Analyses of thrombocytopenia in idiopathic thrombocytopenic purpura-prone mice by platelet transfer experiments between (NZW x BXSB)F1 and normal mice

Male (NZW x BXSB) F1 (W/B F1) mice, which develop lupus nephritis, myocardial infarction, and thrombocytopenia, showed reduced platelet lifespan (PLS) and increased platelet-associated antibody (PAA) values. There were statistically significant correlations between the increase in PAA values and either the reduction in PLS or the decrease in platelet counts. This and the results of platelet transfer experiments between old male W/B F1 mice and either female W/B F1 or normal BALB/c mice indicate that PAAs on the platelet surface play a crucial role in the destruction of platelets in W/B F1 mice. The mechanism of thrombocytopenia observed here appears similar to that of human idiopathic thrombocytopenic purpura (ITP). Therefore, we think that W/B F1 mice are a potentially useful animal model for investigating the effectiveness and mode of action of therapeutic agents in human ITP, and that they may provide additional information on the basic mechanisms of this autoimmune phenomenon.     

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter,open label clinical trial

Background

To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial.

Comparison of reticulated platelet count with plasma glycocalicin concentration as a marker of platelet turnover in patients with thrombocytopenic disorders

Measurements of plasma glycocalicin (GC) and reticulated platelets (RP) have been reported to be useful for classifying thrombocytopenic disorders. However, there have been no reports comparing the clinical usefulness of the two methods. We measured GC and RP levels simultaneously in 39 patients with idiopathic thrombocytopenic purpura (ITP), 15 patients with aplastic anemia (AA), and 17 patients with hypoplastic thrombocytopenia (HypoT) due to chemotherapy. The GC index (GC level normalized for the individual platelet count) and the percentage of RP (%RP), a parameter of platelet life span, were very high (7.5 +/- 11.4 and 20.8 +/- 13.0%, respectively) in patients with ITP as compared with those of healthy subjects (1.3 +/- 0.5 and 7.9 +/- 2.5%, respectively). However, 6 AA patients and 14 HypoT patients, in whom platelet life span is thought to be normal, also had an elevated GC index, suggestive of a false positive result. The RP, a parameter of platelet production, was low in all AA and HypoT patients except for one in each case. However, the GC level, an additional parameter of platelet production, was normal in 4 AA and 8 HypoT patients, indicating that it is not a sensitive indicator. We conclude that the RP and %RP are more feasible markers of thrombopoiesis and platelet life span, respectively, than the GC level and GC index.     

Demonstration of platelet antigens that bind platelet-associated autoantibodies in chronic ITP by direct immunoprecipitation procedure

Platelet antigens that bind platelet-associated autoantibodies in chronic idiopathic thrombocytopenic purpura (ITP) were demonstrated using a direct immunoprecipitation procedure. ITP platelets, with bound autoantibodies, were radiolabelled and solubilized, and then platelet antigen-antibody complexes adsorbed to protein A-bearing Staphylococcus aureus were analysed by 7.5% sodium dodecyl sulphate, polyacrylamide gel electrophoresis (SDS-PAGE). Direct immunoprecipitation demonstrated the presence of platelet-associated autoantibodies against glycoprotein (GP) IIb/IIIa in four of six ITP patients with an intensive band corresponding to platelet-associated IgG. These results were confirmed by indirect immunoprecipitation using ether eluates from two ITP patients. In addition, only direct immunoprecipitation demonstrated the presence of autoantibodies against an unidentified protein having a molecular mass of 56 kDa in three of the six patients. These three ITP patients having autoantibodies against GP IIb/IIIa and against the 56 kDa protein were studied after splenectomy. Two patients, showing disappearance of autoantibodies against these antigens, attained a complete remission, and one patient, with autoantibodies against the 56 kDa protein despite splenectomy, attained only partial remission. These data suggest that autoantibodies against GP IIb/IIIa and against the 56 kDa protein may play a role in platelet destruction in some ITP patients.     

Elevated total iron-binding capacity as a predictor of response to deferasirox therapy in the setting of chronic iron overload

It is difficult to predict the efficacy of deferasirox (DFX) as its pharmacokinetics varies among patients. The area under the curve (AUC) is reportedly useful for determining adequate DFX dosage; however, serum concentration measurements are often challenging. Effective DFX dosage is thus defined by assessing the efficacy of this agent in clinical practice. To analyze a predictive response marker to DFX therapy for use in adjusting the effective dosage during the early treatment phase, we retrospectively evaluated 39 DFX-treated patients. We defined response as a >40 % decrease in serum ferritin concentration from the pretreatment level. A maximum elevation of the total iron-binding capacity (TIBC) correlated with response in a multivariate analysis of iron metabolic markers (R ² = 0.37, p < 0.001). A receiver operating characteristic curve analysis revealed that TIBC elevation had an AUC of 0.85 (p < 0.001) and the optimal cut-off value of TIBC elevation was 150 µg/dl. TIBC elevation of >150 µg/dl is a favorable predictor of effective ferritin reduction in DFX therapy (hazard ratio 29.6, 95 % confidence interval 4.8–183.6; p < 0.001). DFX therapy with TIBC monitoring may enable the determination of the minimum effective DFX dosage.     

Risk factors for diabetes mellitus and impaired glucose tolerance following allogeneic hematopoietic stem cell transplantation in pediatric patients with hematological malignancies

Long-term surviving recipients of allogeneic hematopoietic stem cell transplantation (HSCT) often suffer from diabetes mellitus (DM). We sought to identify risk factors for the development of post-transplant DM and impaired glucose tolerance (IGT) in pediatric HSCT patients. Glucose tolerance statuses were evaluated in 22 patients aged 6.3–21.8 years who had received allogeneic HSCT between the ages of 0.8–13.5 years. Five patients were diagnosed as having type 2 DM, and treated with insulin or oral hypoglycemic agents. Five patients were included in the IGT group, and the remaining 12 children were in the normal glucose tolerance (NGT) group. The cumulative incidence of DM plus IGT was 11.6 % at 5 years and 69.3 % at 10 years. None of the patients were obese/overweight and none had a family history of DM. There were no significant differences in serum levels of leptin and adiponectin between the DM + IGT and the NGT groups. An average preprandial glucose levels in the DM + IGT group were significantly higher than those in the NGT group from preparative conditioning to 60 days after HSCT. In multivariate analysis, an age of ≥6 years at the time of HSCT was significantly associated with the development of DM + IGT. Additionally, careful follow-up is necessary, even for NGT patients.     

Vascular Ehlers-Danlos Syndrome Without the Characteristic Facial Features: A Case Report

As a type of Ehlers-Danlos syndrome (EDS), vascular EDs (vEDS) is typified by a number of characteristic facial features (eg, large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears). However, vEDs does not typically display hypermobility of the large joints and skin hyperextensibility, which are features typical of the more common forms of EDS. Thus, colonic perforation or aneurysm rupture may be the first presentation of the disease. Because both complications are associated with a reduced life expectancy for individuals with this condition, an awareness of the clinical features of vEDS is important.Here, we describe the treatment of vEDS lacking the characteristic facial attributes in a 24-year-old healthy man who presented to the emergency room with abdominal pain. Enhanced computed tomography revealed diverticula and perforation in the sigmoid colon. The lesion of the sigmoid colon perforation was removed, and Hartmann procedure was performed. During the surgery, the control of bleeding was required because of vascular fragility. Subsequent molecular and genetic analysis was performed based on the suspected diagnosis of vEDS. These analyses revealed reduced type III collagen synthesis in cultured skin fibroblasts and identified a previously undocumented mutation in the gene for a1 type III collagen, confirming the diagnosis of vEDS. After eliciting a detailed medical profile, we learned his mother had a history of extensive bruising since childhood and idiopathic hematothorax. Both were prescribed oral celiprolol. One year after admission, the patient was free of recurrent perforation.This case illustrates an awareness of the clinical characteristics of vEDS and the family history is important because of the high mortality from this condition even in young people. Importantly, genetic assays could help in determining the surgical procedure and offer benefits to relatives since this condition is inherited in an autosomal dominant manner.     

Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: Heterogeneous causes of an unusual immunophenotype

Immunohistochemically p16 (CDKN2A)‐negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16‐negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co‐existing Epstein–Barr virus infection. Another was positive for HPV6 categorized as low‐risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV‐negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16‐negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality.     

Peptidoglycan recognition proteins in Drosophila immunity

Innate immunity is the front line of self-defense against infectious non-self in vertebrates and invertebrates. The innate immune system is mediated by germ-line encoding pattern recognition molecules (pathogen sensors) that recognize conserved molecular patterns present in the pathogens but absent in the host. Peptidoglycans (PGN) are essential cell wall components of almost all bacteria, except mycoplasma lacking a cell wall, which provides the host immune system an advantage for detecting invading bacteria. Several families of pattern recognition molecules that detect PGN and PGN-derived compounds have been indentified, and the role of PGRP family members in host defense is relatively well-characterized in Drosophila. This review focuses on the role of PGRP family members in the recognition of invading bacteria and the activation and modulation of immune responses in Drosophila.     

Low‐carbohydrate diet and risk of cancer incidence: The Japan Public Health Center‐based prospective study

Epidemiological evidence on the effects of a long‐term low‐carbohydrate diet (LCD) on cancer incidence remains sparse. We investigate the association between LCD and the risk of overall and specific cancer site incidence in a Japanese population‐based prospective cohort study among 90 171 participants aged 45‐74. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median 17.0 y of follow‐up, we identified 15 203 cancer cases. A higher overall LCD score was associated with increased overall cancer risk (HR = 1.08 [CI: 1.02‐1.14], P‐trend = .012), while it was associated with decreased gastric cancer (GC) risk (0.81 [0.71‐0.93], P‐trend = .006). A higher animal‐based LCD score was associated with higher risk of overall cancer (1.08 [1.02‐1.14], P‐trend = .003), colorectal cancer (CRC) (1.11 [0.98‐1.25], P‐trend = .018), rectal cancer (RC) (1.24 [1.00‐1.54], P‐trend = .025), lung cancer (LC) (1.16 [1.00‐1.34], P‐trend = .042), and lower risk of GC (0.90 [0.79‐1.01], P‐trend = .033). Furthermore, we found that plant‐based LCD score was related to lower GC incidence (0.87 [0.77‐0.99], P‐trend = .031). Additionally, adjusted for plant fat intake amplified the adverse associations (overall cancer: 1.08 [1.02‐1.14] vs. 1.11 [1.05‐1.18]; CRC: 1.08 [0.95‐1.22] vs. 1.13 [0.99‐1.30]; LC: 1.14 [0.98‐1.33] vs. 1.19 [1.01‐1.41]). We conclude that LCD enriching with animal products was associated with increased overall cancer, CRC, and LC incidence. These adverse associations could be attenuated by plant fat consumption. LCD reduces the risk of developing GC. Long‐term adherence to LCD without paying attention to the balance between animal and plant food source consumption might cause adverse overall cancer incidence consequences.