Evolution of depression during rehabilitation program in patients with cardiovascular diseases.

Background: Cardiovascular diseases represent the main cause of death in the world. Rehabilitation through exercise is more and more used in cardiac patients. Given that these patients suffer from depressive symptoms, the risk of having recurrent cardiovascular problems increases. Thus, the aim of this study is to identify the effects of a rehabilitation program on the physiological and psychological parameters; with a particular attention on the depression scores between the scales.Methods: Twenty-eight cardiac patients participated in this study during a cardiovascular rehabilitation program. They are tested at their entry and at their exit with an evaluation of their physical fitness on an electromagnetic cycle ergometer and by four depression scales (Beck Depression Inventory, Hospital Anxiety and Depression Scale (HADS), Center for Epidemiologic Studies - Depression and Geriatric Depression Screening).Results: We observe that 21.4-50% of these patients have depressive symptoms, according to depression scales. The women have depression scores significantly higher than the men. The rehabilitation program improves their maximal oxygen consumption and their maximal aerobic power. At the end of the rehabilitation program, our analysis identifies a significant decrease in the depression score for the HADS. Regardless of the physical deconditioning level and of the improvement of the maximal oxygen consumption, our results show an effect of the rehabilitation program on the depression scores. No correlation between the physical deconditioning and the different depression scores is observed.Conclusions: This study shows the importance of measuring depression and its severity to improve the care of patients. Our findings show that between 21.4% and 50% of patients have depressive symptoms which challenges the categorical approach of the self-report depression scales.Implications for rehabilitationDepression and cardiovascular diseases have an impact on the patients' physical fitness.The rehabilitation program, primarily based around exercise, reduces depressive symptoms.As soon as cardiovascular diseases patients enter in a rehabilitation program, the depression should be measured by a psychologist.Taking into account the depressive symptoms of the patients as soon as their cardiac event occurs makes it possible to improve the care of patients.

Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations.

BACKGROUND: Whole-genome sequencing studies have recently shown that osteosarcomas (OSs) display high rates of structural variation, i.e. they contain many somatic mutations and copy number alterations. TP53 and RB1 show recurrent somatic alterations in concordant studies, suggesting that they could be key players in bone oncogenesis. PATIENTS AND METHODS: we carried out whole-genome sequencing of DNA from seven high-grade OS samples matched with normal tissue from the same patients. RESULTS: We confirmed the presence of genetic alterations of the TP53 (including novel unreported mutations) and RB1 genes. Most interestingly, we identified a total of 84 point mutations and 4 deletions related to 82 different genes in OS samples, of which only 15 have been previously reported. Interestingly, the number of mutated genes (ranging from 4 to 8) was lower in TP53mut cases compared with TP53wt cases (ranging from 14 to 45). This was also true for the mutated RB1 case. We also observed that a dedifferentiated OS harboring MDM2 amplification did not carry any other mutations. CONCLUSION: This study suggests that bone oncogenesis driven by TP53 or RB1 mutations occurs on a background of relative genetic stability and that the dedifferentiated OS subtype represents a clinico-pathological entity with distinct oncogenic mechanisms and thus requires different therapeutic management.

Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing.

Accelerometer as a tool to assess sedentarity and adherence to physical activity recommendations after cardiac rehabilitation program.

PURPOSE: To objectively assess, in stable cardiac patients, the adherence to physical activity (PA) recommendations using an accelerometer at 2 or 12 months after the discharge of cardiac rehabilitation program (CRP). METHODS: Eighty cardiac patients wore an accelerometer at 2 months (group 1, short-term adherence, n = 41) or one-year (group 2, long-term adherence, n = 39) after a CRP including therapeutic education about regular PA. PA was classified as "light" (1.8-2.9 Metabolic Equivalent of Task [METs]), "moderate" (3-5.9 METs), or "intense" (>6 METs). Energy expenditure (EE, in Kcal) and time (min) spent in these three different levels were measured during a one-week period with the MyWellness Key actimeter (MWK). Motivational readiness for change was also assessed at the end of CRP. Patients were considered as physically active when a minimum of 150 min of moderate PA during the one-week period was achieved. RESULTS: Both groups were comparable, except for exercise capacity at the end of the CRP which was slightly higher in group 1 (167.5 ± 42.3 versus 140.7 ± 46.1 W, P < 0.01). The total weekly active EE averaged 676.7 ± 353.2 kcal and 609.5 ± 433.5 kcal in group 1 and 2, respectively. The time spent within the light-intensity range PA was 319.4 ± 170.9 and 310.9 ± 160.6 min, and the time spent within the moderate-intensity range averaged 157.4 ± 115.4 and 165 ± 77.2 min per week for group 1 and 2, respectively. Fifty-three percent and 41% of patients remained active in both groups respectively. CONCLUSION: About half of the patients are non-adherent to PA after CRP and do not reach target levels recommended by physicians. The first 2 months following the discharge of CRP seem to be of outmost importance for lifestyle modifications maintenance, and further study monitoring more closely PA decrease could help to clarify the optimal follow-up options.

B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells.

B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.

High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice.

The identification of modifiable nutritional risk factors is highly relevant to the development of preventive strategies for neurodegenerative disorders including Parkinson's disease (PD). In this study, adult C57BL/6 mice were fed either a control (CD-12%kcal) or a high-fat diet (HFD-60%kcal) for 8 weeks prior to MPTP exposure, a toxin which recreates a number of pathological features of PD. HFD-fed mice significantly gained weight (+41%), developed insulin resistance and a systemic immune response characterized by an increase in circulating leukocytes and plasmatic cytokines/chemokines (interleukin-1α, MCP-1, MIP-1α). As expected, the MPTP treatment produced nigral dopaminergic degeneration as evidenced by the loss of striatal dopamine and the decreased number of nigral tyrosine hydroxylase (TH)- and dopamine transporter-expressing neurons (23% and 25%, respectively). However, exposure to HFD exacerbated the effects of MPTP on striatal TH (23%) and dopamine levels (32%), indicating that diet-induced obesity is associated with a reduced capacity of nigral dopaminergic terminals to cope with MPTP-induced neurotoxicity. Since high-fat consumption is commonplace in our modern society, dietary fat intake may represent an important modifiable risk factor for PD.

Short-term impact of a 4-week intensive cardiac rehabilitation program on quality of life and anxiety-depression.

INTRODUCTION: Cardiac rehabilitation programs are well recognized as being essential to the comprehensive care of patients with cardiovascular disease and chronic heart failure. These programs aim at reducing cardiovascular risks, promoting healthy lifestyle behaviours and compliance as well as limiting disability and increasing quality of life (QoL) of cardiac patients. PURPOSE: To evaluate the impact of a 4-week cardiac rehabilitation program on physical parameters and several aspects of the QoL of cardiac patients. METHODS: A cohort of 101 cardiac patients (men: 70%) mean age 65±12 years (mean±SD) participated in a cardiac rehabilitation program. Before and after the 4-week cardiac rehabilitation program, the study recorded and assessed the patients' physical parameters such as weight, body mass index (BMI), waist circumference and effort tolerance as well as QoL using different questionnaires: SF-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HAD) and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The patients' physical parameters (BMI and waist circumference) decreased by 3%, while effort tolerance increased by 25% (P<0.0001). Furthermore, for all patients, the PSQI, HAD and physical and mental SF-36 scores improved significantly (P<0.0001). The different SF-36 subscales' scores did also increase after the program (P<0.0001). CONCLUSION: Despite a modest weight loss and reduction in waist circumference, a 4-week cardiac rehabilitation program (short-term) seems to be sufficient for improving patients' physical state and mental well-being.

Cystamine prevents MPTP-induced toxicity in young adult mice via the up-regulation of the brain-derived neurotrophic factor.

Preclinical data suggest that cystamine stands as a promising neuroprotective agent against Huntington's and Parkinson's diseases. To decipher the mechanisms of action of cystamine, we investigated the effects of various doses of cystamine (10, 50, and 200mg/kg) on the regulation of the brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-receptor-kinase B (TrkB) and on the heat shock protein 70 (Hsp70) brain mRNA expression in relation to the time after administration. We have determined that the lower cystamine dose is the most efficient to promote putative neuroprotective effects. Indeed, an acute administration of 10mg/kg of cystamine increased the expression of BDNF mRNA in the substantia nigra compacta (SNc), although it did not significantly influence TrkB or Hsp70 mRNA. Higher cystamine doses resulted in the absence of activation of any of these markers or led to non-specific effects. We have also substantiated the neuroprotective effect of a 21-day treatment of 10mg/kg/day of cystamine in young adult mice against MPTP-induced loss of tyrosine hydroxylase-striatal fiber density, nigral dopamine cells and nigral Nurr1 mRNA expression. The neuroprotective action of cystamine in the same animals was associated with an up-regulation of BDNF in the SNc. Taken together, these results strengthen the neuroprotective potential of cystamine in the treatment of Parkinson's disease and point towards the up-regulation of BDNF as an important mechanism of action.

Investigation of associations of Yarrowia lipolytica, Staphylococcus xylosus, and Lactococcus lactis in culture as a first step in microbial interaction analysis.

The interactions that may occur between microorganisms in different ecosystems have not been adequately studied yet. We investigated yeast-bacterium interactions in a synthetic medium using different culture associations involving the yeast Yarrowia lipolytica 1E07 and two bacteria, Staphylococcus xylosus C2a and Lactococcus lactis LD61. The growth and biochemical characteristics of each microorganism in the different culture associations were studied. The expression of genes related to glucose, lactate, and amino acid catabolism was analyzed by reverse transcription followed by quantitative PCR. Our results show that the growth of Y. lipolytica 1E07 is dramatically reduced by the presence of S. xylosus C2a. As a result of a low amino acid concentration in the medium, the expression of Y. lipolytica genes involved in amino acid catabolism was downregulated in the presence of S. xylosus C2a, even when L. lactis was present in the culture. Furthermore, the production of lactate by both bacteria had an impact on the lactate dehydrogenase gene expression of the yeast, which increased up to 30-fold in the three-species culture compared to the Y. lipolytica 1E07 pure culture. S. xylosus C2a growth dramatically decreased in the presence of Y. lipolytica 1E07. The growth of lactic acid bacteria was not affected by the presence of S. xylosus C2a or Y. lipolytica 1E07, although the study of gene expression showed significant variations.

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study.

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.

Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model.

While we recently reported the beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a mouse model of Parkinson's disease (PD), the mechanisms of action remain largely unknown. Here, we specifically investigated the contribution of the brain-derived neurotrophic factor (BDNF) to the neuroprotective effect of n-3 PUFA observed in a mouse model of PD generated by a subacute exposure to MPTP using a total of 7 doses of 20mg/kg over 5 days. The ten-month high n-3 PUFA treatment which preceded the MPTP exposure induced an increase of BDNF mRNA expression in the striatum, but not in the motor cortex of animals fed the high n-3 PUFA diet. In contrast, n-3 PUFA treatment increased BDNF protein levels in the motor cortex of MPTP-treated mice, an effect not observed in vehicle-treated mice. The mRNA expression of the high-affinity BDNF receptor tropomyosin-related kinase B (TrkB) was increased in the striatum of MPTP-treated mice fed the high n-3 PUFA diet compared to vehicle and MPTP-treated mice on the control diet and to vehicle mice on the high n-3 PUFA diet. These data suggest that the modulation of BDNF expression contributes, in part, to n-3 PUFA-induced neuroprotection in an animal model of PD.

The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia.

The phosphoinositide 3-kinase/Akt pathway is an important signalling pathway governing cell survival and proliferation in acute myeloid leukaemia (AML). As full activation of Akt requires phosphorylation on both threonine 308 (Thr308) and serine 473 (Ser473) residues, we studied the level of phosphorylation on the both sites in 58 AML samples by flow cytometry. The ratio of the mean fluorescence intensity of Thr308 and Ser473 represented a continuum ranging from 0.3 to 5.6 and from 0.4 to 2.87, respectively. There were no significant correlations between age, gender, French-American-British classification, leukocytosis, FLT3-ITD and Akt phosphorylation. However, the level of phosphorylation on Thr308, but not on Ser473, was significantly correlated with high-risk karyotype. Thr308(high) patients had significantly shorter overall survival (11 vs 47 months; P=0.01), event-free survival (9 vs 26 months; P=0.005) and relapse-free survival (10 months vs not reached; P=0.02) than Thr308(low) patients. Neither screening for AKT1 E17K mutation nor changes in the level of PTEN expression and phosphorylation could be linked to increased phosphorylation on Thr308 in high-risk cytogenetic AML cells. However, PP2A activity was significantly reduced in high-risk samples compared with intermediate-risk samples. Moreover, the specific Akt inhibitor, Akti-1/2, inhibited cell proliferation and clonogenic properties, and induced apoptosis in AML cells with high-risk cytogenetics, suggesting that Akt may represent a therapeutic target in high-risk AML.

[Health-related quality of life in women operated on by surgical anti-incontinence procedures: comparison of three techniques]. / Qualité de vie après cure d'incontinence urinaire d'effort: comparaison de trois techniques.

OBJECTIVES: To assess the health-related quality of life (Contilife) after three surgical anti-incontinence procedures (Tension-Free Vaginal Tape [TVT], Transobturator Vaginal Tape [TOT], and Transobturator Vaginal Tape [TVT-O]). PATIENTS AND METHODS: We performed a prospective analysis of 90 women (30 TVT, 30 TOT, 30 TVT-0) with genuine stress incontinence pre- and postoperatively at 18 months. The objective cure rate was determined by clinical and urodynamic examination and the subjective cure rate by the Contilife questionnaire. RESULTS: Prior to surgery, patients complained more of effort activities, followed by global well-being. Postoperatively, all domains improved significantly without statistical difference between the three groups and 90% of the patients would advise the intervention to one of their friends. DISCUSSION AND CONCLUSION: Surgical outcomes vary greatly depending on the methodology of the study. Health-related quality of life seems paramount to decide time of surgery and to evaluate postoperatory results. We have chosen the Contilife questionnaire because of its scientific and clinical validity, reliability, responsiveness and linguistic validation. These results confirm that TVT/TOT/TVT-O procedures are a safe and effective surgical method and that they significantly improved health-related quality of life.

Mammary gland secretion: hormonal coordination of endocytosis and exocytosis.

The mammary epithelium coordinates the uptake of milk precursors and the transport of milk components in order to produce milk of relatively constant composition at a particular stage of lactation, as long as the mammary gland is healthy. The mammary epithelial cell controls the uptake of blood-borne molecules at its basal side and the release of products into milk at its apical side, through mechanisms of internalization (endocytosis) and mechanisms of release (exocytosis). These events are strictly dependent on the physiological stage of the mammary gland. This review addresses the mechanisms responsible for these processes and points out new questions that remain to be answered concerning possible interconnections between them, for an optimal milk secretion.

Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease.

In this study, we examined whether omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may exert neuroprotective action in Parkinson's disease, as previously shown in Alzheimer's disease. We exposed mice to either a control or a high n-3 PUFA diet from 2 to 12 months of age and then treated them with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 140 mg/kg in 5 days). High n-3 PUFA dietary consumption completely prevented the MPTP-induced decrease of tyrosine hydroxylase (TH)-labeled nigral cells (P<0.01 vs. MPTP mice on control diet), Nurr1 mRNA (P<0.01 vs. MPTP mice on control diet), and dopamine transporter mRNA levels (P<0.05 vs. MPTP mice on control diet) in the substantia nigra. Although n-3 PUFA dietary treatment had no effect on striatal dopaminergic terminals, the high n-3 PUFA diet protected against the MPTP-induced decrease in dopamine (P<0.05 vs. MPTP mice on control diet) and its metabolite dihydroxyphenylacetic acid (P<0.05 vs. MPTP mice on control diet) in the striatum. Taken together, these data suggest that a high n-3 PUFA dietary intake exerts neuroprotective actions in an animal model of Parkinsonism.

Malignant transformation of leg ulcers: a retrospective study of 85 cases.

BACKGROUND: Malignant transformation remains a rare, under-recognized and ominous, complication of leg ulcers, although its exact prevalence is unknown. PATIENTS AND METHODS: This retrospective French study included cases of chronic ulcers of vascular origin complicated by histologically proven carcinomas. For squamous cell carcinomas (SCC), the duration of the ulcer had to be longer than 3 years. For basal cell carcinomas (BCC), a negative previous biopsy of the ulcer was considered. RESULTS: Eighty patients, accounting for 85 tumours, were included, with a female : male ratio of 2.5 : 1 and a mean age of 75 years. Eighty-eight percent of the ulcers were of venous origin and their mean duration was 27.5 years. Five patients developed bilateral cancers. Clinical findings included abnormal granulation tissue in 76% of cases, absence of healing in 14% and unusual extension in 6%. Histologically, 83/85 (98%) of tumours were SCC, among which 82% were very well or well differentiated and 18% moderately or poorly differentiated. The two remaining cases were BCC. The overall death rate was 32%; it was higher when lymph-node (66%) or visceral metastases (83%) were present. Leg amputation was performed in 29/51 (57%) of patients, irrespective of the degree of histological differentiation. For well-differentiated (grade I) and localized (stage Ia) SCC, simple surgical excision was preferred to amputation. CONCLUSION: Malignant transformation of chronic leg ulcers of vascular origin is mainly encountered in elderly patients and manifests as an abnormally vegetating lesion, which may be occasionally bilateral. Malignant transformation usually occurs towards well-differentiated SCC and only exceptionally towards BCC. The high death rate, especially in metastatic cases, is at least partly due to delay in diagnosis. Surgery remains the treatment of choice. Leg amputation should be considered in the most extensive cases.

Glyceraldehyde-3-phosphate dehydrogenase regulation in Lactococcus lactis ssp. cremoris MG1363 or relA mutant at low pH.

AIMS: To analyse the phenotype of a relA acid-resistant mutant of Lactococcus lactis ssp. cremoris MG1363, and to compare the glyceraldehyde-3-phosphate dehydrogenase regulation in both strains. METHODS AND RESULTS: Lactococcus lactis ssp. cremoris MG1363 and the relA mutant affected in the (p)ppGpp synthetase were grown in a series of batch-mode fermentation at different pH-regulated conditions with glucose as carbon substrate. All the determinants of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) regulation were quantified. In L. lactis MG1363, the GAPDH was strongly inhibited in vitro by decreased pH values, but this inhibition was totally compensated in vivo by the lower NADH/NAD+ ratio and more efficiently by the important increase in the intracellular amount of GAPDH. In contrast to the wild type, GAPDH activity of the relA strain was not increased when grown at low pH but the level of GAPDH remained constitutively high. However, pH homeostasis was not improved in the relA mutant and it grew slower and exhibited a lower glycolytic flux than the wild-type strain at low pH. CONCLUSIONS: Despite a better resistance to acid stress, the increased survival in L. lactis relA mutant at low pH was not related with an improved pH homeostasis but was associated with a diminished capacity to maintain a high flux through glycolysis. SIGNIFICANCE AND IMPACT OF THE STUDY: The phenotype of a strong acid-resistant L. lactis strain was established in acid conditions and some key metabolic parameters compared with the wild type. This analysis led to the conclusion that growth and survival seem to be antinomic parameters, since improving one of them leads to a decrease in the other one.

Transcript quantification based on chemical labeling of RNA associated with fluorescent detection.

A general method for RNA measurement, based on chemical labeling of RNA with digoxigenin (without retrotranscription), has been established. Labeled RNA is hybridized with nylon membranes containing spot blots of PCR-amplified gene fragments and the fluorescence detection is mediated via specific anti-digoxigenin antibody coupled to alkaline phosphatase. The method was optimized in order to be quantitative, and high precision (less than 24% error) was obtained, allowing analysis of relatively small changes in gene expression. When the quantity of cellular RNA used in this method is maintained constant and the amount of RNA in the cell determined, the true intracellular transcript concentrations can be determined, rather than simple abundance of a messenger in RNA population. This RNA quantification technique was extended to macroarrays blotted automatically and the validity of the method was tested by comparison with expression data obtained by Northern blotting.

Rehabilitation of patients with congestive heart failure with or without beta-blockade therapy.

BACKGROUND: Management of heart failure includes beta-blockade (betaB) therapy and cardiac rehabilitation. The aim of this study was to compare the exercise training response of patients with congestive heart failure (CHF) receiving betaB therapy with that of patients not receiving treatment. METHODS AND RESULTS: Thirty-four consecutive patients with CHF were included in a 4-week training program at their ventilatory threshold (VT); 6 patients received betaB treatment and 18 did not. The patients underwent a cardiopulmonary exercise test before and after training. Oxygen uptake (VO(2)) at peak exercise and at VT increased in both groups (P < or =.0001) without any significant differences between the groups. The same results were found after adjustment to ejection fraction and VO(2) at the start of the training program. There was no difference in VT improvement, measured as a percentage of utilization of maximal oxygen uptake, between the groups. After training, heart rate and ventilation decreased (P < or =.0001) at submaximal levels in both groups without significant differences between the groups. CONCLUSIONS: betaB therapy does not impair functional improvement induced by a rehabilitation program in patients with CHF. betaB therapy does not interfere with exercise training prescription if patient exercise evaluations are made at the time of therapeutic intake.

Glucose metabolism and regulation of glycolysis in Lactococcus lactis strains with decreased lactate dehydrogenase activity.

The distribution of carbon flux at the pyruvate node was investigated in Lactococcus lactis under anaerobic conditions with mutant strains having decreased lactate dehydrogenase activity. Strains previously selected by random mutagenesis by H. Boumerdassi, C. Monnet, M. Desmazeaud, and G. Corrieu (Appl. Environ. Microbiol. 63, 2293-2299, 1997) were found to have single punctual mutations in the ldh gene and presented a high degree of instability. The strain L. lactis JIM 5711 in which lactate dehydrogenase activity was diminished to less than 30% of the wild type maintained homolactic metabolism. This was due to an increase in the intracellular pyruvate concentration, which ensures the maintained flux through the lactate dehydrogenase. Pyruvate metabolism was linked to the flux limitation at the level of glyceraldehyde-3-phosphate dehydrogenase, as previously postulated for the parent strain (C. Garrigues, P. Loubière, N. D. Lindley, and M. Cocaign-Bousquet (1997) J. Bacteriol. 179, 5282-5287, 1997). However, a strain (L. lactis JIM 5954) in which the ldh gene was interrupted reoriented pyruvate metabolism toward mixed metabolism (production of formate, acetate, and ethanol), though the glycolytic flux was not strongly diminished. Only limited production of acetoin occurred despite significant overflow of pyruvate. Intracellular metabolite profiles indicated that the in vivo glyceraldehyde-3-phosphate dehydrogenase activity was no longer flux limiting in the Deltaldh strain. The shift toward mixed acid fermentation was correlated with the lower intracellular trioses phosphate concentration and diminished allosteric inhibition of pyruvate formate lyase.