In vivo annular repair using high-density collagen gel seeded with annulus fibrosus cells.
The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model. Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo. 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair. Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels. AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture. This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential.


The operation, quality and costs of a district hospital laboratory service in Malawi.
Laboratory services are run down in many low-income countries, severely constraining their input to patient care and disease surveillance. There are few data about the quality and cost of individual components of the laboratory service in poorer countries, yet this information is essential if optimal use is to be made of scarce resources. Staff time, range of tests, workload, and safety procedures were monitored over 12 months (1997-98) in a typical district hospital laboratory in Malawi. Data were collected to calculate the total economic cost of these services. Of the 31203 tests performed, 84% were to support blood transfusion and diagnosis of malaria and tuberculosis (TB). Test quality was reasonable for malaria and TB microscopy and blood transfusion, but poor for haemoglobin estimation. The cost per test ranged from US dollars 0.35 for haemoglobin to US dollars 11.7 per unit of blood issued and the total annual cost of the laboratory service was US dollars 32618. Blood transfusion and microscopy for malaria and TB comprised the majority of tests. Ensuring that these tests are of the highest quality will therefore have the most impact in reducing wastage of laboratory resources. Inadequate quality of haemoglobin estimations is a particular problem. The findings of this study are likely to be relevant to other low-income countries with similar disease burdens.


A review of factors that influence individual compliance with mass drug administration for elimination of lymphatic filariasis.
The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA. Papers published between 2000 and 2012 were considered, and 79 publications were included in the final dataset for analysis after two rounds of selection. While results varied in different settings, some common features were associated with successful programs and with compliance by individuals. Training and motivation of drug distributors is critically important, because these people directly interact with target populations, and their actions can affect MDA compliance decisions by families and individuals. Other important programmatic issues include thorough preparation of personnel, supplies, and logistics for implementation and preparation of the population for MDA. Demographic factors (age, sex, income level, and area of residence) are often associated with compliance by individuals, but compliance decisions are also affected by perceptions of the potential benefits of participation versus the risk of adverse events. Trust and information can sometimes offset fear of the unknown. While no single formula can ensure success MDA in all settings, five key ingredients were identified: engender trust, tailor programs to local conditions, take actions to minimize the impact of adverse events, promote the broader benefits of the MDA program, and directly address the issue of systematic non-compliance, which harms communities by prolonging their exposure to LF. This review has identified factors that promote coverage and compliance with MDA for LF elimination across countries. This information may be helpful for explaining results that do not meet expectations and for developing remedies for ailing MDA programs. Our review has also identified gaps in understanding and suggested priority areas for further research.


COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin.
Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474-83. ©2017 AACR.


Electrostatic environment at the active site of prolyl oligopeptidase is highly influential during substrate binding.
The positive electrostatic environment of the active site of prolyl oligopeptidase was investigated by using substrates with glutamic acid at positions P2, P3, P4, and P5, respectively. The different substrates gave various pH rate profiles. The pKa values extracted from the curves are apparent parameters, presumably affected by the nearby charged residues, and do not reflect the ionization of a simple catalytic histidine as found in the classic serine peptidases like chymotrypsin and subtilisin. The temperature dependence of kcat/Km did not produce linear Arrhenius plots, indicating different changes in the individual rate constants with the increase in temperature. This rendered it possible to calculate these constants, i.e. the formation (k1) and decomposition (k-1) of the enzyme-substrate complex and the acylation constant (k2), as well as the corresponding activation energies. The results have revealed the relationship between the complex Michaelis parameters and the individual rate constants. Structure determination of the enzyme-substrate complexes has shown that the different substrates display a uniform binding mode. None of the glutamic acids interacts with a charged group. We conclude that the specific rate constant is controlled by k1 rather than k2 and that the charged residues from the substrate and the enzyme can markedly affect the formation but not the structure of the enzyme-substrate complexes.


Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means.
This article reviews historical aspects of the blood-brain barrier (BBB) and recent advances in mechanisms to deliver therapeutic agents across the BBB for the treatment of intracerebral tumors and other neurological diseases. The development of the osmotic BBB disruption procedure as a clinically useful technique is described. Osmotic BBB disruption is contrasted with alternative methods for opening or bypassing the BBB, including pharmacological modification of the BBB with bradykinin and direct intracerebral infusion. Laboratory studies have played a fundamental role in advancing our understanding of the BBB and delivery of agents to brain. Preclinical animal studies will continue to serve an integral function in our efforts to improve the diagnosis and treatment of a number of neurological disorders. Techniques involving the modification of the BBB and/or blood-tumor barrier to increase delivery of therapeutic agents have been advanced to clinical trials in patients with brain tumors with very favorable results. Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms. As techniques for gene therapy are advanced, manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.


Getting a grip: different actions and visual guidance of the thumb and finger in precision grasping.
We manipulated the visual information available for grasping to examine what is visually guided when subjects get a precision grip on a common class of object (upright cylinders). In Experiment 1, objects (2 sizes) were placed at different eccentricities to vary the relative proximity to the participant's (n = 6) body of their thumb and finger contact positions in the final grip orientations, with vision available throughout or only for movement programming. Thumb trajectories were straighter and less variable than finger paths, and the thumb normally made initial contact with the objects at a relatively invariant landing site, but consistent thumb first-contacts were disrupted without visual guidance. Finger deviations were more affected by the object's properties and increased when vision was unavailable after movement onset. In Experiment 2, participants (n = 12) grasped 'glow-in-the-dark' objects wearing different luminous gloves in which the whole hand was visible or the thumb or the index finger was selectively occluded. Grip closure times were prolonged and thumb first-contacts disrupted when subjects could not see their thumb, whereas occluding the finger resulted in wider grips at contact because this digit remained distant from the object. Results were together consistent with visual feedback guiding the thumb in the period just prior to contacting the object, with the finger more involved in opening the grip and avoiding collision with the opposite contact surface. As people can overtly fixate only one object contact point at a time, we suggest that selecting one digit for online guidance represents an optimal strategy for initial grip placement. Other grasping tasks, in which the finger appears to be used for this purpose, are discussed.


Differences in defensive volatiles of the forked fungus beetle, Bolitotherus cornutus, living on two species of fungus.
Forked fungus beetles, Bolitotherus cornutus, feed, mate, and live on the brackets of several species of shelf fungus that grow on decaying logs. In response to the specific threat stimulus of mammalian breath, B. cornutus beetles produce a volatile defensive secretion. We tested beetles collected from different host fungi to determine whether defensive secretion blends varied with host type. Using solid phase microextraction and gas chromatography-mass spectrometry, we detected large amounts of the alkylated benzoquinones, methyl-p-benzoquinone (toluquinone) and ethyl-p-benzoquinone, and smaller quantities of p-benzoquinone, 3-methylphenol (m-cresol), 3-ethylphenol, 2-methylhydroquinone, and 2-ethylhydroquinone in secretions. Volatile composition did not differ between male and female beetles. Secretions did differ between beetles collected from two species of fungus, Ganoderma applanatum and Fomes fomentarius, with the relative amount of p-benzoquinone secreted being the most important factor. Other relationships among the volatile components are discussed.


A new model of pacing in the mouse intestine.
A simple model of pacing in mouse intestine to longitudinal (LM) as well as circular muscle (CM) has been developed. Undissected segments of LM or CM from mouse ileum or jejunum were prepared to record contractions, nerve functions were inhibited, and regular spontaneous contractions were recorded. These had the properties expected of interstitial cells of Cajal (ICC) paced contractions: ileum slower than jejunum, inhibited but not abolished by nicardipine, reduced in frequency by cyclopiazonic acid, abolished by Ca(2+)-free media, and high temperature dependence (Q10 approximately 2.6-3.2). Nicardipine significantly reduced the pacing frequency in LM and CM. Intestinal segments from W/W(V) mice had few irregular contractions in CM but had regular contractions in LM. Other differences were found between LM and CM that suggest that the control of pacing of LM differed from pacing of CM. Moreover, both LM and CM segments in wild-type and W/W(V) and after cyclopiazonic acid responded to electrical pacing (50 V/cm, 50 or 100 ms) at 1 pulse per second. Temperature <26 degrees C inhibited electrically paced contractions in CM. These findings suggest that the current models of ICC pacing need to be modified to apply to intact segments of mouse intestine.


Adaptation to speed in macaque middle temporal and medial superior temporal areas.
The response of a sensory neuron to an unchanging stimulus typically adapts, showing decreases in response gain that are accompanied by changes in the shape of tuning curves. It remains unclear whether these changes arise purely due to spike rate adaptation within single neurons or whether they are dependent on network interactions between neurons. Further, it is unclear how the timescales of neural and perceptual adaptation are related. To examine this issue, we compared speed tuning of middle temporal (MT) and medial superior temporal neurons in macaque visual cortex after adaptation to two different reference speeds. For 75% of speed-tuned units, adaptation caused significant changes in tuning that could be explained equally well as lateral shifts, vertical gain changes, or both. These tuning changes occurred rapidly, as both neuronal firing rate and Fano factor showed no evidence of changing beyond the first 500 ms after motion onset, and the magnitude of tuning curve changes showed no difference between trials with adaptation durations shorter or longer than 1 s. Importantly, the magnitude of tuning shifts was correlated with the transient-sustained index, which measures a well characterized form of rapid response adaptation in MT, and is likely associated with changes at the level of neuronal networks. Tuning curves changed in a manner that increased neuronal sensitivity around the adapting speed, consistent with improvements in human and macaque psychophysical performance that we observed over the first several hundred ms of adaptation.


District nurses' self-reported clinical activities, beliefs about and attitudes towards obesity management.
To describe district nurses' self-reported clinical activities, beliefs about and attitudes towards obesity management; and to examine associations between the variables. Obesity is increasing worldwide and primary care could play a central role in the management. Questionnaire data were collected from 247 nurses in 33 centres. The most common activities performed weekly were; advice about physical activity (40.1%) and general lifestyle advice (34.8%). However, nearly one third seldom/never performed these activities. Approximately half seldom/never performed BMI assessment and even fewer waist circumference (78.1%). Values for the factors Importance of obesity and Personal effectiveness were skewed towards a positive view and Negative view close to neutral. Multivariate analysis revealed that nurses with specialized tasks, longer working experience and higher perceived personal effectiveness performed more clinical activities. Managers need to make efforts to engage all personnel in obesity management; and strategies to increase self-efficacy are called for.


Model learning analysis of 3D optoacoustic mesoscopy images for the classification of atopic dermatitis.
Atopic dermatitis (AD) is a skin inflammatory disease affecting 10% of the population worldwide. Raster-scanning optoacoustic mesoscopy (RSOM) has recently shown promise in dermatological imaging. We conducted a comprehensive analysis using three machine-learning models, random forest (RF), support vector machine (SVM), and convolutional neural network (CNN) for classifying healthy versus AD conditions, and sub-classifying different AD severities using RSOM images and clinical information. CNN model successfully differentiates healthy from AD patients with 97% accuracy. With limited data, RF achieved 65% accuracy in sub-classifying AD patients into mild versus moderate-severe cases. Identification of disease severities is vital in managing AD treatment.


Improved crystallization and diffraction of caffeine-induced death suppressor protein 1 (Cid1).
The post-transcriptional addition of uridines to the 3'-end of RNAs is an important regulatory process that is critical for coding and noncoding RNA stability. In fission yeast and metazoans this untemplated 3'-uridylylation is catalysed by a single family of terminal uridylyltransferases (TUTs) whose members are adapted to specific RNA targets. In Schizosaccharomyces pombe the TUT Cid1 is responsible for the uridylylation of polyadenylated mRNAs, targeting them for destruction. In metazoans, the Cid1 orthologues ZCCHC6 and ZCCHC11 uridylate histone mRNAs, targeting them for degradation, but also uridylate microRNAs, altering their maturation. Cid1 has been studied as a model TUT that has provided insights into the larger and more complex metazoan enzyme system. In this paper, two strategies are described that led to improvements both in the crystallogenesis of Cid1 and in the resolution of diffraction by ∼1.5 Å. These advances have allowed high-resolution crystallographic studies of this TUT system to be initiated.


Age and gender differences in health services utilization.
The purpose of this study was to examine the health service utilization patterns of elderly male and female enrollees of a large urban staff model Health Maintenance Organization (HMO). This HMO offered a wide spectrum of managed care services for its beneficiaries. A cross-sectional design was employed. The 759 randomly sampled elderly enrollees ranged in age from 66 to 99, with an average of 77.15 years. Approximately 60% were male and 40% were female; thus, the sample was not representative of the national older adult population. Three utilization patterns indicated that there were (a) nonsignificant relationships between age or gender and urgent care visits, prescribed pharmaceuticals, and out-of-pocket costs for pharmaceuticals; (b) linear relationships between age and gender and visits to HMO primary care providers (-), home-health care visits (+), emergency care visits (+), hospitalizations (+), and MD visits during hospitalizations (+); and (c) age was curvilinearly related to use of both HMO specialists and non-HMO specialists. These findings suggest that use of acute care services, including hospitalizations, inpatient physician visits, and emergency services increase with age but the use of primary care providers decreases with age. Gender was not a significant modifier of the relationship between age and utilization.


Ligand-driven activation of the notch pathway in T-ALL and solid tumors: why Not(ch)?
The Notch pathway is an evolutionally conserved cell-cell interaction signalling system involved in several key aspects of cell life, ranging from differentiation and proliferation to apoptosis. As such, it plays an important role in development, homeostasis, angiogenesis and various diseases. Over-activation of the Notch pathway has often been reported in cancer, leading to a variety of effects including increased proliferation, protection from apoptosis and maintenance of cancer initiating cells. Additionally, this signalling pathway has also been involved in tumor angiogenesis. The clearest example of oncogenic Notch signalling is observed in T acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm of immature T-cells, due to genetic alterations leading to ligand-independent increased Notch1 receptor signalling. In solid tumors, however, extrinsic regulation through canonical cell-cell interactions appears to drive activation of the pathway. We recently found that triggering of Notch3 signalling by DLL4 expressed on angiogenic endothelial cells promotes escape of T-ALL cells from tumor dormancy in a xenograft model. This observation discloses un unsuspected role for ligand-dependent regulation of Notch receptors in T-ALL cells, suggesting that blocking extrinsic Notch activation by anti-DLL4 or other ligand-targeted drugs could represent a novel therapeutic approach for this aggressive malignancy.


The geographical configuration of a language area influences linguistic diversity.
Like the transfer of genetic variation through gene flow, language changes constantly as a result of its use in human interaction. Contact between speakers is most likely to happen when they are close in space, time, and social setting. Here, we investigated the role of geographical configuration in this process by studying linguistic diversity in Japan, which comprises a large connected mainland (less isolation, more potential contact) and smaller island clusters of the Ryukyuan archipelago (more isolation, less potential contact). We quantified linguistic diversity using dialectometric methods, and performed regression analyses to assess the extent to which distance in space and time predict contemporary linguistic diversity. We found that language diversity in general increases as geographic distance increases and as time passes-as with biodiversity. Moreover, we found that (I) for mainland languages, linguistic diversity is most strongly related to geographic distance-a so-called isolation-by-distance pattern, and that (II) for island languages, linguistic diversity reflects the time since varieties separated and diverged-an isolation-by-colonisation pattern. Together, these results confirm previous findings that (linguistic) diversity is shaped by distance, but also goes beyond this by demonstrating the critical role of geographic configuration.


A framework for in vitro systems toxicology assessment of e-liquids.
Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands. Acknowledging these challenges, we present here a proposed framework for an in vitro systems toxicology assessment of e-liquids and their aerosols, intended to complement the battery of assays for standard toxicity assessments. The proposed framework utilizes high-throughput toxicity assessments of e-liquids and their aerosols, in which the device-to-device variability is minimized, and a systems-level investigation of the cellular mechanisms of toxicity is an integral part. An analytical chemistry investigation is also included as a part of the framework to provide accurate and reliable chemistry data solidifying the toxicological assessment. In its simplest form, the framework comprises of three main layers: (1) high-throughput toxicity screening of e-liquids using primary human cell culture systems; (2) toxicity-related mechanistic assessment of selected e-liquids, and (3) toxicity-related mechanistic assessment of their aerosols using organotypic air-liquid interface airway culture systems. A systems toxicology assessment approach is leveraged to enable in-depth analyses of the toxicity-related cellular mechanisms of e-liquids and their aerosols. We present example use cases to demonstrate the suitability of the framework for a robust in vitro assessment of e-liquids and their aerosols.


The sodium-dependent inorganic phosphate transporter SLC34A1 (NaPi-IIa) is not localized in the mouse brain: a case of tissue-specific antigenic cross-reactivity.
The sodium-dependent inorganic phosphate transporter NaPi-IIa is expressed in the kidney. Here, the authors used a polyclonal antiserum raised against NaPi-IIa- and NaPi-IIa-deficient mice to characterize its expression in nervous tissue. Western blots showed that a NaPi-IIa immunoreactive band (~90 kDa) was only present in wild-type kidney membranes and not in kidney knockout or wild-type brain membranes. In the water-soluble fraction of wild-type and knockout brains, another band (~50 kDa) was observed; this band was not detected in the kidney. Light and electron microscopic immunohistochemistry using the NaPi-IIa antibodies showed immunolabeling of kidney tubules in wild-type but not knockout mice. In the brain, labeling of presynaptic nerve terminals was present also in NaPi-IIa-deficient mice. This labeling pattern was also produced by the NaPi-IIa preimmune serum. The authors conclude that the polyclonal antiserum is specific toward NaPi-IIa in the kidney, but in the brain, immunolabeling is caused by a cross-reaction of the antiserum with an unknown cytosolic protein that is not present in the kidney. This tissue-specific cross-reactivity highlights a potential pitfall when validating antibody specificity using knockout mouse-derived tissue other than the specific tissue of interest and underlines the utility of specificity testing using preimmune sera.


Complete mitochondrial genome sequences of three Nakaseomyces species reveal invasion by palindromic GC clusters and considerable size expansion.
Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade that includes the pathogenic yeast Candida glabrata, namely, that of Kluyveromyces delphensis, Candida castellii and Kluyveromyces bacillisporus. The gene content is equivalent to that of C. glabrata, but reveals the existence of new group I introns in COX1 and CYTB and new potential intronic endonucleases. Gene order is highly rearranged in these genomes, which contain numerous palindromic GC clusters. The more GC nucleotides these elements contain, the longer and more AT-rich are the intergenes containing them, leading to a direct relationship between the number of Gs and Cs within the elements and the size of the genomes. Thus, there is a fivefold difference in size between the smallest and the largest mitochondrial genome, with the largest being the most AT-rich overall. Sequences are available under EMBL accession numbers FM995164, FM995165, and FM995166.


Impact of Needle Diameter on Long-Term Dry Needling Treatment of Chronic Lumbar Myofascial Pain Syndrome.
To investigate the impact of diameter of needles on the effect of dry needling treatment of chronic lumbar myofascial pain syndrome. Forty-eight patients with chronic lumbar myofascial pain syndrome were randomly allocated to 3 groups. They received dry needling with needles of diameter 0.25 (group A), 0.5 (group B), and 0.9 mm (group C). Visual analog scale evaluation and health survey were conducted at baseline and 3 months after the treatment. Visual analog scale scores were significantly different in all groups from baseline to 3 months. Visual analog scale scores at 3 months showed differences between group C and the other 2 groups. When baseline and 3 months after treatment (0 day and 3 months) in each of the 3 groups was compared, there was a difference between group C and group B. The Short Form (36) Health Survey scores from baseline to 3 months were different within the treatment groups. Visual analog scale score evaluations at 3 months showed efficacy in all groups. Results of 3 months showed that efficacy of treatment with larger needles (0.9-mm diameter) was better than that of smaller ones (0.5-mm diameter). The Short Form (36) Health Survey scores at 3 months indicated that treatments with needles of varying diameters were all effective, and when the results of 3 months were compared, there was no difference between the 3 groups.


Plasticity in major ampullate silk production in relation to spider phylogeny and ecology.
Spider major ampullate silk is a high-performance biomaterial that has received much attention. However, most studies ignore plasticity in silk properties. A better understanding of silk plasticity could clarify the relative importance of chemical composition versus processing of silk dope for silk properties. It could also provide insight into how control of silk properties relates to spider ecology and silk uses. We compared silk plasticity (defined as variation in the properties of silk spun by a spider under different conditions) between three spider clades in relation to their anatomy and silk biochemistry. We found that silk plasticity exists in RTA clade and orbicularian spiders, two clades that differ in their silk biochemistry. Orbiculariae seem less dependent on external spinning conditions. They probably use a valve in their spinning duct to control friction forces and speed during spinning. Our results suggest that plasticity results from different processing of the silk dope in the spinning duct. Orbicularian spiders seem to display better control of silk properties, perhaps in relation to their more complex spinning duct valve.


Psychophysiological influences on personality trajectories in adolescent females exposed to child maltreatment.
Although child maltreatment is a major public health concern, which adversely affects psychological and physical development, we know relatively little concerning psychophysiological and personality factors that may modify risk in children exposed to maltreatment. Using a three-wave, short-term prospective design, we examined the influence of individual differences in two disparate psychophysiological measures of risk (i.e., resting frontal brain electrical activity and respiratory sinus arrhythmia) on the trajectories of extraversion and neuroticism in a sample of female adolescents (N = 55; M age = 14.02 years) exposed to child maltreatment. Adolescents exposed to child maltreatment with relatively higher left frontal absolute alpha power (i.e., lower brain activity) at rest exhibited increasing trajectories of extraversion, and adolescents exposed to child maltreatment with relatively lower respiratory sinus arrhythmia at rest displayed increasing trajectories of neuroticism over 1 year. Individual differences in psychophysiological measures indexing resting central and peripheral nervous system activity may therefore differentially influence personality characteristics in adolescent females exposed to child maltreatment.


Role of the autonomic nervous system in mild human hypertension.
1. Some of the haemodynamic abnormalities in mild (borderline) human hypertension appear to be neurogenic, since they can be completely abolished by pharmacological autonomic blockade. 2. The cardiac output is elevated in 30% of patients through increased sympathetic drive and decreased parasympathetic inhibition. 3. In the remainder, the higher blood pressure is maintained by increased total peripheral vascular resistance. 4. In approximately 30% of this latter group, the higher vascular resistance is maintained solely by increased alpha-adrenergic tone. 5. Elevated plasma renin activities in a proportion of cases are probably due to generalized increase in sympathetic nervous activity. 6. Patients with mild hypertension thus show increased sympathetic drive to the heart and arterioles as well as decreased cardiac parasympathetic inhibition. It is presumed that the increased plasma renin is also neurogenic. 7. Such a widespread distribution of altered autonomic tone suggests aberration of the function of the integrative centres of cardiovascular control. 8. Evidence is presented of a possible psychosomatic origin of these changes in some cases.


TEMPO supported on magnetic C/Co-nanoparticles: a highly active and recyclable organocatalyst.
TEMPO was grafted on graphene-coated nanobeads with a magnetic cobalt core by using a general applicable "click"-chemistry protocol. The new heterogeneous CoNP-TEMPO emerged as a highly active catalyst for the chemoselective oxidation of primary and secondary alcohols using bleach as terminal oxidant. The outstanding stability of the C/Co nanoparticles enables the nanopowder to tolerate several TEMPO-mediated iterative oxidation reactions without any significant loss in catalyst activity. Furthermore, the excellent magnetic properties enable the rapid separation and quantitative recycling of CoNP-TEMPO out of the reaction mixture by simple magnetic decantation. The recovered nanoparticles can be subsequently reused without any further purification.


Dexmedetomidine versus esmolol to attenuate the hemodynamic response to laryngoscopy and tracheal intubation: A randomized double-blind clinical study.
Sympathoadrenal response to laryngoscopy and tracheal intubation manifests as transient, but distinct tachycardia and hypertension. The objective of this study is to compare the clinical effects of dexmedetomidine with esmolol and control in attenuating the presser response during laryngoscopy. A randomized, prospective, double-blind, controlled study. We studied consented, 90 adult, American Society of Anesthesiologists physical status I and II patients of either sex, scheduled for non-cardiac surgery requiring intubation. The patients were randomly divided into three groups (n = 30). Group C received placebo, Group E received 2.0 mg/kg of esmolol and Group D received 1.0 μg/kg of dexmedetomidine, intravenously over 10 min and 3 min before induction of general anesthesia. All patients were uniformly pre-medicated, induced and intubated using thiopentone and succinylcholine as per standard protocol. Heart rate (HR), systemic arterial pressures were recorded at baseline, after study drug infusion, after induction, immediately and 3, 5, 7, 10 min after intubation. Analysis of variance and t-test as appropriate. The mean arterial pressure was significantly increased in patients receiving placebo (P < 0.0001) and esmolol (P < 0.0001) after laryngoscopy and intubation compared with baseline value and Group D (P = 0.6294). The rise in HR (P = 0.08481) and rate pressure product (P = 0.0666) at the time of intubation were minimal and was statistically significant up to 15 min in Group D. Both the drugs attenuated the pressure response. Of the two drugs administered, dexmedetomidine 1.0 μg/kg provides a consistent, reliable and effective attenuation of pressure responses when compared to esmolol 2.0 mg/kg.


Utilization of national patient registries by clinical nurse specialist: opportunities and implications.
The purpose of this article was to describe how clinical nurse specialists can be instrumental in getting involved in the process of joining a national disease registry to improve patient outcomes. Clinical patient data registries provide longitudinal data on developmental outcomes in chronic, lifelong diseases affecting children. Recognition and application of their use have historically allowed for collection of benchmarking data, improved understanding of disease processes and patient outcomes, and improved quality of life. A group of advanced practice nurses in a university-based multispecialty clinic, through evidence-based practice, embarked on the process of joining the National Spina Bifida Patient Registry sponsored by the Centers for Disease Control and Prevention. By taking the lead as project managers, this group of advanced practice nurses obtained buy-in from physicians and multispecialty team members of the Spina Bifida Clinic in the university children's hospital where they practice. An institutional review board application was submitted to their university children's hospital internal review board and currently approved. This project demonstrates how dynamic utilization of core competencies through application of specific knowledge and skill sets supports the advanced practice nurse's instrumental role in actively initiating, promoting, and supporting participation in clinical patient data registries that seek improved patient outcomes at the national level. Clinical nurse specialists quantify their role and purpose when connecting their interventions and influence to patient outcomes with utilization of resources, such as a national patient data registry.


Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality.
Chronic kidney disease (CKD) is recognized as an independent cardiovascular disease (CVD) risk state, particularly in the elderly, and has been defined by levels of estimated glomerular filtration rate (eGFR) and markers of kidney damage. The relationship between CKD and CVD in younger and middle-aged adults has not been fully explored. Community volunteers completed surveys regarding past medical events and underwent blood pressure and laboratory testing. Chronic kidney disease was defined as an eGFR <60 mL x min(-1) x 1.73 m(-2) or urine albumin-creatinine ratio (ACR) > or =30 mg/g. Premature CVD was defined as self-reported myocardial infarction or stroke at <55 years of age in men and <65 years of age in women. Mortality was ascertained by linkage to national data systems. Of 31 417 participants, the mean age was 45.1 +/- 11.2 years, 75.5% were female, 36.8% African American, and 21.6% had diabetes. A total of 20.6% were found to have CKD, with the ACR and eGFR being the dominant positive screening tests in the younger and older age deciles, respectively. The prevalences of premature myocardial infarction (MI), stroke, or death, and the composite were 5.3%, 4.7%, 0.8%, 9.2%, and 2.5%, 2.2%, 0.2%, 4.2% for those with and without CKD, respectively (P < .0001 for composite). Multivariable analysis found CKD (OR 1.44, 95% CI 1.27-1.63), age (OR 1.05 [per year], 95% CI 1.04-1.06), hypertension (OR 1.61, 95% CI 1.40-1.84), diabetes (OR 2.03, 95% CI 1.79-2.29), smoking (OR 1.91, 95% CI 1.66-2.21), and less than high school education (OR 1.59, 95% CI 1.37-1.85) as the most significantly associated factors for premature CVD or death (all P < .0001). Survival analysis found those with premature MI or stroke and CKD had the poorest short-term survival over the next 3 years after screening. Chronic kidney disease is an independent predictor of MI, stroke, and death among men and women younger than age 55 and 65 years, respectively. These data suggest the biologic changes that occur with kidney failure promote CVD at an accelerated rate that cannot be fully explained by conventional risk factors or older age. Screening for CKD by using both the ACR and eGFR can identify younger and middle-aged individuals at high risk for premature CVD and near-term death.


Bedsharing and maternal smoking in a population-based survey of new mothers.
Sudden infant death syndrome (SIDS) remains the number 1 cause of postneonatal infant death. Prone infant sleep position and maternal smoking have been established as risk factors for SIDS mortality. Some studies have found that bedsharing is associated with SIDS, but, to date, there is only strong evidence for a risk among infants of smoking mothers and some evidence of a risk among young infants of nonsmoking mothers. Despite the lack of convincing scientific evidence, bedsharing with nonsmoking mothers remains controversial. In some states, nonsmoking mothers are currently being told that they should not bedshare with their infants, and mothers of infants who died of SIDS are told that they caused the death of their infant because they bedshared. The objective of this study was to explore the relationship between maternal smoking and bedsharing among Oregon mothers to explore whether smoking mothers, in contrast to nonsmoking mothers, are getting the message that they should not bedshare. Oregon Pregnancy Risk Assessment Monitoring System surveys a stratified random sample, drawn from birth certificates, of women after a live birth. Hispanic and non-Hispanic black, non-Hispanic Asian/Pacific Islander and non-Hispanic American Indian/Alaskan Native women, and non-Hispanic white women with low birth weight infants are oversampled to ensure sufficient numbers for stratified analysis. The sample then was weighted to reflect Oregon's population. In 1998-1999, 1867 women completed the survey (73.5% weighted response). The median time from birth to completion of the survey was 4 months. Women were asked whether they shared a bed with their infant "always," "almost always," "sometimes," or "never." Frequent bedsharing was defined as "always" or "almost always"; infrequent was defined as "sometimes" or "never." Of all new mothers, 35.2% reported bedsharing frequently (always: 20.5%; almost always: 14.7%) and 64.8% infrequently (sometimes: 41.4%; never: 23.4%). Bedsharing among postpartum smoking mothers was 18.8% always, 12.6% almost always, 45.1% sometimes, and 23.6% never; this was not statistically different from among nonsmoking mothers. Results for prenatal smokers were similar. When stratified by race/ethnicity, there was no association between smoking and bedsharing in any racial or ethnic group. In univariable and multivariable logistic regression, there were no statistical differences in frequent or any bedsharing among either prenatal or postpartum smoking mothers compared with nonsmokers; the adjusted odds ratio for postpartum smokers who frequently bedshared was 0.73 (95% confidence interval [CI]: 0.42-1.25) and for any bedsharing was 1.05 (95% CI: 0.57-1.94). Results for prenatal smoking were similar. This is the first US population-based study to look at the prevalence of bedsharing among smoking and nonsmoking mothers. Bedsharing is common in Oregon, with 35.2% of mothers in Oregon reporting frequently bedsharing and an additional 41.4% sometimes bedsharing. There was no significant association between smoking and bedsharing for either prenatal or postpartum smokers among any racial or ethnic group. Smoking mothers were as likely to bedshare as nonsmoking mothers. The frequency of bedsharing in Oregon was similar to estimates from other sources. Our study has the advantage of being a population-based sample drawn from birth certificates, weighted for nonresponse. Although a number of case series have raised concerns about the safety of mother-infant bedsharing, even among nonsmoking mothers, this has not yet been confirmed by careful, controlled studies. There have been 9 large-scale case-control studies of the relationship between bedsharing and SIDS. Three case-control studies did not stratify by maternal smoking status, but found no increased risk for SIDS. Six case control studies reported results stratified by maternal smoking status: 1 study, while asserting an association, provided an unexplained range of univariable odds ratios without CIs; 3 found no increased risk for older infants of nonsmoking mothers; and 2 found a risk only for infants <8-11 weeks of age. Despite the preponderance of evidence that bedsharing by nonsmoking mothers does not increase the risk for SIDS among older infants, the recent specter of bedsharing as a cause of SIDS, based on uncontrolled case series and medical examiners' anecdotal experience, has led some medical examiners to label a death "suffocation" or "overlay asphyxiation" simply because the infant was bedsharing at the time of death. This "diagnostic drift" may greatly complicate future studies of the relationship between bedsharing and SIDS. Epidemiologic evidence shows that there is little or no increased risk for SIDS among infants of nonsmoking mothers but increased risk among infants of smoking mothers and younger infants of nonsmoking mothers. It seems prudent to discourage bedsharing among all infants <3 months old. Young infants brought to bed to be breastfed should be returned to a crib when finished. It would be worthwhile for other researchers to reanalyze their previous data to evaluate the consistency of the interaction of young infant age and bedsharing. Large controlled studies that include infants who are identified as dying from SIDS, asphyxia, suffocation, and sudden unexplained infant death, analyzed separately and in combination, are needed to resolve this and other issues involving bedsharing, including the problem of diagnostic drift. Recommendations must be based on solid scientific evidence, which, to date, does not support the rejection of all bedsharing between nonsmoking mothers and their infants. Cribs should be available for those who want to use them. Nonsmoking mothers should not be pressured to abstain from bedsharing with their older infants; they should be provided with accurate, up-to-date scientific information. Infants also should not co-sleep with nonparents. In Oregon, if not elsewhere, the message that smoking mothers should not bedshare is not being disseminated effectively. Because it is not known whether the risk caused by smoking is associated with prenatal smoking, postpartum smoking, or both, bedsharing among either prenatal or postpartum smokers should be strongly discouraged. Much more public and private effort must be made to inform smoking mothers, in culturally competent ways, of the very significant risks of mixing bedsharing and smoking. Public health practitioners need to find new ways to inform mothers and providers that smoking mothers should not bedshare and that putting an infant of a nonsmoking mother to sleep in an adult bed should be delayed until 3 months of age.


Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase.
Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalyzing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. Here we report the synthesis and characterization of three tandem benzophenone amino pyridines as inhibitors of LTC4S in vitro and in vivo. The inhibitors were characterized in vitro using recombinant human LTC4S, MonoMac 6 cells, and a panel of peripheral human immune cells. In vivo, the compounds were tested in the Zymosan A-induced peritonitis mouse model. The molecules, denoted TK04, TK04a, and TK05, were potent and selective inhibitors of LTC4S with IC50 values of 116, 124, and 95 nM, respectively. Molecular docking revealed binding in a hydrophobic crevice between two enzyme monomers and interaction with two catalytic residues, Arg104 and Arg31. The TK compounds potently inhibited cys-LT biosynthesis in immune cells. In coincubations of platelets and polymorphonuclear leukocytes, inhibition of LTC4S led to shunting of LTA4 toward anti-inflammatory lipoxin A4, which was significantly enhanced by simultaneous inhibition of LTA4H. Finally, we found that TK05 (6 mg⋅kg(-1)⋅body weight) reduces LTE4 levels in peritoneal lavage fluid by 88% and significantly decreases vascular permeability in vivo. Our findings indicate that the TK compounds are valuable experimental tools in eicosanoid research in vitro and in vivo. Their chemical structures may serve as leads for further inhibitor design. Novel drugs depleting cys-LT production could be beneficial for treatment of inflammatory diseases associated with overexpression of LTC4S.


Influence of Mirrored Computed Tomograms on Decision-Making for Revising Surgically Treated Orbital Floor Fractures.
This study evaluated whether intraoperative imaging with computer-assisted virtual reconstruction would be advantageous in reconstructions of orbital floor fractures. The surgeon's intention to revise a reconstructed primary orbital floor fracture by evaluating a postoperative mirrored computed tomographic (CT) scan was analyzed intraoperatively before wound closure, during inpatient hospitalization, and after hospitalization. The inter-rater agreement and the match of intention to revise and actual revision were analyzed. Fifty-one anonymized postoperative CT scans of patients with a unilateral orbital floor fracture were mirrored using software. These computer-assisted virtual reconstructions were consecutively examined by 4 examiners. Seven of these patients underwent a revision. In the first part, the inter-rater agreements for all 3 times were analyzed. In the second part, the examiners' intentions to revise were compared with the actual performed revisions. The overall inter-rater agreements were 0.69 for the intraoperative phase, 0.55 for the in-hospital phase, and 0.39 for the post-hospital phase. The intraoperative inter-rater agreement for each examiner was 0.58 to 0.80. The Fleiss κ value for the in-hospital and post-hospital phases was lower. The comparison of the examiners' intention to revise and the actual revisions showed that 15 to 24 additional would have been revised. In contrast, 6 of 7 actual revisions would have been revised intraoperatively. The missed actual revision was the same case by all 4 examiners. The accordance of intention to revise with the actual revisions decreased during hospitalization and even more after hospitalization. This study showed strong agreement among examiners for revising anatomically incorrectly reduced orbital floor fractures intraoperatively by evaluating postoperative mirrored CT scans. During the in-hospital and post-hospital phases, the restraints against revision seemed to increase, thus leading to poorer inter-rater agreement. This analysis of postoperative CT scans with computer-assisted virtual reconstructions of the orbit would have led to considerably more revisions intraoperatively, but all actual revisions were detected except for 1 case. This case was the same for all 4 examiners. Operation time would have been prolonged in the additional revised cases, but a better anatomic reconstruction would have been achieved. Furthermore, the intraoperative result of the reconstruction would have been controlled instantly and corrected immediately, if needed. This study showed that of 6 of 7 actual revisions, implant placement would have been revised intraoperatively by all 4 examiners, if intraoperative imaging with computer-assisted virtual reconstruction of the orbit would have been applied. Therefore, the authors suggest that intraoperative imaging with computer-assisted virtual reconstruction could be advantageous in the prevention of later revisions of orbital floor fractures. In this study, the threshold to revise implant placement intraoperatively seemed to be lower when using intraoperative imaging with virtual reconstructions, because considerably more cases would have been revised intraoperatively by the examiners. In the in-hospital and post-hospital phases, this threshold increased, suggesting the more important role of clinical findings. It is uncertain whether the actual surgeons would have revised the same cases as the examiners if they had used intraoperative imaging with virtual reconstructions for their deliberation. However, the intraoperative inter-rater agreement was good and cost-intensive postoperative revisions might be prevented.


Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function.
Down-regulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) overexpressing human FOXP1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-Fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared with wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-Fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible for Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify down-regulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo.


[Influence of metal elements in Pd alloys on the bonding to porcelain].
The influence of metal elements in three Pd alloys on the bonding to porcelain was examined. The high-temperature oxidation behavior of metal elements in alloys, structure and morphology of oxidation zones on the alloy surface and the appearance of bonding between alloy and fused porcelain at the interface were studied by ESCA and EPMA. From ESCA analysis, metal oxides such as PdO, SnO2, In2O3, CuO or Cu2O, Sb2O3 or Sb2O5 were formed on the surface of the alloy after degassing (preheating) and heating following casting. The amount of metal elements concentrated on the alloy surface was measured by their characteristic X-rays using area analysis of EPMA under the technical conditions of A) Acc. voltage 10 kV, Abs. current 40 nA, and B) Acc. voltage 20 kV, Abs. current 10 nA. Consequently, the amount of additive metal elements concentrated on the alloy surface which was detected in condition A) was larger than that detected in condition B). However, the amount of main element (Pd) concentrated on the alloy surface which was detected in condition A) was smaller than that detected in condition B). From the EPMA observation of the interface between alloy and fused porcelain, cross-section of alloys showed that the additive metal elements were oxidized in the alloy matrix, forming an internal oxide layer or particles. The structure and morphology of oxidation zones showed a significant difference between degassed and not-degassed alloys. Cross-sections inclined approximately 5 degrees 43' to the fusing boundary were also analyzed to enlarge the oxidation zones. This analytical technique effectively revealed the structure and morphology of oxidation zones. In conclusion, not only additive metal elements but also the main element at the surface of alloys play important roles on the bonding to porcelain. Degassing of the alloy was considered to an essential procedure to obtain the adequate bonding to porcelain.


Monotreme IGF2 expression and ancestral origin of genomic imprinting.
IGF2 (insulin-like growth factor 2) and M6P/IGF2R (mannose 6-phosphate/insulin-like growth factor 2 receptor) are imprinted in marsupials and eutherians but not in birds. These results along with the absence of M6P/IGF2R imprinting in the egg-laying monotremes indicate that the parental imprinting of fetal growth-regulatory genes may be unique to viviparous mammals. In this investigation, we have cloned IGF2 from two monotreme mammals, the platypus and echidna, to further investigate the origin of imprinting. We report herein that like M6P/IGF2R, IGF2 is not imprinted in monotremes. Thus, although IGF2 encodes for a highly conserved growth factor in chordates, it is only imprinted in therian mammals. These findings support a concurrent origin of IGF2 and M6P/IGF2R imprinting in the late Jurassic/early Cretaceous period. The absence of imprinting in monotremes, despite apparent interparental conflicts over maternal-offspring exchange, argues that a fortuitous congruency of genetic and epigenetic events may have limited the phylogenetic breadth of genomic imprinting to therian mammals. J. Exp. Zool. (Mol. Dev. Evol.) 291:205-212, 2001.


Inter-relationships among gonadotrophins, reproductive steroids and inhibin in freemartin ewes.
Freemartins are sterile XX/XY chimaeras that occur as a result of placental fusion between male and female fetuses during early pregnancy. Freemartins occur predominantly in cattle, although the prevalence of ovine freemartinism is increasing. In this study, the reproductive endocrinology of ovine freemartins was compared with that of normal sheep. Freemartins had significantly (P < 0.001) higher basal concentrations of LH and FSH than did normal ewes or rams, although the response of LH to GnRH (10 microg) was similar in freemartins, ewes and rams. Resting concentrations of oestradiol were similar in freemartins and ewes and were increased in both after eCG administration. Testosterone concentrations were higher in freemartins than in ewes, but were unresponsive to GnRH or eCG. Administration of 62.5 mg progesterone or 25 lg oestradiol twice a day for 3 days suppressed LH concentrations to baseline values in freemartins, ewes and rams. In ewes, 500 microg oestradiol administered twice a day caused preovulatory surges in LH concentrations, but suppressed LH in freemartins to baseline values. Thus, LH secretion can potentially be regulated in freemartins by gonadal steroids. FSH concentrations in freemartins were not suppressed by doses of inhibin that were effective in ewes and rams. Therefore, freemartins behave in part like castrated animals, as they have high basal concentrations of LH and FSH, which can be stimulated by GnRH and suppressed by gonadal steroids. Conversely, inhibin does not suppress FSH concentrations in freemartins, and freemartins have circulating concentrations of steroids intermediate between those of castrated and normal animals.


Striving for the thin ideal post-pregnancy: a cross-sectional study of intuitive eating in postpartum women.
Objective: To conduct a cross-sectional study of women in the postpartum period to identify relationships between intuitive eating, body image satisfaction, eating attitudes and depressive symptomology.Methods: Women with at least one child born in the previous 6-48 months were recruited via Facebook to complete an online survey which included: sociodemographic and health questions, the Intuitive Eating Scale, the Body Shape Questionnaire, the Multi-dimensional Body-Self Relations Questionnaire, the Eating Attitudes Test-26 and the Edinburgh Postnatal Depression Scale. Descriptive statistics were calculated for all variables and hierarchical regressions used to examine associations between intuitive eating styles, body image satisfaction, eating attitudes and depressive symptomology.Results: Of the 419 women (mean age 32 ± 5.3 years), 32% were classified with intuitive eating styles and were more likely to have higher body image satisfaction (F = 476.80, p < .001), less disordered eating attitudes (F = 30.74, p < .001) and lower depressive symptomology (F = 4.14, p = .042).Conclusions: The postpartum period is a time of high risk for developing/maintaining eating styles that may negatively impact psychological health and well-being. Providing education to new mothers about the benefits of intuitive eating could positively influence their health and well-being.


The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions.
Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases. This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases. S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP. Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces. This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.


Principles, organization, and operation of a DNA bank for clinical trials: a Department of Veterans Affairs cooperative study.
The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program.


A reproductive justice perspective on the Purvi Patel case.
In the spring of 2015, news media across the world displayed images of a young, South Asian American woman in handcuffs, her long, untied black hair flowing forward and shielding her face as a Caucasian male police officer led her into a US court room. In another image, mug shot frontal and profile views of her face as a criminal, dotted online press reports, blogs and the social media. Although criminalised people of colour occupy a permanent space in the US media, her image jars. What is a young woman from a so-called "model minority" doing in handcuffs?


Effects of endurance exercise training on risk components for metabolic syndrome, interleukin-6, and the exercise capacity of postmenopausal women.
We conducted this study to investigate how an exercise program affects the risk components of metabolic syndrome (MS), serum interleukin (IL)-6 levels, and exercise capacity in postmenopausal women. A randomized clinical trial design was used. Women in an exercise group participated in a treadmill-exercise program for 12 weeks, whereas women in a control group maintained their customary lifestyle. Data on variables were collected at baseline and after 12 weeks of the study, which was completed by 46 women (mean age, 56.0 ± 7.0 y). Our results indicate endurance exercise exerted significant beneficial effects on waist circumference, serum high-density lipoprotein cholesterol (HDL-C) and IL-6 levels, and exercise capacity (all P < 0.05). The beneficial effects on IL-6 and exercise capacity were correlated with improvements in HDL-C levels (r = -0.33, P = 0.03 and r = 0.31, P = 0.04, respectively). Our results suggest that health-care providers can incorporate an exercise program in treatments to improve the health of postmenopausal women.


Necrobiotic xanthogranuloma with paraproteinemia: an evolving presentation.
Necrobiotic xanthogranuloma with paraproteinemia is a progressive and destructive process that is often confused both clinically and histologically with other granulomatous and xanthomatous entities. It was first described by Kossard and Winkelmann in 1980. Prior to this, the entity was reported under a variety of names such as atypical multicentric reticulohistiocytosis with paraproteinemia, atypical xanthoma disseminatum, and atypical necrobiosis lipoidica. A 69-year-old woman experienced slightly pruritic and painful papules, plaques, and nodules. Initial biopsy specimens showed a granulomatous process consistent with granuloma annulare. Later biopsy specimens demonstrated histologic changes indicative of necrobiosis lipoidica. The most recent histologic findings are those of necrobiotic xanthogranuloma, with results of laboratory studies revealing a coexistent IgG kappa paraproteinemia. Patients with necrobiotic xanthogranuloma who demonstrate a benign monoclonal proteinemia and are evaluated for several years show a 9 to 11 percent risk of myeloma, amyloidosis, or macroglobulinemia. Multiple treatment regimens have been attempted, none of which are curative. We propose that this entity may be part of an evolutionary process that may start as a granulomatous entity and culminate in a xanthogranulomatous process with an accompanying paraproteinemia.


Contaminant concentrations in Asian carps, invasive species in the Mississippi and Illinois Rivers.
Populations of invasive fishes quickly reach extremely high biomass. Before control methods can be applied, however, an understanding of the contaminant loads of these invaders carry is needed. We investigated differences in concentrations of selected elements in two invasive carp species as a function of sampling site, fish species, length and trophic differences using stable isotopes (delta (15)N, delta (13)C). Fish were collected from three different sites, the Illinois River near Havana, Illinois, and two sites in the Mississippi River, upstream and downstream of the Illinois River confluence. Five bighead carp (Hypophthalmichthys nobilis) and five silver carp (Hypophthalmichthys molitrix) from each site were collected for muscle tissue analyses. Freshwater mussels (Amblema plicata) previously collected in the same areas were used as an isotopic baseline to standardize fish results among sites. Total fish length, trophic position, and corrected (13)C, were significantly related to concentrations of metals in muscle. Fish length explained the most variation in metal concentrations, with most of that variation related to mercury levels. This result was not unexpected because larger fish are older, giving them a higher probability of exposure and accumulation of contaminants. There was a significant difference in stable isotope profiles between the two species. Bighead carp occupied a higher trophic position and had higher levels of corrected (13)C than silver carp. Additionally bighead carp had significantly lower concentrations of arsenic and selenium than silver carp. Stable isotope ratios of nitrogen in Asian carp were at levels that are more commonly associated with higher-level predators, or from organisms in areas containing high loads of wastewater effluent.


Performance of a previously validated CT colonography computer-aided detection system in a new patient population.
A computer-aided detection (CAD) system with high sensitivity in the detection of adenomatous polyps in varied CT colonography (CTC) data sets increases the utility of CAD in the clinical setting. The purpose of this study was to evaluate the standalone performance of an existing CAD system with a new set of CTC data from screening patients at an institution and geographic location different from those at which the CAD system was trained. CTC data were collected from the records of 104 patients undergoing screening for colorectal neoplasia. Most of the patients were at average risk, had CTC findings suggestive of polyps, and underwent colonoscopy. Patients underwent cathartic bowel preparation, were given an oral contrast agent, and underwent imaging in the prone and supine positions. The patients had 86 adenomas confirmed at same-day optical colonoscopy; 47 of these tumors were 10 mm in diameter or larger, and 39 measured 6-9 mm. The CTC data were analyzed with an existing CAD system for colonography that was trained with previously acquired data. In a previous non-polyp-enriched screening cohort, the standalone performance of the CAD system was 93.3% (28/30) sensitivity for adenomatous polyps 10 mm or larger, 51.1% (47/92) sensitivity for adenomas 6-9 mm, and a mean false-positive rate of 8.6 per patient. Sensitivity comparisons were made with findings in the previous study. The CAD system had per-polyp sensitivities of 91.5% (43/47; 95% CI, 78.7-97.2%; p = 1.0) for adenomas 10 mm or larger and 82.1% (32/39; 65.9-91.9%; p = 0.0009) for adenomas 6-9 mm. The per-patient sensitivities were 97.6% (40/41; 85.6-99.9%; p = 0.6) for patients with adenomas 10 mm or larger and 82.4% (28/34; 64.8-92.6%; p = 0.047) for patients with adenomas 6-9 mm. The mean and median false-positive rates were 9.6 +/- 9.6 and 7.0 per patient, respectively. Common reasons for CAD misses (false-negative findings) were the presence of adherent contrast medium, flat adenomas, and adenomas located on or adjacent to normal colonic folds. In a random sample, 72.5% (29/40) of false-positive findings were attributable to folds or residual feces. The CAD system evaluated has a high level of performance in the detection of adenomatous polyps with CTC data from a polyp-enriched cohort different from that used to train the system.


Adult and offspring size in the ocean over 17 orders of magnitude follows two life history strategies.
Explaining variability in offspring vs. adult size among groups is a necessary step to determine the evolutionary and environmental constraints shaping variability in life history strategies. This is of particular interest for life in the ocean where a diversity of offspring development strategies is observed along with variability in physical and biological forcing factors in space and time. We compiled adult and offspring size for 407 pelagic marine species covering more than 17 orders of magnitude in body mass including Cephalopoda, Cnidaria, Crustaceans, Ctenophora, Elasmobranchii, Mammalia, Sagittoidea, and Teleost. We find marine life following one of two distinct strategies, with offspring size being either proportional to adult size (e.g., Crustaceans, Elasmobranchii, and Mammalia) or invariant with adult size (e.g., Cephalopoda, Cnidaria, Sagittoidea, Teleosts, and possibly Ctenophora). We discuss where these two strategies occur and how these patterns (along with the relative size of the offspring) may be shaped by physical and biological constraints in the organism's environment. This adaptive environment along with the evolutionary history of the different groups shape observed life history strategies and possible group-specific responses to changing environmental conditions (e.g., production and distribution).


Older people's views of advice about falls prevention: a qualitative study.
The aim of this study was to gain an understanding of older people's perceptions of falls prevention advice, and how best to design communications that will encourage older people to take action to prevent falls. Focus groups and interviews were carried out with 66 people aged 61-94 years recruited from a variety of settings, using falls prevention messages to stimulate discussion. Thematic analysis revealed that participants interpreted 'falls prevention' principally as meaning hazard reduction, use of aids and restriction of activity. Only one participant was aware that falls risk could be reduced by carrying out exercises to improve strength and balance. Falls prevention advice was typically regarded as useful in principle but not personally relevant or appropriate. Advice about falling was often depicted as common sense, only necessary for older or more disabled individuals, and potentially patronizing and distressing. Our findings suggest that older people do not reject falls prevention advice because of ignorance of their risk of falling, but because they see it as a potential threat to their identity and autonomy. Messages that focus on the positive benefits of improving balance may be more acceptable and effective than advice on falls prevention.


Effects of high dose oestrogen and testosterone treatment in adolescents upon trabecular and compact bone measured by 125I computed tomography. A preliminary study.
125I Computed Tomography (CT) allows for the selective determination of trabecular and compact bone mineral parameters in the radius. Using this technique the effects of high dose oestrogen treatment in 11 tall girls, and of high dose testosterone treatment in 5 tall boys were monitored. In both groups trabecular bone density (TBD) increased steadily during treatment at a rate of about 1% per month. Also in both groups the compact bone mineral increased steadily. These results are compared with those from a cross sectional study on 49 normal children and 36 normal adults, in whom TBD was found to be independent of age and sex, so that the increases in TBD in both treatment groups can be attributed directly to the influence of the sex hormones. Since the compact bone mineral is higher in adults than in children it cannot yet be decided whether the increases seen in the treated patients are related to the sex hormone treatment, or reflect only the normal development of the bone during adolescence.


Transcriptional activation of insulin-like growth factor-binding protein-4 by 17beta-estradiol in MCF-7 cells: role of estrogen receptor-Sp1 complexes.
Insulin-like growth factor-binding protein-4 (IGFBP-4) is expressed in MCF-7 human breast cancer cells, and treatment of these cells with 17beta-estradiol (E2) resulted in induction of IGFBP-4 gene expression (>3-fold) and protein secretion (>6-fold). To identify genomic sequences associated with E2 responsiveness, the 5'-promoter region (-1214 to +18) of the IGFBP-4 gene was cloned into a vector upstream from the firefly luciferase reporter gene, and E2 induced a 10-fold increase in luciferase activity in MCF-7 cells transiently transfected with this construct. Deletion analysis of this region of the IGFBP-4 gene promoter identified two GC-rich sequences at -559 to -553 and -72 to -64 that were important for E2-induced trans-activation. Gel mobility shift assays using 32P-labeled -569 to -540 and -83 to -54 oligonucleotides from the IGFBP-4 gene promoter showed that Sp1 protein bound these oligonucleotides to form a retarded band, and the intensity of the band was competitively decreased after coincubation with unlabeled IGFBP-4-derived and consensus Sp1 oligonucleotides. Mutation of the GC-rich sites within these sequences resulted in loss of the retarded band formation. Wild-type human estrogen receptor did not bind directly to the IGFBP-4 oligonucleotides; however, human estrogen receptor enhanced Sp1-DNA binding in a concentration-dependent manner. The results of this study demonstrate that at least two GC-rich sequences at -559 to -553 and -72 to -64 are required for induction of IGFBP-4 gene expression by E2 in MCF-7 cells.


Translocation of Y-linked genes to the dot chromosome in Drosophila pseudoobscura.
One of the most striking cases of sex chromosome reorganization in Drosophila occurred in the lineage ancestral to Drosophila pseudoobscura, where there was a translocation of Y-linked genes to an autosome. These genes went from being present only in males, never recombining, and having an effective population size of 0.5N to a state of autosomal linkage, where they are passed through both sexes, may recombine, and their effective population size has quadrupled. These genes appear to be functional, and they underwent a drastic reduction in intron size after the translocation. A Y-autosome translocation may pose problems in meiosis if the rDNA locus responsible for X-Y pairing had also moved to an autosome. In this study, we demonstrate that the Y-autosome translocation moved Y-linked genes onto the dot chromosome, a small, mainly heterochromatic autosome with some sex chromosome-like properties. The rDNA repeats occur exclusively on the X chromosome in D. pseudoobscura, but we found that the new Y chromosome of this species harbors four clusters bearing only the intergenic spacer region (IGS) of the rDNA repeats. This arrangement appears analogous to the situation in Drosophila simulans, where X-rDNA to Y-IGS pairing could be responsible for X-Y chromosome pairing. We postulate that the nascent D. pseudoobscura Y chromosome acquired and amplified copies of the IGS, suggesting a potential mechanism for X-Y pairing in D. pseudoobscura.


School nurses' self-assessed cultural competence when encountering children of foreign origin: A cross-sectional study.
The purpose of this study was to investigate associations between school nurses' self-assessed cultural competence in health visits with children of foreign origin and demographic variables, by using a cross-sectional design. A Web-based questionnaire assessing cultural competence and demographic variables was distributed to a nationally representative sample (n = 816) of school nurses in Sweden. Data were analyzed using regression analysis. School nurses assessed themselves as culturally aware and moderately culturally competent, but not as culturally knowledgeable, culturally skilled, or comfortable in cultural encounters. Cultural competence was related to education in cultural diversity, how often nurses encounter children of foreign origin, and nurses' country of origin. In total, these variables explained 23.6% of the variation in school nurses' cultural competence. Because school nurses regard themselves as moderately culturally competent, a foundation for promoting children's health on equal terms in school health care exists. However, education in cultural diversity combined with other additional strategies is needed to further strengthen school nurses' cultural knowledge, skills, and comfort level in encounters with children of foreign origin.


Health status as measured by SF-36 reflects changes and predicts outcome in chronic musculoskeletal pain: a 3-year follow up study in the general population.
The SF-36 is a well-validated health status instrument measuring eight different health concepts. One aim of this study was to compare health status as measured by SF-36 in subjects from the general population with no chronic pain (NCP), chronic regional pain (CRP), and chronic widespread pain (CWP). A second aim was to assess if SF-36 could reflect changes in pain status over time. A third aim was to study if health status at baseline, measured by SF-36, could predict pain status 3 years later. The study was designed as a 3-year follow up with a postal questionnaire, including the SF-36 health survey, to 2357 subjects from the general population aged 20-74 years. The results were controlled for age, sex, co-morbidity, and socio-economic status. At baseline, all eight health concepts of SF-36 discriminated between subgroups with NCP, CRP and CWP. Changes in SF-36 over the 3-year follow up time coincided with improvement or deterioration of pain status. Baseline SF-36 scores predicted pain outcome 3 years later. These results support that both physical and mental aspects of health status as measured by SF-36 are affected by the burden of musculoskeletal pain, are sensitive to changes in pain status, and also predict the further development of pain.


Counselling for Alcohol Problems (CAP), a lay counsellor-delivered brief psychological treatment for harmful drinking in men, in primary care in India: a randomised controlled trial.
Although structured psychological treatments are recommended as first-line interventions for harmful drinking, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of Counselling for Alcohol Problems (CAP), a brief psychological treatment delivered by lay counsellors to patients with harmful drinking attending routine primary health-care settings. In this randomised controlled trial, we recruited male harmful drinkers defined by an Alcohol Use Disorders Identification Test (AUDIT) score of 12-19 who were aged 18-65 years from ten primary health centres in Goa, India. We excluded patients who needed emergency medical treatment or inpatient admission, who were unable to communicate clearly, and who were intoxicated at the time of screening. Participants were randomly allocated (1:1) by trained health assistants based at the primary health centres to enhanced usual care (EUC) alone or EUC combined with CAP, in randomly sized blocks of four to six, stratified by primary health centre, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC and those assessing outcomes were masked. Primary outcomes were remission (AUDIT score of <8) and mean daily alcohol consumed in the past 14 days, at 3 months. Secondary outcomes were the effect of drinking, disability score, days unable to work, suicide attempts, intimate partner violence, and resource use and costs of illness. Analyses were on an intention-to-treat basis. We used logistic regression analysis for remission and zero-inflated negative binomial regression analysis for alcohol consumption. We assessed serious adverse events in the per-protocol population. This trial is registered with the ISCRTN registry, number ISRCTN76465238. Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 377 participants (188 [50%] to the EUC plus CAP group and 190 [50%] to the EUC alone group [one of whom was subsequently excluded because of a protocol violation]), of whom 336 (89%) completed the 3 month primary outcome assessment (164 [87%] in the EUC plus CAP group and 172 [91%] in the EUC alone group). The proportion with remission (59 [36%] of 164 in the EUC plus CAP group vs 44 [26%] of 172 in the EUC alone group; adjusted prevalence ratio 1·50 [95% CI 1·09-2·07]; p=0·01) and the proportion abstinent in the past 14 days (68 [42%] vs 31 [18%]; adjusted odds ratio 3·00 [1·76-5·13]; p<0·0001) were significantly higher in the EUC plus CAP group than in the EUC alone group, but we noted no effect on mean daily alcohol consumed in the past 14 days among those who reported drinking in this period (37·0 g [SD 44·2] vs 31·0 g [27·8]; count ratio 1·08 [0·79-1·49]; p=0·62). We noted an effect on the percentage of days abstinent in the past 14 days (adjusted mean difference [AMD] 16·0% [8·1-24·1]; p<0·0001), but no effect on the percentage of days of heavy drinking (AMD -0·4% [-5·7 to 4·9]; p=0·88), the effect of drinking (Short Inventory of Problems score AMD-0·03 [-1·93 to 1·86]; p=0.97), disability score (WHO Disability Assessment Schedule score AMD 0·62 [-0·62 to 1·87]; p=0·32), days unable to work (no days unable to work adjusted odds ratio 1·02 [0·61-1·69]; p=0.95), suicide attempts (adjusted prevalence ratio 1·8 [-2·4 to 6·0]; p=0·25), and intimate partner violence (adjusted prevalence ratio 3·0 [-10·4 to 4·4]; p=0·57). The incremental cost per additional remission was $217 (95% CI 50-1073), with an 85% chance of being cost-effective in the study setting. We noted no significant difference in the number of serious adverse events between the two groups (six [4%] in the EUC plus CAP group vs 13 [8%] in the EUC alone group; p=0·11). CAP delivered by lay counsellors plus EUC was better than EUC alone was for harmful drinkers in routine primary health-care settings, and might be cost-effective. CAP could be a key strategy to reduce the treatment gap for alcohol use disorders, one of the leading causes of the global burden among men worldwide. Wellcome Trust.


Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993-2003.
Exposure to certain environmental toxicants may be associated with increased risk of developing diabetes. The authors' aim was to investigate the relation between lifetime exposure to specific agricultural pesticides and diabetes incidence among pesticide applicators. The study included 33,457 licensed applicators, predominantly non-Hispanic White males, enrolled in the Agricultural Health Study. Incident diabetes was self-reported in a 5-year follow-up interview (1999-2003), giving 1,176 diabetics and 30,611 nondiabetics for analysis. Lifetime exposure to pesticides and covariate information were reported by participants at enrollment (1993-1997). Using logistic regression, the authors considered two primary measures of pesticide exposure: ever use and cumulative lifetime days of use. They found seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor, and cyanazine) for which the odds of diabetes incidence increased with both ever use and cumulative days of use. Applicators who had used the organochlorine insecticides aldrin, chlordane, and heptachlor more than 100 lifetime days had 51%, 63%, and 94% increased odds of diabetes, respectively. The observed association of organochlorine and organophosphate insecticides with diabetes is consistent with results from previous human and animal studies. Long-term exposure from handling certain pesticides, in particular, organochlorine and organophosphate insecticides, may be associated with increased risk of diabetes.


Identification, rearing, and distribution of stick insects of Madeira Island: an example of raising biodiversity awareness.
Two species of stick insects are currently known to be present in the Macaronesian archipelagos: Clonopsis gallica (Charpentier) (Phasmatodea: Bacillidae) on the Canary Islands and in the Azores and Carausius morosus (Sinéty) (Phasmatidae) in the Azores. Here, we provide the first reliable records of the presence and distribution of C. gallica and C. morosus on Madeira Island. Egg and adult stages are briefly described along with some notes on the life history of these species in captivity. Data on islandwide distribution are based on specimens donated by the public in response to an article published in a daily newspaper. This method of data collection raised great popular interest in stick insects. The role of newspapers as a means of communicating awareness in biodiversity issues is discussed.


Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer.
Retinoic acid (RA) is required for normal airway epithelial cell growth and differentiation both in vivo and in vitro. One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR beta) mRNA. Previous work established that many lung cancer cell lines and primary tumors display abnormal RAR beta mRNA expression, most often absence or weak expression of the RAR beta 2 isoform, even after RA treatment. Restoration of RAR beta 2 into RAR beta-negative lung cancer cell lines has been reported to inhibit tumorigenicity. Since RAR beta 2 inactivation may contribute to lung cancer, we have investigated the molecular mechanism of defective RAR beta 2 expression. Nuclear run-on assays and transient transfections with RAR beta 2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE). These defects cannot be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting transcription from both types of RARE. Studies using chimeras between RAR alpha, TR alpha, and other transcription factors suggest the existence of novel RAR-thyroid hormone receptor AF-2-specific cofactors, which are necessary for high levels of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.


A comparative study of policosanol vs lovastatin on intimal thickening in rabbit cuffed carotid artery.
Policosanol is a cholesterol-lowering drug isolated from sugar cane wax, which acts by inhibiting cholesterol biosynthesis. Previous studies have demonstrated that policosanol inhibited smooth muscle cell (SMC) proliferation in the cuffed carotid artery of the rabbit and in arterial wall damage induced by forceps in the central artery of the ear of rabbits. The present study was undertaken to compare the effects of policosanol and lovastatin on SMC proliferation in the cuffed carotid artery of rabbits. Collars were placed around the left carotid for 7 and 15 days. The contralateral artery was sham operated. We studied eight experimental groups: two controls groups receiving vehicle for 7 and 15 days, respectively, a satellite sham operated control group, four groups treated with policosanol at 5 and 25 mg kg(-1)for 7 and 15 days and a reference group receiving lovastatin at 20 mg kg(-1)for 15 days. Samples of arteries were examined by light and electron microscopy. To evaluate intimal thickening the cross-sectional areas of intima and media were measured. Neointima was significantly reduced in treated animals compared with controls, but the reduction in lovastatin animals was significantly lower than in policosanol-treated groups. The SMC proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen and the reduction observed in policosanol-treated rabbits was significantly larger than in lovastatin-treated animals. It is concluded that the protective effect of policosanol against neointima formation in this experimental model was slightly better than that of lovastatin.


Experimental toxoplasmosis in chimpanzees.
Two chimpanzees were given by mouth large numbers of viable oocysts of Toxoplasma gondii obtained from the faeces of experimentally infected cats. Before the experiment the first chimpanzee had a positive dye test reaction (1:250), an indication that it had undergone an earlier infection of toxoplasmosis; the serum antibody titres remained unchanged, no evidence of illness was found, and oocysts did not appear in its faeces during the subsequent six weeks. The second chimpanzee showed a negative dye test reaction before infection, and this converted to positive on the 7th day, rose to a peak on the 35th day, and remained high for six months. This animal appeared unwell during the first week, and on the 7th day its blood proved infective to mice; on the 40th day the lymph nodes became enlarged and biopsy specimens of a node and muscle in the 11th week were also infective to mice. No oocysts were passed in the faeces. The presumed cycle in the chimpanzee and in man and the relationships between Toxoplasma and Isospora are discussed.


HMO marketing and selection bias: are TEFRA HMOs skimming?
The research evidence indicates that health maintenance organizations (HMOs) participating in the Tax Equity and Fiscal Responsibility Act of 1982 (TEFRA) At-Risk Program tend to experience favorable selection. Although favorable selection might result from patient decisions, a common conjecture is that it can be induced by HMOs through their marketing activities. The purpose of this study is to examine the relationship between HMO marketing strategies and selection bias in TEFRA At-Risk HMOs. A purposive sample of 22 HMOs that were actively marketing their TEFRA programs was selected and data on organizational characteristics, market area characteristics, and HMO marketing decisions were collected. To measure selection bias in these HMOs, the functional health status of approximately 300 enrollees in each HMO was compared to that of 300 non-enrolling beneficiaries in the same area. Three dependent variables, reflecting selection bias at the mean, the low health tail, and the high health tail of the health status distribution were created. Weighted least squares regressions were then used to identify relationships between marketing elements and selection bias. Subject to the statistical limitations of the study, our conclusion is that it is doubtful that HMO marketing decisions are responsible for the prevalence of favorable selection in HMO enrollment. It also appears unlikely that HMOs were differentially targeting healthy and unhealthy segments of the Medicare market.


Glycemic control in patients with diabetes in Finland.
To evaluate the quality of diabetes care at a national level in Finland, using level of glycemia as a determinant of success in treatment. Physicians and diabetes nurses in 76 randomly selected clinics (59 primary care units and 17 hospitals) evenly covering the whole of Finland were asked to fill in a questionnaire asking for data based on the 1993 medical records of a random sample of 50 diabetic patients from each center (total n = 3,800). HbAlc was used as an index of glycemic control. Information on 3,195 (84%) diabetic patients was received. HbAlc was measured in 67% of the patients in 1993. The mean HbAlc in the whole population was 8.6 +/- 1.9% (normal range 4-6%). Some 25% of patients had HbAlc < or = 7.3%, while 25% had HbAlc > or = 9.7%. The mean HbAlc was 8.8 +/- 1.9% in type 1 and 8.5 +/- 1.9% in type 2 diabetic patients. There was no sex difference in the HbAlc level in type 1 diabetic patients. However, male type 2 diabetic patients had better glycemic control than female patients (8.3 +/- 1.9 vs. 8.8 +/- 1.9%, P < 0.0001). The sex difference was independent of the type of therapy. The mean level of glycemic control was lowest among individuals with the shortest duration of diabetes. After 7-9 years after the diagnosis, there was no change in the mean level of glycemia. Average glycemic control is poor in a majority of the diabetic patients in Finland. Better treatment strategies and methods should be used to improve glycemic control and to reduce long-term complications.


Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)- and calmodulin-mediated mechanism.
Human aquaporin 4 (AQP4) is the primary water channel protein in brain astrocytes. Hypothermia is known to cause astrocyte swelling in culture, but the precise role of AQP4 in this process is unknown. Primary human cortical astrocytes were cultured under hypothermic (32 °C) or normothermic (37 °C) conditions. AQP4 transcript, total protein and surface-localized protein were quantified using RT-qPCR, sandwich ELISA with whole cell lysates or cell surface biotinylation, followed by ELISA analysis of the surface-localized protein, respectively. Four-hour mild hypothermic treatment increased the surface localization of AQP4 in human astrocytes to 155 ± 4% of normothermic controls, despite no change in total protein expression levels. The hypothermia-mediated increase in AQP4 surface abundance on human astrocytes was blocked using either calmodulin antagonist (trifluoperazine, TFP); TRPV4 antagonist, HC-067047 or calcium chelation using EGTA-AM. The TRPV4 agonist (GSK1016790A) mimicked the effect of hypothermia compared with untreated normothermic astrocytes. Hypothermia led to an increase in surface localization of AQP4 in human astrocytes through a mechanism likely dependent on the TRPV4 calcium channel and calmodulin activation. Understanding the effects of hypothermia on astrocytic AQP4 cell surface expression may help develop new treatments for brain swelling based on an in-depth mechanistic understanding of AQP4 translocation.


Caffeine protects human skin fibroblasts from acute reactive oxygen species-induced necrosis.
Oxidative damage by reactive oxygen species (ROS) plays a major role in aging and carcinogenesis. Little is known about either the effects of acute ROS in necrosis and inflammation of skin or the therapeutic agents for prevention and treatment. Previously, our laboratory identified caffeine as an inhibitor of hydrogen peroxide (H2O2)-generated lipid peroxidation products in human skin fibroblasts. Here, we study effects of caffeine on acute ROS-mediated necrosis. Human skin fibroblasts were incubated with caffeine, followed by H2O2 challenge. Flow cytometry was used to analyze cell morphology, counts, apoptosis and necrosis, and ROS. We found that caffeine protects from H2O2 cell damage at lower (0.01 mM) and intermediate (0.1 mM) doses. The beneficial effects of caffeine appear to be mediated by a mechanism other than antioxidant function.