A naturalistic longitudinal study of extended inpatient treatment for adults with borderline personality disorder: An examination of treatment response, remission and deterioration

BACKGROUND: Experts express reluctance to hospitalize patients with borderline personality disorder (BPD) for more than a few days, arguing that extended inpatient care leads to deterioration and adverse events. To date, there is no empirical support for these assertions. AIMS: The current study examined the assumption of iatrogenic effects among BPD adults. Methods: Clinically significant and reliable change in symptoms, functional capacities, and adverse events were quantified for both inpatients with BPD (n=245) and a well-matched inpatient reference (n=220) sample. Latent growth curve (LGC) models were used to evaluate moderators of the trajectory of PHQ-9 depression scores over the course of hospitalization. RESULTS: Large effect size improvements were observed in depression, anxiety, suicidal ideation and functional disability among patients with BPD (Cohen’s d ≥ 1.0) and those in the reference sample (Cohen’s d ≥.80). Clinical deterioration and adverse events were rare (occurring in no more than 1.1% of BPD and reference patients on any outcome) with no difference across patient cohorts. BPD diagnosis failed to influence the trajectory of continuous depression severity. Rather, trait emotion dysregulation was associated with initial depression severity. CONCLUSIONS: Twenty-five years ago it was assumed that adults with BPD could not benefit from psychiatric treatment. Today there are a number of effective evidence-based outpatient treatments for BPD, but beliefs about extended inpatient treatment have changed little. Current results indicate that extended inpatient treatment can result in significant and clinically meaningful symptomatic and functional improvement in BPD patients without iatrogenic effects

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Mutations in maltose-binding protein that alter affinity and solubility properties

Maltose-binding protein (MBP) from Escherichia coli has been shown to be a good substrate for protein engineering leading to altered binding (Marvin and Hellinga, Proc Natl Acad Sci U S A 98:4955–4960, 2001a) and increased affinity (Marvin and Hellinga, Nat Struct Biol 8:795–798, 2001b; Telmer and Shilton, J Biol Chem 278:34555–34567, 2003). It is also used in recombinant protein expression as both an affinity tag and a solubility tag. We isolated mutations in MBP that enhance binding to maltodextrins 1.3 to 15-fold, using random mutagenesis followed by screening for enhanced yield in a microplate-based affinity purification. We tested the mutations for their ability to enhance the yield of a fusion protein that binds poorly to immobilized amylose and their ability to enhance the solubility of one or more aggregation-prone recombinant proteins. We also measured dissociation constants of the mutant MBPs that retain the solubility-enhancing properties of MBP and combined two of the mutations to produce an MBP with a dissociation constant 10-fold tighter than wild-type MBP. Some of the mutations we obtained can be rationalized based on the previous work, while others indicate new ways in which the function of MBP can be modified

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Advancing specificity in delirium: The delirium subtyping initiative

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning

Computational Analysis of Constraints on Noncoding Regions, Coding Regions and Gene Expression in Relation to Plasmodium Phenotypic Diversity

Malaria-causing Plasmodium species exhibit marked differences including host choice and preference for invading particular cell types. The genetic bases of phenotypic differences between parasites can be understood, in part, by investigating constraints on gene expression and genic sequences, both coding and regulatory.We investigated the evolutionary constraints on sequence and expression of parasitic genes by applying comparative genomics approaches to 6 Plasmodium genomes and 2 genome-wide expression studies. We found that the coding regions of Plasmodium transcription factor and sexual development genes are relatively less constrained, as are those of genes encoding CCCH zinc fingers and invasion proteins, which all play important roles in these parasites. Transcription factors and genes with stage-restricted expression have conserved upstream regions and so do several gene classes critical to the parasite's lifestyle, namely, ion transport, invasion, chromatin assembly and CCCH zinc fingers. Additionally, a cross-species comparison of expression patterns revealed that Plasmodium-specific genes exhibit significant expression divergence.Overall, constraints on Plasmodium's protein coding regions confirm observations from other eukaryotes in that transcription factors are under relatively lower constraint. Proteins relevant to the parasite's unique lifestyle also have lower constraint on their coding regions. Greater conservation between Plasmodium species in terms of promoter motifs suggests tight regulatory control of lifestyle genes. However, an interspecies divergence in expression patterns of these genes suggests that either expression is controlled via genomic or epigenomic features not encoded in the proximal promoter sequence, or alternatively, the combinatorial interactions between motifs confer species-specific expression patterns

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression

Choledochocele: an unusual form of choledochal cyst

Choledochocele, or type III choledochal cyst, is a rare anomaly. Two children with choledochocele, both younger than any previously reported patient, were recently cared for at the University of Michigan Medical Center and prompted a literature review of this subject. Since 1974, 40 cases of choledochocele have been reported with enough clinical information for critical review. Ten of these patients were 21 years of age or younger. Presenting symptoms were not specific for choledochocele; they were generally interpreted to result from other biliary or gastrointestinal disorders that are more common for each age group. In pediatric patients the most frequent signs and symptoms of choledochocele were abdominal pain (70%), nausea and/or vomiting (60%), jaundice (30%), and acute pancreatitis (30%). While two-thirds of adult patients with choledochocele had undergone prior cholecystectomy (with stones rarely found), this was observed only once in children. Obstructive symptoms led to evaluation of the stomach and duodenum with either barium upper GI series or endoscopy in all children. These demonstrated an extrinsic mass effect in 90% of the patients. Endoscopic retrograde cholangiopancreatography identified a choledochocele in all cases in which the study was successfully executed. Intravenous cholangiography was sensitive in children, but less so in the adult patients reviewed. Other imaging efforts (computerized tomography, ultrasound, radionuclide scanning) were less dependable. Transduodenal marsupialization is the treatment of choice for patients of all ages and was provided in both of these newly reported children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47183/1/383_2004_Article_BF00179633.pd