A role for Msx genes in mammalian embryonic diapause.

Mammalian embryonic diapause is a reproductive phenomenon defined by the reversible arrest in blastocyst development and metabolic activity within the uterus which synchronously becomes quiescent to implantation. This natural strategy, evident in over 130 species across eight orders, can temporally uncouple conception from delivery until conditions are favorable for the survival of the mother and newborn. While the maternal endocrine milieu has been shown to be important for this process, the local molecular mechanisms by which the uterus and embryo achieve quiescence, maintain blastocyst survival and then resumes blastocyst activation with subsequent implantation in response to endocrine cues remains unclear. Here we review the first evidence that the proximal molecular control of embryonic diapause is conserved in three unrelated mammalian species which employ different endocrine programs to initiate diapause. In particular, uterine expression of muscle segment homeobox (Msx) genes Msx1 or Msx2 persists during diapause, followed by downregulation with blastocyst reactivation and implantation. Mice (Mus musculus) with conditional inactivation of Msx1 and Msx2 in the uterus fail to achieve diapause and reactivation. Remarkably, the mink (Neovison vison) and tammar wallaby (Macropus eugenii) share this pattern of MSX1 or MSX2 expression as in mice during delay - it persists during diapause and is rapidly downregulated upon implantation. Therefore, these findings were the first to provide evidence that there are common conserved molecular regulators in the uterus of unrelated mammals during embryonic diapause.

Regulation of diapause in carnivores.

Embryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation. In mustelids, the regulation of diapause and reactivation is influenced by photoperiod, which then acts to regulate the secretion of pituitary prolactin. Prolactin in turn regulates ovarian steroid function. Reciprocal embryo transplant studies indicate that this state of embryonic arrest is conferred by uterine conditions and is presumed to be due to a lack of specific factors necessary for continued development. Studies of global gene expression in the mink (Neovison vison) revealed reduced expression of a cluster of genes that regulate the abundance of polyamines in the uterus during diapause, including the rate-limiting enzyme in polyamine production, ornithine decarboxylase (ODC). In addition, in this species, in vivo inhibition of the conversion of ornithine to the polyamine, putrescine, induces a reversible arrest in embryonic development and an arrest in both trophoblast and inner cell mass proliferation in vitro. Putrescine, at 0.5, 2 and 1,000 µM concentrations induced reactivation of mink embryos in culture, indicated by an increase in embryo volume, observed within five days. Further, prolactin induces ODC1 expression in the uterus, thereby regulating uterine polyamine levels. These results indicate that pituitary prolactin acts on ovarian and uterine targets to terminate embryonic diapause. In summary, our findings suggest that the polyamines, with synthesis under the control of pituitary prolactin, are the uterine factor whose absence is responsible for embryonic diapause in mustelid carnivores.

Detecting drawdowns masked by environmental stresses with water-level models.

Detecting and quantifying small drawdown at observation wells distant from the pumping well greatly expands the characterized aquifer volume. However, this detection is often obscured by water level fluctuations such as barometric and tidal effects. A reliable analytical approach for distinguishing drawdown from nonpumping water-level fluctuations is presented and tested here. Drawdown is distinguished by analytically simulating all pumping and nonpumping water-level stresses simultaneously during the period of record. Pumping signals are generated with Theis models, where the pumping schedule is translated into water-level change with the Theis solution. This approach closely matched drawdowns simulated with a complex three-dimensional, hypothetical model and reasonably estimated drawdowns from an aquifer test conducted in a complex hydrogeologic system. Pumping-induced changes generated with a numerical model and analytical Theis model agreed (RMS as low as 0.007 m) in cases where pumping signals traveled more than 1 km across confining units and fault structures. Maximum drawdowns of about 0.05 m were analytically estimated from field investigations where environmental fluctuations approached 0.2 m during the analysis period.

Evaluation of the short-term impact of counseling in general practice.

This paper describes the findings of a randomised controlled trial of the short-term impact of counseling in the general practice setting. Compared with patients who received usual advice from their general practitioner for acute problems such as relationship difficulties, anxiety and depression, those who received counseling from qualified counselors working within the primary health care context showed greater improvement in psychological health as measured by the General Health Questionnaire. Significantly fewer of those counselled were prescribed anti-depressant drugs by the general practitioners in the study, or were referred to psychiatrists or clinical psychologists for care. In addition those patients who attended sessions with the practice counselor were more likely to report that they were satisfied with their treatment and more expressed feelings of well-being.

Evaluation of creatinine clearance estimation in an elderly male population.

Thirty-one medically stable, elderly males (age 75 +/- 8.3 yrs) participated in a prospective study evaluating the accuracy of 16 methods of estimating creatinine clearance. Serum creatinine values were determined on the mornings of days 1, 4, and 5 to assure stable renal function. On the morning of day 3, a 24-hour urine collection was initiated. A statistically significant correlation existed between the measured and estimated clearance values for all 16 formulas. The correlation (r less than 0.65) was lower than that in previously published studies, however. Five of the formulas (1A, 5A, 5B, 7A, 7B) demonstrated no statistical difference between mean measured and estimated values. In this population, formula 2B was the least biased and formula 9B the most accurate. For all 16 methods, the bias was minimal and the relative accuracy of the estimated methods was comparable. The results support using methods to estimate creatinine clearance only as a rough bedside prediction of renal function in elderly males.

Imipramine blood levels and clinical outcome.

Fifty-one depressed inpatients, after 1 drug-free week, were treated for 5 weeks with imipramine 4 mg/kg day. Plasma levels of imipramine (IMI) and its active metabolite desmethylimipramine (DMI) were measured weekly, 15 hours after the last drug intake. Steady state blood levels (IMI + DMI) ranged from 60 to 585 ng/ml. The mean value for plasma concentration (IMI + DMI) at day 42 was 271 ng/ml. In the same way, therapeutic effectiveness was assessed every week using the Hamilton Rating Scale for Depression (HDRS). There was a significant correlation between plasma concentration and the decrease of Hamilton scores. The IMI/DMI ratio showed a responder-nonresponder difference; 86% patients with a ratio between 0.4 and 1 were responders. Conversely, most patients with a ratio below 0.4 or above 1 were nonresponders. The ideal ratio for clinical response would be 0.68. The ratio is a subject-specific feature, able to be an early predictor of clinical outcome.

[Study of blood calcium in a population of 3148 women. Variations with age. Correlation with other biological values]. / Etude de la calcémie dans une population de 3148 femmes. Variations avec l'age. Corrélations avec d'autres valeurs biologiques

The authors studied calcaemia and its correlations with other biochemical values in a population of 3,148 women. Calcaemia was 95.53 mg/litre +/- 3.54, a level equal to that found in 6,048 men. In 82 women (2.6 percent) the level of calcaemia was less than 90 mg/litre, and in 21 (0.66 percent) the level of calcaemia was less than 88 mg/litre. In 13 women (0.41 percent) the level of calcaemia was more than 105 mg/litre. Calcaemia in women decreased with age up to 50 years, increased again from 50 to 60 years and then fell again. There was a strong positive correlation between calcaemia and protidaemia (r = + 0.53) and a weak positive correlation between calcaemia and cholesterolaemia (r = + 0.19).