An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield.
Are meiotic and developmental competence of human oocytes from small (2-8 mm) antral follicles improved by applying an optimized IVM method involving a prematuration step in presence of C-Type Natriuretic Peptide (CNP) followed by a maturation step in presence of FSH and Amphiregulin (AREG)? A strategy involving prematuration culture (PMC) in the presence of CNP followed by IVM using FSH + AREG increases oocyte maturation potential leading to a higher availability of Day 3 embryos and good-quality blastocysts for single embryo transfer. IVM is a minimal-stimulation ART with reduced hormone-related side effects and risks for the patients, but the approach is not widely used because of an efficiency gap compared to conventional ART. In vitro systems that enhance synchronization of nuclear and cytoplasmic maturation before the meiotic trigger are crucial to optimize human IVM systems. However, previous PMC attempts have failed in sustaining cumulus-oocyte connections throughout the culture period, which prohibited a normal cumulus-oocyte communication and precluded an adequate response by the cumulus-oocyte complex (COC) to the meiotic trigger. A first prospective study involved sibling oocytes from a group of 15 patients with polycystic ovary syndrome (PCOS) to evaluate effects of a new IVM culture method on oocyte nuclear maturation and their downstream developmental competence. A second prospective study in an additional series of 15 women with polycystic ovaries characterized and fine-tuned the culture conditions. Fifteen women with PCOS (according to Rotterdam criteria) underwent IVM treatment after 3-5 days of highly purified human menopausal gonadotropin (HP-hMG) stimulation and no human chorionic gonadotropin (hCG) trigger before oocyte retrieval. A first study was designed with sibling oocytes to prospectively evaluate the impact of an IVM culture method: 24 h PMC with CNP + 30 h IVM with FSH and AREG, on embryo yield, in comparison to the standard (30 h) IVM clinical protocol (Group I, n = 15). A second prospective study was performed in 15 women with polycystic ovaries, to characterize and optimize the PMC conditions (Group II, n = 15). The latter study involved the evaluation of oocyte meiotic arrest, the preservation of cumulus-oocyte transzonal projections (TZPs), the patterns of oocyte chromatin configuration and cumulus cells apoptosis following the 24 and 46 h PMC. Furthermore, oocyte developmental potential following PMC (24 and 46 h) + IVM was also evaluated. The first 20 good-quality blastocysts from PMC followed by IVM were analysed by next generation sequencing to evaluate their aneuploidy rate. PMC in presence of CNP followed by IVM using FSH and AREG increased the meiotic maturation rate per COC to 70%, which is significantly higher than routine standard IVM (49%; P ≤ 0.001). Hence, with the new system the proportion of COCs yielding transferable Day 3 embryos and good-quality blastocysts increased compared to routine standard IVM (from 23 to 43%; P ≤ 0.001 and from 8 to 18%; P ≤ 0.01, respectively). CNP was able to prevent meiosis resumption for up to 46 h. After PMC, COCs had preserved cumulus-oocyte TZPs. The blastocysts obtained after PMC + IVM did not show increased aneuploidy rates as compared to blastocysts from conventional ART. The novel IVM approach in PCOS patients was tested in oocytes derived from small antral follicles which have an intrinsically low developmental potential. Validation of the system would be required for COCs from different (larger) follicular sizes, which may involve further adjustment of PMC conditions. Furthermore, considering that this is a novel strategy in human IVM treatment, its global efficiency needs to be confirmed in large prospective randomized controlled trials. The further application in infertile patients without PCOS, e.g. cancer patients, remains to be evaluated. The findings of this pilot study suggest that the efficiency gap between IVM and conventional IVF can be reduced by fine-tuning of the culture methods. This novel strategy opens new perspectives for safe and patient-friendly ART in patients with PCOS. IVM research at the Vrije Universiteit Brussel has been supported by grants from: the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie-IWT, project 110680); the Fund for Research Flanders (Fonds Wetenschappelijk Onderzoek-Vlaanderen-FWO, project G.0343.13), the Belgian Foundation Against Cancer (HOPE project, Dossier C69). The authors have no conflicts of interest.


Impact of dissociative experiences in migraine and its close relationship with osmophobia.
Migraine is a complex episodic disease manifested by dysfunction of the sympathetic nervous system along with numerous neuropsychiatric symptoms. The aim of this study was to identify the dissociative symptoms with neurobiological similarities in episodic and chronic migraine patients and to evaluate their correlation with migraine frequency and severity of attacks. The study included 61 episodic, 45 chronic migraine patients diagnosed using the criteria of the International Headache Society and 54 healthy control subjects. Dissociative Experiences Scale, Beck Anxiety Scale and Beck Depression Inventory were filled with the interviews. Demographic, clinical and headache characteristics of the patients were recorded according to migraine types. Results were analyzed by Kruskal-Wallis method and Spearman's correlation tests. Dissociative symptoms were more common in the patients with chronic migraine, and there was a statistically significant difference between the chronic migraine group and the episodic migraine and control groups (p = 0.001, p < 0.001). Dissociative experiences were correlated with depression and anxiety findings, and in both groups, there was a significant correlation between clinical characteristics of migraine and osmophobia in the controlled partial correlation analysis (p < 0.05). This study revealed that dissociative symptoms are more common especially in patients with chronic migraine and there is a significant association with osmophobia in both migraine groups. According to these data, we think that dissociative symptoms in chronic migraine patients will be questioned and osmophobia may be a guide in this regard.


Enantiospecific Recognition at the A2B Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates.
A novel family of structurally simple, potent, and selective nonxanthine A2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, Ki = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A2BAR, with the (S)-16b enantiomer retaining all the affinity (Ki = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A2B adenosine receptor and opens new possibilities in ligand design for this receptor.


Version 3 of the historical-clinical-risk management-20 (HCR-20V3): relevance to violence risk assessment and management in forensic conditional release contexts.
The conditional release of insanity acquittees requires decisions both about community risk level and the contextual factors that may mitigate or aggravate risk. This article discusses the potential role of the newly revised Historical-Clinical-Risk Management-20 (HCR-20, Version 3) within the conditional release context. A brief review of the structured professional judgment (SPJ) approach to violence risk assessment and management is provided. Version 2 of the HCR-20, which has been broadly adopted and evaluated, is briefly described. New features of Version 3 of the HCR-20 with particular relevance to conditional release decision-making are reviewed, including: item indicators; ratings of the relevance of risk factors to an individual's violence; risk formulation; scenario planning; and risk management planning. Version 3 of the HCR-20 includes a number of features that should assist evaluators and decision-makers to determine risk level, as well as to anticipate and specify community conditions and contexts that may mitigate or aggravate risk. Research on the HCR-20 Version 3 using approximately 800 participants across three settings (forensic psychiatric, civil psychiatric, correctional) and eight countries is reviewed.


Selenoprotein T is required for pathogenic bacteria avoidance in Caenorhabditis elegans.
Selenoprotein T (SELENOT) is an endoplasmatic reticulum (ER)-associated redoxin that contains the amino acid selenocysteine (Sec, U) within a CXXU motif within a thioredoxin-like fold. Its precise function in multicellular organisms is not completely understood although it has been shown in mammals to be involved in Ca2+ homeostasis, antioxidant and neuroendocrine functions. Here, we use the model organism C. elegans to address SELENOT function in a whole organism throughout its life cycle. C. elegans possess two genes encoding SELENOT protein orthologues (SELT-1.1 and SELT-1.2), which lack Sec and contain the CXXC redox motif instead. Our results show that a Sec→Cys replacement and a gene duplication were two major evolutionary events that occurred in the nematode lineage. We find that worm SELT-1.1 localizes to the ER and is expressed in different cell types, including the nervous system. In contrast, SELT-1.2 exclusively localizes in the cytoplasm of the AWB neurons. We find that selt-1.1 and selt-1.2 single mutants as well as the double mutant are viable, but the selt-1.1 mutant is compromised under rotenone-induced oxidative stress. We demonstrate that selt-1.1, but not selt-1.2, is required for avoidance to the bacterial pathogens Serratia marcescens and Pseudomonas aeruginosa. Aversion to the noxious signal 2-nonanone is also significantly impaired in selt-1.1, but not in selt-1.2 mutant animals. Our results suggest that selt-1.1 would be a redox transducer required for nociception and optimal organismal fitness. The results highlight C. elegans as a valuable model organism to study SELENOT-dependent processes.


Fetal Alcohol Spectrum Disorder (FASD): neurobehavioral profile, indications for diagnosis and treatment.
It is now known that exposure to alcohol in utero produces a wide spectrum of morphological and behavioural outcomes in the offspring, commonly referred as fetal alcohol spectrum disorders (FASD). A large body of literature documents cognitive deficits and behavioural-emotional difficulties in children with FASD. Researchers have found that individuals with FASD often experience a range of adverse life outcomes, called secondary disabilities, which include disrupted school experience, troubles with the law, confinement, inappropriate sexual behaviours on repeated occasions, and alcohol/drug related problems. Additionally, despite considerable data published on cognitive and behavioural disabilities in children with FASD, relatively little information is available on behavioural or pharmacological interventions for alcohol affected children. This paper will provide a comprehensive review of the neuropsychological and behavioural effects of prenatal alcohol exposure, including a discussion of the emerging neurobehavioral profile. Finally, we will summarize published intervention studies of FASD focusing on their strengths and weaknesses.


Insect population control by homing endonuclease-based gene drive: an evaluation in Drosophila melanogaster.
Insects play a major role as vectors of human disease as well as causing significant agricultural losses. Harnessing the activity of customized homing endonuclease genes (HEGs) has been proposed as a method for spreading deleterious mutations through populations with a view to controlling disease vectors. Here, we demonstrate the feasibility of this method in Drosophila melanogaster, utilizing the well-characterized HEG, I-SceI. In particular, we show that high rates of homing can be achieved within spermatogonia and in the female germline. We show that homed constructs continue to exhibit HEG activity in the subsequent generation and that the ectopic homing events required for initiating the strategy occur at an acceptable rate. We conclude that the requirements for successful deployment of a HEG-based gene drive strategy can be satisfied in a model dipteran and that there is a reasonable prospect of the method working in other dipterans. In characterizing the system we measured repair outcomes at the spermatogonial, spermatocyte, and spermatid stages of spermatogenesis. We show that homologous recombination is restricted to spermatogonia and that it immediately ceases when they become primary spermatocytes, indicating that the choice of DNA repair pathway in the Drosophila testis can switch abruptly during differentiation.


Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors.
Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-x(L), Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-x(L) were predicted by molecular modeling simulations, which were confirmed by structure-activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-x(L), referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds and critical structural information for further development of more potent and specific inhibitors of antiapoptotic Bcl-2 family proteins.


Elementary-field analysis of partially coherent beam shaping.
We consider spatial shaping of partially coherent fields in two types of optical systems: a 2F Fourier-transforming system with the beam shaping element in the input plane and a 4F imaging system with the element in the intermediate Fourier plane. Different representations of the spatially partially coherent field in terms of fully coherent fields are examined to permit reduction of the dimensionality of the propagation integrals. The standard Mercer-type coherent-mode representation of the incident cross-spectral density (CSD) function is compared to expansions of CSD in either spatially or angularly shifted elementary field modes, all sharing the same spatial profile. In Fourier-transforming systems, the angular elementary-field representation proves computationally superior, while in imaging systems the spatially shifted elementary-field expansion is the best choice. Considering the Fourier-plane element as a generalized pupil, the latter leads to the concept's generalized amplitude associated with the elementary field and to a generalized transfer function of the system. These concepts reduce to the standard point spread function and the optical transfer function in the limit of spatial incoherence at the object plane. Examples of the effects of partial coherence in spatial beam shaping are given.


[Bilateral pneumothorax complicating cavitary pulmonary metastases in angiosarcoma].
Metastatic pulmonary angiosarcomas are a common complication of a rare condition. Generally, they are presented as peripheral solid nodules, infiltrates, and pleural effusions. We report the case of a 65 year-old man with bilateral recurrent pneumothorax secondary to metastatic cavitary lesions from angiosarcoma of the scalp. In this case, videothoracoscopy allowed tumor resection, inspection, and pleurodesis. There weren't complications or tumor recurrence at six months follow up.


Choice of Polymer, but Not Mesh Structure Variation, Reduces the Risk of Bacterial Infection with Staphylococcus aureus In Vivo.
Synthetic mesh material is of great importance for surgical incisional hernia repair. The physical and biochemical characteristics of the mesh influence mechanical stability and the foreign body tissue reaction. The influence on bacterial infections, however, remains ill-defined. The aim of the present study was to evaluate the influence of a modified mesh structure with variation in filament linking on the occurrence of bacterial infection that is indicated by the occurrence of CD68+, CD4+, and CD8+ cells in two different materials. A total of 56 male Sprague Dawley rats received a surgical mesh implant in a subcutaneous abdominal position. The mesh of two different polymers (polypropylene (PP) and polyvinylidenfluoride (PVDF)) and two different structures (standard structure and bold structure with higher filament linking) were compared. During the implantation, the meshes were infected with Staphylococcus (S.) aureus. After 7 and 21 days, meshes were explanted, and the early and late tissue responses to infection were histologically evaluated. Overall, the inflammatory tissue response was higher at 7 days when compared to 21 days. At 7 days, PP meshes of the standard structure (PP-S) showed the strongest inflammatory tissue response in comparison to all the other groups. At 21 days, no statistically significant difference between different meshes was detected. CD8+ cytotoxic T cells showed a significant difference at 21 days but not at 7 days. PP meshes of both structures showed a higher infiltration of CD8+ T cells than PVDF meshes. CD4+ T helper cells differed at 7 days but not at 21 days, and PVDF meshes in a bold structure showed the highest CD4+ T cell count. The number of CD68+ macrophages was also significantly higher in PP meshes in a standard structure when compared to PVDF meshes at 21 days. The inflammatory tissue response to S. aureus infection appears to be highest during the early period after mesh implantation. PP meshes showed a higher inflammatory response than PVDF meshes. The mesh material appears to be more important for the risk of infection than the variation in filament linking.


Prognostic Value of miR-1826 in Prostate Cancer and Its Regulatory Effect on Tumor Progression.
miRNAs can act as oncogenes or tumor suppressors and participate in the development and progression of tumors, thus affecting the prognosis and survival of cancer patients. In this paper, we mainly studied the role of miR-1826 in prostate cancer. The expression of miR-1826 was studied by quantitative real-time PCR (qRT-PCR). Kaplan-Meier curves were used to analyze the relationship between the expression of miR-1826 and the survival rate of PC patients. Cox regression analysis was used to study the risk factors affecting the prognosis of PC patients. PC cells were transfected with miR-1826 mimic, mimic negative control (mimic NC), miR-1826 inhibitor, or inhibitor NC. The effect of miR-1826 on the proliferation of PC cells was studied by the CCK-8 method and colony formation assay. Transwell assays were used to detect the effect of miR-1826 on the migratory and invasive abilities of tumor cells. The expression of miR-1826 in PC tissues was lower than that in adjacent normal tissues, and that the expression levels of miR-1826 in four PC cell lines were all lower than normal human prostate epithelial cell lines. Patients with low expression of miR-1826 had shorter overall survival compared with those with high expression. The downregulation of miR-1826 promoted PC cell proliferation, migration, and invasion. In summary, the low expression of miR-1826 may promote the progression of PC, and the low expression of miR-1826 is also associated with a poor prognosis in PC patients.


Neurite outgrowth on muscle cell surfaces involves extracellular matrix receptors as well as Ca2+-dependent and -independent cell adhesion molecules.
To identify the molecules on the neuronal surface that mediate axonal growth on myotubes, we have examined neurite formation by ciliary neurons grown on myotubes in the absence or presence of specific antibodies. Dramatic inhibition of neurite outgrowth was seen only when antibodies blocked simultaneously the functions of two cell adhesion molecules--neural cell adhesion molecule (N-CAM) and neural Ca2+-dependent CAM (N-Cal-CAM)--and the neuronal receptors for several extracellular matrix (ECM) proteins. Although the antibody used to block ECM receptors (JG22) has been shown to eliminate almost all neurite growth on ECMs, it had only small effects on neurite growth on myotubes, reducing somewhat the length of neurites. Similarly, antibodies to the two CAMs, when used alone, had no detectable effects on neurite length and, when used together, had only small inhibitory effects on neurite growth. Combination of anti-ECM receptor (JG22) with antibodies to either CAM, however, greatly shortened the length of neurites. These results imply that ECM receptors and the CAMs N-CAM and N-Cal-CAM are major macromolecules used by neuronal growth cones for interactions with myotubes. Each provides a distinct mechanism for regulating growth cone motility.


SK3 channel expression during pregnancy is regulated through estrogen and Sp factor-mediated transcriptional control of the KCNN3 gene.
Overexpression of the small-conductance calcium-activated K(+) channel 3 (SK3) in transgenic mice compromises parturition, suggesting that the SK3 channel plays a role in pregnancy. In wild-type mouse myometrium, expression of SK3 transcript and protein is significantly reduced during pregnancy, but the mechanism(s) responsible for this attenuation of channel expression is unknown. The promoter region of the SK3-encoding mouse KCNN3 gene contains two binding sites for specificity protein (Sp) transcription factors, two of which are expressed in the uterus: Sp1, which enhances gene transcription in response to estrogen; and Sp3, which competes for the same binding motif as Sp1 and can repress gene expression. We investigated the hypothesis that Sp1 and Sp3 regulate SK3 channel expression during pregnancy. In mouse myometrium, Sp1 expression was reduced during late gestation, whereas Sp3 expression levels were constant throughout pregnancy. Using a reporter system, we found that Sp1 overexpression resulted in a significant increase in SK3 promoter activation and that Sp3 cotransfection reduced promoter activation to basal levels. These findings indicate that Sp3 outcompetes Sp1 to decrease SK3 transcription. To determine whether high levels of estrogen in vivo can affect the regulation of SK3 protein levels by Sp factors, ovariectomized mice were implanted with a 17β-estradiol or placebo pellet for 3 wk; estrogen-treated mice had reduced uterine SK3 protein expression compared with placebo-treated counterparts. In human myometrial cells overexpressing Sp1, estrogen treatment stimulated expression of the SK3 transcript. Overall, our findings indicate that Sp1 and Sp3 compete to regulate SK3 channel expression during pregnancy in response to stimulation by estrogen.


Denitrification enzyme activity of fringe salt marshes in New England (USA).
Coastal salt marshes are a buffer between the uplands and adjacent coastal waters in New England (USA). With increasing N loads from developed watersheds, salt marshes could play an important role in the water quality maintenance of coastal waters. In this study we examined seasonal relationships between denitrification enzyme activity (DEA) in salt marshes of Narragansett Bay, Rhode Island, and watershed N loadings, land use, and terrestrial hydric soils. In a manipulative experiment, the effect of nutrient enrichment on DEA was examined in a saltmeadow cordgrass [Spartina patens (Aiton) Muhl.] marsh. In the high marsh, DEA significantly (p < 0.05) increased with watershed N loadings and decreased with the percent of hydric soils in a 200-m terrestrial buffer. In the low marsh, we found no significant relationships between DEA and watershed N loadings, residential land development, or terrestrial hydric soils. In the manipulation experiment, we measured increased DEA in N-amended treatments, but no effect in the P-amended treatments. The positive relationships between N loading and high marsh DEA support the hypothesis that salt marshes may be important buffers between the terrestrial landscape and estuaries, preventing the movement of land-derived N into coastal waters. The negative relationships between marsh DEA and the percent of hydric soils in the adjacent watershed illustrate the importance of natural buffers within the terrestrial landscape. Denitrification enzyme activity appears to be a useful index for comparing relative N exposure and the potential denitrification activity of coastal salt marshes.


Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care.
Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, but might be useful for various other physical symptoms, including nausea, fatigue, dyspnea, and constipation. However, few studies have used TENS for treating the physical symptoms of patients with advanced cancer. In this crossover trial, we assess the effects of TENS on pain and other physical symptoms in 20 in-patients with advanced cancer receiving palliative care. For 5-day phases between wash out periods of 5 days, patients received TENS or non-TENS. TENS was delivered at four points: the center of the back for mainly nausea and dyspnea, on the back at the same dermatomal level as the origin of the pain (100 Hz), and on both ankle joints for constipation (10 Hz). The intensity of pain and the total opioid dose used during phases were recorded. Physical symptoms were evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care (QLQ-C15-PAL). Hematological and biochemical data were recorded before and after the TENS phase. The average pain and total number of opioid rescue doses were significantly reduced by TENS. TENS tended to improve nausea and appetite loss, but not constipation. There were no effects on hematological and biochemical parameters. Use of TENS could safely improve pain, nausea, and appetite loss in patients with advanced cancer. Although it cannot be used as a substitute for opioids and other pharmaceutical treatment, it may be useful to support palliative care.


The Acceptability of an Electronically Delivered Acceptance- and Mindfulness-Based Physical Activity Intervention for Survivors of Breast Cancer: One-Group Pretest-Posttest Design.
Survivors of breast cancer can face internal barriers to physical activity, such as uncertainty and frustration stemming from physical limitations, decreased physical functioning, fatigue, and pain. Interventions that draw from the principles of Acceptance and Commitment Therapy (ACT) may help survivors of breast cancer overcome some of the internal barriers associated with physical activity. The primary aim of this study was to investigate the acceptability of an electronically delivered physical activity intervention for survivors of breast cancer, centered on ACT processes. This study used a 1-group pretest-posttest design. We recruited 80 insufficiently active female survivors of breast cancer using a web-based recruitment strategy. The 8-week intervention consisted of weekly modules that featured didactic lessons and experiential exercises targeting key ACT processes in the context of physical activity promotion (namely, values, committed action, acceptance, defusion, and contacting the present moment). We determined intervention acceptability according to study retention (≥70%), adherence rates (≥75% of the participants completing ≥50% of the modules), and posttest survey scores reflecting the perceived ease of use, perceived usefulness, and interest and enjoyment of the intervention (≥5 on a 7-point Likert-type scale). We also evaluated changes in self-reported aerobic and muscle strengthening-physical activity, physical activity acceptance, physical activity regulation, and health-related outcomes. The retention rate (61/80, 76%), adherence rate (60/80, 75%), average perceived ease of use (6.17, SD 1.17), perceived usefulness (5.59, SD 1.40), and interest and enjoyment scores (5.43, SD 1.40) met the acceptability criteria. Participants increased their self-reported aerobic physical activity (Cohen d=1.04), muscle strengthening-physical activity (Cohen d=1.02), physical activity acceptance (cognitive acceptance: Cohen d=0.35; behavioral commitment: Cohen d=0.51), physical activity regulation (identified regulation: Cohen d=0.37; integrated regulation: Cohen d=0.66), increased their ability to participate in social roles and activities (Cohen d=0.18), and reported less fatigue (Cohen d=0.33) and sleep disturbance (Cohen d=0.53). Electronically delivered acceptance- and mindfulness-based interventions may be useful for promoting physical activity in survivors of breast cancer. Further research is needed to refine these approaches and evaluate their effectiveness.


Surface depinning of smectic-A edge dislocations.
Using a Landau-de Gennes approach, we model the formation of an edge dislocation in a smectic-A cell initially in the bookshelf structure. The driving force is the mismatch between the layer thickness in a bulk smectic-A liquid crystal and that imposed by confining plates. The core structure of the dislocation is calculated taking into account spatial variations of the smectic translational order parameter. We numerically determine the critical condition for the surface-driven formation and depinning of the dislocation. By exploiting this phenomenon, we show how the value of the positional anchoring strength at the surface can be determined.


Accumulation of cadmium in insulin-producing β cells.
Evidence suggests that chronic low level cadmium exposure impairs the function of insulin-producing β cells and may be associated with type-2 diabetes mellitus. Herein, we describe the cadmium content in primary human islets and define the uptake kinetics and effects of environmentally relevant cadmium concentrations in cultured β cells. The average cadmium content in islets from 10 non-diabetic human subjects was 29 ± 7 nmol/g protein (range 7 to 72 nmol/g protein). Exposure of the β-cell line MIN6 to CdCl 2 concentrations between 0.1 and 1.0 µmol/L resulted in a dose- and time-dependent uptake of cadmium over 72 h. This uptake resulted in an induction of metallthionein expression, likely enhancing cellular cadmium accumulation. Furthermore, cadmium accumulation resulted in an inhibition of glucose stimulated insulin secretion in MIN6 cells and primary mouse islets. Our results indicate that this impairment in β-cell function is not due to an increase in cell death or due to an increase in oxidative stress. We conclude that mouse β cells accumulate cadmium in a dose- and time-dependent manner over a prolonged time course at environmentally relevant concentrations. This uptake leads to a functional impairment of β-cell function without significant alterations in cell viability, expression of genes important for β-cell function or increase in oxidative stress.


Refinement of a model of repeated cerebrospinal fluid collection in conscious rats.
The cannulation of the cisterna magna in rats for in vivo sampling of cerebrospinal fluid serves as a valuable model for studying the delivery of new drugs into the central nervous system or disease models. It offers the advantages of repeated sampling without anesthesia-induced bias and using animals as their own controls. An established model was retrospectively reviewed for the outcomes and it was hypothesized that by refining the method, i.e. by (1) implementing pathophysiological-based anesthesia and analgesia, (2) using state-of-the-art peri-operative monitoring and supportive care, (3) increasing stability of the cement-cannula assembly, and (4) selecting a more adaptable animal strain, the outcome in using the model - quantified by peri-operative mortality, survival time and stability of the implant - could be improved and could enhance animal welfare. After refinement of the technique, peri-operative mortality decreased significantly (7 animals out of 73 compared with 4 out of 322; P = 0.001), survival time increased significantly (36 ± 14 days compared with 28 ± 18 days; P < 0.001), as well as the stability of the cement-cannula assembly (47 ± 8 days of adhesion compared with 33 ± 15 days and 34 ± 13 days using two other cement types; P < 0.001). Overall, the 3R concept of Russell and Burch was successfully addressed and animal welfare was improved by (1) the reduction in the total number of animals needed as a result of lower mortality or fewer euthanizations due to technical failure, and frequent use of individual rats over a time frame; and (2) improving the scientific quality of the model.


Characteristics of rural crack and powder cocaine use: gender and other correlates.
Little is known about the relationship of gender with cocaine use in rural areas. This study describes these relationships among stimulant users residing in rural areas of Arkansas, Kentucky, and Ohio. Understanding the characteristics of crack and powder cocaine users in rural areas may help inform prevention, education, and treatment efforts to address rural stimulant use. Participants were 690 stimulant users, including 274 (38.6%) females, residing in nine rural counties. Cocaine use was measured by self-report of cocaine use, frequency of use, age of first use, and cocaine abuse/dependence. Powder cocaine use was reported by 49% of this sample of stimulant users and 59% reported using crack cocaine. Differing use patterns emerged for female and male cocaine users in this rural sample; females began using alcohol, marijuana, and cocaine at later ages than males but there were no gender differences in current powder cocaine use. Females reported more frequent use of crack cocaine and more cocaine abuse/dependence than males, and in regression analyses, female crack cocaine users had 1.8 times greater odds of reporting frequent crack use than male crack users. These findings suggest differing profiles and patterns of cocaine use for male and female users in rural areas, supporting previous findings in urban areas of gender-based vulnerability to negative consequences of cocaine use. Further research on cocaine use in rural areas can provide insights into gender differences that can inform development and refinement of effective interventions in rural communities.


Early and late forms of cyclosporine nephrotoxicity: studies in cardiac transplant recipients.
To characterize the two forms of cyclosporine nephrotoxicity, we examined renal function in the immediate and late postoperative periods after cardiac transplantation. Moderate azotemia occurred during the first postoperative week in 58% of 43 cyclosporine-treated recipients, but in only 34% of 41 azathioprine-treated recipients, and 4% of 25 patients undergoing cardiopulmonary bypass for nontransplant surgery (both P less than .01 v cyclosporine). Acute renal failure developed in an additional 12% of the cyclosporine-treated group. Late postoperative renal dysfunction also occurred with a high prevalence. Life-table analysis indicated that at 6 months 55%, at 12 months 17%, at 24 months 4%, and at 36 months no cyclosporine-treated recipients retained normal renal function. Three renal biopsies performed in subjects with late nephrotoxicity demonstrated prominent interstitial fibrosis. Although one patient subsequently required chronic dialysis, reduction of cyclosporine dosage from a mean of 5.3 +/- 0.7 mg/kg/d to a mean of 2.3 +/- 0.3 mg/kg/d 9 to 21 months after transplantation with concurrent initiation of azathioprine therapy to prevent rejection led to an improvement of renal function in the five patients so treated. These data indicate that there are two distinct forms of cyclosporine nephrotoxicity. Although both occur with high prevalence, the early form does not appear to be a specific risk factor for the late form.


Associations of Alcohol and Tobacco Retail Outlet Rates with Neighborhood Disadvantage.
Tobacco causes 29% of cancer-related deaths while alcohol causes 5.5% of cancer-related deaths. Reducing the consumption of these cancer-causing products is a special priority area for the National Cancer Institute. While many factors are linked to tobacco and alcohol use, the placement and density of retail outlets within neighborhoods may be one community-level risk factor contributing to greater use of these products. To elucidate associations between tobacco, alcohol, and tobacco and alcohol retail outlets (TRO, ARO, and TARO) and neighborhood disadvantage over a large geographic area, we employed a novel Bayesian index modeling approach to estimate a neighborhood disadvantage index (NDI) and its associations with rates of the three types of retailers across block groups in the state of North Carolina. We used a novel extension of the Bayesian index model to include a shared component for the spatial pattern common to all three types of outlets and NDI effects that varied by outlet type. The shared component identifies areas that are elevated in risk for all outlets. The results showed significant positive associations between neighborhood disadvantage and TROs (relative risk (RR) = 1.12, 95% credible interval (CI = 1.09, 1.14)) and AROs (RR = 1.15, 95% CI = 1.11, 1.17), but the association was greatest for TAROs (RR = 1.21, 95% CI = 1.18, 1.24). The most important variables in the NDI were percent renters (i.e., low home ownership), percent of homes built before 1940 (i.e., old housing stock), and percent without a high school diploma (i.e., low education).


Recovery of Shoulder, Elbow, and Forearm Movement After Nerve Reconstruction for Neonatal Brachial Plexus Palsy.
There is a relative dearth of published data with respect to recovery of upper extremity movement after nerve reconstruction for neonatal brachial plexus palsy (NBPP). This study aimed to demonstrate long-term recovery of active range of motion (AROM) at the shoulder, elbow, and forearm after nerve reconstruction for NBPP and to compare that with patients managed nonoperatively. We interrogated a prospectively collected database of all patients evaluated for NBPP at a single institution from 2005 to 2020. AROM measurements for shoulder, elbow, and forearm movements were collected at every visit up to 5 years of follow-up and normalized between 0 and 1. We used generalized estimated equations to predict AROM for each movement within local age windows over 5 years and compared the operative and nonoperative cohorts at each age interval. In total, >13 000 collected datapoints representing 425 conservatively and 99 operatively managed children were included for analysis. At 5 years, absolute recovery of AROM after nerve reconstruction was ∼50% for shoulder abduction and forward flexion, ∼65% for shoulder external rotation, and ∼75% for elbow flexion and forearm supination, with ∼20% loss of elbow extension AROM. Despite more limited AROM on presentation for the operative cohort, at 5 years, there was no significant difference between the groups in AROM for shoulder external rotation, elbow extension, or forearm supination, and, in Narakas grade 1-2 injury, shoulder abduction and forward flexion. We demonstrate recovery of upper extremity AROM after nerve surgery for NBPP. Despite more severe presenting injury, operative patients had similar recovery of AROM when compared with nonoperative patients for shoulder external rotation, elbow extension, forearm supination, and, for Narakas grade 1-2 injury, shoulder abduction and forward flexion.


Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation.
Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.


Evolution of bacterial and archaeal multicomponent monooxygenases.
We report the results of a comparative analysis of the sequences of multicomponent monooxygenases, a family of enzymes of great interest for bioremediation of contaminated soil. We show that their function, in terms of substrate specificity, can be deduced from their subunit organization and composition, that rearrangements of subunits as well as recruitments of new ones can be used to explain their different properties and functionalities, and that the observed pattern can be rationalized invoking a number of evolutionary events, including horizontal gene transfer. Our analysis highlights the plasticity and modularity of this family of enzymes, which might very well be the reason underlying the extremely rapid emergence of new bacterial strains able to grow on contaminated soils.


Proteins with highly similar native folds can show vastly dissimilar folding behavior when desolvated.
Proteins can be exposed to vastly different environments such as the cytosol or membranes, but the delicate balance between external factors and intrinsic determinants of protein structure, stability, and folding is only poorly understood. Here we used electron capture dissociation to study horse and tuna heart Cytochromes c in the complete absence of solvent. The significantly different stability of their highly similar native folds after transfer into the gas phase, and their strikingly different folding behavior in the gas phase, can be rationalized on the basis of electrostatic interactions such as salt bridges. In the absence of hydrophobic bonding, protein folding is far slower and more complex than in solution.


Energy trapping and detrapping by wild type and mutant reaction centers of purple non-sulfur bacteria.
Time-correlated single photon counting was used to study energy trapping and detrapping kinetics at 295 K in Rhodobacter sphaeroides chromatophore membranes containing mutant reaction centers. The mutant reaction centers were expressed in a background strain of Rb. sphaeroides which contained only B880 antenna complexes and no B800-850 antenna complexes. The excited state decay times in the isolated reaction centers from these strains were previously shown to vary by roughly 15-fold, from 3.4 to 52 ps, due to differences in the charge separation rates in the different mutants (Allen and Williams (1995) J Bioenerg Biomembr 27: 275-283). In this study, measurements were also performed on wild type Rhodospirillum rubrum and Rb. sphaeroides B880 antenna-only mutant chromatophores for comparison. The emission kinetics in membranes containing mutant reaction centers was complex. The experimental data were analyzed in terms of a kinetic model that involved fast excitation migration between antenna complexes followed by reversible energy transfer to the reaction center and charge separation. Three emission time constants were identified by fitting the data to a sum of exponential decay components. They were assigned to trapping/quenching of antenna excitations by the reaction center, recombination of the P(+)H(-) charge-separated state of the reaction center reforming an emitting state, and emission from uncoupled antenna pigment-protein complexes. The first varied from 60 to 160 ps, depending on the reaction center mutation; the second was 200-300 ps, and the third was about 700 ps. The observed weak linear dependence of the trapping time on the primary charge separation time, together with the known sub-picosecond exciton migration time within the antenna, supports the concept that it is energy transfer from the antenna to the reaction center, rather than charge separation, that limits the overall energy trapping time in wild type chromatophores. The component due to charge recombination reforming the excited state is minor in wild type membranes, but increases substantially in mutants due to the decreasing free energy gap between the states P(*) and P(+)H(-).


Effect of liver fibrosis on long-term mortality in HIV/hepatitis C virus-coinfected individuals who are evaluated to receive interferon therapies in the highly active antiretroviral therapy era.
The factors associated with overall mortality and liver decompensation in HIV and hepatitis C virus (HCV)-coinfected patients who are evaluated to receive HCV antiviral therapy with a known liver histological fibrosis stage were evaluated in a prospective cohort study. A total of 387 consecutive HIV/HCV-coinfected patients attending an outpatient clinical unit between January 1997 and December 2007 who fulfilled criteria to be treated with interferon and to whom liver biopsy was performed were included and followed every 6 months from time of liver biopsy to death or to December 2008. The follow-up period was 6.2 years (IQR: 3.5-9.2). The median age at time of liver biopsy was 38 years. This included 73% men; 28% had advanced liver fibrosis (F3-F4) and a CD4 cell count of 556 cells/mm(3), 72% had HIV RNA <400 copies/ml and a mean CD4 nadir of 207 cell/mm(3), 21% had a previous diagnosis of AIDS, and 92% were on antiretroviral therapy. During follow-up 48% underwent HCV antiviral therapy, with a sustained virological response in 33%. The overall mortality rate and the incidence of liver decompensation or liver-related death were 1.17 and 0.72 per 100 patients-year, respectively. End stage liver disease (9/28 patients) and non-AIDS-related cancer (6/28) were the main causes of death. F3-F4 (HR: 3.74, 95% CI: 1.69-8.26, p=0.001) and previous AIDS diagnosis (HR: 3.04, 95% CI: 1.36-6.81) were the factors independently associated with death. Mortality rates in patients who received and who did not receive HCV antiviral therapy were 0.44 and 2.04 per 100 patients-year, respectively (p=0.003). In addition to the low mortality rate observed, HIV/HCV-coinfected patients with poor predictors of survival are candidates for intensive clinical management.


Impact of vertebral deformities, osteoarthritis, and other chronic diseases on quality of life: a population-based study.
Vertebral deformities and spinal osteoarthritis are common disorders in elderly persons and are associated with back pain, impaired physical functioning, and loss of quality of life. The objectives of this study were to assess the impact of vertebral deformities and osteoarthritis on quality of life in a population-based sample, and to compare this with the impact of six other important chronic diseases on quality of life. The study was performed as a substudy of the Longitudinal Aging Study Amsterdam. Vertebral deformities and osteoarthritis were assessed by spinal radiographs; chronic diseases were assessed by self-report; quality of life was estimated by the SF-12, EQ-5D (EuroQol) and Qualeffo-41 (n = 336). In univariate analyses, severe osteoporosis of the vertebrae significantly worsened the physical component summary scale of the SF-12 and the total score of Qualeffo-41, while osteoarthritis of the spine did not significantly reduce quality of life. The other chronic diseases reduced quality of life, although not all changes reached statistical significance. In multivariate analyses, severe osteoporosis of the vertebrae, cardiac disease, peripheral arterial disease, and diabetes mellitus significantly reduced quality of life. In conclusion, most persons in an elderly population suffer from one or more chronic diseases, and therefore experience loss of quality of life. After adjustment for age, sex, and other chronic diseases, severe osteoporosis of the vertebrae, cardiac disease, peripheral arterial disease, and diabetes mellitus significantly reduced quality of life in the general population.


Operational definitions improve reliability of the age-related white matter changes scale.
Although the age-related white matter changes (ARWMC) scale has been advocated to be applicable to both MRI and CT for assessing the severity of WMC, its inter-rater reliability on CT is only fair. We aimed to operationalize the ARWMC scale and investigate the effect of this operationalization on the reliability and validity on MRI and CT. Operational definitions of the ARWMC scale were derived from Erkinjuntti research criteria for subcortical vascular dementia and Scheltens scale. Using original and operationalized ARWMC scale, eight observers recorded the time for rating per MRI and per CT. We investigated the inter-rater and intrarater reliability as well as validity against volume using data from 97 stroke patients. Inter-rater reliability of the operationalized scale on CT (0.874, 95% confidence interval [0.780-0.934]) was better than the original scale (0.569, 95% confidence interval [0.247-0.775]). Its intrarater reliability on CT (0.869) and reliability on MRI (inter-rater: 0.860; intrarater: 0.838) was comparable with the original scale (CT intrarater: 0.750 and on MRI inter-rater: 0.845; intrarater: 0.853). The time required to administer the operationalized scale (4'2″ for MRI and 1'18″ for CT) was similar to that of the original scale (3'56″ for MRI and 1'16″ for CT). The original scale and operationalized scale also significantly correlated with WMC volume (operationalized scale ρ = 0.613, P < 0.001, original scale ρ = 0.638, P < 0.001). Operational definitions improve the inter-rater reliability of ARWMC scale on CT, and it correlates with volumetric measurement.


COVLIAS 1.0: Lung Segmentation in COVID-19 Computed Tomography Scans Using Hybrid Deep Learning Artificial Intelligence Models.
COVID-19 lung segmentation using Computed Tomography (CT) scans is important for the diagnosis of lung severity. The process of automated lung segmentation is challenging due to (a) CT radiation dosage and (b) ground-glass opacities caused by COVID-19. The lung segmentation methodologies proposed in 2020 were semi- or automated but not reliable, accurate, and user-friendly. The proposed study presents a COVID Lung Image Analysis System (COVLIAS 1.0, AtheroPoint™, Roseville, CA, USA) consisting of hybrid deep learning (HDL) models for lung segmentation. The COVLIAS 1.0 consists of three methods based on solo deep learning (SDL) or hybrid deep learning (HDL). SegNet is proposed in the SDL category while VGG-SegNet and ResNet-SegNet are designed under the HDL paradigm. The three proposed AI approaches were benchmarked against the National Institute of Health (NIH)-based conventional segmentation model using fuzzy-connectedness. A cross-validation protocol with a 40:60 ratio between training and testing was designed, with 10% validation data. The ground truth (GT) was manually traced by a radiologist trained personnel. For performance evaluation, nine different criteria were selected to perform the evaluation of SDL or HDL lung segmentation regions and lungs long axis against GT. Using the database of 5000 chest CT images (from 72 patients), COVLIAS 1.0 yielded AUC of ~0.96, ~0.97, ~0.98, and ~0.96 (p-value < 0.001), respectively within 5% range of GT area, for SegNet, VGG-SegNet, ResNet-SegNet, and NIH. The mean Figure of Merit using four models (left and right lung) was above 94%. On benchmarking against the National Institute of Health (NIH) segmentation method, the proposed model demonstrated a 58% and 44% improvement in ResNet-SegNet, 52% and 36% improvement in VGG-SegNet for lung area, and lung long axis, respectively. The PE statistics performance was in the following order: ResNet-SegNet > VGG-SegNet > NIH > SegNet. The HDL runs in <1 s on test data per image. The COVLIAS 1.0 system can be applied in real-time for radiology-based clinical settings.


The genetics of levamisole resistance in the nematode Caenorhabditis elegans.
We have characterized a small group of genes (13 loci) in the nematode Caenorhabditis elegans that, when mutated, confer resistance to the potent anthelmintic levamisole. Mutants at the 7 loci conferring the most extreme resistance generally possess almost identical visible and pharmacological phenotypes: uncoordinated motor behavior, most severe in early larval life, extreme resistance to cholinergic agonists and sensitivity to hypo-osmotic shock. Mutants with exceptional phenotypes suggest possible functions for several of the resistance loci. The most extreme mutants can readily be selected by their drug resistance (211 mutants, as many as 74 alleles of one gene). The more common resistance loci are likely to be unessential genes, while loci identified by only a few alleles may be essential genes or genes conferring resistance only when mutated in a special way. We propose that these mutants represent a favorable system for understanding how a small group of related genes function in a simple animal. The extreme drug resistance of these mutants makes them useful tools for the genetic manipulation of C. elegans. And, as the most resistant class of mutants might lack pharmacologically functional acetyl-choline receptors (LEWIS et al. 1980), these mutants may also be of some neurobiological significance.


Characterization of a novel facultative Methylocystis species capable of growth on methane, acetate and ethanol.
A non-motile strain of Methylocystis, strain SB2, isolated from a spring bog in southeast Michigan, had a curved rod morphology with a typical type II intracytoplasmic membrane system. This organism expressed the membrane-bound or particulate methane monooxygenase (pMMO) as well as a chalkophore with high affinity for copper and did not express the cytoplasmic or soluble methane monooxygenase (sMMO). Strain SB2 was found to grow within the pH range of 6-9, with optimal growth at 6.8. Growth was observed at temperatures ranging between 10°C and 30°C, with no growth at 37°C. The DNA G+C content was 62.9 mol%. Predominant fatty acids were 18:1ω7c (72.7%) and 18:1ω9c (24%) when grown on methane. Phylogenetic comparisons based on both pmoA and 16S rRNA sequences indicated that this organism belonged to the Methylocystis genus, and was closely related to Methylocystis rosea SV97(T) and Methylocystis echinoides IMET10491(T) (98% 16S rRNA gene sequence similarity to both strains). DNA : DNA hybridizations indicated that strain SB2 had 70% similarity with M. rosea SV97(T) . Unlike M. rosea SV97(T) , strain SB2 was able to utilize not only methane for growth, but also ethanol and acetate. Furthermore, the predominant fatty acids in strain SB2 were different from those found in M. rosea SV97(T) , i.e. 54.2% and 39.7% of fatty acids are 18:1ω8 and 18:1ω7 in M. rosea SV97(T) , while 18:1ω8 is completely absent in strain SB2.


Oxidative stress and total antioxidant status in myocardial infarction.
Coronary artery disease is caused by the additive and interactive effects of inherited and environmental factors. Substantial evidence shows that reactive oxygen species (ROS) play a vital role in the aetiopathogenesis of atherosclerosis. Our study has been designed to evaluate the oxidative stress due to ROS and assess the antioxidant protection against ROS, in addition to the major risk factors, like lipid profiles, habit of smoking and conditions such as diabetes mellitus and hypertension, in myocardial infarction (MI) patients. World Health Organisation criteria were followed in the selection of the subjects. 150 patients with MI were included in the study along with equal number of age- and gender-matched controls. Malondialdehyde (MDA) and nitrite/nitrate levels were measured as markers of oxidative stress of free radical induced injury, and total antioxidant status was determined to assess the antioxidant protection against ROS, along with the lipid profiles. The levels of total cholesterol, low density lipoprotein cholesterol, triglycerides, MDA and nitrite/nitrate were found to be significantly high, while high density lipoprotein cholesterol and total antioxidant capacity were significantly low in MI patients compared to controls. Our study revealed the importance of determining the total antioxidant status in MI, in addition to the markers of oxidative stress and lipid profiles to enable the formulation of specific antioxidant therapies for an early intervention and better management of the disease. The study also suggests initiating lifestyle modifications as a preventive measure to reduce the burden of the disease.


Location of lesions associated with age-related maculopathy over a 10-year period: the Beaver Dam Eye Study.
To describe cumulative incidence and changes in retinal lesions associated with age-related maculopathy (ARM) by location over a 10-year period and to examine the relation of location of those lesions to progression of ARM. Persons ranging in age from 43 to 84 years and living in Beaver Dam, Wisconsin, at the time of a census (1987-1988) were examined two to three times over a 10-year period (n = 3684). Drusen area, size, and type; retinal pigment epithelium depigmentation; increased pigment; geographic atrophy; and neovascular macular degeneration were determined in each of nine macular subfields: central, inner and outer superior, inner and outer nasal, inner and outer inferior, and inner and outer temporal by grading of stereoscopic color fundus photographs. Late ARM was defined as presence of either geographic atrophy or neovascular ARM. Lesions were more likely to change or develop in specific locations. Drusen area increased most in the central circle. Compared with other quadrants, drusen greater than 125 micro m in diameter and soft indistinct or reticular drusen were most likely to develop in the superior or temporal quadrants, whereas pigmentary abnormalities were most likely to occur in the nasal or superior quadrants. In general, large drusen, soft indistinct drusen, and pigmentary abnormalities were more likely to develop in the inner circle versus the central and outer circles. The quadrant location of early ARM lesions in 72 persons in whom late ARM developed was generally similar to that in persons who did not have late ARM. However, persons who had geographic atrophy were more likely to have large drusen in the inner circle than in the outer circle, while those who did not have late ARM were more likely to have large drusen in the outer circle. Lesions associated with early ARM were more likely to develop in specific locations in the macular area, and persons with lesions closer to the fovea may be related to a higher risk of development of late ARM. The quadrant location of early ARM lesions does not appear to add additional information to the risk of development of late ARM.


Grignard reagents as deprotonation agents for oxazoline-amido-phenolate ligands: structural and catalytic implications with the role of halogen ions.
In this study, various halogen-substituted Grignard reagents were assessed as deprotonating agents for the oxazoline-amido-phenolate ligand, leading to the formation of magnesium complexes. The newly synthesized complexes with halogen substituents displayed three distinct coordinative modes, all extensively characterized through crystallographic methods. The introduction of halogen substituents induced changes in the Lewis acid properties of the complexes, thereby impacting their structural attributes and catalytic behavior during the initiation and propagation of ring polymerization of cyclic esters.


Impact of IDO activation and alterations in the kynurenine pathway on hyperserotonemia, NAD+ production, and AhR activation in autism spectrum disorder.
Hyperserotonemia is the most replicated biochemical anomaly associated with autism spectrum disorder (ASD) and has been reported in 35-46% of individuals with ASD. Serotonin is synthesised from the essential amino acid tryptophan (TRP). However, the main catabolic route of TRP is the kynurenine pathway (KP), which competes with serotonin synthesis when indoleamine dioxygenase (IDO) is activated. Using the same cohort of individuals with ASD, we used to report extensive studies of the serotonin/melatonin pathway, and found increased kynurenine (KYN), suggesting IDO activation in 58.7% of individuals with ASD (159/271), supported by a strong negative correlation between KYN/TRP ratio and miR-153-3p plasma levels, which negatively regulates IDO. IDO activation was associated with normoserotonemia, suggesting that IDO activation could mask hyperserotonemia which meant that hyperserotonemia, if not masked by IDO activation, could be present in ~94% of individuals with ASD. We also identified several KP alterations, independent of IDO status. We observed a decrease in the activity of 3-hydroxyanthranilate dioxygenase which translated into the accumulation of the aryl hydrocarbon receptor (AhR) selective ligand cinnabarinic acid, itself strongly positively correlated with the AhR target stanniocalcin 2. We also found a deficit in NAD+ production, the end-product of the KP, which was strongly correlated with plasma levels of oxytocin used as a stereotypical neuropeptide, indicating that regulated neuropeptide secretion could be limiting. These results strongly suggest that individuals with ASD exhibit low-grade chronic inflammation that is mediated in most cases by chronic AhR activation that could be associated with the highly prevalent gastrointestinal disorders observed in ASD, and explained IDO activation in ~58% of the cases. Taken together, these results extend biochemical anomalies of TRP catabolism to KP and posit TRP catabolism as a possible major component of ASD pathophysiology.


Proficiency of pediatric residents in performing neonatal endotracheal intubation.
Current guidelines of the Accreditation Council for Graduate Medical Education have restricted the amount of intensive care experience obtained during pediatric residency. The impact on performing procedures has not been evaluated. To determine the current level of competency in 1 common procedure, we investigated the proficiency of pediatric residents in performing neonatal endotracheal intubation during the academic years 1998-1999 and 2000-2001. Indication for intubation, number of attempts, and achievement of success were recorded by the respiratory therapist present for the procedure. Each intubation was scored according to the attempt on which intubation was successful. Indications for intubation were categorized as respiratory failure, delivery room resuscitation, and meconium-stained amniotic fluid. Competency was defined as a successful intubation occurring on the first or second attempt >or=80% of the time. Intubation scores were compared between residents at various stages of training and analyzed by multivariate logistic regression analysis for significance. Comparisons were then performed to determine percentage success with confidence intervals. We also surveyed previous graduates of the training program not included in the observations for this study and asked them to indicate how frequently they perform intubation in current practice and to assess their own competence in the procedure. A total of 449 resident procedures were observed during the study periods: 192 by postgraduate year 1 (PGY-1) residents, 126 by PGY-2 residents, and 131 by PGY-3 residents. A total of 35% (160 of 449) of intubation procedures were never successful by pediatric house officers. Intubation was successful on the first or second attempt for 50% of PGY-1 residents (95% confidence interval [CI]: 42.6-56.8), 55% of PGY-2 residents (95% CI: 46-63.5), and 62% of PGY-3 residents (95% CI: 53.9-70.7). The third-year residents exhibited a significantly higher likelihood of performing a successful intubation compared with first-year residents. The first-year residents in 1998-1999 showed no improvement by their third year in 2000-2001. Surveys were sent to 56 graduates of our residency program (1998-2000). Completed surveys were received from 31 (66%) of 47. A total of 71% of the respondents are practicing general pediatrics, and 36% attend deliveries or perform intubations. A total of 87% reported that their level of confidence with endotracheal intubation was good or excellent after completion of residency training. We provide objective and subjective data concerning the proficiency of pediatric residents in performing neonatal endotracheal intubation. None of our resident groups met the specified definition of technical competence, although there was improvement with advancing training level in bivariate analyses. However, graduates of our training program felt confident with their intubation skills in contrast to our objective findings. As exposure to these important skills becomes limited, methods to ensure attainment of technical competency during training may need to be redefined.


A nanotree-like CdS/ZnO nanocomposite with spatially branched hierarchical structure for photocatalytic fine-chemical synthesis.
Branched hierarchical CdS/ZnO nanocomposites have been synthesized for application toward photocatalytic fine-chemical synthesis. Growing ZnO nanorods on the surface of CdS nanowires boosts the light harvesting efficiency and charge separation as well as fast charge transport and collection. A Z-scheme mechanism under artificial solar light is also proposed.


Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1.
Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the μ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n=383), we identified a genome-wide significant association between therapeutic methadone dose (mean=68.0 mg, s.d.=30.1 mg) and rs73568641 (P=2.8 × 10-8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg day-1 of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8 mg, s.d.=33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n=241, P=3.9 × 10-2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n=1410, genetic score P=1.3 × 10-3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.


Laparoscopic duodenum and spleen-preserving total pancreatectomy: A novel surgical technique for pancreatic intraductal papillary mucinous neoplasms.
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is no longer a rarely diagnosed disease, because of the development of medical imaging. With a high incidence of canceration, especially in the main duct type, surgery is strongly recommended. Pancreatoduodenectomy, distal pancreatectomy and central pancreatectomy are applied in those cases. For this potentially malignant disease, function-preserving surgery seems more appropriate. An old female was enrolled in our research, who was diagnosed with IPMN. Diameter of the main pancreatic duct (MPD) was > 5 mm and lesions distributed to the whole pancreas. laparoscopic duodenum and spleen-preserving total pancreatoduodenectomy was carried out, which has not reported previously. We successfully performed laparoscopic duodenum and spleen-preserving total pancreatectomy, without major complications such as severe pancreatic fistula, postoperative bleeding, and delayed ischemia of duodenum and spleen. We consider laparoscopic duodenum and spleen-preserving total pancreatectomy is technically feasible, but a large sample of randomized controlled trials is needed to evaluate its safety, effectiveness and long-term outcome.


Gonadotropin-inhibitory hormone (GnIH) receptor gene is expressed in the chicken ovary: potential role of GnIH in follicular maturation.
Gonadotropin-inhibitory hormone (GnIH), an RFamide peptide, has been found to inhibit pituitary LH secretion in avian and mammalian species. The gene encoding a putative receptor for GnIH (GnIHR) was recently identified in the chicken and Japanese quail brain and pituitary gland. GnIHR appears to be a seven-transmembrane protein belonging to a family of G-protein-coupled receptors. In the present study, we have characterized the expression of GnIHR mRNA in the chicken ovary and demonstrate that GnIHR may exert an inhibitory effect on ovarian follicular development. By RT-PCR, we detected GnIHR mRNA in the chicken testis and in the ovary, specifically both thecal and granulosa cell layers. Real-time quantitative PCR analysis revealed greater GnIHR mRNA quantity in theca cells of prehierarchial follicles compared with that of preovulatory follicles. GnIHR mRNA quantity was significantly decreased in sexually mature chicken ovaries versus ovaries of sexually immature chickens. Estradiol (E(2)) and/or progesterone (P(4)) treatment of sexually immature chickens significantly decreased ovarian GnIHR mRNA abundance. Treatment of prehierarchial follicular granulosa cells in vitro with chicken GnIH peptide significantly decreased basal but not FSH-stimulated cellular viability. Collectively, our results indicate that the ovarian GnIHR is likely to be involved in ovarian follicular development. A decrease in ovarian GnIHR mRNA abundance due to sexual maturation or by E(2) and/or P(4) treatment would implicate an inhibitory role for GnIHR in ovarian follicular development. Furthermore, GnIH may affect follicular maturation by decreasing the viability of prehierarchial follicular granulosa cells through binding to GnIHR.


Representations of the Americans with Disabilities Act employment-related issues in the Wall Street Journal (1990-2008): a feasibility study.
This feasibility study examines the coverage of employment-related issues related to people with disabilities in the Americans with Disabilities Act of 1990. The study is a first in a series of future studies focusing on disability issues in the international economic media. A survey of 39 newspaper articles published in the Wall Street Journal, a leading and most circulated business newspaper in the USA. Specifically, it comprised articles taken from three periods: 1990, the year the Americans with Disabilities Act was enacted; 2000, a decade later; and 2008, the year the amendments were revised with respect to definitions and employment. Data were analyzed by quantitative and qualitative content analysis. The results suggest a mixed representation: a decline in negative representations of disability throughout the years alongside the emergence of a legal-fiscal discourse of a disability that depicts persons with disabilities as a fiscal burden on employers. It seems that the new image of disability presents conflicting interests between the mission of the law, promoting employers' hiring of people with disabilities, and the economic realities of accommodating them at the workplace. Additional research is needed to examine whether this image is unique to the economic media or may reflect a concern in the business community.


The irrelevant speech effect: a PET study.
Positron emission tomography (PET) was performed in normal volunteers during a serial recall task under the influence of irrelevant speech comprising both single item repetition and multi-item sequences. An interaction approach was used to identify brain areas specifically related to the irrelevant speech effect. We interpreted activations as compensatory recruitment of complementary working memory processing, and decreased activity in terms of suppression of task relevant areas invoked by the irrelevant speech. The interaction between the distractors and working memory revealed a significant effect in the left, and to a lesser extent in the right, superior temporal region, indicating that initial phonological processing was relatively suppressed. Additional areas of decreased activity were observed in an a priori defined cortical network related to verbal working memory, incorporating the bilateral superior temporal and inferior/middle frontal cortices extending into Broca's area on the left. We also observed a weak activation in the left inferior parietal cortex, a region suggested to reflect the phonological store, the subcomponent where the interference is assumed to take place. The results suggest that the irrelevant speech effect is correlated with and thus tentatively may be explained in terms of a suppression of components of the verbal working memory network as outlined. The results can be interpreted in terms of inhibitory top-down attentional mechanisms attenuating the influence of the irrelevant speech, although additional studies are clearly necessary to more fully characterize the nature of this phenomenon and its theoretical implications for existing short-term memory models.


Studies on a testosterone glucuronyltransferase from the cytosol fraction of human liver.
An enzyme that conjugates the 17beta-hydroxyl group of testosterone was found in the cytosol fraction of human liver. The same enzyme preparation also conjugates the 16alpha-hydroxyl group of oestriol. The enzymic activity could not be sedimented by centrifuging the cytosol fraction at 158000g(av.) for 120min. The testosterone-conjugating as well as the oestriol-conjugating activities were found in the precipitate obtained after 30% saturation of the cytosol fraction with ammonium sulphate. Filtration of the precipitate through Sephadex G-200 enriched the testosterone-conjugating enzyme 50-fold and the oestriol-conjugating enzyme 100-fold. No separation of the two activities was achieved. With labelled testosterone the product of the reaction, testosterone 17beta-glucuronide, was identified by paper chromatography and by crystallization to constant specific radioactivity. Testosterone 17beta-glucuronyltransferase was active between pH7.0 and 8.6 in tris-HCl and tris-maleate buffers. The apparent K(m) values for testosterone and UDP-glucuronic acid were 6.4 and 25mum respectively. The enzyme was active between 37 and 45 degrees C; the activation energy was calculated to be 5kcal/mol. Oestriol did not influence the glucuronidation of testosterone. Controlled heating as well as alternate freezing and thawing of the purified enzyme preparation led to an inactivation of both testosterone-conjugating and oestriol-conjugating activities at similar rates. Testosterone and oestriol, when incubated together, gave a reaction rate that was approximately equal to the sum of the rates when the two substrates were incubated separately. The present findings suggest that testosterone and oestriol are conjugated by two separate enzymes.


Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress.
Kallistatin, via its two structural elements - an active site and a heparin-binding domain - displays a double-edged function in angiogenesis, apoptosis and oxidative stress. First, kallistatin has both anti-angiogenic and pro-angiogenic effects. Kallistatin treatment attenuates angiogenesis and tumor growth in cancer-bearing mice. Kallistatin via its heparin-binding site inhibits angiogenesis by blocking vascular endothelial growth factor (VEGF)-induced growth, migration and adhesion of endothelial cells. Conversely, kallistatin via the active site promotes neovascularization by stimulating VEGF levels in endothelial progenitor cells. Second, kallistatin inhibits or induces apoptosis depending on cell types. Kallistatin attenuates organ injury and apoptosis in animal models, and its heparin-binding site is essential for blocking tumor necrosis factor (TNF)-α-induced apoptosis in endothelial cells. However, kallistatin via its active site induces apoptosis in breast cancer cells by up-regulating miR-34a and down-regulating miR-21 and miR-203 synthesis. Third, kallistatin can act as an antioxidant or pro-oxidant. Kallistatin treatment inhibits oxidative stress and tissue damage in animal models and cultured cells. Kallistatin via the heparin-binding domain antagonizes TNF-α-induced oxidative stress, whereas its active site is crucial for stimulating antioxidant enzyme expression. In contrast, kallistatin provokes oxidant formation, leading to blood pressure reduction and bacterial killing. Kallistatin-mediated vasodilation is partly mediated by H2O2, as the effect is abolished by the antioxidant enzyme catalase. Moreover, kallistatin exerts a bactericidal effect by stimulating superoxide production in neutrophils of mice with microbial infection as well as in cultured immune cells. Thus, kallistatin's dual roles in angiogenesis, apoptosis and oxidative stress contribute to its beneficial effects in various diseases.


Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.
Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular) and more rarely directly through endothelial cells (transcellular). Recently, we reported that unlike in wild-type (wt) mice, Mac-1-/- (CD11b) neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt). In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/-) were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.


Factors significant in the diagnostic accuracy of lung cytology in bronchial washing and sputum samples. II. Sputum samples.
Some factors influencing the detection of malignant cells in sputum samples were evaluated in 449 consecutive cases of primary lung carcinoma seen between 1959 and 1974. Diagnostic accuracy increased during the years under study; the reasons are discussed. The overall accuracy was 82.8%. Detection of malignant cells was 85% for small-cell carcinoma, squamous-cell carcinoma and large-cell carcinoma, 75% for adenocarcinoma, bronchioloalveolar carcinoma and adenosquamous carcinoma and 64% for the uncommon tumors. Accuracy was 87% for central tumors and 42% for peripheral lesions. Tumors less than 2 cm in diameter yielded only 39% accuracy as compared to 90% for larger tumors. The specificity of diagnosis of cell type in those specimens with malignant cells was 95% for small-cell carcinoma and squamous-cell carcinoma, more than 80% for adenocarcinoma and large-cell carcinoma, 65% for bronchioloalveolar-cell carcinoma and adenosquamous carcinoma and less than 30% for the uncommon tumors. Diagnostic accuracy was optimal in those cases with three or more sputum samples: 83% for those with three samples and 90% for those with five or more samples per case. The use of both sputum and bronchial specimens was complementary and increased the accuracy further. Reasons for unsatisfactory specimens included no deep cough, limited cellular material, excessive blood or leukocytes and drying artifacts; the first two were the most common causes.


A thyroid hormone analog stimulates angiogenesis in the post-infarcted rat heart.
In view of the evidence that thyroid hormone administration has angiogenic effects on the hypertrophic myocardium, we tested the hypothesis that the capillary supply in the hypertrophic myocardium surviving infarction would be improved by administration of the thyroid hormone analog, diiodothyroproprionic acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to rats for 10 days following experimental infarction of the left ventricle (LV). Morphometric methods were used to assess capillarity and myocyte cross-sectional area in three regions of the left ventricle: (1) border (next to the scar of infarction); (2) adjacent (next to the border); and (3) remote (interventricular septum). Infarct size ranged from 20-85% of the LV free-wall, and both groups had similar mean infarct size. Capillary length density (LV) was significantly higher in the remote region of the treated group than in the MI-saline rats. LV in the border region, which experienced the most marked increase in cardiocyte cross-sectional area, was not significantly lower than in the other regions, indicating a more marked angiogenic response. In hearts with large infarcts (> or = 40%) LV in the border region was higher in the DITPA group than in the non-treated rats. In the MI-DITPA group, cardiocyte size in the border region was positively correlated with that of the other regions, which contrasts with the negative correlations noted for the MI-saline rats. These data suggest that DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied myocardium surviving a myocardial infarction, and (2) is selectively effective in the border region of hearts with large infarcts.


Drivers and barriers in the practice of health-specific leadership: A qualitative study in healthcare.
Managers have a significant impact on the health and well-being of employees, particularly when the managers lead in a health-specific way and intentionally foster their employees' health. However, the data on contextual and individual factors influencing the practice of health-specific leadership is at present limited. To survey the experiences of healthcare managers with health-specific leadership skills and identify the drivers and barriers in the practice of health-specific leadership. Semi-structured interviews were conducted with 51 managers from 18 geriatric-care facilities in Germany, between November 2014 and February 2015. The interviews were analysed through qualitative content analysis. In their reports, managers mentioned several drivers and barriers in the practice of health-specific leadership. These drivers and barriers were found at the leader level, the employee level, and the organizational level. The factors identified relate to the theoretical aspects of health-specific leadership: health value, health awareness, health behaviour, and role modelling. For successful practice of health-specific leadership, the findings suggest a more holistic approach for worksite health promotion. Managers should promote personal initiative that benefit employee health, encourage their employees to exhibit healthy behaviour themselves, address organizational resources and restrictions, and gain competencies in change management.


Primary cutaneous CD30+ lymphoproliferative disorders with DUSP22 translocation.
Primary cutaneous CD30+ lymphoproliferative disorders (LPD) encompass a broad category of clonal T cell proliferations with varied clinical presentations. Classically, lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) have been recognized as distinct clinicopathological entities according to their differing clinical features. Recently, a subset of LyP and both cutaneous and systemic ALCL have been shown to carry a DUSP22 translocation [1-3], a defining molecular feature for the novel entity "LyP with DUSP22t" [1]. In cutaneous biopsies, both primary cutaneous DUSP22-translocated ALCL and LyP with DUSP22 rearrangements are characterized by a biphasic pattern with significant small cell epidermotropism. A distinct protein expression profile with preserved T Cell Receptor (TCR) expression, positivity for CD30, LEF1, HLA, and CD58, and negativity for cytotoxic marker expression as well as phospho-STAT3 protein is consistently found in these cases.


The all-ceramic, inlay supported fixed partial denture. Part 1. Ceramic inlay preparation design: a literature review.
The effect of cavity design is a controversial and underrated factor in the clinical success of ceramic inlays and inlay supported prosthesis. Many articles and studies have been conducted into the advantages and disadvantages of isolated aspects of preparation design, but lacking is a review of the most relevant papers which bring together a consensus on all the critical features. Hence, a review and analysis of cavity depth, width, preparation taper and internal line angles is warranted in our attempts to formulate preparation guidelines that will lead to clinically successful, all-ceramic inlay restorations and ceramic inlay supported prosthesis.


Mistletoe lectins and their A and B chains.
Mistletoe lectins are of high biological activity. The mistletoe lectin I (ML I) is a naturally occurring conjugate of an enzyme (A chain) and a lectin (B chain). Its cytotoxicity is caused by inhibiting the protein synthesis on the ribosomal level. Prominent properties of the A chain are mitogenicity and inhibition of the protein synthesis in cell-free systems. The A chain is also a candidate for the construction of immunotoxins. The B chain as well as the intact lectins activate macrophages and release lymphocytes. They both inhibit the allergen-induced histamine release from leukocytes and the collagen-induced serotonin release from platelets. It cannot be excluded that the combination of selectively cytotoxic and immunopotentiating properties of mistletoe lectins and their chains are decisive for the therapeutic effects of mistletoe preparations.


Studies of all-trans-retinal as a photooxidizing agent.
The photophysical properties of all-trans-retinal (RAL) have been extensively studied because of the importance of the retinoids in the visual process. However, little information is available regarding the participation of RAL in photochemical transformations such as photoxidation. RAL is one of several native chromophores that have been suggested to act as photosensitizers of damage in the human retina, and this damage would likely occur through oxidative pathways. Time-resolved and steady state techniques have been used to examine the photoreactivity of RAL toward several suitable substrates. The lifetime of the RAL triplet excited state is observed to decrease with increasing concentration of the well-known electron and hydrogen atom donors, 2,3,5,6-tetramethyl-1,4-phenylenediamine (DAD), hydroquinone (HQ), methylhydroquinone (MHQ), 2,3-dimethylhydroquinone (DMHQ) and trimethylhydroquinone (TMHQ), although the bimolecular rate constants for the reaction are much less than that of diffusion controlled (2.9 x 10(7) M-1 s-1, 1.2 x 10(5) M-1 s-1, 1.2 x 10(5) M-1 s-1, 1.5 x 10(5) M-1 s-1 and 1.6 x 10(6) M-1 s-1, for DAD, HQ, MHQ, DMHQ and TMHQ, respectively). In the presence of the donors, new absorptions grow concomitant with the decay of the triplet excited state, and for DAD and TMHQ, the observed spectra are similar to the spectra of p-phenylenediamine and TMHQ radicals. Irradiation of RAL in argon-saturated methanol results in fairly efficient photobleaching of RAL and in the formation of two new compounds having absorption spectra that are shifted below 300 nm. Irradiation of RAL in argon-saturated acetonitrile also results in photobleaching of RAL, but the reaction proceeds at a slower rate.


Neutralization of influenza virus by normal human sera: mechanisms involving antibody and complement.
All normal human sera examined neutralized WS/33 H1N1 influenza virus efficiently by one of two antibody-dependent mechanisms. A minority of the sera contained moderate levels of IgG antibody directed against the viral hemagglutinin that had the ability to directly neutralize the virus. The majority of sera tested contained very low levels of IgG anti-hemagglutinin antibody, which was detectable with a specific ELISA but not by conventional HAI assays. Such IgG antibody was unable to directly neutralize the virus. Studies with agammaglobulinemic serum and with sera depleted of and reconstituted with complement components established essential roles for IgG and the components of the classical complement pathway through C3 for neutralization. The components of the alternative and membrane attack pathways were not needed for neutralization. As anticipated from the requirement for IgG and exclusive mediation of neutralization by the classical pathway, the virus-IgG immune complex activated purified C1. Binding of C3 and C4 to the virus was demonstrated, as was classical pathway-mediated triggering of the alternative pathway, with recruitment of properdin. In addition, the H1N1 influenza virus also directly activated the alternative complement pathway in human serum, leading to C3 and properdin deposition on the viral envelope. Such direct alternative pathway activation also required immunoglobulin. However, the alternative pathway alone was unable to neutralize the virus. Thus, most normal sera examined contain low levels of IgG anti-hemagglutinin antibody, which activate the classical pathway of the complement system and neutralize WS/33 influenza virus by deposition of C3 and C4 on the viral envelope.


Negative inotropic effect of platelet-activating factor on human myocardium: a pharmacological study.
Because platelet-activating factor (PAF) has prominent depressant effects on cardiac contractility in various mammalian species, we assessed the negative inotropic effect of PAF on non-coronary perfused human right atrial pectinate muscles paced at constant rate. We found that PAF is a potent negative inotropic agent (EC50 approximately equal to 160 pM), whose action is unmodified by atropine, indomethacin and the leukotriene receptor antagonist compound FPL 55712. The negative inotropic effect of PAF was, however, antagonized by drugs known to inhibit PAF-induced platelet aggregation: the order of relative potency was SRI 63-441 greater than CV-3988 greater than alprazolam greater than or equal to triazolam; i.e., the same order in which these compounds antagonize the effects of PAF on platelets. Thus, the potent negative inotropic effect of PAF on human myocardium is independent of coronary flow changes, involves neither cholinergic mechanisms nor arachidonate metabolites and is probably mediated by specific receptors.


Characteristics of fetal and maternal heart rate tracings during labor: A prospective observational study.
Fetal well-being is assured during labor and delivery with the employment of electronic fetal heart monitoring (EFHM). In uncommon instances, maternal heart rate (MHR) instead of fetal heart rate (FHR) can be the source of signals on monitors (signal ambiguity) leading to erroneous interpretation and management. Information about MHR characteristics are comparatively inadequate. We aim to analyze and compare MHR and FHR characteristics during the first and second stages of labor. A prospective cohort study was conducted in a single tertiary care center during a one year period. Fifty one healthy full term women with singleton pregnancies during labor were enrolled. Uterine contractions, MHR and FHR were recorded simultaneously during both stages of labor by monitors designed for twin gestation. When compared to FHR, MHR had significantly lower baseline rate during 1st and 2nd stages (p < 0.0001). It demonstrated also more marked beat-to-beat variability during both stages (p < 0.0001). MHR showed significantly more accelerations (p = 0.03 and p = 0.008) and less decelerations (p < 0.0001 and p = 0.021) during 1st and 2nd stages respectively. All characteristic parameters and patterns produced by FHR could be mimicked by MHR as well, though, at different frequencies. Understanding EFHM patterns suspected to be MHR artefacts and the employment of modern monitors that simultaneously obtain and display FHR and MHR can unmask ambiguity and avert related misinterpretation problems. Similar studies should be conducted in high-risk groups where the potential for fetal hypoxia/acidosis is increased.


Direct mail solicitation of contributions from poison center users--success or failure?
Funding problems seem to be an ever present obstacle for Regional Centers. To date, there has not been an effective solution for many, if not all, the centers. An often raised suggestion is the direct solicitation of the users of the services of the Poison Center. On March 1, 1985, the Blodgett Regional Poison Center (BRPC) initiated a direct solicitation project. For most BRPC calls involving a "patient", a packet containing informational and educational materials was mailed to the caller. This packet also included a letter requesting a donation to BRPC to help defray operational expenses. The letter suggested a $10.00 donation, or any amount the individual could afford. Results through the first 5 months of this project are presented with copies of all materials used in the solicitation.


Recent developments of DNA poisons--human DNA topoisomerase IIα inhibitors--as anticancer agents.
DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field. The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase IIα inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase IIα. In particular, this review focuses on the currently available structure-based standpoint of molecular design and on the medicinal chemist's perspective of this field of anticancer drug design.