Chemical Transformations of 2D Kaolinic Clay Mineral Surfaces from Sulfuric Acid Exposure.

A combined experimental and computational approach is used to investigate the chemical transformations of kaolinite and metakaolin surfaces when exposed to sulfuric acid. These clay minerals are hydrated ternary metal oxides and are shown to be susceptible to degradation by loss of Al as the water-soluble salt Al2(SO4)3, due to interactions between H2SO4 and aluminum cations. This degradation process results in a silica-rich interfacial layer on the surfaces of the aluminosilicates, most prominently observed in metakaolin exposed to pH environments of less than 4. Our observations are supported by XPS, ATR-FTIR, and XRD experiments. Concurrently, DFT methodologies are used to probe the interactions between the clay mineral surfaces and H2SO4 as well as other sulfur-containing adsorbates. An analysis performed using a DFT + thermodynamics model shows that the surface transformation processes that lead to the loss of Al and SO4 from metakaolin are favorable at pH below 4; however, such transformations are not favorable for kaolinite, a result that agrees with our experimental efforts. The data obtained from both experimental techniques and computational studies support that the dehydrated surface of metakaolin interacts more strongly with sulfuric acid and provide atomistic insight into the acid-induced transformations of these mineral surfaces.

Effect of the first wave of COVID-19 on Poison Control Centre activities in 21 European countries: an EAPCCT initiative.

BACKGROUND: Public health emergencies often affect Poison Control Centre (PCC) operations. We examined possible effects of the coronavirus disease 2019 (COVID-19) pandemic on call volume, call characteristics, and workload in European PCCs. METHOD: All 65 individual European PCCs were requested to supply data on the number of calls and call characteristics (caller, age groups, reason and specific exposures) from March to June in 2018, 2019, and 2020 (Part 1). Number of calls with specific characteristics was normalised to all calls. Calls (N) and call characteristics (%) were compared between 2020 and 2018/2019 (average), within PCCs/countries and grouped. Correlation between call volume and COVID-19 cases per PCC/country was examined. All PCCs received a survey on workload (Part 2). Parts 1 and 2 were independent. RESULTS: For Part 1, 36 PCCs (21 countries) supplied 26 datasheets. PCCs in the UK and in France merged data and supplied one datasheet each with national data. Summed data showed an increase of 4.5% in call volume from 228.794 in 2018/2019 (average) to 239.170 in 2020 (p < 0.001). Within PCCs/countries, calls significantly increased for 54% of PCCs/countries (N = 14/26) and decreased for 19% (N = 5/26), three of which (N = 3/5) only serve medical professionals. Correlation between call volume and COVID-19 cases was (non-significant) positive (Rho >0.7) in 5/26 PCCs/countries (19%), and negative in 6/26 (23%). Call characteristics (median proportion of grouped data in 2018/2019 vs. 2020) changed: fewer medical professionals called (40 vs. 34%, p < 0.001), calls on intentional exposures decreased (20 vs. 17%, p < 0.012), as did calls on patients between 13 and 17 years (5 vs. 4%, p < 0.05). Calls on specific exposures increased; disinfectants from 1.9 to 5.2%, and cleaning products from 4.4 to 5.7% (p < 0.001). For Part 2, 38 PCCs (24 countries) filled the survey on workload (number/length of shifts and time on PCC duties), which increased in 23/38 PCCs (61%), while 10/38 (26%) worked with fewer employees. CONCLUSIONS: Obtaining aggregated European PCC data proved challenging but showed an increase in overall call volume and workload during the first COVID-19 wave. Call characteristics changed including fewer calls from professionals and more calls on specific exposures. Within single PCCs/countries a variety of effects was observed.

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies.

Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.

Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults.

BACKGROUND & AIMS: Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. METHODS: Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. RESULTS: The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 µmol/l) increase vs. individuals without (delta BA ≤1 µmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. CONCLUSION: A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut-liver axis.

Fracture Diodes: Directional Asymmetry of Fracture Toughness.

Toughness describes the ability of a material to resist fracture or crack propagation. It is demonstrated here that fracture toughness of a material can be asymmetric, i.e., the resistance of a medium to a crack propagating from right to left can be significantly different from that to a crack propagating from left to right. Such asymmetry is unknown in natural materials, but we show that it can be built into artificial materials through the proper control of microstructure. This paves the way for control of crack paths and direction, where fracture-when unavoidable-can be guided through predesigned paths to minimize loss of critical components.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-α biologicals and an Infliximab-biosimilar.

INTRODUCTION: TNF-α-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-α antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. AIM: To determine the neutralizing capacity of first- and second generation anti-TNF-α antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). METHODS: TNF-α neutralization was measured using a quantitative TNF-α sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF-кB response element. All available anti-TNF-α drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-α-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab2-fragment, biosimilar CT-P13 (Inflectra) and ADA. RESULTS: TNF-α strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of first-generation anti-TNF-α drugs were required to neutralize TNF-α compared to the second-generation anti-TNF-α drugs. Serum of IBD patients with proven ATI blocked TNF-α-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA. CONCLUSION: The second-generation anti-TNF-α drugs show increased TNF-α-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar.

Validation and determination of taselisib, a ß-sparing phosphoinositide 3-kinase (PI3K) inhibitor, in human plasma by LC-MS/MS.

A liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of taselisib (GDC-0032, RO5537381) concentrations in human plasma has been developed and validated to support bioanalysis of clinical samples. Solid phase extraction (SPE) was used to extract plasma samples (50µL) and the resulting samples were analyzed using reversed phase chromatography and mass spectrometry coupled with an atmospheric pressure chemical ionization interface. The mass analysis of taselisib was performed using multiple reaction monitoring transitions in positive ionization mode. The method was validated over the calibration curve range 0.400-400ng/mL using linear regression and 1/x(2) weighting. The within-run relative standard deviation (%RSD) ranged from 1.3 to 5.6%, while the between-run %RSD varied from 2.0 to 4.5% for LLOQ, low, medium, medium high and high QCs. The accuracy ranged from 94.7 to 100.3% of nominal for within-run and 96.0-99.0% of nominal for between-run for the same QCs. Extraction recovery of taselisib was between 83.8% and 92.9%. Stability of taselisib was established in human plasma for 977days at -20°C and -70°C and established in sample extracts for 96h when stored at 2 - 8°C. Stable-labeled internal standard was used to minimize matrix effects. Mean single dose pharmacokinetic parameters determined using this method for a phase I/II clinical trial were: Cmax=35.2ng/mL, AUC0-inf=1570ngh/mL, and T1/2=39.3h.

A supported liquid extraction-LC-MS/MS method for determination of GDC-0980 (Apitolisib), a dual small-molecule inhibitor of class 1A phosphoinositide 3-kinase and mammalian target of rapamycin, in human plasma.

A liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of GDC-0980 (Apitolisib) concentrations in human plasma has been developed and validated to support clinical development. Supported liquid extraction (SLE) was used to extract plasma samples (80µL) and the resulting samples were analyzed using reverse-phase chromatography and mass spectrometry coupled with a turbo-ionspray interface. The mass analysis of GDC-0980 was performed using multiple reaction monitoring (MRM) transitions in positive ionization mode. The method was validated over the calibration curve range 0.0500-25.0ng/mL using linear regression and 1/x(2) weighting. Within-run relative standard deviation (%RSD) ranged from 0.4 to 3.9%, while the between-run %RSD varied from 1.1 to 1.5% for QCs. The accuracy ranged from 96.1% to 106.7% of nominal for within-run and 96.7-106.7% of nominal for between-run at all concentrations including the LLOQ quality control at 0.0500ng/mL. Extraction recovery of GDC-0980 was between 72.4% and 75.5%. Stability of GDC-0980 was established in human plasma for 547 days at -20°C and -70°C and established in reconstituted sample extracts for 146h when stored at 2-8°C. Stable-labeled internal standard was used to minimize matrix effects. Mean pharmacokinetic parameters determined using this method for the day 1 control group in a phase I trial were: Cmax=11.1ng/mL, AUC0-inf=108ngh/mL, and T1/2=13.1h.

Characterization of the genetic diversity of Mycobacterium tuberculosis in São Paulo city, Brazil.

BACKGROUND: Tuberculosis is a major health problem in São Paulo, Brazil, which is the most populous and one of the most cosmopolitan cities in South America. To characterize the genetic diversity of Mycobacterium tuberculosis in the population of this city, the genotyping techniques of spoligotyping and MIRU were applied to 93 isolates collected in two consecutive years from 93 different tuberculosis patients residing in São Paulo city and attending the Clemente Ferreira Institute (the reference clinic for the treatment of tuberculosis). FINDINGS: Spoligotyping generated 53 different spoligotype patterns. Fifty-one isolates (54.8%) were grouped into 13 spoligotyping clusters. Seventy- two strains (77.4%) showed spoligotypes described in the international databases (SpolDB4, SITVIT), and 21 (22.6%) showed unidentified patterns. The most frequent spoligotype families were Latin American Mediterranean (LAM) (26 isolates), followed by the T family (24 isolates) and Haarlem (H) (11 isolates), which together accounted for 65.4% of all the isolates. These three families represent the major genotypes found in Africa, Central America, South America and Europe. Six Spoligo-International-types (designated SITs by the database) comprised 51.8% (37/72) of all the identified spoligotypes (SIT53, SIT50, SIT42, SIT60, SIT17 and SIT1). Other SITs found in this study indicated the great genetic diversity of M. tuberculosis, reflecting the remarkable ethnic diversity of São Paulo city inhabitants. The MIRU technique was more discriminatory and did not identify any genetic clusters with 100% similarity among the 93 isolates. The allelic analysis showed that MIRU loci 26, 40, 23 and 10 were the most discriminatory. When MIRU and spoligotyping techniques were combined, all isolates grouped in the 13 spoligotyping clusters were separated. CONCLUSIONS: Our data indicated the genomic stability of over 50% of spoligotypes identified in São Paulo and the great genetic diversity of M. tuberculosis isolates in the remaining SITs, reflecting the large ethnic mix of the São Paulo city inhabitants. The results also indicated that in this city, M. tuberculosis isolates acquired drug resistance independently of genotype and that resistance was more dependent on the selective pressure of treatment failure and the environmental circumstances of patients.

Monocytes and their pathophysiological role in Crohn's disease.

Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn's disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn's disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn's disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account.

Idiopathic neuralgic amyotrophy in childhood.

In addition to the review by van Alfen et al., which has been published in 2000, we would like to report a seven-week-old boy with bilateral idiopathic brachial plexus neuropathy that did not show any signs of osteomyelitis on repeated scintigraphy. To our knowledge this is the first child reported with bilateral plexus involvement.

Effects of different immunosuppressive regimens on regulatory T-cells in noninflamed colon of liver transplant recipients.

BACKGROUND: Regulatory T-cells (Treg) are natural suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients. METHODS: Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR. RESULTS: No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and 1 specific drug was detected. CONCLUSIONS: These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.

Review article: The function and regulation of proteins involved in bile salt biosynthesis and transport.

BACKGROUND: Bile salts are produced and secreted by the liver and are required for intestinal absorption of fatty food components and excretion of endobiotics and xenobiotics. They are reabsorbed in the terminal ileum and transported back to the liver via the portal tract. Dedicated bile salt transporters in hepatocytes and enterocytes are responsible for the unidirectional transport of bile salts in the enterohepatic cycle. AIM: To give an overview of the function and regulations of proteins involved in bile salt synthesis and transport. METHODS: Data presented are obtained from PubMed-accessible literature combined with our own recent research. RESULT: Hepatocytes and enterocytes contain unique bile salt importers (sodium-taurocholate cotransporting polypeptide and apical sodium-dependent bile acid transporter, respectively) and exporters (bile salt export pump and organic solute transporter alpha-beta, respectively). Enzymes involved in bile salt biosynthesis reside in different subcellular locations, including the endoplasmic reticulum, mitochondria, cytosol and peroxisomes. Defective expression or function of the transporters or enzymes may lead to cholastasis. The bile salt-activated transcription factor Farnesoid X receptor controls expression of genes involved in bile salt biosynthesis and transport. CONCLUSIONS: Detailed knowledge is available about the enzymes and transporters involved in bile salt homeostasis and how their defective function is associated with cholestasis. In contrast, the process of intracellular bile salt transport is largely unexplored.

Biocatalytic approaches for the quantitative production of single stereoisomers from racemates.

Strategies for the chemoenzymatic transformation of a racemate into a single stereoisomeric product in quantitative yield have been developed. A range of industrially relevant alpha-hydroxycarboxylic acids was deracemized in a stepwise fashion via lipase-catalysed enantioselective O-acylation, followed by mandelate racemase-catalysed racemization of the remaining non-reacted substrate enantiomer. Alternatively, aliphatic alpha-hydroxycarboxylic acids were enzymatically isomerized using whole resting cells of Lactobacillus spp. Enantioselective hydrolysis of rac-sec-alkyl sulphate esters was accomplished using novel alkyl sulphatases of microbial origin. The stereochemical path of catalysis could be controlled by choice of the biocatalyst. Whereas Rhodococcus ruber DSM 44541 and Sulfolobus acidocaldarius DSM 639 act through inversion of configuration, stereo-complementary retaining sulphatase activity was detected in the marine planctomycete Rhodopirellula baltica DSM 10527.

The prevalence of wrist ganglia in an asymptomatic population: magnetic resonance evaluation.

Magnetic resonance imaging (MRI) was performed on the wrists of 103 asymptomatic volunteers. The images were evaluated independently by two musculoskeletal radiologists and one orthopaedic surgeon. Wrist ganglia were identified in 53 out of the 103 wrists. The average long and short axes measurements were 8 mm (range 3-22) and 3 mm (range 2-10), respectively. Seventy per cent of the ganglia originated from the palmar capsule in the region of the interval between the radioscaphocapitate ligament and the long radiolunate ligament. Fourteen per cent of the ganglia were dorsal and originated from the dorsal, distal fibres of the scapholunate ligament. Two ganglia had surrounding soft tissue oedema and one had an associated intraosseous component. Unlike previous surgical and pathological series, our study showed that palmar wrist ganglia are more common than dorsal wrist ganglia. The vast majority of these asymptomatic ganglia occur without associated ligamentous disruption, soft tissue oedema or intraosseous communication.

The detection of loose bodies in the elbow: the value of MRI and CT arthrography.

Our aim was to determine the clinical value of MRI and CT arthrography in predicting the presence of loose bodies in the elbow. A series of 26 patients with mechanical symptoms in the elbow had plain radiography, MRI and CT arthrography, followed by routine arthroscopy of the elbow. The location and number of loose bodies determined by MRI and CT arthrography were recorded. Pre-operative plain radiography, MRI and CT arthrography were compared with arthroscopy. Both MRI and CT arthrography had excellent sensitivity (92% to 100%) but low to moderate specificity (15% to 77%) in identifying posteriorly-based loose bodies. Neither MRI nor CT arthrography was consistently sensitive (46% to 91%) or specific (13% to 73%) in predicting the presence or absence of loose bodies anteriorly. The overall sensitivity for the detection of loose bodies in either compartment was 88% to 100% and the specificity 20% to 70%. Pre-operative radiography had a similar sensitivity and specificity of 84% and 71%, respectively. Our results suggest that neither CT arthrography nor MRI is reliable or accurate enough to be any more effective than plain radiography alone in patients presenting with mechanical symptoms in the elbow.

Osteoblastoma of the clavicle.

A 14-year-old female with a 1-year history of a painful clavicle mass underwent resection and reconstruction with an intercalated autograft and rigid plate fixation. The histopathology was diagnostic for osteoblastoma. Although a clavicle mass is a common entity following clavicle trauma, less common disorders such as bone tumors need to be considered in the differential diagnosis. Osteoblastoma is an uncommon, benign bone tumor representing 1% of all primary bone tumors. An extensive review of the literature reveals only one reported case of clavicular osteoblastoma.

ATP binding cassette transporter gene expression in rat liver progenitor cells.

BACKGROUND AND AIM: Liver regeneration after severe liver damage depends in part on proliferation and differentiation of hepatic progenitor cells (HPCs). Under these conditions they must be able to withstand the toxic milieu of the damaged liver. ATP binding cassette (ABC) transporters are cytoprotective efflux pumps that may contribute to the preservation of these cells. The aim of this study was to determine the ABC transporter phenotype of HPCs. METHODS: HPC activation was studied in rats treated with 2- acetylaminofluorene (2-AAF) followed by partial hepatectomy (PHx). ABC transporter gene expression was determined by real time detection reverse transcription-polymerase chain reaction in isolated HPCs, hepatocytes, cholangiocytes, and cultured progenitor cell-like RLF phi 13 cells and by immunohistochemistry of total liver samples. ABC transporter efflux activity was studied in RLF phi 13 cells by flow cytometry. RESULTS: 2-AAF/PHx treated animals showed increased hepatic mRNA levels of the genes encoding multidrug resistance proteins Mdr1b, Mrp1, and Mrp3. Immunohistochemistry demonstrated expression of Mrp1 and Mrp3 proteins in periportal progenitor cells and of the Mdr1b protein in periportal hepatocytes. Freshly isolated Thy-1 positive cells and cultured RLF phi 13 progenitor cells highly expressed Mrp1 and Mrp3 mRNA while the hepatocyte specific transporters Mdr2, Bsep, Mrp2, and Mrp6 were only minimally expressed. Blocking Mrp activity by MK-571 resulted in accumulation of the Mrp specific substrate carboxyfluorescein in RLF phi 13 cells. CONCLUSION: HPCs express high levels of active Mrp1 and Mrp3. These may have a cytoprotective role in conditions of severe hepatotoxicity.