all K. pneumoniae isolates were multi-drug resistant including carbapenems and colistin. The isolates belonged to three different sequence types namely, ST-11, ST-16 and ST-101. The isolates harboured carbapenemase genes, mainly bla NDM-1 , bla NDM-5 and bla OXA-232 besides extended-spectrum β-lactamases however the colistin resistance gene mcr-1 , mcr-2 and mcr-3 could not be detected. Extensive environmental screening of the ward and healthcare personnel led to the isolation of K. pneumoniae ST101 from filtered incubator water, harboring bla NDM-5 , bla OXA-232 and ESBL genes ( bla CTX-M ) but was negative for the mcr genes. Strict infection control measures were applied and the outbreak was contained. This study emphasizes that early detection of such high-risk clones of multi-drug resistant isolates, surveillance and proper infection control practices are crucial to prevent outbreaks and further spread into the community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pathak, Tejan, Dubey, Chauhan, Fatima, Jyoti, Singh, Bhayana and Sahu.)

Six samarium (III) complexes were synthesised by employing the β-ketocarboxylic acid as main ligand and five N-donor systems as ancillary ligands through the environmentally safe liquid-assisted grinding method. Various characterisation techniques were employed to determine the structure of the complexes i.e. NMR, IR, XRD and SEM. Photoluminescent studies were carried out in solid as well as in solution form. In solid and solution form emission spectra show maximum intensity peak at 604 and 602 nm, respectively, assigned to 4 G 5/2  →  6 H 7/2 transition which explains orange emission on UV excitation in complexes. CCT, CP, colorimetric parameters and quantum yield (relative and intrinsic) of the synthesized complexes were calculated. With the help of reflectance spectra, band gap and Urbach energy were determined. Lasing parameters were also calculated by employing FWHM values obtained from Gaussian fitting. Energy transfer study revealed the efficacious energy transfer from ligand to metal's emissive level. Further antimicrobial studies revealed higher activity in case of complexes in comparison to ligand., (© 2022. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Introduction: Given the negative outcomes associated with uncontrolled diabetes mellitus, non-insulin therapies with glycemic, cardiovascular, and weight-loss benefits in the general population, such as the glucagonlike peptide-1 receptor agonists (GLP1-RA) have become a more alluring therapeutic option in transplant populations. However, limited evidence exists to demonstrate its safety and efficacy in solid organ transplant. Methods: This program evaluation included adult kidney, liver, lung transplant recipients initiated on a GLP1-RA for diabetes mellitus management for a minimum of 3 months, had at least one follow-up visit after starting therapy, and had at least one hemoglobin A1c (HbA1c) level drawn between 3-12 months after GLP1-RA initiation. Outcomes were assessed at time of initiation of GLP1-RA (baseline) and 3-12 months post-initiation. Nadir values between 3-12 months were utilized to assess outcomes. Results: One-hundred eighteen patients met study inclusion criteria. Seventy-percent of patients received a kidney transplant, 19.5% received a liver transplant, and 6.8% received a lung transplant. A statistically significant difference was observed in median fasting blood glucose and HbA1c at baseline to 3-12-month nadir (P < 0.0001). A significant weight loss benefit was also observed. The rate of adverse drug reactions was low. Seven-percent of patients experienced nausea, 4.2% developed pancreatitis, and 7.1% reported having had at least one hypoglycemic event. Discussion: This is the largest study evaluating GLP1-RA in organ transplantation and demonstrates GLP1-RA is both safe and effective. Further assessment on long-term use of these agents on cardiovascular and renal outcomes is still needed.

Chronic kidney disease (CKD) can progress to kidney failure and require dialysis or transplantation, while early diagnosis can alter the course of disease and lead to better outcomes in both pediatric and adult patients. Significant CKD comorbidities include the manifestation of cardiovascular disease, heart failure, coronary disease, and hypertension. The pathogenesis of chronic kidney diseases can present as subtle and especially difficult to distinguish between different glomerular pathologies. Early detection of adult and pediatric CKD and detailed mechanistic understanding of the kidney damage can be helpful in delaying or curtailing disease progression via precise intervention toward diagnosis and prognosis. Clinically, serum creatinine and albumin levels can be indicative of CKD, but often are a lagging indicator only significantly affected once kidney function has severely diminished. The evolution of proteomics and mass spectrometry technologies has begun to provide a powerful research tool in defining these mechanisms and identifying novel biomarkers of CKD. Many of the same challenges and advances in proteomics apply to adult and pediatric patient populations. Additionally, proteomic analysis of adult CKD patients can be transferred directly toward advancing our knowledge of pediatric CKD as well. In this review, we highlight applications of proteomics that have yielded such biomarkers as PLA2R, SEMA3B, and other markers of membranous nephropathy as well as KIM-1, MCP-1, and NGAL in lupus nephritis among other potential diagnostic and prognostic markers. The potential for improving the clinical toolkit toward better treatment of pediatric kidney diseases is significantly aided by current and future development of proteomic applications., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Children with malignancies are facing new challenges in post-COVID-19 era. We report an interesting case of a child on treatment for acute lymphoblastic leukemia having a very protracted course of illness with complications not often seen with standard therapy. It intends to make pediatric oncologists and intensive care specialists wary of potential newer complications., How to Cite This Article: Bhayana S, Kalra M, Sachdeva P, Sachdev A, Sachdeva A. Unique Challenges Faced by a Child with Standard Risk Leukemia in Post-COVID Era: A Case Report. Indian J Crit Care Med 2022;26(6):733-735., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; The Author(s).)

Introduction: Recurrent urinary tract infections remain a challenge in solid organ transplant and have a negative impact on morbidity/mortality., Project Aim: The purpose of this program evaluation was to determine the impact of methenamine on recurrent urinary tract infection in kidney and liver-kidney transplant recipients., Design: This retrospective review included patients > 18 years of age who received a kidney or liver-kidney transplant. Patients were divided into the following groups: (1) Methenamine therapy initiation received methenamine for ≥ 180 days or (2) Non-methenamine therapy: did not receive recurrent urinary tract infection prophylaxis. A total of 60 patients were included., Results: When comparing outcomes between methenamine therapy initiation and non-methenamine therapy group, a significant reduction in the rate of recurrent urinary tract infection was reported in the methenamine therapy initiation group (0.6 vs 1.3 per 180 patient days follow-up, P = 0.0005). A significant reduction was also noted with rate of asymptomatic bacteriuria, treatment failures, bacteremia, hospitalizations due to recurrent urinary tract infection, multi-drug resistant organism isolated, and the average duration of antibiotic use. A significant difference in the time to failure of methenamine therapy initiation versus non-methenamine therapy is noted up to 180 patient-days follow-up (RR 1.56, P = 0.0019)., Conclusion: This evaluation supported methenamine therapy for recurrent urinary tract infection in kidney and liver-kidney transplant. The most significant impact of methenamine recurrent urinary tract infection was seen in the first 30 days after initiation.

Importance: Aging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans., Objective: To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center in Seattle, Washington, from March 1, 2018, to July 30, 2020. Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 months, and 4 months. Six-minute walk distance and maximal ATP production were assessed using magnetic resonance spectroscopy at baseline and at the end of study at 4 months. The analysis used an intention-to-treat approach., Interventions: Participants were randomized to receive daily oral supplementation with either 1000 mg urolithin A or placebo for 4 months., Main Outcomes and Measures: The primary end point was change from baseline in the 6-minute walk distance and change from baseline to 4 months in maximal ATP production in the hand skeletal muscle. The secondary end points were change in muscle endurance of 2 skeletal muscles (tibialis anterior [TA] in the leg and first dorsal interosseus [FDI] in the hand). Cellular health biomarkers were investigated via plasma metabolomics. Adverse events were recorded and compared between the 2 groups during the intervention period., Results: A total of 66 participants were randomized to either the urolithin A (n = 33) or the placebo (n = 33) intervention group. These participants had a mean (SD) age of 71.7 (4.94) years, were predominantly women (50 [75.8%]), and were all White individuals. Urolithin A, compared with placebo, significantly improved muscle endurance (ie, increase in the number of muscle contractions until fatigue from baseline) in the FDI and TA at 2 months (urolithin A: FDI, 95.3 [115.5] and TA, 41.4 [65.5]; placebo: FDI, 11.6 [147.4] and TA, 5.7 [127.1]). Plasma levels of several acylcarnitines, ceramides, and C-reactive protein were decreased by urolithin A, compared with placebo, at 4 months (baseline vs 4 mo: urolithin A, 2.14 [2.15] vs 2.07 [1.46]; placebo, 2.17 [2.52] vs 2.65 [1.86]). The mean (SD) increase from baseline in the 6-minute walk distance was 60.8 (67.2) m in the urolithin A group and 42.5 (73.3) m in the placebo group. The mean (SD) change from baseline to 4 months in maximal ATP production in the FDI was 0.07 (0.23) mM/s in the urolithin A group and 0.06 (0.20) mM/s in the placebo group; for the TA, it was -0.03 (0.10) mM/s in the urolithin A group and 0.03 (0.10) mM/s in the placebo group. These results showed no significant improvement with urolithin A supplementation compared with placebo. No statistical differences in adverse events were observed between the 2 groups., Conclusions and Relevance: This randomized clinical trial found that urolithin A supplementation was safe and well tolerated in the assessed population. Although the improvements in the 6-minute walk distance and maximal ATP production in the hand muscle were not significant in the urolithin A group vs the placebo group, long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers, suggesting that urolithin A may counteract age-associated muscle decline; however, future work is needed to confirm this finding., Trial Registration: ClinicalTrials.gov Identifier: NCT03283462.

The present scenario of agricultural sector is dependent hugely on the use of chemical-based fertilizers and pesticides that impact the nutritional quality, health status, and productivity of the crops. Moreover, continuous release of these chemical inputs causes toxic compounds such as metals to accumulate in the soil and move to the plants with prolonged exposure, which ultimately impact the human health. Hence, it becomes necessary to bring out the alternatives to chemical pesticides/fertilizers for improvement of agricultural outputs. The rhizosphere of plant is an important niche with abundant microorganisms residing in it. They possess the properties of plant growth promotion, disease suppression, removal of toxic compounds, and assimilating nutrients to plants. Utilizing such beneficial microbes for crop productivity presents an efficient way to modulate the crop yield and productivity by maintaining healthy status and quality of the plants through bioformulations. To understand these microbial formulation compositions, it becomes essential to understand the processes going on in the rhizosphere as well as their concrete identification for better utilization of the microbial diversity such as plant growth-promoting bacteria and arbuscular mycorrhizal fungi. Hence, with this background, the present review article highlights the plant microbiome aboveground and belowground, importance of microbial inoculants in various plant species, and their subsequent interactive mechanisms for sustainable agriculture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Vishwakarma, Kumar, Shandilya, Mohapatra, Bhayana and Varma.)

The effects of two different mitochondrial-targeted drugs, SS-31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload. Metabolomic analysis revealed that both NMN and the Combined treatment increased nicotinamide and 1-methylnicotinamide levels, indicating greater NAD + turnover, but only the Combined treatment resulted in significantly greater steady-state NAD(H) levels. A novel magnetic resonance spectroscopy approach was used to assess how metabolite levels responded to changing cardiac workload. PCr/ATP decreased in response to increased workload in Old Control, but not Young, hearts, indicating an age-related decline in energetic capacity. Both drugs were able to normalize the PCr/ATP dynamics. SS-31 and NMN treatment also increased mitochondrial NAD(P)H production under the higher workload, while only NMN increased NAD + in response to increased work. These measures did not shift in hearts given the Combined treatment, which may be owed to the enhanced NAD(H) levels in the resting state after this treatment. Overall, these results indicate that both drugs are effective at restoring different aspects of mitochondrial and heart health and that combining them results in a synergistic effect that rejuvenates Old hearts and best recapitulates the Young state., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Nuclear radiation and radioactive fallouts resulting from a nuclear weapon detonation or reactor accidents could result in injuries affecting multiple sensitive organs, defined as acute radiation syndrome (ARS). Rapid and early estimation of injuries to sensitive organs using markers of radiation response is critical for identifying individuals who could potentially exhibit ARS; however, there are currently no biodosimetry assays approved for human use. We developed a sensitive microRNA (miRNA)-based blood test for radiation dose reconstruction with ±0.5 Gy resolution at critical dose range. Radiation dose-dependent changes in miR-150-5p in blood were internally normalized by a miRNA, miR-23a-3p , that was nonresponsive to radiation. miR-23a-3p was not highly expressed in blood cells but was abundant in circulation and was released primarily from the lung. Our assay showed the capability for dose estimation within hours to 1 week after exposure using a drop of blood from mice. We tested this biodosimetry assay for estimation of absorbed ionizing radiation dose in mice of varying ages and after exposure to both improvised nuclear device (IND)-spectrum neutrons and gamma rays. Leukemia specimens from patients exposed to fractionated radiation showed depletion of miR-150-5p in blood. We bridged the exposure of these patients to fractionated radiation by comparing responses after fractionated versus single acute exposure in mice. Although validation in nonhuman primates is needed, this proof-of-concept study suggests the potential utility of this assay in radiation disaster management and clinical applications., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The NanoString nCounter System has been widely used in basic science and translational science research for the past decade. The System consists of two instruments: the PrepStation and the Digital Analyzer, and both have been continuously improved with evolving technologies. A great amount of research data have been generated at multiple research laboratories with the employment of different generations of the System. With the need of integrating multiple datasets, researchers are interested to know whether signals are comparable between different generations of the System. Toward this end, we designed a profiling study to compare performance of two generations of the NanoString nCounter System using a common set of biological samples. Using graphical tools and statistical models, we found that two different generations of NanoString nCounter System produced equivalent signals and signal deviations are in the range of random background noises for the medium-high expression levels., Competing Interests: The authors have declared that no competing interests exist.

Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin α4β1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. This liposomal contrast agent has a high T1 relaxivity (~2 × 10 5  mM -1 s -1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE -/- mice on a 1 Tesla small animal MRI scanner. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event.

Radiation nephropathy is one of the common late effects in cancer survivors who received radiotherapy as well as in victims of radiation accidents. The clinical manifestations of radiation nephropathy occur months after exposure. To date, there are no known early biomarkers to predict the future development of radiation nephropathy. This study focuses on the development of urinary biomarkers providing readout of acute responses in renal tubular epithelial cells. An amplification-free hybridization-based nCounter assay was used to detect changes in mouse urinary miRNAs after irradiation. After a single LD 50 of total-body irradiation (TBI) or clinically relevant fractionated doses (2 Gy twice daily for 3 days), changes in urinary levels of microRNAs followed either an early pattern, peaking at 6-8 h postirradiation and gradually declining, or later pattern, peaking from 24 h to 7 days. Of 600 miRNAs compared, 12 urinary miRNAs showed the acute response and seven showed the late response, common to both irradiation protocols. miR-1224 and miR-21 were of particular interest, since they were the most robust acute and late responders, respectively. The early responding miR-1224 also exhibited good dose response after 2, 4, 6 and 8 Gy TBI, indicating its potential use as a biomarker for radiation exposure. In situ hybridization of irradiated mouse kidney sections and cultured mouse primary renal tubular cells confirmed the tubular origin of miR-1224. A significant upregulation in hsa-miR-1224-3p expression was also observed in human proximal renal tubular cells after irradiation. Consistent with mouse urine data, a similar expression pattern of hsa-miR-1224-3p and hsa-miR-21 were observed in urine samples collected from human leukemia patients preconditioned with TBI. This proof-of-concept study shows the potential translational utility of urinary miRNA biomarkers for radiation damage in renal tubules with possible prediction of late effects.

Introduction: Non-invasive 3D imaging that enables clear visualization of placental margins is of interest in the accurate diagnosis of placental pathologies. This study investigated if contrast-enhanced MRI performed using a liposomal gadolinium blood-pool contrast agent (liposomal-Gd) enables clear visualization of the placental margins and the placental-myometrial interface (retroplacental space). Non-contrast MRI and contrast-enhanced MRI using a clinically approved conventional contrast agent were used as comparators., Materials and Methods: Studies were performed in pregnant rats under an approved protocol. MRI was performed at 1T using a permanent magnet small animal scanner. Pre-contrast and post-liposomal-Gd contrast images were acquired using T1-weighted and T2-weighted sequences. Dynamic Contrast enhanced MRI (DCE-MRI) was performed using gadoterate meglumine (Gd-DOTA, Dotarem ® ). Visualization of the retroplacental clear space, a marker of normal placentation, was judged by a trained radiologist. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated for both single and averaged acquisitions. Images were reviewed by a radiologist and scored for the visualization of placental features. Contrast-enhanced CT (CE-CT) imaging using a liposomal CT agent was performed for confirmation of the MR findings. Transplacental transport of liposomal-Gd was evaluated by post-mortem elemental analysis of tissues. Ex-vivo studies in perfused human placentae from normal, GDM, and IUGR pregnancies evaluated the transport of liposomal agent across the human placental barrier., Results: Post-contrast T1w images acquired with liposomal-Gd demonstrated significantly higher SNR (p = 0.0002) in the placenta compared to pre-contrast images (28.0 ± 4.7 vs. 6.9 ± 1.8). No significant differences (p = 0.39) were noted between SNR in pre-contrast and post-contrast liposomal-Gd images of the amniotic fluid, indicating absence of transplacental passage of the agent. The placental margins were significantly (p < 0.001) better visualized on post-contrast liposomal-Gd images. DCE-MRI with the conventional Gd agent demonstrated retrograde opacification of the placenta from fetal edge to the myometrium, consistent with the anatomy of the rat placenta. However, no consistent and reproducible visualization of the retroplacental space was demonstrated on the conventional Gd-enhanced images. The retroplacental space was only visualized on post-contrast T1w images acquired using the liposomal agent (SNR = 15.5 ± 3.4) as a sharply defined, hypo-enhanced interface. The retroplacental space was also visible as a similar hypo-enhancing interface on CE-CT images acquired using a liposomal CT contrast agent. Tissue analysis demonstrated undetectably low transplacental permeation of liposomal-Gd, and was confirmed by lack of permeation through a perfused human placental model., Conclusions: Contrast-enhanced T1w-MRI performed using liposomal-Gd enabled clear visualization of placental margins and delineation of the retroplacental space from the rest of the placenta; the space is undetectable on non-contrast imaging and on post-contrast T1w images acquired using a conventional, clinically approved Gd chelate contrast agent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Mammalian target of rapamycin (mTOR) inhibitors are increasingly used as immunosuppressive agents in kidney transplantation. In the experimental setting it has been shown that mTOR inhibitors promote autophagy, but the concept that this might also occur in transplant patients has not been addressed., Objectives: This study was designed to investigate the association between mTOR inhibition and autophagy in renal transplants under routine clinical conditions., Materials and Methods: Protocol transplant biopsies of patients receiving sirolimus were compared to biopsies of patients treated without mTOR inhibitor. Electron microscopy was used for quantitative stereological analysis of autophagosomal volume fractions. Ultrastructural analysis was focused on podocytes to avoid cell type bias. Autophagy-related gene products were profiled by QPCR from laser assisted microdissected glomeruli and by immunohistochemistry for semiquantitative evaluation., Results: By electron microscopy, we observed a significant > 50% increase in podocytic autophagosomal volume fractions in patients treated with sirolimus. Evaluation of biopsy material from the same patients using transcriptional profiling of laser capture microdissected glomeruli revealed no differences in autophagy-related gene expressions. Immunohistochemical evaluation of autophagic degradation product p62 was also unaltered whereas a significant increase was observed in podocytic LC3 positivity in biopsies of sirolimus treated patients., Conclusions: These results indicate an association of sirolimus treatment and autophagosome formation in transplant patients. However, they might reflect autophagosomal buildup rather than increased autophagic flux. Further research is needed to investigate the potential functional consequences in short- and long-term outcome of patients treated with mTOR inhibitors.

Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after γ-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.

Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Δ) (flox/) (Δ) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Δ) (flox/) (Δ) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD., (Copyright © 2016 by the American Society of Nephrology.)

Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease., (Copyright © 2015 by the American Society of Nephrology.)

The aim of the study was to compare intravitreal bevacizumab (IVB) and posterior subtenon triamcinolone (PST) as an adjunct to laser treatment in diffuse diabetic macular edema (Diffuse DME). Prospective-randomized control trial of 30 eyes of 30 diabetic patients having Diffuse DME with maximum retinal thickness (MRT) was more than or equal to 350 µm. The subjects were randomly allocated into two groups. Group A (12 eyes) received IVB and group B received PST (18 patients) before laser treatment. Grid laser treatment was done when the MRT decreased to less than 350 µm. OCT thickness-guided repeat injections were given if required. The patients had minimum follow-up of 6 months. At 6-month follow-up, the two groups were compared for (1) Maximum change in visual acuity letter score using logMAR chart (2) Reduction in MRT on OCT. The mean logMAR visual acuity at baseline was 0.63 ± 0.45 (0-1.6) in group A and was 0.76 ± 0.38 (0.2-1.3) in group B. The mean logMAR visual acuity at 6 month in group A was 0.34 ± 0.21 (0-0.6) and in group B was 0.64 ± 0.37 (0.3-1.3). The mean visual acuity at last follow-up was significantly better in group A than group B (p = 0.02). The mean change in MRT in Group A and Group B was 177.8 ± 85.64 and 156.07 ± 102.86, respectively, which was significantly better than the baseline in both the groups and was comparable in both groups. The study provides evidence to support the use of IVB over PST in diffuse diabetic macular edema.

Objective: To study factors leading to mortality or hospitalization in children with Down syndrome and its effect on the quality of life of their parents., Methods: The study was retrospective questionnaire based study conducted over 2 mo period at a genetic outpatient setting of a teaching medical college hospital. Seventy children with suggestive phenotype and confirmed Trisomy 21 on karyotyping were included. An essential criterion was a reasonable understanding of the language to construct history. The primary outcome variable evaluated was the co-morbidity in these children which led to either hospitalization or mortality. Pretested and validated questionnaire was given to parents/primary caregiver and data was constructed with help of previous hospital records or from verbal autopsy in patients who had lost all papers., Results: The mean age of Down syndrome (DS) patients in study group was 5.09 ± 2.5 y. All cases were diagnosed postnatally at a mean age of 5 y. The major reasons for hospitalization were congenital heart disease (cyanotic/acyanotic), multiple episodes of pneumonia and wheeze associated with lower respiratory infection. Cardiovascular failure was the major reason for mortality. Majority of parents in the study (57.5 %) agreed that there were changes requiring adaptation after the birth of a DS baby while 22.5 % reported this effort to cost them heavily and 3 % quoted that this had changed the life drastically., Conclusions: Cardiorespiratory system is major cause of morbidity/mortality in cases with DS. Majority of parents accepted the challenge of rearing a DS child but with adaptation.

Importance: There are reports in the literature of anaplastic thyroid carcinoma in cervical lymph nodes with evidence of only papillary carcinoma in the thyroid gland. There have been no cases of this clinical scenario with only papillary microcarcinoma in the thyroid gland., Observations: We describe the case of a 60-year-old man who initially presented with an enlarged right, level 5, supraclavicular lymph node. Initial fine-needle aspiration demonstrated evidence of papillary thyroid carcinoma. The final pathologic finding in the thyroid gland showed only multiple foci of papillary thyroid microcarcinoma. The index neck mass showed evidence of anaplastic thyroid carcinoma., Conclusions and Relevance: This is the first instance in the literature in which anaplastic thyroid carcinoma has appeared in metastatic cervical lymph nodes with only a focus of papillary microcarcinoma in the thyroid gland. With this case, we hope to build awareness of this rare finding.

Background: To optimize available organs, kidneys from young donors traditionally believed to be suboptimal are transplanted to adults. The purpose of this study is to compare graft survival (GS) of en bloc kidney (EBK) from young pediatric donors to other deceased donor transplants in adult recipients., Methods: We analyzed United Network of Organ Sharing/STAR data on primary deceased donor kidney transplants to adult recipients (1988-2006). EBK (age younger than 5 years, n=1696) was compared with solitary pediatric (SP; age younger than 5 years) kidneys (n=1502), and matched standard adult donors (age 18-59 years, n=9594) and expanded criteria donor (ECD; n=6396). The adjusted GS was obtained using Cox proportional hazard model and hazard ratios were calculated., Results: EBK had lowest acute rejection rates (6.0%) but similar to standard adult transplants (6.3%), and lower than SP and ECD (9.0% and 8.2%; P<0.0001). Delayed graft function rates were lowest in EBK (17.9%), highest in ECD (34.8%; P<0.0001), and similar among SP and standard adult transplants (24.4% and 24.2%). The estimated glomerular filtration rate (eGFR) was best in EBK and worst in ECD (P<0.0001). The eGFR of EBK and SP transplants continuously improved but the eGFR of standard adult and ECD declined. Graft loss was higher in EBK and SP transplants than adult donor transplants during the first 6 months. Despite the highest thrombosis rates in EBK (5.0%) (SP, 3.3%; standard adult, 1.8%; ECD, 2.0%, P<0.0001), GS of EBK became similar to standard adult donor transplants by 5 years and best at 10 years posttransplant (64.0%) and worst in ECD (39.6%; P<0.0001)., Conclusion: EBK had the best long-term outcomes among deceased donor transplants and offer unique options for adult kidney transplant recipients.

Congenital erythropoietic porphyria (Gunther's disease) is one of the least common porphyrias. This article describes the life and career of Hans Gunther (after whom the disease is named), his contributions to the field of porphyrias and the current understanding of Gunther's disease.

Context: Persistently elevated GH and IGF-I levels are associated with increased mortality. Their response to somatostatin analogs (SSA) is variable., Objective: The objective of this study was to examine the significance of somatotroph adenoma type on response to SSA., Design: This study was a retrospective examination of postoperatively treated acromegalic patients with the SSA octreotide., Setting: The study was performed at a university-affiliated tertiary care center., Patients: Forty patients with acromegaly were studied., Main Outcome Measures: Normalization of IGF-I levels and GH responses were the main outcome measures., Results: Univariate analysis revealed that responders were more likely to have densely granulated somatotroph adenomas (80% vs. 43.8%; P = 0.024), to be older (51.3 vs. 38.2 yr; P < 0.003), to have smaller tumors (stage < or =3; 78.6% vs. 35.7%; P = 0.022), to have lower baseline IGF-I (453 vs. 716 microg/liter; P < 0.001) and GH levels (2.7 vs. 7.8 microg/liter; P < 0.05), and to require a lower maximum dose of SSA (24 vs. 31 mg every 4 wk; P = 0.013). Multivariate analysis confirmed that a densely granulated adenoma was the strongest predictor of complete response [adjusted odds ratio (OR), 58.41; 95% confidence interval (CI), 1.24-1000.00; P = 0.04] compared with other covariates, including older age at time of diagnosis (OR, 1.15/yr; 95% CI, 1.01-1.31; P = 0.03), and tumor stage of 3 or less (OR, 29.77; 95% CI, 1.01-885.45; P < 0.05)., Conclusions: Somatotroph tumor type represents a strong clinical predictor of response to SSA treatment and will help to identify patients who warrant more vigilant management of their disease.

Objectives: Hyperinsulinemia is often associated with a cluster of metabolic abnormalities, which usually presents before the onset of frank diabetes. Lipodystrophy syndromes are frequently associated with hyperinsulinemia and may act as models for insulin resistance. Lipodystrophy is characterized in broad terms by loss of subcutaneous adipose tissue. Despite heterogeneous causes, which include both genetic and acquired forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes., Results: Recently, the molecular basis of two genetic forms of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD; MIM 151660) and Berardinelli-Seip complete lipodystrophy (BSCL; MIM 269700) have been reported. There is evidence for genetic heterogeneity for both types of lipodystrophy. In addition, murine models of lipodystrophy have provided key insights into alterations of metabolic pathways in lipodystrophy., Conclusions: Delineation of the human molecular genetic basis of two distinct forms of inherited lipodystrophy may have relevance for the common insulin resistance syndrome and for acquired lipodystrophy syndromes.

Background: Primary meningeal melanomas of the central nervous system (CNS) are a rare malignant process with the majority originating from the leptomeninges. Primary dural melanomas have been reported to occur in isolation or in conjunction with Nevus of Ota. The association of primary dural melanoma with multiple cutaneous blue nevi has not been reported previously., Objective: To describe a case of a 41-year-old Asian woman patient with a primary dural melanoma that arose in association with ocular melanosis and multiple cutaneous blue nevi. The patient is alive almost more than 8 years after subtotal and subsequent total resection of her primary tumor. Primary dural melanomas, Nevus of Ota, and blue nevi are discussed in relation to their coexistence and potential for intracranial melanoma., Conclusion: CNS melanoma is regarded as an extremely aggressive disease with poor prognosis. This case and previous reports of dural melanomas occurring in isolation or with Nevus of Ota have demonstrated relatively prolonged survival after surgical intervention. We conclude that dural melanomas are less aggressive tumors requiring surgical extirpation only.

We previously reported nine children with an autosomally recessive form of congenital hypothyroidism due to an iodide transport defect in a large Hutterite family with extensive consanguinity living in central Canada. Since the original report, we have diagnosed congenital hypothyroidism by newborn TSH screening in 9 additional children from the family. We performed direct sequencing of the PCR products of each NIS (sodium/iodide symporter) gene exon with flanking introns amplified from genomic DNA extracted from peripheral blood cells of the patients. We identified a novel NIS gene mutation, G395R (Gly395-->Arg; GGA-->AGA), in 10 patients examined in the present study. All of the parents tested were heterozygous for the mutation, suggesting that the patients were homozygous. The mutation was located in the 10th transmembrane helix. Expression experiments by transfection of the mutant NIS complimentary DNA into COS-7 cells showed no perchlorate-sensitive iodide uptake, confirming that the mutation is the direct cause of the iodide transport defect in these patients. A patient who showed an intermediate saliva/serum technetium ratio (14.0; normal, > or = 20) and was considered to have a partial or less severe defect in the previous report (IX-24) did not have a NIS gene mutation. It is now possible to use gene diagnostics of this unique NIS mutation to identify patients with congenital hypothyroidism due to an iodide transport defect in this family and to determine the carrier state of potential parents for genetic counseling and arranging rapid and early diagnosis of their infants.