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.

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.

Genomic views of human history.

New tools of genomic analysis shed light on historical puzzles. Migrations of ancient peoples, differences in migration patterns of males and females, historical demography of cultures with ancient roots, and patterns of human genetic diversity are increasingly the focus of integrated analysis by historians, anthropologists, and geneticists.

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?

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.

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.

Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

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.

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.

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.

New cryoprotectant for cryorefractive surgery.

Cryorefractive surgeries, keratomileusis, keratophakia, and epikeratophakia cause destruction of keratocytes, which may result in postoperative corneal haze. We examined the effects of two cryoprotectants on keratocyte survival following freeze injury. We compared the ability of CPTES and the standard cryoprotectant KM-26 to prevent keratocyte death by altering the length of time corneal tissue was exposed to the cryoprotectant. When corneal stroma was immersed in CPTES for five minutes prior to freezing, 66.5% of the keratocytes survived; when tissue was immersed in KM-26 for the same length of time, 27.5% survived (P less than .01). Immersion for one to 30 minutes in CPTES prior to freezing produced keratocyte viabilities that were 40% to 80% of those of fresh, unfrozen tissue; immersion in KM-26 produced keratocyte viabilities of 20% to 60%. We compared the ability of these cryoprotectants to reduce corneal haze following freeze injury using our rabbit model of lamellar keratoplasty. The postoperative data were comparable to those in the cell culture experiments. Based on our findings in rabbit corneas, a cryoprotective medium such as CPTES may promote cell survival and thereby speed recovery from cryorefractive procedures in humans.

Long-term storage of frozen lenticules for cryorefractive surgery.

We studied freezing rates, cryoprotectants, and storage times on keratocyte viability, using rabbit corneal buttons incubated in either KM-26, CPTES, K-Sol, or TC 199 for 30 minutes at 4 degrees C. Using a controlled freezing rate (2 degrees/min to -40 degrees C), viabilities were 69 +/- 7% for KM-26, 113 +/- 21% for CPTES, 0.1 +/- 0.08% for K-Sol, and 0 +/- 0% for TC 199. The KM-26 and CPTES were further studied in corneas stored one to 30 days at -80 or -196 degrees C; CPTES had a better cryoprotective efficacy over one, three, and seven days of -80 degrees storage, and at liquid nitrogen storage temperature (-196 degrees) over one, 14, and 30 days storage. The findings demonstrate the superiority of CPTES. It provides better viability than KM-26 under similar conditions, and may enable long-term frozen storage of lenticules for later use in cryorefractive surgeries, with minimal loss of keratocyte viability.

Remodelling of the corneal stroma after lamellar keratoplasty. A synchrotron x-ray diffraction study.

Patients healing from lamellar keratorefractive surgeries invariably experience postoperative corneal haze. In our lamellar keratoplasty (LKP) rabbit model, visual recovery is concomitant with the invasion of the grafted tissue by viable keratocytes from adjacent host tissue, and the return of corneal clarity is attributed to the remodelling of the stromal tissue by these keratocytes. We used synchrotron x-ray diffraction techniques to elucidate the ultrastructure of the stromal collagen fibrils in rabbit corneas at various time points in the 3 months after LKP surgery. Lenticules were frozen in 50% of the cases. The average spacing of the collagen molecules, which constitute the stromal fibrils, remains unchanged by LKP in both frozen (1.69-1.73 nm) and nonfrozen (1.58-1.75 nm) cases. In the nonfrozen case, the collagen fibril diameters are initially slightly larger than normal (38.3-41.9 nm) but have receded by 2 months postoperatively [similar to the frozen cases (37.7-41.9 nm)]. The post-LKP spacing of the collagen fibrils in the nonfrozen corneas is unremarkable (56.2-69.2 nm). In contrast, the increased collagen interfibrillar spacing in the frozen case is considerable (56.7 to > 94.6 nm) and variable up to 21 days postoperatively. Because the changes in interfibrillar spacing did not always mirror pachymetry changes in the frozen cases, we suspect occasional graft malapposition or the formation of intrastromal, fluid-filled, collagen-free "lakes."

Gynecologic care of medically complicated adolescents.

Gynecologic care of adolescents presents a challenge under the best of circumstances, but when the patient has significant medical processes that interact with the process of puberty, the care of these patients may become extremely difficult. A review of the more common medical illnesses of adolescents and the interaction on the events of puberty and normal menstrual function is presented with emphasis on contraception and future fertility. Although many of the contraceptive options present a possible increased risk to these patients, it must be kept in mind that these adolescent patients will develop emotionally and become sexually active at some point in their lives, and the potential risk of the resultant pregnancy must be weighed carefully. The various options of management for gynecologic problems are discussed.

PIP: This paper discusses issues on gynecologic care of medically complicated adolescents. Gynecologists and health personnel should give special attention to the chronic medical illness or disabilities of adolescents throughout their development. They must understand the interactions of the normal endocrinology of development and the pathophysiology of the medical illness. Chronically ill and disabled adolescents are least likely to receive information and guidance on sexual issues. They need to know the potential impact of their illness on pregnancy; genetic risk of their illness, treatment, and disability pose to their unborn children; and their limitations on both sexual function and fertility. In addition, it¿s important that these adolescents be given counseling addressing social and judgmental skills in cases of social isolation. Illnesses related to pubertal developments include: diabetes mellitus; cystic fibrosis; renal insufficiency and failure; gynecologic issues with various other chronic illnesses; sickle cell disease; seizure disorders; asthma; tuberculosis; inflammatory bowel disease; chronic yeast infections; menstrual abnormalities and coagulopathies or thrombocytopenia; adolescent and childhood malignancies; and developmental delayed and physical disability.

Endogenous lipolytic activities during autolysis of highly enriched hepatic lysosomes.

High enriched (50- to 70-fold) fractions of "native" lysosomes were isolated using continuous flow electrophoresis from livers of rats which had not been pretreated with Triton WR-1339. Incubation of lysosomes for 30 min at pH 5.0 in the presence of 5 mM EDTA resulted in a dramatic loss in the content of fatty acids bound to triacylglycerols (137 down to 10 mumol/mg protein) and to phospholipids and an elevation in the level of unesterified fatty acid. Phosphatidylcholine, phosphatidylethanolamine and sphingomyelin concentrations decreased whereas those of lysophosphatidylethanolamine (0.8 up to 8.5% of total lipid-P) and lysophosphatidylcholine (1.9 up to 16.7%) rose in a manner parallel to their respective, fully acylated lipids. Other phospholipids, including phosphatidylinositol, did not change in concentration during incubation. These results indicate that lysosomal phospholipase A, sphingomyelin and triacylglycerol lipase are activated by incubation at acid pH, enabling them to hydrolyze endogenous lysosomal lipids. However, lysosomal phosphatidylinositol-directed phospholipase C is apparently unable to interact with phosphatidylinositol of the lysosomal membrane.

Lipids of myocardial membranes: susceptibility of a fraction enriched in sarcolemma to hydrolysis by an exogenous mammalian phospholipase A2.

A myocardial membrane fraction enriched in sarcolemma was used to determine the susceptibility of the lipids to hydrolysis by a phospholipase A2 from granulocytes. After incubation (37 C, pH 7.0, 5 mM Ca2+) with the phospholipase A2 for 30 min, a more than 3-fold increase in unesterified fatty acids was found (up to 47 nmol/mg protein; P < 0.001) relative to a control incubated without phospholipase A2 or Ca2+. This included a 10-fold increase in the arachidonic acid content (up to 42 mol%) and at least a 7-fold increase in lysophosphatidylethanolamine (up to 7.4 mol% total phospholipid-P). However, the exogenous phospholipase did not augment the quantity of lysophosphatidylcholine produced by endogenous phospholipases in the presence of Ca2+ (5 mM). These results demonstrate the in vitro susceptibility of phospholipids of myocardial membranes, particularly phosphatidylethanolamine, to the neutral-active, Ca2+-dependent phospholipase A2 from granulocytes. This work may be relevant to myocardial inflammation and tissue damage during ischemia, where heterolytic injury of the myocardium may occur subsequent to the accumulation of granulocytes.

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.

Experimental transmission of Chlamydia psittaci to turkeys from wild birds.

Wild birds were inoculated with Chlamydia psittaci to determine species that could be potential hosts and vectors in transmitting the agent to domestic turkeys. Infection occurred in turkeys exposed to starlings (Sturnus vulgaris), common grackles (Quiscalus quiscula), brown-headed cowbirds (Molothrus ater), and Inca doves (Cardafella inca). Mourning doves (Zenaidura macroura) shed the agent sparingly, but turkeys exposed to them did not become infected, These findings and knowledge of the habits of these various species are discussed. It was concluded that the Inca dove should be considered a potential source of turkey chlamydiosis in Texas. The species studied and other species not studied should be included in serologic surveys and surveillance studies attempting isolation of chlamydiae.