Cardiometabolic risk prediction algorithms for young people with psychosis: a systematic review and exploratory analysis.

OBJECTIVE: Cardiometabolic risk prediction algorithms are common in clinical practice. Young people with psychosis are at high risk for developing cardiometabolic disorders. We aimed to examine whether existing cardiometabolic risk prediction algorithms are suitable for young people with psychosis. METHODS: We conducted a systematic review and narrative synthesis of studies reporting the development and validation of cardiometabolic risk prediction algorithms for general or psychiatric populations. Furthermore, we used data from 505 participants with or at risk of psychosis at age 18 years in the ALSPAC birth cohort, to explore the performance of three algorithms (QDiabetes, QRISK3 and PRIMROSE) highlighted as potentially suitable. We repeated analyses after artificially increasing participant age to the mean age of the original algorithm studies to examine the impact of age on predictive performance. RESULTS: We screened 7820 results, including 110 studies. All algorithms were developed in relatively older participants, and most were at high risk of bias. Three studies (QDiabetes, QRISK3 and PRIMROSE) featured psychiatric predictors. Age was more strongly weighted than other risk factors in each algorithm. In our exploratory analysis, calibration plots for all three algorithms implied a consistent systematic underprediction of cardiometabolic risk in the younger sample. After increasing participant age, calibration plots were markedly improved. CONCLUSION: Existing cardiometabolic risk prediction algorithms cannot be recommended for young people with or at risk of psychosis. Existing algorithms may underpredict risk in young people, even in the face of other high-risk features. Recalibration of existing algorithms or a new tailored algorithm for the population is required.

The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition.

Snail family genes encode DNA binding zinc finger proteins that act as transcriptional repressors. Mouse embryos deficient for the Snail (Sna) gene exhibit defects in the formation of the mesoderm germ layer. In Sna(-/-) mutant embryos, a mesoderm layer forms and mesodermal marker genes are induced but the mutant mesoderm is morphologically abnormal. Lacunae form within the mesoderm layer of the mutant embryos, and cells lining these lacunae retain epithelial characteristics. These cells resemble a columnar epithelium and have apical-basal polarity, with microvilli along the apical surface and intercellular electron-dense adhesive junctions that resemble adherens junctions. E-cadherin expression is retained in the mesoderm of the Sna(-/-) embryos. These defects are strikingly similar to the gastrulation defects observed in snail-deficient Drosophila embryos, suggesting that the mechanism of repression of E-cadherin transcription by Snail family proteins may have been present in the metazoan ancestor of the arthropod and mammalian lineages.

Acute chest syndrome after abdominal surgery in children with sickle cell disease: Is a laparoscopic approach better?

BACKGROUND/PURPOSE: Acute chest syndrome (ACS) is the leading cause of hospitalization and death among patients with sickle cell disease (SCD). Surgery is a risk factor for the development of ACS. It has been suggested that laparoscopic surgery could diminish the risk of sickle-related complications; therefore, more procedures may be encouraged in asymptomatic patients. The goal of the authors was to determine the incidence of postoperative ACS and assess for predisposing factors in all sickle cell patients undergoing abdominal surgery. METHODS: A retrospective analysis of all sickle cell patients receiving abdominal surgery (open and laparoscopic) between 1994 and 1998 was conducted. Data pertaining to demographics, perioperative clinical status, postoperative care, and outcome were collected and analyzed using Student's t test or chi(2) where appropriate. RESULTS: Fifty-four children underwent 62 procedures (35 abdominal and 27 extracavitary). All abdominal cases were either cholecystectomy or splenectomy (22 laparoscopic and 13 open). ACS occurred in 7 of 62 (11.3%) overall, and all were in abdominal cases 7 of 35 (20%). ACS occurred in 5 of 22 (22.7%) laparoscopic cases and 2 of 13 (15.4%) open cases. Operating time was significantly longer in the laparoscopic group compared with open cases (P <.05). A higher percentage of patients who had ACS had at least 1 previous episode (71.4% v 39.3%; P value not significant) and a smaller percentage of ACS patients received a preoperative blood transfusion (14.3% v 32.1%; P value not significant). Postoperative hospitalization was prolonged if ACS occurred (9 +/- 2 v 3 +/- 2 days; P <.05). CONCLUSIONS: Abdominal surgery carries a significantly high risk (20%) of ACS. Laparoscopy does not decrease the incidence of ACS compared with open approach. Predisposing factors were not significant in predicting postoperative ACS. There is considerable morbidity and potential cost implications in patients with ACS.

Location of mouse and human genes corresponding to conserved canine olfactory receptor gene subfamilies.

Olfactory receptors are G protein-coupled, seven-transmembrane-domain proteins that are responsible for binding odorants in the nasal epithelium. They are encoded by a large gene family, members of which are organized in several clusters scattered throughout the genomes of mammalian species. Here we describe the mapping of mouse sequences corresponding to four conserved olfactory receptor genes, each representing separate, recently identified canine gene subfamilies. Three of the four canine genes detected related gene clusters in regions of mouse Chromosomes (Chrs) 2, 9, and 10, near previously mapped mouse olfactory genes, while one detected a formerly unidentified gene cluster located on mouse Chr 6. In addition, we have localized two human gene clusters with homology to the canine gene, CfOLF4, within the established physical map of Chr 19p. Combined with recently published studies, these data link the four conserved olfactory gene subfamilies to homologous regions of the human, dog, and mouse genomes.

Photon scanning-tunneling microscopy of unstained Mammalian cells and chromosomes.

The photon scanning-tunneling microscope (PSTM) yields optical topographical images of samples that are thin or that are transparent at the wavelength used. A range of sample sizes can be imaged extending to well below the diffraction limit for sufficiently flat samples. But samples of the order of several to many micrometers in size can be analyzed with less-refined resolution if total internal reflection can be made to occur in the sample. We used the PSTM to examine the optical topography of mouse and human cells and of chromosomes that are unstained. Our objectives were to demonstrate the images as an alternative to conventional microscopy and to provide a sample-preparation methodology that will later permit localized, simultaneous fluorescence or absorption spectroscopy with the signals collected by the probe tip. Furthermore, the PSTM's ability to produce optical profiles in air and in water was tested to establish the basis for future investigation of possible abnormalities in the chromosomes. That is, we considered both physical and biological objectives. To this end we utilized the 442-nm line of a He-Cd laser as well as the 633-nm line from a He-Ne laser, the resulting image quality being tested partly to ascertain the increased effects of scattering at the smaller wavelength. It is shown that adequate resolution and signal-to-noise ratio can be obtained with the shorter wavelength even in the presence of intensity fluctuations from the laser, thus showing that fluorescence and absorption studies can be expected to be practicable.

Induced mouse chromosomal rearrangements as tools for identifying critical developmental genes and pathways.

Due to the rapid advances that have been made in molecular and genetic technology during the past decade, the genes associated with a large number of human hereditary diseases have been isolated and analyzed in detail. These cloned genes provide new tools for research geared toward a better understanding of normal human development, and also of the many ways that basic, essential morphologic pathways can be disturbed. Chromosomal rearrangements, especially deletions and translocations, have been especially beneficial in the mapping and isolation of human disease genes because of their visibility on both the cytogenetic and molecular levels. However, these useful types of mutations occur with low frequency in the human population. Chromosomal rearrangements can be induced relatively easily in mice, and several large, independent collections of translocation and deletion mutants have been generated in the course of risk-assessment and mutagenesis studies over the past several decades. Combined with new molecular technologies, these collections of mutant animals provide a means of gaining ready access to genes associated with developmental defects including craniofacial abnormalities, hydrocephaly, skeletal deformities, and complex neurologic disorders. As an illustration of this approach, we briefly review our progress in the study of three mutations associated with defects in palate development, juvenile growth, fitness and sterility, and neurologic development in mice, respectively.

Generation and characterization of heritable reciprocal translocations in mice.

Reciprocal translocations have provided crucial tools for the localization of genes associated with a variety of human cancers and hereditary diseases. Although heritable translocations are relatively rare in humans, they can be easily induced in mice through exposure of male germ cells at specific spermatogenic stages to different types of radiation and chemicals. Mutagenesis schemes that produce translocations at high frequencies in the progeny of treated males are summarized, and the use of these valuable mutations for analyzing developmental consequences of partial aneuploidy, for identification of mutant genes, and for other purposes is reviewed. Preliminary studies of a large collection of translocation mutants, including several stocks that display dominantly or recessively inherited phenotypes caused by the disruption of critical genes are described. These combined studies demonstrate that several mutagenesis protocols can be used to generate easily mapped, novel mouse mutations with high efficiency and highlight the unique value of reciprocal translocations as tools for gaining access to the biological functions of mammalian genes.

Zooming in on the human-mouse comparative map: genome conservation re-examined on a high-resolution scale.

Over the past decade, conservation of genetic linkage groups has been shown in mammals and used to great advantage, fueling significant exchanges of gene mapping and functional information especially between the genomes of humans and mice. As human physical maps increase in resolution from chromosome bands to nucleotide sequence, comparative alignments of mouse and human regions have revealed striking similarities and surprising differences between the genomes of these two best-mapped mammalian species. Whereas, at present, very few mouse and human regions have been compared on the physical level, existing studies provide intriguing insights to genome evolution, including the observation of recent duplications and deletions of genes that may play significant roles in defining some of the biological differences between the two species. Although high-resolution conserved marker-based maps are currently available only for human and mouse, a variety of new methods and resources are speeding the development of comparative maps of additional organisms. These advances mark the first step toward establishment of the human genome as a reference map for vertebrate species, providing evolutionary and functional annotation to human sequence and vast new resources for genetic analysis of a variety of commercially, medically, and ecologically important animal models.

Detailed comparative map of human chromosome 19q and related regions of the mouse genome.

One of the larger contiguous blocks of mouse-human genomic homology includes the proximal portion of mouse chromosome 7 and the long arm of human chromosome 19. Previous studies have demonstrated the close relationship between the two regions, but have also indicated significant rearrangements in the relative orders of homologous mouse and human genes. Here we present the genetic locations of the homologs of 42 human chromosome 19q markers in the mouse, with an emphasis on genes also included in the human chromosome 19 physical map. Our results demonstrate that despite an overall inversion of sequences relative to the centromere, apparent "transpositions" of three gene-rich segments, and a local inversion of markers mapping near the 19q telomere, gene content, order, and spacing are remarkably well conserved throughout the lengths of these related mouse and human regions. Although most human 19q markers have remained genetically linked in mouse, one small human segment forms a separate region of homology between human chromosome 19q and mouse chromosome 17. Three of the four rearrangements of mouse versus human 19q sequences involve segments that are located directly adjacent to each other in 19q13.3-q13.4, suggesting either the coincident occurrence of these events or their common association with unstable DNA sequences. These data permit an unusually in-depth examination of this large region of mouse-human genomic homology and provide an important new tool to aid in the mapping of genes and associated phenotypes in both species.

Dopamine receptors mediate cocaine-induced temperature responses in spontaneously hypertensive and Wistar-Kyoto rats.

The involvement of dopaminergic receptors in the responses of conscious, restrained spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats to cocaine was examined using antagonists selective for DA-1 (SCH 23390) or DA-2 (sulpiride) dopamine receptors. Following pretreatment with saline vehicle, SCH 23390 (50 mg/kg, SC), sulpiride (50 mg/kg, IP) or SCH 23390 and sulpiride, cocaine was infused (1.25 mg/kg.min, IV) until death. Cocaine caused an initial pressor and tachycardiac response, which was followed by a progressively developing secondary pressor response. Combined (DA-1 and DA-2) antagonist pretreatment abolished the initial tachycardic response to cocaine. Rectal temperature during cocaine infusion increased in 38.5% of vehicle-treated SHR (designated SHRH), but decreased in the remaining SHR (SHRL) and all vehicle-treated WKY. The time-to-onset of cocaine-induced convulsions (Tc) was reduced in vehicle-treated SHRH compared to vehicle-treated SHRL and WKY. Sulpiride elevated rectal temperature in response to cocaine in SHR and WKY but reduced Tc only in SHR. SCH 23390 abolished hyperthermic responses to cocaine in SHR without altering toxicity in SHR or WKY. Combined pretreatment virtually abolished temperature responses to cocaine in SHR and WKY, but increased the Tc only in WKY. Dopamine receptors, particularly the DA-1 subtype, are involved in cocaine-induced hyperthermia.