Low serum lipids suggest severe bone marrow failure in children with aplastic anemia

BACKGROUND: Significantly low serum lipid levels are occasionally seen at the time of diagnosis in children with aplastic anemia (AA). The aim of the present study was to clarify the pathologic and clinical significance of pretreatment serum lipid levels in AA. METHODS: A questionnaire seeking precise data about AA in pediatric patients, including the initial laboratory data at the time of onset of AA and the clinical course of these patients, was sent to 18 institutes in Japan; 13 institutes responded to the questionnaire. In this retrospective study, data concerning hematologic examination and serum lipids were available for analysis in 127 children with AA. Serum lipoprotein patterns were analyzed using conventional agarose electrophoresis in eight patients. In order to elucidate the cause of hypolipidemia in AA, we assayed serum macrophage colony stimulating factor (M-CSF), which is well known to have apparent cholesterol-lowering activity, by using an enzyme-linked immunosorbent assay in seven patients with hypocholesterolemia and compared the results with those obtained in patients with iron-deficiency anemia (IDA). RESULTS: We found that pretreatment total cholesterol (TC) and triglyceride levels in the serum correlated well with counts of both nucleated cells and hemopoietic cells in the bone marrow (BM) and were inversely correlated with the lymphocyte ratio in both the BM and peripheral blood. Patients with serum TC lower than 150 mg/dL showed a poor response to any form of therapy except BM transplantation. There was no difference in the serum lipoprotein patterns between the controls and patients examined. The serum M-CSF level was significantly higher in patients with TC levels lower than 150 mg/dL compared with controls. CONCLUSIONS: These results indicate that the pretreatment serum lipid level may reflect hematopoietic activity within the BM and can help to predict the therapeutic response of each case of AA to treatment with immunosuppressive drugs, corticosteroids and anabolic steroids. These results also indicate that M-CSF may be one of the contributing causes of the hypocholesterolemia that occurs in both AA and IDA.     

Air plethysmographic assessment of external valvuloplasty in patients with valvular incompetence of the saphenous and deep veins

PURPOSE: The indications for deep venous valvuloplasty remain controversial in patients with incompetent deep vein valves associated with primary varicose veins. The purpose of this study was to evaluate the usefulness of external femoral valvuloplasty performed simultaneously with varicose vein surgery from the standpoint of venous function determined with air plethysmography. PATIENTS AND METHODS: Thirty-one limbs of 25 patients (12 men, 13 women; mean age, 56.3 years; range, 33 to 80 years) with chronic venous insufficiency caused by valvular incompetence of both deep veins and saphenous veins were studied in a prospective, nonrandomized fashion. Descending phlebography showed moderate to severe reflux of grade 3 or 4 with Herman and Kistner classifications. Clinical severity of disease was CEAP classification 2S (in six limbs), classification 3 (in three limbs), classification 4 (in 16 limbs), classification 5 (in two limbs), and classification 6 (in four limbs). We performed superficial venous surgery alone in 14 limbs (control group), which consisted of stripping or ligation of incompetent saphenous veins and ligation of all incompetent perforators. In the remaining 17 limbs (study group), we performed superficial venous surgery simultaneously with external valvuloplasty of the femoral vein with intraoperative endoscopic observation. Venous reflux of the limbs was evaluated with air plethysmographic examination before surgery and at 1, 6, 12, and 24 months after surgery in both groups. RESULTS: Preoperative venous filling index (mean +/- standard deviation) in the control and study groups was 9.4 +/- 3.8 mL/min and 8.8 +/- 3.5 mL/min, respectively (not significant), and it decreased to 7.0 +/- 3.6 mL/min (P <.01) and 2.8 +/- 1.0 mL/min (P <.01), respectively, 1 month after surgery. Postoperative index values in the study group were significantly lower than values in the control group (P <.01), and this difference continued for more than 2 years after surgery (P <.05). After a follow-up period of 12 to 37 months (average, 25 months), the venous clinical severity score was higher in the control group (3.4 +/- 1.7) than in the study group (2.1 +/- 0.3; P <.05), and the venous disability score was higher in the control group (1.4 +/- 0.6) than in the study group (0.8 +/- 0.8; P <.05). CONCLUSION: Although further follow-up study is necessary, these results point to the functional and clinical usefulness of femoral valvuloplasty performed simultaneously with varicose vein surgery in patients with moderate to severe deep venous reflux. The venous filling index obtained with air plethysmography is an excellent predictor of the clinical severity of the disease and of postoperative clinical results.     

Mitral valve repair for severe mitral valve regurgitation during left ventricular assist device implantation

Background

The management of severe mitral regurgitation (MR) at the time of left ventricular assist device (LVAD) implantation is controversial. We adopted an approach of systematic repair of severe MR at the time of LVAD implantation and report our experience.

Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE)

Acute renal failure with severe loin pain induced by anaerobic exercise (ALPE) is a rare condition that is accompanied by wedge-shaped contrast enhancement on computed tomography (CT) without evidence of rhabdomyolysis. In two pediatric cases with ALPE, we tried to determine the relationship between findings from CT and magnetic resonance imaging (MRI). Case 1 involved a 13-year-old Japanese girl with a diagnosis of ALPE with normo-uricemia. Contrast-enhanced CT after 24 and 48 h showed a wedge-shaped excretion delay for the contrast media. A clear wedge-shaped signal hyperintensity matching the CT images was obtained by diffusion-weighted MRI. Case 2 involved a 16-year-old boy who presented with a second attack of ALPE after diagnosis of ALPE with hypouricemia 1 year earlier. Only diffusion-weighted imaging was performed. Clear wedge-shaped signal hyperintensity was apparent, similar to Case 1. MRI is safer than contrast-enhanced CT for patients with ALPE. Diffusion-weighted MRI is a very useful examination for diagnosing ALPE, providing noninvasive detection of lesions peculiar to ALPE.     

The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase

The non-pathogenic Gram-positive soil bacterium Streptomyces davawensis synthesizes the riboflavin (vitamin B₂) analogs roseoflavin (RoF) and 8-demethyl-8-amino-riboflavin (AF). Both compounds are antibiotics. Notably, a number of other riboflavin analogs are currently under investigation with regard to the development of novel antiinfectives. As a first step towards understanding the metabolism of riboflavin analogs in humans, the key enzymes flavokinase (EC 2.7.1.26) and FAD synthetase (EC 2.7.7.2) were studied. Human flavokinase efficiently converted RoF and AF to roseoflavin mononucleotide (RoFMN) and 8-demethyl-8-amino-riboflavin mononucleotide (AFMN), respectively. Human FAD synthetase accepted RoFMN but not AFMN as a substrate. Consequently, roseoflavin adenine dinucleotide (RoFAD) was synthesized by the latter enzyme but not 8-demethyl-8-amino-riboflavin adenine dinucleotide (AFAD). The cofactor analogs RoFMN, AFMN and RoFAD have different physicochemical properties as compared to FMN and FAD. Thus, the cofactor analogs have the potential to render flavoenzymes inactive, which may negatively affect human metabolism. RoF, but not AF, was found to inhibit human flavokinase. In summary, we suggest that AF has a lower toxic potential and may be better suited as a lead structure to develop antimicrobial compounds.     

Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma

Constitutive nuclear factor-kappa B (NF-κB) activation has been reported in ocular adnexal lymphoma (OAL). TNFAIP3/A20 is a "global" inhibitor of NF-κB pathway. We have shown that OAL has preferential loss of the 6q23.3 region where TNFAIP3/A20 exist, which is suggested to involve in lymphomagenesis of OAL. The mechanisms causing NF-κB activity in OAL remain elusive. Recently, NF-κB canonical pathway genes including CARD11, CD79B and MYD88 were shown to be frequently mutated in diffuse large B-cell lymphomas. In this study, we analyzed the mutation status of these genes by direct sequencing in 24 OAL cases including 9 cases with loss of 6q23.3 previously identified by array comparative genomic hybridization. We showed that genetic alterations of these genes were not found in OAL, a finding differing from that of most B-cell lymphomas. Genetic or epigenetic alterations in other genes are likely to be relevant in pathogenesis of OAL case without A20 loss.     

The role of Syk/CARD9 coupled C-type lectins in antifungal immunity

Fungal infections are affecting an increasing number of people, and the failure of current therapies in treating systemic infection has resulted in an unacceptably high mortality rate. It is therefore of importance that we understand immune mechanisms operating during fungal infections, in order to facilitate development of adjunctive immunotherapies for the treatment of these diseases. C-type lectin receptors (CLRs) are pattern recognition receptors (PRRs) that are critical for immune responses to fungi. Many of these receptors are coupled to Syk kinase, which allows these receptors to signal via CARD9 leading to NF-κB activation, which in turn contributes to the induction of both innate and adaptive immunity. Dectin-1, Dectin-2 and Mincle are all CLRs that share this common signalling mechanism and have been shown to play key roles in antifungal immunity. This review aims to update existing paradigms and summarise the most recent findings on these CLRs, their signal transduction mechanisms and the collaborations between these CLRs and other PRRs.     

Establishment and intra‐/inter‐laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation

A reactive oxygen species (ROS) assay was previously developed for photosafety evaluation of pharmaceuticals, and the present multi‐center study aimed to establish and validate a standard protocol for ROS assay. In three participating laboratories, two standards and 42 coded chemicals, including 23 phototoxins and 19 nonphototoxic drugs/chemicals, were assessed by the ROS assay according to the standardized protocol. Most phototoxins tended to generate singlet oxygen and/or superoxide under UV–vis exposure, but nonphototoxic chemicals were less photoreactive. In the ROS assay on quinine (200 µm ), a typical phototoxic drug, the intra‐ and inter‐day precisions (coefficient of variation; CV) were found to be 1.5–7.4% and 1.7–9.3%, respectively. The inter‐laboratory CV for quinine averaged 15.4% for singlet oxygen and 17.0% for superoxide. The ROS assay on 42 coded chemicals (200 µm ) provided no false negative predictions upon previously defined criteria as compared with the in vitro/in vivo phototoxicity, although several false positives appeared. Outcomes from the validation study were indicative of satisfactory transferability, intra‐ and inter‐laboratory variability, and predictive capacity of the ROS assay. Copyright © 2012 John Wiley & Sons, Ltd.     

Visit-to-Visit Blood Pressure Variability Is a Novel Risk Factor for the Development and Progression of Diabetic Nephropathy in Patients With Type 2 Diabetes

OBJECTIVE

Recent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 ± 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model.

RESULTS

Multiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (β = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008–1.302).

CONCLUSIONS

Visit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in patients with type 2 diabetes, and several risk factors including smoking, hypertension, and dyslipidemia have been shown to accelerate the progression of CVD (1,2). Elevated albumin excretion rate, which is a useful marker for diabetic nephropathy, has been reported to be associated with increased risk of cardiovascular mortality and the progression of CVD (3,4). The presence of hypertension and the variability in blood pressure are strong predictors of all mortality (5), CVD (6–8), and organ damage such as chronic kidney disease (9). However, there is a recent study that does not favor a prognostic role of variability in blood pressure. Mancia et al. (10) reported that in patients with mild-to-moderate hypertension, carotid intima-media thickness and cardiovascular outcomes were not related to on-treatment visit-to-visit clinic or 24-h blood pressure variability. A recent study suggested that visit-to-visit variability in blood pressure was associated with the development of diabetic nephropathy in patients with type 1 diabetes (9). Also, we recently reported that visit-to-visit variability in systolic blood pressure (SBP) is correlated with albuminuria in a cross-sectional study (11). However, a relationship between visit-to-visit variability in blood pressure and the progression or development of diabetic nephropathy in patients with type 2 diabetes has not been investigated. Therefore, we evaluated the relationship between visit-to-visit variability in SBP and change in the urinary albumin excretion (UAE) or the development of albuminuria in patients with type 2 diabetes.