Faster increase in body mass index between ages 8 and 13 is associated with risk factors for cardiovascular morbidity and mortality.

BACKGROUND AND AIMS: Excess childhood weight is associated with cardiovascular disease (CVD) in adulthood. Whether this is mediated through adult body mass index (BMI) and associated risk factors such as metabolic derangements remains unclear. The aim was to examine whether childhood BMI velocity (Δkg m(-2) per year) was associated with adult CVD mortality and to examine how adult BMI and cardiometabolic risk factors contribute to the association. METHODS AND RESULTS: Subjects were 1924 Icelanders born between 1921 and 1935 and living in Reykjavik when recruited into a longitudinal study from 1967 to 1991. From ages 8-13 years, BMI velocity was calculated to quantify the association between childhood growth and adult CVD mortality. Deaths from recruitment to 31 December 2009 were extracted from the national register. There were 202 CVD deaths among men and 90 CVD deaths among women (mean follow-up: 25.9 years). Faster BMI velocity from ages 8-13 years was associated with CVD mortality when comparing those in the highest versus lowest tertile with corresponding hazard ratio (HR) (95% confidence interval (CI)): 1.49 (1.03, 2.15) among men and 2.32 (1.32, 4.08) among women after adjustment for mid-life BMI and CVD risk factors. Faster childhood BMI velocity was associated with elevated CVD risk factors among men at mid-life but these associations were less pronounced among women. CONCLUSION: Faster increase in BMI from ages 8-13 years was associated with an increased CVD mortality risk. Children with early growth spurts coupled with excess weight gain during this transition period from childhood into adolescence should be closely monitored to ensure better health in adulthood.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Safety and efficacy of rosuvastatin therapy for the prevention of hyperlipidemia in adult cardiac transplant recipients.

BACKGROUND: Hyperlipidemia after orthotopic heart transplantation (OHT) is associated with immunosuppression. Many OHT patients have increased lipid levels above published guidelines despite treatment with high doses of statins. Treatment with rosuvastatin (ROS) in OHT patients has not yet been evaluated. Therefore, we assessed its efficacy and safety in an OHT population. METHODS: Twenty-one OHT recipients, median age 66 years, whose lipid levels were sub-optimal on the highest tolerated doses of statins, received ROS in addition to standard immunosuppression. Total cholesterol (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), liver transaminases (AST) and creatinine kinase (CK) were measured before and during treatment with ROS. RESULTS: After 6 weeks on an average ROS dose of 10 mg/day, a TC:HDL-C ratio of <4 was reached in 76% of patients, and 70% of patients reached an LDL-C level of <2.5 mmol/liter (100 mg/dl). TC decreased to <5.2 mmol/liter (200 mg/dl) in 80% of patients and TG decreased to <2 mmol/liter (175 mg/dl) in 61% of patients. Except for the HDL-C increase, all changes were statistically significant. The decrease in the median TC:HDL-C ratio between baseline and 6 weeks was also statistically significant (p = 0.001). There were no significant changes in CK or AST levels, and no clinical evidence of myositis. One patient developed myalgia and 2 were withdrawn from the study because of mild elevation of CK (<3-fold upper limit of normal [ULN]). CONCLUSIONS: In the setting of tertiary referral centers, ROS appears to be safe and effective in lowering LDL-C in OHT recipients in whom treatment with other statins failed to achieve target LDL-C. No evidence of liver or muscle dysfunction was noted. Long-term studies are needed to ascertain the effect of ROS therapy on incidence of coronary artery disease (CAD) in this population.

Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.

To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.

Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia.

Deficient expression of BLNK, an adaptor molecule crucial for normal B-cell development, is associated with increased pro-B/pre-B-cell expansion in mice. It has been proposed that BLNK deficiency is a primary cause of B-lineage acute lymphoblastic leukemia (ALL). We studied BLNK expression in the leukemic cells from 352 patients with childhood ALL (309 B-lineage; 43 T-lineage). By HG_U95Av2 Affymetrix GeneChip analysis, BLNK was expressed in 275 of 284 (96.8%) B-lineage ALL samples but in only one of 43 (2.3%) T-lineage ALL samples. Of 118 B-lineage ALL samples analyzed with the HG_U133A GeneChip, 117 (99.2%) expressed BLNK. All 30 primary B-lineage ALL samples studied by RT-PCR expressed BLNK transcripts; all 19 samples studied by Western blotting or flow cytometry expressed BLNK protein. Levels of BLNK in B-lineage ALL were as high as those of their normal counterparts; they were not related with genetic subgroups or differentiation stage. These results indicate that BLNK deficiency is a rare occurrence in childhood B-lineage ALL and is unlikely to be a common leukemogenic event as previously proposed.

Ileal uptake of oleic acid: evidence for adaptive response to high fat feeding.

When I-14C oleic acid at 120 micron Eq/hr was infused into the duodenum in normal rats in a micellar solution with mono-olein (60 mu moles/hr) in 15 mM taurocholate over 6 hr uptake was nearly complete (97%). However, when this same solution was infused into the mid small bowel in control animals uptake was incomplete (88.9 +/- 2.6%, mean +/- SEM, P < 0.01). After 4 weeks on a high fat diet, containing 45% vegetable oil by weight, oleic acid uptake increased to 98.1 +/- 0.1% (P < 0.01 compared to controls). The improved uptake of oleic acid was associated with increased dry weight of mucosa in the proximal half of the ileum from 109 +/- 8.8/20 cm in controls to 135.6 +/- 7.3 mg/20 cm in high fat diet fed rats (P < 0.05), while protein increased from 107.4 +/- 6.5 to 124.9 +/- 4.8 mg/20 cm (P < 0.05). There was no increase in DNA expressed as mg/g wet weight of mucosa or in number of cells per villus. Lipid content of the mucosa and degree of esterification of absorbed oleic also were unaltered. These results indicate that the mucosa of the proximal ileum responds to high fat feeding by hypertrophy (increased mass and protein, with no change in DNA content or cell number) and that this change is associated with more complete uptake of oleic acid reaching this part of the small bowel.

Effects of meal ingestion and active standing on blood pressure in patients > or = 60 years of age.

Postprandial hypotension and orthostatic hypotension occur often in elderly patients. In the present study, we examined hemodynamic and humoral responses to meal ingestion and active standing in 20 patients > or = 60 years of age who were free of apparent autonomic and cardiac dysfunction. For a time-control study, water was given instead of a meal to 19 of the 20 patients. After the meal ingestion, there was a fall in systolic blood pressure (BP) in 6 patients of > 20 mm Hg, whereas the fall in systolic BP during the control study was not > 20 mm Hg in any patient. The low-frequency power of the systolic BP wave, an index of peripheral sympathetic activity, was significantly increased only in the patients without postprandial hypotension. The postprandial changes in systolic BP were correlated with the changes in the low-frequency power of the systolic BP wave (r = 0.61; p < 0.01), but they were not correlated with the changes in plasma norepinephrine, insulin, cardiac output, or parameters obtained by the spectral analysis of the RR interval. The systolic BPs in the upright position were comparable after the meal and the water ingestion. Thus, the effects of meal ingestion and upright position on BP are not additive. Dysfunction of peripheral sympathetic control of vascular tone may contribute to the postprandial hypotension in elderly patients.

A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients.

The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels.

Tissue-type plasminogen activator inhibits aggregation of platelets in vitro.

The effects of tissue-type plasminogen activator (t-PA) on the platelet aggregation were studied using citrated whole blood and platelet-rich plasma (PRP) obtained from human donors. t-PA suppressed adenosine 5'-diphosphate (ADP)- or collagen-induced platelet aggregation in a dose-dependent manner. The 50% inhibitory concentration (IC50) for t-PA was lower by one order of magnitude than that for urokinase (UK) in whole blood and PRP. The suppression of platelet aggregation was not completely inhibited by alpha-2-antiplasmin. t-PA did not cause the degradation of fibrinogen or fibrin in PRP, whereas UK caused the reduction of fibrinogen and fibrin, and the increase of fibrinogen- and fibrin-degradation products (FDP). These results suggest that the mode of action of t-PA in inhibiting platelet aggregation may be different from that of UK.

Genetic modification of T cells for cancer therapy.

The use of immune cells with restricted specificities for the treatment of cancer is a rapidly emerging area of clinical research. Chimeric receptors composed of the single-chain variable domain of murine antibodies and human signaling molecules are a promising tool to redirect the specificity of autologous or allogeneic immune cells. The success of this approach depends on the identification of target molecules expressed preferentially on cancer cells. Moreover, appropriate primary and secondary stimuli must be delivered to generate vigorous and durable immune responses. Since cancer cells often lack ligands for key co-stimulatory molecules, the addition of molecules such as CD28 or 4-1BB to the chimeric receptors can significantly improve their function. Studies in vitro and in animal models indicate that immune cells expressing chimeric receptors can have remarkable anti-cancer activity, while experimental and clinical data indicate that long-term persistence of adoptively transferred cells is feasible. Therefore, testing of this approach in clinical trials is warranted. We here review the principles and methodologies for designing chimeric receptors and delivering them into immune cells, as well as some of the potential complications associated with this form of cell therapy.

Behavior of enterococci in egg processing operations.

Since enterococci were detected in dried and frozen egg products (whole egg and egg yolk), the origin of the enterococci and their behavior in the different stages of egg processing were surveyed. The bacterial survey of unwashed and washed eggs, gathered from several parts of Japan, showed the presence of an average of 60 enterococci per egg on the shell surface of unwashed eggs. Smaller numbers of enterococci were detected on the shell surface of washed eggs. Most of the detected enterococci were Streptococcus faecalis and S. faecalis var. liquefaciens. The contents of two eggs were contaminated with enterococci when 120 washed eggs were examined. Enterococci were destroyed to some extent by the disinfectants used for washing the shell eggs, but they seemed to have greater resistance than Escherichia coli and Pseudomonas fluorescens used for comparison. In whole egg and egg yolk, enterococci grew rapidly at 25 C, slowly at 10 C, and very slowly at 2.5 C. The frozen storage of both whole egg and egg yolk at -20 C for 3 months only slightly decreased the number of enterococci. They were decreased only slightly by normal pasteurization but were destroyed in the desugaring process by the glucose oxidase method. Enterococci numbers were only slightly decreased by spray-drying whole egg and yolk. Considering these characteristics of enterococci, it appears to be difficult to produce enterococci-free egg products in a normal production line.

Egg yolk paste for determining some food poisoning bacteria.

Egg yolk, aseptically prepared from fresh eggs, was partially dehydrated with a 40% high fructose corn syrup solution, and 10% salt was added. This salted yolk paste was added to mannitol salt agar for the detection of Staphylococcus aureus, to NaCl-glycine Kim and Goepfert medium for detection of Bacillus cereus, to Clostridium welchii agar for detection of C. perfringens, and to Gifu anaerobic medium for detection of C. botulinum. These food poisoning bacteria showed the same lecithovitellin (LV) reaction on these media as on the same media prepared with fresh egg yolk. The yolk paste could be stored at -20 C without freezing and did not show any bacterial growth after holding at 25 C for 30 days. The increased salt content resulted from the addition of salted yolk paste to the media did not inhibit the growth of the food poisoning bacteria used in these experiments. For the identification of the food poisoning bacteria used in this work, and which give a LV reaction, salted yolk paste is more convenient to use than yolk separated from fresh shell eggs.

[Serotypes and drug susceptibility of Pseudomonas aeruginosa isolated from clinical specimens].

Between January, 1982 and December, 1994, 236 Pseudomonas aeruginosa strains were isolated from clinical specimens at our division, and were tested for serotypes and drug-susceptibilities to 15 antibiotics. Serotype G strains were isolated at the highest frequency (32.6%), and followed by strains of serotype B (15.7%), A (11.9%), E (9.3%), I (7.2%), F and M (5.5%), non-typable (5.1%), D (3.4%), H (2.1%), C and K (0.8%). We examined the changes of isolation frequencies of different serotypes annually. Isolation frequencies of serotypes E and F showed tendency to decrease, whereas serotype I has been isolated increasingly year by year. MIC90's of the 15 antibiotics were as follows, tosufloxacin: 0.78 microgram/ml, biapenem (BIPM) and ofloxacin (OFLX): 3.13 micrograms/ml, imipenem (IPM), ceftazidime, cefozopran, cefsulodin and gentamicin: 6.25 micrograms/ml, aztreonam and amikacin: 12.5 micrograms/ml, piperacillin, cefoperazone and minocycline (MINO): 25 micrograms/ml, fosfomycin: > 100 micrograms/ml and chloramphenicol: > 200 micrograms/ml. MIC90'S of IPM, BIPM, MINO and OFLX increased 4-fold from stage I (1982-1987) through stage III (1992-1994) and the isolation frequency of drug-resistant strains increased year by year. In other words, antibiotic resistant strains appeared increasing with time. No relationship between serotypes and drug-resistance were observed.

[Drug susceptibility of clinically isolated Helicobacter pylori].

Between January 1995 and March 1997, 78 Helicobacter pylori strains were isolated from patients with gastritis and gastric ulcer and their drug-susceptibilities to 8 antimicrobial agents and 3 anti-ulcer drugs were determined. Imipenem was the most active agent and its MICs to all the strains tested were lower than 0.013 microgram/ml. Amoxicillin, cefaclor and minocycline were active against H. pylori with MIC90s of 0.05 microgram/ml, 0.78 microgram/ml and 0.39 microgram/ml, respectively, and no resistant strains against these drugs were isolated. However, resistant strains to clarithromycin (isolation frequency: 9%), erythromycin (13%), ofloxacin (8%) and metronidazole (13%) were isolated. Triple, double and single resistant strains to above 4 antimicrobial agents were noted. No quadruple resistant strain was isolated. Frequencies of those resistance patterns were 14.3% (triple), 28.6% (double), and 57.1% (single), respectively. Seven erythromycin-resistant strains were shown to be cross-resistant to clarithromycin but 3 erythromycin-resistant strains were susceptible to clarithromycin. It seems likely that this phenomenon is caused by the fact that clarithromycin is more active to H. pylori than erythromycin. The MIC90 value of lansoprazole was lower than those of omeprazole and famotidine.

[Epidemiological studies on drug-resistance patterns, coagulase types, and MRSA-phage types of MRSA isolates during 1990-1994].

We examined drug-resistance patterns, coagulase types, and MRSA-phage types of 125 MRSA strains isolated from clinical specimens during the period of January 1990 and December 1994. No vancomycin-resistant strain was isolated. Twenty one antibiotics were divided into three classes, low-intermediate- and high-isolation-frequency class, based on isolation frequencies of resistant strains. Minocycline, chloramphenicol, streptomycin, and imipenem were found to be included in low-isolation-frequency class (16.8-40%). In intermediate-isolation-frequency class (45.6-62.9%), cefmetazole, amikacin, gentamicin, and tetracycline were included. Oxacillin, ampicillin, piperacillin, ceftizoxime, cefoperazone, cefazolin, erythromycin, oleandomycin, kitasamycin, clindamycin, kanamycin, tobramycin, and ofloxacin belonged to high-isolation-frequency class (97.6-100%). MIC90s of vancomycin and minocycline (1.56 and 25 micrograms/ml) were lower than that of other 13 drugs. Comparing medical ward with dental ward, imipenem-, gentamicin-, and minocycline-resistant strains at medical ward, chloramphenicol- and streptomycin-resistant strains at dental ward were isolated dominantly on each ward, MRSA isolates were classified to 39 types by drug-resistance patterns. The isolation frequencies of coagulase type II and type IV strains were 65.6% and 29.6%, respectively. At dental ward, the isolation frequency of coagulase type IV strains was higher than that of coagulase type II strains during 1990-1992. However, coagulase type II strains were isolated considerably more than type IV strains during 1993-1994. By MRSA-phage typing, MRSA isolates were grouped into 18 MRSA-phage types. One hundred and twenty five MRSA isolates were divided into 56 types by using drug-resistance patterns, coagulase typing, and MRSA-phage typing. It was considered that such classification in combination of three methods is useful to make decision of epidemic by the same MRSA strain.

[Analysis of human sera obtained from lung cancer patients by two-dimensional electrophoresis after schizophyllan (SPG) treatment].

Schizophyllan (SPG) was administered to 13 lung cancer patients (i.m. 20mg X 2/week) for 3 weeks without chemo or irradiation therapies, and serum proteins were analyzed by two-dimensional electrophoresis (TDE). Additionally, immunosuppressive acidic protein (IAP) was quantitatively determined by single radial immunodiffusion (SRID). By TDE analysis, human serum proteins were separated into more than 100 spots, and about 14 spots were found to show quantitative changes in cancer patients. Quantitative examination was therefore conducted on changes of 8 components among these spots, including alpha 1-acidic glycoprotein (alpha 1 AG), acidic alpha 2-macroglobulin (acidic alpha 2 M), haptoglobin (Hp) and IAP. The protein which showed the most marked decrease in cancer patients, located between transferrin and IgG on the above TDE patterns, was ascertained to have a molecular weight of about 150,000 using a gel filtration method. This protein was increased in 7 of 13 patients after SPG treatment.