Bacterial infection-related glomerulonephritis in patients with diabetes.

AIM: Diabetic patients are prone to infections, thus making them a unique cohort at risk of developing bacterial infection-related glomerulonephritis (IRGN). METHODS: In total, 1693 adult diabetic patients underwent kidney biopsy between 2005 and 2021 at our tertiary care hospital in South India. Of these, 121 consecutive cases which met criteria of bacterial IRGN were included in this study. RESULTS: The mean age of the cohort was 53.1 ± 10.1 years and 83/121 (68.5%) were males. Majority (98.3%) had type 2 diabetes for a median duration of 6 (IQR, 2-12) years. The most common sites of infection were skin (47/121, 38.8%) and urinary tract (15/121, 12.4%). Fifty percent (58/121) of patients had underlying advanced diabetic kidney disease (DKD). Isolated C3 deposits (without immunoglobulin) occurred in 66/121 (54.5%) patients predominantly in advanced DKD patients. IgA-dominant glomerulonephritis occurred in only 9/121 (7.4%) patients. Short-course oral steroid was given to 86/121 (71.1%) patients. Steroid related dysglycemia and immunosuppression related infections occurred in 9/61 (14.8%) and 16/61 (26.2%) patients respectively. Of the 90 patients with follow up details >3 months, 46 (51.1%) progressed to kidney failure over a median period of 0.5 (IQR, 0-7.2) months. Patients diagnosed in the latter half of our study period (2013-2021) were older, less commonly presented with fever, had more pronounced hypocomplementemia and severe renal histology predominantly with a 'starry sky' immunofluorescence pattern. CONCLUSION: Superimposed bacterial IRGN on underlying DKD is associated with poor renal outcomes. Use of short course steroid was associated with significant toxicity.

Profile, Risk Factors, and Outcomes of Asymptomatic Bacteriuria in Kidney Transplant Recipients with Normal Pretransplant Genitourinary Tract: A Single-Center Experience.

Introduction: There is a paucity of studies on asymptomatic bacteriuria (ASB) among kidney transplant recipients (KTR) in developing countries. This study assessed the clinical profile, risk factors, outcomes, and impact of treatment of ASB in KTRs with a normal genitourinary tract. Methods: Consecutive KTRs from 2009 to 2018 with no clinical or radiological evidence of obstructive uropathy were included. Urinary tract infection (UTI) after ASB was defined as occurrence of cystitis, pyelonephritis, or urosepsis, with ASB being the first bacteriuric episode. Results: Seven hundred ten out of 794 patients with median follow up of 47 months were included. The mean age was 35.5 ± 12 years. Eighty-one patients (11.4%) developed ASB at a median of 25 days (IQR 10, 134.5). Fifty-three percent and 4.9% of ASB episodes were extended-spectrum beta-lactamase (ESBL) positive and carbapenem-resistant organisms, respectively. Eighteen patients (32.1%) with early ASB (<3 months) and 5 (20%) with late ASB developed UTI on follow-up. Fifty-five percent of early and 16% of late ASB episodes were treated, with no significant difference observed in the risk of development of UTI when compared to untreated ASB episodes. Conclusion: The incidence of ASB as first bacteriuric episode in our cohort was 11.4%, with there being significant antimicrobial resistance. Female gender, pretransplant UTI, and delayed graft function were independently associated with development of ASB. Treatment of ASB episodes either early or late did not decrease the risk of development of UTI.

Allantoin alleviates chromium phytotoxic effects on wheat by regulating osmolyte accumulation, secondary metabolism, ROS homeostasis and nutrient acquisition.

Allantoin is a nitrogen metabolite with significant potential to mediate plant defense responses under salinity. However, the impact of allantoin on ions homeostasis and ROS metabolism has yet to be established in plants under Cr toxicity. In the current study, chromium (Cr) notably diminished growth, photosynthetic pigments, and nutrient acquisition in two wheat cultivars (Galaxy-2013 and Anaj-2017). Plants subjected to Cr toxicity displayed excessive Cr accumulation. Chromium produced substantial oxidative stress reflected as higher levels of O2•, H2O2, MDA, methylglyoxal (MG) and lipoxygenase activity. Plants manifested marginally raised antioxidant enzyme activities due to Cr stress. Further, reduced glutathione (GSH) levels diminished with a concurrent rise in oxidized glutathione levels (GSSG). Plants exhibited a considerable abridge in GSH:GSSG due to Cr toxicity. Allantoin (200 and 300 mg L1) subsided metal phytotoxic effects by strengthening the activities of antioxidant enzymes and levels of antioxidant compounds. Plants administered allantoin displayed a considerable rise in endogenous H2S and nitric oxide (NO) levels that, in turn, lessened oxidative injury in Cr-stressed plants. Allantoin diminished membrane damage and improved nutrient acquisition under Cr stress. Allantoin markedly regulated the uptake and distribution of Cr in wheat plants, abridging the degree of metal phytotoxic effect.

When to Suspect Non-diabetic Kidney Disease in a Diabetic Patient?

The diagnosis of non-diabetic kidney disease (NDKD) in a diabetic patient has significant therapeutic and prognostic implications. There are certain proven clinical predictors of NDKD, which, when present in an appropriate clinical setting, would warrant a kidney biopsy. Herein, we describe four cases of NDKD diagnosed in rather unusual clinical settings, which add to the list of clinical predictors of NDKD. The first case was a "parainfectious glomerulonephritis" diagnosed in a 50-year-old diabetic woman who presented with persistent renal dysfunction despite successful treatment of urinary tract infection. The second case was "membranous nephropathy" diagnosed in a 43-year-old man with long-standing type 1 diabetes, which was associated with other microvascular complications. In this case, the only predictor was disproportionately low serum albumin. The third case was "amyloid light chain (AL) amyloidosis" diagnosed in an elderly diabetic who presented with progressive anasarca over six months. In this case, the only clinical predictor was a disassociation observed between urine dipstick and 24-hour protein estimation. In the fourth case, an elderly diabetic woman without underlying diabetic retinopathy presented with sudden onset nephrotic syndrome. A kidney biopsy was suggestive of diffuse nodular glomerulosclerosis. Immunofluorescence and electron microscopic evaluation were diagnostic of "gamma heavy chain deposition disease." In all four cases, diagnosis of NDKD led to major therapeutic changes and attainment of renal remission. We have extensively reviewed all major biopsy cohorts of NDKD and have formulated an approach to the diagnosis of NDKD.

IL-6-174 G/C and ApoE gene polymorphisms in Alzheimer's and vascular dementia patients attending the cognitive disorder clinic of the All India Institute of Medical Sciences, New Delhi.

BACKGROUND: Remarkable improvement in the life expectancy of the Indian population is expected to commensurate with the increase in number of dementia cases. Among various types of dementia, Alzheimer's disease (AD) and vascular dementia (VaD) are common and widely studied. We evaluated the role of apolipoprotein E (ApoE) and interleukin-6 (IL-6)-174 G/C gene polymorphism along with serum IL-6 levels in AD and VaD patients. METHODS: The polymorphisms in ApoE and IL-6-174 G/C genes were assessed using RFLP. Serum IL-6 level was measured by ELISA. RESULTS: The allele ε4 of the ApoE gene was found to be associated with AD and VaD patients (p < 0.05). No association of IL-6-174 G/C polymorphism was observed in AD patients, while the IL-6-174 C allele increased the odds of having VaD twofold. Regression analysis to assess possible interaction between ApoE and the IL-6-174 G/C genes revealed that presence of both the ε4 and C alleles increased the odds of having AD 13.75-fold and VaD 14.7-fold. Serum IL-6 levels did not correlate with either presence or severity of disease among AD or VaD patients. CONCLUSION: The ApoE ε4 allele is an important genetic marker for AD and VaD. Presence of both ApoE ε4 and IL-6 C genes increases the OR of having AD and VaD markedly.

Subclinical inflammation and endothelial dysfunction are linked to cardiac autonomic neuropathy in type 2 diabetes.

PURPOSE: The present study aimed to examine association between inflammatory and endothelial function biomarkers and indices of cardiac autonomic control in T2DM patients. METHODS: 50 T2DM patients were recruited for this study. For cardiac autonomic function, cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV) analysis was performed. Blood samples were collected for evaluating inflammatory and endothelial function biomarkers. Multivariable linear regression analysis adjusted for diabetes duration, glycemic control, waist circumference, hypertension, dyslipidemia, metformin, and statins was performed to examine the association between the biomarkers and cardiac autonomic function parameters. RESULTS: Interleukin-6 was inversely related to total power (p = .009) and low frequency power (p = .04). Interleukin-18 and high sensitivity C-reactive protein inversely correlated with measures of cardiac vagal control (p < .05). Both nitric oxide and endothelial nitric oxide synthase were positively linked with cardiac vagal control indices (p < .05) whereas endothelin-1 did not show any independent association with cardiac autonomic function parameters. CONCLUSIONS: Biomarkers of inflammation and endothelial function are associated with measures of cardiac vagal control and global HRV which suggest that there is some pathophysiological link between subclinical inflammation, endothelial dysfunction and cardiac autonomic dysfunction in T2DM.

Effect of glycemic control and disease duration on cardiac autonomic function and oxidative stress in type 2 diabetes mellitus.

PURPOSE: Cardiac autonomic neuropathy (CAN) is a commonly overlooked complication of type 2 diabetes mellitus (T2DM), with a complex pathogenesis involving hyperglycemia-induced oxidative stress which results in neuronal ischemia and cellular death. The level of hyperglycemia as well as disease duration might be significant determinants of the prognosis of T2DM, but limited studies have explored their relationship with these diabetic complications. Therefore, the purpose of this study was to examine the effect of glycemic control and disease duration on cardiac autonomic function and oxidative stress in patients with T2DM. METHODS: 60 T2DM patients along with 63 healthy controls were recruited for the study. Diabetic patients were further classified based on glycemic control (HbA1c levels <8% vs. ≥8%) and disease duration (<5 vs. 5-10 vs. >10 years). All participants were assessed for cardiac autonomic function (HRR: heart rate recovery; HRV: heart rate variability), levels of antioxidant enzymes (CAT: catalase; SOD: superoxide dismutase), serum nitric oxide (NO) and other cardiometabolic risk factors (resting blood pressure, glycemic and lipid profile). RESULTS: T2DM patients showed a significant reduction in HRR, HRV, CAT, SOD and an increase in LFnu, LF: HF ratio and NO. These impairments were significantly greater for the group with poor glycemic control (p < 0.05). However, no difference for these parameters was observed with respect to different disease durations. CONCLUSION: Cardiac autonomic regulation and endogenous antioxidant defense were compromised and levels of nitric oxide found to be raised in patients with Type 2 diabetes. These findings were more pronounced in subjects with poor glycemic control.

Pre-diagnostic dynamic HPV16 IgG seropositivity and risk of oropharyngeal cancer.

OBJECTIVE: The aim of this study was to determine the association of HPV16 antibodies (Abs) and oropharyngeal cancer (OPC) risk in sera obtained prior to clinical diagnosis. METHODS: We identified 92 participants with incident OPC and 460 matched controls from the Janus Serum Bank Cohort in Norway. Archived tumor specimens were requested for a subset of the cases. Serum samples were collected from cases, on average, 9.3years before diagnosis (range, 0.1-14.9years). Ten cases had serum samples from multiple time points. IgG seropositivity to 8 HPV16 antigens was determined, and a logistic regression classifier of a panel of all early-antigen (EA) Abs for the predictive diagnosis of OPC was applied. RESULTS: HPV16 EA seropositivity was present in 25.0% of patients with OPC and 7.6% of controls (odds ratio (OR), 4.1; 95% CI, 2.3-7.2, p<0.0001). Abs to E2 were strongly associated with cases 0-2years pre- diagnosis (OR, 150.1; 95% CI, 27.4-1040.0, p<0.0001), and the probability of seropositivity was inversely associated with time to diagnosis (OR, 0.7 per additional year; 95% CI, 0.6-0.9, p=0.0002). Abs to E2 were also strongly associated with tumor HPV status (OR, 35.6; 95% CI, 8.7-200.0, p<0.0001). A positive score on the binary classifier was associated with an overall OR of 15.8 (95% CI, 5.6-53.4) compared with controls (p<0.05), and was strongly associated with tumor HPV status (OR, 27.4; 95% CI, 8.6-99.6, p<0.001). CONCLUSIONS: HPV16 Abs are detectable years prior to diagnosis of OPC, and the probability of seropositivity increases closer to diagnosis.

Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers.

PURPOSE: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53-specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. EXPERIMENTAL DESIGN: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum samples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation-specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N- and C-terminal deletions spanning the length of the wild-type p53 protein. RESULTS: We detected p53-AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53-AAb contained broadly reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53-AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N- and C-terminus as well as the DNA-binding domain. CONCLUSION AND CLINICAL RELEVANCE: In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity.

HPV16 antibodies as risk factors for oropharyngeal cancer and their association with tumor HPV and smoking status.

BACKGROUND: Antibodies (Abs) to the HPV16 proteome increase risk for HPV-associated OPC (HPVOPC). The goal of this study was to investigate the association of a panel of HPV16 Abs with risk for OPC as well as the association of these Abs with tumor HPV and smoking status among patients with OPC. METHODS: IgG Abs to the HPV16 antigens E1, E2, E4, E5, E6, E7, L1, L2 were quantified using a programmable ELISA assay. Sera were obtained from 258 OPC patients at diagnosis and 250 healthy controls. HPV16 tumor status was measured by PCR for 137 cases. Multivariable logistic regression was used to calculate odds ratios for the association of HPV16 Abs with risk for OPC. RESULTS: HPV16 E1, E2, E4, E5, E6, E7 and L1-specific IgG levels were elevated in OPC patients compared to healthy controls (p<0.05). After multivariable adjustment, Ab positivity for NE2, CE2, E6, and/or E7 was associated with OPC risk (OR [95% CI], 249.1 [99.3-624.9]). Among patients with OPC, Ab positivity for these antigens was associated with tumor HPV status, especially among never or light smokers (OR [95% CI], 6.5 [2.1-20.1] and OR [95% CI], 17.5 [4.0-77.2], respectively). CONCLUSIONS: Antibodies to HPV16 proteins are associated with increased risk for HPVOPC. Among patients with OPC, HPV16 Abs are associated with tumor HPV status, in particular among HPV positive patients with no or little smoking history.

Biologic predictors of serologic responses to HPV in oropharyngeal cancer: The HOTSPOT study.

OBJECTIVES: We hypothesized that viral and host factors impact the serologic responses to HPV early antigens in HPV-positive oropharyngeal cancer (HPVOPC). MATERIALS AND METHODS: We conducted a multicenter study to measure HPV16-specific IgG among patients with HPVOPC, their long-term sexual partners, and healthy volunteers. Risk factor surveys and rinse and gargle specimens were collected. Peripheral blood samples at diagnosis were evaluated for IgG Abs to HPV16 antigens using a programmable ELISA assay. Predictors for HPV16 serologic responses were evaluated using univariate and multivariable linear regression. RESULTS: 116 patients with HPVOPC, 43 partners, and 81 healthy volunteers were enrolled and had baseline sera for analysis. Cases were primarily male (90%), with a median age of 56 years. Abs to E1, E2, E6 or E7 antigens were detected more often in HPVOPC compared with volunteers or partner sera (p<0.0001). HPV16 Abs to at least one early protein (E1, E2, E4, E5, E6, or E7) were detected in the sera of 90.6% of cases, 0% of partners and 7.4% of healthy volunteers. Gender, race, sexual behavior, and viral integration were not associated with antibody response. Younger age and higher oral HPV16 copy number were associated with higher HPV16 E6 and NE2 antibody levels. CONCLUSIONS: HPV16 seroreactivity is commonly detected among patients with HPVOPC at diagnosis, but not among partners or healthy volunteers. Seroreactivity among cases are correlated with viral load and stage and not with other demographic or behavioral factors. Positive HPV16 serology was strongly associated with HPV 16 oropharyngeal cancer.

Synergistic epistasis of paraoxonase 1 (rs662 and rs85460) and apolipoprotein E4 genes in pathogenesis of Alzheimer's disease and vascular dementia.

Genetic polymorphism and epistasis play a role in etiopathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). In this case-control study, a total of 241 patients were included in the study to see the effect of paraoxonase 1 (PON1; rs662 and rs85460) and apolipoprotein E (ApoE) genes in altering the odds of having AD and VaD along with serum PON and lipid profile. The presence of at least 1 variant allele of rs662, but not rs85460, increased the risk of having AD by 1.8-fold (95% confidence interval [CI]: 0.97-3.40) and VaD by 3.09-fold (95% CI: 1.4-6.9). The interaction between PON1 genes (rs662 and rs85460) and ApoE genes showed synergistic epistasis in altering the odds of significantly having both AD and VaD. On the other hand, low serum level of high-density lipoprotein and low level of serum PON activity were found associated significantly (P ≤ .001 in both cases) only in patients with VaD as compared to healthy control.

Serum folic acid and RFC A80G polymorphism in Alzheimer's disease and vascular dementia.

Low level of vitamin B12 and folic acid has been reported to play an important role in the pathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). Serum folic acid and vitamin B12 were assayed in 80 AD and 50 VaD cases and in 120 healthy controls. The reduced folate carrier (RFC1) gene, rs1051266, which encodes the RFC 1, protein was analyzed for polymorphism by polymerase chain reaction-restriction fragment length polymorphism. It was observed that the patients having folic acid <8.45 ng/mL had 2.4 (95% confidence interval [CI]: 1.4-4.5) times higher odds of having AD and 2.1 (95% CI: 1.1-4.2) times higher odds of having VaD than patients having folic acid ≥8.45 ng/mL. Serum vitamin B12 level did not show any such statistically significant effect in altering the odds. No direct association was found between variant (G) allele or genotype of rs1051266 with AD and VaD cases. On serum folate level no association was observed with gene polymorphism.

Do gene polymorphism in IL-1ß, TNF-α and IL-6 influence therapeutic response in patients with drug refractory epilepsy?

PURPOSE: Pro-inflammatory cytokines may play an important pathophysiological role in patients with epilepsy. To understand the role of genes encoding pro-inflammatory cytokines in epilepsy, this study aimed to evaluate the polymorphisms of the promoter regions of IL-1ß-511C>T (rs16944), TNF-α-308G>A (rs1800629) and IL-6-174G>C (rs1800795) genes and to look into the interaction between these genes in influencing seizure susceptibility, seizure frequency and response to therapy. METHODS: The comparative frequency of polymorphism was determined in rs16944, rs1800629 and rs1800795 using PCR-RFLP in a group of 120 persons with epilepsy (PWE) and 110 ethnically matched healthy subjects of comparable age and sex in the North Indian population. RESULTS: Alleles and genotypes of rs16944, rs1800629 and rs1800795 were not found to influence the odds ratio of having susceptibility to epilepsy. Also gene-gene interaction of possible nine combinations of these genes did not show any positive association with epilepsy. The genotype and allelic frequency of rs1800795 showed a significant association (p<0.05) in seizure frequency (number of seizures/6-months) and drug refractory epilepsy. However, the genotype and allelic frequency of rs16944 and rs1800629 were not found to have such effect. CONCLUSION: This study demonstrates that the rs16944, rs1800629 and rs1800795 polymorphism does not act as a strong susceptibility factor for epilepsy in North Indian population. The genotypic association of rs1800795 with seizure frequency and drug-refractory epilepsy raises the issue that a specific set of polymorphic genes can influence seizures and therapeutic response in epilepsy.

MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction.

Genetic risk factors play an important role in the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD). In this case-control study, we examined C677T and A1298C (rs1801133 and rs1801131) polymorphism in the methylenetetrahydrofolate reductase (MTHFR) genes and their correlation with plasma levels of homocysteine (Hcy) in AD and VaD cases and evaluated the gene-gene interaction (epistasis) with IL-6-174 G/C (rs1800795). CC genotype was associated with elevated levels of plasma homocysteine (p = 0.004) as compared with genotype AA of rs1801131. In AD, we observed a significant (p = 0.04) association with C alleles of rs1801131. Regression analysis revealed that the presence of both rs1801133 T and rs1800795 C alleles increased the odds of developing AD by 2.5 and VaD by 3.7-fold. While rs1800795 (CC or GC) genotypes alone increased the odds of developing VaD by 2.2-fold, the presence of CC genotype of rs1801131 nullified this effect. The findings support the hypothesis that multiple genes are involved to alter the odds of developing AD and VaD.