Late-onset X-linked sideroblastic anemia following hemodialysis

X-linked sideroblastic anemia (XLSA) is due to deficient activity of erythroid-specific 5-aminolevulinate synthase (ALAS2). We report here a patient who developed sideroblastic anemia at the age of 81 years while undergoing hemodialysis. The diagnosis of sideroblastic anemia was established by the presence of ringed sideroblasts in the bone marrow, and treatment with oral pyridoxine completely eliminated the ringed sideroblasts. We identified a novel point mutation in the fifth exon of this patient's ALAS2 gene, which resulted in an amino acid change at residue 159 from aspartic acid to asparagine (Asp159Asn). In vitro analyses of recombinant Asp159Asn ALAS2 revealed that this mutation accounted for the pyridoxine-responsiveness of this disease. The very late onset in this case of XLSA emphasizes that nutritional deficiencies caused either by dietary irregularities in the elderly or, as in this case, by maintenance hemodialysis therapy, may uncover occult inherited enzymatic deficiencies in the heme biosynthetic pathway.     

Clinical characteristics of Japanese reflux esophagitis patients as determined by Los Angeles classification

BACKGROUND: Recent studies have shown that the number of patients with reflux esophagitis is increasing in Japan, but the prevalence and risk factors associated with reflux esophagitis in Japanese patients are not well defined. METHODS: By using all endoscopic records in the Katta General Hospital from April through to September 1999, we identified 392 patients. We examined the Los Angeles classification, peptic ulcer, gastric mucosal atrophy, hiatal hernia and other medical variable factors for their contribution to esophagitis in the patients. RESULTS: Patients (13.8%) were diagnosed as having reflux esophagitis with a mucosal break. In a multivariate analysis, reflux esophagitis was associated with hiatal hernia (odds ratio (OR) 2.276, 95% confidence interval (CI) 1.164-4.450), with patients over 65 years of age (OR 2.521, 95% CI 1.238-5.134) and the open type of gastric mucosal atrophy (OR 0.420, 95% CI 0.225-0.785). There was no significant difference between esophagitis and Helicobacter pylori infection and peptic ulcer. CONCLUSIONS: We observed that age, hiatal hernia and a lower rate of gastric mucosal atrophy were associated with the proportion of mucosal breaks accompanying esophagitis.     

Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection

HIV-1 infection in the brain induces neuronal apoptosis leading to HIV-associated dementia. To explore the underlying mechanism, we developed a murine model by using human peripheral blood mononuclear cell (PBMC)-transplanted nonobese diabetic (NOD)-severe combined immunodeficiency (SCID) (hu-PBMC-NOD-SCID) mice. Administration of lipopolysaccharide (LPS) to HIV-1-infected hu-PBMC-NOD-SCID mice induced infiltration of HIV-1-infected human cells into the perivascular region of the brain and neuronal apoptosis was found in macrophage (M)-tropic but not T cell (T)-tropic HIV-1-infected brains. The apoptotic neurons were frequently colocalized with the HIV-1-infected macrophages that expressed tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Administration of a neutralizing antibody against human TRAIL but not human TNF-alpha or Fas ligand (FasL) blocked the neuronal apoptosis in the HIV-1-infected brain. These results strongly suggest a critical contribution of TRAIL expressed on HIV-1-infected macrophages to neuronal apoptosis.     

Ameliorating effect of anti-inducible costimulator monoclonal antibody in a murine model of chronic colitis

BACKGROUND & AIMS: Inducible costimulator (ICOS)/B7RP-1 represents a newly described receptor/ligand pair involved in costimulation of T cells by antigen-presenting cells. We investigated the involvement of the ICOS/B7RP-1 interaction in the pathogenesis of colitis and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in experimental colitis METHODS: We administered anti-ICOS or anti-B7RP-1 mAb to mice with experimental colitis induced by transfer of CD4(+)CD45RB(high) T cells from normal mice into SCID mice. The ability of CD4(+)CD45RB(high) cells derived from ICOS-/- mice to induce colitis was assessed. Th2 cytokine production and apoptosis in infiltrating T cells was examined after administration of anti-ICOS mAb. RESULTS: ICOS was strongly induced on CD4(+) T cells, and B7RP-1 was expressed by macrophages in the inflamed mucosa of colitic mice. Anti-ICOS mAb, but not anti-B7RP-1, ameliorated chronic colitis when administered in prevention or therapeutic protocols. Transfer of CD4(+)CD45RB(high) T cells from ICOS-/- mice induced colitis. Treatment with anti-ICOS mAb did not enhance the production of Th2 cytokines, but a single dose of anti-ICOS mAb induced massive apoptosis of infiltrating ICOS-expressing T cells. CONCLUSIONS: ICOS/B7RP-1 interactions are not required for the development of colitis. However, treatment with anti-ICOS mAb can prevent and reverse intestinal inflammation by inducing apoptosis of ICOS-expressing T lymphocytes.     

TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.     

High plasma fibrinogen level is associated with poor clinical outcome in DIC patients

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.     

The polymorphism of the beta3-adrenergic receptor gene is associated with reduced low-density lipoprotein particle size

People with a predominance of small, dense low-density lipoprotein (LDL) particles appear to be at increased risk for coronary disease, independent of LDL cholesterol levels. The Trp64Arg variant of the beta3-adrenergic receptor gene is reported to be associated with abdominal obesity and resistance to insulin, and as a consequence, this variant may be a genetic factor in the development of atherosclerosis. Therefore, we investigated whether the beta3-adrenergic receptor polymorphism contributes to the distribution of LDL particle size in 136 Japanese subjects, aged 33 to 59 years, who visited for a routine annual checkup. None of these subjects were taking any medication. The diameter of LDL particles was determined at their peak size using nondenaturing 2% to 16% polyacrylamide gradient gels using fresh plasma samples. The genotype frequencies were: Trp/Trp, 71.3%; Try/Arg, 22.1%; and Arg/Arg, 6.6%, with allele frequencies of 0.82 for Trp64 and 0.18 for Arg64. The subjects with the Arg/Arg genotype had significantly higher levels of fasting plasma insulin and triglycerides and an insulin resistance index of homeostasis model assessment (HOMA-R), and significantly smaller LDL particle size than did the subjects with the Trp/Trp genotype. After adjusting for fasting insulin, body mass index (BMI), and HOMA-R index, there was no longer an observed difference in LDL particle size. The number of the Arg64 allele in individuals was significantly related with fasting insulin, BMI, triglycerides, glycosylated hemoglobin (HbA1c), and fasting glucose, and it was inversely related with LDL particle size. After adjusting for triglyceride, fasting insulin levels, and HOMA-R index, LDL particle size was no longer inversely correlated with the Arg allele. These findings suggest that the Trp64Arg variant in the beta3-adrenergic receptor gene may be associated with reducing LDL particle size, probably due to insulin resistance.     

Cronkhite-Canada syndrome with colon cancer, portal thrombosis, high titer of antinuclear antibodies, and membranous glomerulonephritis

A 64-year-old man, who came to us with diarrhea, presented with ectodermal changes such as hyperpigmentation, alopecia, and onychatrophy, and was affected by polyposis in the colorectum and stomach. The polyps were histologically consistent with those in Cronkhite-Canada syndrome (CCS). Interestingly, the patient also had colon cancer, as well as portal thrombosis and a high concentration of antinuclear antibody. Treatment with prednisolone ameliorated the symptoms and the gastrointestinal polyposis, while the cancer was successfully treated with a hemicolectomy. Six months after the surgery, the patient developed nephropathy, with nephrotic-range proteinuria, without recurrence of the cancer. The biopsied renal specimen showed membranous glomerulonephritis. This is a rare case of CCS associated with various complications such as colon cancer, portal vein thrombosis, a high titer of antinuclear antibodies, and membranous glomerulonephritis. Although the pathogenesis of CCS is essentially unknown, these complications might have been indicative of an underlying immunological abnormality.     

Investigation of the optimal treatment strategy for atrial fibrillation in Japan.

The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM study) is a randomized comparative evaluation of rate control and rhythm control, both combined with antithrombotic therapy, as therapeutic strategies for the treatment of atrial fibrillation (AF). This study differs from the earlier AFFIRM and RACE studies in that it has a composite primary end-point representing mortality and also physical/psychological disablement (total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure requiring intravenous administration of diuretics, and patient disablement). Patients' will to change the therapeutic strategy to the other is also considered as an end-point representing disablement under the assigned strategy. The secondary end-point includes quality of life scores and the efficacy and safety of drugs used in treating AF. The J-RHYTHM study emphasizes patient-reported experience and perception of AF-specific disablement, and the safety of antiarrhythmics available in Japan; it will follow 2600 patients treated at more than 150 sites in Japan for a 3-year period.     

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.