Juvenile Hemochromatosis With Non-transfused Hemolytic Anemia Caused by a De Novo PIEZO1 Gene Mutation.

Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-transfused hemolytic anemia in children and young adults.

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.

Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.

Locomotor-reducing effects and structural characteristics of inhaled zerumbone and tetrahydrozerumbone derivatives.

Zerumbone 1 is an 11-membered cyclic sesquiterpene obtained from the rhizomes of Zingiber zerumbet SMITH (Zingiberaceae). In this study, we investigated the structure-activity relationship of 1, α-humulene (2), tetrahydrozerumbone stereoisomers (3-5), and tetrahydrozerumbone derivatives (6-9). The oxygen-containing functional groups and the configurations at C1 and C2 contributed to the spontaneous locomotor activity reduction of zerumbone 1 and derivatives 2-9.

Sedative effects of inhaled benzylacetone and structural features contributing to its activity.

Benzylacetone is released by heated agarwood, when inhaled it has a potent effect on reducing the locomotor activity of mice. This study investigated the relationships between the sedative activities of benzylacetone and its derivatives as well as the chemical structures of these compounds by comparing their activities in mice treated with a series of compounds. It was demonstrated that benzylacetone-like compounds had sedative activities and their intensities varied depending on the functional group in the carbon chain, the substituent in the benzene ring, and their combinations. A quantitative structure-activity relationship study was carried out using a series of 17 benzylacetone derivatives to determine the structural features with significant for the sedative activity.

[Acquired hemophilia presenting as gross hematuria and perineal subcutaneous hemorrhage after prostate biopsy: a case report].

Acquired hemophilia is a rare disease that can result in life threatening bleeding associated with coagulation factor VIII inhibitors. A 61-year-old man presented gross hematuria and urinary retention. A retrograde pyelography, cystoscopy, abdominal computed tomography and prostate biopsy showed no finding suggestive of malignancy. Extensive subcutaneous hemorrhage over the perineal region and severe hematuria were observed after the prostate biopsy. Further hematological evaluation showed the presence of coagulation factor VIII inhibitors, which led to the diagnosis of acquired hemophilia. All symptoms disappeared without complication after administration of predonisolone and recombinant activated factor VII.

Low-grade B cell lymphoma in the perirenal space of the left kidney associated with high titer cold agglutinin disease.

Cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia caused by monoclonal cold agglutinins produced by clonally expanded B lymphocytes. In primary CAD, lymphoproliferative bone marrow disorder is noted, while as one of the secondary cold agglutinin syndromes (CAS), the initial manifestation of CAD is followed by development of lymphoma. Here, we report a case of low-grade B cell lymphoma developed 3 months after an initial CAD diagnosis. The patient had an extremely high serum cold agglutinin titer (1:16,384) and slightly elevated serum IgM (452 mg/dL; reference, 31-200) with positive monoclonal IgM-kappa chain. After diagnosis of lymphoma-associated CAS, he was managed successfully with six cycles of a BR (bendamustine and rituximab) regimen. Cold agglutinin titers fell rapidly to 1:2048 at 5 months and to 1:512 at 10 months after chemotherapy, and the patient has been in a complete remission for 34 months.

Methotrexate-induced subacute myelopathy: a serious but treatable complication.

Subacute myelopathy is a rare but serious complication of methotrexate (MTX) that may cause paraplegia. Although its underlying mechanisms have not been fully elucidated, homocysteine is thought to play a role in the pathogenesis of this adverse effect. Herein, we report the case of a 34-years old female patient with diffuse large B-cell lymphoma who developed progressive paraplegia accompanied by dysfunctional bladder and bowel movements after treatment with a modified CODOX-M/IVAC regimen, including high-dose intravenous MTX and intrathecal (IT-) MTX. Neurological symptoms gradually improved to almost normal levels within 4.5 months of onset following treatment with a combination of S-adenosylmethionine, methionine, cyanocobalamin, and folate. During chemotherapy, including high-dose MTX and IT-MTX for hematological malignancies, MTX-induced subacute neuronal damage should be carefully evaluated, and appropriate treatment should be initiated as early as possible.

Efficacy of elotuzumab for multiple myeloma in reference to lymphocyte counts and kappa/lambda ratio or B2 microglobulin.

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower ß2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/µL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/µL and 1 point for < 1400/µL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system.

Monocyte or white blood cell counts and ß2 microglobulin predict the durable efficacy of daratumumab with lenalidomide.

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower ß2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/µl; 1 point for <200/µl) or WBC counts (0 points for ⩾3500/µl; 1 point for <3500/µl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.

Ozone production by amino acids contributes to killing of bacteria.

Reactive oxygen species produced by phagocytosing neutrophils are essential for innate host defense against invading microbes. Previous observations revealed that antibody-catalyzed ozone formation by human neutrophils contributed to the killing of bacteria. In this study, we discovered that 4 amino acids themselves were able to catalyze the production of an oxidant with the chemical signature of ozone from singlet oxygen in the water-oxidation pathway, at comparable level to antibodies. The resultant oxidant with the chemical signature of ozone exhibited significant bactericidal activity in our distinct cell-free system and in human neutrophils. The results also suggest that an oxidant with the chemical signature of ozone produced by neutrophils might potentiate a host defense system, when the host is challenged by high doses of infectious agents. Our findings provide biological insights into the killing of bacteria by neutrophils.

Hyperhomocysteinemia-related lung disease and hemolytic anemia with bone marrow features masquerading as myelodysplasia.

Hyperhomocysteinemia is linked to TMA-related clinical symptoms such as apparent thromboembolism, microangiopathic hemolytic anemia (MAHA), and various types of end-organ damage due to microvascular thrombi; this is because high plasma levels of homocysteine impair the vascular endothelium. However, the association between hyperhomocysteinemia and pulmonary involvement is unclear. Here, we describe a 63-year-old male who was hospitalized with respiratory failure and MAHA with MDS-like features in the bone marrow. Plasma homocysteine levels were elevated significantly with 199.4 µmol/L (reference: 6.3-18.9) due to a homozygous (T/T) polymorphism for the 677C>T mutation within the MTHFR gene associated with chronic alcoholism-induced folate deficiency. Pulmonary lesions showed ground-glass opacity and there was pleural effusion. The patient was managed successfully with a combination of folate/mecobalamin supplementation, plasma exchange, and a methylprednisolone pulse, followed by oral prednisolone. Clinical symptoms, lung disease, MAHA, and bone marrow abnormalities improved as plasma homocysteine levels normalized.

The role of endothelial interleukin-8/NADPH oxidase 1 axis in sepsis.

Sepsis is a generalized inflammatory disease, caused by the hyperinflammatory response of the host, rather than by invading organisms. Endothelial cells play a crucial role in the pathogenesis of sepsis. In this study, we investigated the effects of interleukin-8 (IL-8), a known neutrophil chemoattractant, on lipopolysaccharide (LPS) -induced reactive oxygen species (ROS) production by endothelial cells, and its significance in the pathogenesis of LPS-mediated sepsis. The results revealed that IL-8 directly induced ROS production in human umbilical vein endothelial cells (HUVECs), and also mediated LPS-induced ROS production by HUVECs. Stimulation of HUVECs by LPS strongly enhanced tissue factor expression, a hallmark of severe sepsis, which was suppressed by IL-8 knockdown. We further discovered that NADPH oxidase (Nox) 1 expression in LPS-stimulated HUVECs was markedly repressed by IL-8 knockdown, and Nox1 knockdown reduced tissue factor expression, suggesting that the LPS/IL-8 signalling in endothelial cells was predominantly mediated by Nox1. In conclusion, LPS stimulation of endothelial cells causes activation of the IL-8-Nox1 axis, enhances the production of ROS, and ultimately contributes to the progression of severe sepsis.

The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.

Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 microM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 microM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 microM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.

Familial Mediterranean fever gene as a possible modifier of Sweet syndrome with chronic myelogenous leukemia.

Sweet syndrome is a multisystem inflammatory disorder characterized by acute fever, as well as painful erythematous plaques infiltrated with mature neutrophils in the absence of vasculitis. The pathogenesis of the disease has not yet been clarified, although several proinflammatory cytokines have been reported to be involved in the disease process. We describe here a patient clinically diagnosed with Sweet syndrome with chronic myelogenous leukemia. The mutational analysis of the patient revealed a compound heterozygous E148Q/R202Q mutation in exon 2 of MEFV gene, which is a causative gene for familial Mediterranean fever. This is the first report to describe MEFV gene mutations in Sweet syndrome. Our results suggest that Sweet syndrome may be mediated though similar inflammatory mechanisms to those of familial Mediterranean fever.

Analysis of serum angiogenic factors in a young multiple myeloma patient with high-output cardiac failure.

Angiogenesis is believed to be involved in the pathogenesis and progression of multiple myeloma (MM). In some young patients, the MM has been reported to be complicated with high-output cardiac failure (HOCF), in which an increase in the vascular bed may be involved in the pathogenesis; however, no throughput studies have been conducted to determine what angiogenic factors are associated with HOCF in MM patients. We experienced a 34-year-old MM patient with HOCF and used the cytokine array system to investigate the expression of angiogenic cytokines and related factors in his serum before and after treatment and to compare the results with those of a healthy volunteer. We treated the patient with chemotherapy in combination with autologous peripheral blood stem cell transplantation. Following the treatment, he showed a good partial response without any signs of cardiac failure. The patient had experienced dramatic increases in the expression levels of angiopoietin 2, insulin-like growth factor-binding protein 6, and glial cell line-derived neurotrophic factor. After treatment, the levels of these factors decreased remarkably in association with an improvement in the patient's clinical condition. We review previous case reports in our discussion of the significance of these findings in the pathogenesis of MM with HOCF.

Leukemic and meningeal relapse of CD5+ intravascular large B-cell lymphoma with down-modulation of CD20 after rituximab therapy.

Although CD20- relapses of B-cell lymphoma following rituximab therapy have increasingly been reported recently, coexistence of both the original and selected clones on relapse in a single patient have not been described. We experienced such a case with rare CD5+ intravascular lymphomatosis (IVL). A 46-year-old woman was admitted because of IVL complicated with cauda equina syndrome and pulmonary infarction. Complete remission was successfully achieved with multidrug chemotherapy in combination with rituximab. However, the disease recurred after 8 months with leukemic progression and meningeal involvement. The phenotype of the abnormal lymphocytes in the peripheral blood was fundamentally the same (CD20+CD5+CD10-CD19+CD23-sIglambda+) as that of the cells in the cerebrospinal fluid (CSF). However, CD20 expression was decreased remarkably compared with that in the CSF and that in the bone marrow before therapy. The targeting of CD20 molecules on the tumor cell surface by rituximab may have provided a selective pressure on lymphoma cells. The escape phenomenon of the lymphoma cells from rituximab was observed by simultaneously comparing the CD20 expression of cells in the peripheral blood and in a site of sanctuary from rituximab, the CSF.