Concordance of 3 alternative teratogenicity assays with results from corresponding in vivo embryo-fetal development studies: Final report from the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe working group 2.

An IQ DruSafe working group evaluated the concordance of 3 alternative teratogenicity assays (rat whole embryo culture, rWEC; zebrafish embryo culture, ZEC; and murine embryonic stem cells, mESC) with findings from rat or rabbit embryo-fetal development (EFD) studies. Data for 90 individual compounds from 9 companies were entered into a database. In vivo findings were deemed positive if malformations or embryo-fetal lethality were reported in either species. Each company used their own criteria for deciding whether the alternative assay predicted the in vivo findings. Standard concordance parameters were calculated, positive and negative predictive values (PPV and NPV) were adjusted for the aggregate portfolio prevalence of positive compounds (established by a survey of participating companies), and positive and negative likelihood ratios (LR+ and iLR-) were calculated. Of the 3 assays, only rWEC data were robustly predictive, particularly for negative predictions (NPVadj = 92%). However, both LR+ (4.92) and iLR- (4.72) were statistically significant for the rWEC assay. When analyzed separately for rats, the NPVadj and iLR-values for the rWEC assay increased to 96% and 9.75, respectively. These data suggest that a negative rWEC outcome could defer or replace a rat EFD study in certain regulatory settings.

A chronological expression profile of gene activity during embryonic mouse brain development.

The brain is a functionally complex organ, the patterning and development of which are key to adult health. To help elucidate the genetic networks underlying mammalian brain patterning, we conducted detailed transcriptional profiling during embryonic development of the mouse brain. A total of 2,400 genes were identified as showing differential expression between three developmental stages. Analysis of the data identified nine gene clusters to demonstrate analogous expression profiles. A significant group of novel genes of as yet undiscovered biological function were detected as being potentially relevant to brain development and function, in addition to genes that have previously identified roles in the brain. Furthermore, analysis for genes that display asymmetric expression between the left and right brain hemispheres during development revealed 35 genes as putatively asymmetric from a combined data set. Our data constitute a valuable new resource for neuroscience and neurodevelopment, exposing possible functional associations between genes, including novel loci, and encouraging their further investigation in human neurological and behavioural disorders.

A phase I clinical study of intratumorally administered VB4-845, an anti-epithelial cell adhesion molecule recombinant fusion protein, in patients with squamous cell carcinoma of the head and neck.

VB4-845 is a novel recombinant fusion protein that targets the epithelial cellular adhesion molecule (EpCAM). This initial clinical trial was conducted to determine the maximum tolerated dose of intratumoral injections in patients with advanced squamous cell carcinoma of the head and neck and to assess pharmacokinetics and immunogenicity. Twenty-four patients with advanced, recurrent squamous cell carcinoma of the head and neck received two cycles of five daily intratumoral VB4-845 injections of 20, 40, 80, 130, 200, or 280 microg. The maximum tolerated dose was established to be 280 microg administered daily for 5 days. Common adverse events were pain due to intratumoral injection and reversibly elevated liver enzymes. Of the 24 patients, 15 had detectable blood levels with a mean drug half-life of 4.0 +/- 0.3 h. VB4-845 reduced or stabilized tumors in 71.4% of epithelial cell adhesion molecule-positive patients. VB4-845 intratumoral injection therapy was well tolerated and feasible.

Provision of long-term monitoring and late effects services following adult allogeneic haematopoietic stem cell transplant: a survey of UK NHS-based programmes.

Despite international guidelines, optimal delivery models of late effects (LE) services for HSCT patients are unclear from the clinical, organizational and economic viewpoints. To scope current LE service delivery models within the UK NHS (National Health Service), in 2014, we surveyed the 27 adult allogeneic HSCT centres using a 30-question online tool, achieving a 100% response rate. Most LE services were led and delivered by senior physicians (>80% centres). Follow-up was usually provided in a dedicated allograft or LE clinic for the first year (>90% centres), but thereafter attrition meant that only ~50% of patients were followed after 5 years. Most centres (69%) had a standard operating procedure for long-term monitoring but access to a LE Multi-Disciplinary Team was rare (19% centres). Access to medical specialities necessary for LE management was good, but specialist interest in long-term HSCT complications was uncommon. Some screening (endocrinopathy, cardiovascular) was near universal, but other areas were more limited (mammography, cervical smears). Funding of extra staff and investigations were the most commonly perceived barriers to implementation of LE services. This survey shows variation in the long-term follow-up of allogeneic HSCT survivors within the UK NHS and further work is warranted to optimize effective, sustainable and affordable models of LE service delivery among this group.

Precise predictions for V + jets dark matter backgrounds.

High-energy jets recoiling against missing transverse energy (MET) are powerful probes of dark matter at the LHC. Searches based on large MET signatures require a precise control of the Z ( ν ν ¯ ) +  jet background in the signal region. This can be achieved by taking accurate data in control regions dominated by Z ( ℓ + ℓ - ) +  jet, W ( ℓ ν ) +  jet and γ +  jet production, and extrapolating to the Z ( ν ν ¯ ) +  jet background by means of precise theoretical predictions. In this context, recent advances in perturbative calculations open the door to significant sensitivity improvements in dark matter searches. In this spirit, we present a combination of state-of-the-art calculations for all relevant V +  jets processes, including throughout NNLO QCD corrections and NLO electroweak corrections supplemented by Sudakov logarithms at two loops. Predictions at parton level are provided together with detailed recommendations for their usage in experimental analyses based on the reweighting of Monte Carlo samples. Particular attention is devoted to the estimate of theoretical uncertainties in the framework of dark matter searches, where subtle aspects such as correlations across different V +  jet processes play a key role. The anticipated theoretical uncertainty in the Z ( ν ν ¯ ) +  jet background is at the few percent level up to the TeV range.

Treatment of severe falciparum malaria during pregnancy with quinidine and exchange transfusion.

Malaria during pregnancy may be associated with significant morbidity and mortality in both mother and fetus. Treatment of severe chloroquine-resistant malaria during pregnancy may be problematic since quinine and related compounds may have a deleterious effect on the course of labor. This article reports the case of a 21-year-old primigravida Liberian woman who presented with high-grade (greater than 12%) parasitemia with Plasmodium falciparum. The patient was initially treated with chloroquine; however, she developed bilateral pulmonary infiltrates and premature labor, and her condition appeared to clinically deteriorate. Therapy was changed to intravenous quinidine, and red blood cell exchange transfusion was instituted. This resulted in a decreased parasitemia and clinical improvement. The patient underwent a cesarean section, and a healthy child was delivered. Although most cases of malaria may be managed with conventional chemotherapy, the use of intravenous quinidine in combination with exchange transfusion with careful monitoring should be considered in selected cases of severe, complicated malaria in pregnant women.

Relation between p53 overexpression and established prognostic factors in breast cancer.

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.

Glucose-lowering properties of vanadium compounds: comparison of coordination complexes with maltol or kojic acid as ligands.

Bis(kojato)oxovanadium(IV) [abbreviated VO(ka)2], a close chemical analog of the insulin-mimetic lead compound bis(maltolato)oxovanadium(IV)--abbreviated BMOV or VO(ma)2--is reported and its reaction chemistry and insulin-mimetic properties are presented. VO(ka)2 [log K1 = 7.61(10), log K2 = 6.89(6), log beta 2 = 14.50(16)] has a reaction chemistry which directly parallels that of VO(ma)2. In aqueous solution it is more slowly oxidized by molecular oxygen to [VO2(ka)2]- than is VO(ma)2 to [VO2(ma)2]-. Variable pH electrochemistry and variable pH 51V NMR of solutions of VO(ka)2 are presented and contrasted with the corresponding results for VO(ma)2. Time course studies (24 hr) in STZ-diabetic rats following the oral or i.p. administration of VO(ka)2, VO(ma)2, VO2+ (vanadyl) as vanadyl sulfate (VOSO4), and [VO2(ma)2]- as its [NH4]+ salt have been performed, as have chronic oral studies comparing VO(ka)2 and VO(ma)2 over a six week period. In all studies, the most potent form of vanadium was the neutrally charged, water soluble, complex VO(ma)2.

Examining the accuracy of foodservice in a hospital setting.

Although a great deal of research has been conducted to determine the appropriate diets for the prevention and treatment of various illnesses, there is very little in the literature about research that directly assesses the accuracy of the prescribed diets served to patients in a hospital setting. The present study was designed to evaluate the accuracy of meals served to patients by identifying critical errors and more general errors on trays about to be served. The results indicated that the error rate was greater on weekends and holidays than during the week. Significantly, a correlational analysis revealed that error rate was inversely related to the total number of foodservice supervisors and more specifically to the number of food production supervisors and registered dietitians present. The implications of the results for possible interventions and training are discussed.

Play therapy and art therapy for substance abuse clients who have a history of incest victimization.

This article discusses the use of play therapy and art therapy treatment techniques for persons in substance abuse treatment who have a history of incest victimization. While substance abuse treatment focuses on substance abuse, neglecting to address issues related to past incest contact may increase the potential for relapse. This population displays unique characteristics that may prevent them from participating in, or benefitting from, traditional treatment modalities (which are highly dependent upon the verbal interactions between clients and therapists). Play therapy and art therapy are discussed in terms of history, rationale, and benefits to clients.

Incest and substance abuse: implications for treatment professionals.

Seventy-seven volunteer participants enrolled in eight substance abuse treatment facilities were surveyed using the Substance Abuse and Incest Survey. Of the sample, 36 (48%) reported histories of incest. For participants reporting incest, data on substance abuse history, perceptions of the relationship between incest and substance abuse, and opinions regarding incest-related counseling in the context of substance abuse treatment are presented. Recommendations for substance abuse professionals and facilities are made, including intake screening, barriers to treatment, counselor education, and future research.

Substance abuse and past incest contact. A national perspective.

Seven hundred thirty-two volunteer participants enrolled in 35 substance abuse treatment facilities across the United States were surveyed to examine the prevalence and nature of incest contacts among adults receiving substance abuse treatment. Results indicated that approximately 36% of the sample reported histories of incest: by gender, 29% of the male and 55% of the female participants reported incest histories. Data are presented regarding the age during incest contact, frequency of contacts and involvement of force, alcohol, and drugs. In addition, comparisons between incest and nonincest groups of participants are presented. Implications for substance abuse treatment facilities and staff are presented.

Isolation and identification of nontuberculous mycobacteria from foods as possible exposure sources.

A variety of foods collected from local supermarkets and produce stands were examined as possible sources of nontuberculous mycobacterial exposure. Food samples were combined with sterile ultrapure water and manually shaken. To remove large particles, the suspensions were filtered through a sterile strainer, centrifuged, and the supernatants were discarded. The food pellets were stored at -75 degrees C. The pellets were treated with either oxalic acid or sodium hydroxide-sodium citrate solutions to reduce contamination by nonmycobacterial organisms. Decontaminated pellets were cultured on both Middlebrook 7H10C agar and Middlebrook 7H10C agar with supplemental malachite green. Plates were observed for growth at 2 and 8 weeks. Isolates demonstrating acid-fastness were identified to species using polymerase chain reaction and restriction enzyme analysis. Nontuberculous mycobacteria (NTM) were recovered from 25 of 121 foods. Six different species of NTM were isolated, the most predominant being Mycobacterium avium.

Client perceptions of incest and substance abuse.

Clients receiving substance abuse treatment from 35 treatment facilities throughout the United States were surveyed using the Substance Abuse and Incest Survey-Revised (SAIS-R). A total of 732 participants responded to the survey; 518 (71%) were males, 204 (28%) were females, and 10 (1%) did not indicate gender. Participants had a mean age of 33.8 years, were predominately Caucasian (61.6%), never married (45.2%), were currently unemployed (69.4%), and had completed an average of 11.7 years of education. Of the entire sample, 266 (36.3%) reported having been victims of incest; 151 were males and 113 were females (2 did not indicate gender). The group reporting incest histories had a significantly greater percentage of females that did the group not reporting incest histories (chi 2 = 48.1, p < .001). Participants with incest histories were asked about their perceptions regarding incest, substance abuse, and counseling. Item responses were examined using descriptive statistics and factor analysis. The factor analysis on SAIS-R perception items identified five factors that accounted for 68.9% of the variance; these factors were Stigma and Resistance to Counseling; Substance Abuse and Incest; Ambivalence; Fear and Anticipation; and Receptivity to Counseling. Results are presented and the implications for substance abuse treatment and counseling are discussed.

Improved radiotherapy treatment planning for spinal cord tumors using gadolinium enhanced MR imaging.

Primary intramedullary spinal cord tumors are frequently difficult to localize for radiation treatment planning. Conventional imaging techniques, including unenhanced magnetic resonance (MR) scans, cannot clearly distinguish residual tumor from surrounding normal spinal cord. Recently, contrast agents have been developed for MR that have considerable promise for improving tumor volume definition. This report describes the impact of contrast-enhanced MR on the treatment planning process for four patients with primary spinal cord tumors and discusses the significance of this technique for patients with these neoplasms.

Comparison of Faxitron™ versus MicroCT imaging of the skeleton of the suckling rat.

Currently, in pre and postnatal development studies or in juvenile rat studies, bone growth is assessed "for cause" by simple measurements of long bone length in vivo and at termination. This manuscript compares two radiographic methods for in vivo assessment of long bones in suckling rats; 2D imaging using a Faxitron™ and 3D imaging using µCT. This paper illustrates that it is possible to image the unanaesthetised postnatal day 1 rat by Faxitron™ using a simple Micropore™ tape restraint method. With isoflurane anaesthesia, it was possible to obtain high quality µCT images of pups from day of birth. No pups were rejected by their mothers following either technique. The Faxitron™ was straightforward and fast, however the µCT 3D images were of greater overall utility. Either method could be used for longitudinal investigation of long bone observations made previously in embryofetal development studies, or for other mechanistic work.