This report prospectively examines the 4-year course, and predictors of course, of body dysmorphic disorder (BDD), a common and often severe disorder. No prior studies have prospectively examined the ...course of BDD in individuals ascertained for BDD. Method The Longitudinal Interval Follow-Up Evaluation (LIFE) assessed weekly BDD symptoms and treatment received over 4 years for 166 broadly ascertained adults and adolescents with current BDD at intake. Kaplan-Meier life tables were constructed for time to remission and relapse. Full remission was defined as minimal or no BDD symptoms, and partial remission as less than full DSM-IV criteria, for at least 8 consecutive weeks. Full relapse and partial relapse were defined as meeting full BDD criteria for at least 2 consecutive weeks after attaining full or partial remission respectively. Cox proportional hazards regression examined predictors of remission and relapse.
Over 4 years, the cumulative probability was 0.20 for full remission and 0.55 for full or partial remission from BDD. A lower likelihood of full or partial remission was predicted by more severe BDD symptoms at intake, longer lifetime duration of BDD, and being an adult. Among partially or fully remitted subjects, the cumulative probability was 0.42 for subsequent full relapse and 0.63 for subsequent full or partial relapse. More severe BDD at intake and earlier age at BDD onset predicted full or partial relapse. Eighty-eight percent of subjects received mental health treatment during the follow-up period.
In this observational study, BDD tended to be chronic. Several intake variables predicted greater chronicity of BDD.
Infections due to Aspergillus species cause significant morbidity and mortality. Most are attributed to Aspergillus fumigatus, followed by Aspergillus flavus and Aspergillus terreus. Aspergillus ...niger is a mould that is rarely reported as a cause of pneumonia. A 72-year-old female with chronic obstructive pulmonary disease and temporal arteritis being treated with steroids long term presented with haemoptysis and pleuritic chest pain. Chest radiography revealed areas of heterogeneous consolidation with cavitation in the right upper lobe of the lung. Induced bacterial sputum cultures, and acid-fast smears and cultures were negative. Fungal sputum cultures grew A. niger. The patient clinically improved on a combination therapy of empiric antibacterials and voriconazole, followed by voriconazole monotherapy. After 4 weeks of voriconazole therapy, however, repeat chest computed tomography scanning showed a significant progression of the infection and near-complete necrosis of the right upper lobe of the lung. Serum voriconazole levels were low-normal (1.0 microg ml(-1), normal range for the assay 0.5-6.0 microg ml(-1)). A. niger was again recovered from bronchoalveolar lavage specimens. A right upper lobectomy was performed, and lung tissue cultures grew A. niger. Furthermore, the lung histopathology showed acute and organizing pneumonia, fungal hyphae and oxalate crystallosis, confirming the diagnosis of invasive A. niger infection. A. niger, unlike A. fumigatus and A. flavus, is less commonly considered a cause of invasive aspergillosis (IA). The finding of calcium oxalate crystals in histopathology specimens is classic for A. niger infection and can be helpful in making a diagnosis even in the absence of conidia. Therapeutic drug monitoring may be useful in optimizing the treatment of IA given the wide variations in the oral bioavailability of voriconazole.
Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant ...DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.
DSM-IV’s classification of body dysmorphic disorder (BDD) is controversial. Whereas BDD is classified as a somatoform disorder, its delusional variant is classified as a psychotic disorder. However, ...the relationship between these BDD variants has received little investigation. In this study, we compared BDD’s delusional and nondelusional variants in 191 subjects using reliable and valid measures that assessed a variety of domains. Subjects with delusional BDD were similar to those with nondelusional BDD in terms of most variables, including most demographic features, BDD characteristics, most measures of functional impairment and quality of life, comorbidity, and family history. Delusional and nondelusional subjects also had a similar probability of remitting from BDD over 1 year of prospective follow-up. However, delusional subjects had significantly lower educational attainment, were more likely to have attempted suicide, had poorer social functioning on several measures, were more likely to have drug abuse or dependence, were less likely to currently be receiving mental health treatment, and had more severe BDD symptoms. However, when controlling for BDD symptom severity, the two groups differed only in terms of educational attainment. These findings indicate that BDD’s delusional and nondelusional forms have many more similarities than differences, although on several measures delusional subjects evidenced greater morbidity, which appeared accounted for by their more severe BDD symptoms. Thus, these findings offer some support for the hypothesis that these two BDD variants may constitute the same disorder. Additional studies are needed to examine this issue, which may have relevance for other disorders with both delusional and nondelusional variants in DSM.
The membrane-permeant oxidizing agent 2,2'-dithiodipyridine (DTDP) can induce Zn(2+) release from metalloproteins in cell-free systems. Here, we report that brief exposure to DTDP triggers apoptotic ...cell death in cultured neurons, detected by the presence of both DNA laddering and asymmetric chromatin formation. Neuronal death was blocked by increased extracellular potassium levels, by tetraethylammonium, and by the broad-spectrum cysteine protease inhibitor butoxy-carbonyl-aspartate-fluoromethylketone. N,N,N', N'-Tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and other cell-permeant metal chelators also effectively blocked DTDP-induced toxicity in neurons. Cell death, however, was not abolished by the NMDA receptor blocker MK-801, by the intracellular calcium release antagonist dantrolene, or by high concentrations of ryanodine. DTDP generated increases in fluorescence signals in cultured neurons loaded with the zinc-selective dye Newport Green. The fluorescence signals following DTDP treatment also increased in fura-2- and magfura-2-loaded neurons. These responses were completely reversed by TPEN, consistent with a DTDP-mediated increase in intracellular free Zn(2+) concentrations. Our studies suggest that under conditions of oxidative stress, Zn(2+) released from intracellular stores may contribute to the initiation of neuronal apoptosis.
Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ...ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nm rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, approximately 5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.
Objective
To investigate the risk for preterm birth associated with vaginal infections in pregnancies after a loop electrosurgical excision procedure (LEEP), compared with women with no prior LEEP.
...Design
Multicentre retrospective cohort study.
Setting
USA.
Population
Women with LEEP between 1996 and 2006 were compared with two unexposed groups who had cervical biopsy or Pap test, without any other cervical procedure, in the same calendar year.
Methods
The first pregnancy progressing beyond 20 weeks of gestation in women with prior LEEP was compared with pregnancy in women without LEEP. Stratified analysis according to the presence or the absence of vaginal infection during pregnancy was used to investigate whether the risk for preterm birth differed according to the presence or the absence of infection. The interaction between LEEP and vaginal infection was investigated using multivariable logistic regression with interaction terms, as well as the Mantel–Haenszel test for homogeneity.
Main outcome measures
Spontaneous preterm birth (<37 and <34 weeks of gestation).
Results
Of 1727 patients who met the inclusion criteria, 34.4% (n = 598) underwent LEEP prior to an index pregnancy. There was no increased risk for vaginal infections among women with LEEP compared with women without LEEP. Chlamydia infection and LEEP demonstrated significant interaction, suggesting that the presence of chlamydia infection in women with a history of LEEP augments the risk for preterm birth, compared with women with no history of LEEP.
Conclusions
Vaginal infections during pregnancy in women with a history of LEEP may be associated with an increased risk for preterm birth, compared with women with no history of LEEP.
Purpose Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related ...quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL— Quality of Life in Neurological Disorders and PROMIS— Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. Methods New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. Results Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between NeuroQoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. Conclusions HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.
We have investigated the role of mitochondrial calcium buffering in excitotoxic cell death. Glutamate acts at NMDA receptors in cultured rat forebrain neurons to increase the intracellular free ...calcium concentration. Although concurrent inhibition of mitochondrial calcium uptake substantially enhanced this cytoplasmic calcium increase, it significantly reduced glutamate-stimulated neuronal cell death. Mitochondrial inhibition did not affect nitric oxide production or MAP kinase phosphorylation, which have been proposed to mediate excitotoxicity. These results indicate that very high levels of cytoplasmic calcium are not necessarily toxic to forebrain neurons, and that potential-driven uptake of calcium into mitochondria is required to trigger NMDA-receptor-stimulated neuronal death.
To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to ...mutations in ABCA4.
Nonrandomized multicenter phase I/IIa clinical trial.
Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment.
The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography.
The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment.
Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.
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