Late first relapses in APL treated with all-trans-retinoic acid- and anthracycline- based chemotherapy: the European APL group experience (APL 91 and APL 93 trials).
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Adult↗
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Homozygosity at the dopamine D3 receptor gene is associated with opiate dependence.
Anatomical, pharmacological and human post-mortem studies suggest the dopamine D3 receptor (DRD3) gene as a candidate for drug dependence. We thus performed an association study of the Bal I polymorphism at the DRD3 gene, including 54 opiate addicts and 70 controls. Opiate addicts had a higher sensation-seeking score (on the Zückerman scale) than controls (P = 0.001), particularly a subgroup (70%) who had a distinctly higher score, exceeding 24. There were no marked differences in genotypes between patients as a whole and controls. However, patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (P = 0.038) or controls (P = 0.034). Although obtained in a sample of limited size, these results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores. This hypothesis is consistent with the role of DRD3 in mediating responses to drugs of abuse in animals and the association of homozygosity at the Bal I polymorphism with drug abuse in schizophrenic patients (see companion article by Krebs et al).
Adult↗
Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia.
In high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), blasts constitutively activate the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB). Here, we show that this NF-kappaB activation relies on the constitutive activation of the IkappaB kinase (IKK) complex, which is formed by the IKKalpha, IKKbeta and IKKgamma/NF-kappaB essential modulator (NEMO) subunits. A cell-permeable peptide that mimics the leucine zipper subdomain of IKKgamma, thus preventing its oligomerization, inhibited the constitutive NF-kappaB activation and induced apoptotic cell death in a panel of human MDS and AML cell lines (P39, MOLM13, THP1 and MV4-11). Small interfering RNA-mediated knockdown of the p65 NF-kappaB subunit or the three IKK subunits including IKKgamma/NEMO also induced apoptotic cell death in P39 cells. Cell death induced by the IKKgamma/NEMO-antagonistic peptide involved the caspase-independent loss of the mitochondrial transmembrane potential as well as signs of outer mitochondrial membrane permeabilization with the consequent release of cytochrome c, apoptosis-inducing factor and endonuclease G. Primary bone marrow CD34(+) cells from high-risk MDS and AML patients also succumbed to the IKKgamma/NEMO-antagonistic peptide, but not to a mutated control peptide. Altogether, these data indicate that malignant cells in high-risk MDS and AML cells critically depend on IKKgamma/NEMO to survive. Moreover, our data delineate a novel procedure for their therapeutic removal, through inhibition of IKKgamma/NEMO oligomerization.
Acute Disease↗
The purification of a novel amylase from Bacillus subtilis and its inhibition by wheat proteins.
A new alpha-amylase (EC 3.2.1.1) from Bacillus subtilis was purified by affinity chromatography. The molecular weight of the purified enzyme, estimated from sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, was 93000, which is very different from the molecular weights of two well-characterized amylases from B. subtilis. Electrofocusing showed an isoelectric point of 5. Amylase shows a broad maximum of activity between pH 6 and 7; maximal inhibition of enzyme by wheat-protein alpha-amylase inhibitors is displayed at pH 7.
Amylases↗
Regulation of production of delta-aminolaevulinate synthase in tissues of chick embryos. Effects of porphyrogenic agents and of haem precursors.
Studies conducted by several groups have established that porphyrogenic agents which caused elevations in chick-embryo liver delta-aminolaevulinate (ALA) synthase activity also increased the concentrations of the enzyme's RNA, and that haemin inhibited these elevations. We have determined in this study, using immune-blot analyses, that administration in ovo of allylisopropylacetamide (AIA) in combination with diethyl 1,4-dihydro-2,4,6-trimethyl,3,5-pyridinedicarboxylate (DDC) increased the mass of ALA synthase in intestine and kidney of chick embryos. Furthermore, the molecular mass of the subunit of the enzyme in those tissues appeared identical with that of liver ALA synthase. Using a synthetic oligonucleotide complementary to ALA synthase mRNA, we determined by solution hybridization and Northern-blot analyses that AIA and DDC also increased the concentrations of ALA synthase mRNA in intestine and kidney and that testosterone elevated the concentration of the RNA in kidney. In analyses of RNA obtained from chick-embryo liver, intestine, kidney, heart, brain and lung, the probe bound primarily in each case to a single 2.3 kb RNA. Finally, the haem precursors ALA and FeCl3, when injected together into the fluid surrounding embryos, inhibited both the elevations in ALA synthase mass and RNA concentration brought about by porphyrogenic agents in liver, kidney and intestine. Thus the results indicated that: (1) certain porphyrogenic agents increased ALA synthase mass and RNA in chick-embryo intestine and kidney, in addition to liver; (2) ALA and FeCl3 inhibited the elevations; and (3) the sizes of ALA synthase's subunit as well as the enzyme's mRNA appeared identical, in each case, in all tissues examined.
5-Aminolevulinate Synthetase↗
On the mechanism of induction of chick embryo hepatic delta-aminolaevulinate synthase by translational blockers.
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5-Aminolevulinate Synthetase↗
Guidelines for the management of the acute painful crisis in sickle cell disease.
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Adult↗
Lifetime treatment costs of beta-thalassaemia major.
Beta-thalassaemia major is a serious genetic disorder, which results in a considerable increase in both acute and chronic morbidity, and mortality. Although beta-thalassaemia major is a rare disease affecting approximately 600 people in the UK, treatment is intensive and predictions of the costs incurred may aid health care planning. In this report, the cost to the health service of providing treatment services for beta-thalassaemia major patients, over the course of a lifetime, is calculated in order to assist resource allocation decisions. A cost model was developed, incorporating data from disparate sources. The undiscounted lifetime cost of treating a beta-thalassaemia major patient was estimated to be pound 803,002, although when the costs were discounted at a rate of 6%, the lifetime cost was reduced to pound 219,068. Within sensitivity analyses, the discounted cost ranged from approximately pound 188,000 to pound 226,000. This report may act as a guide to those involved in the planning of health care provision with regard to the resources required to treat beta-thalassaemia major patients. Such information may also be incorporated into the decision-making process for the provision of antenatal screening programmes for beta-thalassaemia major.
Adolescent↗
Gender differences in resting metabolic rate and noradrenaline kinetics in older individuals.
The physiological factors mediating gender differences in resting metabolic rate (RMR) in older individuals are presently unclear. We examined the contribution of sympathetic nervous system activity to gender differences in resting metabolic rate in older men and women and its relation to body fat distribution. We performed measurements of noradrenaline (NA) kinetics from infusions of [3H]-NA, RMR, body fat distribution, body composition, peak Vo2 and dietary intake in 29 older men (69 +/- 6 years) and 26 older women (65 +/- 5 years). Older men weighed more (P < 0.01) and had a greater fat-free mass (P < 0.01) and a larger waist circumference (P < 0.01) than older women. Older men had a higher RMR (P < 0.05) than older women, which persisted after controlling for differences in fat-free mass and fat mass. Older men also showed a greater NA appearance rate (P < 0.01) at rest than older women. The higher NA appearance rate in older men was partly related to their greater waist circumference (r = 0.50, P < 0.01). We explored the sympathetic contribution to gender differences in RMR by statistically controlling for differences in body composition and NA appearance rate. After this procedure, we found no gender differences in adjusted RMR between older men (4.3 +/- 0.5 kJ min(-1)) and older women (4.3 +/- 0.4 kJ min(-1)). Our results suggest that: (a) older men have a higher RMR than older women independent of differences in body composition; (b) the higher RMR in older men may be partly due to higher levels of sympathetic nervous system activity; (c) the higher sympathetic nervous system activity in older men is partly related to their greater waist circumference, a proxy measure of central body fatness.
Aged↗
Menopause-associated changes in plasma lipids, insulin-like growth factor I and blood pressure: a longitudinal study.
We examined the effects of the menopause transition on plasma lipids, insulin-like growth factor I (IGF-I) and blood pressure. An initial cohort of 38, non-smoking, healthy premenopausal women (44-48 years) were examined at baseline and after a 6-year follow-up period. At follow-up, 18 women had spontaneously stopped menstruating, whereas 17 women remained premenopausal. Women who experienced natural menopause showed a greater decline in high-density lipoproteins (-5 +/- 4 mg dL-1 vs. -1 +/- 3 mg dL-1; P < 0.01) and a greater increase in low-density lipoproteins (13 +/- 12 vs. 5 +/- 10 mg dL-1; P < 0.05) and fasting triglycerides (14 +/- 15 vs. 5 +/- 11 mg dL-1; P < 0.05) than women who remained premenopausal. No menopause effect was noted for total cholesterol. We noted a greater decline in IGF-I levels in women who experienced a natural menopause (-21 +/- 11 ng mL-1) than women who remained postmenopausal (-4 +/- 10 ng mL-1). Systolic blood pressure increased in postmenopausal (13 +/- 10 mmHg) compared with premenopausal women (5 +/- 4 mmHg: P < 0.01), whereas no menopause effect was noted for diastolic blood pressure. The increase in the waist-to-hip ratio was related to a decrease in high-density lipoprotein (r = -0.49; P < 0.05) and increase in low-density lipoprotein (r = 0.48; P < 0.05). The decline in IGF-I was related to the decline in reported leisure time physical activity (0.44: P < 0.05). We conclude that the natural menopause transition is associated with a worsening of the lipid profile and decline in IGF-I, which might be mitigated by deleterious changes in body fat distribution and physical activity.
Adult↗
Child malaria treatment practices among mothers in the district of Yanfolila, Sikasso region, Mali.
We studied child malaria treatment practices among mothers living in the District of Yanfolila in southern Mali. For sampling, we first chose five of 13 health areas with probability proportional to size. Then villages, compounds and mothers with at least one child aged 1-5 years were randomly chosen. We assessed the spleen size of one 1-5 year-old child of each mother, collected a thick blood film and recorded the body temperature of every child whose mother thought he/she was sick. 399 mothers in 28 villages were interviewed with a structured questionnaire divided into two parts. If the child had had soumaya (a term previously associated with uncomplicated malaria) during the past rainy season, we asked about signs and symptoms, health-seeking behaviour (who the mother consulted first) and treatment. If not, information about knowledge of the disease and treatment to be given was collected. 86% of the mothers interviewed stated that their child had been sick and almost half of them had had soumaya. All mothers named at least one sign by which they recognized the disease. Vomiting, fever and dark urine/yellow eyes/jaundice were the three most common signs mentioned. 75.8% managed their child's disease at home and used both traditional and modern treatment. The most common anti-malarial drug was chloroquine, often given at inappropriate dosage. The sensitivity and specificity of the mothers' diagnosis was poor, although this might be explained by the large percentage of children who had already been treated at the time of the interview. The results of our survey call for prompt educational action for the correct treatment of uncomplicated malaria/soumaya, particularly for mothers and possibly for shopkeepers. The high spleen rate (58.1%) among randomly selected children confirms that malaria is a common disease in this area. Improved case-management at home could only be beneficial.
Adult↗
Preferential pre-mRNA utilisation of an upstream cryptic 5' splice site created by a single base deletion mutation in exon 37 of the FBN-1 gene.
A heterozygous deletion of a single base (A4704) from exon 37 of the fibrillin-1 gene was defined in a patient with Marfan syndrome and subsequently in his previously undiagnosed father. The deletion created a cryptic 5' splice site in exon 37 which was utilised in preference to the normal 5' splice site during pre-mRNA processing in skin fibroblasts cultured from the proband. The mutant mRNA showed a 48-bp deletion from the 3' end of exon 37 which was predicted to restore the reading frame in the mutant mRNA and result in the deletion of a 16-amino-acid sequence from a central eight-cysteine repeat motif of the fibrillin-1 molecule. Interestingly, the cryptic 5' splice site in exon 37 and the normal 5' splice site had equally strong consensuses for splice-site selection. The preferential utilisation of the cryptic site is discussed in relation to current theories on the mechanisms involved in pre-mRNA splicing. Analysis by reverse-transcription PCR indicated that, in the patients skin fibroblasts, the steady-state level of the mis-spliced mutant mRNA was close to that from the normal allele. In addition, evidence from immunoblotting and pulse-chase biosynthetic labelling indicated that close to normal amounts of fibrillin-1 were being synthesised and secreted by the cells. However, in contrast to control cells cultured from an unaffected individual, little fibrillin-1 was detected, either biosynthetically or by immunofluorescence, in the extracellular matrix produced by the proband's fibroblasts. Thus, the slightly shorter mutant fibrillin-1 molecules appeared to be exerting a powerful dominant-negative effect on the incorporation of normal fibrillin-1 molecules into microfibrils in this culture system. This severe inhibition of microfibril synthesis in cell culture contrasts with the 'classic' phenotype of the proband, suggesting that factors influencing microfibril formation may differ greatly between in vivo and in vitro environments.
Amino Acid Sequence↗
Upper pole heminephrectomy: is complete ureterectomy necessary?
OBJECTIVE: To determine the re-operation rate on the distal ureter after upper pole heminephrectomy with incomplete ureterectomy. PATIENTS AND METHODS: The case notes from one institution were reviewed retrospectively; 60 upper pole heminephrectomies with incomplete ureterectomy were undertaken in 39 girls and 16 boys (mean age at primary surgery 27 months, range 3--88). RESULTS: Thirty-two children (58%) had an antenatal diagnosis while 12 (22%) presented with a urinary tract infection (UTI) and six (11%) with urinary incontinence. Twenty-nine of the 60 renal units (48%) had an associated ureterocele and in nine (15%) the ureter was ectopic. Ten infants (18%) underwent initial puncture of a ureterocele. Five patients (8%), all females, required lower urinary tract re-operation. The indications for secondary surgery were recurrent UTIs in all and a prolapsed ureterocele in one. All five had ultrasonographic evidence of a dilated ureteric stump. Reflux into the retained stump was detected in one child. CONCLUSIONS: The re-operation rate for a redundant ureteric stump in this series was 8%. The risk of injury to the good ureter may outweigh the benefits of a complete ureterectomy.
Child↗
Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease: A randomized, sham-controlled trial.
BACKGROUND & AIMS: The aim of this study was to determine the effectiveness of endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease (GERD) in comparison with a sham procedure. METHODS: Patients with symptomatic GERD requiring maintenance proton pump inhibitor (PPI) therapy were entered into a randomized, single-blind, prospective, multicenter trial. Seventy-eight patients were randomly assigned to undergo endoscopic full-thickness restructuring of the gastric cardia with transmural suture. Eighty-one patients underwent a sham procedure. Group assignments were revealed following the 3-month evaluation. The primary end point was > or =50% improvement in GERD health-related quality of life (HRQL) score. Secondary end points included medication use and esophageal acid exposure. RESULTS: By intention-to-treat analysis, at 3 months, the proportion of patients achieving > or =50% improvement in GERD-HRQL score was significantly greater in the active group (56%) compared with the sham group (18.5%; P < .001). Complete cessation of PPI therapy was higher among patients in the active group than in the sham group by intention-to-treat analysis (50% vs 24%; P = .002). The percent reduction in median percent time pH < 4 was significantly improved within the active group versus baseline (7 vs 10, 18%, P < .001) but not in the sham group (10 vs 9, -3%, P = .686). Between-group analysis revealed the active therapy to be superior to the sham in improving median percent time pH < 4 (P = .010). There were no perforations or deaths. CONCLUSIONS: Endoscopic full-thickness plication more effectively reduces GERD symptoms, PPI use, and esophageal acid exposure than a sham procedure.
Endoscopy, Gastrointestinal↗
T cryptantigen activation is associated with advanced necrotizing enterocolitis.
BACKGROUND/PURPOSE: Thomsen-Friedenreich cryptantigen activation (TCA) exposes neonates with necrotizing enterocolitis NEC to the risk of hemolysis after transfusion of blood products. The authors aimed to determine the prevalence of TCA in neonates with NEC and to correlate TCA with severity of disease and outcome. METHODS: One hundred four neonates with NEC were tested for TCA on admission. Patients with TCA requiring transfusion were given packed red cells, low-titer anti-T fresh frozen plasma, and washed platelets to avoid hemolysis. RESULTS: Twenty-three infants had TCA, and 96% of these had stage III disease. The incidence of TCA was significantly higher in infants with stage III disease compared with those with stage II (30% v 4%; P <.01). A total of 91% of infants with TCA required laparotomy compared with 81% of those with no activation. At laparotomy, widespread disease was more common in the TCA group (71% v 55%). TCA did not significantly increase mortality rate (TCA, 39% v no TCA, 28%); this may reflect the transfusion policy of our unit. CONCLUSIONS: Twenty-two percent of neonates with NEC referred to our unit had TCA. There is an association between TCA and advanced NEC. Screening of neonates with advanced NEC for TCA is advised to identify those at risk of hematologic complications.
Antigens, Tumor-Associated, Carbohydrate↗
Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes.
Diabetic dyslipidemia is featured by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and elevated low-density lipoprotein (LDL) cholesterol commonly in the form of small, dense LDL particles. First-line treatment, fibrates versus statins or both, of dyslipidemia in diabetic patients has been the focus of debate. We investigated the potential hypolipidemic effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor with good triglyceride lowering properties, in patients with combined dyslipidemia and evidence of impaired fasting glucose or type 2 diabetes. Twenty patients were recruited for the study, and after a 60-day wash out period, baseline measurements of lipoprotein parameters, LDL particle diameter, and apolipoprotein B (apoB) degradation fragments were obtained. The group was then randomized, in a double-blinded manner, into 2 subgroups. Group A received atorvastatin (80 mg) and group B received placebo daily for 60 days. After the first treatment period, all patients were reanalyzed for the above parameters. The treatment regime then crossed over for the second treatment period in which group A received placebo and group B received atorvastatin (80 mg) daily for 60 days. All parameters were remeasured at the end of the study. Treatment with atorvastatin resulted in a statistically significant reduction in total cholesterol (41%), LDL cholesterol (55%), triglycerides (TG) (32%), and apoB (40%). Mean LDL particle diameter significantly increased from 25.29 +/- 0.24 nm (small, dense LDL subclass) to 26.51 < 0.18 nm (intermediate LDL subclass) after treatment with atorvastatin (n = 20, P <.005). At baseline, LDL particles were predominantly found in the small, dense subclass; atorvastatin treatment resulted in a shift in the profile to the larger and more buoyant LDL subclass. Atorvastatin treatment did not produce consistent changes in the appearance of apoB degradation fragments in plasma. Our results suggest that atorvastatin beneficially alters the atherogenic lipid profile in these patients and significantly decreases the density of LDL particles produced resulting in a shift from small, dense LDL to more buoyant and less atherogenic particles.
Apolipoproteins B↗
Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity.
A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster has been previously documented to exhibit considerable hepatic very-low-density lipoprotein (VLDL) overproduction concomitant with the development of whole body insulin resistance. Here, we investigated whether hepatic lipoprotein overproduction can be ameliorated by treatment with a hydroxymethyl glutaryl conenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, using a series of ex vivo experiments. Hamsters were fed a fructose-enriched diet for 14 days to induce a state of insulin resistance, and then continued on a fructose-enriched diet supplemented with or without 40 mg/kg atorvastatin per day for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride levels. There was a significant decline in plasma triglyceride levels following supplementation with the inhibitor (50% to 59%; P <.05). Experiments with primary hepatocytes revealed a decreased VLDL-apolipoprotein B (apoB) production (37.4% +/- 10.4%; P <.05) in hamsters treated with atorvastatin. Interestingly, atorvastatin treatment partially attenuated (by 23%) the elevated hepatic level of microsomal triglyceride transfer protein (MTP) induced by fructose feeding. There was molecular evidence of improved hepatic insulin sensitivity with atorvastatin treatment based on assessment of the phosphorylation status of the insulin receptor and the expression of protein tyrosine phosphatase-1B. The improvement in insulin signaling was not mediated by a change in hepatic triglyceride accumulation as no significant difference was observed in liver triglyceride levels. Taken together, these data suggest that statins can ameliorate the VLDL-apoB overproduction state observed in a fructose-fed, insulin-resistant hamster model, and may potentially contribute to an enhanced hepatic insulin sensitivity.
Animals↗
Is there a threshold of visceral fat loss that improves the metabolic profile in obese postmenopausal women?
It is presently unclear how much visceral adipose tissue (VAT) loss is needed to induce favorable metabolic changes. Cross-sectional studies have proposed that a threshold level of VAT exceeding 110 cm(2) in women induces deleterious changes in the metabolic profile. It is presently unclear, however, if significant decreases in VAT below this given threshold significantly improve the metabolic profile more as compared to decreases that remain below 110 cm(2). To examine whether achieving versus not achieving the proposed VAT threshold impacts differently on the metabolic profile in postmenopausal women, we examined the effects of a VAT loss below the 110-cm(2) threshold versus those individuals who remained higher than 110 cm(2) after a weight loss program. Twenty-five sedentary obese (baseline % body fat, 47.7% +/- 4.1%; [mean +/- SD]) postmenopausal women aged between 51 and 71 years (59.7 +/- 5.6 years) and displaying high baseline levels of VAT accumulation (223 +/- 45 cm(2)) were submitted to a 1-year weight loss program with weight stabilization periods before and after weight reduction. Based on their loss of VAT after weight loss, subjects were characterized as "attainers" (post VAT levels < 110 cm(2); average, 96 +/- 10 cm(2); n = 10) or "non-attainers" (post VAT levels > 110 cm(2); average, 171 +/- 34 cm(2); n = 15). We compared changes in (1) plasma lipid-lipoprotein levels, (2) insulin sensitivity (euglycemic/hyperinsulinemic clamp), and (3) supine resting blood pressure between groups who achieved these 2 distinct levels of VAT. Attainers showed a 2-fold greater loss of VAT compared to non-attainers (-51.5% v -27.5%, P <.001). Attainers also showed a greater loss of body weight (-19.0% v -12.5%, P <.01) and fat mass (-34.8% v -18.4%, P <.001) after the program compared to non-attainers. Despite significant differences in the loss of total fat and VAT after the weight loss program, attainers and non-attainers showed comparable improvements for plasma high-density lipoprotein-cholesterol (HDL-chol) levels (+62.5% v +50.0%, P = not significant [NS]), cholesterol/HDL-chol ratio (-45.5% v -36.5%, P = NS), insulin sensitivity (+34.1% v +23.2%, P = NS), and resting systolic (-6.9% v -5.1%, P = NS) and diastolic (-11.3% v -11.1%, P = NS) blood pressure. These results do not favor the idea that attaining levels of VAT below a threshold of 110 cm(2) is necessary to favorably improve the metabolic profile in obese postmenopausal women. Achieving or not the proposed threshold of VAT, independently of baseline values, appears to yield similar metabolic improvements in obese postmenopausal women. More moderate losses of VAT appear to yield similar metabolic improvements as large losses.
Adipose Tissue↗