Psychotic Illness in First-Time Mothers with No Previous Psychiatric Hospitalizations: A Population-Based Study

Background

Psychotic illness following childbirth is a relatively rare but severe condition with unexplained etiology. The aim of this study was to investigate the impact of maternal background characteristics and obstetric factors on the risk of postpartum psychosis, specifically among mothers with no previous psychiatric hospitalizations.

Methods and Findings

We investigated incidence rates and potential maternal and obstetric risk factors of psychoses after childbirth in a national cohort of women who were first-time mothers from 1983 through 2000 (n = 745,596). Proportional hazard regression models were used to estimate relative risks of psychoses during and after the first 90 d postpartum, among mothers without any previous psychiatric hospitalization and among all mothers. Within 90 d after delivery, 892 women (1.2 per 1,000 births; 4.84 per 1,000 person-years) were hospitalized due to psychoses and 436 of these (0.6 per 1,000 births; 2.38 per 1,000 person-years) had not previously been hospitalized for any psychiatric disorder. During follow-up after the 90 d postpartum period, the corresponding incidence rates per 1,000 person-years were reduced to 0.65 for all women and 0.49 for women not previously hospitalized. During (but not after) the first 90 d postpartum the risk of psychoses among women without any previous psychiatric hospitalization was independently affected by: maternal age (35 y or older versus 19 y or younger; hazard ratio 2.4, 95% confidence interval [CI] 1.2 to 4.7); high birth weight (≥ 4,500 g; hazard ratio 0.3, 95% CI 0.1 to 1.0); and diabetes (hazard ratio 0).

Conclusions

The incidence of psychotic illness peaks immediately following a first childbirth, and almost 50% of the cases are women without any previous psychiatric hospitalization. High maternal age increases the risk while diabetes and high birth weight are associated with reduced risk of first-onset psychoses, distinctly during the postpartum period.     

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.     

A hot-deck multiple imputation procedure for gaps in longitudinal recurrent event histories

We propose a regression-based hot-deck multiple imputation method for gaps of missing data in longitudinal studies, where subjects experience a recurrent event process and a terminal event. Examples are repeated asthma episodes and death, or menstrual periods and menopause, as in our motivating application. Research interest concerns the onset time of a marker event, defined by the recurrent event process, or the duration from this marker event to the final event. Gaps in the recorded event history make it difficult to determine the onset time of the marker event, and hence, the duration from onset to the final event. Simple approaches such as jumping gap times or dropping cases with gaps have obvious limitations. We propose a procedure for imputing information in the gaps by substituting information in the gap from a matched individual with a completely recorded history in the corresponding interval. Predictive mean matching is used to incorporate information on longitudinal characteristics of the repeated process and the final event time. Multiple imputation is used to propagate imputation uncertainty. The procedure is applied to an important data set for assessing the timing and duration of the menopausal transition. The performance of the proposed method is assessed by a simulation study.     

Numerical studies of unreactive contractile networks.

We present a finite difference algorithm for integrating the reactive flow model of contractile biological polymer networks on a fixed Eulerian mesh. We discuss the accuracy and limits of the algorithm. To illustrate the application of the algorithm, we carry out a family of computations involving an unreactive contractile network contained in a two-dimensional square reaction vessel. By numerical experiments using different values of the physical parameters of the model, we find that for this simple sort of system two major dynamical modes of contraction are predicted to occur. There is the squeezing type contraction in which the network contracts to a single small clump with gradual expulsion of solution material, and the rending type contraction in which the network tears itself into a number of separate pieces. We find that to a good approximation the transition between the squeezing mode and the rending mode is controlled by a single nondimensional number (the rending number). We discuss the relevance of these results for the analysis of various experimental observations.     

Polyomavirus large T mutants affected in retinoblastoma protein binding are defective in immortalization.

To clarify the relationship between the various activities of the polyomavirus large T antigen and the contribution of this oncogene to neoplastic transformation, we constructed a series of mutants with small deletions or single-amino-acid substitutions in two separate regions of the protein. These sequences were targeted because they showed considerable similarity to conserved regions 1 and 2 of adenovirus E1A which are thought to be binding sites for the retinoblastoma gene product (pRB). The pRB-binding properties of the large T mutants were assessed with an in vitro coimmunoprecipitation assay. pRB binding was readily detected with wild-type large T, but coprecipitation was completely abolished by as little as a single amino acid substitution (Asp-141----Glu or Glu-146----Asp) in region 2 of the polyomavirus large T antigen. Mutants defective in pRB binding were unable to immortalize primary rat embryo fibroblasts, suggesting that association with pRB is an important component of immortalization mediated by polyomavirus large T. The mutations in region 1 affected pRB binding only marginally, yet some of them severely impaired immortalization, indicating that pRB binding may be essential but not sufficient for immortalization.     

Chemical modification of Salmonella typhimurium phosphoribosylpyrophosphate synthetase with 5'-(p-fluorosulfonylbenzoyl)adenosine. Identification of an active site histidine

Liquid chromatographic procedures have been developed for rapidly locating the site of reaction of chemical modification reagents with Salmonella typhimurium 5-phosphoribosyl-alpha-1-pyrophosphate (PRPP) synthetase. The enzyme was reacted with the active site-directed reagent 5'-(p-fluorosulfonylbenzoyl)adenosine (FSBA). FSBA bound to the enzyme with an apparent KD of 1.7 +/- 0.4 mM. The enzyme was inactivated during the reaction, and a limiting stoichiometry of 1.2 mol of FSBA/mol of enzyme subunit corresponded to complete inactivation. Inclusion of ATP in the reaction protected the enzyme from inactivation and incorporation of the reagent. Inclusion of ribose 5-phosphate increased the rate of reaction of PRPP synthetase with FSBA. Amino acid analyses of acid hydrolysates of modified enzyme failed to detect any known FSBA-amino acid adducts. Tryptic digestion of 5'-(p-fluorosulfonylbenzoyl)-[3H]adenosine-modified enzyme at pH 7.0 yielded a single radioactive peptide. The peptide, TR-1, was subjected to combined V8 and Asp-N protease digestion, and a single radioactive peptide was isolated. This radioactive peptide yielded the sequence Asp-Leu-His-Ala-Glu, which corresponded to amino acid residues 128-132 in S. typhimurium PRPP synthetase. No radioactivity was associated with any of the phenylthiohydantoin-amino acid fractions, all of which were recovered in good yield. A majority of the radioactivity was found in the waste effluent (64%) and on the glass fiber filter loaded into the sequenator (23%). The lability of the modification and the sequence of this peptide indicate His130 as the site of reaction with FSBA.     

Monoclonal antibodies specific for adenovirus early region 1A proteins: extensive heterogeneity in early region 1A products

Hybridomas secreting monoclonal antibodies specific for the adenovirus early region 1A (E1A) proteins were prepared from BALB/c mice immunized with a bacterial trpE-E1A fusion protein. This protein is encoded by a hybrid gene that joins a portion of the Escherichia coli trpE gene and a cDNA copy of the E1A 13S mRNA (Spindler et al., J. Virol. 49:132-141, 1984). Eighty-three hybridomas that secrete antibodies which recognize the immunogen were isolated and single cell cloned. Twenty-nine of these antibodies are specific for the E1A portion of the fusion protein. Only 12 of the monoclonal antibodies can efficiently immunoprecipitate E1A polypeptides from detergent lysates of infected cells. E1A polypeptides were analyzed on one-dimensional, sodium dodecyl sulfate-polyacrylamide gels and two-dimensional, isoelectric focusing polyacrylamide gels. The E1A proteins that are specifically immunoprecipitated by the monoclonal antibodies are heterogeneous in size and charge and can be resolved into approximately 60 polypeptide species. This heterogeneity is due not only to synthesis from multiple E1A mRNAs, but also at least in part to post-translational modification. Several of the monoclonal antibodies divide the E1A polypeptides into immunological subclasses based on the ability of the antibodies to bind to the antigen. In particular, two of the monoclonal antibodies bind to the polypeptides synthesized from the 13S E1A mRNA, but not to other E1A proteins.