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.

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.

Analysis of gene mutations in four cases of dermatofibrosarcoma protuberans.

Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor B-chain (PDGFB) gene has been described in dermatofibrosarcoma protuberans (DFSP). Various exons of the COL1A1 gene have been shown to be involved in the fusion with exon 2 of the PDGFB gene. We examined the breakpoints of the COL1A1 gene using the tumour specimens from four patients with DFSP. The COL1A1-PDGFB fusion transcripts were detected from the cultured tumour cells by reverse transcriptase polymerase chain reaction. Sequence analysis revealed that the ends of exons 23, 25, 26 and 36 in the COL1A1 gene were fused with the start of exon 2 in the PDGFB. This study identified three novel COL1A1 breakpoints: exons 23, 26 and 36 of the COL1A1 gene. In one case, the tumour was composed of two areas that differed in cytological atypia, cellularity and mitotic activity, indicating the dedifferentiation of the tumour. In tumour cells from two different areas the same aberrant fusion transcripts were identified. These results suggest that the dedifferentiation of tumour cells has nothing to do with the specific breakpoints of the COL1A1 gene, but depends on other unknown factors.

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.

Charcot-Marie-Tooth families in Japan with MPZ Thr124Met mutation.

BACKGROUND: The MPZ Thr124Met mutation is characterised by a late onset, pupillary abnormality, deafness, normal or moderate decreased motor nerve conduction velocity, and axonal damage in sural nerve biopsy. OBJECTIVE: To investigate the clinical manifestations of the axonal or demyelinating forms of the Japanese MPZ Thr124Met mutation originating in four different areas: Tottori, Nara, Aichi, and Ibaragi. RESULTS: Genotyping with DNA microsatellite markers linked to the MPZ gene on chromosome 1q22-q23 showed shared allelic characteristics between 12.65 cM and revealed a common haplotype in all Tottori families. Aichi and Ibaragi families shared parts of the haplotype around the MPZ gene. However, there was no consistency with a Nara family. CONCLUSIONS: The high frequency of this peculiar genotype in the Tottori CMT population is presumably due to a founder effect, but in Thr124 it might constitute a mutation hotspot in the MPZ gene.

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.

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.

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.

Morphological differences between glomerular epithelial cells (GEC) excreted during chemotherapy with antineoplastic drugs and GEC excreted in renal diseases.

BACKGROUND: To better understand the mechanisms of glomerular epithelial cell (GEC) injuries in various diseases, we compared GEC excreted during chemotherapy (antineoplastic drugs) and GEC excreted in renal diseases. METHODS: For 19 patients undergoing chemotherapy (85 courses), 69 patients with IgA nephropathy and 16 patients with Henoch-Schölein purpura nephritis, the number of excreted GEC and GEC casts were counted by an immunofluorescent study. The morphological features of GEC were also studied in an immunofluorescent study combined with Hoechst stain. RESULTS: Glomerular epithelial cells were detected in 78% of the chemotherapy courses and in 94% of the patients with renal diseases. The GEC casts were observed in 2% of chemotherapy courses, while in renal diseases GEC casts were observed in 60% of the patients. Proteinuria (>30 mg/dL) and hematuria were not identified in any of the chemotherapy courses. The morphology and size of GEC were more variable than that in patients with nephropathy. Furthermore, GEC in patients undergoing chemotherapy often showed small nuclei and fragmented nuclei, which were rarely observed in patients with nephropathy. CONCLUSIONS: These results showed that the detachment of podocytes was not directly associated with proteinuria or hematuria. The findings also suggest that GEC are damaged via an apoptotic process by chemotherapy. On the contrary, GEC may be detached through a non-apoptotic process in renal diseases.

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.

[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.

Contingent negative variation in children with anorexia nervosa.

BACKGROUND: Central catecholamines, particularly dopaminergic and noradrenergic systems, have affected the appetitive behavior in patients with anorexia nervosa (AN). The purpose of this study is to distinguish the characteristics of contingent negative variation (CNV) and postimperative negative variation (PINV), which may reflect the level of catecholamine in children with AN. METHODS: Eight children with AN aged 10 to 15 years and 23 age-matched healthy children were recruited. Contingent negative variation was recorded from the frontal midline (Fz), central midline (Cz) and parietal midline (Pz) referenced to linked earlobes during 30 trials consisting of a warning stimulus and an imperative stimulus with an interstimulus interval of 2 s and an intertrial interval of 10 s. The imperative stimulus of each trial required a button press. RESULTS: Children with AN had a diminished amplitude of the CNV. They had a significantly more attenuated early CNV and late CNV amplitude at Cz than normal children. No significant differences were observed between AN children and normal children in the amplitude of PINV at all three electrode sites. No difference could be found between the two groups in the frequencies of normal and abnormal duration of PINV. CONCLUSION: These findings suggest that early CNV may be diminished by norepinephrine deficiency and late CNV may be attenuated by dopaminergic deficiency in children with AN. Reduced CNV may represent impaired cognitive processes which reflect impaired appetitive behavior in AN children.

Ratio of eosinophil cationic protein/eosinophil count as a new marker in children with acute asthma.

BACKGROUND: It is a matter of concern whether serum eosinophil cationic protein (ECP) can be considered as a disease marker in children with acute asthma being treated without corticosteroids. METHODS: Fourteen children (nine male, five female, aged 6-12 years) with acute asthmatic exacerbation, administered the appropriate drugs, with the exception of systemic or inhaled corticosteroids, were examined. They were all free from apparent asthmatic attacks during a follow-up period of 1 month. Serum ECP, eosinophil count and forced expiratory volume in 1 s (FEV1) were measured at referral, on the day of discharge, 1 week and 4 weeks after discharge, respectively. RESULTS: The ratio of ECP/eosinophil count (ECP:Eo ratio), expressed as micrograms of ECP (microgram/L)/the number of eosinophil (/microL) x 1000, was also evaluated as a marker of eosinophil activation. Compared with the value at referral, FEV1 (% predicted) significantly increased on the day of discharge (P < 0.05), 1 week after (P < 0.05) and 4 weeks after discharge (P < 0.05). However, serum ECP concentrations showed no significant changes during the follow-up period. Eosinophil count showed no significant changes on the day of discharge or 1 week after discharge, but significantly increased 4 weeks after discharge (P < 0.05). In contrast, the ECP:Eo ratio significantly decreased on the day of discharge (P < 0.05), 1 week after (P < 0.05) and 4 weeks after discharge (P < 0.05). CONCLUSION: These data suggest that serum ECP is a poor disease marker in asthmatic children with acute exacerbation who receive no corticosteroid therapy, probably due to marked changes in the eosinophil count. However, the ECP:Eo ratio might be a better marker than serum ECP in such patients.

[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.

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.

Effect of weight loss on body fat distribution in obese children.

The intra-abdominal visceral fat to subcutaneous fat ratio (V/S ratio) has been reported to be strongly related to disorders of glucose and lipid metabolism, and hypertension. It is a matter of concern as to whether weight loss causes an improvement of the V/S ratio or not in obese children. Changes in body fat distribution during weight loss in 23 obese children were quantified by weight, bioelectrical impedance analysis (BIA) and computed tomography (CT scan of the abdomen). Twenty-three patients were divided into two groups; six were in the inpatient group and 17 were in the outpatient group. Bodyweight, body fat percentage, subcutaneous fat and visceral fat were significantly higher in the inpatient group than in the outpatient group before weight loss. Whereas the V/S ratio was almost equal between the two groups before weight loss. Bodyweight, body fat percentage, subcutaneous fat and visceral fat were found to decrease significantly during weight loss in the two groups. The V/S ratio of the outpatient group did not change after weight loss. In contrast, the V/S ratio of the inpatient group decreased significantly during weight loss. These preliminary findings suggest that a large amount of body fat and a high obesity rate are not always accompanied by a high V/S ratio in obese children. The fat pattern changes during weight loss with strict dietary therapy and therapeutic exercise. A larger sample of obese children should be studied to test this conjecture.