Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy

Background

The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.

Methods

We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.

Results

Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.

Conclusion

Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.     

Protective effects of adiponectin on uncoupling of glomerular VEGF–NO axis in early streptozotocin-induced type 2 diabetic rats

Purpose

To determine whether adiponectin could reduce microalbuminuria and provide renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular vascular endothelial growth factor (VEGF)–nitric oxide (NO) axis in streptozotocin-induced type 2 diabetic rats.

Methods

Wistar rats were randomly divided into normal control group, diabetic nephropathy (DN) group induced by high-fat feeding and streptozotocin, diabetic rats injected with adenovirus-expressed adiponectin (AD-AdipoQ), and diabetic rats injected with AD-IRES-EGFP as control. Blood and urine samples were collected. Endothelium-dependent vasodilatation (EDV) of the aorta was measured. Renal tissues were collected for CD34 immunohistochemistry. Glomerular NO and VEGF levels were measured by the Griess reaction and Western blot testing, respectively.

Results

Injections of AD-AdipoQ significantly increased serum adiponectin levels and reduced the urinary albumin-to-creatinine ratio in diabetic rats (P < 0.05). The levels of plasma glucose, serum insulin, high-sensitivity C-reactive protein, and malondialdehyde were significantly reduced in diabetic rats after injections of AD-AdipoQ (P < 0.05). Severe EDV impairment was observed in the DN group, which was improved by AD-AdipoQ. CD34 expression in the glomeruli was also higher in diabetic rats, indicating increased proliferation of glomerular endothelial cells. However, AD-AdipoQ improved the increased proliferation of endothelial cells in the glomeruli. Diabetic rats showed increased glomerular VEGF levels and reduced NO levels. This uncoupling of the VEGF–NO axis was partially improved by AD-AdipoQ.

Conclusion

Adiponectin reduces the degree of microalbuminuria and has renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular VEGF–NO axis in early diabetic nephropathy.     

Correlation study of chronic nonbacterial prostatitis with the levels of COX-2 and PGE2 in prostatic secretion

Objective

The prostatitis syndrome is a multifactorial condition of largely unknown etiology. This study is to analyze the relationship between cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) with the chronic nonbacterial prostatitis (CNBP).

Methods

A total of 172 CNBP patients and 151 healthy males were recruited as CNBP and control group, respectively. The prostatic fluid was collected and tested by pre- and post-massage test. White blood cell (WBC) number was counted, and the contents of COX-2 and PGE2 were determined by double antibody-based sandwich enzyme-linked immuno-sorbent assay. The pain and discomfort of each patient were scored according to the National Institutes of Health chronic prostatitis symptom index.

Results

Compared with the control group, CNBP group displayed significantly higher WBC count, COX-2 level, and PGE2 level. Contents of COX-2 and PGE2 in prostatic secretion of CNBP group were positively correlated with pain scores (r = 0.855 and 0.675, respectively, P < 0.01) and total symptom scores (r = 0.674 and 0.566, respectively, P < 0.01). A significantly positive correlation between COX-2 and PGE2 levels was also discovered (r = 0.493, P < 0.05). The WBC number was not obviously correlated with the accumulations of COX-2 and PGE2 or the clinic symptoms of CNBP.

Conclusion

Increase in PGE2 concentration caused by activated COX-2 pathway may contribute to the pain or discomfort symptom of the CNBP patients. Our results indicate that selective COX-2 inhibitors have application prospect in CNBP treatment.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.     

Ileal Effect on Blood Glucose,HbA1c,and GLP-1 in Goto-Kakizaki Rats

Background

There have been enumerable studies on the effects of glucagon-like peptide-1 (GLP-1) on satiety and pancreatic islet function, stimulating the advocacy of surgical transposition of the ileum (rich in GLP-1-generating L-cells) higher in the gastrointestinal tract for earlier stimulation. In the Goto-Kakizaki rat with naturally occurring type 2 diabetes, we studied the influence of ileal exclusion (IE) and ileal resection (IR) on blood glucose, hemoglobin A1c (HbA1c), and GLP-1.

Methods

In six control (Ctrl), 10 IE, and 10 IR rats, over 12 weeks of follow-up, we determined blood glucose, HbA1c, and GLP-1.

Results

Two animals in the IE and IR groups did not survive to week 13. Both operated groups weighed more than the Ctrl group at baseline and at 13 weeks; thus, IE and IR did not retard weight gain (p?HbA1c percentages at week 13: 14.7?±?28 Ctrl, 11.7?±?3.4 IE, 13.8?±?3.5 IR (%?±?SEM). The end-study GLP-1 values (pM?±?SEM) were 5?±?0.9 Ctrl, 33?±?8.9 IE, and 25?±?6.7 IR. P values for intergroup differences were IE vs. Ctrl 0.02, IR vs. Ctrl 0.02, and IE vs. IR 0.59.

Conclusions

Neither IE nor IR resulted in a decrease in the mean GLP-1 level. On the contrary, the exclusion or resection of the L-cell rich ileum raised GLP-1 levels 5- to 6-fold. This increase in the GLP-1 was not associated with the mitigation of hyperglycemia or elevated HbA1c levels.     

Five-year results of arthroscopic techniques for the treatment of acetabular chondral lesions in femoroacetabular impingement

Purpose

This study assesses and compares the clinical outcomes of the arthroscopic matrix-induced autologous chondrocyte implant (MACI) and autologous matrix-induced chondrogenesis (AMIC) techniques for the treatment of acetabular chondral defects between 2 and 4 cm² consequent to femoral acetabular impingement.

Methods

Fifty-seven consecutive patients were treated with the MACI (n?=?26) or AMIC (n?=?31) technique. Patients were assessed pre-operatively and up to five years using the modified Harris Hip Score (mHHS) to compare outcomes.

Results

In both the MACI and AMIC groups, significant hip score improvements were measured over baseline levels at six months post-op (81.2?±?8.4 for MACI, 80.3?±?8.3 for AMIC, both p?MACI and AMIC, respectively (NS). Subgroup analysis of both MACI and AMIC treatment outcomes for patients with an initial chondral defect larger than 3 cm² yielded comparable results at each time point.

Conclusions

This study suggests that both arthroscopic MACI and AMIC are valid procedures to repair medium-sized chondral defects on the acetabular side of the hip found during treatment of femoroacetabular impingement. Due to its high sustainability and minimal invasiveness, the single-stage AMIC procedure can reduce total treatment time and minimise morbidity while providing the same beneficial effects as the two-stage MACI intervention.     

The incidence of a first major osteoporotic fracture in Iceland and implications for FRAX

Summary

Based on an extensive cohort study over 25 years, the present study supports the assumption that major osteoporotic fractures can be reasonably predicted from hip fracture rates.

Introduction

The construct for FRAX models depends on algorithms to adjust for double counting of fracture outcomes in some models and in others, to estimate the incidence of a major fracture from hip fracture rates. The aim of the present study was to test the validity of these algorithms in a large prospective cohort.

Methods

The incidence of hip, clinical spine, distal forearm, and humerus fracture was determined in the prospective and ongoing population-based Reykjavik Study with follow up of 257,001 person-years. The incidence of a first major fracture was compared with the correction factors used in FRAX to adjust the incidence of several fracture outcomes for double counting. In addition, the incidence of a major osteoporotic fracture estimated from the Icelandic hip fracture rates was compared with the Malmo ratios used in FRAX.

Results

The adjustments necessary to account for multiple fracture outcomes were similar to those previously derived from Sweden. Additionally, incidence of a first major osteoporotic fracture was similar to that derived for FRAX models.

Conclusion

The findings of the present study support the algorithms used in FRAX to estimate the incidence of a first major fracture and the predictive value of hip fracture for other major fractures.     

Clinical relevance of decreased oxygen saturation during 6-min walk test in preoperative physiologic assessment for lung cancer surgery

Objective

The Japanese Association for Chest Surgery (JACS) has released guidelines on preoperative physiologic assessment for lung cancer surgery. However, cardiopulmonary exercise testing (CPET), which is recommended for patients with poor pulmonary function, is available only in limited institutions. We investigated the possibility of 6-min walk test (6MWT) as a substitute of maximum oxygen consumption test (VO₂max) on preoperative physiologic assessment for lung cancer surgery.

Methods

The relationship between VO₂max and 6MWT was retrospectively analyzed in 51 subjects other than lung cancer patients. Following the preliminary analysis, we modified the risk assessment in the JACS guidelines by substituting 6MWT for VO₂max, and patients who underwent lung cancer surgery were retrospectively assessed using the modified assessment.

Results

Analysis of the correlation between VO₂max and 6MWT revealed VO₂max to be significantly correlated to minimum SpO₂ (SpO₂min) and maximum decrease in SpO₂ (ΔSpO₂) during 6MWT. Receiver operating characteristic analysis revealed that SpO₂min and ΔSpO₂ were predictable for a VO₂max of 15 mL/kg/min, which is the borderline between the average- and increased-risk groups in the JACS guidelines. A total of 1,066 patients were assigned to the average- or increased-risk group according to the modified JACS guidelines using the criteria of SpO₂min < 91 % and ΔSpO₂ > 4 %. The increased-risk group was significantly inferior to the average-risk group in Home Oxygen Therapy induction rate, cardiopulmonary-related 30- and 90-day mortality (p < 0.001).

Conclusions

In clinical practice, decreased saturation during 6MWT may be simple and substitutive for CPET in risk assessment for lung cancer surgery using the JACS guidelines.     

Transcystic or Transductal Stone Extraction during Single-Stage Treatment of Choledochocystolithiasis: A Systematic Review

Background

Choledochocystolithiasis can be managed by endoscopic retrograde cholangiopancreaticography (ERCP) or laparoscopically by transcystic (TC) or transductal (TD) stone extraction.

Objective

The aim of this study was to systematically review safety and effectiveness of combined endoscopic/laparoscopic management versus total laparoscopic management for choledochocystolithiasis with specific emphasis on TC versus TD stone extraction.

Methods

MEDLINE/PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov were searched systematically to identify trials on combined endoscopic/laparoscopic and total laparoscopic management for choledochocystolithiasis. Laparoscopic common bile duct (CBD) exploration was divided into TD and TC approach. Primary outcomes were successful stone clearance from CBD, postoperative/procedural morbidity, and mortality.

Results

Eight randomized trials with 965 patients were included. Successful bile duct clearance varied between 52.6 and 97 % in the ERCP groups, 80.4 and 100 % in the TC groups, and 58.3 and 100 % in the TD groups. There were more bile leaks after TD stone extraction (11 %) than after ERCP (1 %) and TC stone extraction (1.7 %). Total morbidity varied between 9.1 and 38.3 % in the ERCP groups, 7 and 10.5 % in the TC groups, and 18.4 and 26.7 % in the TD groups. Methodological and statistical heterogeneity among the trials precluded a meaningful meta-analysis.

Conclusion

Stone clearance rates are comparable between the three modalities, but TD stone extraction is associated with a higher risk of bile leaks and should only be performed by highly experienced surgeons. TC stone extraction seems a more accessible technique with lower complication rates. If unsuccessful, per- or postoperative endoscopic stone extraction is a viable option.     

Predictors that Influence Contralateral Prophylactic Mastectomy Election Among Women with Ductal Carcinoma In Situ Who Were Evaluated for BRCA Genetic Testing

Background

Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We evaluated factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA testing.

Methods

This retrospective study involved 165 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristics were age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election.

Results

Of 165 patients, 44 (27 %) underwent CPM. Patients <45 years of age were more likely to elect CPM (p = 0.0098). A BRCA+ mutation was found in 17 patients (10.3 %), and BRCA+ women were more likely to elect CPM than BRCA or untested women (p = 0.0001). Patients who had a family history of OC (57.7 %) were more likely to choose CPM than those with no family history (p = 0.0004). Younger age, BRCA+, and an OC family history remained significant in the multivariate model (p < 0.008).

Conclusion

The CPM rate among patients with DCIS who undergo genetic counseling is high. Factors associated with increased likelihood of CPM among this group were age, BRCA+, and a family history of OC. Further studies are needed to evaluate patients’ perceptions of CBC risk and their role in the likelihood of CPM choice.     

Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

An ignored cause of inflammation in patients undergoing continuous ambulatory peritoneal dialysis: periodontal problems

Aim

We aimed to assess whether there is a significant relation between periodontal health status and inflammation in uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and also to reveal the efficiency of periodontal treatment in patients with various degrees of periodontal problems.

Patients and methods

Overall, 68 patients undergoing CAPD were included in the study. Clinical indices and measurements were obtained at baseline and panoramic radiographies were used for the diagnosis. According to the baseline values, patients were stratified into four groups according to the severity of periodontal problems as follows: healthy/gingivitis, slight-to-moderate, and severe periodontitis. A control examination was performed 3 months after the periodontal treatment for only 43 patients. Clinical and laboratory parameters before and after treatment were compared.

Results

The frequency of periodontal disease was found to be high in uremic patients on CAPD. The frequency and severity of periodontitis was also found to be significantly (p < 0.01) higher in patients with high sensitive C-reactive protein levels and longer duration of peritoneal dialysis (p < 0.01). In addition, the periodontitis rate was found to be higher in patients with cardiovascular disease (p < 0.05) and diabetes mellitus (p < 0.01).

Conclusion

A meticulous periodontal examination should be a routine part of management of the uremic patients on CAPD because periodontal disease could be one of the hidden sources of unexplained inflammatory status.     

Eculizumab treatment for rescue of renal function in IgA nephropathy

Background

Immunoglobulin A (IgA) nephropathy is a chronic glomerulonephritis with excessive glomerular deposition of IgA1, C3 and C5b-9, which may lead to renal failure.

Case Diagnosis/Treatment

We describe the clinical course of an adolescent with rapidly progressive disease leading to renal failure in spite of immunosuppressive treatment. Due to refractory disease the patient was treated with eculizumab (anti-C5) for 3 months in an attempt to rescue renal function. Treatment led to clinical improvement with stabilization of the glomerular filtration rate and reduced proteinuria. Discontinuation of treatment led to a rapid deterioration of renal function. This was followed by a single dose of eculizumab, which again reduced creatinine levels temporarily.

Conclusions

Early initiation of eculizumab therapy in patients with progressive IgA nephropathy may have a beneficial effect by blocking complement-mediated renal inflammation.     

The True Incidence of Gastric GIST—a Study Based on Morbidly Obese Patients Undergoing Sleeve Gastrectomy

Background

Gastrointestinal stromal tumor (GIST) is a rare neoplasm of the alimentary tract. Previous reports described an incidence of 1 per 100,000. Laparoscopic sleeve gastrectomy (LSG) provides pathological specimens of the majority of the stomach. We examined the pathology from LSG and the incidence and location of GIST. The aim of this study was to study the incidence of asymptomatic GISTs found during LSG at our institution.

Methods

A search was conducted in a prospectively maintained bariatric registry. Data collected included the following: gender, age, body mass index (BMI), and concomitant hypertension or diabetes mellitus. Histopathology reports were reviewed for incidental GIST. We compared the patients with incidental GIST to the rest of the cohort.

Results

Pathology reports of 827 patients that underwent LSG between 2007 and 2014 were reviewed. Five patients had GIST in the resected stomach, an incidence of 0.6 %. The group of patients with GIST had lower BMI and older age compared to the remaining 822 patients. All tumors were located close to the lesser curvature.

Conclusions

The incidence of GIST found in this cohort is significantly higher than previously reported. This may be due to an association between these tumors and obesity or because asymptomatic GISTs are underdiagnosed in the general population. These tumors are particularly common in older patients and special attention must be given when performing LSG on this subpopulation. The stomach should be inspected thoroughly before resection. A tumor on the lesser curvature may necessitate changing the surgical plan or aborting the procedure.     

The effect of underlying liver disease on short-term outcomes following bariatric surgery

Background

Morbid obesity is strongly associated with nonalcoholic fatty liver disease. However, the effect of underlying liver disease on clinical outcomes following bariatric surgery has not been well studied. This study aims to determine the effect of underlying liver disease on short-term outcomes in bariatric patients using the model of end-stage liver disease (MELD) scoring system as a practical measure of hepatic dysfunction.

Methods

A retrospective cohort analysis was performed using data from the American College of Surgeons’ National surgery quality improvement program participant use files. The study population consisted of patients that underwent elective laparoscopic-stapled bariatric surgery for morbid obesity between 2005 and 2012. Patients were excluded if they had a bleeding disorder or renal failure requiring dialysis. The optimal MELD cut-off score to predict 30-day adverse events was determined and used to stratify patients into two groups. The primary outcome was 30-day adverse events, defined as a postoperative complication or reoperation. The secondary outcome was 30-day mortality. A multiple logistic regression was performed to adjust the odds ratio (OR) estimate for 30-day adverse events based on the MELD cut-off score.

Results

38,875 patients were included in the study population. A MELD score of 7.9 was determined to be the optimal cut-off to predict 30-day adverse events based on the maximized linear combination of specificity and sensitivity. After adjusting for confounding, the OR estimates for 30-day adverse events and mortality using the cut-off score as the key predictor were 1.22 [95 % CI 1.06–1.41] and 2.33 [95 % CI 1.19–4.56], respectively.

Conclusions

Using this large national surgical registry, bariatric patients with MELD scores ≥7.9 had a significant but marginal risk of 30-day adverse events and mortality. This suggests that severity of liver disease may affect bariatric surgery outcomes and should be considered during preoperative evaluations.     

Neutrophil gelatinase-associated lipocalin protects renal tubular epithelial cells in hypoxia–reperfusion by reducing apoptosis

Purpose

The aim of this study was to elucidate the role of neutrophil gelatinase-associated lipocalin (NGAL) in regulating apoptosis of tubular epithelial cells in a hypoxia–reperfusion model.

Methods

A hypoxia–reperfusion model was established with NRK-52E cells to assess apoptosis and cell cycle progression after the addition of NGAL. We investigated the expression of four apoptosis factors, Bcl-2, Bax, Fas and FasL, as well as the expression level of two NGAL receptors, 24p3R and megalin, by both Western blot and real-time PCR.

Results

NGAL induced cell proliferation and reduced apoptosis by regulating four apoptosis factors Bcl-2, Bax, Fas and FasL. Western blot demonstrated that the two NGAL receptors, 24p3R and megalin, were increased after hypoxia–reperfusion, which was reduced by exogenous NGAL. Moreover, overexpression of the two receptors induced the expression of the anti-apoptotic factor Bcl-2 and reduced the expression of pro-apoptotic Bax, Fas and FasL.

Conclusions

These findings indicate that NGAL reduces apoptosis by regulating the four apoptosis factors Bcl-2, Bax, Fas and FasL through its two receptors 24p3R and megalin. These results also suggest that ectopic expression of NGAL in renal cells might provide a therapeutic strategy in ischemia–reperfusion by reducing apoptosis and promoting renal cell proliferation.     

Duodenal–Jejunal Bypass Improves Glucose Homeostasis in Association with Decreased Proinflammatory Response and Activation of JNK in the Liver and Adipose Tissue in a T2DM Rat Model

Background

There is accumulating evidence that obesity leads to a proinflammatory state, which plays crucial roles in insulin resistance and development of type 2 diabetes mellitus (T2DM). Previous studies demonstrated that weight loss after bariatric surgery was accompanied by a suppression of the proinflammatory state. However, the effect of bariatric surgery on the proinflammatory state and associated signaling beyond weight loss is still elusive. The objective of this study was to investigate the effect of duodenal–jejunal bypass (DJB) on glucose homeostasis, the proinflammatory state and the involving signaling independently of weight loss.

Methods

A high-fat diet and low-dose streptozotocin administration were used to induce T2DM in male Sprague–Dawley rats. The diabetic rats underwent DJB or sham surgery. The blood glucose, glucose tolerance and insulin resistance were determined to evaluate the glucose homeostasis. Serum insulin, GLP-1 and hsCRP were detected by ELISA. The gene expression of TNF-α, IL-6, IL-1β and MCP-1 in liver and fat was determined by quantitative real-time RT-PCR. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were determined by Western blotting.

Results

Compared to the S-DJB group, DJB induced significant and sustained glycemic control with improved insulin sensitivity and glucose tolerance independently of weight loss. DJB improved the proinflammatory state indicated by decreased circulating hsCRP and proinflammatory gene expression in the liver and adipose tissue. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were significantly reduced after DJB.

Conclusions

DJB achieved a rapid and sustainable glycemic control independently of weight loss. The data indicated that the improved proinflammatory state and decreased JNK activity after DJB may contribute to the improved glucose homeostasis.     

Minimal change disease: a dysregulation of the podocyte CD80–CTLA-4 axis?

Background

Minimal Change Disease (MCD) is associated with CD80 expression in podocytes and elevated urinary CD80 excretion during active renal disease. We have evaluated the urinary excretion of CTLA-4 and CD80 during different stages of the nephrotic syndrome in patients with MCD to test the hypothesis that persistent increased urinary CD80 excretion in patients with MCD in relapse is due to an ineffectual CTLA-4 response of the host to curtail the activation of CD80.

Methods

Thirty-two children with biopsy-proven MCD were studied during relapse and/or remission. Eleven healthy subjects served as controls.

Results

Urinary CD80 excretion was significantly increased in MCD patients in relapse relative to that in MCD patients in remission (p?p?CTLA-4 excretion was higher in MCD patients in relapse than in MCD patients in remission (p?=?0.01) and controls (p?=?0.03), no significant correlation was observed between urinary CD80 excretion and urinary CTLA-4 level in MCD patients at the time of relapse (p?=?0.06). At the time of remission, CD80 had decreased significantly in all patients, but CTLA-4 levels either decreased or remained unchanged in all but five patients, and no correlation was observed between urinary CD80 excretion and CTLA-4 level (p?=?0.7).

Conclusions

Urinary CTLA-4 levels do not correlate with urinary CD80 excretion, suggesting the possibility that the CTLA4 response may be suboptimal in this disease during relapse.