An observational study to investigate the relationship between plasma glucosylsphingosine (lyso-Gb1) concentration and treatment outcomes of patients with Gaucher disease in Japan.

BACKGROUND: Gaucher disease (GD) is an autosomal recessive disease caused by GBA1 mutations resulting in glucosylceramide accumulation in macrophages. GD is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone complications, and neurological complications. Glucosylsphingosine (lyso-Gb1), a deacylated form of glucosylceramide, has been identified as a promising biomarker for the diagnosis and treatment response in GD. The aim of this study was to examine the relationship between plasma lyso-Gb1 and therapeutic goals for GD (improvements in hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis), as well as disease type and GBA1 mutation type, in Japanese patients with GD receiving velaglucerase alfa, an enzyme replacement therapy (ERT). Furthermore, this study compared the plasma lyso-Gb1 concentration observed in Japanese patients included in this study with that observed in a previous non-Japanese clinical study. RESULTS: This non-interventional, open-label, multicenter observational cohort study (October 2020 to March 2021) included a total of 20 patients (of any age) with GD (type 1: n = 8; type 2: n = 9; type 3: n = 3) treated with velaglucerase alfa for ≥ 3 months. Median (minimum-maximum) duration of velaglucerase alfa treatment was 49.5 (3-107) months. A total of 14 (70.0%) patients achieved all therapeutic goals (i.e., 100% achievement; improvements in hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis). Overall, median (minimum-maximum) lyso-Gb1 concentration was 24.3 (2.1-150) ng/mL. Although not statistically significant, numerically lower plasma lyso-Gb1 concentrations were observed in patients with 100% achievement compared with those without; no statistically significant difference in plasma lyso-Gb1 concentration was observed between patients with different disease type or mutation type. Furthermore, lyso-Gb1 concentrations observed in Japanese patients were numerically lower than that observed in a previous study of non-Japanese patients with GD receiving ERT. CONCLUSIONS: In this study, high achievement rates of therapeutic goals with low lyso-Gb1 concentration were observed, demonstrating a correlation between therapeutic goals and lower plasma lyso-Gb1 concentration in Japanese patients with GD treated with velaglucerase alfa. This study further suggests that plasma lyso-Gb1 concentration may be a useful biomarker for treatment response in patients with GD.

Lead suppresses interferon γ to induce splenomegaly via modification on splenic endothelial cells and lymphoid tissue organizer cells in mice.

Splenomegaly is a symptom characterized by the presence of an enlarged spleen. The impact of environmental factors on splenomegaly is largely unknown. In this study, C57BL/6 mice were treated with 125 ppm or 1250 ppm lead (Pb) via drinking water for 8 wk, and the process of splenomegaly was evaluated. Treatment with 1250 ppm Pb, but not 125 ppm Pb, caused splenomegaly, which was associated with increased capacity for erythrocyte clearance. Intriguingly, Pb-caused splenomegaly was independent of lymphoid tissue inducer (LTi) cells, which produce lymphotoxins α and ß (LTα/ß) to activate endothelial cells and LT organizer (LTo) cells and drive the development of spleen physiologically. A direct action of Pb on endothelial cells and LTo cells did not impact their proliferation. On the other hand, during steady state, a tonic level of interferon (IFN)γ acted on endothelial cells and LTo cells to suppress splenomegaly, as IFNγ receptor (IFNγR)-deficient mice had enlarged spleens relative to wild-type mice; during Pb exposure, splenic IFNγ production was suppressed, thus leading to a loss of the inhibitory effect of IFNγ on splenomegaly. Mechanically, Pb acted on splenic CD4+ T cells to suppress IFNγ production, which impaired the Janus kinase (Jak)1/ signal transducer and activator of transcription (STAT)1 signaling in endothelial cells and LTo cells; the weakened Jak1/STAT1 signaling resulted in the enhanced nuclear factor-κB (NF-κB) signaling in endothelial cells and LTo cells, which drove their proliferation and caused splenomegaly. The present study reveals a previously unrecognized mechanism for the immunotoxicity of Pb, which may extend our current understanding for Pb toxicology.

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice.

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

Noncirrhotic Portal Hypertension after Trastuzumab Emtansine in HER2-positive Breast Cancer as Determined by Deep Learning-measured Spleen Volume at CT.

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.

The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Clinical, genetic profile and therapy evaluation of 55 children and 5 adults with sitosterolemia.

BACKGROUND: Sitosterolemia is a rare autosomal recessive disease characterized by phytosterol accumulation in the blood and tissues. However, the detailed clinical and genetic spectra are lacking. OBJECTIVE: To describe and compare the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 55 pediatric and five adult sitosterolemia patients. METHODS: Clinical, genetic and therapeutic data from 60 patients at Xinhua Hospital from January 2016 to June 2021 were retrospectively collected. RESULTS: Pediatric patients' manifestations included xanthomas(93%), hematological disorders(30%), arthralgia(24%), splenomegaly(11%), atherosclerosis(10%). Adult patients had symptoms such as atherosclerosis(5/5), xanthomas(4/5), hematological disorders(3/5), arthralgia(3/5), splenomegaly(3/5). Elevated total cholesterol(TC) and low-density lipoprotein cholesterol(LDL-C) were observed in 96% patients (pediatric 98%, adult 3/4), and phytosterol levels in 100% patients. The age of onset was also negatively correlated with blood TC (P < 0.0001, r = -0.5548) and LDL-C (P = 0.0001, r = -0.4859) levels. Targeted treatments resulted in symptomatic remission(pediatric 96%, adult 4/5), and significantly decreased lipid and phytosterol levels(all P<0.05). In the dietary-therapy cohort(n=34), blood lipid levels decreased(all P<0.05). In the 13 pediatric patients from the dietary-therapy cohort who switched from dietary to combination therapy with ezetimibe, dietary therapy decreased TC and LDL-C levels by 54% and 52%, and ezetimibe further decreased them by 18% and 20%, respectively. Further, we identified 15 novel ABCG5/ABCG8 variants. CONCLUSIONS: This study expands the clinical and genetic spectra of sitosterolemia. The low-phytosterol diet is the cornerstone of sitosterolemia treatment. Ezetimibe can further decrease blood lipid levels and increase daily dietary phytosterol tolerance.

Exposure to a combination of MWCNTs and DBP causes splenic toxicity in mice.

The large conjugated π bond in the molecular structure of carbon nanotubes (CNTs) interacts with the benzene ring structure in di (n-butyl) phthalates (DBP) through a π - π bond. Compounds of CNTs and DBP form easily, becoming another environmental pollutant of concern. We explore whether CNTs entering animals slow down the degradation of the DBP adsorbed in the CNT cavity, thereby prolonging the "hormonal activity" of DBP. In our study, male BALb/c mice were used as experimental subjects divided into four groups: the control group; the multi-walled carbon nanotubes (MWCNTs) exposure group (10mg/kg/d); the DBP exposure group (2.15 mg/kg/d); and the compound exposure group (MWCNTs + DBP). After 30 days of exposure, the mice were sacrificed and their spleens used for immunotoxicology study. The results showed that the exposure groups exhibited splenomegaly and suffered severe oxidative damage to the spleen. In the compound exposure group: levels of IgA and IgG in the serum of the mice changed, and were significantly different from levels in both the MWCNTs and DBP exposure groups (p <0.05); the pathological sections of the spleen showed that the boundary between the white pulp area (WP) and the red pulp area (RP) was blurred, that the cell arrangement was loose, and that more red blood cells were retained in the spleen. Proteomics mass spectrometry analysis showed that compared with the control group, 70 proteins were up-regulated and 27 proteins were down-regulated in the MWCNTs group, 36 proteins were up-regulated and 23 proteins were down-regulated in the DBP group, 87 proteins were up-regulated and 21 proteins were down-regulated in the compound exposure group. The results of GO enrichment analysis and KEGG enrichment analysis of the differentially expressed proteins showed that the compound exposure harmed the spleen antigen recognition, processing, and presentation, inhibited the activation and proliferation of B cells and T cells, and hindered the adaptive immune responses. Our results showed that MWCNTs and DBP compounds can damage the spleen, and impair the innate and adaptive immune functions of the body.

Immunomodulatory Activity of Carboxymethyl Pachymaran on Immunosuppressed Mice Induced by Cyclophosphamide.

The effects of immunomodulatory activity of two types of carboxymethyl pachymaran (CMP-1 and CMP-2) on cyclophosphamide (CTX)-induced mice were investigated. Both CMP-1 and CMP-2 were found to restore the splenomegaly and alleviate the spleen lesions and the mRNA expressions of TLR4, MyD88, p65 and NF-κB in spleen were also increased. CMP-1 and CMP-2 could enhance the immunity by increasing the levels of TNF-α, IL-2, IL-6, IFN-γ, Ig-A and Ig-G in serum. In addition, CMP-1 could increase the relative abundance of Bacteroidetes and reduce the relative richness of Firmicutes at the phylum level. CMP-1 and CMP-2 could reduce the relative abundance Erysipelatoclostridum at the genus level. CMP-1 and CMP-2 might enhance the immune function of immunosuppression mice by regulating the gene expression in the TLR4/NF-κB signaling pathway and changing the composition and abundance of the intestinal microbiota. The results suggested that CMP-1 and CMP-2 would be as potential immunomodulatory agents in functional foods.

Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.

Hairy cell leukaemia diagnosed in a polysensitized patient with atypical haemorrhagic skin lesions / Atípusos haemorrhagiás bortünetek hátterében igazolt hajas sejtes leukaemia poliszenzibilizált betegen.

As the topical use of non-steroidal anti-inflammatory drugs (NSAIDs) has gained popularity recently, adverse reactions related to their application have also become more common. The authors present the case of a 49-year-old man, who used etofenamate gel to treat leg pain. Following sun exposure, haemorrhagic, atypical lesions appeared and after rapid spread of the symptoms, the patient was hospitalized. In the area of the etofenamate application as well as on both legs, arms, trunk and face, confluent, erythematous sero-papules and macules were found, along with petechiae on the oral mucosa. Splenomegaly and thrombocytopenia accompanied the skin symptoms, which prompted an oncohematological workup, and the patient was diagnosed with hairy cell leukaemia. Epicutaneous testing (ET) was performed and found a positive reaction to etofenamate gel as well wood tar, propylen glycol, fragrance mix I, methylisothiazolinone, benzoic acid and balsam of Peru. The lymphocyte transformation test (LTT) and CD69 expression were negative for etofenamate. Orv Hetil. 2020; 161(38): 1646-1651.

Oxaliplatin-induced haematological toxicity and splenomegaly in mice.

PURPOSE: Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients. METHODS: Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome. RESULTS: Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1ß, IL-12p40, MIP-1ß, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis. CONCLUSION: Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome.

A benzimidazole inhibitor attenuates sterile inflammation induced in a model of systemic autoinflammation in female mice.

Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans.

Glyphosate induces benign monoclonal gammopathy and promotes multiple myeloma progression in mice.

BACKGROUND: Glyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL. METHODS: Vk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks. RESULTS: Vk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice. CONCLUSIONS: These data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces peripheral blood abnormalities and plasma cell neoplasms resembling multiple myeloma in mice.

Although epidemiologic studies have suggested a possible association between occupational exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the risk of development of multiple myeloma, definitive evidence in support of this association is lacking. In the present study, we employed the Vk*Myc mouse model of multiple myeloma to assess the impact of TCDD exposure on multiple myeloma pathogenesis. TCDD induced splenomegaly and multiple peripheral blood abnormalities, including anemia and high serum IgG levels. In addition, TCDD triggered bone lytic lesions, as well as renal tubular casts, a phenomenon associated with human myeloma kidney disease. Even in wild-type C57BL/6 mice, TCDD increased serum IgG levels, induced anemia, and increased plasma cell presence in the spleen and bone marrow, hallmarks of benign monoclonal gammopathy. Lastly, TCDD induced AKT activation and the DNA damage response, key pathogenic events in myeloma pathogenesis, in animal spleen and/or bone marrow. These data indicate that TCDD accelerates monoclonal gammopathy development and promotes progression to multiple myeloma in genetically-predisposed mice. This work offers the first direct experimental evidence establishing TCDD as an environmental risk factor for monoclonal gammopathy of undetermined significance and multiple myeloma.

How I treat myelofibrosis after failure of JAK inhibitors.

The introduction of JAK inhibitors, leading to regulatory approval of ruxolitinib, represents a major therapeutic advance in myelofibrosis (MF). Most patients experience reduction in splenomegaly and improved quality of life from symptom improvement. It is a paradox, however, that, despite inhibition of signaling downstream of disease-related driver mutations, JAK inhibitor treatment is not associated with consistent molecular or pathologic responses in MF. Furthermore, there are important limitations to JAK inhibitor therapy including development of dose-limiting cytopenias and/or nonhematological toxicities such as neuropathy or opportunistic infections. Over half of the patients discontinue treatment within 3 years of starting treatment. Although data are sparse, clinical outcome after JAK inhibitor "failure" is likely poor; consequently, it is important to understand patterns of failure to select appropriate salvage treatment(s). An algorithmic approach, particularly one that incorporates cytogenetics/molecular data, is most helpful in selecting stem cell transplant candidates. Treatment of transplant-ineligible patients relies on a problem-based approach that includes use of investigational drugs, or consideration of splenectomy or radiotherapy. Data from early phase ruxolitinib combination studies, despite promising preclinical data, have not shown clear benefit over monotherapy thus far. Development of effective treatment strategies for MF patients failing JAK inhibitors remains a major unmet need.

Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats - Improving Yield and Reproducibility.

Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p < 0.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p < 0.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.

Allylpyrocatechol attenuates methotrexate-induced hepatotoxicity in a collagen-induced model of arthritis.

The cornerstone of treatment for rheumatoid arthritis is low dose methotrexate (MTX), but its use is limited by concerns regarding its potential for hepatotoxicity. Allylpyrocatechol (APC), a phytoconstituent sourced from leaves of Piper betle demonstrated antioxidant, anti-inflammatory, and antiarthritic properties. The present study aimed to evaluate the combined effect of APC and MTX on limiting progression of lipopolysaccharide accelerated collagen-induced arthritis, along with reduction of MTX-induced hepatic damage. A collagen-induced arthritis (CIA) model was established by immunising Sprague-Dawley rats with bovine collagen type II (CII) and lipopolysaccharide, followed by a booster dose of CII on day 15. Rats from days 11-27 were administered APC (20 mg/kg), methotrexate (1.5 mg/kg), or a combination of MTX and APC. The combinatorial therapy of APC and MTX significantly improved the parameters of arthritis as evident from the reduction in paw oedema and arthritic score and was endorsed by radiological and histopathological changes. This combination prevented the rise in levels of proinflammatory cytokines, tumour necrosis factor (TNF-α), and interleukin 6 (IL-6). Furthermore, unlike MTX-monotherapy, the APC-MTX combination decreased the associated cachexia, splenomegaly, and oxidative stress. Importantly, the hepatic damage mediated by MTX monotherapy was effectively attenuated by the inclusion of APC. Taken together, antioxidants such as APC when combined with MTX not only potentiated the antiarthritic effect but importantly alleviated the MTX-induced hepatic damage, thus endorsing its effectiveness in preventing progression of articular diseases such as rheumatoid arthritis.

Ceftriaxone-induced drug reaction mimicking acute splenic sequestration crisis in a child with hemoglobin SC disease.

BACKGROUND: Acute splenic sequestration crisis is a complication of sickle cell disease (SCD) occurring when intrasplenic red blood cell (RBC) sickling prevents blood from leaving the spleen, causing acute splenic enlargement. Although typically seen in young children, it has been reported in older children with hemoglobin (Hb)SC disease, eventually resulting in functional asplenia. Ceftriaxone is a frequently used antibiotic of choice for children with SCD, because of its efficacy against invasive pneumococcal disease. CASE REPORT: We report a case of a 9-year-old female with HbSC disease, who had a fatal reaction after receiving a dose of ceftriaxone in the outpatient clinic for fever. Her Hb level decreased abruptly from 9.3 to 2.3 mg/dL. RBC clumps with no visible hemolysis were observed in the postreaction sample. Autopsy examination revealed marked splenomegaly with acute congestion and sickled cells in the spleen and liver. Serologic testing revealed a positive direct antiglobulin test with polyspecific antibody, anti-C3, and anti-C3d, but negative with anti-immunoglobulin G. Ceftriaxone-dependent RBC antibodies were detected in her serum and RBC eluate when tested in the presence of the drug. CONCLUSION: We report a new presentation of ceftriaxone-induced drug reaction in a patient with SCD mimicking an acute splenic sequestration crisis. Review of the literature for cases of ceftriaxone-induced drug reactions in pediatric patients revealed nine previously reported cases of ceftriaxone-induced immune hemolytic anemia in children with SCD since 1995, but none with an initial presentation suggestive of acute splenic sequestration crisis.

Long-term risk of portal hypertension and related complications in children treated with 6-thioguanine for acute lymphoblastic leukemia: A single-center experience.

Long-term follow-up of 11 children with 6-thioguanine-induced hepatoportal toxicity is described. Features of persistent portal hypertension in eight patients after 9.7 ± 3.4 years (mean ± SD) of treatment were more common in late presenters. Splenomegaly, thrombocytopenia and altered hepatic echotexture were seen in six, eight and seven patients, respectively. One of the thrombocytopenic patients had heavy menstrual bleeding and pregnancy loss. Five of six patients who underwent upper gastrointestinal endoscopy had esophageal varices and four underwent banding. Late presentation in a subset of patients mandates long-term surveillance and follow-up for all patients treated with 6-thioguanine for early detection and management of hepatoportal complications.