Gene expression in the suprachiasmatic nuclei and the photoperiodic time integration.

In mammals, the 24 h-rhythmicity of many physiological events is driven by the circadian clock contained in the suprachiasmatic nuclei (SCN). In the SCN, clock gene expressions produce the rhythmicity and control the expression of clock-controlled genes which play a role in the distribution of daily messages. The daily expression of all these genes is modulated by the duration of the light phase (i.e. photoperiod). The aim of this study was first to determine if these daily changes of expression reflect a real integration of a new photoperiod by the circadian clock or reflect only a passive effect of the light. In this way, we performed a time course of the modifications of gene expression after a transfer of Syrian hamsters from long to short photoperiod (LP and SP). Our results demonstrate that the core of the SCN (clock genes) integrates quickly a new photoperiod which entrains a slow adaptation of the clock-controlled gene expressions and induces a differential daily functioning of an SCN-target tissue, the pineal gland. We next asked the question whether SCN are involved in the photorefractory phase observed in Syrian hamsters exposed to SP for 26 weeks. All genes analyzed present a similar daily expression in SP-refractory and in SP with the exception of Clock. Its particular expression in SP-refractory is different than ones observed in SP or in LP. Thus, Clock seems to play a role in the development of the photorefractory phase, or this physiological state may modify the expression of Clock in the SCN. As a conclusion, it appears that the photoperiodic time measurement involves daily modifications of the molecular functioning of the SCN and that SCN also play a role in the measurement of the duration of the time passed in a short photoperiod.

Expression of Tgfalpha in the suprachiasmatic nuclei of nocturnal and diurnal rodents.

Transforming growth factor alpha (TGFalpha) in the suprachiasmatic nuclei (SCN) has been proposed as an inhibitory signal involved in the control of daily locomotor activity. This assumption is based mainly on studies performed in nocturnal hamsters. To test whether the transcriptional regulation of Tgfalpha can be correlated with the timing of overt activity in other species, we compared Tgfalpha expression in the SCN of nocturnal Swiss mice and of diurnal Arvicanthis housed under a light/dark cycle (LD) or transferred to constant darkness (DD). In agreement with data on hamsters, Tgfalpha mRNA levels in the mouse SCN showed peak and trough levels around (subjective) dawn and dusk, respectively, roughly corresponding to the period of rest and activity in this species. In contrast, in Arvicanthis housed in DD, the circadian rhythm of SCN Tgfalpha was similar to that of the mice in spite of opposite phasing of locomotor activity. Furthermore, in Arvicanthis exposed to LD, Tgfalpha mRNA levels were constitutively high throughout the day. A tonic role of light in the regulation of Tgfalpha in Arvicanthis was confirmed by an increased expression of Tgfalpha in response to a 6-h exposure to light during daytime in animals otherwise kept in DD. In conclusion, this study shows that, contrary to what is observed in mice, Tgfalpha mRNA levels in the SCN of Arvicanthis do not match timing of locomotor activity and are modulated by light.

Photoperiod differentially regulates clock genes' expression in the suprachiasmatic nucleus of Syrian hamster.

The suprachiasmatic nuclei (SCN) contain the master circadian pacemaker in mammals. Generation and maintenance of circadian oscillations involve clock genes which interact to form transcriptional/translational loops and constitute the molecular basis of the clock. There is some evidence that the SCN clock can integrate variations in day length, i.e. photoperiod. However, the effects of photoperiod on clock-gene expression remain largely unknown. We here report the expression pattern of Period (Per) 1, Per2, Per3, Cryptochrome (Cry) 1, Cry2, Bmal1 and Clock genes in the SCN of Syrian hamsters when kept under long (LP) and short (SP) photoperiods. Our data show that photoperiod differentially affects the expression of all clock genes studied. Among the components of the negative limb of the feedback loop, Per1, Per2, Per3, Cry2 but not Cry1 genes show a shortened duration of their peak expression under SP compared with LP. Moreover, mRNA expression of Per1, Per3 and Cry1 are phase advanced in SP compared with LP. Per3 shows an mRNA peak of higher amplitude under SP conditions whereas Per1 and Per2 peak amplitudes are unaffected by photoperiod changes. Bmal1 expression is phase advanced without a change of duration in SP compared with LP. Furthermore, the expression of Clock is rhythmic under SP whereas no rhythm is observed under LP. These results, which provide further evidence that the core clock mechanisms of the SCN integrate photoperiod, are discussed in the context of the existing molecular model.

Assessment of neutron dosemeters around standard sources and nuclear fissile objects.

In order to evaluate the neutron doses around nuclear fissile objects, a comparative study has been made on several neutron dosemeters: bubble dosemeters, etched-track detectors (CR-39) and 3He-filled proportional counters used as dose-rate meters. The measurements were made on the ambient and the personal dose equivalents H*(10) and Hp(10). Results showed that several bubble dosemeters should have been used due to a low reproducibility in the measurements. A strong correlation with the neutron energy was also found, with about a 30% underestimation of Hp(10) for neutrons from the PuBe source, and about a 9% overestimation for neutrons from the 252Cf source. Measurements of the nuclear fissile objects were made using the CR-39 and the dose-rate meters. The CR-39 led to an underestimation of 30% with respect to the neutron dose-rate meter measurements. In addition, the MCNP calculation code was used in the different configurations.

Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.

BACKGROUND: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies METHODS: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily) RESULTS: Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin CONCLUSIONS: The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.

[Evaluation of patient compliance among hypertensive patients treated by specialists]. / Evaluation de l'observance par l'interrogatoire au cours du suivi des hypertendus dans des consultations spécialisées.

OBJECTIVES: To evaluate compliance with antihypertensive therapy by a self-report in patients referred to hypertension specialists. METHODS: We studied 484 treated hypertensive subjects referred to several hypertension clinics and who were treated since at least one year. Patients were asked to fill in the Compliance Evaluation Test (CET), a questionnaire with 6 questions previously validated to assess factors that could affect medication compliance. We defined patients as "good compliant" when "No" was answered to the 6 items, as "minor noncompliant" when 1 or 2 "Yes" were answered, and as "noncompliant" when 3 or more "Yes" were answered. A good agreement was demonstrated between CET score and compliance evaluated by the number of pills missed during the previous month according to patient interview. RESULTS: We observed 8% of "noncompliant", 53% of "minor noncompliant" and 39% of "good compliant". [table: see text] Logistic regression analysis including age, sex, education level, blood pressure level and the number of antihypertensive tablets confirm the statistical differences observed. CONCLUSIONS: In clinical practice, a method of assessing medication compliance is to ask the patient for a self-report interview. We demonstrated that the compliance evaluation test is able to detect factors usually associated with poor compliance (young age, elevated blood pressure, number of tablets per day). The use of the compliance evaluation test may help physicians to face the problem of nonadherence among their hypertensive patients.

Decreased flow-induced dilation and increased production of cGMP in spontaneously hypertensive rats.

-We investigated flow (shear stress)- and agonist-induced cGMP release in mesenteric vascular beds of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The mesenteric vascular bed was perfused in situ with Tyrode's solution. Vascular relaxation and cGMP release in the perfusate were determined on stimulation by flow or by acetylcholine (0.1 micromol/L) or sodium nitroprusside (0.1 mmol/L). Flow-induced release of cGMP was significantly greater in SHR than in WKY (P<0.01), despite a lower flow-induced dilation in SHR. In both strains, NG-nitro-L-arginine methyl ester (L-NAME) completely inhibited cGMP release in response to flow (P<0.001), although flow-induced dilation was not affected by L-NAME in SHR. Moreover, the activity of the constitutive nitric oxide synthase (NOS) was significantly greater in SHR (82+/-3.5 fmol/min) than in WKY (66+/-3.5 fmol/min; P<0.05) and was associated with increased expression of endothelial NOS mRNA in SHR. Sodium nitroprusside induced larger increases in cGMP release in SHR (3593+/-304 fmol/min) than in WKY (2467+/-302 fmol/min; P<0.05). The release of cGMP in response to acetylcholine was significantly lower in SHR (292+/-80 fmol/min) than in WKY (798+/-218 fmol/min; P<0.05) in parallel with smaller acetylcholine-induced relaxation in SHR. Despite increased cGMP production in response to flow and NOS activity, flow-induced dilation was decreased in SHR, suggesting an upregulation of the NO/cGMP pathway to compensate for the increased vascular tone in SHR.

Determination of total effective vascular compliance in patients with sepsis syndrome.

Changes in capacitance vessels have important consequences on cardiac filling pressure and fluid volume distribution in patients with sepsis syndrome. Vascular compliance may be evaluated from the slope of the relationship between changes in total blood volume (deltaTBV) and changes in central venous pressure (deltaCVP) during acute volume expansion (450 ml of gelatin fluid over 6 min), i.e., from the deltaTBV/deltaCVP ratio. The mean ratio (ml x mm Hg-1 x kg-1) was 2.03 +/- 0.21 in control subjects, 1.43 +/- 0.25 in mechanically ventilated patients without sepsis syndrome, and 0.94 +/- 0.24 in mechanically ventilated patients with sepsis syndrome (p < 0.0001 versus the other two groups). Based on echocardiographic determinations, cardiac performance was constantly found within the normal range (cardiac output ranged from 5.6 +/- 1.2 to 6.7 +/- 2.0 L/min in nonseptic patients from 6.8 +/- 1.9 to 7.8 +/- 2.2 in septic patients). Effective compliance of the total vascular bed is therefore reduced in patients with sepsis syndrome, independently of the hemodynamic modifications due to mechanical ventilation.

Psychosocial factors in nutrition education for hypercholesterolemic children.

The goals were to assess psychosocial effects of labeling children as hypercholesterolemic and to measure changes in child well-being as a function of participation in nutrition education interventions. Older (6-10 years old) and younger (4-6 years old) children with (> 4.55 mmol/l; > 176 mg/dL) and without elevated total cholesterol levels were identified by cholesterol screening. Psychosocial functioning (self-esteem, perceived dietary competence, health beliefs, parental control of eating) was assessed and at-risk children were randomized into a home-based, self-contained nutrition education program (the Parent-Child Autotutorial, or PCAT program), dietary counseling with a registered dietician, or an at-risk control group. At three, six, and twelve months following baseline, children's psychosocial functioning again was assessed; parents also provided data at baseline, three months, and twelve months. Analyses of data from 189 at-risk and 74 not-at-risk children revealed that: (a) Older hypercholesterolemic children reported poorer health beliefs than non-labeled children; (b) Older girls in nutrition education programs reported lower self-esteem than control group girls; (c) Older children's feelings of efficacy at choosing a healthful diet were positively related to their health beliefs and self-esteem; (d) Younger children's reports of parents' dietary control were negatively related to children's feelings of acceptance; and (e) Parents of older children in the PCAT program reported increases over time in children's ability to choose a healthful diet. The quasi-experimental design means that conclusions about negative labeling effects should be drawn cautiously, but the evidence suggests that education interventions can have an impact on child efficacy and potentially child adjustment. Factors associated with adverse reactions to labeling (parental control or feelings of efficacy) should be taken into account in the development of intervention programs for children.

[Prevention of acquired pneumonia during artificial ventilation (excluding the use of anti-infectious agents)]. / Moyens de prévention des pneumopathies acquises lors de la ventilation artificielle (à l'exclusion de l'utilisation des anti-infectieux).

Nosocomial pneumonia remains a serious complication which occurs in patients who are artificially ventilated; as neither frequency nor important sequelae have altered recently inspite of the progress which has been achieved both with diagnosis and treatment. Preventative measures ought to be developed and realistically assessed before their introduction. Today it is indispensable to measure the impact of these measures, whether they have been previously or recently proposed by therapeutic trials. The current techniques proposed to prevent the appearance of nosocomial pneumonia are integrated in the usual conventional group of measures in the struggle against nosocomial infection which rests predominantly on standard approaches to hospital hygiene. These may be more specifically directed at good practical measures for the care of the ventilated patient. Regular toilet to the digestive and respiratory pathway, care of the ventilator material, absence of the changing of ventilation tubing during the stay. A certain number of measures are specifically suggested to prevent pneumonias: they have been imperfectly evaluated in clinical practice and remain controversial. Thus selective decontamination of the digestive system has not been dealt with her but also the sitting position, the utilisation of turning or oscillating beds, the continuous aspiration of oropharyngeal secretions or the use of Sucralfate as a means of prevention stress ulcers. Today, and until a complete evaluation of different techniques, the prevention of acquired pneumopathy during artificial ventilation rests above all on extremely simple measures; these cost little and are essentially meticulous care of the upper respiratory and digestive apparatus, to tracheal aspiration and physiotherapy which assure effective drainage and secretions, the use of the semi-sitting position, a well positioned gastric tube, in other words, basic care of the ventilated patient of a very good quality.

Acute stroke trials: Reasons for patient withdrawal.

Knowing why patients fail to complete a clinical trial should help in planning such trials and in estimating their costs. We analyzed reasons why subjects failed to complete two similar acute stroke trials of calcium-channel antagonists. The trials were double-blind, placebo-controlled, and lasted 2 and 3 weeks, respectively. We enrolled 43 patients in the first trial and 37% were withdrawn; 30 patients were enrolled in the second trial and 47% were withdrawn. Reasons for withdrawal were similar in the two trials. When data from the two trials were combined, reasons for withdrawal were errors in administering medication (11%), use of a proscribed drug (7%), early death (7%), a disqualifying illness discovered after enrollment (8%), withdrawal of consent (4%), and enrollment beyond the time limit (<1%). Presence of stroke risk factors, age, sex, and even stroke severity did not significantly increase withdrawal frequency. Since most patients were lost early in the trial, its length did not contribute substantially to premature withdrawal.