Effect of total parathyroidectomy in patients with secondary hyperparathyroidism: a retrospective study.

PURPOSE: To investigate the therapeutic efficacy, feasibility, and safety of total parathyroidectomy (tPTX) in the treatment of secondary hyperparathyroidism (SHPT). METHODS: The clinical data of 34 SHPT patients admitted to the Department of Nephrology, Yuxi People's Hospital, from January 2018 to January 2021 who had received tPTX, were retrospectively analyzed. The indications for tPTX were severe SHPT that did not respond to medical treatment and was ineligible for kidney transplantation. tPTX without autotransplantation was adopted to compare the level of symptom relief and changes in serum intact parathyroid hormone (iPTH), blood calcium, and blood phosphorus pre- and postoperatively. RESULTS: In 34 patients, 142 parathyroid glands were removed, including 21 ectopic parathyroid glands (14.78%). Six patients (17.64%, 6/34) had supernumerary parathyroid glands. At 6 h postoperatively, arthralgia and bone pain were significantly reduced to almost zero in 94.12% (32/34) of patients. At 24 h postoperatively, relief of bone pain and improvement of limb movement were observed in 100% (34/34) of patients, and pruritus almost disappeared in 86.36% (19/22) of patients. There were significant differences in iPTH (χ2 = 134.93, P < 0.05), calcium (χ2 = 23.02, P < 0.05), and phosphorus (χ2 = 102.11, P < 0.05) levels preoperatively and 40 min, 24 h, 1 week, half a year, and last available (> 1 year) postoperatively. The patients were followed up for 15-47 months (median 33 months). Hypoparathyroidism was observed in three patients, who underwent neck dissection or partial thymotomy concurrently for different reasons. No intractable hypocalcemia or adynamic bone disease occurred during the follow-up period. CONCLUSION: In SHPT patients who were ineligible for renal transplantation, tPTX was effective, safe, and reliable, with a low recurrence rate. However, when tPTX was performed alone without autologous transplantation, bilateral neck exploration was sufficient, and central neck dissection and thymic resection were inadvisable.

Effects of active vitamin D on insulin resistance and islet ß-cell function in non-diabetic chronic kidney disease patients: a randomized controlled study.

PURPOSE: The purpose of the study is to observe the effects of active vitamin D supplementation on insulin resistance and islet ß-cell function (HOMA-ß) in patients with non-diabetic chronic kidney disease (NDCKD). METHODS: A total of 134 patients with NDCKD who met the inclusion criteria were enrolled in the prospective controlled study and categorized as such: 60 patients in the non-dialysis (ND) group; 36, hemodialysis (HD) group; and 38, peritoneal dialysis (PD) group. Each group was divided into two equal-numbered subgroups for vitamin D supplementation. Those in the experimental subgroups received calcitriol 0.5 ug/day orally, and were followed-up for 6 months. A total of 117 patients were followed-up, including 57 patients in the ND group; 29, HD group; and 31, PD group. Changes in the insulin resistance index (HOMA-IR) and HOMA-ß index were calculated and compared at the time of enrollment and after 1, 3, and 6 months of intervention. RESULTS: (1) Mean HOMA-IR value: In the ND group, mean HOMA-IR value of the experimental group significantly decreased compared with that of the control group after 3 months of intervention (P = 0.02). In the HD and PD groups, there was no statistical difference between the experimental and control groups (P > 0.05). (2) Mean HOMA-ß index: In the ND group, mean HOMA-ß index of the experimental group was higher than that of the control group after 1 month of active vitamin D treatment (P = 0.03), and, with an extended intervention time, the index gradually increased (P < 0.001). In the HD group, mean HOMA-ß index of the experimental group was higher than that of the control group after 3 months of active vitamin D treatment (P = 0.01). Among PD patients, mean HOMA-ß index of the patients in the experimental group was higher than that of the control group after 6 months of active vitamin D treatment (P = 0.02). CONCLUSIONS: Active vitamin D supplementation improved insulin resistance and HOMA-ß after 6 months in ND patients, but only improved HOMA-ß in the dialysis patients, with no significant effect on insulin resistance.

Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-).

Rationale: Ascorbate is an essential micronutrient known for redox functions at normal physiologic concentrations. In recent decades, pharmacological ascorbate has been found to selectively kill tumour cells. However, the dosing frequency of pharmacologic ascorbate in humans has not yet been defined. Methods: We determined that among five hepatic cell lines, Huh-7 cells were the most sensitive to ascorbate. The effects of high-dose ascorbate on hepatoma were therefore assessed using Huh-7 cells and xenograft tumour mouse model. Results: In Huh-7 cells, ascorbate induced a significant increase in the percentage of cells in the G0/G1 phase, apoptosis and intracellular levels of ROS. High doses of ascorbate (4.0 pmol cell-1), but not low doses of ascorbate (1.0 pmol cell-1), also served as a pro-drug that killed hepatoma cells by altering mitochondrial respiration. Furthermore, in a Huh-7 cell xenograft tumour mouse model, intraperitoneal injection of ascorbate (4.0 g/kg/3 days) but not a lower dose of ascorbate (2.0 g/kg/3 days) significantly inhibited tumour growth. Gene array analysis of HCC tumour tissue from xenograft mice given IP ascorbate (4.0 g/kg/3 days) identified changes in the transcript levels of 192 genes/ncRNAs involved in insulin receptor signalling, metabolism and mitochondrial respiration. Consistent with the array data, gene expression levels of AGER, DGKK, ASB2, TCP10L2, Lnc-ALCAM-3, and Lnc-TGFBR2-1 were increased 2.05-11.35 fold in HCC tumour tissue samples from mice treated with high-dose ascorbate, and IHC staining analysis also verified that AGER/RAGE and DGKK proteins were up-regulated, which implied that AGER/RAGE and DGKK activation might be related to oxidative stress, leading to hepatoma cell death. Conclusions: Our studies identified multiple mechanisms are responsible for the anti-tumour activity of ascorbate and suggest high doses of ascorbate with less frequency will act as a novel therapeutic agent for liver cancer in vivo.

Identification of Unequally Represented Founder Viruses Among Tissues in Very Early SIV Rectal Transmission.

Characterizing the transmitted/founder (T/F) viruses of multi-variant SIV infection may shed new light on the understanding of mucosal transmission. We intrarectally inoculated six Chinese rhesus macaques with a single high dose of SIVmac251 (3.1 × 104 TCID50) and obtained 985 full-length env sequences from multiple tissues at 6 and 10 days post-infection by single genome amplification (SGA). All 6 monkeys were infected with a range of 2 to 8 T/F viruses and the dominant variants from the inoculum were still dominant in different tissues from each monkey. Interestingly, our data showed that a cluster of rare T/F viruses was unequally represented in different tissues. This cluster of rare T/F viruses phylogenetically related to the non-dominant SIV variants in the inoculum and was not detected in any rectum tissues, but could be identified in the descending colon, jejunum, spleen, or plasma. In 2 out of 6 macaques, identical SIVmac251 variants belonging to this cluster were detected simultaneously in descending colon/jejunum and the inoculum. We also demonstrated that the average CG dinucleotide frequency of these rare T/F viruses found in tissues, as well as non-dominant variants in the inoculum, was significantly higher than the dominant T/F viruses in tissues and the inoculum. Collectively, these findings suggest that descending colon/jejunum might be more susceptible than rectum to SIV in the very early phase of infection. And host CG suppression, which was previously shown to inhibit HIV replication in vitro, may also contribute to the bottleneck selection during in vivo transmission.

Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui.

Cells harboring latent HIV-1 pose a major obstacle to eradication of the virus. The 'shock and kill' strategy has been broadly explored to purge the latent reservoir; however, none of the current latency-reversing agents (LRAs) can safely and effectively activate the latent virus in patients. In this study, we report an ingenol derivative called EK-16A, isolated from the traditional Chinese medicinal herb Euphorbia kansui, which displays great potential in reactivating latent HIV-1. A comparison of the doses used to measure the potency indicated EK-16A to be 200-fold more potent than prostratin in reactivating HIV-1 from latently infected cell lines. EK-16A also outperformed prostratin in ex vivo studies on cells from HIV-1-infected individuals, while maintaining minimal cytotoxicity effects on cell viability and T cell activation. Furthermore, EK-16A exhibited synergy with other LRAs in reactivating latent HIV-1. Mechanistic studies indicated EK-16A to be a PKCγ activator, which promoted both HIV-1 transcription initiation by NF-κB and elongation by P-TEFb signal pathways. Further investigations aimed to add this compound to the therapeutic arsenal for HIV-1 eradication are in the pipeline.

Polyphenol extracts from Punica granatum and Terminalia chebula are anti-inflammatory and increase the survival rate of chickens challenged with Escherichia coli.

Avian pathogenic Escherichia coli (APEC) causes inflammation in multiple organs of chickens called avian colibacillosis, and results in serious economic loss to the chicken industry. Polyphenolic compounds possess a wide range of physiological activities that may contribute to their beneficial effects against inflammation-related diseases. In this study, the curative effect and mechanism of action of the polyphenolic extracts from Punica granatum L. and Terminalia chebula Retz. in chickens challenged with APEC were studied. Specific-pathogen-free white Leghorn chickens (males, 21-d old) were challenged with APEC and then given oral administration of extracts of P. granatum and T. chebula. The extracts decreased the morbidity and inflammation induced by APEC. Data from quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay showed that the extracts of P. granatum and T. chebula polyphenols (GCP) reversed the over-expression genes of the Toll-like receptor (TLR) 2, 4, and 5, down-regulated the activation of nuclear factor-kappa B signal transduction pathways, and inhibited the production of pro-inflammatory cytokines. Naturally occurring GCP may be a potential alternative medicine for the prevention or treatment of avian colibacillosis.

As a genetic adjuvant, CTA improves the immunogenicity of DNA vaccines in an ADP-ribosyltransferase activity- and IL-6-dependent manner.

Cholera toxin (CT) and its subunits (A and B) have been intensively investigated as adjuvants for protein-based vaccines. Their underlying mechanisms vary with respect to the inoculation route used. By fusing the CTA gene to either the HIV-1-derived Tat-Rev-Vif-Integrase-Nef fusion gene or the OVA gene, our study showed that the fusion of CTA in these DNA vaccines had no cytotoxic effect in vitro and significantly improved both the quantity and quality of the elicited CD8(+) T cell responses. Further experiments identified that the fusion of CTA in these DNA vaccines augmented the secretion of IL-6 in a manner that was dependent on its ADP-ribosyltransferase activity, and protein kinase A (PKA) was found to be the major mediator of its downstream signaling. By site-directed mutagenesis of the ADP-ribosyltransferase catalytic center and in vivo RNAi, we demonstrated that the ADP-ribosyltransferase activity and the upregulation of IL-6 were required for the CTA gene-mediated adjuvant effect. These findings demonstrate that when fused to an immunogen gene, the CTA gene could serve as a potent genetic adjuvant, providing new insights into the mechanisms of CTA as an adjuvant.

Minocycline down-regulates topical mucosal inflammation during the application of microbicide candidates.

An effective anti-human immunodeficiency virus-1 (HIV-1) microbicide should exert its action in the absence of causing aberrant activation of topical immunity that will increase the risk of HIV acquisition. In the present study, we demonstrated that the vaginal application of cellulose sulfate (CS) gel induced topical mucosal inflammatory responses; the addition of minocycline to CS gel could significantly attenuate the inflammation in a mice model. The combined gel of CS plus minocycline not only reduced the production of inflammatory cytokines in cervicovaginal lavages (CVLs), also down-regulated the activation of CD4+ T cells and the recruitment of other immune cells including HIV target cells into vaginal tissues. Furthermore, an In vitro HIV-1 pseudovirus infection inhibition assay showed that the combined gel decreased the infection efficacy of different subtypes of HIV-1 pseudoviruses compared with that of CS gel alone. These results implicate that minocycline could be integrated into microbicide formulation to suppress the aberrant activation of topical mucosal immunity and enhance the safety profile during the application of microbicides.