Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients.

Deletions of the 1p region appear as a pejorative prognostic factor in multiple myeloma patients (especially 1p22 and 1p32 deletions) but there is a lack of data on the real impact of 1p abnormalities on an important and homogeneous group of patients. To address this issue we studied by fluorescence in situ hybridization (FISH) the incidence and prognostic impact of 1p22 and 1p32 deletions in 1195 patients from the IFM (Institut Francophone du Myélome) cell collection. Chromosome 1p deletions were present in 23.3% of the patients (271): 15.1% (176) for 1p22 and 7.3% (85) for 1p32 regions. In univariate analyses, 1p22 and 1p32 appeared as negative prognostic factors for progression-free survival (PFS): 1p22: 19.8 months vs 33.6 months (P<0.001) and 1p32: 14.4 months vs 33.6 months (P<0.001); and overall survival (OS): 1p22: 44.2 months vs 96.8 months (P=0.002) and 1p32: 26.7 months vs 96.8 months (P<0.001). In multivariate analyses, 1p22 and 1p32 deletions still appear as independent negative prognostic factors for PFS and OS. In conclusion, our data show that 1p22 and 1p32 deletions are major negative prognostic factors for PFS and OS for patients with MM. We thus suggest that 1p32 deletion should be tested for all patients at diagnosis.

Higher mental stimulation at work is associated with improved cognitive functioning in both young and older workers.

The study examined whether mental stimulation received in the workplace positively affects cognitive functioning and rate of cognitive change. Data taken from the VISAT (ageing, health and work) longitudinal study concerned 3237 workers who were seen three times (in 1996, 2001 and 2006) and who were aged between 32 and 62 years at baseline. Measures of cognitive stimulation both at work and outside work were available at baseline. Cognitive efficiency was assessed on the three occasions through episodic verbal memory, attention and processing speed tests. Greater cognitive stimulation (at work and outside work) was associated with higher levels of cognitive functioning and a more favourable change over the 10-year follow-up. These results were obtained after adjustment for age, education, sex and a variety of medical, physical and psychosocial confounders. The study thus supports the hypothesis that exposure to jobs that are mentally demanding and that offer learning opportunities increases the level of cognitive functioning and possibly attenuates age-related decline. STATEMENT OF RELEVANCE: The effect of occupational activity on cognitive functioning is under-researched. This paper reports results from a substantive longitudinal study, with findings indicating that exposure to jobs that are mentally demanding are beneficial in increasing levels of cognitive functioning and possibly attenuating age-related decline.

Viability and surface properties of spores subjected to a cleaning-in-place procedure: consequences on their ability to contaminate surfaces of equipment.

This study was designed to evaluate how conditions encountered by spores during cleaning-in-place (CIP) procedures affected their surface properties, their viability and ability to contaminate materials. Spores from five Bacillus cereus strains were treated with NaOH at high temperature. Results revealed that high temperatures (exceeding 60 degrees C) and NaOH concentrations (over 0.5%) were required to significantly decrease spore viability (3-5log decrease). In these conditions, modifications were also clearly observed by microscopy to various surface structures of spores (appendages, exosporium, and especially to the hair-like nap) but also to their coat. Therefore, the ability of culturable spores to adhere decreased for the majority of strains tested. We then demonstrated that spores in suspension in NaOH could adhere to surfaces of a CIP rig and that the contamination level was controlled by flow pattern. Consequently, re-adhesion along the processing line might occur during CIP procedures and this phenomenon must be taken into account when defining cleaning strategies.

A 'DNA replication' signature of progression and negative outcome in colorectal cancer.

Colorectal cancer is one of the most frequent cancers worldwide. As the tumor-node-metastasis (TNM) staging classification does not allow to predict the survival of patients in many cases, additional prognostic factors are needed to better forecast their outcome. Genes involved in DNA replication may represent an underexplored source of such prognostic markers. Indeed, accidents during DNA replication can trigger 'replicative stress', one of the main features of cancer from earlier stages onward. In this study, we assessed the expression of 47 'DNA replication' genes in primary tumors and adjacent normal tissues from a homogeneous series of 74 patients. We found that genes coding for translesional (TLS) DNA polymerases, initiation of DNA replication, S-phase signaling and protection of replication forks were significantly deregulated in tumors. We also observed that the overexpression of either the MCM7 helicase or the TLS DNA polymerase POLQ (if also associated with a concomitant overexpression of firing genes) was significantly related to poor patient survival. Our data suggest the existence of a 'DNA replication signature' that might represent a source of new prognostic markers. Such a signature could help in understanding the molecular mechanisms underlying tumor progression in colorectal cancer patients.

Physico-chemical and hygienic property modifications of stainless steel surfaces induced by conditioning with food and detergent.

The effect of repeated conditioning procedures (25 runs), consisting of soiling (milk and meat products) and cleaning steps, on the hygienic status, physico-chemical properties and surface chemical composition of stainless steel (SS) surfaces, was investigated. Five SSs differing in grade and finish were used. Both soiling and surface cleaning/conditioning procedures resulted in a similar increase in the surface contamination with carbon, while the changes in the basic component of the surface free energy depended on the conditioning procedure. The passive film was also affected, the Fe/Cr ratio in particular. The hygienic status was also changed, especially with milk as shown by monitoring the number of residual adhering Bacillus cereus spores after contaminating the surface with spores followed by cleaning. The results show that in food environments, the presence and the nature of conditioning molecules play a major role in the hygienic status of SS surfaces.

Signal enhancement in electronic detection of DNA hybridization.

Electronic detection of the specific recognition between complementary DNA sequences is investigated. DNA probes are immobilized at different lateral positions on a Poly( L -lysine)-coated surface of an integrated silicon transistor array. Hybridization and field effect detection are done with the solid surface immersed in electrolyte solutions. Differential measurements are performed, where DNA hybridization leads to surface potential shifts between the transistors of the array. We experimentally show that these differential signals of hybridization can be enhanced significantly by changing the salt concentration between hybridization and detection.

Rastreamento familiar do fator V de Leiden: a importância da deteccão de portadores heterozigotos / Familiar tracking of factor V Leiden: the importance of detection in heterozygous carriers

O fator de Leiden é uma mutacão genética que predispõe seus portadores ao tromboembolismo venoso. O objetivo do estudo foi investigar a distribuicão dos alelos em 21 membros da família de três pacientes portadores de trombose com a presenca da mutacão do fator V de Leiden. A deteccão da mutacão no gene do fator V foi realizada entre portadores da mutacão no estado heterozigoto. Este estudo foi realizado no Centro de Hematologia e Hemoterapia do Ceará - Hemoce. Observou-se a presenca da mutacão no estado heterozigoto na família 1 (83,3 por cento), na família 2 (40 por cento) e na família 3 (50 por cento). No total de 24 membros (pacientes e familiares) analisados, 50 por cento (12/24) apresentaram a mutacão, todos no estado heterozigoto, 66,7 por cento (8/12) não apresentaram trombose. A deteccão do fator V de Leiden em pacientes portadores de eventos trombóticos é recomendado para esclarecimento das causas e para efetuar o rastreamento em membros de sua família, ainda sem o aparecimento de eventos trombóticos, de forma a avaliar os riscos associados e assim determinar um acompanhamento médico preventivo.

Spatially resolved electronic detection of biopolymers.

An integrated array of field-effect transistor structures is used to detect two oppositely charged biopolymers: poly(L-lysine) and DNA. Local deposition of polymer solutions on part of the array induces sizeable variations in the dc current-voltage characteristics of the transistors exposed to the molecular charge. The whole transistor array is measured in the presence of a common electrolyte. Differential signals are studied as a function of electrolyte salt and polymer concentrations. The measurements provide information on the interface electrostatic potentials of the (semiconductor/biopolymer/electrolyte) system and the experimental data are compared to an analytical model which accounts for screening of the adsorbed charge by mobile ions.

Nycthemeral variations in core temperature and heart rate: continuous cycling exercise versus continuous rest.

Circadian rhythms have formed the subject of many researches in man during bed rest or usual routine, but have been little studied during continuous and sustained physical exercise. This study deals with the influence of time of day on biological markers in competitive cyclists during continuous physical exercise versus continuous rest. Ultra-distance cyclists were studied over a 24 h period (13:00 to 13:00 h the next day) in the laboratory. The subjects were requested to maintain a constant speed (set at 65% - 70% of their maximal aerobic speed obtained during a preliminary test) on their own bicycles which were equipped with home trainers. Workload, core temperature and heart rate were monitored continuously. The same measures were also recorded while the athletes were resting awake until 13:00 h the next day. Results show that in both situations, core temperature and heart rate exhibited significant circadian variations (p < 0.001). Furthermore, during exercise, an accentuation of amplitude and mean of every rhythm (p < 0.05) with a phase lag (p < 0.05) were observed. Despite a strenuous and continuous physical exercise requiring special physiological adaptations, the rhythmic variations observed at rest persisted, which highlighted the influence of biological clocks.

Simulating mechanical consequences of voluntary movement upon whole-body equilibrium: the arm-raising paradigm revisited.

Voluntary arm-raising movement performed during the upright human stance position imposes a perturbation to an already unstable bipedal posture characterised by a high body centre of mass (CoM). Inertial forces due to arm acceleration and displacement of the CoM of the arm which alters the CoM position of the whole body represent the two sources of disequilibrium. A current model of postural control explains equilibrium maintenance through the action of anticipatory postural adjustments (APAs) that would offset any destabilising effect of the voluntary movement. The purpose of this paper was to quantify, using computer simulation, the postural perturbation due to arm raising movement. The model incorporated four links, with shoulder, hip, knee and ankle joints constrained by linear viscoelastic elements. The input of the model was a torque applied at the shoulder joint. The simulation described mechanical consequences of the arm-raising movement for different initial conditions. The variables tested were arm inertia, the presence or not of gravity field, the initial standing position and arm movement direction. Simulations showed that the mechanical effect of arm-raising movement was mainly local, that is to say at the level of trunk and lower limbs and produced a slight forward displacement of the CoM (1.5 mm). Backward arm-raising movement had the same effect on the CoM displacement as the forward arm-raising movement. When the mass of the arm was increased, trunk rotation increased producing a CoM displacement in the opposite direction when compared to arm movement performed without load. Postural disturbance was minimised for an initial standing posture with the CoM vertical projection corresponding to the ankle joint axis of rotation. When the model was reduced to two degrees of freedom (ankle and shoulder joints only) the postural perturbation due to arm-raising movement increased compared to the four-joints model. On the basis of these results the classical assumption that APAs stabilise the CoM is challenged.

[Predictive factors of virologic response to antiretroviral treatment with a protease inhibitor in HIV infection]. / Facteurs prédictifs de réponse virologique à un traitement antirétroviral avec inhibiteur de protéase au cours de l'infection à VIH.

OBJECTIVE: To investigate factors related to early virological response among a cohort of 224 patients who started a protease inhibitor (PI) for the first time. To determine which factors are associated with persistent response among patients with early response. PATIENTS AND METHODS: Early complete response was defined as an undetectable plasma viral load 2 to 3 months after treatment onset (< 400 copies/ml, Quantiplex HIV 2.0 Chiron diagnostics), incomplete response as at least 1 log reduction of viral load. In patients with an undetectable plasma viral load at 2 or 3 months, we also assessed the persistence of the response on the same regimen. Virology failure was defined by two consecutive viral load levels above the detection limit. RESULTS: In the total cohort, 66% of the patients had an early complete response, 11% a partial response and 23% no response. Complete virological response was significantly more frequent in naive (89%) than in pretreated (59%) patients (p < 0.001). Multivariate analysis of factors predictive of early response in pretreated patients (n = 169) showed that viral load (p = 0.001), the number of nucleoside analogs previously received (p = 0.06) and a full or partial treatment switch (p = 0.10) were associated with complete response. Analysis of later response in the 45 naive patients with prolonged follow-up showed that 22% had treatment failure after 3 to 16 months. None of the baseline variables (viral load, CD4+ cell count or nature of the PI) were associated with duration of response. The only factor associated with persistent response in pretreated patients was a low number of antiretroviral drugs previously received (log-rank test, p = 0.04). CONCLUSIONS: The absence of previous antiretroviral treatment as the main factor associated with an early complete virological response. In patients pretreated with nucleoside analogs who presented early virological success, the number of drugs previously received, often associated with full or partial switch of nucleoside analog, significantly influence the persistence of response to a given triple-drug regimen.

A primary malarial infection is composed of a very wide range of genetically diverse but related parasites.

To address the question of how many distinct parasites are injected when a mosquito bites, we have characterized isolates resulting most probably from a single sporozoite inoculum. We describe the direct and immediate cloning on hepatocyte feeder layers of a Thai and an African Plasmodium falciparum primary isolate and the characterization of 67 independent clones by four techniques totaling nine different markers. This led to three main conclusions: (a) both the phenotypic and genotypic markers revealed an unexpectedly large degree of diversity within the clones from a single isolate; (b) the clones are nonetheless genetically related; and (c) a single mosquito inoculum would most likely be sufficient to generate considerable isolate complexity in the absence of repeated exposure. This diversity, which has been greatly underestimated in previous studies, does not bode well for the development of successful malaria control means.

Circadian rhythm in the torque developed by elbow flexors during isometric contraction. Effect of sampling schedules.

Time-dependent changes in elbow flexion torque have been documented according to two different sampling schedules. Seven physical education students took part in the first series of experiments, and 7 other similar subjects in the second. In both sets of experiments, the subjects performed isometric contractions: maximal and submaximal at 90 degrees in the first experiments and maximal at different angular positions in the second. After a 30-minute rest period, the torque developed was measured at 00:00, 06:00, 09:00, 12:00, 15:00, 18:00, and 21:00 h on the day of the experiment. These subjects remained in the laboratory for 24 h. In the second series of experiments, the torque developed was measured at 01:00, 05:00, 09:00, 13:00, 17:00, and 21:00 h over the subsequent 6 days with only one test session per day. In this case, there was an interval of 20 h between two successive test sessions. In the first experiment, a significant time-of-day effect was observed for the torque of the elbow flexors under isometric conditions with an acrophase at 17:58 h. The 24 h normalized mean score was 92.85% with an amplitude of 7.63% of the daily mean. In the second series of experiments, there was evidence of a circadian rhythm in the torque developed by the elbow flexors at every angle position, especially at 90 degrees, the angle investigated in the first set of experiments. The peak torque was calculated to have occurred at 17:55 h. The amplitude of the rhythm was equal to 6.99% of the daily mean. There were no statistically significant differences in the characteristics of the circadian rhythm observed between the two experimental designs. We concluded that an experiment extending over several days could be employed to evaluate circadian rhythms in muscular activity reliably.

Effects of corticosterone administration on local cerebral glucose utilization of rats.

The local cerebral glucose utilization (LCGU) of control and 2 day corticosterone-administered rats was investigated using the method of Sokoloff (labelled 2-deoxy-D-glucose). The overall LCGU of both groups was similar, but discrete areas of the corticosterone-administered rat brains displayed both increases and decreases in their utilization of 2-deoxyglucose. These areas were associated with the limbic cortex and included the hippocampus, the septum and some thalamic and hypothalamic nuclei. It is well known that these regions are interconnected and that acetylcholine is one of the main neurotransmitters. Some of these pathways (as measured electrophysiologically) have reportedly inhibitory influences, whilst others have excitatory ones within the limbic region. It was therefore striking to observe that these inhibitory or stimulatory effects were corroborated by a selective, corticosterone-induced decrease or increase in 2-deoxyglucose uptake, respectively. This gives corticosterone a putative role in the regulation of the limbic system. As the latter has been reported to be abnormal in genetically obese hypercorticosteronemic fa/fa rats, it is suggested that these corticosterone-induced changes within the limbic system may contribute to the overall phenotypic expression of this obesity state.

Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats.

The mechanism by which glucocorticoids induce insulin resistance was studied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone administration induced a slight hyperglycaemia, hyperinsulinaemia and increased non-esterified fatty acid levels. It impaired insulin-stimulated total glucose utilization (corticosterone 15.7 +/- 0.7; controls 24.6 +/- 0.8 mg.kg-1 x min-1), as well as residual hepatic glucose production (corticosterone 4.9 +/- 1.0; controls 2.0 +/- 0.7 mg.kg-1 x min-1). During the clamps, insulin did not decrease the elevated non-esterified fatty acid levels in corticosterone-administered rats (corticosterone 1.38 +/- 0.15, controls 0.22 +/- 0.04 mmol/l). Corticosterone administration decreased the in vivo insulin-stimulated glucose utilization index by individual muscles by 62 +/- 6%, and the de novo glycogen synthesis by 78 +/- 2% (n = 8-9 muscles). GLUT4 protein and mRNA levels were either unchanged or slightly increased by corticosterone administration. Inhibition of lipid oxidation by etomoxir prevented corticosterone-induced muscle but not hepatic insulin resistance. In conclusion, glucocorticoid-induced muscle insulin resistance is due to excessive non-esterified fatty acid oxidation, possibly via increased glucose fatty-acid cycle ultimately inhibiting glucose transport, or via decreased glycogen synthesis, or by a direct effect on glucose transporter translocation or activity or both.

Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat.

Adrenalectomy has been shown to reverse most facets of the syndrome of the genetically obese fa/fa rat. However, a detailed analysis of the hypothalamo-pituitary-adrenal (HPA) axis in these animals is lacking. In the present study, morning corticosteronemia was higher in obese rats of both sexes than in lean ones, whereas evening corticosteronemia was higher only in obese male rats. The HPA axis was further investigated using stressful stimuli. Immobilization, ether, and cold stresses resulted in greater corticosterone levels in obese than in lean animals. These abnormalities consisted in upward shifts of the corticosterone response in obese females and absolute increases in that of obese males, indicating that such alterations were more pronounced in obese male than obese female rats. Due to this, the putative origin of the increased corticosterone output of obese rats was studied in males. Greater levels of ACTH were reached in obese than in lean rats when submitted to a cold stress (6 C). Dexamethasone produced a complete suppression of corticosterone output in both lean and obese rats. During the recovery from such suppression, corticosterone levels rose to higher values in obese than in lean rats. This observation together with the greater cold-induced ACTH output in obese rats suggest that the increased activity of the HPA axis of these animals is of central origin. Whatever its precise etiology within the central nervous system, it is proposed that the increased HPA axis activity in obese rats and its resultant hypercorticism play a role in the establishment and maintenance of their syndrome.