Birth and rapid subcellular adaptation of a hominoid-specific CDC14 protein

Gene duplication was prevalent during hominoid evolution, yet little is known about the functional fate of new ape gene copies. We characterized the CDC14B cell cycle gene and the functional evolution of its hominoid-specific daughter gene, CDC14Bretro. We found that CDC14B encodes four different splice isoforms that show different subcellular localizations (nucleus or microtubule-associated) and functional properties. A microtubular CDC14B variant spawned CDC14Bretro through retroposition in the hominoid ancestor 18-25 million years ago (Mya). CDC14Bretro evolved brain-/testis-specific expression after the duplication event and experienced a short period of intense positive selection in the African ape ancestor 7-12 Mya. Using resurrected ancestral protein variants, we demonstrate that by virtue of amino acid substitutions in distinct protein regions during this time, the subcellular localization of CDC14Bretro progressively shifted from the association with microtubules (stabilizing them) to an association with the endoplasmic reticulum. CDC14Bretro evolution represents a paradigm example of rapid, selectively driven subcellular relocalization, thus revealing a novel mode for the emergence of new gene function

Parental post-traumatic reactions after premature birth: implications for sleeping and eating problems in the infant.

BACKGROUND: Progress in perinatal medicine has made it possible to increase the survival of very or extremely low birthweight infants. Developmental outcomes of surviving preterm infants have been analysed at the paediatric, neurological, cognitive, and behavioural levels, and a series of perinatal and environmental risk factors have been identified. The threat to the child's survival and invasive medical procedures can be very traumatic for the parents. Few empirical reports have considered post-traumatic stress reactions of the parents as a possible variable affecting a child's outcome. Some studies have described sleeping and eating problems as related to prematurity; these problems are especially critical for the parents. OBJECTIVE: To examine the effects of post-traumatic reactions of the parents on sleeping and eating problems of the children. DESIGN: Fifty families with a premature infant (25-33 gestation weeks) and a control group of 25 families with a full term infant participated in the study. Perinatal risks were evaluated during the hospital stay. Mothers and fathers were interviewed when their children were 18 months old about the child's problems and filled in a perinatal post-traumatic stress disorder questionnaire (PPQ). RESULTS: The severity of the perinatal risks only partly predicts a child's problems. Independently of the perinatal risks, the intensity of the post-traumatic reactions of the parents is an important predictor of these problems. CONCLUSIONS: These findings suggest that the parental response to premature birth mediates the risks of later adverse outcomes. Preventive intervention should be promoted.

Clinical experience to date with nilotinib in gastrointestinal stromal tumors.

Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα--the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)--nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator's discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician's armamentarium for the management of GIST.

Circadian and circaseptan patterns of natality and perinatal mortality of infants with different birth weights

OBJECTIVE. Data on human natality, stillbirth and perinatal mortality from Switzerland (1979-1987), available in four birthweight categories, are reexamined to assess any about-weekly (circaseptan) and changes in about-daily (circadian) patterns in central Europe over a century and a halfDESIGN. Retrospective analyses on archived data.SETTING. Federal Office of Statistics for Switzerland.RESULTS. In addition to prominent circadians, weekly patterns are also documented.CONCLUSION. Exogenous variations, prominent in early extrauterine life, such as changes of scheduling in obstetrics, may contribute to circadian and cireaseptan natality patterns. Information on these patterns serves in the optimization of neonatal care. Partly endogenous, partly physical environmental aspects, at least of about-weekly patterns, remain to be elucidated in series consisting exclusively of spontaneous parturitions.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

A joint back calculation model for the imputation of the date of HIV infection in a prevalent cohort.

In studies of the natural history of HIV-1 infection, the time scale of primary interest is the time since infection. Unfortunately, this time is very often unknown for HIV infection and using the follow-up time instead of the time since infection is likely to provide biased results because of onset confounding. Laboratory markers such as the CD4 T-cell count carry important information concerning disease progression and can be used to predict the unknown date of infection. Previous work on this topic has made use of only one CD4 measurement or based the imputation on incident patients only. However, because of considerable intrinsic variability in CD4 levels and because incident cases are different from prevalent cases, back calculation based on only one CD4 determination per person or on characteristics of the incident sub-cohort may provide unreliable results. Therefore, we propose a methodology based on the repeated individual CD4 T-cells marker measurements that use both incident and prevalent cases to impute the unknown date of infection. Our approach uses joint modelling of the time since infection, the CD4 time path and the drop-out process. This methodology has been applied to estimate the CD4 slope and impute the unknown date of infection in HIV patients from the Swiss HIV Cohort Study. A procedure based on the comparison of different slope estimates is proposed to assess the goodness of fit of the imputation. Results of simulation studies indicated that the imputation procedure worked well, despite the intrinsic high volatility of the CD4 marker.