Serum Prolidase Activity and Oxidative Stress in Diabetic Nephropathy and End Stage Renal Disease: A Correlative Study with Glucose and Creatinine

Association of oxidative stress and serum prolidase activity (SPA) has been reported in many chronic diseases. The study was aimed at evaluating the correlation of glucose and creatinine to SPA and oxidative stress in patients with diabetic nephropathy (DN) and end stage renal disease (ESRD) concerned with T2DM. 50 healthy volunteers, 50 patients with T2DM, 86 patients with DN, and 43 patients with ESRD were considered as control-1, control-2, case-1, and case-2, respectively. Blood glucose, creatinine, SPA, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were measured by colorimetric tests. SPA, TOS, and OSI were significantly increased in case-1 and case-2 than control-1 and control-2, while TAS was significantly decreased (P<0.001). Blood glucose was linearly correlated to SPA, TOS, TAS, and OSI in control-2, case-1 and case-2 (P<0.001). Serum creatinine was linearly correlated with SPA, TOS, TAS and OSI in control-2 and case-1 (P<0.001). In case-2, serum creatinine was significantly correlated with SPA only (P<0.001). Thus, the study concluded that SPA and oxidative stress significantly correlated with blood glucose and creatinine. SPA, TOS, TAS, and OSI can be used as biomarkers for diagnosis of kidney damage

Oscillatory spin-orbit torque switching induced by field-like torques

Deterministic magnetization switching using spin-orbit torque (SOT) has recently emerged as an efficient means to electrically control the magnetic state of ultrathin magnets. The SOT switching still lacks in oscillatory switching characteristics over time, therefore, it is limited to bipolar operation where a change in polarity of the applied current or field is required for bistable switching. The coherent rotation based oscillatory switching schemes cannot be applied to SOT because the SOT switching occurs through expansion of magnetic domains. Here, we experimentally achieve oscillatory switching in incoherent SOT process by controlling domain wall dynamics. We find that a large field-like component can dynamically influence the domain wall chirality which determines the direction of SOT switching. Consequently, under nanosecond current pulses, the magnetization switches alternatively between the two stable states. By utilizing this oscillatory switching behavior we demonstrate a unipolar deterministic SOT switching scheme by controlling the current pulse duration

ARL3 mutations cause Joubert syndrome by disrupting ciliary protein composition

Joubert syndrome (JBTS) is a genetically heterogeneous autosomal recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTSrelated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997-109106128 (hg 19)), and exome sequencing revealed two missense variants in ARL3 within the candidate locus. The encoded protein, ADP Ribosylation Factor-Like GTPase 3, ARL3, is a small GTP-binding protein that is involved in directing lipid-modified proteins into the cilium in a GTP-dependent manner. Both missense variants replace the highly conserved Arg149 residue, which we show to be necessary for the interaction with its guanine nucleotide exchange factor ARL13B, such that the mutant protein is associated with reduced INPP5E and NPHP3 localisation in cilia. We propose that ARL3 provides a potential hub in the network of encoded ciliopathy genes, whereby perturbation of ARL3 results in the mislocalisation of multiple ciliary proteins due to abnormal displacement of lipidated protein cargo

SGLT2-Inhibition in patients with Alport syndrome

Introduction Large-scale trials showed positive outcomes of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome has not yet been investigated specifically in larger cohorts. Methods This observational, multi-center, international study (NCT02378805) assessed 112 patients with Alport syndrome after start of SGLT2i. The study’s primary endpoint was change of albuminuria in albumin/gram creatinine from start of therapy. Results Compared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (38±14 years) and had a better estimated glomerular filtration rate, eGFR, (63±35 ml/min/1.73m2; n=98). Maximum follow up was 32 months. Compared to baseline, at the first three follow-up visits (months 1 to 3, 4 to 8 and 9 to 15) after initiation of SGLT2i-therapy, a significant reduction of albuminuria in milligrams albumin/gram creatinine (>30%) was observed. Mean loss of eGFR was 9±12 ml/min/1.73 m2 almost one year after initiation of SGLT2i-therapy (n=35). At a total of 71 patient-years at risk, 0.24 adverse events per patient year on SGLT2i were reported. Conclusion This study indicates that, additive to RAS-inhibition, SGLT2i have the potential to reduce the amount of albuminuria in patients with Alport syndrome. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with Alport syndrome to assess whether the observed reduction in albuminuria translates to a delay in kidney failure

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Background: Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. Methods: People aged 0–96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan–Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). Findings: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9–16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32–0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Interpretation: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3–5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. Funding: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

INVESTIGATION OF MATERIALS AND ANALYSIS TECHNIQUES FOR PERFORMANCE ENHANCEMENT OF PERPENDICULAR MAGNETIC TUNNEL JUNCTIONS

Ph.DDOCTOR OF PHILOSOPH

Asymptotic efficiency properties of least squares in an ultrastructural model

Measurement errors, direct regression, reverse regression, ultrastructural model, 62J05, 62F12,

Giant cell Granuloma: Histological comparison and a review

Central giant cell granulomas (CGCG) constitute about 10% of benign jawbone lesions. Approximately one-third of CGCG exhibit local aggressive behavior with bone destruction and a tendency to recur.1 Jaffe (1953) was the first to distinguish central giant cell granulomas (CGCG) of the jawbones from other giant cell lesions of bones and originally called them“central giant cell reparative granulomas” since they were believed to be a reactive-reparative process that might heal spontaneously.1 Recently the World Health Organization has defined it as localized benign but sometimes aggressive osteolytic proliferation consisting of fibrous tissue with hemorrhage and haemosiderin depo­sits, presence of osteoclast-like giant cells and reactive bone formation. Many authors have established the differences with other lesions of giant cells. The clinical behavior of CGCG varies from a slowly asymptomatic swelling to an aggressive lesion that manifests with pain, cortical perforation, and root resorption.2 On the other hand the peripheral giant cell granuloma is a reactive exophytic lesion of the gingiva and alveolar ridge that usually occurs as a result of local irritating factors such as plaque, calculus, chronic infection, chronic irritation, tooth extraction, inproperly finished filling, unstable dental prosthesis, and impacted food which originates from the periosteium or periodontal ligament.&nbsp

Many Genes—One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders

Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required