Elevated Alkaline Phosphatase Research Articles

18F-AlF-NOTA-octreotide PET/CT in the localization of tumor-induced osteomalacia: case series and literature review.

This study explores tumor-induced osteomalacia (TIO) through a case series and literature review, assessing the diagnostic potential of 18F-AlF-NOTA-octreotide (18F-OC) positron emission tomography/computed tomography (PET/CT). We analyzed TIO patients who underwent 18F-OC PET/CT. Parameters such as tumor dimension, the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) were meticulously assessed. Clinical features and imaging characteristics pertinent to TIO were reviewed. 6 patients with clinical suspicion of TIO exhibited hypophosphatemia (0.25 to 0.64 mmol/L), elevated alkaline phosphatase (ALP) levels (142 to 506 U/L), and increased parathyroid hormone (PTH) levels (92.9 to 281.7 pg/mL). Of these patients, two underwent FGF-23 testing, with results of 3185.00 pg/ml and 17.56 pg/ml, respectively. Conventional imaging modalities depicted widespread osteoporosis, with several cases demonstrating fractures indicative of osteomalacic and associated pathological fractures. Subsequent 18F-OC PET/CT facilitated the accurate localization of causative tumors, with histopathological examination confirming the diagnosis of phosphaturic mesenchymal tumor (PMT). The interval from initial clinical presentation to definitive TIO diagnosis spanned approximately 2.5 years (range: 1 - 4 years), with tumors varying in size (maximum diameter: 7.8 to 40.0mm), SUVmax (5.47 to 25.69), SUVmean (3.43 to 7.26), and MTV (1.27 to 18.59 cm3). The implementation of whole-body 18F-OC PET/CT imaging emerges as a critical tool in the identification of occult tumors causing TIO. Future investigations incorporating a broader cohort are imperative to further delineate the diagnostic and therapeutic implications of 18F-OC PET/CT in managing TIO.

A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors.

e15106 Background: HX301 (narazaciclib) is a promising novel multi-kinase inhibitor with potent activity against Colony Stimulating Factor 1 Receptor (CSF1R), Cyclin-Dependent Kinase 4/6 (CDK4/6), and Aurora Kinase 5 (ARK5), with a half-maximal inhibitory concentration (IC50) values in 0.29-4.95 nM range. It is an oral bioavailable agent and has the ability to cross blood-brain barrier. Preclinical data have showed significant antitumor activities, warranting further clinical trials to evaluate the safety, and potential efficacy in human subjects. Methods: Utilizing the standard 3+3 design, the study aimed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of HX301. Patients with heavily pretreated advanced solid tumors received HX301single agent via oral administration, with doses ranging from 40mg to 200mg once daily for the first 21 days of each 28-day cycle. Results: As of December 27, 2023, a total of 20 patients (5 males, 15 females) were enrolled in the study, with varying doses of HX301 administered: 40 mg (n=3), 80 mg (n=3), 120 mg (n=4), 160 mg (n=3), and 200 mg (n=7). The median age of the patients was 55 years, ranging from 30 to 71. Notably, 15 patients (75%) had metastatic breast cancers. Dose-limiting toxicities (DLTs) were observed in 2 patients in the 200 mg group. These included a Grade 4 increase in alanine aminotransferase (ALT) and a Grade 3 decrease in platelet counts with associated epistaxis, both of which resolved after discontinuation of treatment. The most common treatment-related adverse events (AEs) observed were elevated aspartate aminotransferase (AST) (65.0%), decreased white blood cell count (50%), decreased neutrophil count (50%), elevated ALT (45%), elevated creatine kinase (45%), and elevated creatinine (35%). Additionally, 4 patients experienced Grade 3 or higher treatment-related AEs, including 1 patient in the 160 mg group with Grade 3 elevated γ-glutamyl transferase and alkaline phosphatase, and 3 patients in the 200 mg group with Grade 4 elevated ALT and Grade 3 elevated AST and Dyspepsia, Grade 3 decreased neutrophil and platelet counts, and Grade 3 hyperglycemia. Notably, no AEs led to death. Among the 20 patients evaluable for tumor assessment using RECIST 1.1 by Investigators, 4 obtained stable disease, including 2 patients in the 200 mg group, 1 in the 120 mg group, and 1 in the 80 mg group. Furthermore, 1 patient with HR+ breast cancer in the 200 mg group received study drug for over a year and achieved prolonged stable disease for more than 12 months, highlighting a notable clinical outcome. Conclusions: HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934 .

Patient-derived reference intervals for alkaline phosphatase to support appropriate utility for isoenzymes determinations and hypophosphatasia.

Appropriate age- and sex-specific reference intervals for alkaline phosphatase (ALP) are essential to identify patients with hypophosphatasia (low ALP) and to avoid unnecessary ALP isoenzymes analysis (elevated ALP). This study used patient ALP historical data to statistically derive sex- and age-specific reference intervals. The ALP values reported as part of clinical management during an 18 month period (from July 2021 to March 2023) were obtained. Following logarithmic transformation of ALP data and repeated removal of outliers, cumulative frequency plots were generated using a modified Hoffmann approach to derive age- and sex-specific reference intervals. Age-specific ALP reference intervals ranged from 110 to 250 and 120 to 295 U/L for males and females <15 days old, 80 to 400 and 90 to 380 U/L for males and females 15 days to 1 year old, 105 to 280 and 90 to 290 U/L for males and females 1 to 10 years old, 75 to 300 and 90 to 300 U/L for males and females 10 to 13 years old, 80 to 300 and 60 to 175 U/L for males and females 13 to 15 years old, 55 to 150 and 60 to 180 U/L for males and females 15 to 18 years old, and 55 to 140 and 60 to 147 U/L for male and female adults, respectively (>18 years old). By applying derived ranges, a retrospective review of ALP isoenzymes would eliminate 24.5% of requests. Additionally, 9 neonates would have required investigation for possible hypophosphatasia.

Benign transient hyperphosphatasemia in the pediatric population: a single center cohort study.

Alkaline phosphatase (ALP) can be increased in a benign condition known as benign-transient hyperphosphatasemia (BTH). We aimed to evaluate the demographic, and clinical characteristics of infants and children with BTH. In our retrospective study, infants and children diagnosed with BTH between September 2019 and September 2023 were included. Of 249 children with elevated ALP levels, 95 (38.1 %) had BTH. The mean age at diagnosis of children with BTH was 2.4±1.3 years (min 0.6- max 6.2 years). ALP mean value was 2,587±1252 U/L (min 972- max 5757 U/L). ALP value was an average 7.4±3.6 times higher than the corresponding upper limit of normal. The second measurement was made after an average of 13.2±6days, and a statistically significant difference was detected compared to the first value, with a decrease of 61±23 % in the ALP value (p<0.001). ALP value returned to normal in an average of 44±29.2days. Elevated ALP was detected during infection in 49 (51.6 %) children. When the sample was divided into those under 2 years of age and aged 2 and over, no statistical difference was observed in ALP levels in the time it took for ALP levels to return to the normal range (p=0.480). BTH should be kept in mind if high serum ALP is detected in children without clinical or laboratory suspicion of bone or liver disease. In the follow up detecting a significant decrease trend compared to the first value may be guiding for BTH.

Dietary supplementation of Astragalus fermentation products improves the growth performance, immunological characteristics, and disease resistance of crucian carp (Carassius auratus)

The fermentation products of Astragalus have been acknowledged for their ability to enhance immune functions. This study assessed the impact of incorporating Astragalus, fermented with Lactobacillus plantarum and Bacillus coagulans, on crucian carp’s growth, disease resistance, and immunological characteristics. The experimental groups were fed with common feed (C), C + Astragalus (A), A + Lactobacillus plantarum (AL), A + Bacillus coagulans (AB), and AL + Bacillus coagulans (ALB). The fermented products were mixed with common feed at a 1:99 ratio, and crucian carp were fed 2% of their body weight for four weeks, with sampling conducted on days 3, 7, 14, 21, and 28. Disease resistance was evaluated using Aeromonas hydrophila (A. hydrophila) at a concentration of 0.2 mL (1.0×107 CFU/mL). The final weights in the AL, AB, and ALB groups significantly increased compared to the C group. The ALB group exhibited elevated serum albumin levels, alkaline phosphatase, intestinal lipase, protease enzyme, C3, and IgM gene expression compared to the C group. At the same time, alanine aminotransferase, aspartate aminotransferase, and glucose contents were significantly reduced. The survival rate significantly increased in all experimental groups after treatment with A. hydrophila. In conclusion, Astragalus products fermented with Lactobacillus plantarum and Bacillus coagulans could effectively improve crucian carp’s growth, disease resistance, and immune response.

Improving the anti-diabetic and anti-hyperlipidemic activities of extra virgin olive oil by the incorporation of diallyl sulfide.

Development of novel functional foods is trending as one of the hot topics in food science and food/beverage industries. In the present study, the anti-diabetic, anti-hyperlipidemic and histo-protective effects of the extra virgin olive oil (EVOO) enriched with the organosulfur diallyl sulfide (DAS) (DAS-rich EVOO) were evaluated in alloxan-induced diabetic mice. The ingestion of EVOO (500µL daily for two weeks) attenuated alloxan-induced elevated glucose, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), urea and creatinine. It also normalized the levels of triglycerides (TG), total cholesterols (TC), low-density lipoprotein-cholesterol (LDL-c) and their consequent atherogenic index of plasma (AIP) in diabetic animals. Additionally, EVOO prevented lipid peroxidation (MDA) and reduced the level of hydrogen peroxide (H2O2) in diabetic animals. Concomitantly, it enhanced the activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), reducing thereby tissue oxidative stress injury. The overall histologic (pancreas, liver, and kidney) alterations were also improved after EVOO ingestion. The manifest anti-diabetic, lipid-lowering and histo-protective properties of EVOO were markedly potentiated with DAS-rich EVOO suggesting possible synergistic interactions between DAS and EVOO lipophilic bioactive ingredients. Overall, EVOO and DAS-rich EVOO show promise as functional foods and/or adjuvants for the treatment of diabetes and its complications.

Blinatumomab-induced macrophage activating syndrome (MAS) in adult with B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab as a single agent has demonstrated superiority over salvage chemotherapy in patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), with manageable safety and efficacy. Though known to have anticipated drug toxicities including cytokine release syndrome (CRS) and neurotoxicity, there is only one prior report of macrophage activating syndrome (MAS) due to blinatumomab. Case Presentation: We report the first case of blinatumomab-induced MAS in an adult. The patient presented with fever, cough, and weakness on the second cycle of blinatumomab. Complete blood count was notable for severe leukopenia, with comprehensive metabolic panel notable for elevated alkaline phosphatase, AST, ALT, LDH, and hyperferritinemia consistent with MAS. The patient was already in MRD-negative remission at presentation with MAS. She responded rapidly to withholding the drug and administration of both tocilizumab and dexamethasone. She was able to restart therapy with blinatumomab dosed at 9 mcg/day with no recurrence of symptoms. Though MAS is not an expected association with blinatumomab, the risk for CRS is. Secondary MAS in this case likely shares a mechanism with other hyperinflammatory conditions. Management includes holding the offending agent, like blinatumomab, and administering tocilizumab and dexamethasone. Future research will be needed to predict which patients are at highest risk to develop MAS after similar T-cell therapies.

Longitudinal analysis of vitamin D levels considering sunshine duration and suggestion for a standardised approach for vitamin D supplementation in children and adolescents with obesity

BackgroundChildren with obesity have low 25 hydroxy-vitamin D (25-OH-D3) levels compared to lean children. Recommendations on when to start vitamin D supplementation differ largely between countries. Longitudinal data on 25-OH-D3 levels to guide treatment decisions are scarce since they are largely influenced by solar radiation and are difficult to compare.MethodsWe carried out a retrospective analysis of multiple 25-OH-D3 and parathyroid hormone (PTH) measurements in a cohort of 543 patients without vitamin D supplementation. All measurements were taken at the local paediatric obesity clinic as documented in the German-Austrian-Swiss APV (Prospective Documentation of Overweight Children and Adolescents) registry from 2009 to 2019. Serial 25-OH-D3 and PTH levels were adjusted for sunshine duration over the last 30 days to account for seasonal variation, as well as for sex and body mass index (BMI). We further performed an exploratory analysis of the association of sunshine duration, sex, BMI SDS (standard deviation score), abnormal lipid levels or dysglycemia with the 25-OH-D3 trend.Results229 obese patients (mean BMI SDS: 2,58 (± 0,56), 53% females, mean age: 12 (± 3) years, range: 2–21 years) with two, 115 with three and 96 with four repeated 25-OH-D3 measurements were identified. Mean adjusted 25-OH-D3 (48.2 nmol/l) and PTH (34.9 ng/l) levels remained stable over 120 weeks. 5% of the patients had an elevated PTH > 65 ng/l. High total cholesterol ≥ 200 mg/dl and high triglycerides ≥ 130 mg/dl were associated with higher 25-OH-D3 levels.ConclusionWe propose a simple method to include sunshine duration in the analysis of 25-OH-D3 levels to minimise the bias of seasonal variation. Based on our data we established the pragmatic strategy of limiting vitamin D supplementation to patients with biochemical signs of mineralisation disorders such as elevated PTH and alkaline phosphatase (AP). In children with normal PTH and AP we recommend adjustment of calcium intake and increase of outdoor activity instead.

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders.

The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). Biallelic variants of the phosphatidylinositol glycan (PIG) biosynthesis, type V (PIGV) gene identified in Mabry syndrome became evidence of the first in a phenotypic series that is numbered HPMRS1-6 in the order of discovery. HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. Similarly, HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. By contrast, HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4). The GPI biosynthesis disorders (GPIBDs) are currently numbered GPIBD1-21. Working with Dr. Mabry, in 2020, we were able to use improved laboratory diagnostics to complete the molecular diagnosis of patients he had originally described in 1970. We identified biallelic variants of the PGAP2 gene in the first reported HPMRS patients. We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry's patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

Evaluation of dental pulp stem cells response to flowable nano-hybrid dental composites: A comparative analysis.

Flowable resin composites (FRC) are tooth-colored restorative materials that contain a lower filler particle content, and lower viscosity than their bulk counterparts, making them useful for specific clinical applications. Yet, their chemical makeup may impact the cellular population of the tooth pulp. This in-vitro study assessed the cytocompatibility and odontogenic differentiation capacity of dental pulp stem cells (DPSCs) in response to two recent FRC material extracts. Extracts of the FRC Aura easyflow (AEF) and Polofil NHT Flow (PNF) were applied to DPSCs isolated from extracted human teeth. Cell viability of DPSCs was assessed using MTT assay on days 1, 3 and 7. Cell migration was assessed using the wound healing assay. DPSCs' capacity for osteo/odontogenic differentiation was assessed by measuring the degree of mineralization by Alizarin Red S staining, alkaline phosphatase enzyme (ALP) activity, and monitoring the expression of osteoprotegerin (OPG), RUNX Family Transcription Factor 2 (RUNX2), and the odontogenic marker dentin sialophosphoprotein (DSPP) by RT-PCR. Monomer release from the FRC was also assessed by High-performance liquid chromatography analysis (HPLC). DPSCs exposed to PNF extracts showed significantly higher cell viability, faster wound closure, and superior odontogenic differentiation. This was apparent through Alizarin Red staining of calcified nodules, elevated alkaline phosphatase activity, and increased expression of osteo/odontogenic markers. Moreover, HPLC analysis revealed a higher release of TEDGMA, UDMA, and BISGMA from AEF. PNF showed better cytocompatibility and enhancement of odontogenic differentiation than AEF.

Psoriasis Area and Severity Index and its Correlation with Liver Function Test

Objective: To determine Psoriasis Area and Severity Index score and its association with LFT values in patients of psoriasis. Methodology: This cross-sectional study, was done on patients visiting the skin OPD of LUMHS Jamshoro/Hyderabad. Diagnosed patients of Psoriasis, aged between 18 and 50 years and both genders were included. A 5cc blood sample was collected from each individual to evaluate the LFT. Psoriasis Area and Severity Index (PASI) scores was defined based on the percentage of body surface area affected by psoriasis lesion. All the information was entered and analyzed using SPSS version 26. Results: The mean age of the patients was 44.81±11.10 years. Out of the total 102 patients, 74.5% were male patients and 25.5% were female. The mean duration of psoriasis was 6.46 ± 4.49 years. Out of all 32.4% had mild psoriasis (PASI &lt; 7), 40.2% had moderate psoriasis (PASI 8-12), and 27.5% had severe psoriasis (PASI &gt; 12). Regarding LFT values, 73.5% had elevated alanine transaminase (ALT), 32.4% had elevated aspartate transaminase (AST), 70.6% had elevated alkaline phosphatase (ALP), 68.6% had elevated bilirubin, and 67.6% had elevated gamma-glutamyl transferase (GGT). AST and GGT levels rise significantly linked to PASI (p- &lt;0.05). Conversely, for ALP and Bilirubin levels, there is no significant difference across severity of PASI (p- &gt;0.05). Conclusion: Patients with severe psoriasis exhibit a predisposition to hepatic dysfunction. Study observed abnormalities in liver function tests (LFT) among psoriatic patients, suggesting a potential link to liver disease development.

Alkaline phosphatase activatable near-infrared fluorescent probe for in-situ diagnosis of cholestatic liver injury

Cholestatic liver injury (CLI) is a clinical syndrome caused by impaired bile excretion and is almost asymptomatic in early-stage. If CLI is not recognized timely, it will elicit more severe liver diseases. Therefore, earlier diagnosis of CLI is urgently needed but remains challenging. On the basis of the consensus that elevation of serum alkaline phosphatase (ALP) is the most susceptible indicator of earlier cholestatic diseases. Herein, we conjugated dicyanoisophorone with hydroxyl-substituted coumarin derivative to afford an intramolecular charge transfer (ICT)-based fluorophore TX-OH, and successfully constructed an enzyme activatable fluorescent probe TX-PS, which enables specifically detecting ALP with near-infrared emission (720 nm), large stokes shift (198 nm) and excellent linear relationship (R2 = 0.9969) between fluorescence intensity and the concentrations of ALP (0–100 U/L). Moreover, TX-PS exhibits applicable for imaging of ALP activities in living cells and zebrafish with ignorable toxicity and shows great potential to visually screen ALP inhibitors. Importantly, the liver tissues from CLI mice displayed remarkably higher fluorescence intensity than that from normal mice, suggesting the valuable capability of TX-PS for evaluating CLI degree. Overall, this work affords a powerful tool for earlier diagnosis of CLI and high-throughput screening of ALP inhibitors or new drugs for CLI therapeutics.

Dengue-related acute liver failure-A scoping review.

Infection by dengue virus is common in tropical countries. Hepatic involvement in dengue can range from asymptomatic elevation of transaminases to life-threatening acute liver failure (ALF). Dengue-related ALF (DALF) is responsible for significant morbidity and mortality, especially in Southeast Asia. However, there is a scarcity of literature on DALF, necessitating a thorough examination of its clinical determinants and management strategies. All relevant studies related to DALF were reviewed until December 2023. Case reports, case series and studies reporting ALF in dengue infection were included. Demographics, clinical profiles, management and outcomes of DALF cases were analyzed, which revealed a predominance of DALF incidence in pediatric patients (1.1% to 15.8%) and an upward trend over the years, particularly in India. The proportion of ALF cases attributable to dengue was also higher among pediatric ALF patients (6.7% to 34.3%). Age ≤ 40years, persistent nausea, vomiting and elevated serum bilirubin and alkaline phosphatase (ALP) with aspartate aminotransferase (AST) > 1000IU/mL within the first five days of illness, more than 10% of atypical lymphocytes in peripheral blood, platelet count of < 50,000/cu·mm, severe hepatitis at presentation and baseline model for end-stage liver disease (MELD) > 15 were the risk factors for the development of DALF. Histopathological features of DALF included multi-lobular hepatic necrosis, steatosis and occasional cholestasis. Mortality in DALF ranged from 0% to 80%; admission pH and lactate strongly predicted mortality, while mortality was found to be significantly higher in patients with cirrhosis. N-Acetyl cysteine (NAC) has been used as a treatment modality with varying results. There is limited evidence regarding the use of extra-corporeal support systems, while candidate selection for liver transplantation (LT) in DALF remains poorly defined.

Skeletal consequences of preterm birth in pigs as a model for preterm infants.

Preterm birth affects about 10% of all live births with many resultant health challenges, including metabolic bone disease of prematurity (MBDP) which is characterized by elevated alkaline phosphatase, suppressed phosphate, and deficient skeletal development. Because of the lack of an animal model, very little is known about bone structure, strength, and quality after preterm birth. This study investigated the utility of a pig model to replicate clinical features of preterm birth, including MBDP, and sought to determine if early postnatal administration of insulin-like growth factor (IGF)-1 was an effective treatment. Preterm pigs, born by caesarean section at 90% gestation, were reared in intensive care facilities (respiratory, thermoregulatory and nutritional support) and compared with sow-reared term pigs born vaginally. Preterm pigs were systemically treated with vehicle or IGF-1 (recombinant human IGF-1/BP-3, 2.25mg/kg/day). Tissues were collected at postnatal days 1, 5, and 19 (the normal weaning period in pigs). Most bone-related outcomes were affected by preterm birth throughout the study period whereas IGF-1 supplementation had almost no effect. By day 19, alkaline phosphatase was elevated, phosphate and calcium were reduced, and the bone resorption marker CTX-1 was elevated in preterm pigs compared to term pigs. Preterm pigs also had decrements in femoral cortical cross-sectional properties, consistent with reduced whole-bone strength. Thus, the preterm pig model replicates many features of preterm bone development in infants, including features of MBDP, and allows for direct interrogation of skeletal tissues, enhancing the field's ability to examine underlying mechanisms.

Association of liver function and prognosis in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an epidemic emerging infectious disease with high mortality rate. We investigated the association between liver injury and clinical outcomes in patients with SFTS. A total of 291 hospitalized SFTS patients were retrospectively included. Cox proportional hazards model was adopted to identify risk factors of fatal outcome and Kaplan-Meier curves were used to estimate cumulative risks. 60.1% of patients had liver injury at admission, and the median alanine transaminase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) levels were 76.4 U/L, 152.3 U/L, 69.8 U/L and 9.9 μmol/L, respectively. Compared to survivors, non-survivors had higher levels of AST (253.0 U/L vs. 131.1 U/L, P < 0.001) and ALP (86.2 U/L vs. 67.9 U/L, P = 0.006), higher proportion of elevated ALP (20.0% vs. 4.4%, P < 0.001) and liver injury (78.5% vs. 54.9%, P = 0.001) at admission. The presence of liver injury (HR 2.049, P = 0.033) at admission was an independent risk factor of fatal outcome. Liver injury was a common complication and was strongly associated with poor prognosis in SFTS patients. Liver function indicators should be closely monitored for SFTS patients.

Metabolic profiling of Verbena bonariensis L. extract by LC/MS and evaluation of the hepatoprotective potential with isoniazid- and rifampicin-induced hepatotoxicity in rats.

The study explored the hepatoprotective activity and metabolic profile of Verbena bonariensis L. methanol extract (VBM) and fractions using isoniazid as well as rifampicin-triggered liver toxicity in Wistar albino rats. Metabolite profiling of VBM using HPLC-PDA-ESI-MS identified 12 compounds, mainly iridoids, phenylpropanoids, and flavonoids, where verbascoside represents the major compound. Different biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), bilirubin, and total protein levels were used to assess liver functions. All the evaluated samples exhibited hepatoprotective potential, but VBM exhibited maximum activity and a notable decline in ALP (p < 0.05, significant), even better than the standard drug (silymarin). VBM significantly reduced the elevated ALT, AST, ALP, and total bilirubin. It also triggered a significant elevation in total proteins compared with diseased animals. This was further consolidated by histopathological studies. Verbena bonariensis L. could serve as a potent hepatoprotective agent and may alleviate liver ailments.

Leflunomide with prednisone or nonsteroidal anti-inflammatory drug therapy is safe and tolerated for long-term treatment of immune-mediated polyarthritis in 27 dogs.

To retrospectively evaluate safety and tolerance of leflunomide for long-term treatment of canine idiopathic immune-mediated polyarthritis (IMPA). 27 dogs with clinical signs and synovial fluid cytology supportive of IMPA with ≥ 6 months' follow-up after starting leflunomide. Medical records were reviewed to identify dogs prescribed leflunomide for treatment of IMPA from February 2012 to May 2022. Initial leflunomide doses of 2 to 4 mg/kg once daily were prescribed and were titrated to the lowest effective dose with concurrent anti-inflammatory therapy. Complete blood count, serum chemistry, and clinical signs were monitored throughout the course of treatment. Adverse effects potentially attributable to leflunomide noted in 9 of 27 dogs (33%) included vomiting, diarrhea, lethargy, decreased or absent appetite, polyuria and polydipsia, and secondary antibiotic responsive infection and were self-limiting or resolved with outpatient therapy. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) elevation were documented in all dogs prescribed leflunomide plus prednisone, with persistent liver enzyme elevation in 6 of 9 dogs (67%) and normalization after antibiotic therapy in 3 of 9 dogs (33%). The majority of dogs prescribed leflunomide plus NSAID (11/17 [65%] dogs) did not experience liver enzyme elevation; 2 of 17 (12%) dogs developed transient antibiotic-responsive liver enzyme elevations, and 4 of 17 (23%) dogs had persistent liver enzyme elevation. Leflunomide was well tolerated for long-term management of IMPA. A significant difference in liver enzyme elevation was identified between dogs prescribed prednisone versus NSAID in combination with leflunomide. Leflunomide with NSAID therapy resulted in less hepatotoxicity compared with leflunomide with prednisone.

Safety of naltrexone in patients with cirrhosis

Safety of naltrexone in patients with cirrhosis

Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study.

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

Macrophage-derived exosomes rescue the TNF-ɑ-suppressed osteo-/cementogenic differentiation of hPDLCs.

Inflammatory stimuli compromise the differentiation potency of human periodontal ligament cells (hPDLCs). Macrophage-derived exosomes (M-Exo) play a role in several aspects of cellular activity. This study investigated how M-Exo contributes to the osteo-/cementogenic differentiation of hPDLCs under inflammation and the mechanism involved. M-Exo was identified by transmission electron microscopy, western blotting (WB), and dynamic light scattering. The internalization of M-Exo by hPDLCs was observed. After M-Exo treatment, the osteo-/cementogenic markers were detected by RT-qPCR and WB, and alkaline phosphatase (ALP) activity by ALP staining. Tumor necrosis factor alpha (TNF-ɑ) was applied to simulate inflammation. The rescue effect of M-Exo on TNF-ɑ-suppressed differentiation was validated. The p38 MAPK pathway activity was tested and a specific inhibitor was applied to explore the mechanism. M-Exo was successfully isolated, identified and internalized by hPDLCs. M-Exo enhanced the osteo-/cementogenic differentiation of hPDLCs, as indicated by upregulated osteo-/cementogenic markers and elevated ALP activity. Moreover, TNF-ɑ inhibited the differentiation capabilities of hPDLCs, on which M-Exo showed a rescue effect. M-Exo activated the p38 MAPK pathway and SB203580 attenuated its promotion effect. This study showed that M-Exo ameliorated the TNF-ɑ-suppressed osteo-/cementogenic differentiation of hPDLCs partly through the p38 MAPK pathway.