Multi-task diagnosis for autism spectrum disorders using multi-modality features: A multi-center study.
Autism spectrum disorder (ASD) is a neurodevelopment disease characterized by impairment of social interaction, language, behavior, and cognitive functions. Up to now, many imaging-based methods for ASD diagnosis have been developed. For example, one may extract abundant features from multi-modality images and then derive a discriminant function to map the selected features toward the disease label. A lot of recent works, however, are limited to single imaging centers. To this end, we propose a novel multi-modality multi-center classification (M3CC) method for ASD diagnosis. We treat the classification of each imaging center as one task. By introducing the task-task and modality-modality regularizations, we solve the classification for all imaging centers simultaneously. Meanwhile, the optimal feature selection and the modeling of the discriminant functions can be jointly conducted for highly accurate diagnosis. Besides, we also present an efficient iterative optimization solution to our formulated problem and further investigate its convergence. Our comprehensive experiments on the ABIDE database show that our proposed method can significantly improve the performance of ASD diagnosis, compared to the existing methods. Hum Brain Mapp 38:3081-3097, 2017. © 2017 Wiley Periodicals, Inc.


The "STATE" of home care & hospice.
This issue of CARING is focusing on the new dimensions in home care technology. As a group, the home care industry's trade associations have been in the vanguard, promoting technological advancements to their provider members. Many of our home care and hospice associations, including the National Association for Home Care & Hospice (NAHC), have made the idea of promoting the use of new technology, a strategic priority.


Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease.
Background: Most research in genomics of Parkinson's disease (PD) has been done in subjects of European ancestry, leading to sampling bias and leaving Latin American populations underrepresented. We sought to clinically characterize PD patients of Costa Rican origin and to sequence familial PD and atypical parkinsonism-associated genes in cases and controls. Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, and motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, and ATP13A2. Results: Mean age of PD probands was 62.12 ± 13.51 years; 57.6% were male. The frequency of risk and protective factors averaged ~45%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders, and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD; six were located between amino acids p.1620 and 1623 in the C-terminal-of-ROC (COR) domain of Lrrk2. Non-synonymous GBA variants (p.T369M, p.N370S, and p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R. Discussion: This is the first study that describes sociodemographics, risk factors, clinical presentation, and genetics of Costa Rican patients with PD, adding information to genomics research in a Latino population.


Chemotherapy-induced hypomethylation of N-myc downstream-regulated gene 4 in the bone marrow of patients with acute myeloid leukemia.
N-myc downstream-regulated gene 4 (NDRG4) has previously been investigated as a possible tumor suppressor. Hypermethylation of tumor suppressor genes contributes to the occurrence and development of certain types of cancer, including acute myeloid leukemia (AML). The current study aimed to assess the contribution of chemotherapy-induced NDRG4 changeable methylation to the development of AML. A total of 30 patients (13 males and 17 females) were involved in the present study. The DNA methylation levels of five C-phosphate-G sites of the NDRG4 gene were measured using bisulfite pyrosequencing techniques. The results indicated significantly reduced gene-body methylation levels of NDRG4 during chemotherapy (prior to chemotherapy: 9.35±4.22%; following chemotherapy: 7.54±3.11%; P=0.030). Further analysis of AML subtypes revealed the methylation reductions were principally contributed by patients with M2 subtype AML (prior to chemotherapy: 9.91±4.76%; following chemotherapy: 5.26±1.16%; P=0.038). A significant association was also observed between the patient age and the altered levels of NDRG4 gene-body methylation in patients with M2 subtype AML (r=0.761; P=0.047), suggesting that reductions in induced-methylation may be age-dependent in patients with M2 subtype AML during chemotherapy. Therefore, age may affect the induced methylation levels of NDRG4 gene-body in patients with AML (particularly patients with M2 subtype AML) during chemotherapy.


Staphylococcus aureus Multiplexes Death-Effector Deoxyribonucleosides to Neutralize Phagocytes.
Adenosine synthase A (AdsA) is a key virulence factor of Staphylococcus aureus, a dangerous microbe that causes fatal diseases in humans. Together with staphylococcal nuclease, AdsA generates deoxyadenosine (dAdo) from neutrophil extracellular DNA traps thereby igniting caspase-3-dependent cell death in host immune cells that aim at penetrating infectious foci. Powered by a multi-technological approach, we here illustrate that the enzymatic activity of AdsA in abscess-mimicking microenvironments is not restricted to the biogenesis of dAdo but rather comprises excessive biosynthesis of deoxyguanosine (dGuo), a cytotoxic deoxyribonucleoside generated by S. aureus to eradicate macrophages of human and animal origin. Based on a genome-wide CRISPR-Cas9 knock-out screen, we further demonstrate that dGuo-induced cytotoxicity in phagocytes involves targeting of the mammalian purine salvage pathway-apoptosis axis, a signaling cascade that is concomitantly stimulated by staphylococcal dAdo. Strikingly, synchronous targeting of this route by AdsA-derived dGuo and dAdo boosts macrophage cell death, indicating that S. aureus multiplexes death-effector deoxyribonucleosides to maximize intra-host survival. Overall, these data provide unique insights into the cunning lifestyle of a deadly pathogen and may help to design therapeutic intervention strategies to combat multidrug-resistant staphylococci.


CM-Net: Concentric Mask Based Arbitrary-Shaped Text Detection.
Recently fast arbitrary-shaped text detection has become an attractive research topic. However, most existing methods are non-real-time, which may fall short in intelligent systems. Although a few real-time text methods are proposed, the detection accuracy is far behind non-real-time methods. To improve the detection accuracy and speed simultaneously, we propose a novel fast and accurate text detection framework, namely CM-Net, which is constructed based on a new text representation method and a multi-perspective feature (MPF) module. The former can fit arbitrary-shaped text contours by concentric mask (CM) in an efficient and robust way. The latter encourages the network to learn more CM-related discriminative features from multiple perspectives and brings no extra computational cost. Benefiting the advantages of CM and MPF, the proposed CM-Net only needs to predict one CM of the text instance to rebuild the text contour and achieves the best balance between detection accuracy and speed compared with previous works. Moreover, to ensure that multi-perspective features are effectively learned, the multi-factor constraints loss is proposed. Extensive experiments demonstrate the proposed CM is efficient and robust to fit arbitrary-shaped text instances, and also validate the effectiveness of MPF and constraints loss for discriminative text features recognition. Furthermore, experimental results show that the proposed CM-Net is superior to existing state-of-the-art (SOTA) real-time text detection methods in both detection speed and accuracy on MSRA-TD500, CTW1500, Total-Text, and ICDAR2015 datasets.


A concept analysis of the role of fatherhood: a Japanese perspective.
A concept analysis of the father's role is presented from a Japanese perspective. To conceptualize the term father's role, the process for concept analysis was employed. The analysis resulted in a definition of the term and four defining attributes. Two dimensions of the father's role emerged as being most commonly used or implied: a behavioral dimension and a consequential dimension. Each of these dimensions had another four subcategories in terms of the direction of the consequences: those were to the child, the mother, the family, and the father himself. The findings will assist in instrument development and to a further understanding of the concept that will stimulate nursing theory development and research.


Diprolene cream in the treatment of severe or resistant corticosteroid-responsive dermatoses.
In a 2-week open study Diprolene Cream was administered to fifty patients with severe or resistant psoriasis, atopic dermatitis or other corticosteroid-responsive dermatoses. Patients applied 3.5 grams of medication twice daily. Efficacy and safety of this preparation were evaluated in forty-seven and fifty patients, respectively. By the third treatment day, therapeutic response was observed in forty-three of forty-seven (91%) evaluable patients. By treatment Day 14, an 83% decrease in the mean total severity score of signs and symptoms was observed in twenty-two psoriatic patients. Similarly, a 91% reduction in the mean total severity score of signs and symptoms was observed in the twenty-five patients with other severe or resistant corticosteroid-responsive dermatoses. Transient burning was reported by twenty-five patients, one of whom also developed laminar scaling. Therapy was not discontinued in any of these patients, and none required treatment. Morning plasma cortisol levels remained within normal limits during and after therapy.


Involvement of liver carboxylesterases in the in vitro metabolism of lidocaine.
Although lidocaine has been used clinically for more than half a century, the metabolism has still not been fully elucidated. In the present study we have addressed the involvement of hydroxylations, deethylations, and ester hydrolysis in the metabolism of lidocaine to 2,6-xylidine. Using microsomes isolated from male rat liver, we found that lidocaine is mainly metabolized by deethylation to N-(N-ethylglycyl)-2,6-xylidine, and N-(N-ethylglycyl)-2,6-xylidine is mainly metabolized to N-glycyl-2,6-xylidine, also by deethylation. However, 2,6-xylidine can be formed both from lidocaine and N-(N-ethylglycyl)-2,6-xylidine, but not from N-glycyl-2,6-xylidine, in an NADPH-independent reaction, suggesting that the amido bond in these compounds can be directly hydrolyzed by esterases. To test this hypothesis, we incubated lidocaine, N-(N-ethylglycyl)-2,6-xylidine, and N-glycyl-2,6-xylidine with purified liver carboxylesterases. Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzed lidocaine and N-(N-ethylglycyl)-2,6-xylidine to 2,6-xylidine, identifying this esterase as a candidate enzyme in the metabolism of lidocaine.


Indication criteria for monoclonal antibody treatment for COVID-19 in the era of vaccination: is an update needed?
This study describes a cohort of 223 patients who received anti-S protein monoclonal antibody (mAb) treatment for COVID-19 after having met the indication criteria set by the national guidelines in the Czech Republic at the time. The authors compare the vaccinated and unvaccinated subpopulations of this cohort. The results show that most of the patients (73.5%) already had significant circulating levels of anti-S antibodies detectable at the time of treatment. The authors confirm a positive correlation between number of vaccine doses and S-protein antibody levels. The data show, that vaccinated patients are overall less likely to be hospitalized than unvaccinated ones. The authors recommend a change in the national guidelines for mAb treatment in the Czech Republic.


Comparative Analysis of the Impact of Three Drying Methods on the Properties of Citrus reticulata Blanco cv. Dahongpao Powder and Solid Drinks.
Citrus reticulata Blanco cv. Dahongpao is a traditional Chinese citrus variety. Due to the high investment in storage and transport of Citrus reticulata Blanco cv. Dahongpao and the lack of market demand, the fresh fruit is wasted. The processing of fresh fruit into fruit drinks can solve the problem of storage and transport difficulties and open up new markets. Investigating the effects of different drying processes (hot air, freeze, and spray drying) on fruit powders is a crucial step in identifying a suitable production process. The experiment measured the effects of different drying methods (hot air drying, freeze drying, and spray drying) on the nutrient, bioactive substance, and physical characteristics of fruit powder. This study measured the influence of three different drying methods (hot air, freeze, and spray drying) on the nutritional, bioactive substance, and physical characteristics of fruit powder. The results showed that compared to vacuum freeze-drying at low temperature (-60 °C) and spray-drying at high temperatures (150 °C), hot air drying at 50 °C produced fruit powder with superior nutritional quality, higher levels of active substances, and better physical properties. Hot air drying produced fruit powder that had the highest content of amino acids (11.48 ± 0.08 mg/g DW), vitamin C (112.09 ± 2.86 μg/g DW), total phenols (14.78 ± 0.30 mg/g GAE DW), total flavonoids (6.45 ± 0.11 mg/g RE DW), organic acids, and antioxidant activity capacity. Additionally, this method yielded the highest amounts of zinc (8.88 ± 0.03 mg/Kg DW) and soluble sugars, low water content, high solubility, and brown coloration of the fruit powder and juice. Therefore, hot air drying is one of the best production methods for producing high-quality fruit powder in factory production.


Diverse characters of Brennan's paw incision model regarding certain parameters in the rat.
Brennan's rodent paw incision model has been extensively used for understanding mechanisms underlying postoperative pain in humans. However, alterations of physiological parameters like blood pressure and heart rate, or even feeding and drinking patterns after the incision have not been documented as yet. Moreover, though eicosanoids like prostaglandins and leukotrienes contribute to inflammation, tissue levels of these inflammatory mediators have never been studied. This work further investigates the antinociceptive effect of protein C after intra-wound administration. Separate groups of Sprague-Dawley rats were used for quantitation of cyclooxygenase (COX) activity and leukotriene B4 level by enzyme-linked immunosorbent assay, as well as estimation of cardiovascular parameters and feeding and drinking behavior after paw incision. In the next part, rats were subjected to incision and 10 µg of protein C was locally administered by a micropipette. Both evoked and non-evoked pain parameters were then estimated. COX, particularly COX-2 activity and leukotriene B4 levels increased after incision. Hemodynamic parameters were normal. Feeding and drinking were affected on days 1 and 3, and on day 1, respectively. Protein C attenuated non-evoked pain behavior alone up to day 2. Based upon current observations, Brennan's rodent paw incision model appears to exhibit a prolonged period of nociception similar to that after surgery, with minimal interference of physiological parameters. Protein C, which is likely converted to activated protein C in the wound, attenuated the guarding score, which probably represents pain at rest after surgery in humans.


The impact of dose of FSH (Folltropin) containing LH (Lutropin) on follicular development, estrus and ovulation responses in prepubertal gilts.
FSH is favored over chorionic gonadotropins for induction of estrus in various species, yet little data are available for its effects on follicle development and fertility for use in pigs. For Experiment 1, prepubertal gilts (n = 36) received saline, 100 mg FSH, or FSH with 0.5 mg LH. Treatments were divided into six injections given every 8 h on Days 0 and 1. Proportions of gilts developing medium follicles were increased for FSH and FSH-LH (P < 0.05) compared to saline, but follicles were not sustained and fewer hormone-treated gilts developed large follicles (P < 0.05). No gilts expressed estrus and few ovulated. Experiment 2 tested FSH preparations with greater LH content. Prepubertal gilts (n = 56) received saline, FSH-hCG (100 mg FSH with 200 IU hCG), FSH-LH5 (FSH with 5 mg LH), FSH-LH10 (FSH with 10 mg LH), or FSH-LH20 (FSH with 20 mg LH). FSH-LH was administered as previously described, while 100 IU of hCG was given at 0 h and 24 h. Hormone treated gilts showed increased (P < 0.05) medium and large follicle development, estrus (>70%), ovulation (100%), and ovulation rate (>30 CL) compared to saline. There was an increase (P < 0.05) in the proportion of hormone-treated gilts with follicular cysts at Day 5, but these did not persist to Day 22. These gilts also showed an increase in poorly formed CL (P < 0.05). FSH alone or with small amounts of LH can induce medium follicle growth but greater amounts of LH at the same time is needed to sustain medium follicles, stimulate development of large follicles and induce estrus and ovulation in prepubertal gilts.


Synchronous identification of a dysembryoplastic neuroepithelial tumor (DNET) and an oligodendroglioma in a patient: A case report.
Synchronous gliomas of different histopathology are quite rare in non-syndromic, non-irradiated patients. Although "mixed" gliomas are not infrequent, and malignant gliomas often contain areas of disparate differentiation (e.g., glioblastoma with ependymal differentiation), it is unusual to find gliomas of different lineage presenting concurrently. We present a case of synchronous gliomas, one dysembryoplastic neuroepithelial tumor (DNET) and the other oligodendroglioma.


Application of two neutral MspI DNA polymorphisms in the analysis of hereditary protein C deficiency.
Screening of restriction enzyme digested DNA from normal and protein C deficient individuals with a variety of probes derived from the protein C locus has revealed the existence of two neutral MspI polymorphism. One polymorphism (MI), which is located approximately 7 kb upstream of the protein C gene, has allelic frequencies of 69 and 31%, and was used to exclude extensive gene deletions as a likely cause of type I protein C deficiency in 50% of cases in a panel of 22 families. Furthermore, the same polymorphism has been used in 5 doubly affected individuals establishing compound heterozygosity in 3 of these. The second, intragenic, polymorphism (MII) has allelic frequencies of 99 and 1% in the normal population. The frequency of the rare allele of this RFLP was with 7% much higher in a panel of 22 Dutch families with protein C deficiency. Interestingly, in all three probands that were heterozygous for MII the rare allele of MII coincided with a point mutation that leads to a stop codon in amino acid position 306 of the protein C coding sequence. This mutation may account for 14% of the protein C deficient individuals in The Netherlands.


Evaluation of traumatic brain injury by optical technique.
Traumatic brain injury (TBI), usually due to brain shaking or impact, affects the normal brain function and may lead to severe disability or even death. However, there is paucity of information regarding changes in the physiologic state of humans or animals after brain shaking. In this study, near-infrared spectroscopy (NIRS) was used to continuously monitor the concentration change of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (HbR) to understand changes in the physiological state during and after brain shaking. Laser Doppler flowmetry was also used to monitor changes in cerebral blood flow under TBI to supplement the investigation. Triphenyltetrazolium chloride (TTC) staining was used to monitor changes of infarction volume corresponding to different impact strengths. The experimental results indicated that concentration changes of HbO2 and total-hemoglobin (HbT) were significantly related to the impact strength. The infarction volume was also significantly related to the impact strength. Therefore, the non-invasive monitoring of concentration changes in HbO 2 , HbR, and HbT using NIRS may have a clinical application for the evaluation of TBI.


GC-MS Profile of Hua-Feng-Dan and RNA-Seq Analysis of Induced Adaptive Responses in the Liver.
Background: Hua-Feng-Dan is a patent Chinese medicine for stroke recovery and various diseases. This study used GC-MS to profile its ingredients and RNA-Seq to analyze the induced adaptive response in the liver. Methods: Hua-Feng-Dan was subjected to steam distillation and solvent extraction, followed by GC-MS analysis. Mice were orally administered Hua-Feng-Dan and its "Guide drug" Yaomu for 7 days. Liver pathology was examined, and total RNA isolated for RNA-Seq, followed by bioinformatic analysis and quantitative real-time PCR (qPCR). Results: Forty-four volatile and fifty liposoluble components in Hua-Feng-Dan were profiled and analyzed by the NIST library and their concentrations quantified. The major components (>1%) in volatile (5) and liposoluble (10) were highlighted. Hua-Feng-Dan and Yaomu at hepatoprotective doses did not produce liver toxicity as evidenced by histopathology and serum enzyme activities. GO Enrichment revealed that Hua-Feng-Dan affected lipid homeostasis, protein folding, and cell adhesion. KEGG showed activated cholesterol metabolism, bile secretion, and PPAR signaling pathways. Differentially expressed genes (DEGs) were identified by DESeq2 with p < 0.05 compared to controls. Hua-Feng-Dan produced more DEGs than Yaomu. qPCR on selected genes largely verified RNA-Seq results. Ingenuity Pathways Analysis of the upstream regulator revealed activation of MAPK and adaptive responses by Hua-Feng-Dan, and Yaomu was less effective. Hua-Feng-Dan-induced DEGs were highly correlated with the Gene Expression Omnibus database of chemical-induced adaptive transcriptome changes in the liver. Conclusion: GC-MS primarily profiled volatile and liposoluble components in Hua-Feng-Dan. Hua-Feng-Dan at the hepatoprotective dose did not produce liver pathological changes but induced metabolic and signaling pathway activations. The effects of Hua-Feng-Dan on liver transcriptome changes point toward induced adaptive responses to program the liver to produce hepatoprotective effects.


Elemental Mass Size Distribution for Characterization, Quantification and Identification of Trace Nanoparticles in Serum and Environmental Waters.
Accurate characterization, quantification, and identification of nanoparticles (NPs) are essential to fully understand the environmental processes and effects of NPs. Herein, the elemental mass size distribution (EMSD), which measures particle size, mass, and composition, is proposed for the direct size characterization, mass quantification, and composition identification of trace NPs in complex matrixes. A one-step method for the rapid measurement of EMSDs in 8 min was developed through the online coupling of size-exclusion chromatography (SEC) with inductively coupled plasma mass spectrometry (ICP-MS). The use of a mobile phase with a relatively high ionic strength (a mixture of 2% FL-70 and 2 mM Na2S2O3) ensured the complete elution of different-sized NPs from the column and, therefore, a size-independent response. After application of a correction for instrumental broadening by a method developed in this study, the size distribution of NPs by EMSD determination agreed closely with that obtained from transmission electron microscopy (TEM) analysis. Compared with TEM, EMSD allows a more rapid determination with a higher mass sensitivity (1 pg for gold and silver NPs) and comparable size discrimination (0.27 nm). The proposed EMSD-based method was capable of identifying trace Ag2S NPs and core-shell nanocomposite Au@Ag, as well as quantitatively tracking the dissolution and size transformation of silver nanoparticles in serum and environmental waters.


Mirabegron: a Beta-3 agonist for overactive bladder.
To review the literature regarding the efficacy and safety of mirabegron for the treatment of overactive bladder (OAB). A literature search was performed using MEDLINE (PubMed) prior to December 31, 2013, using the terms "mirabegron" and "randomized-controlled trial." All published, double-blind, randomized-controlled trials assessing mirabegron were included. Articles were reviewed and included if mirabegron was used as monotherapy and if the primary outcome analyzed drug efficacy. The efficacy of mirabegron for the treatment of OAB has been demonstrated in the selected five randomized, placebo-controlled trials. The majority of these trials lasted 12 weeks and compared various doses of mirabegron with placebo and/or tolterodine extended-release (ER). Primary efficacy outcomes for the trials included mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Included trials showed statistically significant reductions in both efficacy outcomes for various doses of mirabegron when compared with placebo. Based on the trials reviewed, mirabegron has been efficacious in reducing mean number of micturitions and incontinence episodes per 24 hours, as well as in improving other secondary outcomes such as OAB symptoms and quality-of-life measures. Common adverse drug events seen with mirabegron include: hypertension, nasopharyngitis, urinary tract infections, headache, constipation, upper respiratory tract infection, arthralgia, diarrhea, tachycardia, abdominal pain, and fatigue. Given the efficacy and safety data currently available, mirabegron represents a reasonable alternative to antimuscarinics for patients with OAB. Future studies are needed to determine the utility of mirabegron for OAB in a variety of demographics.


Bipolar pathophysiology and development of improved treatments.
The purpose of this review is to provide strategies and their rationale which can facilitate scientifically productive investigations into genetic, neuronal, brain functional and clinical aspects of bipolar disorder. The presentation addresses both factors that have impeded and those that have facilitated landmark advances on the pathophysiology and treatment of bipolar disorders. Application of the strategies can provide a scientific platform that may be useful to basic and clinical scientists for the purposes of achieving seminal advances in understanding pathophysiology, including inherited and experience based contributors to disease expression. Current diagnostic criteria omit certain key symptoms, do not include illness course or family history and lack specification of the importance of fundamental symptomatology. Consideration of such factors in inclusion and exclusion criteria, and in assessment instruments in basic and clinical studies, serves to strengthen the capability of a research plan to test key hypotheses regarding moderating and mediating factors of this complex illness. For example, most studies of brain structure and function and of new interventions have selected subjects on the basis of traditional full syndromal criteria. Evidence indicates that additional consideration of principal behavioral domains of bipolar symptomatology, e.g., anxiety, psychosis, impulsivity, elevated psychomotor and cognitive processing speed, rather than strictly depressive or manic syndromes can provide more homogeneous samples for study, and increase the focus of experimental hypotheses.


ECOLOGICAL GENETICS OF A MOSAIC HYBRID ZONE: MITOCHONDRIAL, NUCLEAR, AND REPRODUCTIVE DIFFERENTIATION OF CRICKETS BY SOIL TYPE.
We investigated the effects that habitat variation has on the structure and dynamics of a hybrid zone between two closely related crickets in Connecticut. A collecting protocol was developed in which crickets were sampled from characteristic habitats on either side of the hybrid zone and from two distinct habitat types within the zone. Presumptive pure Gryllus pennsylvanicus were sampled from fields in northwestern Connecticut and represent "inland" populations. "Pure" Gryllus firmus were sampled from beaches along the coast and represent the "coastal" populations. Crickets from within the hybrid zone were sampled from two different soil types: the "loam" populations from loamy soils and the "sand" populations from sandy soils. Moreover, an attempt was made to identify closely adjacent sand and loam localities to determine the scale of habitat variation and its possible effects on hybrid-zone structure. In general, there was little variation in morphological traits or in allozyme and mtDNA genotype frequencies among localities from within each of the four habitat types. Between each of the closely situated sand and loam localities within the hybrid zone, however, there were very significant differences in each of these sets of markers. In addition, crickets from hybrid-zone populations were tested for reproductive isolation. The asymmetric outcome of hybrid crosses that exists across the zone (Harrison, 1983) also exists on a finer ecological scale within the zone. Thus, this hybrid zone is a mosaic of strikingly differentiated populations. The dynamics of hybrid zones with mosaic structures are discussed in contrast to the traditional clinal models. The data are also discussed in light of the semipermeable nature of species boundaries. The extent to which a species boundary is permeable varies not only from one genetic marker to the next, but also with the ecological and geographic context of species interaction.


[Doctors and apothecaries as botanists in the renaissance].
It is often claimed, that the late attempts in the renaissance to classify plants according to Aristotelian principles were caused by insufficient morphological knowledge and terminology, by problems with identification of the plants described by the ancient authorities and by the overwhelming number of new plants from the hitherto unknown parts of the world. These explanations are in the present paper not contested but supplemented with information achieved by analysis of two dialogues on botanical problems, both published in the 1530s, in which the ambiguities of the then new science are discussed. The main object of the studies in botany made by medical doctors was identification of simplicia in the pharmacies and drug-dealers shops. Control of the simplicia sold was a public duty demanded of university professors and medical doctors, and the teaching in plant science consequently concentrated on parmacognosy. As even the best Aristotelian classification is useless in identification of small plant parts, systematic botany in the modern sense was not needed and it is concluded that this fact also contributed to the late interest in classification.


Rabies antibody testing and the UK Pet Travel Scheme.
The Pet Travel Scheme (PETS) commenced on February 28, 2000, allowing pet dogs and cats from named countries to enter the UK without spending six months in quarantine as long as they met specific criteria. Since the start of the scheme to the end of February 2002, more than 45,000 animals have successfully entered the UK under PETS. In this article, Dr Tony Fooks and colleagues consider the results of serological testing under the scheme at the Veterinary Laboratories Agency and look to future developments.


Drug-Associated Gastropathy: Diagnostic Criteria.
Drugs are widely used to treat different diseases in modern medicine, but they are often associated with adverse events. Those located in the gastrointestinal tract are common and often mild, but they can be serious or life-threatening and determine the continuation of treatment. The stomach is often affected not only by drugs taken orally but also by those administered parenterally. Here, we review the mechanisms of damage, risk factors and specific endoscopic, histopathological and clinical features of those drugs more often involved in gastric damage, namely NSAIDs, aspirin, anticoagulants, glucocorticosteroids, anticancer drugs, oral iron preparations and proton pump inhibitors. NSAID- and aspirin-associated forms of gastric damage are widely studied and have specific features, although they are often hidden by the coexistence of Helicobacter pylori infection. However, the damaging effect of anticoagulants and corticosteroids or oral iron therapy on the gastric mucosa is controversial. At the same time, the increased use of new antineoplastic drugs, such as checkpoint inhibitors, has opened up a new area of gastrointestinal damage that will be seen more frequently in the near future. We conclude that there is a need to expand and understand drug-induced gastrointestinal damage to prevent and recognize drug-associated gastropathy in a timely manner.


Effectiveness of long-acting risperidone in a patient with comorbid intellectual disability, catatonic schizophrenia, and oneiroid syndrome.
A patient with comorbid intellectual disability, catatonic schizophrenia, and recurrent oneiroid state of consciousness improved on long-acting risperidone and remains well at the three-year follow-up. We report a case treated with 50 mg long-acting risperidone administered every 14 days, who has been followed-up for three years. We studied his regional cerebral blood flow through technetium-99 m hexamethylpropyleneamine oxime single-photon emission computed tomography after two years of treatment. Symptoms of catatonic schizophrenia improved after two months of treatment, followed suit by oneiroid syndrome remission. Two years later, his brain perfusion was normal. No side effect has occurred since the patient was started on long-acting risperidone. Long-acting risperidone proved to be safe and effective in treating symptoms of catatonia and oneiroid syndrome.


Advances in targeting signal transduction pathways.
Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.


Activation of the NMDA receptor-neuronal nitric oxide synthase pathway within the ventral bed nucleus of the stria terminalis mediates the negative affective component of pain.
Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate-nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test. Intra-vBNST injection of either CNQX (an AMPA receptor antagonist) or MK-801 (an NMDA receptor antagonist) dose-dependently attenuated intraplantar formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. In vivo microdialysis showed that extracellular oxidative NO metabolites (NOx) levels were significantly increased by intraplantar formalin injection. Intra-vBNST injection of NPLA (a selective neuronal NO synthase (nNOS) inhibitor), c-PTIO (a NO scavenger), or ZL006 (a postsynaptic density-95 (PSD-95)-nNOS interaction inhibitor) dose-dependently suppressed F-CPA without attenuating nociceptive behaviors. Intra-vBNST injection of NOR3 (a NO donor) produced CPA in a dose-dependent manner in the absence of noxious stimulation. Furthermore, whole-cell patch-clamp electrophysiology in the vBNST slices revealed that NOR3 induced depolarization of hyperpolarization-activated cation current (Ih)-positive vBNST neurons, which was blocked by the NO scavenger. These results suggest that activation of glutamatergic transmission and subsequent nNOS-derived NO production within the vBNST mediate the negative affective component of pain and that NO-evoked excitation of Ih-positive vBNST neurons may be among the cellular mechanisms underlying pain-induced aversion.


A call to action towards an evidence-based approach to using verbal encouragement during maximal exercise testing.
By definition, maximal exercise testing inherently requires participants to give a maximal effort. This is an important practical issue as submaximal efforts can produce invalid test results. Verbal encouragement is commonly used to motivate participants to maintain or increase effort investment during maximal exercise testing. Accordingly, studies have reported significant increases in time to exhaustion of between 8% and 18% during VO2max and multistage shuttle run tests, and a significant 30·5 m mean increase in 6-min walk test distance. Significant improvements during shorter tests, such as the Wingate and 2-min walk tests, have not been observed however. Although participants typically perceive verbal encouragement positively during maximal exercise testing, around one-third have neutral or negative perceptions. Despite the ubiquity and importance of verbal encouragement during maximal exercise testing, surprisingly little research has investigated the characteristics of effective encouragement with respect to its content, timing and frequency. The only randomized controlled trial to investigate one of these issues observed that verbal encouragement delivered every 20 s increased time to exhaustion during VO2 max testing, but not every 60 or 180 s. Of particular concern is that several exercise testing guidelines have incorporated specific guidelines for the use of verbal encouragement, but not provided any theoretical or empirical justification, presumably because of the limited research to inform practice. Recent empirical research does provide some important insight into participant preference for the content and timing of verbal encouragement during maximal exercise testing; however, much more research is clearly required to establish comprehensive evidence-based guidelines.


A novel method for assessing oral mixing ability based on the spatial clusters quantified by variogram.
The two-colour chewing test (TCCT) has been widely used for assessing oral mixing ability, a critical component of masticatory performance. Most studies focused on quantifying the evenness of colour distribution. It remained unknown if the variation of colour clustering was a valid index of oral mixing ability. The study aims to investigate the oral mixing ability based on the spatial clusters quantified by variogram. Fifty older people (15 male/35 female, age: 66.0 ± 7.8 years) were assessed for the TCCT and the colour-changeable chewing gum test (CCGT). For the CCGT, we quantified the degree of colour change (ΔE). For the TCCT, the highest peak in colour histogram (HP), the standard deviation of colour values (SDC) and the range of variogram from colour spatial distribution (VARG) were quantified. The participants were grouped according to the contacts of posterior teeth, as assessed by Eichner Index (EI). Highest peak, SDC and VARG showed statistically significant differences between the EI groups (two-tailed independent t test P < .05). Higher VARG (ie a lower degree of clustering) was significantly negatively correlated with ΔE (r = -.36, one-tailed P < .01). The binary logistic regression revealed that among the spatial indices (HP, SDC and VARG), only VARG achieved statistical significance in prediction to the EI group. Eliminating other indices was insignificant to the model performance. Our results show that the averaged cluster sizes, quantified by variogram, are a valid index for quantifying the TCCT. Compared with other spatial indices, it had the best predictability to the condition of posterior contact.


T-lymphocyte subsets in peripheral blood and liver tissue of patients with chronic hepatitis B and C.
To evaluate the immune response in peripheral blood and liver tissue, through the measurement of T-cell subsets, in patients with chronic hepatitis B (CHB) and C (CHC). Thirty-four patients with CHB (21 with active HBV infection and 13 inactive HBV carriers) and 20 patients with CHC were included in the study. We also evaluated 21 biopsies from patients with active CHB infection and 20 patients with CHC. We measured CD3, CD4, CD8 and CD4/CD8 ratio in peripheral blood and liver tissue. We found no differences in the numbers of all T-lymphocyte subpopulations between patients with active HBV infection and inactive carriers. We found a significant increase in the absolute numbers of CD3(+), CD4(+) and CD8(+) T-lymphocytes in CHC compared to CHB patients (p=0.005, p=0.034 and p<0.0001 respectively). There was a significant increase in the number of CD3(+) and CD8(+) T-lymphocytes in the area of portal tracts (p=0.012 and p=0.009 respectively) and lobules (p=0.011 and p=0.01 respectively) in patients with CHC compared to those with CHB. In both groups there was a direct correlation between CD3(+) cells in portal tracts and HAI score (r=0.783, p=0.008), while we noted a correlation between CD8(+) cells in portal tracts and HAI score only in patients with CHC. Interface hepatitis correlated to CD3(+) cells in lobules of patients with CHC and CHB but a direct relationship between CD8(+) cells and HAI score was found only in those with CHC. Insufficient cellular immune response is critical for the ineffective virus clearance and liver damage in chronic hepatitis B, while in chronic hepatitis C, immune response, as represented by CD8(+) T-cells, is present in the peripheral blood and the liver. However, there is an immunological escape of HCV, which seems to survive in the presence of an adequate immune response. The significant correlation between portal and periportal CD8(+) T-lymphocyte expression and interface hepatitis may be considered evidence of the occurrence of cytotoxic immune-mediated toxicity.


Parenteral Nutrition: Amino Acids.
There is growing interest in nutrition therapies that deliver a generous amount of protein, but not a toxic amount of energy, to protein-catabolic critically ill patients. Parenteral amino acids can achieve this goal. This article summarizes the biochemical and nutritional principles that guide parenteral amino acid therapy, explains how parenteral amino acid solutions are formulated, and compares the advantages and disadvantages of different parenteral amino acid products with enterally-delivered whole protein products in the context of protein-catabolic critical illness.


For Debate: Testicular Volume Development along Ages: Evaluation by Different Methods.
In the last five decades an increasing number of studies and clinical reports demonstrated the importance of testicular volume assessment in pediatric and adolescent population. Reliable and accurate determination of testicular volume (TV) through infancy and adolescence is of great importance for assessing normal pubertal development to diagnose disturbances in development and to suspect certain genetic and endocrine diseases. Various approaches are available for the assessment of TV, including orchidometry, rulers, callipers, and ultrasonography (USG). Our report focuses on the importance of the evolution of TV from birth to adulthood and debates the main factors influencing the accuracy of different TV measurements. We endorse that any method for the evaluation of TV must satisfy certain criteria: a. be applicable to persons of all ages from pre-adolescence, through the pubertal spurt to full maturity, b. be simple to use, c. be free from observer error as possible, and d. have a high degree of correlation with other observable developmental characteristics.


Decision-making and techniques in hypogastric artery revascularization.
The aim of this article was to describe and discuss the currently available endovascular and open surgical techniques to preserve or occlude the hypogastric artery during aortoiliac aneurysm repair and thus support the process of decision-making in hypogastric artery revascularization.


Evaluation of the enhanced rapid identification method for Gardnerella vaginalis.
The enhanced rapid identification method (RIM; Austin Biological Laboratories), a micromethod for the identification of Gardnerella vaginalis, is based on starch and raffinose fermentation and hippurate hydrolysis. We tested 105 clinical isolates of G. vaginalis with both the RIM and standard biochemical tests. The RIM agreed with the standard biochemical methods for 96 (91.4%) of the strains; nine isolates which were hippurate hydrolysis positive by standard biochemical tests were hippurate hydrolysis negative in the RIM. RIM may serve as a useful adjunct to Gram stain and colony morphology for the identification of G. vaginalis.


The origin and use of the terms competitive and non-competitive in interactions among chemical substances in biological systems.
The terms competition and competitive were in use for appropriate types of interaction in human and animal behaviour from the seventeenth century. In the nineteenth and early twentieth centuries they reached more technical uses in biology, especially in darwinian studies; and in chemistry in describing competing reactions, surface phenomena and the influence of substituent groupings in reactant molecules. Use of competitive and non-competitive to describe enzyme inhibitors had a specific beginning when J. B. S. Haldane (following premonitory work of others) applied the terms in 1927 and 1930 to types of inhibition already differentiated by Michaelis and co-workers. The theoretical background in kinetics and stereochemistry so acquired gave a firmness to the application of the terms in biochemistry. The first examples concerned glycosidases, especially beta-D-fructofuranosidase or invertase, and interactions of carbon monoxide and oxygen at iron-porphyrin systems. They were thus of interest in toxicology and in enzyme and carrier studies. The sphere of application of the biochemically-defined terms expanded greatly when, following investigation of sulphonamide action, it was realized that concepts of enzyme inhibition by structurally related compounds offered a route to understanding the action of existing medicaments and to the production of new ones. Ideas and terminology based on competitive and non-competitive enzyme inhibition and receptor occupancy have subsequently been applied in many ways. Examples include application to the analysis of feedback inhibition and other processes of metabolic control; to receptor relationships among neurotransmitters and medicaments; and to understanding interactions at sensory receptors.


Chemotherapy followed by abdominal cavity irradiation for feline lymphoblastic lymphoma.
Combination chemotherapy is standard care for feline lymphoma, although clinically relevant improvements in remission duration are unlikely to result from manipulations of chemotherapy agents alone. Lymphopoietic tissues generally are sensitive to radiation, and support for chemoradiotherapy as a treatment for lymphoma is found in both humans and dogs. The goal of this prospective pilot study was to determine the normal tissue tolerance to 15 Gy total abdomen fractionated radiation therapy following induction chemotherapy in cats with lymphoblastic lymphoma. Eight cats with lymphoblastic gastrointestinal or multicentric lymphoma confined to the abdominal cavity were treated with a 6-week combination chemotherapy protocol followed 2 weeks later by whole-abdomen radiation therapy consisting of 10 daily fractions of 1.5 Gy. Treatment was well tolerated; renal insufficiency documented in one cat at the start of radiation therapy progressed to stable chronic renal failure. One cat not in complete remission at the time of radiation therapy relapsed 2 weeks later, one cat with multicentric lymphoma relapsed with hepatic large granular lymphoma, and one cat was euthanatized 3 weeks following completion of radiation therapy for other reasons; no evidence of lymphoma or radiation toxicoses was identified on post mortem evaluation. The remaining five cats remain in remission at least 266 days after starting therapy; median remission duration has not been reached (range, > 266 to > 1332 days). Results of this study suggest that 15 Gy total abdomen fractionated radiation therapy after induction chemotherapy is tolerated satisfactorily. This protocol is suitable for further testing to quantify efficacy.


Murine cells carrying integrated tandem genomes of hepatitis B virus DNA transcribe RNAs from endogenous promoters on both viral strands and express middle and major viral envelope proteins.
Clone 4.10 cells were isolated as a methotrexate-resistant clone arising after cotransfection of mouse 3T3 cells with plasmid DNA containing a head-to-tail dimer of the hepatitis B virus (HBV) genome and DNA coding for methotrexate-resistant dihydrofolate reductase. The majority of methotrexate-resistant clones derived by this procedure have been found to contain multiple copies of the HBV genome, but the intact HBV dimer was rarely preserved. In contrast, 4.10 cells contained at least 40 copies of intact HBV dimer per cell. These cells produced large amounts of 22-nm hepatitis B surface antigen particles that included viral envelope proteins reactive with the pre-S2 region-specific antibody, indicating transcription and translation of the pre-S2 and S regions of the integrated viral genomes. The cells also synthesized viral e antigen, which was released into the culture medium. Characterization of polyadenylated viral RNAs transcribed from the long (minus) strand of the integrated HBV DNA demonstrated the presence of shorter-than-genome-length RNAs containing only X region sequences, shorter-than-genome-length RNAs containing both X and S region sequences, and longer-than-genome-length RNAs containing core, X, and S region sequences. Start sites for transcripts were mapped 5' to and within the pre-S region and 5' to and within the precore region at approximately the same sites as those utilized for HBV transcription during viral replication in infected livers. Polyadenylated RNA transcripts complementary to the short (plus) strand of HBV that initiated and terminated within the intact and integrated head-to-tail tandem viral genomes were also detected.


Metal-organic frameworks based on octafluorobiphenyl-4,4'-dicarboxylate: synthesis, crystal structure, and surface functionality.
In contrast to aromatic carboxylates, the coordination polymers based on their perfluorinated analogues are not numerous. Here we present a series of six Zn(ii) coordination polymers of different dimensionalities (1D, 2D, and 3D) and porosities based on octafluorobiphenyl-4,4'-dicarboxylate (oFBPDC2-) and N-containing co-ligands (ur, dabco, and bpy). These complexes are characterized by single-crystal X-ray diffraction, PXRD, FT-IR, elemental analysis, and TGA. The metal-organic frameworks [Zn2(CH3CONH2)2(oFBPDC)2] (1) and [Zn2(oFBPDC)2(dabco)] (4) are shown to be porous with BET surface areas of 470 m2 g-1 and 441 m2 g-1, respectively. In addition, compound 4 shows selectivity factors of 11.3, 4.9 and more than 6 for the binary gas mixtures CO2/N2, CO2/CH4 and benzene/cyclohexane, respectively. The measurements for pressed powders and water droplet give water contact angles of 136° for 4 and 133° for (H2bpy)[Zn2(bpy)(oFBPDC)3] (5). Low water uptake indicates that both 4 and 5 belong to highly hydrophobic solids.


School contact among persons with Hodgkin's disease.
The authors evaluated the hypothesis that Hodgkin's disease is transmitted among high school students (in a contagious manner) by determining whether members of a population-based series of young adult cases attended school together more frequently than expected. Cases of Hodgkin's disease were diagnosed from July 1, 1973 through December 31, 1977. Of the 245 cases and 483 matched population controls interviewed, 196 cases and 371 controls attended schools in Massachusetts. School histories of subjects obtained by personal interviews were analyzed to determine the frequency with which subjects had been in the same class or had attended the same school at the same time. In high school, cases were schoolmates more often than expected (relative risk (RR) = 1.2), as well as classmates (RR = 1.9). However, in junior high school, cases were schoolmates less often than expected (RR = 0.8), and none were classmates with four expected. In elementary school, cases were somewhat more likely to be schoolmates (RR = 1.4) with no excess of classmates. The 95% confidence interval for all relative risks includes 1.0.


F-18 FDG uptake in cutaneous metastases from breast cancer.
Cutaneous metastases from internal malignancies are rare with a reported incidence between 0.7% and 10%. Among all malignancies the highest incidence of cutaneous metastasis is seen in breast cancer. We report the detection of distant dermal metastases from breast cancer on F-18 FDG PET imaging. A 73-year-old woman with metastatic left breast cancer was referred for F-18 FDG PET/CT scan, which showed multiple FDG avid lesions along cutaneous and subcutaneous nodules in the posterior neck, bilateral proximal arms, anterior chest wall, and trunk. A punch biopsy of a right lower chest wall lesion revealed invasive ductal carcinoma involving the deep dermis.


Perivascular epithelioid cell tumor (PEComa) in the genitourinary tract.
Perivascular epithelioid cell tumors (PEComas) are mesenchymal tumors composed of histologically, immunohistochemically, ultrastructurally, and genetically distinctive cells. PEComas have been described in different organs and are considered ubiquitous tumors. In this review we discuss recent informations related to PEComas in the genitourinary tract.


Onset of coronary artery disease prior to initiation of haemodialysis in patients with end-stage renal disease.
To determine whether the onset of coronary artery disease may precede the initiation of dialysis in patients with end-stage renal disease, we performed coronary angiography within 1 month of initiation of maintenance haemodialysis in 24 patients (age range 42-78 years; mean 63.7 +/- 11). Coronary angiography was performed regardless of the absence or presence of angina. Fifteen patients had diabetic nephropathy, and nine had non-diabetic nephropathy. Significant coronary stenosis was defined as at least 75% narrowing of the reference segment. Fifteen patients (62.5%) with a total of 49 lesions were classified as the coronary artery disease present group. Eleven of those 15 (73.3%) had multivessel disease. The average number of stenotic lesions was 3.3 per patient. The most common patterns of stenosis were complex (23 lesions; 47%), and diffuse lesions over 20 mm long (14 lesions; 29%). None of the clinical or haematological factors evaluated differed significantly between the groups with and without coronary artery disease. The prevalence of coronary artery disease was 72.7% in the symptomatic patients and 53.8% in the asymptomatic patients. The diagnosis of coronary artery disease at the start of maintenance haemodialysis based only on chest symptoms and clinical factors proved to be difficult. Coronary angiography is thus essential for evaluating coronary artery disease in uraemic patients. Many patients with end-stage renal disease had coronary artery disease prior to the start of haemodialysis.


Communicating with patients and their families about the end of life.
Nurses, in collaboration with the primary care provider, have the skills and opportunities to communicate with patients and their families about care at the end of life. Application of effective strategies for discussing a poor prognosis and end-of-life care options will result in determining patient and family needs, identifying care preferences, and avoiding unwanted treatment.


Mechanisms of Black-White disparities in health among older adults: Examining discrimination and personality.
We tested whether personality traits help explain the association between discrimination and racial health disparities in a sample of 1033 Black and White older adults. Participants completed measures of discrimination, personality, and self-reported physical and mental health. Elevated discrimination among Black participants was indirectly linked to worse physical and mental health outcomes through elevated neuroticism and lower agreeableness, controlling income, education, and gender. The specific facets of depression, impulsiveness, and trust were the most robust intervening personality factors. Interventions that target cognitive, emotional, and behavioral sequelae of discrimination may lessen its impact on health disparities.


Evolution of variants of yeast site-specific recombinase Flp that utilize native genomic sequences as recombination target sites.
As a tool in directed genome manipulations, site-specific recombination is a double-edged sword. Exquisite specificity, while highly desirable, makes it imperative that the target site be first inserted at the desired genomic locale before it can be manipulated. We describe a combination of computational and experimental strategies, based on the tyrosine recombinase Flp and its target site FRT, to overcome this impediment. We document the systematic evolution of Flp variants that can utilize, in a bacterial assay, two sites from the human interleukin 10 gene, IL10, as recombination substrates. Recombination competence on an end target site is acquired via chimeric sites containing mixed sequences from FRT and the genomic locus. This is the first time that a tyrosine site-specific recombinase has been coaxed successfully to perform DNA exchange within naturally occurring sequences derived from a foreign genomic context. We demonstrate the ability of an Flp variant to mediate integration of a reporter cassette in Escherichia coli via recombination at one of the IL10-derived sites.


Ultralow-threshold Raman lasing with CaF2 resonators.
We demonstrate efficient Raman lasing with CaF2 whispering-gallery-mode resonators. Continuous-wave emission threshold is shown to be possible below 1 microW with a 5mm cavity, which is to our knowledge orders of magnitude lower than in any other Raman source. Low-threshold lasing is made possible by the ultrahigh optical quality factor of the cavity, of the order of Q=5x10(10). Stokes components of up to the fifth order were observed at a pump power of 160 microW, and up to the eighth order at 1 mW. A lasing threshold of 15 microW was also observed in a 100 microm CaF2 microcavity. Potential applications are discussed.


Notch and minichromosome maintenance (MCM) proteins: integration of two ancestral pathways in cell cycle control.
Notch transmembrane receptors govern a highly evolutionarily conserved intercellular signaling mechanism activated by the engagement of Notch receptors by their cognate ligands expressed on neighboring cells. The subsequently cleaved intracellular domain of Notch receptors translocates to the nucleus where it interacts with the transcriptional regulator CSL, thereby regulating expression of target genes. The Notch pathway controls cell fate by regulating proliferation, differentiation, and apoptosis. Mini-chromosome maintenance (MCM) proteins are components of the prereplicative complex (pre-RC) that are essential for DNA replication. It has recently been shown that activated Notch downregulates mini-chromosome-maintenance (MCM) proteins MCM2 and MCM6 by a CSL-dependent mechanism. Here, we review the canonical pathway mediated by Notch receptors and discuss recent findings connecting the Notch pathway with the ancestral MCM complex during cell cycle progression.


In vivo studies on lysosubtilin. 2. Efficacy for treatment of post-partum endometritis in cows.
Lysosubtilin is a broad-spectrum preparation of lytic enzymes from Bacillus subtilis designed for veterinary medicine. This study demonstrates its efficacy for the treatment of post-partum endometritis in cows. Prior to the determination of optimal therapeutic doses, samples taken from the uterus of sick animals were examined microbiologically. The examinations revealed a high incidence of polymicrobial infections (65.0%) caused by various mixtures of bacteria (both Gram-positive and Gram-negative) and fungi/yeasts. Dose-determination studies involved 160 cows with clinical signs of post-partum endometritis. For treatment both aqueous and oil-based formulations were tested and the optimal dose was found to be 2 x 10(6) U lysosubtilin dissolved in 100 mL of distilled water. When administered intrauterinarily twice a week until recovery this dose resulted in a 100% clinical recovery rate (versus 90%) and a statistically significant decrease (73 +/- 5 d), when compared with cows treated with neofur (92 +/- 9 d, P < 0.05) in the calving-to-conception interval. These findings were confirmed by results of field trials performed in four Former Soviet Union republics (Byelarus, Estonia, Lithuania, Russia) on 932 cows. Increases in clinical recovery (93.7 versus 80.2%, P < 0.05) and conception rates (64.4 versus 45.8%, P < 0.01) were found to be statistically significant when compared with cows treated with neofur or uterosan. We therefore conclude that lytic enzyme preparations are prospective antimicrobial drugs and when used to combat animal diseases they may serve as a possible alternative to common antibiotics.


To evaluate dexmedetomidine as an additive to propofol for sedation for elective cardioversion in a cardiac intensive care unit: A double-blind randomized controlled trial.
Propofol may lead to patient recall and discomfort when used for sedation in elective cardioversion. The aim of the present study was to evaluate dexmedetomidine as an additive to propofol for sedation in elective cardioversion. A total of 500 patients undergoing elective cardioversion were randomized into Group 1 (n = 250) and Group 2 (n = 250) on the basis of computer-generated randomization table. Patients in Group 1 were given dexmedetomidine (1 mcg/kg) over 10 min before giving propofol (1 mg/kg), while patients in Group 2 were given only propofol (1 mg/kg). One or two additional doses of 0.5 mg/kg propofol were given if modified Ramsay Sedation Score (mRSS) was <5. Number of patients requiring additional doses were noted. Any hemodynamic or respiratory complication along with the mean time to recovery (mRSS = 1) was recorded. Patient recall, patient discomfort, and further requirement of cardioversion in the next 24 h were also noted. About 10% patients in Group 1 and 64% patients in Group 2 required the first additional dose of propofol. While no patient in Group 1 required second dose, 16% patients in Group 2 required second dose of propofol. The mean time to recovery in Group 1 was 8.36 ± 3.08 min and 8.22 ± 2.38 min in Group 2 (P = 0.569). Sixty-seven patients (26.8%) in Group 1 and 129 patients (51.6%) in Group 2 reported remembering something (P < 0.0001), i.e., recall. Thirty-five patients (14%) in Group 1 and 79 patients (31.6%) in Group 2 reported dreaming during the procedure (P < 0.0001). Visual analog scale score was higher in Group 1 as compared to Group 2. Six patients in Group 1 and 24 patients in Group 2 had a requirement of repeat cardioversion in 24-h follow-up (P = 0.001). Dexmedetomidine is a useful adjunct to propofol for elective cardioversion.


Identification of candidates for prevention of venous thromboembolism.
The rationale for prophylaxis of venous thromboembolism (VTE) is based on the frequently clinically silent nature of the disease. A number of risk factors for VTE have been known for a long time, even if some of them are still controversial. Many studies have been performed in the surgical field, and have established different risk classes for VTE. Such risk stratification is especially determined by type of surgery and to some extent by personal characteristics of patients, and it defines operations at high, intermediate, and low risk for VTE. According to this classification, prophylaxis of VTE is mandatory in some cases, less useful in others. Less information is available on medical diseases, in which the clinical conditions and the intrinsic characteristics of patients determine the class of risk for VTE. Different strategies for identifying patients who should undergo prophylaxis have been proposed based on risk factor evaluation in the individual patient. However, even if such an approach may be of help for the physician, its validity is still impaired by the difficulty of taking into account all of the variables possibly involved in VTE occurrence.


Mechanical energy fluctuations during walking of healthy and ACL-reconstructed subjects.
In a clinical gait analysis, mechanical energy is the gait variable which can validate the energetic state of the disorder of patient's movement. The purpose of this study was to explore the possibilities of employing the total mechanical energy in estimating the mechanical cost of transport in normal and pathological human gait. One of the basic methods of determining mechanical energy (inverted pendulum model) was used to estimate the external mechanical work performed by the walking subjects based on externally observable measurements. Gait data was collected for healthy able-bodied men and patients after ACL reconstruction during physiotherapy process who demonstrate larger lateral center of gravity (CoG) excursions during gait. Based on predictions of the body's CoG trajectory during walking, algorithms were developed to determine the changes in components of total mechanical energy in normal and pathological gait. The utility of calculating mechanical energy in a patient population is questioned.


Magnetic resonance angiography in patients with brain infarction.
This study evaluated the role of magnetic resonance angiography (MRA) in detecting extra- or intracranial vascular disease in 118 patients with brain infarction and the accuracy of MRA diagnosis when compared with conventional angiography in patients who had both investigations. Magnetic resonance angiography ruled out extra- and intracranial large vessel disease in 36% of the patients. MRA also demonstrated extra- or intracranial disease in 56% (probably symptomatic in 31, possibly symptomatic in 18, and asymptomatic in 17 patients), and provided no information in 8% of the 118 patients. Among the 176 major vessels visualized by both MRA and conventional angiography, conventional angiography confirmed the presence of 9/10 extracranial and 32/40 intracranial large vessel abnormalities detected on MRA. There were two false-negative findings on MRA: occlusion of a distal branch of middle cerebral artery, and an asymptomatic posterior cerebral artery stenosis. Magnetic resonance angiography is a clinically useful method for screening extra- and intracranial disease in patients with brain infarction and selecting high-yield patients for conventional angiography.


MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK.
The role of microRNA-18a (miRNA/miR-18a) as a tumor suppressor or promoter in a number of different types of cancer has been reported. However, to date, the expression and the effects of miR-18a in epithelial ovarian cancer (EOC) remain elusive. In the present study, the expression of miR-18a in patient EOC tissues and ovarian cancer cell lines was investigated using the reverse transcription-quantitative polymerase chain reaction. Luciferase assays and western blotting were performed to detect the potential direct targets of miR-18a. An A2780cp intraperitoneal mouse model, and Cell Counting Kit 8, flow cytometry and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays, were used to investigate the effect of miR-18a on tumor growth in vivo and in vitro. The results indicated that the expression of miR-18a was reduced in EOC tissue and in the investigated ovarian cancer cell lines compared with non-malignant (normal) ovarian tissues and the human ovarian epithelium cell line, respectively. Overexpression of miR-18a in the A2780s and A2780cp cell lines significantly induced cell cycle arrest and apoptosis. It was demonstrated that miR-18a directly targets tumor protein p53-regulating inhibitor of apoptosis gene 1 and inositol phosphate multikinase, hence regulating the expression of downstream targets. The A2780cp intraperitoneal mouse model was employed and the results indicated that miR-18a may inhibit A2780cp intraperitoneal tumor growth in vivo by inhibiting proliferation and inducing apoptosis. Together, the results of the present study demonstrated that miR-18a has a role as a tumor suppressor by inhibiting proliferation and inducing apoptosis. Assessment of miR-18a expression may provide a novel method for diagnosis and be a therapeutic target for EOC.


Young Children's Food Neophobia Characteristics and Sensory Behaviors Are Related to Their Food Intake.
Food neophobia in children has been associated with poor dietary variety and nutrient intakes. Underlying characteristics that may predispose a child to neophobia have not been widely studied. We investigated the associations between children's food neophobia, sensory sensitivity, and dietary intake in a diverse sample of typically developing preschoolers. Caregiver reports of children's food neophobia and sensory behaviors (SBs) as measured by the Food Neophobia Scale and the Sensory Profile, children's observed weight outcome [body mass index z score (BMIz)], and children's food intake as estimated from the Block Kids Food Screener were collected at baseline in the Colorado LEAP (Longitudinal Eating and Physical Activity Study) study of childhood obesity. Preschool-aged children (n = 249; 136 girls, 113 boys; aged 55.6 ± 4.7 mo; BMIz = 0.54 ± 1.14) and caregivers [n = 180; 57 Hispanic, 119 non-Hispanic white (NHW), 4 unknown] participated. Data were analyzed by Pearson correlations and multivariate hierarchical linear regression analyses. Lower scores for children's oral sensory characteristics (i.e., more atypical) were related to higher neophobia ratings (r = -0.53, P < 0.001), and neophobia was negatively associated with reported vegetable intake (r = -0.31, P = 0.001) and dietary variety (r = -0.22, P < 0.001). Hispanic caregivers reported more atypical child SB scores (46.2 ± 8.8) than did NHW caregivers (50.5 ± 7.6; P = 0.006); however, no differences were noted for neophobia and SB scores by parent income and education or child sex. Neophobia was negatively associated with vegetable intake and dietary variety (P < 0.001 for both). SBs were associated with children's energy intake from sugar-sweetened beverages in bivariate analyses (r = -0.18, P < 0.05); however, in regression models, only ethnicity was significantly associated with energy from sugar-sweetened beverages (P < 0.001). Hispanic ethnicity was positively associated with sugar-sweetened beverage consumption (P < 0.001). Children's neophobia and sensory sensitivity may be important in understanding underlying issues related to limited food acceptance in typically developing young children and for helping caregivers facilitate healthy dietary intake patterns for their children. This trial was registered at clinicaltrials.gov as NCT01937481.


Pressure cycling technology for challenging proteomic sample processing: application to barnacle adhesive.
Successful proteomic characterization of biological material depends on the development of robust sample processing methods. The acorn barnacle Amphibalanus amphitrite is a biofouling model for adhesive processes, but the identification of causative proteins involved has been hindered by their insoluble nature. Although effective, existing sample processing methods are labor and time intensive, slowing progress in this field. Here, a more efficient sample processing method is described which exploits pressure cycling technology (PCT) in combination with protein solvents. PCT aids in protein extraction and digestion for proteomics analysis. Barnacle adhesive proteins can be extracted and digested in the same tube using PCT, minimizing sample loss, increasing throughput to 16 concurrently processed samples, and decreasing sample processing time to under 8 hours. PCT methods produced similar proteomes in comparison to previous methods. Two solvents which were ineffective at extracting proteins from the adhesive at ambient pressure (urea and methanol) produced more protein identifications under pressure than highly polar hexafluoroisopropanol, leading to the identification and description of >40 novel proteins at the interface. Some of these have homology to proteins with elastomeric properties or domains involved with protein-protein interactions, while many have no sequence similarity to proteins in publicly available databases, highlighting the unique adherent processes evolved by barnacles. The methods described here can not only be used to further characterize barnacle adhesive to combat fouling, but may also be applied to other recalcitrant biological samples, including aggregative or fibrillar protein matrices produced during disease, where a lack of efficient sample processing methods has impeded advancement. Data are available via ProteomeXchange with identifier PXD012730.


[A lump in the breast. A rare first symptom of ovarian cancer].
The breast is an uncommon site for metastasis from extramammary primaries. A 43-year-old woman presented with a lump in the left breast. A tumour with atypical microcalcifications was seen on the mammogram. Needle aspiration cytology revealed adenocarcinoma cells. The final histological diagnosis was papillary adenocarcinoma with psammoma bodies, probably secondary to an ovarian carcinoma. A bilateral carcinoma of the ovaries was subsequently diagnosed and treated. A mammary tumour with an atypical growth pattern and the absence of in situ carcinoma should always prompt the pathologist to considering the possibility of a metastatic tumour even though this is a rare occurrence. Earlier recognition of metastatic tumours to the breast may result in initiation of appropriate therapy and will preclude unnecessary surgical procedures.


Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin.
Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP) is a principal component of the sarcomere. The three prevalent isoforms of ZASP in skeletal muscle are generated by alternative splicing of exons 9 and 10. The long isoforms, either having (ZASP-L) or lacking exon 10 (ZASP-LΔex10), include an N-terminal PDZ domain, an actin-binding region (ABR) with a conserved motif (ZM), and three C-terminal LIM domains. The short isoform (ZASP-S) lacks the LIM domains. Mutations, A147T and A165V, within the ZM of ZASP-LΔex10 cause myofibrillar myopathy, but the mechanism is unknown. We have prepared these proteins, their ABR, and the respective mutant variants in recombinant form, characterized them biophysically, and analyzed their actin-binding properties by surface plasmon resonance and electron microscopy. All the proteins were physically homogeneous and monomeric and had circular dichroic spectra consistent with partially folded conformations. Comparison of the NMR HSQC spectra of ZASP-S and the PDZ domain showed that the ABR is unstructured. ZASP-S and its mutant variants and ZASP-LΔex10 all bound to immobilized G-actin with high affinity (Kd ≈ 10-8 to 10-9 M). Constructs of the isolated actin-binding region missing exon 10 (ABRΔ10) bound with lower affinity (Kd ≈ 10-7 M), but those retaining exon 10 (ABR+10) did so only weakly (Kd ≈ 10-5 M). ZASP-S, and the ABRΔ10, also induced F-actin and array formation, even in conditions of low ionic strength and in the absence of KCl and Mg2+ ions. Interestingly, the ZM mutations A147T and A165V did not affect any of the results described above.


Effects of captopril on cardiac and renal damage, and metabolic alterations in the nitric oxide-deficient hypertensive rat.
Chronic inhibition of nitric oxide (NO) synthesis is characterized by increased blood pressure accompanied with both cardiac hypertrophy as well as renal damage. We investigated whether the angiotensin-converting enzyme (ACE) inhibitor captopril can inhibit the cardiac hypertrophy and reverse the renal failure. We tested the influence of captopril on the nitrate-nitrite (NO(x)) in plasma and heart and kidney tissues. Oxidative stress, in terms of glutathione and thiobarbituric acid-reactive substances measured as malondialdehyde, was monitored examining their involvement in the cardioprotective and renoproptective actions. Three groups of Wistar rats were used: untreated group, and rats treated with the NO synthase inhibitor N(w)-nitro-L-arginine methyl ester (L-NAME) and L-NAME plus captopril (10 mg/kg/day). Systolic, diastolic and mean blood pressure (BPs, BPd and BPm respectively) was measured weekly in addition to the heart rate using rat-tail plethysmography. After 3 weeks, L-NAME significantly increased BPs, BPd and BPm. Captopril treatment reversed the increments in pressure back to normal values by the fourth week. ACE inhibition by captopril reverted the L-NAME-induced hypertrophy and inhibited the enzymatic indices of cardiac damage (glutamate oxaloacetate transaminase and lactate dehydrogenase) back to normal values. Furthermore, the NO synthesis inhibition produced renal damage as indicated by significant increase in creatinine. Captopril ameliorated the raised creatinine to normal. Chronic L-NAME treatment increased serum NO(x) levels but concomitant treatment with captopril was without effect.


Activity level and balance in subjects with mild Alzheimer's disease.
To clarify if Alzheimer's disease has an impact on activity level and postural control, we examined 17 elderly diagnosed with mild Alzheimer's disease (MMSE scores 21-29) and 18 age- and gender-matched healthy controls (MMSE scores 27-30) using the Frenchay Activities Index, Bergs Balance Scale, Timed Up & Go and Walking in a Figure of Eight. Mild AD subjects were less active and had lower scores on Bergs Balance Scale, performed Timed Up & Go in longer time and took more steps outside the Figure of Eight, as compared to healthy elderly. This study shows that motor performance is affected already at mild stages of Alzheimer's disease and also that functional performance other than gait may also be impaired.


Comparison of fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis.
Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (ABCD; Sequus), AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of experimental systemic cryptococcosis. A model was established in 10-week-old female CD-1 mice by intravenous (i.v.) injection of 6.25 x 10(5) viable Cryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v. administration three times per week for 2 weeks. Mice received either no treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD, AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per kg and 90% of mice given 10 mg of ABLC per kg survived, whereas < or =50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting in a significantly better outcome than Fungizone (P < 0.001). Among the three formulations, ABCD and AmBi were equally effective, both being better than ABLC at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or 10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC. Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of ABLC, particularly in the brain; a comparative rank order of efficacies was ABCD approximately equal to AmBi > ABLC >> Fungizone. This is the first study that compared all four amphotericin B formulations.


Evolution of the genetic code.
The structure of the genetic code suggests that amino acid biosynthesis and hydrophobicity were important factors in shaping the genetic code, as the primitive code coevolved with new varieties of amino acids generated by the expanding pathways of biosynthesis. The current code is exceptionally stable. Deviant codes nonetheless have been observed in a number of mitochondrial and cellular genomes. Even the membership of encoded amino acids is undergoing expansion to include phosphoserine and selenocysteine. Experimental mutation of the code also has proven feasible, in a replacement of tryptophan by 4-fluorotryptophan as a component constituent of proteins. Such mutations, introducing novel varieties of encoded amino acids, will open up a new dimension in protein engineering and design.


Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.
Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m) amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid fibrils is described.


Abdominal prehospital ultrasound impacts treatment decisions in a Dutch Helicopter Emergency Medical Service.
The aim of this study was to determine the impact of abdominal prehospital ultrasound (PHUS) on patient care in a Dutch physician-staffed Helicopter Emergency Medical Service (HEMS) and to determine its diagnostic performance. We carried out a retrospective analysis of abdominal ultrasound (US) examinations performed by the HEMS of Nijmegen, the Netherlands, from January 2007 until December 2016. Data including patient demographics, type of incident, abdominal US findings, impact on treatment decisions, and the physicians' narrative report were retrieved from the HEMS database and analyzed. PHUS diagnostic performance was compared with computed tomography scan or laparotomy. Of 17 077 recorded scrambles and 8699 patients treated, 1583 underwent 1631 abdominal US examinations. After eliminating missing data, 251 impacts on treatment in 194 out of 1539 PHUS examinations were identified (12.6%, 95% confidence interval: 10.9-14.3). This affected 188 out of 1495 (12.6%) patients. The four main categories of treatment decisions impacted by PHUS were information provided to the destination hospital (45.4%); mode of transportation (23.5%); choice of destination hospital (13.1%); and fluid management (11.6%). The sensitivity of prehospital abdominal US for hemoperitoneum was 31.3%, specificity was 96.7%, and accuracy was 82.1%. Abdominal PHUS in our setting impacts treatment decisions significantly. Therefore, it is a valuable tool in the Dutch HEMS setting and probably beyond.


Chemical etching of fission tracks in polyfluoro plastics.
A method has been developed for the chemical etching of fission tracks in polyfluoro plastics. The formation of fine holes several tens of nanometers in diameter in polyvinylidene fluoride films, bombarded by fission fragments in oxygen and etched in 5-normal sodium hydroxide solution at 85 degrees C, was confirmed by electron microscopy.


Synthesis of beta-carboline-benzodiazepine hybrid molecules: use of the known structural requirements for benzodiazepine and beta-carboline binding in designing a novel, high-affinity ligand for the benzodiazepine receptor.
Hybrid molecules incorporating pharmacologically important structural features of both 3-carboxy-beta-carbolines and 1,4-benzodiazepines were synthesized, and their affinities for the benzodiazepine receptor were determined in vitro. One of these hybrids, 8,14-dioxo-13,14-dihydro-8H-indolo[3',2':4,5]pyrido[2,1-c] [1,4]benzodiazepine (13), demonstrated high affinity for the receptor, displacing both benzodiazepines (IC50 = 23 nM) and beta-carbolines (IC50 = 47 nM) from their binding sites. Of the compounds synthesized, 13 also most closely satisfied the structural requirements that generally ensure a high affinity of both beta-carbolines and benzodiazepines for the receptor (e.g., aromaticity of the beta-carboline, presence of a carbonyl at C-3 of the beta-carboline and of a pi 2-region on the benzodiazepine). The hybrids not fulfilling these requirements had no affinity for the receptor. In vivo pharmacological properties of 13 could not be demonstrated because of its metabolic instability and/or its poor transport into the brain. The results are discussed in terms of a possible overlapping of beta-carboline binding sites with those of benzodiazepines on the receptor.


Access and attitudinal barriers to engagement in integrated primary care mental health treatment for rural populations.
Compared to urban areas, rural populations are less likely to engage in mental health care. Using data from the Study to Promote Innovation in Rural Integrated Telepsychiatry, we examined the effect of rurality on engagement in mental health treatment as well as the role of potential mediators. Data were obtained from medical records and surveys. We defined rurality using the rural-urban commuting area codes. Baseline mediators included the Endorsed and Anticipated Stigma Inventory and the Assessment of Perceived Access to Care. Engagement outcomes included number of psychotherapy visits and self-reported medication use. We used path analysis to examine the relationship between rurality and engagement and the influence of mediating variables. Rural participants were less likely to initiate psychotherapy (OR = 0.49; adjusted P = .036), although rurality was not associated with number of psychotherapy sessions or medication use. Rurality was associated with a small elevation in negative beliefs about mental health, but this potential mediator was not associated with engagement. Rurality was negatively associated with lower perceived need for treatment (OR = 0.67, adjusted P = .040), which was in turn positively associated with initiating psychotherapy (OR = 1.99, adjusted P = .001). Neither rurality itself nor the potential mediators had a large effect on engagement. Federally Qualified Health Centers offering colocated and/or integrated mental health care appear to be mostly mitigating rural-urban disparities in mental health engagement. Improving rates of psychotherapy initiation for rural patients should remain a policy goal.


The antifungal activity of widdrol and its biotransformation by Colletotrichum gloeosporioides (penz.) Penz. & Sacc. and Botrytis cinerea Pers.: Fr.
Widdrol (1) was tested against the necrotrophic plant pathogens Botrytis cinerea and Colletotrichum gloeosporioides. While 1 was found to be inactive against C. gloeosporioides, it showed a selective and effective control of B. cinerea, significantly inhibiting the mycelial growth of the fungus at concentrations of 100 ppm and above. In addition, the biotransformation of 1 by both fungi was studied. Incubation with C. gloeosporioides and B. cinerea afforded four and one biotransformation products (2-6), respectively. Biotransformation with C. gloeosporioides was highly regioselective, yielding for the most part oxidation products at C-10: 10-oxowiddrol (2), 10beta-hydroxywiddrol (3), 10alpha-hydroxywiddrol (4), and 14alpha-hydroxywiddrol (5). The structures of all products were determined on the basis of their spectroscopic data, including coupling constants, two-dimensional NMR analysis (heteronuclear multiple quantum coherence, heteronuclear multiple bond correlation, and nuclear Overhauser enhancement spectroscopy), and nuclear Overhauser effect. The biotransformation products were then tested against B. cinerea and found to be inactive. These results shed further light on the structural modifications, which may be necessary to develop selective fungal control agents against B. cinerea.


Effect of early reperfusion on use of triphenyltetrazolium chloride to differentiate viable from non-viable myocardium in area of risk.
STUDY OBJECTIVE - The aim of the study was to assess the value of triphenyltetrazolium chloride (TTC) staining as an indicator of non-viable myocardium after early reperfusion of ischaemic myocardium. DESIGN - Left anterior descending artery occlusion was performed in pigs for various lengths of time and at two different sites (proximal and distal). After 120 min reperfusion, TTC was injected distal to the occlusion while the remainder of the myocardium was stained with Evans Blue. Myocardial enzymes were measured in non-ischaemic zone, regions of risk and in necrotic zones and related to staining characteristics. SUBJECTS - 31 male Hampshire pigs, weight 34-39 kg, were studied. Twelve were excluded because of resistant ventricular fibrillation or poorly defined areas of infarction. In the remaining 19 pigs, proximal occlusion was carried out in 15 and distal in four. Occlusion lasted for 15 min in six animals, for 30 min in eight (four of which were the animals with distal occlusions), and for 45 min in five. MEASUREMENTS and RESULTS - Biopsies from non-ischaemic zones, regions of risk and necrotic zones were analysed for creatine kinase and lactate dehydrogenase. In the 15 min group, myocardial creatine kinase in the region of risk (red stained) was similar to the non-ischaemic (blue) zone, but in the 30 min distal occlusion group it was reduced. After 30 and 45 min of proximal occlusion, creatine kinase activity in the necrotic (white) zone was reduced compared to the red zone in the same group, and in the red zone of both groups it was reduced compared to the non-ischaemic area. CONCLUSIONS - The red zone, as defined by TTC staining, may be associated with significant creatine kinase depletion after relatively brief periods of occlusion and subsequent reperfusion. This suggests that the red region may be a heterogeneous area of dead and viable cells.


Community pharmacists' use, perception and knowledge on dietary supplements: a cross sectional study.
Pharmacists are commonly tasked with recommending the appropriate dietary supplement and advising the patients of their correct and safe use. Previous research, conducted on pharmacy students, showed that they did not always use the evidence based sources of information, with personal use identified as a significant predictor influencing the decision to recommend a supplement. To compare use, perceptions and knowledge of dietary supplements of pharmacists with different years of work experience and to explore factors that could influence their recommendation of supplements. A questionnaire based cross-sectional study was conducted on Croatian community pharmacists in September 2017. The questionnaire explored pharmacists' demographic characteristics, use, perceptions and knowledge of dietary supplements. Pharmacists (N=102) were divided in two groups based on their work experience: P0 (<10 years) and P1 (≥10 years). All included pharmacists had high knowledge scores without differences between groups (P0=10, IQR 9-12 vs P1=11, IQR 9-12, expressed as median and interquartile range (IQR), p=0.275). Less experienced pharmacists perceived there was less research conducted on the dietary supplements compared to their more experienced counterparts (P0=1, IQR 1-2 vs P1=2, IQR 2-3, expressed as median and interquartile range, p<0.001). Groups differed in sources used when choosing the appropriate supplement with P0 using higher quality sources such as systematic reviews in comparison to P1 (32.1% vs 8.7%, p=0.004). Pharmacists' decision to recommend a dietary supplement was influenced by their personal use (odds ratio 0.216, 95%CI 0.068:0.689, p=0.01) and work experience (odds ratio 0.154, 95%CI 0.045:0.530, p=0.003). Pharmacists did not use the high quality sources when recommending dietary supplements and their decision to recommend the supplement was not based on objective evaluation of evidence. Further education about the practice of evidence-based pharmacy is necessary, with special emphasis on senior pharmacists who might have missed that aspect during their formal education.


Associations of ambient hydrogen sulfide exposure with self-reported asthma and asthma symptoms.
Whether long-term, low-level hydrogen sulfide (H2S) gas is a cause of health effects, including asthma, is uncertain. Rotorua city, New Zealand, has the largest population exposed, from geothermal sources, to relatively high ambient levels of H2S. In a cross-sectional study, the authors investigated associations with asthma in this population. A total of 1637 adults, aged 18-65 years, were enrolled during 2008-2010. Residences and workplaces were geocoded. H2S exposures at homes and workplaces were estimated using city-wide networks of passive H2S samplers and kriging to create exposure surfaces. Exposure metrics were based on (1) time-weighted exposures at home and work; and (2) the maximum exposure (home or work). Exposure estimates were entered as quartiles into regression models, with covariate data. Neither exposure metric showed evidence of increased asthma risk from H2S. However, some suggestion of exposure-related reduced risks for diagnosed asthma and asthma symptoms, particularly wheezing during the last 12 months, emerged. With the maximum exposure metric, the prevalence ratio for wheeze in the highest exposure quartile was 0.80 (0.65, 0.99) and, for current asthma treatment, 0.75 (0.52, 1.08). There was no evidence that this was caused by a "survivor effect". The study provided no evidence that asthma risk increases with H2S exposure. Suggestions of a reduced risk in the higher exposure areas are consistent with recent evidence that H2S has signaling functions in the body, including induction of smooth muscle relaxation and reduction of inflammation. Study limitations, including possible confounding, preclude definitive conclusions.