On-treatment decline in MELD score predicts one-month transplant-free survival in rodenticidal hepatotoxicity patients treated with low-volume plasma exchange.

BACKGROUND AND AIM: Plasma exchange (PLEX) improves survival in patients with rodenticidal hepatotoxicity. However, predictors of treatment response are unknown. We aimed at assessing predictors of response to PLEX treatment in these patients. METHODS: Patients with rodenticidal hepatotoxicity from 2014 to 2023 managed in our department were included in this study. Kochi criteria (model for end-stage liver disease [MELD] score ≥ 36 or international normalized ratio [INR] ≥ 6 with hepatic encephalopathy [HE]) derived specifically for rodenticidal hepatotoxicity (PubMed IDentifier [PMID]: 26310868) were used to assess need for liver transplantation. We analyzed predictors of survival at one month. ∆Bilirubin, ∆MELD score and ∆INR were calculated as percentage change of the parameter after third PLEX session (or after last PLEX if < 3 PLEX sessions done) from baseline pre-PLEX value. RESULTS: Of 200 patients with rodenticidal hepatotoxicity, 114 patients were treated with low-volume PLEX (PLEX-LV). No patient had liver transplantation. Of 78 patients who fulfilled Kochi criteria, 32 patients were PLEX-LV eligible and underwent PLEX-LV (M: 10; age: 20.5, 7-70 years; median, range; acute liver failure: 24). Twenty-two (69%; acute liver failure: 14) of the 32 patients were alive at one month. Presence of HE (p = 0.03) and ∆MELD (p < 0.001) were significant predictors on univariate analysis, while ∆MELD (aOR = 0.88, 95% CI: 0.79-0.98, p = 0.01) was the only significant independent predictor of one-month transplant-free survival. Area under receiver operating characteristic (ROC) for ∆MELD was 0.93 (95% CI:0.85-1.00) and a decrease of ≥ 20% in MELD score while on PLEX-LV had 90% sensitivity and 90% specificity in predicting one-month survival. CONCLUSIONS: Decline in MELD while on PLEX-LV independently predicted one-month transplant-free survival in rodenticidal hepatotoxicity patients. This may help guide decision on stopping PLEX-LV in patients predicted to respond to treatment and to consider alternate treatment options in non-responders.

Basic science meets clinical medicine: identification of a CD2AP-deficient patient.

Recent years have witnessed an explosion of research into the molecular basis of glomerular disease resulting in nephrotic- range urinary protein leak using both human genetics and animal models. Löwik et al. describe the first case report of an early-onset nephrotic syndrome presenting in conjunction with a homozygous CD2AP mutation. These data demonstrate the convergence between basic and clinical approaches and their potential to transform our understanding of the pathogenetic mechanisms underlying human glomerular disease.

Quantitative gene expression profiling implicates genes for susceptibility and resistance to alveolar bone loss.

Periodontal disease is one of the most prevalent chronic inflammatory diseases. There is a genetic component to susceptibility and resistance to this disease. Using a mouse model, we investigated the progression of alveolar bone loss by gene expression profiling of susceptible and resistant mouse strains (BALB/cByJ and A/J, respectively). We employed a novel and sensitive quantitative real-time PCR method to compare basal RNA transcription of a 48-gene set in the gingiva and the spleen and the subsequent changes in gene expression due to Porphyromonas gingivalis oral infection. Basal expression of interleukin-1 beta (Il1b) and tumor necrosis factor alpha (Tnf) mRNA was higher in the gingiva of the susceptible BALB/cByJ mice than in the gingiva of resistant A/J mice. Gingival Il1b gene expression increased further and Stat6 gene expression was turned on after P. gingivalis infection in BALB/cByJ mice but not in A/J mice. The basal expression of interleukin-15 (Il15) in the gingiva and the basal expression of p-selectin (Selp) in the spleen were higher in the resistant A/J mice than in the susceptible BALB/cByJ mice. In the resistant A/J mice the expression of no genes detectably changed in the gingiva after infection. These results suggest a molecular phenotype in which discrete sets of differentially expressed genes are associated with genetically determined susceptibility (Il1b, Tnf, and Stat6) or resistance (Il15 and Selp) to alveolar bone loss, providing insight into the genetic etiology of this complex disease.

Efficient chromosomal mapping of a methylcholanthrene-induced tumor antigen by CTL immunoselection.

It has been difficult to genetically map the genes encoding tumor Ags because they arise as a consequence of somatic mutational events. CTL-mediated immunoselection can impose potent immunoselective pressure against tumor cells, resulting in the survival of rare tumor Ag-loss variants. We subjected a heterozygous 3-methylcholanthrene-induced murine sarcoma cell line to CTL immunoselection, selecting for the loss of a tumor-specific Ag, recognized antigen from MCA-induced tumor 1 (Ram1). Several variants eluded CTL recognition by genetic loss of the hemizygously expressed tumor-specific Ag epitope. A frequently observed genetic escape mechanism was spontaneous mitotic recombination resulting in loss of heterozygosity on chromosome 4. Higher density genetic analyses along with functional confirmation with an independently produced chromosome 4 loss of heterozygosity variant positioned the Ram1 locus to a distal 7.1 cM interval on chromosome 4. This region of the mouse genome is rich in tumor-modifier genes and this positioning of Ram1 may thus provide insight into the genetic basis of 3-methycholanthrene-induced tumor Ags.

Isothermal titration calorimetry measurements of Ni(II) and Cu(II) binding to His, GlyGlyHis, HisGlyHis, and bovine serum albumin: a critical evaluation.

The binding of Ni(II) and Cu(II) to histidine, to the tripeptides GlyGlyHis and HisGlyHis, and to the protein bovine serum albumin has been studied by isothermal titration calorimetry (ITC) to determine the experimental conditions and data analysis necessary to reproduce literature values for the binding constants and thermodynamic parameters. From analysis of the ITC data, we find that there are two major considerations for the use of this method to accurately quantify metal ion interaction with biological macromolecules. First, to determine true pH-independent binding constants, ITC data must be corrected for metal ion competition with protons by accounting for the experimental pH and pKa values of the metal-binding residues. Second, metal interaction with the buffer (stability and enthalpy of formation of metal-buffer complex(es)) must be included in the analysis of the ITC data to determine the binding constants and the change in enthalpy. While it may be possible to use a buffer that forms only weak, and therefore negligible, complexes with the metal, a buffer that has a strong and well-characterized interaction has the benefit of suppressing metal ion hydrolysis and precipitation, and of allowing the quantification of high-affinity metal-binding sites on biological macromolecules. This study has also quantified the contribution of the N-terminal imidazole of HisGlyHis to the stability of the Cu(II) and Ni(II) complexes of this protein sequence and has provided new insight about Cu(II) binding to albumin.