Wernicke's Encephalopathy in Acute and Chronic Kidney Disease:A Systematic Review

Thiamine (vitamin B1) deficiency is relatively common in patients with kidney disease. Wernicke's encephalopathy (WE) is caused by vitamin B1 deficiency. Our aim was to systematically review the signs and symptoms of WE in patients with kidney disease. We conducted a systematic literature review on WE in kidney disease and recorded clinical and radiographic characteristics, treatment and outcome. In total 323 manuscripts were reviewed, which yielded 46 cases diagnosed with acute and chronic kidney disease and WE published in 37 reports. Prodromal characteristics of WE were loss of appetite, vomiting, weight loss, abdominal pain, and diarrhea. Parenteral thiamine 500 mg 3 times per day often led to full recovery, while Korsakoff's syndrome was found in those receiving low doses. To prevent WE in kidney failure, we suggest administering high doses of parenteral thiamine in patients with kidney disease who present with severe malnutrition and (prodromal) signs of thiamine deficiency.</p

Comparison of the chromosomal pattern of primary testicular nonseminomas and residual mature teratomas after chemotherapy

About 70 to 75% of patients with nonseminomatous testicular germ cell tumors (NSs) present with metastases. When these metastases are treated with chemotherapy, often residual mature teratoma (RMT) is left. RMT is composed of fully differentiated somatic tissue. Untreated metastases of NSs rarely consist exclusively of mature somatic tissue. Apparently, after chemotherapy treatment there is a shift towards higher degrees of differentiation. Investigating tumor progression and the mechanism(s) involved in therapy-related differentiation, we compared the cytogenetically abnormal karyotypes of a series of 70 NSs with those of 31 RMTs. In NSs and RMTs, the modal total chromosome number does not differ and is in the triploid range. Both the frequency and the average copy number of i(12p) are the same, and the pattern of chromosomal over-and underrepresentation and distribution of breakpoints do not differ significantly in these series. So, we found the chromosomal pattern of RMTs as abnormal as those of primary NSs. Based on cytogenetics, we found no indication that specific chromosomal alterations parallel metastasis and therapy-related differentiation of the metastases. The cytogenetic data suggest that both induction of differentiation of (selected) cells or selection of cells with capacity to differentiate are possible mechanisms for the therapy-related differentiation of RMTs. (C) Elsevier Science Inc., 1997

Effect of Terbinafine on the Pharmacokinetics of Cyclosporin in Humans

Cyclosporin is largely metabolized by hepatic cytochrome P450 enzymes, and azole drugs that inhibit cytochrome P450 may precipitate cyclosporin toxicity. The allylamine terbinafine binds to a small subfraction of hepatic cytochrome P450 in type I fashion, and has no effect upon hepatic metabolism of cyclosporin in vitro. The purpose of this study was to determine whether oral terbinafine alters the pharmacokinetics of oral cyclosporin in vivo.Twenty male volunteers (age 19–44 years), were randomly allocated to two groups. The first group received three single oral doses of cyclosporin 300mg at intervals of 21 d. The second and third doses of cyclosporin were preceded by a 6-d course of oral terbinafine 250mg each morning. A further 250mg of terbinafine was taken with the second and third doses of cyclosporin. Blood levels of cyclosporin and terbinafine were monitored for 36h after each dose. The second group received a 7-d course of terbinafine 250mg each morning. On the seventh day a single dose of cyclosporin 300mg was taken together with the terbinafine. Blood levels of both cyclosporin and terbinafine were monitored for 36kh. Two further single doses of cyclosporin 300mg were given at intervals of 2 weeks and the cyclosporin levels again monitored. In both groups each cyclosporin dose was preceded by an 8-h fast.The mean peak blood concentration of cyclosporin when taken alone was 958 μg/I, and 822 when taken with terbinafine. The mean area under the curve for cyclosporin was 4207 μg/l/h when taken alone and 3665 when taken with terbinafine. The mean absorption half-life for cyclosporin when taken alone was 0.29 h, and 0.33 when taken with terbinafine. The mean time of maximum concentration and elimination half-life of cyclosporin were unaltered by terbinafine. The results suggest that terbinafine is likely to prove a safe systemic anti-fungal treatment for patients who are taking cyclosporin

Haemostatic changes in urogenital schistosomiasis haematobium: A case-control study in Gabonese schoolchildren

In many tropical areas schistosomiasis is a major health problem causing hepatosplenic, intestinal or urogenital complaints. Hepatosplenic schistosomiasis mansoni is also characterized by blood coagulation abnormalities. Liver pathology plays a role in the development of haemostatic changes and the parasitic infection may directly affect coagulation. However, these contributing factors cannot be studied separately in hepatosplenic schistosomiasis infections. This pilot study provides insight in haemostatic changes in urinary schistosomiasis by studying coagulation parameters in schistosomiasis haematobium-infected Gabonese schoolchildren. Selection on urinary schistosomiasis patients without hepatosplenic complaints allows for the investigation of the direct effects of the parasite on haemostasis. Levels of von Willebrand Factor (VWF) antigen, active VWF and osteoprotegerin were elevated, indicating inflammation-mediated endothelial activation. In contrast to hepatosplenic schistosomiasis, thrombin-antithrombin complex and D-dimer levels were not affected. Despite its small sample size, this study clearly indicates that Schistosoma haematobium directly alters the activation status of the endothelium, without initiation of coagulation

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome

B-cell targeting with anti-CD38 daratumumab:implications for differentiation and memory responses

B cell–targeted therapies, such as CD20-targeting mAbs, deplete B cells but do not target the autoantibody-producing plasma cells (PCs). PC-targeting therapies such as daratumumab (anti-CD38) form an attractive approach to treat PC-mediated diseases. CD38 possesses enzymatic and receptor capabilities, which may impact a range of cellular processes including proliferation and differentiation. However, very little is known whether and how CD38 targeting affects B-cell differentiation, in particular for humans beyond cancer settings. Using in-depth in vitro B-cell differentiation assays and signaling pathway analysis, we show that CD38 targeting with daratumumab demonstrated a significant decrease in proliferation, differentiation, and IgG production upon T cell–dependent B-cell stimulation. We found no effect on T-cell activation or proliferation. Furthermore, we demonstrate that daratumumab attenuated the activation of NF-κB in B cells and the transcription of NF-κB–targeted genes. When culturing sorted B-cell subsets with daratumumab, the switched memory B-cell subset was primarily affected. Overall, these in vitro data elucidate novel non-depleting mechanisms by which daratumumab can disturb humoral immune responses. Affecting memory B cells, daratumumab may be used as a therapeutic approach in B cell–mediated diseases other than the currently targeted malignancies.</p

B-cell targeting with anti-CD38 daratumumab:implications for differentiation and memory responses

B cell–targeted therapies, such as CD20-targeting mAbs, deplete B cells but do not target the autoantibody-producing plasma cells (PCs). PC-targeting therapies such as daratumumab (anti-CD38) form an attractive approach to treat PC-mediated diseases. CD38 possesses enzymatic and receptor capabilities, which may impact a range of cellular processes including proliferation and differentiation. However, very little is known whether and how CD38 targeting affects B-cell differentiation, in particular for humans beyond cancer settings. Using in-depth in vitro B-cell differentiation assays and signaling pathway analysis, we show that CD38 targeting with daratumumab demonstrated a significant decrease in proliferation, differentiation, and IgG production upon T cell–dependent B-cell stimulation. We found no effect on T-cell activation or proliferation. Furthermore, we demonstrate that daratumumab attenuated the activation of NF-?B in B cells and the transcription of NF-?B–targeted genes. When culturing sorted B-cell subsets with daratumumab, the switched memory B-cell subset was primarily affected. Overall, these in vitro data elucidate novel non-depleting mechanisms by which daratumumab can disturb humoral immune responses. Affecting memory B cells, daratumumab may be used as a therapeutic approach in B cell–mediated diseases other than the currently targeted malignancies

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe