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Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure–activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound 28), a potent and selective pan-SIK inhibitor (IC50: 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for SIK3). Characterization of the first human SIK3 crystal structure provided an understanding of the binding mode and kinome selectivity of the chemical series. GLPG3312 demonstrated both anti-inflammatory and immunoregulatory activities in vitroin human primary myeloid cells and in vivoin mouse models.

Low doses of heparin may be administered to reduce the risk of deep venous thrombosis, a condition in which clotting elements accumulate and attach to a point on the interior wall of the vein. New, low-molecular-weight types of heparin have been introduced and are supposed to be superior to standard heparin; these new drugs are currently being evaluated in clinical studies. A report is presented of a study undertaken to evaluate the prophylactic effectiveness of Logiparin (a low-molecular-weight heparin) given in two different dosages (2,500 or 3,500 units daily), compared with the standard unfractionated heparin, for preventing deep venous thrombosis. All 1,290 patients were medium- to high-risk patients undergoing major general surgery. Patients were randomly assigned to one of three treatment groups; all patient groups were well matched for age, sex, weight, diagnosis, and type of surgery. Fibrinogen uptake tests were performed to identify deep venous thrombosis, and diagnosis was confirmed using angiography (X-ray visualization of the vessels). Patients were followed for one month after surgery. The incidence of confirmed deep venous thrombosis was 3 percent in the standard heparin group, 2.3 percent in the higher-dose Logiparin group, and 5.6 percent in the lower-dose Logiparin group. The incidence of major complications, requirement for reintervention, and incidence of bleeding complications were not significantly different among the three groups. The usefulness of 3,500 units Logiparin and standard heparin was similar; however, 2,500 units Logiparin was found to be less effective in preventing deep venous thrombosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Patients who survive a heart attack have an increased risk of sudden death or recurrent heart attack. Studies show that the death rate among survivors of heart attack exceeds 20 percent. In early studies, beta blocking drugs were shown to decrease the mortality of heart attack survivors. The effectiveness of the beta blocking agent acebutolol in preventing death was assessed in patients who survived a heart attack. High-risk patients were selected from a registry in France, the Essai de Prevention Secondaire de l'Infarctus du Myocarde Registry. The study included 309 patients who received a placebo, or substance with no therapeutic effect, and 298 patients who were treated with acebutolol. After 318 days, there were 17 deaths among the acebutolol-treated patients and 34 deaths in the placebo-treated group. Acebutolol was associated with a 48 percent decrease in the death rate among high-risk survivors of heart attack. Vascular disorders accounted for 30 deaths in the placebo group and 12 deaths in the acebutolol group. Acebutolol decreased mortality due to cardiovascular disease by 58 percent, and the incidence of all cardiovascular-related deaths was lower among acebutolol-treated patients. Decreased mortality was not correlated with secondary risk factors. These findings suggest that beta blockers, including those with the ability to activate the sympathetic nervous system, can reduce the death rate in survivors of heart attack. (Consumer Summary produced by Reliance Medical Information, Inc.)

Acebutolol et Prevention Secondaire de I'Infarctus (APSI), a randomized, placebo-controlled trial, was designed to test long-term acebutolol, 200 mg twice dally, a [Beta]-blocker with mild intrinsic sympathomimetic activity, in the prevention of late death in high-risk postacute myocardial infarction (AMI) patients. APSI was planned because patients with a death rate [greater than] 20% have not been enrolled in significant numbers in previous trials and in such high-risk patients, it remained to be proven that [Beta]-blockers have a beneficial effect. Patients with an expected average risk of [greater than] 20% were to be selected based on clinical criteria. At the time of the second interim analysis, the placebo group 1-year mortality was much lower than expected (12%). The ethical board recommended to stop the trial: 309 patients had been allocated to placebo, 298 to acebutolol. The average delay between onset of symptoms and inclusion was 10.5 days. The average follow-up was 318 days after inclusion. About the same number of patients were discontinued from study treatment in both groups. All patients were included in the analysis. There were 17 deaths in the acebutolol group and 34 in the placebo group, a 48% decrease (p = 0.019). The vascular mortality decreased by 58% (p = 0.006), the highest ever observed with a [Beta]-blocker. All cardiovascular causes of death, including congestive heart failure, were less frequent in the acebutolol group. Although the objective was not achieved, APSI patients were at a higher risk than the average of the 9 previous trials with [Beta]-blockers (12% instead of 7%). In addition, the total mortality reduction did not decrease in 9 subgroups with increasing mortality risk from 2 to 23%. APSI shows that moderately severe postAMI patients can benefit from a [Beta]-blocking treatment and a [Beta]-blocker with mild intrinsic sympathomimetic activity can be effective. (Am J Cardiol 1990;66:251-260), In the first year after an acute myocardial infarction (MI, heart attack), patients have a greater than 20 percent risk of dying. Beta blockers have been demonstrated in previous clinical trials to be effective in decreasing mortality; however, most patients studied had low to moderate risk. A French study called Acebutolol et Prevention Secondaire de l'Infarctus (APSI) (Acebutolol in the Secondary Prevention of Infarction) was designed to evaluate the beta blocker acebutolol in high-risk patients. A total of 298 patients received acebutolol, while 309 received placebo (controls). Over the course of 320 days, mortality in the control group was 11 percent, which is well below the 20 percent or over expected. Cardiovascular causes of death were less frequent in patients treated with acebutolol. There were a total of 17 deaths in the active drug group and 34 in the placebo group, a 48 percent decrease, and there was a decrease of 58 percent in cardiovascular mortality, the greatest amount ever observed with a beta blocking agent. A comparison of the risk profiles of the patients studied with those of the patients who were excluded revealed that the highest-risk patients were not included, and therefore this trial failed to accomplish its goal. Nevertheless, there were benefits seen from acebutolol use when compared with placebo in terms of mortality. The investigators could not prove that acebutolol was better than any other beta blocker in the prevention of secondary (late) death after a myocardial infarction, but that was not the intent of the study. Patients at moderately severe risk can benefit from beta blockers following a myocardial infarction. Further research is needed to define the profiles of patients who should not receive a drug of this type after an MI. (Consumer Summary produced by Reliance Medical Information, Inc.)

Philippe de La Hire s’est installé avec toute sa famille à l’Observatoire royal de Paris le 22 janvier 1682 et y a vécu et travaillé jusqu’à sa mort le 21 avril 1718. Il a occupé successivement deux appartements dans le bâtiment, et non pas un seul comme on l’a cru jusqu’ici, tous deux situés au second étage. Après quelques années passées dans l’ancien logement de Rømer à l’entresol côté ouest, il demeura ensuite côté est sur les deux niveaux des anciens appartements de Huygens et de Picard. Cinq inventaires après décès de membres de sa famille dressés à l’Observatoire, dont le sien et celui de sa seconde femme, permettent de se représenter concrètement le contenu des pièces de son second appartement et notamment de son cabinet de travail où se trouvaient la plupart de ses livres et de ses instruments personnels. À partir du cas de La Hire, l’étude ouvre des perspectives nouvelles pour l’histoire de l’Observatoire.

This photograph, taken last October, shows the most tomatoes I've ever raised on one bush. It still had 150 tomatoes toward the end of October. William Picolet. Springfield, [...]

BackgroundFlu vaccination in otherwise healthy infants and young children is important to prevent severe disease, as well as to control epidemic spread of influenza infection.AimsTo examine the safety and immunogenicity of a paediatric presentation of a purified, inactivated, triton split influenza vaccine.MethodsTwo doses of the vaccine, provided in prefilled syringes of 0.25 ml, were administered, one month apart, to 67 children under 3 years of age.ResultsNine cases of immediate reaction to vaccination (macules/papules) were observed after the second injection only. During the study period, 9% of children experienced at least one delayed local reaction, and 28% of children presented at least one systemic reaction. Almost all reactions were mild and transient. Immunogenicity results surpassed the European Community recommendations for a 0.50 ml dose of vaccine in adults.ConclusionThis paediatric formulation of inactivated flu vaccine appears safe and immunogenic in children from 6 months to 3 years of age; the convenient presentation in a prefilled syringe of 0.25 ml volume will facilitate administration of the dose recommended for young children.

In the frame of a multicenter controlled study comparing the efficacy of low-molecular-weight heparin to standard heparin in the prevention of postsurgical thrombosis, 94 phelbograms were centrally evaluated by two independent radiologists. Three months after the first central evaluation, a new reading was performed with the same radiologists, and discrepancies were adjudicated by a senior radiologist. The number of discrepancies between the first and the second evaluation was high: 33 interpretations (35%) had a least one difference, including 14 (14.9%) discrpeancies regarding the main issue, i.e. the presence of venous thrombosis. After the adjudication by the senior radiologist, this number decreased but was still large: 22 films (23.4%) with at least one discrepant item in all and 11 related to the presence of venous thrombosis. This report shows that venous thrombosis assessed by phlebography, which is usually considered as a golden standard in clinical trials, deserves a thorough quality control procedure.

To determine a possible influence on sodium balance or blood pressure of a normal treatment with dydrogesterone, a randomized cross-over double-blind study was performed on 22 healthy young women.Each woman had (in random order) 1 cycle o treatment with dydrogesterone (20 mg/day during the last 12 days of the menstrual cycle) and 1 with equivalent placebo. On days 15 and 27 of each cycle the following data were noted: weight, systolic (SBP) and diastolic (DBP) blood pressures (mean of 13 measurements during 1 hour), natriuresis, kaliuresis, plasma renin activity (PRA) and plasma aldosterone concentration (P aid). For each variable the difference between day 27 and day 15 was calculated. The comparison between progesterone and placebo influence was made on these differences.Neither for sodium balance nor for blood pressure were there any statistically significant differences between placebo and dydrogesterone. However, the confidence intervals of the differences were rather large.There is a need for a more extensive study to confirm the absence of influence of progesterone on sodium balance and blood pressure.