Disruptive mood dysregulation disorder at the age of 6 years and clinical and functional outcomes 3 years later.

BACKGROUND: Little is known about the predictive validity of disruptive mood dysregulation disorder (DMDD). This longitudinal, community-based study examined associations of DMDD at the age of 6 years with psychiatric disorders, functional impairment, peer functioning and service use at the age of 9 years. METHOD: A total of 473 children were assessed at the ages of 6 and 9 years. Child psychopathology and functional impairment were assessed at the age of 6 years with the Preschool Age Psychiatric Assessment with parents and at the age of 9 years with the Kiddie-Schedule of Affective Disorders and Schizophrenia (K-SADS) with parents and children. At the age of 9 years, mothers, fathers and youth completed the Child Depression Inventory (CDI) and the Screen for Child Anxiety Related Disorders, and teachers and K-SADS interviewers completed measures of peer functioning. Significant demographic covariates were included in all models. RESULTS: DMDD at the age of 6 years predicted a current diagnosis of DMDD at the age of 9 years. DMDD at the age of 6 years also predicted current and lifetime depressive disorder and attention-deficit/hyperactivity disorder (ADHD) at the age of 9 years, after controlling for all age 6 years psychiatric disorders. In addition, DMDD predicted depressive, ADHD and disruptive behavior disorder symptoms on the K-SADS, and maternal and paternal reports of depressive symptoms on the CDI, after controlling for the corresponding symptom scale at the age of 6 years. Last, DMDD at the age of 6 years predicted greater functional impairment, peer problems and educational support service use at the age of 9 years, after controlling for all psychiatric disorders at the age of 6 years. CONCLUSIONS: Children with DMDD are at high risk for impaired functioning across childhood, and this risk is not accounted for by co-morbid conditions.

Personality diatheses and Hurricane Sandy: effects on post-disaster depression.

BACKGROUND: According to diathesis-stress models, personality traits, such as negative emotionality (NE) and positive emotionality (PE), may moderate the effects of stressors on the development of depression. However, relatively little empirical research has directly examined whether NE and PE act as diatheses in the presence of stressful life events, and no research has examined whether they moderate the effect of disaster exposure on depressive symptoms. Hurricane Sandy, the second costliest hurricane in US history, offers a unique opportunity to address these gaps. METHOD: A total of 318 women completed measures of NE and PE 5 years prior to Hurricane Sandy. They were also assessed for lifetime depressive disorders on two occasions, the latter occurring an average of 1 year before the hurricane. Approximately 8 weeks after the disaster (mean = 8.40, s.d. = 1.48 weeks), participants completed a hurricane stress exposure questionnaire and a measure of current depressive symptoms. RESULTS: Adjusting for lifetime history of depressive disorders, higher levels of stress from Hurricane Sandy predicted elevated levels of depressive symptoms, but only in participants with high levels of NE or low levels of PE. CONCLUSIONS: These findings support the role of personality in the development of depression and suggest that personality traits can be useful in identifying those most vulnerable to major stressors, including natural disasters.

DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children.

BACKGROUND: Despite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds. METHOD: DMDD was assessed in 6-year-old children (n = 462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment. RESULTS: The 3-month prevalence rate for DMDD was 8.2% (n = 38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility. CONCLUSIONS: A number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning.

Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains.

Congenic breeding strategies are becoming increasingly important as a greater number of complex trait linkages are identified. Traditionally, the development of a congenic strain has been a time-consuming endeavour, requiring ten generations of backcrosses. The recent advent of a dense molecular genetic map of the mouse permits methods that can reduce the time needed for congenic-strain production by 18-24 months. We present a theoretical evaluation of marker-assisted congenic production and provide the empirical data that support it. We present this 'speed congenic' method in a user-friendly manner to encourage other investigators to pursue this or similar methods of congenic production.

SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein.

Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide, are important for the pathogenesis of Alzheimer's dementia. We found that transgenic mice overexpressing APP have a profound and selective impairment in endothelium-dependent regulation of the neocortical microcirculation. Such endothelial dysfunction was not found in transgenic mice expressing both APP and superoxide dismutase-1 (SOD1) or in APP transgenics in which SOD was topically applied to the cerebral cortex. These cerebrovascular effects of peptides derived from APP processing may contribute to the alterations in cerebral blood flow and to neuronal dysfunction in Alzheimer's dementia.

Genetics of prion infections.

Although the infectious prions causing scrapie and several human transmissible neurodegenerative diseases resemble viruses in many respects, molecular and genetic analyses indicate that prions are fundamentally different from viruses in their structure and the mechanisms by which they cause disease. The only macromolecule that has been identified in infectious prion preparations is a disease-specific isoform of the prion protein, which is encoded by a host gene. A growing body of data supports the contention that prion infections represent a novel host-pathogen interaction.

Genetics and polymorphism of the mouse prion gene complex: control of scrapie incubation time.

The mouse prion protein (PrP) gene (Prn-p), which encodes the only macromolecule that has been identified in scrapie prions, is tightly linked or identical to a gene (Prn-i) that controls the duration of the scrapie incubation period in mice. Constellations of restriction fragment length polymorphisms distinguish haplotypes a to f of Prn-p. The Prn-pb allele encodes a PrP that differs in sequence from those encoded by the other haplotypes and, in inbred mouse strains, correlates with long scrapie incubation time (Westaway et al., Cell 51: 651-662, 1987). In segregating crosses of mice, we identified rare individuals with a divergent scrapie incubation time phenotype and Prn-p genotype, but progeny testing to demonstrate meiotic recombination was not possible because scrapie is a lethal disease. Crosses involving the a, d, and e haplotypes demonstrated that genes unlinked to Prn-p could modulate scrapie incubation time and that there were only two alleles of Prn-i among the mouse strains tested. All inbred strains of mice that had the Prnb haplotype were probably direct descendants of the I/LnJ progenitors. We established the linkage relationship between the prion gene complex (Prn) and other chromosome 2 genes; the gene order, proximal to distal, is B2m-II-1a-Prn-Itp-A. Recombination suppression in the B2m-Prn-p interval occurred during the crosses involved in transferring the I/LnJ Prnb complex into a C57BL/6J background. Transmission ratio distortion by Prna/Prnb heterozygous males was also observed in the same crosses. These phenomena, together with the founder effect, would favor apparent linkage disequilibrium between Prn-p and Prn-i. Therefore, transmission genetics may underestimate the number of genes in Prn.

Unraveling prion diseases through molecular genetics.

Prions are transmissible pathogens that cause degenerative diseases in humans and animals. Unique attributes of prion diseases include infectious, sporadic and genetic manifestations, as well as progression to death, all in the absence of a detectable immune response. Prions are resistant to chemical procedures that modify or destroy nucleic acids and are composed largely of a protein, designated PrPSc. Molecular cloning of a cognate cDNA established a cellular host origin for PrPSc protein and a convergence with the genetics of host susceptibility. The murine PrP gene is linked to the Prn-i gene which determines incubation times in experimental scrapie. Mice with long incubation times have unusual PrP alleles encoding phenylalanine and valine at codons 108 and 189. Moreover, the ataxic form of Gerstmann-Sträussler syndrome (a rare human neurodegenerative disorder) has been defined as an autosomal dominant disorder with a PrP mis-sense mutation at codon 102 linked to the predisposition locus. These studies argue that amino acid substitutions in 'PrP' genes may modulate initiation and development of prion diseases.

On safari with PrP: prion diseases of animals.

Prions are infectious pathogens that cause fatal neurodegeneration in humans and animals and are composed largely, or entirely, of an aberrant isoform of the host-encoded prion protein (PrP). A post-translational process involving a conformational change in PrP is a significant feature of their replication. Differences in PrP sequences modify the incubation times, neuropathology and properties of prion 'strains'.

Routine chest roentgenography is unnecessary in the work-up of stage I and II breast cancer.

PURPOSE: Clinical practice guidelines of many professional societies call for routine staging chest x-rays (SCXR) for all patients with invasive cancer. Given the estimated 157,000 patients annually for whom this recommendation pertains, this screening examination represents a considerable health care expenditure. If it were shown that SCXR rarely changed the management of low-risk subsets of this population, it might be possible to selectively omit this practice from the care of these patients with substantial resultant cost savings. PATIENTS AND METHODS: All patients with clinical stage I and II breast cancer presenting to the Baystate Medical Center from 1989 through 1997 were identified through the Tumor Registry. Their hospital records were reviewed for clinical presentation and documentation of SCXR. RESULTS: One thousand four hundred ninety-four patients were identified with clinical stage I and II disease. SCXR were available for review on 1,003 patients. Only one asymptomatic patient was upstaged to stage IV based on a SCXR. Two patients with primary lung tumors were also identified. These data demonstrate an asymptomatic pulmonary metastasis detection rate of 0. 099% (95% confidence interval, 0.0% to 0.6%). The total charges of SCXR for this group approached $180,000. CONCLUSION: These data demonstrate the low diagnostic yield and high cost of routine SCXR in the management of asymptomatic patients with clinical stage I and stage II breast cancer. Because other studies have shown that SCXR changes neither quality of life nor overall survival, SCXR should be limited to symptomatic patients in whom metastatic disease is suspected.

Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel.

The novel locus Prnd is 16 kb downstream of the mouse prion protein (PrP) gene Prnp and encodes a 179 residue PrP-like protein designated doppel (Dpl). Prnd generates major transcripts of 1.7 and 2.7 kb as well as some unusual chimeric transcripts generated by intergenic splicing with Prnp. Like PrP, Dpl mRNA is expressed during embryogenesis but, in contrast to PrP, it is expressed minimally in the CNS. Unexpectedly, Dpl is upregulated in the CNS of two PrP-deficient (Prnp(0/0)) lines of mice, both of which develop late-onset ataxia, suggesting that Dpl may provoke neurodegeneration. Dpl is the first PrP-like protein to be described in mammals, and since Dpl seems to cause neurodegeneration similar to PrP, the linked expression of the Prnp and Prnd genes may play a previously unrecognized role in the pathogenesis of prion diseases or other illnesses.

Delimiting the location of the scrapie prion incubation time gene on chromosome 2 of the mouse.

Scrapie is a transmissible neurodegenerative disease caused by unusual pathogens called prions. The interval between inoculation and illness for experimental mouse scrapie is dramatically influenced by an incubation time gene (Prn-i) that is linked to Prn-p, the structural gene for prion protein (PrP). Although prion proteins from mouse strains with short and long scrapie incubation times differ by two amino acids, mice with discordant disease phenotype and Prn-p genotype occur in segregating crosses, suggesting recombination between Prn-p and a distinct incubation time locus. In addition, expression of Prn-pb transgenes from long incubation time mice shortened, rather than prolonged, incubation time. In this study, mice carrying chromosomes with meiotic crossovers near Prn-p were analyzed for scrapie incubation time phenotype. The results indicated that Prn-i (should it exist) must lie within an interval 0.67 cM proximal and 0.22 cM distal to Prn-p. The results also suggest that the cumulative effects of other genes, rather than meiotic recombination, were responsible for the putative recombinants of earlier studies. However, the effect of Prn-pb transgene expression in abbreviating scrapie incubation time was mitigated when the transgenes were transferred to mice with an endogenous long incubation time allele. Thus, Prn-pb transgenes and Prn-i may modulate scrapie pathogenesis by different mechanisms.

Some engineering aspects of insulin delivery systems.

The characteristics of electronically controlled insulin delivery systems are presented. Early experiments with an external system have shown promise in providing improved glycemic control over conventional methods of single or multiple subcutaneous insulin injections. The encouraging results with external insulin delivery systems have led to the development and early testing in dogs of an implantable system with remote controls to permit variable insulin flow rates. A number of questions remain to be answered before widespread experimentation with external and implanted insulin delivery systems is possible. There appears to be no major development problems with the engineering aspects of such systems.

Electron microscopy of insulin precipitates.

Morphologic characteristics of insulin precipitates were examined by both scanning and transmission electron microscopy. Insulin precipitate obtained after 1 wk of in vivo storage in an implanted dog reservoir was compared with insulin precipitate produced in vitro by isoelectric precipitation, acid-freeze-heat precipitation, and motion-induced precipitation. Insulin precipitate produced in vivo had several morphologic forms, with spherical-lamellar structures predominating. In vitro isoelectric precipitated insulin produced microcrystalline material, whereas acid-freeze-heat and motion-induced precipitated insulin were associated with elongated fibrils. The morphologic appearance of the in vivo precipitated insulin was not entirely reproduced by any of the three in vitro methods of insulin precipitation. We conclude that insulin precipitation in vivo is a process that may involve more than one of the known mechanisms by which insulin precipitates in vitro.

Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice.

Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.

Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes.

Dominant mutations in the Presenilin 1 gene are linked to an aggressive, early-onset form of familial Alzheimer's Disease (FAD). Spatial memory of transgenic (Tg) mice expressing either mutant (lines Tg(M146L)1, Tg(M146L)76, Tg(L286V)198) or wild type (line Tg(PS1wt)195) human PS1 transgenes was investigated in the Morris water maze (WM) test at 6 and 9 months of age. The results showed that the mutated Tg mice had increased swim speed when compared to non-Tg littermates or Tg PS1 wild type mice. The swim speed difference did not, however, significantly affect the spatial learning in the WM test and all groups showed comparable search paths during training and similar spatial bias during probe trials. When re-tested at 9 months, all mice showed significantly improved learning acquisition of spatial information. The lack of progressive spatial learning impairment in mice expressing the mutated human PS1 transgene in the WM does not preclude impairments in other cognitive tasks but suggests that full phenotypic expression of mutant PS1 alleles may require co-expression of human versions of other AD-associated genes.

Cocaine reduction in unmotivated crack users using carbamazepine versus placebo in a short-term, double-blind crossover design.

On the basis of cocaine-caused kindling in animals and the usefulness of carbamazepine in treating kindling-type seizures, carbamazepine has been tried in clinical settings with cocaine-dependent individuals. This report presents findings of a 20-day, double-blind, placebo-controlled crossover study in 32 nontreatment-motivated, paid, chronic crack cocaine users. Carbamazepine significantly lowered the mean number of positive urine specimens compared with placebo. Of clinical importance, serum carbamazepine levels of 4 micrograms/ml (17 mumol/L) or more were associated with greater improvement. A consistent, clinically important trend linked therapeutic levels with improvement for all subjective and objective outcome variables. Comparison of daily acknowledged cocaine use or professed cocaine abstinence, with cocaine use indicated by daily urinalysis in these chronic cocaine users, has suggested the possibility of cocaine saturation as an important methodologic limitation inherent in outpatient studies of cocaine use in humans.

Phenomenology of major depression from childhood through adulthood: analysis of three studies.

The frequency of depressive symptoms was compared in four psychiatrically referred populations: preschool (N = 9) and prepubertal (N = 95) children, adolescents (N = 92), and adults (N = 100). All had been systematically interviewed and diagnosed according to very similar criteria. Symptoms of depressed mood, diminished concentration, insomnia, and suicidal ideation occurred with similar frequencies across this developmental span. Anhedonia, diurnal variation, hopelessness, psychomotor retardation, and delusions increased with age; depressed appearance, low self-esteem, and somatic complaints decreased with age. The authors conclude that age modifies symptom frequency but does not alter basic phenomenology.

Seriously depressed preschoolers.

In a prospective and comprehensive evaluation (including DSM-III diagnoses) of 1,000 preschoolers in a child development unit, nine children were found to meet the criteria for major depressive disorder. The symptoms of these children are described and compared with those of a control group of children from the same sample. The diagnosis of major depressive disorder was associated with physical symptoms, including somatic complaints, and the likelihood of parental abuse or neglect.