A pragmatic factorial randomized controlled trial of transdiagnostic internet-delivered cognitive behavioural therapy: Exploring benefits of homework reflection questionnaires and twice-weekly therapist support.

With the growing demand for internet-delivered cognitive behavioural therapy (iCBT), this pragmatic factorial (2 × 2 × 2) randomized controlled trial evaluated strategies for facilitating iCBT engagement and outcomes in routine care. Specifically, the benefits to patients and therapists of using homework reflection questionnaires and offering patients twice-weekly therapist support were examined. Patients (n = 632) accepted into iCBT for depression and/or anxiety were randomly assigned to complete homework reflection questionnaires or not (factor 1), receive once- or twice-weekly support (factor 2), and to receive care from therapists employed in one of two settings (iCBT clinic or a community mental health clinic; factor 3). Outcomes were measured at pre-treatment, and 8, 12, and 24-weeks post-enrollment. Therapist time was tracked and a focus group was conducted to examine therapist experiences. No differences in patient outcomes were found between therapists employed in the two settings; as such, these two groups were combined for further analyses. In terms of engagement, homework reflection questionnaires were associated with fewer website log-ins and days accessing iCBT; twice-weekly support was associated with more patient emails sent to therapists. Despite engagement differences, homework reflection questionnaires and twice-weekly support did not significantly impact primary outcomes; all groups showed large improvements in depression and anxiety that were maintained at 24-week follow-up. Therapists perceived a number of benefits and challenges associated with responding to homework reflection questionnaires and offering twice-weekly support; most notably the strategies did not benefit all patients. Twice-weekly support was associated with increased therapist time and organizational challenges. It is concluded that neither completion of homework questionnaires nor offering twice-weekly support significantly improve iCBT in routine care.

Screening questionnaires for substance abuse post brain injury: a review.

OBJECTIVE: To assess the psychometric properties of the available assessment questionnaires for substance abuse studied within a brain injury population. METHODS: A literature search was conducted on MEDLINE, PsycINFO, CINAHL, and Embase databases. Articles published in English from inception through March 2018 on the screening questionnaires used to identify substance abuse post brain injury were reviewed. Eligible primary studies had to include: adults (participants ≥18 years old) post brain injury; and report measures of diagnostic accuracy (e.g., sensitivity, specificity, and diagnostic odds ratio). RESULTS: Six screening questionnaires were included: Alcohol Use Disorders Identification Test, Brief Michigan Alcohol Screening Test, CAGE, Drug Abuse Screening Test, Substance Abuse Screening Inventory and the Short Michigan Alcohol Screening Test (SMAST). All questionnaires, except the SMAST, used the Diagnostic and Statistical Manual of Mental Disorders as the criterion measure. While report measures of diagnostic accuracy were reported and summarized, none of the studies provided reliability information or subgroup analysis among those with brain injury. CONCLUSIONS: Concerns of social desirability, population demographics, responsiveness to treatment effects, and administrative burden are important when selecting a questionnaire. Research examining the reliability of substance abuse screening questionnaires in the brain injury population is lacking and future research is warranted.

Sustained Early Disruption of Mitochondrial Function Contributes to Arsenic-Induced Prostate Tumorigenesis.

Arsenic is a well-known human carcinogen that affects millions of people worldwide, but the underlying mechanisms of carcinogenesis are unclear. Several epidemiological studies have suggested increased prostate cancer incidence and mortality due to exposure to arsenic. Due to lack of an animal model of arsenic-induced carcinogenesis, we used a prostate epithelial cell culture model to identify a role for mitochondria in arsenic-induced prostate cancer. Mitochondrial morphology and membrane potential was impacted within a few hours of arsenic exposure of non-neoplastic prostate epithelial cells. Chronic arsenic treatment induced mutations in mitochondrial genes and altered mitochondrial functions. Human non-neoplastic prostate epithelial cells continuously cultured for seven months in the presence of 5 µM arsenite showed tumorigenic properties in vitro and induced tumors in SCID mice, which indicated transformation of these cells. Protein and mRNA expression of subunits of mtOXPHOS complex I were decreased in arsenic-transformed cells. Alterations in complex I, a main site for reactive oxygen species (ROS) production as well as increased expression of ROS-producing NOX4 in arsenic-transformed cells suggested a role of oxidative stress in tumorigenic transformation of prostate epithelial cells. Whole genome cGH array analyses of arsenic-transformed prostate cells identified extensive genomic instability. Our study revealed mitochondrial dysfunction induced oxidative stress and decreased expression of p53 in arsenic-transformed cells as an underlying mechanism of the mitochondrial and nuclear genomic instability. These studies suggest that early changes in mitochondrial functions are sustained during prolong arsenic exposure. Overall, our study provides evidence that arsenic disruption of mitochondrial function is an early and key step in tumorigenic transformation of prostate epithelial cells.

Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase.

Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-ß (TGF-ß) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-ß through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-ß. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-ß to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis.

Cognitive components of simulated driving performance: Sleep loss effects and predictors.

Driving is a complex task, which can be broken down into specific cognitive processes. In order to determine which components contribute to drowsy driving impairments, the current study examined simulated driving and neurocognitive performance after one night of sleep deprivation. Nineteen professional drivers (age 45.3±9.1) underwent two experimental sessions in randomised order: one after normal sleep and one after 27h total sleep deprivation. A simulated driving task (AusEd), the psychomotor vigilance test (PVT), and neurocognitive tasks selected from the Cognitive Drug Research computerised neurocognitive assessment battery (simple and choice RT, Stroop Task, Digit Symbol Substitution Task, and Digit Vigilance Task) were administered at 10:00h in both sessions. Mixed-effects ANOVAs were performed to examine the effect of sleep deprivation versus normal sleep on performance measures. To determine if any neurocognitive tests predicted driving performance (lane position variability, speed variability, braking RT), neurocognitive measures that were significantly affected by sleep deprivation were then added as a covariate to the ANOVAs for driving performance. Simulated driving performance and neurocognitive measures of vigilance and reaction time were impaired after sleep deprivation (p<0.05), whereas tasks examining processing speed and executive functioning were not significantly affected by sleep loss. PVT performance significantly predicted specific aspects of simulated driving performance. Thus, psychomotor vigilance impairment may be a key cognitive component of driving impairment when sleep deprived. The generalisability of this finding to real-world driving remains to be investigated.

Construction of a river buffalo (Bubalus bubalis) whole-genome radiation hybrid panel and preliminary RH mapping of chromosomes 3 and 10.

The buffalo (Bubalus bubalis) is a source of milk and meat, and also serves as a draft animal. In this study, a 5000-rad whole-genome radiation hybrid (RH) panel for river buffalo was constructed and used to build preliminary RH maps for BBU3 and BBU10 chromosomes. The preliminary maps contain 66 markers, including coding genes, cattle expressed sequence tags (ESTs) and microsatellite loci. The RH maps presented here are the starting point for mapping additional loci that will allow detailed comparative maps between buffalo, cattle and other species whose genomes may be mapped in the future. A large quantity of DNA has been prepared from the cell lines forming the river buffalo RH panel and will be made publicly available to the international community both for the study of chromosome evolution and for the improvement of traits important to the role of buffalo in animal agriculture.

Optimization of emergency department management of infants with bronchiolitis.

Bronchiolitis is the most common lower respiratory tract infection in infants < 2 years of age; in the last decades both incidence and hospitalization rate had increased, thus increasing sanitary burden. From November 2006 to March 2007, an experimental protocol was followed in the Emergency Department at G. Gaslini Children's Hospital, Genoa, Italy, which attempted to optimise the management of patients with bronchiolitis and to reduce the overall hospitalization rate therefore admitting only those patients with severe illness. All clinical evaluations of the patients were obtained administering a score (Bronchiolitis Clinical Score - BCS), to quantify both initial severity of illness and response to treatment. All patient were at first treated with inhaled epinephrine, supplemented with or substituted by other drugs, if needed, according to clinical evolution. Moreover, strict admission and discharge criteria were defined, taking into consideration the BCS, response to treatment and the presence of risk factors for severe disease, attempting to increase the role of the Short Stay Unit (SSU). The outcome evaluated were the percentage of patients discharged, admitted and managed through the SSU respectively, the length of stay and the readmission rate after discharge; data collected were then compared to that regarding patients with bronchiolitis presented at the ED from November 2005 to March 2006. Our data showed an increasing of both discharged patients (37.5% vs 25.22%) and patients managed through the SSU (25.83% vs 19.57%) and a related decrease of hospitalization (36.67% vs 55.22%); no significative difference was observed regarding the readmission rate between the two populations. We also observed a statistically significant reduction of the length of stay in the study population (2.07 +/- 2.56 vs 2.84 +/- 3.25, p = 0.005). In conclusion, the protocol proposed showed to be useful in optimizing the ED management of the patient with bronchiolitis, being able to safely reduce both admission rate and lenght of stay.

New instrumentation for automated tinnitus psychoacoustic assessment.

CONCLUSION: Although tinnitus is a major health problem, techniques to quantify its perceptual aspects are not standardized. This study represents a key step in our efforts to develop clinical methodology to accurately and reliably quantify the sensation of tinnitus, using a uniform method for obtaining a battery of tinnitus measures. OBJECTIVES: The purpose of this study was to evaluate the performance of the automated system, which was redesigned to reduce time of testing and to add new testing capabilities. The primary difference in function was the use of a 'knob' device that enabled patient control of auditory stimuli. The new tests included assessment of minimum masking level (MML) and residual inhibition (RI). MATERIALS AND METHODS: As with previous iterations of the system, a computer program ran all testing and subjects read instructions and provided responses via a computer touch-screen. Three separate studies were conducted. Study 1 evaluated within- and between-session test-retest response reliability of tinnitus loudness matches (LMs) and pitch matches (PMs). Study 2 was conducted to evaluate differences in LMs and PMs between subjects with and without tinnitus - to obtain pilot data to assist in the development of a test for 'tinnitus malingering.' Study 3 evaluated the system's capability of obtaining MMLs and RI as well as the between-session reliability of these measures. RESULTS: Study 1 documented that the new system could obtain LMs and PMs within approximately 20 min, while maintaining clinically acceptable reliability. Study 2 revealed characteristic differences in LM and PM test results for individuals who did not experience tinnitus. Study 3 documented the system's ability to obtain measures of MML and RI that were reliable across sessions.

Synthesis of nodulisporic acid 2' '-oxazoles and 2' '-thiazoles.

[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

Silver cluster interferences in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of nonpolar polymers.

Potential difficulties associated with background silver salt clusters during matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of nonpolar polymers are reported. Silver salt cluster ions were observed from m/z 1500 to 7000 when acidic, polar matrices, such as 2,5-dihydroxybenzoic acid (DHB), all-trans-retinoic acid (RTA) or 2-(4-hydroxyphenylazo)benzoic acid (HABA), were used for the analysis of nonpolar polymers. These background signals could be greatly reduced or eliminated by the use of nonpolar matrices such as anthracene or pyrene. Representative examples of these background interferences are demonstrated during the analysis of low molecular weight nonpolar polymers including polybutadiene and polystyrene. Nonpolar polymers analyzed with acidic, polar matrices (e.g., RTA) and silver cationization reagents can yield lower quality mass spectral results when interferences due to silver clusters are present. Replacing the polar matrices with nonpolar matrices or the silver salts with copper salts substantially improved the quality of the analytical results. In addition, it was found that silver contamination cannot be completely removed from standard stainless steel sample plates, although the presence of silver contamination was greatly reduced after thorough cleaning of the sample plate with aluminum oxide grit. Carry-over silver may cationize polymer samples and complicate the interpretation of data obtained using nonpolar matrices in the absence of added cationization reagents.

Collagen membrane resorption in dogs: a comparative study.

Guided tissue barriers using materials such as collagen are used in the hope of excluding epithelium and the gingival corium from the root surface or alveolar bone to facilitate regeneration. Convention suggests that the longer a membrane remains intact, the better the regeneration results. The purpose of this study was to determine the resorption rates of various collagen membranes in the oral cavity of dogs. Twelve adult mongrel dogs had three different collagen membranes (BioGide, AlloDerm porcine-derived, and AlloDerm human-derived) randomly inserted and secured into surgical pouches made in their palates. Full-thickness tissue punch biopsy specimens taken at 1, 2, 3, or 4 months after surgery were evaluated histologically for membrane intactness and other associated changes. At 1 month, all membranes had slight to moderate degradation. At 2 months, all membranes had moderate to severe degradation with the exception of one AlloDerm human-derived membrane that was intact. At 3 months, all membranes had severe degradation to not identifiable. At 4 months, all membranes had severe degradation to completely absent. Blood vessel penetration varied from none to moderate. Inflammation was found in only two samples. In the dog, all three tested collagen membranes showed slight to moderate degradation at 1 month and were severely degraded to completely absent at 4 months. Within the limits of transferring animal data to humans, clinicians need to be aware of these resorption rates when selecting membranes for guided tissue and bone regeneration.

Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors.

Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location.

Modifications of the topical Japanese medaka (Oryzias latipes) embryo larval assay for assessing developmental toxicity of pentachlorophenol and p, p'-dichlorodiphenyltrichloroethane.

One method currently available for investigating developmental toxicity in teleost species is the Japanese medaka embryo larval assay (MELA). In the present study, the MELA was modified to evaluate repeated topical exposures to pentachlorophenol (PCP) and p, p'-dichlorodiphenyltrichloroethane (DDT) and to identify sensitive stages of embryonic development. A single topical exposure using embryos at 48 h postfertilization resulted in a statistically significant increase in embryo mortality at 688 and 1250 ng PCP/egg compared with controls. In contrast, the toxicity following exposure to 11, 36, 78, 120, 208, and 400 ng DDT/egg was expressed only in larvae after hatching. Results further demonstrate that the MELA can be optimized to accommodate repeated daily topical exposures starting at 48 h postfertilization and ending at 120 h postfertilization. In addition, the neurula stage (24 h postfertilization) represented the most sensitive embryonic stage following a single topical exposure of PCP. However, no differences were observed in the sensitivity of embryonic stages following DDT exposure. The modified MELA was also used to evaluate sediment extracts contaminated with DDT metabolites obtained from the Tensas River, Louisiana. Results indicate that there is a low potential for developmental toxicity using the present extraction and exposure scenario even though elevated levels of DDE and toxaphene currently exist in several adult fish species at this site. The MELA as a screen for evaluating the potential for developmental toxicity of contaminated sediments is discussed.

Vacuum-assisted stereotactic breast biopsy: histologic underestimation of malignant lesions.

HYPOTHESIS: The histopathologic correlation between stereotactic core needle biopsy and subsequent surgical excision of mammographically detected nonpalpable breast abnormalities is improved with a larger-core (11-gauge) device. DESIGN: Retrospective medical record and histopathologic review. SETTING: University-based academic practice setting. PATIENTS: Two hundred one patients who underwent surgical excision of mammographic abnormalities that had undergone biopsy with an 11-gauge vacuum-assisted stereotactic core biopsy device. MAIN OUTCOME MEASURE: Correlation between stereotactic biopsy histologic results and the histologic results of subsequent surgical specimens. RESULTS: Results of stereotactic biopsy performed on 851 patients revealed atypical hyperplasia in 46 lesions, ductal carcinoma in situ (DCIS) in 89 lesions, and invasive cancer in 73 mammographic abnormalities. Subsequent surgical excision of the 46 atypical lesions revealed 2 cases of DCIS (4.3%) and 4 cases of invasive carcinoma (8.7%). Lesions diagnosed as DCIS on stereotactic biopsy proved to be invasive carcinoma in 10 (11.2%) of 89 patients on subsequent excision. Stereotactic biopsy completely removed 21 (23.6%) of 89 DCIS lesions and 20 (27.4%) of 73 invasive carcinomas. CONCLUSIONS: In summary, 11-gauge vacuum-assisted core breast biopsy accurately predicts the degree of disease in the majority of malignant lesions; however, understaging still occurs in 11% to 13% of lesions showing atypical hyperplasia or DCIS.

Vestibular dysfunction in Gulf War syndrome.

METHODS: Vestibular complaints of Gulf War veterans were characterized by a nested case-control study of 23 veterans with 3 different Gulf War syndromes and 20 matched control subjects. All subjects completed a standardized symptom questionnaire and underwent standard audiovestibular tests administered by audiologists blinded to group identities. RESULTS: The prevalence of reported dizzy spells was higher in veterans with Gulf War syndromes 1 (100%), 2 (85%), and 3 (100%) than in controls (25%, P < 0.0001). Dizzy spells were more frequent, lasted longer, and involved a wider variety of accompanying symptoms in veterans with syndrome 2 than in those with syndromes 1 and 3. Audiovestibular testing showed greater interocular asymmetry of nystagmic velocity on sinusoidal harmonic acceleration in syndromes 1 (P = 0.015) and 2 (P = 0.002), greater asymmetry of saccadic velocity in syndrome 2 (P = 0.4), diminished nystagmic velocity after caloric stimulation bilaterally in syndrome 3 (P = 0.02 to 0.04), more subjects with pathologic nystagmus (P = 0. 09), and greater interside asymmetry of wave I to III interpeak latency on auditory brain stem response in syndromes 1 (P = 0.005) and 2 (P = 0.07). Asymmetry of gain on sinusoidal harmonic acceleration and pathologic nystagmus were most strongly associated with symptoms of paroxysmal vertigo (P = 0.002 and 0.07, respectively); asymmetry of saccadic velocity, with the severity of vertigo (P = 0.004); and abnormal caloric response, with chronic dysequilibrium (P = 0.006). CONCLUSIONS: The findings are compatible with a subtle neurologic injury from organophosphate-induced delayed neurotoxicity.

Insights into the functions of BRCA1 and BRCA2.

Since BRCA1 and BRCA2 were cloned five years ago, unraveling their normal functions has posed fascinating problems for cancer biologists. Both genes are novel, and little of their normal function was revealed by their sequence. Both genes contribute to homologous recombination and DNA repair, to embryonic proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination. But questions regarding BRCA1 and BRCA2 biology remain, and their resolution is critical for clinical development. Why do ubiquitously expressed genes that participate in universal pathways lead, when mutant, specifically to breast and ovarian cancer? Why are the same genes required for embryonic proliferation and for tumor suppression?