Podocytes are likely the therapeutic target of IgA nephropathy with isolated hematuria: Evidence from repeat renal biopsy

Background: The present study aimed to prove the progression of immunoglobulin A nephropathy (IgAN) patients with isolated hematuria based on repeat renal biopsy data for the first time.Methods: 29 IgAN patients with isolated hematuria who received repeat renal biopsies were analyzed retrospectively, while 29 non-isolated hematuria IgAN patients with similar age and background were randomly selected as the control group. Clinical parameters were collected at the time of biopsy. The treatment strategies (conservative treatment with RASS blocker or immunosuppressive treatment) were choosen according to the pathological results at the first renal biopsy. The activity and chronicity indexes of renal lesions were evaluated. Markers of cell inflammation and proliferation were tseted by immunochemistry. The ultrastructure of podocytes was observed by transmission electron microscopy (TEM). Podocyte and oxidative stress marker (NPHS2 and 4-HNE) were detected by immunofluorescence.Results: The IgAN patients with isolated hematuria had better clinical indicators than those with no-isolated hematuria, such as better renal function, higher albumin and lower uric acid. The interval between two biopsies in IgAN patients with isolated hematuria was 630 (interquartile range, 409.5–1,171) days. The hematuria of the patients decreased significantly from 30 (IQR, 4.00–35.00) RBC/ul in the first biopsy to 11 (IQR, 2.50–30.00) RBC/ul in the repeated biopsy (p < 0.05). The level of triglyceride decreased significantly (p < 0.05). The other clinical indicators were not statistically significant (p > 0.05). Deposits of IgA and C3 in the glomerulus were persistent. The activity index decreased, especially cellular crescent formation, while the chronicity index increased. The ultrastructure of podocytes was improved after treatment. The oxidative stress products of podocytes reduced after treatment.Conclusion: Although the clinical indicators of the IgAN patients with isolated hematuria were in the normal range, various acute and chronic pathological changes have occurred, and irreversible chronic changes have been progressing. Cell inflammation and proliferation persisted. Oxidative stress of podocytes was likely to be the therapeutic target. This study provided a strong basis for the progress of IgAN with isolated hematuria through pathological changes before and after treatment. This study will help clinicians recognize the harm of hematuria, change the traditional treatment concept, and help such patients get early treatment

Model predictive direct power control of energy storage quasi-Z-source grid-connected inverter

In order to overcome the shortcoming of large switching losses caused by variable switching frequency appears in the conventional finite control set model predictive control (FCS-MPC) algorithm, a model predictive direct power control (MP-DPC) for an energy storage quasi-Z-source inverter (ES-qZSI) is proposed. Firstly, the power prediction model of the ES-qZSI is established based on the instantaneous power theory. Then the average voltage vector in the coordinate system is optimized by the power cost function. Finally, the average voltage vector is used as the modulation signal, and the corresponding switching signal with fixed frequency is generated by the shoot-through segment space vector pulse width modulation (SVPWM) technology. The simulation results show that the ES-qZSI realizes six shoot-through actions per control cycle and achieves the constant frequency control of the system, which verifies the correctness of the proposed control strategy

Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice

Background: The capacity of toll-like receptor (TLR) 7/8 agonist-conjugated hepatitis B virus (HBV) proteins (HBV-Ag) to overcome established hepatitis B surface antigen (HBsAg)-specific immune tolerance was explored. Methods: A TLR7/8 agonist, CL097, was conjugated with alum-absorbed HBsAg and hepatitis B core antigen (HBcAg), as confirmed by ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS). Mice from two independently generated HBV-transgenic (HBV-Tg) colonies, C57BL/6J-TgN (AlblHBV) 44Bri/J mice and C57BL/6-HBV-1.3 genome-eq mice, were immunized with CL097-conjugated HBV-Ag every 2 weeks, four times. Results: After immunization, 8/11 (72.7%) of the AlblHBV mice and 10/13 (76.9%) of the HBV-1.3 genome-eq mice generated serum detectable antibodies against HBsAg (anti-HBs). HBsAg-specific interferon gamma (IFN-γ)-producing CD4+ and CD8+ T-cells were detected in splenocytes from these mice. Naïve normal mice receiving splenocytes from the mice immunized with CL097-conjugated HBV-Ag generated immediate recall immune responses, e.g., the mice that received CD4+CD25+-depleted splenocytes generated anti-HBs on day 3 after HBsAg challenge while those receiving cells from sham-immunized mice did not. Conclusions: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state

Association between dialysis effluent leukocyte count after initial antibiotic treatment and outcomes of patients with peritoneal dialysis-associated peritonitis: a retrospective study

AbstractBackground Among patients with peritoneal dialysis-associated peritonitis (PDAP), It has been regarded as an indicator of deterioration of clinical condition that peritoneal dialysis effluent leukocyte count (PDELC) cannot be restored to normal after initial antibiotic therapy. However, the precise relationship between PDELC on day 5 and the clinical outcomes of PDAP episodes remains uncertain.Aims To explore the association between PDELC on day 5 and clinical outcomes of PDAP episodes.Methods This retrospective study was based on the medical chart database of the Affiliated Hospital of Guangdong Medical University. Multivariable regressions were used to evaluate the association between PDELC on day 5 and 60-day mortality, half-year mortality, treatment failure, and the length of stay in hospital with adjustment for confounding factors.Results A total of 549 PDAP episodes in 309 patients were enrolled. The total 60-day mortality, half-year mortality, and rate of treatment failure was 6.0%, 9.8%, and 14.2%, respectively. Compared with patients with normal PDELC, those with PDELC ≥2000 × 106/L on day 5 had significantly higher 60-day mortality (31.1% vs 2.7%), half-year mortality (35.6% vs 5.6%), and treatment failure (46.7% vs 5.7%). In multivariate adjusted regression, the ORs (95%CI) were 6.99 (2.33, 20.92; p = 0.001), 4.97(1.93, 12.77; p = 0.001), and 5.77 (2.07, 16.11; p = 0.001), respectively. Patients with PDELC were 100–2000 × 106/L on day 5 had a higher rate of treatment failure than those with normal PDELC (26.9% vs 5.7%) (OR = 3.03, 95%CI 1.42, 6.46; p = 0.004). After sensitivity analysis, the results remained robust.Conclusions Among patients with PDAP, increased PDELC on day 5 was associated with a greater risk of 60-day mortality, half-year mortality, and treatment failure

Efficacy and safety of sequential immunosuppressive treatment for severe IgA nephropathy: A retrospective study

Background: This study compared the efficacy and safety of sequential immunosuppressive therapy in patients with non-end-stage IgA nephropathy (IgAN) with Lee’s classification of IV ∼ V and provided evidence for the use of immunotherapy in patients with severe IgAN.Methods: We retrospectively analyzed the clinical data of patients with Lee’s IV ∼ V non-end-stage IgA nephropathy.Results: 436 patients were diagnosed with IgAN, and 98 patients who met the inclusion criteria were included in this retrospective study. Of these, 17 were in the supportive care group, 20 in the P group (prednisone-only), 35 in P + CTX group (the prednisone combined with cyclophosphamide followed by mycophenolate mofetil), and 26 in the P + MMF group (prednisone combined with mycophenolate mofetil). The four groups showed differences in the segmental glomerulosclerosis score and the proportion of patients with Lee’s grade IV (p < 0.05), but no differences in other indicators. Compared with the baseline values, urine protein-to-creatinine ratio (PCR) significantly decreased and serum albumin increased (p < 0.05), but there was no significant difference between the groups. The estimated Glomerular Filtration Rate (eGFR) of the P, P + MMF, and P + CTX groups were higher than that of the supportive care group at the 6th and 24th month after treatment (all p < 0.05). At the 24th month, the eGFR in the P + CTX group was higher than that in the P + MMF group (p < 0.05). The effective remission rate of the P + CTX group was higher than that of the supportive care group (p < 0.05). At 12 months, the effective remission rate of the P group was higher than that of the supportive care group (p < 0.05). At the 24th month, there was no significant difference in the effective remission rates among the three groups (P, P + MMF, and P + CTX). Nine patients with severe IgA nephropathy reached the endpoint.Conclusion: This study showed that immunosuppressive therapy insevere IgAN patient scan effectively reduce urinary protein, increase albumin, and protect renal function in the early stages of IgAN. P + CTX is the most commonly used, which has a high effective remission rate of urine protein and a low incidence of end-point events

A novel oncolytic herpes simplex virus type 2 has potent anti-tumor activity.

Oncolytic viruses are promising treatments for many kinds of solid tumors. In this study, we constructed a novel oncolytic herpes simplex virus type 2: oHSV2. We investigated the cytopathic effects of oHSV2 in vitro and tested its antitumor efficacy in a 4T1 breast cancer model. We compared its effect on the cell cycle and its immunologic impact with the traditional chemotherapeutic agent doxorubicin. In vitro data showed that oHSV2 infected most of the human and murine tumor cell lines and was highly oncolytic. oHSV2 infected and killed 4T1 tumor cells independent of their cell cycle phase, whereas doxorubicin mainly blocked cells that were in S and G2/M phase. In vivo study showed that both oHSV2 and doxorubicin had an antitumor effect, though the former was less toxic. oHSV2 treatment alone not only slowed down the growth of tumors without causing weight loss but also induced an elevation of NK cells and mild decrease of Tregs in spleen. In addition, combination therapy of doxorubicin followed by oHSV2 increased survival with weight loss than oHSV2 alone. The data showed that the oncolytic activity of oHSV2 was similar to oHSV1 in cell lines examined and in vivo. Therefore, we concluded that our virus is a safe and effective therapeutic agent for 4T1 breast cancer and that the sequential use of doxorubicin followed by oHSV2 could improve antitumor activity without enhancing doxorubicin's toxicity

Association between dialysis effluent leukocyte count after initial antibiotic treatment and outcomes of patients with peritoneal dialysis-associated peritonitis: a retrospective study

Among patients with peritoneal dialysis-associated peritonitis (PDAP), It has been regarded as an indicator of deterioration of clinical condition that peritoneal dialysis effluent leukocyte count (PDELC) cannot be restored to normal after initial antibiotic therapy. However, the precise relationship between PDELC on day 5 and the clinical outcomes of PDAP episodes remains uncertain. To explore the association between PDELC on day 5 and clinical outcomes of PDAP episodes. This retrospective study was based on the medical chart database of the Affiliated Hospital of Guangdong Medical University. Multivariable regressions were used to evaluate the association between PDELC on day 5 and 60-day mortality, half-year mortality, treatment failure, and the length of stay in hospital with adjustment for confounding factors. A total of 549 PDAP episodes in 309 patients were enrolled. The total 60-day mortality, half-year mortality, and rate of treatment failure was 6.0%, 9.8%, and 14.2%, respectively. Compared with patients with normal PDELC, those with PDELC ≥2000 × 106/L on day 5 had significantly higher 60-day mortality (31.1% vs 2.7%), half-year mortality (35.6% vs 5.6%), and treatment failure (46.7% vs 5.7%). In multivariate adjusted regression, the ORs (95%CI) were 6.99 (2.33, 20.92; p = 0.001), 4.97(1.93, 12.77; p = 0.001), and 5.77 (2.07, 16.11; p = 0.001), respectively. Patients with PDELC were 100–2000 × 106/L on day 5 had a higher rate of treatment failure than those with normal PDELC (26.9% vs 5.7%) (OR = 3.03, 95%CI 1.42, 6.46; p = 0.004). After sensitivity analysis, the results remained robust. Among patients with PDAP, increased PDELC on day 5 was associated with a greater risk of 60-day mortality, half-year mortality, and treatment failure.</p

Oncolytic spectrum of oHSV2.

<p><b>A</b>) oHSV2 and oHSV1 were used to infect human tumor cells, including BGC823, HT29, Krause, T47D, U2OS, CNE2Z, HuH7, PG and TSU, at the indicated MOIs and times. <b>B</b>) oHSV2 and oHSV1 were used to infect mouse tumor cells, including 4T1, GL261, TC-1, B16F10 and B16R, at the indicated MOIs and times. A and B were observed with an inverted phase contrast microscope at 100× objective magnification. <b>C</b>) U2OS cells were infected by oHSV2 at MOI = 1, and typical syncytia were observed at 100×, 200× and 400× objective magnification.</p

<i>In vitro</i> comparison of oHSV2 with oHSV1.

<p>Both oHSV1 and oHSV2 induces necrosis in cancer cells. A) Flow cytometry analysis of cancer cell lines after oHSV2 or oHSV1 infection at the indicated MOIs for 24 h. B) The necrosis rates of the cancer cell lines were measured after oHSV2 or oHSV1 infection. Each value represents the mean ± SED of three independent samples. ns, no significant differences.</p

The cell viability of cancer cells was examined.

<p><b>A</b>) The 4T-1 cells were treated with oHSV1 or oHSV2 at the indicated MOIs for the indicated times. <b>B</b>) The B16R cells were treated with oHSV1 or oHSV2 at the indicated MOIs for the indicated times. <b>C</b>) The B16F10 cells were treated with oHSV1 or oHSV2 at the indicated MOIs for the indicated times. <b>D</b>) The 4T-1 cells were treated with oHSV2 of different MOIs for 24h. DOX was used as a positive control. Each value represents the mean ± SED of three independent samples.</p