Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice.
Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg(null) strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin-CD34+CD38- human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR alphabeta+ T cells and CD4-CD8- and CD8+ TCR gammadelta+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from naïve to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.


[Modification of crossing over frequency and mechanism of chromosomal control of exchange distribution in Drosophila females].
Features of main recombination stages in eukaryotes-homologous pairing, cleavage of specific DNA sites and their delayed repair, formation of heteroduplexes (X-structures), resolution of X-structures by crossing over or gene conversion--and various factors affecting these stages and changing the number of X-structures and frequency of crossing-over are reviewed. Formation of X-structures is thought to result from coinciding breaks of DNA that participate in homologous synapsis. Resolution of X-structures (realization of exchanges) occurs after termination of homologous pairing in pericentromeric regions and after reorganization of meiotic chromosomes and the chromocenter, which has a regular structure in Drosophila. Resolution of X-structures and chiasma distribution along a chromosome are controlled by intrinsic elasticity generated by deformation of axial chromosomal elements (lateral elements of the synaptonemal complex). The deformation is caused by the formation of links between chromosomes in pericentromeric regions of chromosome arms (the centromeric effect) and by random formation of the first exchange and chiasma (chromosomal interference). The deformational energetic barrier prevents reciprocal crossover exchanges, and the X-structure is realized as a gene conversion. Decompacted chromosome regions suppress both the centromeric effect and interference, resulting, e.g., in the absence o f interference across the centromere. Chiasmatic halfspirals act as primers for further spiralization of chromatids.


Double-blind crossover comparison of enoximone and placebo in patients with congestive heart failure.
The efficacy of oral enoximone, a new positive inotropic and vasodilator agent, was assessed in 12 patients with chronic congestive heart failure (New York Heart Association [NYHA] class II or III) in a double-blind randomized crossover comparison with placebo. Duration of each treatment was 6 weeks and the dose of enoximone was 150 mg tid. Efficacy was assessed by exercise tolerance, symptoms, radionuclide angiography for ejection fraction at rest and during exercise, and Holter monitoring. Two patients were withdrawn before completion of the study, one with pulmonary edema after 1 week on placebo and the other for noncompliance with enoximone therapy. Symptom-limited exercise capacity improved with enoximone by 30% and 43% (p less than .01) compared with baseline after 2 and 6 weeks treatment, respectively. Ejection fraction improved at rest (p less than .02) with enoximone but not with placebo. No change was found during exercise. Heart rate and blood pressure remained unaltered. During treatment with enoximone symptoms of exertional dyspnea and fatigue were improved and NYHA class decreased by at least one class for every patient. Holter monitoring revealed an overall increase (NS) in ectopic activity during enoximone therapy. There were no serious adverse effects and laboratory values did not change significantly. The addition of enoximone to the existing therapy of patients with moderately severe congestive heart failure provided clear and sustained subjective and objective benefit when compared with placebo.


Chronic health effects of microbial foodborne disease.
The acute effects of foodborne disease are sometimes not the end of the illness. Several significant foodborne pathogens are capable of triggering chronic disease, and even permanent tissue or organ destruction, probably via immune mechanisms. Arthritis, septic and reactive, inflammatory bowel disease, haemolytic uraemic syndrome, Guillain-Barré syndrome, and possible several autoimmune disorders can be triggered by foodborne pathogens or their toxins. Research is needed to more fully understand the mechanisms by which the immune system is inappropriately activated by these common foodborne disease-causing agents.


A fast iterative greedy algorithm for MEG source localization.
Recent dynamic source localization algorithms for the Magnetoencephalographic inverse problem use cortical spatio-temporal dynamics to enhance the quality of the estimation. However, these methods suffer from high computational complexity due to the large number of sources that must be estimated. In this work, we introduce a fast iterative greedy algorithm incorporating the class of subspace pursuit algorithms for sparse source localization. The algorithm employs a reduced order state-space model resulting in significant computational savings. Simulation studies on MEG source localization reveal substantial gains provided by the proposed method over the widely used minimum-norm estimate, in terms of localization accuracy, with a negligible increase in computational complexity.


GPCR Dynamics: Structures in Motion.
The function of G protein-coupled receptors (GPCRs)-which represent the largest class of both human membrane proteins and drug targets-depends critically on their ability to change shape, transitioning among distinct conformations. Determining the structural dynamics of GPCRs is thus essential both for understanding the physiology of these receptors and for the rational design of GPCR-targeted drugs. Here we review what is currently known about the flexibility and dynamics of GPCRs, as determined through crystallography, spectroscopy, and computer simulations. We first provide an overview of the types of motion exhibited by a GPCR and then discuss GPCR dynamics in the context of ligand binding, activation, allosteric modulation, and biased signaling. Finally, we discuss the implications of GPCR conformational plasticity for drug design.


The nuclear exportin Msn5 is required for nuclear export of the Mig1 glucose repressor of Saccharomyces cerevisiae.
Mig1 is a transcriptional repressor responsible for glucose repression of many genes in the budding yeast Saccharomyces cerevisiae. Glucose regulates Mig1 function by affecting its phosphorylation, which is catalyzed by the Snf1 protein kinase. Phosphorylation alters the subcellular localization of Mig1, causing it to be nuclear when glucose is present, and cytoplasmic when glucose is absent. Here, we report that Msn5, a member of the importin beta family of nuclear transport receptors, is required to export Mig1 from the nucleus when glucose is removed. Mig1 and Msn5 interacted in a yeast two-hybrid assay. Within the portion of Mig1 that regulates its nuclear transport, we found a region that directed its nuclear export. Within this region, two leucine-rich sequences similar to known nuclear export signals were not required for Mig1 export. The corresponding domain of the yeast Kluyveromyces lactis Mig1 conferred glucose-regulated Msn5-dependent protein export from the nucleus in S. cerevisiae. Sequence comparison with S. cerevisiae Mig1 revealed short patches of homology in K. lactis and K. marxianus Mig1 that might be Msn5-interaction domains. These regions overlapped with the serine residues predicted to be Snf1 phosphorylation sites, suggesting that Msn5 and Snf1 recognize similar sequences in Mig1. Altering these serines abolished glucose-dependent phosphorylation of Mig1 and caused it to be a constitutive repressor that was retained in the nucleus. Mig1 contains a new nuclear export signal that is phosphorylated by Snf1 upon glucose removal, causing it to be recognized by the nuclear exportin Msn5 and carried out of the nucleus into the cytoplasm where it contributes to derepression of glucose-repressed genes.


A global social contract to reduce maternal mortality: the human rights arguments and the case of Uganda.
Progress towards Millennium Development Goal 5a, reducing maternal deaths by 75% between 1990 and 2015, has been substantial; however, it has been too slow to hope for its achievement by 2015, particularly in sub-Saharan Africa, including Uganda. This suggests that both the Government of Uganda and the international community are failing to comply with their right-to-health-related obligations towards the people of Uganda. This country case study explores some of the key issues raised when assessing national and international right-to-health-related obligations. We argue that to comply with their shared obligations, national and international actors will have to take steps to move forward together. The Government of Uganda should not expect additional international assistance if it does not live up to its own obligations; at the same time, the international community must provide assistance that is more reliable in the long run to create the 'fiscal space' that the Government of Uganda needs to increase recurrent expenditure for health - which is crucial to addressing maternal mortality. We propose that the 'Roadmap on Shared Responsibility and Global Solidarity for AIDS, TB and Malaria Response in Africa', adopted by the African Union in July 2012, should be seen as an invitation to the international community to conclude a global social contract for health.


Digital Therapy for Visual Acuity and Binocular Function in Children with Anisometropic Amblyopia.
Amblyopia affects development of children's monocular vision and binocular function and becomes a largely intractable problem with increasing aging. This study is to investigate the binocular function and evaluate efficacy of digital therapy in children 8-13 years of age with anisometropic amblyopia. The patients in the digital therapy group performed the training with the digital amblyopia therapeutic software. The visual acuity and binocular function (perceptual eye position [PEP], suppression, and stereopsis) were examined at the first visit and 3-month post-treatment. Twenty-three cases in the control group and 25 cases in the digital therapy group were enrolled. The results revealed that 3-month digital therapy can effectively improve corrected distance visual acuity (CDVA) and improve the binocular function, including PEP, suppression, and second-order stereopsis in children with anisometropic amblyopia, 8-13 years of age. Digital therapy for amblyopia can effectively improve monocular CDVA of amblyopic eyes and binocular function in older children with anisometropic amblyopia.


"Nurses' use of visual management in hospitals-A longitudinal, quantitative study on its implications on systems performance and working conditions".
The aim of this study was to examine potential benefits provided by daily visual management tool use and explore its association with systems performance and working conditions among hospital nurses. Visual management tools used in everyday work and improvement work in health care theoretically contribute to shared understanding of complex work systems and provide certain user benefits. Cognitive load, miscommunication within and between professional groups, and pressure to engage in care process redesign add to nurses' strained working conditions. Quantitative longitudinal. Questionnaires were distributed at T0, (N = 948, 66% response rate), T1 (N = 900, 70% response rate), and T2 (N = 621, 72% response rate) to nurses at five hospitals. Three groups of users (daily users, start users, and non-daily users) were compared by means T1-T2 (significance tested with Wilcoxon signed rank test) and by mixed model repeated measures T0, T1, T2. Daily use associated to better overview of work, collaboration, social capital, and clinical engagement. Job resources were rated higher by daily users. Mental stress increased and development opportunities decreased over time among non-daily users. There were associations between use and perceptions of systems performance, though the differences between groups were small. This study specifically explores visual management tool use in the hospital setting, which contributes to research by broadening the understanding of cognitive, social, and emotional benefits provided by visual management tool use. Daily use was associated to positive working conditions, small but positive differences in systems performance, and indicated a buffering effect on nurses' mental stress.


Diet effects on fatty acid metabolism in lean and obese humans.
The primary role of adipose tissue is to serve as a temporary storage site for energy in the form of nonesterified fatty acids. The regulation of adipose tissue lipolysis, which allows the appropriate delivery of fatty acids to meet the lipid fuel needs of lean tissue, is affected by the amount and the location of fat, as well as by the diet. Excessive accumulation of triacylglycerol fatty acids (obesity) is associated with an increased risk of insulin resistance, diabetes, hyperlipidemia, and hypertension. Some of these abnormalities may be related to dysregulation of fatty acid metabolism. Body fat distribution exerts a major influence on endogenous nonesterified fatty acid metabolism, which may in turn mediate some of the metabolic abnormalities associated with upper-body obesity. The effects of diet on fatty acid metabolism can be dramatic and are not the same in upper-body and lower-body obesity. Different obesity phenotypes may respond differently to low-fat, high-complex-carbohydrate diets, and the response is further modified depending on whether the diet is isoenergetic or restricted in energy.


Treatment resistant depression.
Despite major research efforts in mood disorders, careful scientific studies and evaluations of "treatment resistant depression" (TRD) are limited. Treatment resistant depression often encompasses several conflicting definitions and concepts: (1) the distinction between 'absolute' TRD and 'relative' TRD is seldom made; (2) the combination of a dysthymic disorder and a major depression ("double depression") can lead to diagnostic confusion when one disorder improves while the similar symptoms of the other persist; and (3) the literature becomes confused when ineffective prophylaxis and ineffective acute treatment are not separated. The research at our Center continues to suggest that the primary problem in this area remains 'relative' TRD. In a recent study of 114 patients referred to our Mood Disorders Service with a diagnosis of TRD, 59 of 98 (60.2%) had complete depressive symptom remission with appropriate treatment interventions. Further, the majority of these 59 successful treatment interventions were the 'bread and butter' treatments available to all physicians; 9 (15.3%) patients responded to an adequate trial of a tricyclic, 12 (20.3%) to a monoamine oxidase inhibitor, and 17 (28.8%) to a course of electroconvulsive therapy.


Care delivery team composition effect on hospitalization risk in African Americans with congestive heart failure.
The care delivery team (CDT) is critical to providing care access and equity to patients who are disproportionately impacted by congestive heart failure (CHF). However, the specific clinical roles that are associated with care outcomes are unknown. The objective of this study was to examine the extent to which specific clinical roles within CDTs were associated with care outcomes in African Americans (AA) with CHF. Deidentified electronic medical record data were collected on 5,962 patients, representing 80,921 care encounters with 3,284 clinicians between January 1, 2014 and December 31, 2021. Binomial logistic regression assessed associations of specific clinical roles and the Mann Whitney-U assessed racial differences in outcomes. AAs accounted for only 26% of the study population but generated 48% of total care encounters, the same percentage of care encounters generated by the largest racial group (i.e., Caucasian Americans; 69% of the study population). AAs had a significantly higher number of hospitalizations and readmissions than Caucasian Americans. However, AAs had a significantly higher number of days at home and significantly lower care charges than Caucasian Americans. Among all CHF patients, patients with a Registered Nurse on their CDT were less likely to have a hospitalization (i.e. 30%) and a high number of readmissions (i.e., 31%) during the 7-year study period. When stratified by heart failure phenotype, the most severe patients who had a Registered Nurse on their CDT were 88% less likely to have a hospitalization and 50% less likely to have a high number of readmissions. Similar decreases in the likelihood of hospitalization and readmission were also found in less severe cases of heart failure. Specific clinical roles are associated with CHF care outcomes. Consideration must be given to developing and testing the efficacy of more specialized, empirical models of CDT composition to reduce the disproportionate impact of CHF.


The selection and design of GPCR ligands: from concept to the clinic.
Virtual screening methods using structure-based, pharmacophore-based and descriptor based protocols may be used to identify ligands for the G-protein coupled receptor target family. A complementary approach is the synthesis and screening of compound libraries designed using privileged motifs and/or based on validated hit molecules. A virtual screening approach based on molecular docking performed with GOLD using a templated homology model and a consensus scoring procedure can identify vasopressin 1a receptor antagonists. In a separate project a library design and synthesis approach based around validated hit GPCR ligands led to the identification of potent oxytocin antagonists. Subsequent optimisation of the initial library compounds has provided compounds that are now being evaluated in the clinic for the treatment of preterm labour.


Oral isotretinoin as part of the treatment of cutaneous aging.
A number of drugs have been used to prevent aging changes. However, studies of oral isotretinoin, the commonly used acne drug, as an antiaging drug are lacking. To determine improvement in cutaneous aging utilizing oral isotretinoin combined with different procedures of facial rejuvenation. Sixty patients ranging in age from 35 to 65 years, in whom additional modalities of rejuvenation were also used, were randomly assigned to receive treatment with oral isotretinoin (10-20 mg three times a week for 2 months, group A). Their results were compared with 60 patients who had undergone the same surgical procedures but with no oral isotretinoin (group B). All patients treated with oral isotretinoin noted improvement in wrinkles, thickness and color of the skin, size of pores, skin elasticity, tone, and reduction in pigmented lesions and mottled hyperpigmentation. A statistically significant difference was found in the improvement of group A (Wilcoxon test <0.01). Using minimal amounts of this drug, the side effects were practically negligible. Utilizing various procedures with oral isotretinoin allowed us to improve the effects of cutaneous aging. Our results using isotretinoin in these cases have been satisfactory. We believe that this is one of the first reports of the use of oral isotretinoin in intrinsic and photoaged skin.


Remodeling of the human dermis after application of salicylate silanol.
Recently, a controlled double-blind study in patients with photo-aged facial skin demonstrated the beneficial role of oral intake of silanol for skin, hair and nails. The aim of our pilot study was to investigate histologic alterations in human skin after injection of silanol. Seven healthy female caucasian volunteers with a moderate degree of photoaged skin received ten sessions of weekly injections of 0.1% salicylate silanol in the left ventral lateral forearm. The histologic features of punch biopsies of the treated area and the nontreated contralateral arm were compared and the collagen and elastic fibers quantified. Texture analysis was performed on digitalized microscopic images by analyzing the Sarkar fractal dimension or amplitudes (inertia values) after Fast Fourier transformation. The treated area revealed a statistically significant increase of the density of both collagen and elastic fibers. Texture analysis showed more compact and homogeneously distributed collagen fibers after silicon injection. Our results suggest that the application of silicon may stimulate the production of collagen and elastic fibers leading to remodeling of the dermal fiber architecture, which may explain the improvement of the skin surface observed in clinical studies.


Electrical burn injury: a five-year survey of 682 patients.
Electrical burn is less prevalent in comparison to other forms of burn injuries, however this type of injury is considered as one of the most devastating due to high morbidity and mortality. Understanding the epidemiologic pattern of electrical burns helps determine the contributing factors leading to this type of injury. Epidemiologic studies on electrical burn are scarce in Iran. This study was conducted to evaluate electrical burn injury at our center. Demographic data, etiology, burn percentage and other measures related to electrical burn injury of 682 electrical burn patients treated from 2007 to 2011 were collected and analyzed. We assessed 682 electrical burn patients (~10.8% of all burn patients); the mean age was 29.4 years and 97.8% were males. The mean hospital stay was 18.5 days and the mean burn extent was 14.43%. Severe morbidities caused 17 (2.5%) deaths. Amputation was performed in 162 cases. The most common amputation site was the fingers (35%). Most victims were workers and employees and 68.5% of electrical burns occurred at their workplace; 72% of electrical burns were due to high voltage electrical current (more than 1000 V). There was a correlation between voltage and amputation (P = 0.001) and also between voltage and fasciotomy (P = 0.033), but there was no correlation between voltage and mortality (P = 0.131). Electrical burn injuries are still amongst the highest accident-related morbidities and mortalities. Educating the population about the dangers and hazards associated with improper use of electrical devices and instruments is imperative.


Rhinovirus as the main co-circulating virus during the COVID-19 pandemic in children.
Changes in the epidemiology of respiratory infections during the restrictions imposed as a response to the coronavirus disease 2019 (COVID-19) pandemic have been reported elsewhere. The present study's aim was to describe the prevalence of a large array of respiratory pathogens in symptomatic children and adolescents during the pandemic in Southern Brazil. Hospitalized and outpatients aged 2 months to 18 years with signs and symptoms of acute COVID-19 were prospectively enrolled in the study from May to November 2020 in two hospitals in a large metropolitan area in a Brazilian city. All participants performed a real-time PCR panel assessing 20 respiratory pathogens (three bacteria and 17 viruses). 436 participants were included, with 45 of these hospitalized. Rhinovirus was the most prevalent pathogen (216/436) followed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 97/436), with a coinfection of these two viruses occurring in 31/436 participants. The remaining pathogens were found in 24 symptomatic participants (adenovirus, n = 6; Chlamydophila pneumoniae, n = 1; coronavirus NL63, n = 2; human enterovirus, n = 7; human metapneumovirus, n = 2; Mycoplasma pneumoniae, n = 6). Hospitalization was more common among infants (p = 0.004) and those with pathogens other than SARS-CoV-2 (p = 0.001). During the period of social distancing in response to COVID-19, the prevalence of most respiratory pathogens was unusually low. Rhinovirus remained as the main virus co-circulating with SARS-CoV-2. COVID-19 in symptomatic children was less associated with hospitalization than with other respiratory infections in children and adolescents.


Antibiotic resistance profile of commensal Escherichia coli isolated from healthy sheep in Qatar.
The uncontrolled antibiotics use in livestock is a leading factor for the emergence and spread of resistant bacteria from food animals to humans through the food chain. This study aims at evaluating the magnitude of the antimicrobial resistance (AMR) in food animals, acknowledging the lack of information on the prevalence of resistance in the veterinary field in Qatar. Rectal samples were collected from 171 sheep across three localities in Qatar between December 2016 and July 2017. These rectal samples were suspended in Phosphate buffer solution (PBS). Then streaked onto a selective CHROMagar E. coli medium plates and incubated at 37°C for 18 to 24 h. Isolated E. coli were tested for antibiotic susceptibility against 16 clinically- relevant antibiotics using the E-test method. Statistical analyses were performed using SPSS statistics 24. E. coli was isolated from 144 samples (84.2%), of which 90% were resistant to at least one antibiotic and 44% were multi-drug resistant (MDR). The highest resistance was against ciprofloxacin 69.4% (100), followed by nitrofurantoin 47.2% (68), trimethoprim/sulfamethoxazole 45.8% (66), cephalothin 43% (62) and amoxicillin/clavulanic acid 18% (26). Low resistance was reported to fosfomycin, amikacin and tigecycline 1.4% (2), 0.7% (1), and 0.7% (1), respectively. We reported high MDR E. coli in rectal swabs of sheep in Qatar. Such resistant bacteria can potentially be transmitted to humans, resulting in public health concerns. This requires a quick response to develop and implement a stewardship program for the monitoring of antibiotic use in the veterinary in Qatar.


Evaluation of the postnatal development of the sternum and sternal variations using multidetector CT.
We aimed to evaluate the postnatal development and the maturation of the sternum and sternal variations using multidetector computed tomography (MDCT). Additionally, we aimed to examine the roles of gender and age in sternal development. Two hundred and fifty patients who underwent thorax MDCT examinations were evaluated for sternal development and variations. Coronal curved planar reconstruction and maximum intensity projection images were used to better assess the ossification centers in the manubrium and the body of the sternum. Multiplanar images were used to accurately measure the thickness and the sagittal dimension of the manubrium, the sagittal dimension of the body, and the total sagittal dimension of the sternum in the sagittal plane. No significant differences in the manubrium measurements were observed between the genders. The thickness and sagittal dimension of the manubrium, sagittal dimension of the body, and total sagittal dimension of the sternum in the sagittal plane were significantly different between the age groups. We evaluated the ossification centers; shape and developmental variations in the manubrium and body; direction, calcification, and termination of the xiphoid process; developmental variations in the xiphoid process; and manubriosternal and sternoxiphoidal fusion. Significant variations were observed from person to person. The anatomy and the developmental properties of the sternum should be well understood in cases of potential chest and sternum injuries and in several surgical procedures. Therefore, knowledge of the development and the maturation of the sternum, and sternal variations and anomalies is important. We suggest that the postnatal development and the morphogenesis of the sternum can be adequately assessed using MDCT.


Challenges and Perspectives in Nutritional Counselling and Nursing: A Narrative Review.
Nutritional counselling has been recognised as the first line approach in the management of numerous chronic diseases. Though usually carried out by dietitians, nutritional counselling may be used by nurses, or other healthcare professionals to improve nutritional status and meet healthcare goals. Healthcare professionals require training and education to facilitate a patient centred approach to effective counselling. Advances in digital technology have the potential to improve access to nutritional counselling for some patients such as those in primary care. However, caution is required to ensure that valuable interpersonal relationships are not lost, as these form the cornerstone of effective nutritional counselling. The aim of this narrative review is to explore aspects of effective nutritional counselling, including advances in e-counselling and areas where nursing input in nutritional counselling might enhance overall nutritional care.


Structural and functional characterization of a frataxin from a thermophilic organism.
Frataxins form an interesting family of iron-binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron-sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X-ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron-binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta-strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron-sulfur cluster synthesis, and act as its inhibitor.


Robust, globally consistent and fully automatic multi-image registration and montage synthesis for 3-D multi-channel images.
The need to map regions of brain tissue that are much wider than the field of view of the microscope arises frequently. One common approach is to collect a series of overlapping partial views, and align them to synthesize a montage covering the entire region of interest. We present a method that advances this approach in multiple ways. Our method (1) produces a globally consistent joint registration of an unorganized collection of three-dimensional (3-D) multi-channel images with or without stage micrometer data; (2) produces accurate registrations withstanding changes in scale, rotation, translation and shear by using a 3-D affine transformation model; (3) achieves complete automation, and does not require any parameter settings; (4) handles low and variable overlaps (5-15%) between adjacent images, minimizing the number of images required to cover a tissue region; (5) has the self-diagnostic ability to recognize registration failures instead of delivering incorrect results; (6) can handle a broad range of biological images by exploiting generic alignment cues from multiple fluorescence channels without requiring segmentation and (7) is computationally efficient enough to run on desktop computers regardless of the number of images. The algorithm was tested with several tissue samples of at least 50 image tiles, involving over 5000 image pairs. It correctly registered all image pairs with an overlap greater than 7%, correctly recognized all failures, and successfully joint-registered all images for all tissue samples studied. This algorithm is disseminated freely to the community as included with the Fluorescence Association Rules for Multi-Dimensional Insight toolkit for microscopy (http://www.farsight-toolkit.org).


Surgical patients' expectations of pain and discomfort: does accuracy of expectations minimise post-surgical pain and distress?
The predictive relationship of expectancies of pain and symptoms to the experience of postoperative pain, symptoms and distress are examined in two studies of adult patients undergoing minor gynaecological surgery. The first hypothesis is based on the clinical wisdom that patients who expect pain to occur will report greater pain intensity than patients who do not hold these expectancies. That is, pain and symptom expectation and experience are positively associated. A second hypothesis based on a cognitive information processing model suggests that the greater the discrepancy between expected and actual pain the greater the experience of postoperative distress. A third hypothesis suggests that the direction of the discrepancy is important such that those patients who expect pain to be more intense than it is in actuality will report being least distressed. Data are presented which partially support all 3 hypotheses. A critical test between the second and third hypotheses did not provide support for either hypothesis. The positive correlations between expected and reported pain and emotional variables suggest that the manipulation of patients' emotional responses may be as effective as manipulating pain expectancies in controlling the pain and distress of surgery. This is supported by the finding that patients who receive accurate preparatory information about their surgery, in comparison to those who had no additional information, reported lower pain intensity but did not differ on expected pain intensity before the operation. However, the experimental manipulation was associated with reduced pain and emotional responses after surgery. The implications for the design of preparatory psychological interventions to reduce the pain and distress of surgery are discussed.


Sporotrichosis in a Renal Transplant Patient: A Rare Case Report with a Review of the Literature.
Sporotrichosis is a rare form of subacute and chronic fungal infection in renal transplant recipients caused by the ubiquitous fungus Sporothrix schenckii. It is usually described in renal allograft recipients who have not been treated with antifungal prophylaxis. We report a rare case of cutaneous sporotrichosis in a 39-year-old renal allograft recipient already on antifungal prophylaxis, who presented with skin lesions. The diagnosis was made from a skin biopsy. The patient had increased tacrolimus levels after starting treatment with itraconazole, which was later changed to terbinafine and cryotherapy. The patient responded to treatment with regression of his lesions.


Reward dysregulation and mood symptoms in an adolescent outpatient sample.
Research on bipolar spectrum disorders (BPSD) in adolescence has burgeoned in the last decade, but continued work is needed to identify endophenotypic markers associated with illness onset and course. The present study examined reward dysregulation--measured via the behavioral activation system (BAS)--as one putative marker of BPSD in adolescence. A diverse group of 425 outpatient adolescents between 11 and 17 years of age (52 % male) completed the Behavioral Inhibition and Activation Scale (BIS-BAS) scale to measure reward dysregulation. Semi-structured interviews determined diagnoses and severity of mood symptoms. Parent-reported BAS was associated with increased symptoms of mania, and parent and adolescent-reported BAS were associated with symptoms of depression. Parent-reported BIS scores were associated with increased symptoms of mania. Results held independent of diagnostic status. Furthermore, parent BIS/BAS reports were stronger predictors for manic symptoms compared to adolescent-reports. Results extend work in adults with BPSD, suggesting a transdiagnostic association between reward dysregulation and mood symptom severity in adolescence.


Parachute mitral valve in adults-a systematic overview.
Parachute mitral valve (PMV) is a rare congenital anomaly of the mitral valve apparatus seen in infants and young children. In most instances PMV is associated with other congenital anomalies of the heart, in particular obstructive lesions of the mitral inflow (mitral valve ring) and left ventricular outflow tract (subaortic stenosis), and coarctation of aorta and is referred to as Shone's complex or Shone's anomaly. PMV may also occur as an isolated lesion or in association with other congenital cardiac anomalies. Not much is known about PMV in adults as an isolated anomaly or in association with other congenital cardiac anomalies. We reviewed the literature to identify cases of PMV (isolated or associated with other lesions) in adults, to address prevalence, clinical presentation, diagnosis, treatment, and outcome of such patients. (Echocardiography 2010;27:581-586).


Detection of endogenous cortisol in equine tears and blood at rest and after simulated stress.
To determine whether cortisol is present in equine tears at rest and during simulated stress and compare tear cortisol to serum free and total cortisol. Fourteen healthy adult horses were included. Paired tear total cortisol and serum total and free cortisol concentrations were measured with ELISA, chemiluminescent immunoassay, and ultrafiltration methodology, respectively, in 10 horses at rest once daily for five consecutive days. In an additional four horses, paired tear and serum samples were collected for cortisol measurement before and after adrenocorticotropic hormone (ACTH) stimulation (cosyntropin, 1 μg/kg IV). Cortisol was detectable in equine tears at rest. Following ACTH stimulation, tear cortisol increased significantly from baseline at 60-120 min (P ≤ 0.001). Serum total and free cortisol also increased significantly at 30-180 min after ACTH stimulation (P ≤ 0.001). Both serum and tear cortisol returned to baseline concentrations by 360 min. Changes in tear cortisol were similarly associated with changes in serum total and free cortisol, although high tear cortisol concentrations suggest a portion of tear cortisol may be protein-bound. Cortisol is present in equine tears and increases in concert with serum cortisol following ACTH stimulation. Further study is needed to determine whether endogenous cortisol in tears contributes to ocular pathology.


Kefir Ameliorates Alcohol-Induced Liver Injury Through Modulating Gut Microbiota and Fecal Bile Acid Profile in Mice.
Alcoholic liver disease (ALD) is the leading cause of liver-related deaths worldwide. Kefir has been studied for its properties of anti-obesity, rebuilding intestinal homeostasis, and alleviating non-alcoholic fatty liver disease. However, the possible role of kefir in the prevention or treatment of ALD has not been carefully considered. Here, it evaluated the protective effects of kefir supplementation on alcohol-induced liver injury. C57BL/6J mice are fed to Lieber-DeCarli liquid diet containing alcohol to build ALD mouse model, followed by oral administration with kefir. Results indicate that kefir treatment improves liver pathological changes, decreases the expression levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and inflammatory markers, and increases antioxidant levels. Kefir supplementation also restores the intestinal barrier and altered microbial composition, indicates as increases of Blautia, Bacteroides, and Parasutterella and decreases in the Firmicutes/Bacteroidetes (F/B) ratio and populations of Psychrobacter, Bacillus, and Monoglobus. Moreover, kefir supplementation decreases the levels of total bile acids (BAs) and primary BAs and increases the secondary/primary BA ratio. Gut microbes play a key role in the conversion of primary to secondary fecal BAs. Kefir can ameliorate ALD through regulating the composition of the gut microbiota.


Spatial correlations in nonequilibrium reaction-diffusion problems by the Gillespie algorithm.
We present a study of the spatial correlation functions of a one-dimensional reaction-diffusion system in both equilibrium and out of equilibrium. For the numerical simulations we have employed the Gillespie algorithm dividing the system into cells to treat diffusion as a chemical process between adjacent cells. We find that the spatial correlations are spatially short ranged in equilibrium but become long ranged in nonequilibrium. These results are in good agreement with theoretical predictions from fluctuating hydrodynamics for a one-dimensional system and periodic boundary conditions.


The experiences of students in interprofessional learning.
This article explores the experiences of undergraduate healthcare students within interprofessional education (IPE) using a qualitative research study. The motive to undertake this study was as a result of mixed evaluations of IPE sessions. The study aimed to analyse student experiences of IPE, and as a result provide greater insight into how this type of education could be enhanced. Participants were selected through voluntary recruitment and data were collected using a focus group involving 12 participants who responded. Data analysis identified two key themes highlighting the barriers to engagement in IPE and factors that enable participants to engage. The study provides guidance for further developments and improvements when designing and delivering IPE.


Glucosamine-supplementation promotes endoplasmic reticulum stress, hepatic steatosis and accelerated atherogenesis in apoE-/- mice.
To determine the effects of glucosamine-supplementation on endoplasmic reticulum (ER) stress levels and atherogenesis, and to investigate the potential role of glucosamine in hyperglycemia-associated accelerated atherosclerosis. Five week old apolipoprotein E-deficient (apoE-/-) mice were provided with normal drinking water or water supplemented with 5% glucosamine (w/v) or 5% mannitol (w/v). To induce hyperglycemia, a separate group of apoE-/- mice received multiple low dose injections of streptozotocin (STZ). All mice were provided with a standard chow diet and were euthanized at 15 weeks of age. Hepatic and vascular ER stress levels and atherosclerotic lesion area at the aortic root were determined. STZ-induced hyperglycemic and glucosamine-supplemented mice had significantly larger and more advanced atherosclerotic lesions than control mice. Indications of ER stress were increased in the livers and atherosclerotic lesions of hyperglycemic and glucosamine-supplemented mice but not in the controls. In glucosamine-supplemented mice accelerated atherosclerosis was independent of detectable changes in blood glucose concentration, glucose tolerance, plasma insulin, or plasma lipid levels. Similar to hyperglycemia, glucosamine-supplementation promotes ER stress, hepatic steatosis and accelerated atherosclerosis. These findings support a model by which hyperglycemia promotes hepatic and vascular complications via a glucosamine intermediate.


Human immunodeficiency virus type 1 fitness and tropism: concept, quantification, and clinical relevance.
Two distinct aspects of human immunodeficiency virus type 1 (HIV-1) biopathology with important implications for the management of treated patients have emerged during the last decade: changes in relative viral fitness, and viral tropism. First, it has been observed that HIV-1 accumulates deleterious mutations leading to drug resistance and different degrees of reduction in relative fitness during antiretroviral therapy (ART). Although the latter normally parallel a failure of ART resulting from selection of resistant mutants, the drop in viral replication capacity may be beneficial for the host. Moreover, specific antiviral compounds aimed at reducing viral fitness could be developed. Analysis of the determinants of viral fitness in highly evolving viral populations has shown that viral extinction may also be obtained by forcing highly dynamic viral populations through increased (lethal) mutagenesis that abolishes viral replication (violation of the error threshold). It could be of great interest in the near future to address this point with strategies specifically planned at the molecular level. Furthermore, diagnostic evaluation limited to the master sequence has low predictive value in rapidly evolving viral populations. These observations, together with the evidence that all of the methodologies currently used for fitness analysis have important limitations, strongly suggest that further research is warranted. This should use highly sensitive and flexible technologies to evaluate viral fitness directly in vivo or ex vivo, not only for the dominant mutants, but also for minority variants. Second, discovery of the two main co-receptors for HIV-1, CCR5 and CXCR4, has led to a better understanding of the interaction of the viral envelope with host cells and to the development of novel therapeutic agents that inhibit viral entry. In this perspective, analysis of HIV-1 tropism has acquired a major diagnostic role.


Unleashing Chk1 in cancer therapy.
The checkpoint kinase 1 (Chk1) is one of the major players in the signal transduction pathway set in motion in response to DNA damage which activates different cell cycle checkpoints including the G 1/S, the intra-S, G 2-M and the mitotic spindle checkpoint, contributing to the maintenance of genomic stability. Chk1 is considered a good molecular target to inhibit, in combination with other anticancer agents, to increase the sensitivity of treatment, especially in tumors with a defective G 1 checkpoint. Experimental evidence highlights the essential role of Chk1 in normal and cancer cells even under unstressed conditions, especially in controlling DNA replication and cell division. This review looks at the main functions of Chk1 and the data on Chk1 inhibitors at their preclinical and clinical development are reported. This information may suggest novel approaches for new treatments with Chk1 inhibitors in combination with anticancer agents or as single agents. The emergent synthetic lethality approach may help define the genetic background features where Chk1 inhibitors alone could be very effective.


106-fold faster C-H bond hydroxylation by a CoIII,IV2(µ-O)2 complex [via a CoIII2(µ-O)(µ-OH) intermediate] versus its FeIIIFeIV analog.
The hydroxylation of C-H bonds can be carried out by the high-valent CoIII,IV2(µ-O)2 complex 2a supported by the tetradentate tris(2-pyridylmethyl)amine ligand via a CoIII2(µ-O)(µ-OH) intermediate (3a). Complex 3a can be independently generated either by H-atom transfer (HAT) in the reaction of 2a with phenols as the H-atom donor or protonation of its conjugate base, the CoIII2(µ-O)2 complex 1a. Resonance Raman spectra of these three complexes reveal oxygen-isotope-sensitive vibrations at 560 to 590 cm-1 associated with the symmetric Co-O-Co stretching mode of the Co2O2 diamond core. Together with a Co•••Co distance of 2.78(2) Å previously identified for 1a and 2a by Extended X-ray Absorption Fine Structure (EXAFS) analysis, these results provide solid evidence for their "diamond core" structural assignments. The independent generation of 3a allows us to investigate HAT reactions of 2a with phenols in detail, measure the redox potential and pKa of the system, and calculate the O-H bond strength (DO-H) of 3a to shed light on the C-H bond activation reactivity of 2a. Complex 3a is found to be able to transfer its hydroxyl ligand onto the trityl radical to form the hydroxylated product, representing a direct experimental observation of such a reaction by a dinuclear cobalt complex. Surprisingly, reactivity comparisons reveal 2a to be 106-fold more reactive in oxidizing hydrocarbon C-H bonds than corresponding FeIII,IV2(µ-O)2 and MnIII,IV2(µ-O)2 analogs, an unexpected outcome that raises the prospects for using CoIII,IV2(µ-O)2 species to oxidize alkane C-H bonds.


Current Understanding of the Neural Stem Cell Niches.
Neural stem cells (NSCs) are self-renewing, multipotent cells which give rise to all components of the central nervous system (CNS) during embryogenesis, but also activate in response to injury and disease and maintain a certain level of neurogenic activity throughout adulthood. This activity takes place in specialized regions of the brain, the neurovascular niches, whose main role is to control the behaviour of the CNS. In adult mammals, two main "canonical" niches have been described: The subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. This review discusses our current understanding of the neural stem cells and their canonical niches, as well as their structure, behaviours, and role in neural disease.


"This New Chapter of Life": Content Analysis of Facebook Posts After Traumatic Brachial Plexus Injury.
Background: After traumatic brachial plexus injuries (BPI), the sudden loss of physical function is often accompanied by psychological distress. Given the complex nature and relative infrequency of the injury, BPI patients will often use online resources for information about their injury as well as emotional support. Questions/Purpose: Recognizing the influence of social media, we sought to search a popular social media platform to identify challenges faced by BPI patients and strategies used to overcome these challenges. Methods: We searched "traumatic brachial plexus injury" on Facebook and selected the 2 most popular BPI support groups. We collected posts regarding traumatic BPI from November 1, 2018 through November 1, 2019. We performed inductive and deductive thematic analysis of the posts to identify recurring topics, knowledge gaps, and peer interaction dynamics. Results: We analyzed 7694 posts from the 2 Facebook support groups. The following themes emerged: (1) BPI patients express discontent regarding the inability to use their arm and the slow or stagnant pace of recovery; (2) BPI patients are frustrated over their inability to retain their preinjury livelihood; and (3) BPI patients emphasize that acceptance and moving on are key components of adjustment to their condition. Some patients described the role of limb amputation in achieving these goals. Conclusions: Our analysis demonstrates the areas in which BPI patients are in need of emotional support. Adjustment to BPI might be facilitated through multidisciplinary care that addresses emotional aspects of recovery and emphasizes self-management skills, in addition to the traditional focus on physical function.


Can Navigation-assisted Surgery Help Achieve Negative Margins in Resection of Pelvic and Sacral Tumors?
Navigation-assisted resection has been proposed as a useful adjunct to resection of malignant tumors in difficult anatomic sites such as the pelvis and sacrum where it is difficult to achieve tumor-free margins. Most of these studies are case reports or small case series, but these reports have been extremely promising. Very few reports, however, have documented benefits of navigation-assisted resection in series of pelvic and sacral primary tumors. Because this technology may add time and expense to the surgical procedure, it is important to determine whether navigation provides any such benefits or simply adds cost and time to an already complex procedure. (1) What proportion of pelvic and sacral bone sarcoma resections utilizing a computer-assisted resection technique achieves negative margins? (2) What are the oncologic outcomes associated with computer-assisted resection of pelvic and sacral bone sarcomas? (3) What complications are associated with navigation-assisted resection? Between 2009 and 2015 we performed 24 navigation-assisted resections of primary tumors of the pelvis or sacrum. Of those, four were lost to followup after the 2-year postoperative visit. In one patient, however, there was a failure of navigation as a result of inadequate imaging, so nonnavigated resection was performed; the remaining 23 were accounted for and were studied here at a mean of 27 months after surgery (range, 12-52 months). During this period, we performed navigation-assisted resections in all patients presenting with a pelvis or sacral tumor; there was no selection process. No patients were treated for primary tumors in these locations without navigation during this time with the exception of the single patient in whom the navigation system failed. We retrospectively evaluated the records of these 23 patients and evaluated the margin status of these resections. We calculated the proportion of patients with local recurrence, development of metastases, and overall survival at an average 27-month followup (range, 12-52 months). We queried a longitudinally maintained surgical database for any complications and noted which, if any, could have been directly related to the use of the navigation-assisted technique. In our series, 21 of 23 patients had a negative margin resection. In all patients the bone margin was negative, but two with sacral resections had positive soft tissue margins. Six of 23 patients experienced local recurrence within the study period. Three patients died during the study period. Seventeen patients demonstrated no evidence of disease at last recorded followup. We noted three intraoperative complications: one dural tear, one iliac vein laceration, and one bladder injury. Eight patients out of 23 had wound complications resulting in operative débridement. Two patients in the series developed transient postoperative femoral nerve palsy, which we believe were caused by stretch of the femoral nerve secondary to the placement of the reference array in the pubic ramus. Navigation-assisted resection of pelvic and sacral tumors resulted in a high likelihood of negative margin resection in this series, and we observed relatively few complications related specifically to the navigation. We have no comparison group without navigation, and future studies should indeed compare navigated with nonnavigated resection approaches in these anatomic locations. We did identify a potential navigation-related complication of femoral nerve palsy in this series and suggest careful placement and observation of the reference array during the operative procedure to lessen the likelihood of this previously unreported complication. We suggest it is worthwhile to consider the use of navigation-assisted surgery in resection of tumors of the pelvis and sacrum, but further study will be needed to determine its precise impact, if any, on local recurrence and other oncologic outcomes. Level IV, therapeutic study.


BAC-derived markers converted from RFLP linked to Phytophthora capsici resistance in pepper (Capsicum annuum L.).
Phytophthora capsici Leonian, an oomycete pathogen, is a serious problem in pepper worldwide. Its resistance in pepper is controlled by quantitative trait loci (QTL). To detect QTL associated with P. capsici resistance, a molecular linkage map was constructed using 100 F(2) individuals from a cross between Capsicum annuum 'CM334' and C. annuum 'Chilsungcho'. This linkage map consisted of 202 restriction fragment length polymorphisms (RFLPs), 6 WRKYs and 1 simple sequence repeat (SSR) covering 1482.3 cM, with an average interval marker distance of 7.09 cM. QTL mapping of Phytophthora root rot and damping-off resistance was performed in F(2:3) originated from a cross between resistant Mexican landrace C. annuum 'CM334' and susceptible Korean landrace C. annuum 'Chilsungcho' using composite interval mapping (CIM) analysis. Four QTL explained 66.3% of the total phenotypic variations for root rot resistance and three 44.9% for damping-off resistance. Of these QTL loci, two were located close to RFLP markers CDI25 on chromosome 5 (P5) and CT211A on P9. A bacterial artificial chromosome (BAC) library from C. annuum 'CM334' was screened with these two RFLP probes to obtain sequence information around the RFLP marker loci for development of PCR-based markers. CDI25 and CT211 probes identified seven and eight BAC clones, respectively. Nine positive BAC clones containing probe regions were sequenced and used for cytogenetic analysis. One single-nucleotide amplified polymorphism (SNAP) for the CDI25 locus, and two SSRs and cleaved amplified polymorphic sequence (CAPS) for CT211 were developed using sequences of the positive BAC clones. These markers will be valuable for rapid selection of genotypes and map-based cloning for resistance genes against P. capsici.


Reversal of contractility as a signature of self-organization in cytoskeletal bundles.
Bundles of cytoskeletal filaments and molecular motors generate motion in living cells, and have internal structures ranging from very organized to apparently disordered. The mechanisms powering the disordered structures are debated, and existing models predominantly predict that they are contractile. We reexamine this prediction through a theoretical treatment of the interplay between three well-characterized internal dynamical processes in cytoskeletal bundles: filament assembly and disassembly, the attachement-detachment dynamics of motors and that of crosslinking proteins. The resulting self-organization is easily understood in terms of motor and crosslink localization, and allows for an extensive control of the active bundle mechanics, including reversals of the filaments' apparent velocities and the possibility of generating extension instead of contraction. This reversal mirrors some recent experimental observations, and provides a robust criterion to experimentally elucidate the underpinnings of both actomyosin activity and the dynamics of microtubule/motor assemblies in vitro as well as in diverse intracellular structures ranging from contractile bundles to the mitotic spindle.


Glass transition by gelation in a phase separating binary alloy.
We use molecular dynamics simulations to show that glass transition in a model phase separating amorphous alloy, Cu(50)Nb(50), occurs by gelation. At the glass transition, a mechanically stiff, percolating network of atoms with icosahedral local packing forms at the interfaces between compositionally enriched regions. This low-energy network halts coarsening of the phase-separated structure and imparts shear resistance. These features of glass transition are remarkably similar to gelation processes in polymeric and colloidal gels.


Proton transfer from 2-naphthol to aliphatic amines in supercritical CO2.
The proton transfer from 2-naphthol to aliphatic amines was studied in supercritical CO(2) (scCO(2)) and in cyclohexane as reference solvent, by absorption and fluorescence spectroscopy and by time-resolved emission. Irradiation of 2-naphthol in scCO(2) in the presence of ethyldiisopropylamine shows dynamic fluorescence quenching of the acidic form of 2-naphthol and emission from the basic form. Fluorescence excitation spectra show that the emission of the basic form is originated upon excitation of the acidic form. The interaction between 2-naphthol and the amines is described by the formation of a complex with proton donor-acceptor character in the ground and excited states of 2-naphthol. The acidity increase of 2-naphthol upon electronic excitation to the first excited singlet in scCO(2) is as high as in water. Proton transfer quantum yields of 0.6 can be easily achieved in scCO(2). The results have implications for carrying out acid-base catalyzed reactions in scCO(2).


Bioanalytical separations using electric field gradient techniques.
The field of separations science will be strongly impacted by new electric-field-gradient-based strategies. Many new capabilities are being developed with analytical targets ranging from particles to small molecules, and soot to living cells. Here we review the emerging area of electric field gradient techniques, dividing the large variety of techniques by the target of separation. In doing so, we have contributions using dielectrophoresis, electric field gradient focusing (including dynamic, true moving bed, and pulsed field), electrocapture and electrophoretic focusing, temperature gradient focusing, and focusing with centrifugal force. We cover the literature from the start of 2007 to June 2008, along with some introductory discussions. Even with the relatively short time frame, this young and dynamic field of inquiry produced some 100 contributions describing new and unique techniques and several new applications.


Fish species richness is associated with the availability of landscape components across seasons in the Amazonian floodplain.
Understanding environmental biodiversity drivers in freshwater systems continues to be a fundamental challenge in studies of their fish assemblages. The present study seeks to determine the degree to which landscape variables of Amazonian floodplain lakes influences fish assemblages in these environments. Fish species richness was estimated in 15 Amazonian floodplain lakes during the high and low-water phases and correlated with the areas of four inundated wetland classes: (i) open water, (ii) flooded herbaceous, (iii) flooded shrubs and (iv) flooded forest estimated in different radius circular areas around each sampling site. Data were analyzed using generalized linear models with fish species richness, total and guilds as the dependent variable and estimates of buffered landscape areas as explanatory variables. Our analysis identified the significance of landscape variables in determining the diversity of fish assemblages in Amazonian floodplain lakes. Spatial scale was also identified as a significant determinant of fish diversity as landscape effects were more evident at larger spatial scales. In particular, (1) total species richness was more sensitive to variations in the landscape areas than number of species within guilds and (2) the spatial extent of the wetland class of shrubs was consistently the more influential on fish species diversity.


Domain requirements and sequence specificity of DNA binding for the forkhead transcription factor FOXP3.
The forkhead, winged-helix transcription factor FOXP3 is preferentially expressed in T regulatory (Treg) cells and is critical for their immunosuppressive function. Mutations that abolish FOXP3 function lead to systemic autoimmunity in mice and humans. However, the manner by which FOXP3 recognizes cognate DNA elements is unclear. Here we identify an in vitro optimized DNA sequence to assess FOXP3 DNA binding by electrophoretic mobility shift assay (EMSA). The optimized sequence contains two tandem copies of a core DNA element resembling, but not identical to, the canonical forkhead (FKH) binding element. The tandem nature of this optimized FOXP3-binding oligonucleotide suggests a requirement for multimerization, and EMSA experiments confirm that both the DNA-binding FKH domain and an intact leucine-zipper domain, which mediates homo-multimerization of FOXP3, are required for DNA binding. These results establish a practical framework for understanding the molecular basis by which FOXP3 regulates gene transcription and programs Treg suppressive function.


Larval ecology and infestation indices of two major arbovirus vectors, Aedes aegypti and Aedes albopictus (Diptera: Culicidae), in Brazzaville, the capital city of the Republic of the Congo.
Invasive mosquito species, such as Aedes albopictus in Congo can affect the distribution of native species, changing the vector composition and pattern of disease transmission. Here, we comparatively establish the geographical distribution and larval habitat preference of Ae. aegypti and Ae. albopictus and the risk of arbovirus disease outbreaks using Stegomyia indices in the city of Brazzaville, the capital of the Republic of the Congo. Human dwelling surveys of water-holding containers for immature stages of Aedes was carried out in December 2017 in Brazzaville through a random cluster sampling method. A total of 268 human dwellings distributed in 9 boroughs and 27 neighbourhoods were surveyed across the city. Overall, 455 potential larval habitats were surveyed. Both Ae. aegypti and Ae. albopictus were collected across the city with an overall high prevalence of Ae. aegypti (53.1%) compared to Ae. albopictus (46.9%). Geographical distribution analysis showed that Ae. aegypti was more abundant (mean = 6.6 ± 1.4) in neighbourhoods located in downtown, while the abundance of Ae. albopictus was low (mean = 3.5 ± 0.6) in suburbs. Peridomestic containers, especially discarded tanks, were the most strongly colonized productive larval habitat for both mosquito species with the prevalence of 56.4% and 53.1% for Ae. aegypti and Ae. albopictus, respectively. Globally, the house index (HI), Breteau index (BI) and container index (CI) were high for Ae. aegypti (26.6%, 38.4% and 22.6%) and Ae. albopictus (33.3%, 49.6% and 26.6%) compared to the transmission risk threshold (5%, 5% and 20%) established by the WHO/PAHO. Overall, pupae-based indices (the pupae index and the pupae per person index) were not significantly different between Ae. aegypti (273.4% and 23.2%) and Ae. albopictus (228.8% and 19.5%). The findings of this study suggest a high risk for transmission of arbovirus diseases in Brazzaville and call for an urgent need to implement vector control strategies against these vectors in the Republic of the Congo.


[Land and space hygienic monitoring of environment quality].
Monitoring of changes occurring in the environment and human health is a basic way of solving the problem of the optimal society-biosphere interaction. The initiated ecological and hygienic studies using the space facilities and techniques of remote probing of the Earth's surface create prerequisites for the land and space monitoring of biospheric solution, for the assessment of the anthropoecological situation and for the prediction environment-related diseases in the population.


Estimating the capacity for improvement in risk prediction with a marker.
Consider a set of baseline predictors X to predict a binary outcome D and let Y be a novel marker or predictor. This paper is concerned with evaluating the performance of the augmented risk model P(D = 1|Y,X) compared with the baseline model P(D = 1|X). The diagnostic likelihood ratio, DLR(X)(y), quantifies the change in risk obtained with knowledge of Y = y for a subject with baseline risk factors X. The notion is commonly used in clinical medicine to quantify the increment in risk prediction due to Y. It is contrasted here with the notion of covariate-adjusted effect of Y in the augmented risk model. We also propose methods for making inference about DLR(X)(y). Case-control study designs are accommodated. The methods provide a mechanism to investigate if the predictive information in Y varies with baseline covariates. In addition, we show that when combined with a baseline risk model and information about the population distribution of Y given X, covariate-specific predictiveness curves can be estimated. These curves are useful to an individual in deciding if ascertainment of Y is likely to be informative or not for him. We illustrate with data from 2 studies: one is a study of the performance of hearing screening tests for infants, and the other concerns the value of serum creatinine in diagnosing renal artery stenosis.


CD3-CD28 costimulation as a means to avoiding T cell preactivation in bispecific monoclonal antibody-based treatment of ovarian carcinoma.
One of the major limitations to the immunotherapy of ovarian carcinoma based on the use of anti-CD3/antitumor bispecific monoclonal antibodies (bi-mAb) is the need for preactivation of effector cells ex vivo, because cross-linking of the T cell receptor-CD3 complex per se may lead to T-cell unresponsiveness or even apoptosis. The bi-mAb OC/TR, which recognizes the folate-binding protein (FBP) overexpressed in 90% of ovarian carcinomas and the CD3 molecule on T cells, has demonstrated efficacy in a clinical setting. Here we investigated the possibility of delivering accessory signals to OC/TR-retargeted peripheral blood mononuclear cells (PBMCs) via an anti-CD28 mAb or an anti-FBP/anti-CD28 bi-mAb. Coculture of resting PBMCs from healthy donors with OC/TR, anti-FBP/anti-CD28 bi-mAb, and FBP+ tumor cell lines resulted in a highly activated phenotype of effector cells and in a dramatic in vitro growth inhibition of the target cells without an increase in OC/TR-redirected lysis. Whereas both the CD4 and CD8 T cell subsets were involved in the growth inhibition, only the CD8 subpopulation accounted for the cytotoxic activity. The in vitro tumor growth inhibition was mediated mainly by soluble factors, which were active on both FBP+ and FBP- ("bystander effect") cell lines. Activation and antitumor activity were also observed, albeit to a lesser extent, using OC/TR and monospecific bivalent anti-CD28 mAb. In vitro analysis demonstrated that cross-linking between tumor and effector cells for at least 24 h was needed to achieve T-cell activation and development of antitumor activities. Thus, ex vivo CD3-CD28 costimulation on resting PBMCs might be of therapeutic utility for local treatment of minimal residual disease.


The exonuclease activity of hPMC2 is required for transcriptional regulation of the QR gene and repair of estrogen-induced abasic sites.
We have previously reported that the expression of antioxidative stress enzymes is upregulated by trans-hydroxytamoxifen (TOT) in breast epithelial cell lines providing protection against estrogen-induced DNA damage. This regulation involves Estrogen Receptor β (ERβ) recruitment to the Electrophile Response Element (EpRE) and a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). We have also demonstrated that ERβ and hPMC2 are required for TOT-dependent recruitment of poly (ADP-ribose) polymerase 1 (PARP-1) and Topoisomerase IIβ (Topo IIβ) to the EpRE. Sequence analysis reveals that the C-terminus of hPMC2 encodes a putative exonuclease domain. Using in vitro kinetic assays, we found that hPMC2 is a 3'-5' non-processive exonuclease that degrades both single-stranded and double-stranded substrates. Mutation of two conserved carboxylate residues drastically reduced the exonuclease activity of hPMC2, indicating the relative importance of the catalytic residues. Western blot analysis of breast cancer cell lines for Quinone Reductase (QR) levels revealed that the intrinsic exonuclease activity of hPMC2 was required for TOT-induced QR upregulation. Chromatin immunoprecipitation (ChIP) assays also indicated that hPMC2 was involved in the formation of strand breaks observed with TOT treatment and is specific for the EpRE-containing region of the QR gene. We also determined that the transcription factor NF-E2-related factor-2 (Nrf2) is involved in the specificity of hPMC2 for the EpRE. In addition, we determined that the catalytic activity of hPMC2 is required for repair of abasic sites that result from estrogen-induced DNA damage. Thus, our study provides a mechanistic basis for transcriptional regulation by hPMC2 and provides novel insights into its role in cancer prevention.


Type I primary neuropathic amyloidosis (Andrade, portuguese).
The authors present a review of 21 cases with the diagnosis of type I amyloid neuropathy based on epidemiological data, clinical evolution and histopathological findings. They call attention to the possibility of cranial nerves involvement (hyposmia, diplopia, masseterian hypotrophy, peripheral facial paralysis, hypoacusis, dysphonia, laryngeal paralysis, dysphagia, and trapezium muscle hypotrophy), to the severeness of the digestive symptoms, to the precocity of the autonomic disorders, and to the rather high incidence (6 cases) of heart involvement. The electromyography showed anterior horn involvement in 3 cases. The electrocardiography showed repolarization disorders in 11 cases, left ventricular overload in 6 cases and atrioventricular block in 5 cases. The serum proteins electrophoresis showed frequent abnormalities, but no typical curve could be obtained. The barium-contrasted X-rays of the gastrointestinal tract showed no anatomical lesions, but functional abnormalities (hypo or hypermotility) were found in 14 examination. The Schilling test showed impairment of vitamin B12 absorption in 50% of the cases. However, with the concomitant administration of intrinsic factor (3 cases) there was improvement of it absorption. This proves that the gastric mucosa plays an important role in the disease malabsorption. The test with labeled-triolein showed slow absorption in 2 cases and steatorrhea in 3 (6 tests). For the confirmation of the amyloid deposits, the best histopathological procedure was nerve biopsy. In men, when the nerve biopsy was negative, testicular biopsy has shown to be a good option.


Gut complex carbohydrates and intestinal microflora in broiler chickens fed with oregano (Origanum vulgare L.) aqueous extract and vitamin E.
One hundred and seventy one-day-old female broiler chicks were randomly divided into three groups fed with different dietary treatments: basal control diet (C); C supplemented (2 g/kg) with an oregano aqueous extract (O); C supplemented (150 mg/kg) with vitamin E (E). Growth performance was evaluated at 21 (T1) and 42 days (T2). On the same days, morphological, histochemical and microbiological analyses were performed. The O group showed the highest (p < 0.01) body weight at T1, while no differences were observed at T2. Light microscopic observation and conventional histochemistry showed no differences with regard to the two sampling times, whereas significant differences emerged among the treatments. The O treatment generally enhanced goblet cell reactivity more than both the C and E treatments. Coliform count was lower in the ileum tract of the O group at both T1 and T2 (p < 0.05) and increased with age in all groups. Escherichia coli showed the lowest values in the caecum of the O group (p < 0.001) at both sampling times. Enterococci, lactobacilli and staphylococci populations showed no differences among the different experimental groups in the caecum. In the ileum, the O group did not exhibit the sharp decline (p < 0.001) in the lactic acid bacteria population observed in the other two experimental groups. In conclusion, oregano aqueous extract supplementation seemed to elicit the best response among treatments, enabling better growth performance, enhancing both the quantity and quality of glycoconjugates involved in indirect defence actions and significantly reducing both the coliform and E. coli counts.


An Introduction to Male Germline Development.
In this introductory chapter, we describe male germline development in plants taking Arabidopsis thaliana as a reference species. We first describe the transition from sporophytic to germline development, then microsporogenesis including meiosis, followed by male gametophyte development prior to pollination, and finally the progamic phase culminating in double fertilization, which leads to the formation of the embryo and the endosperm. For detailed information on some of these processes or on the molecular underpinning of certain fate transitions, we refer the reader to recent reviews. An important but often neglected aspect of male gametophyte development is the formation of the unique pollen cell wall. In contrast to that of other plant cells, the pollen cell wall is composed of two principal layers, the intine and exine. While the intine, the inner pecto-cellulosic cell wall layer, is biochemically and structurally similar to a "classical" plant cell wall, the exine is a unique composite with sporopollenin as its main component. Biosynthesis of the cell wall is remarkably similar between the spores of mosses and ferns, and pollen of seed plants, although slight differences exist, even between closely related species (reviewed in Wallace et al., AoB Plants 2011:plr027, 2011). In the latter sections of this chapter, we will present a brief overview of cell wall development in Arabidopsis pollen, where this aspect has been intensively studied.


Salmonella status of pigs at slaughter--bacteriological and serological analysis.
Apart from Salmonella monitoring of pig herds during the period of growth to evaluate the efficacy of control programmes, monitoring at harvest level is of relevance to assess the Salmonella status of fattening pigs and the associated risk of introducing Salmonella organisms in the slaughter process. Samples from 1830 fattening pigs were gathered at slaughter. Ileocaecal lymph nodes, rectal and caecal content as well as tonsils were collected for bacteriological examinations, and a part of the diaphragm pillar muscle was taken to gain meat-juice for serological analysis. Salmonella spp. was recovered from 13.8% of all pigs examined. Salmonella Typhimurium and Derby were the dominating serovars. The highest detection rates were found in caecal content followed by ileocaecal lymph nodes. By analysing both organs nearly 90% of all Salmonella positive pigs could be identified. Serological examination revealed 9.6% of the pigs as positive using a cut-off value of OD % ≥ 40. Only one quarter of all Salmonella positive pigs showed also a positive serological result. A reduction of the cut-off value does not necessarily result in a higher compliance between bacteriologically and serologically positive slaughter pigs. Detection of antibodies is useful to verify whether pig herds were previously exposed to Salmonella organisms. However, the Salmonella status of pigs at time of slaughter and the associated risk of dissemination of Salmonella organisms can only be assessed by bacteriological examinations which should include both lymph nodes and caecal content.


Lithium chloride: protective and antisecretory properties in rats.
Lithium chloride was evaluated as a potential protective agent against ethanol-induced hemorrhagic gastritis in rats. Rats received lithium chloride intragastrically (30, 60, or 90 mg/kg i.g.) or subcutaneously (3, 5, 10, 15, 20, 30, 60, or 90 mg/kg s.c.), or a placebo (H2O i.g. or 0.9% NaCl s.c.). Ninety minutes later 1 cm3 of 95% ethanol was administered intragastrically. After 30 min, the rats were killed and their stomachs were removed and visually scored for gross hemorrhagic gastritis. Lithium chloride at all doses less than 3 mg/kg significantly improved hemorrhagic gastritis when compared with the placebo. Moreover, rats treated with lithium chloride intragastrically had significantly less hemorrhagic gastritis than those treated subcutaneously even though serum lithium levels were similar. To determine if lithium's protective properties related to acid inhibition, pylorus-ligated and gastric fistula rats were studied. The median effective dose for lithium chloride was 20-30 mg/kg and the nonantisecretory dose was 3 mg/kg. No difference in hemorrhagic gastritis was noted between controls and animals receiving the nonantisecretory dose. However, at higher doses (LiCl 30, 60, and 90 mg/kg), lithium's protective properties persisted in spite of adding 150 mM HCl to the intragastrically administered ethanol (p less than 0.001). To determine further if lithium chloride stimulated endogenous prostaglandins, indomethacin, a prostaglandin inhibitor, was administered. Indomethacin did not alter lithium chloride's protective properties. In fact, when compared with exogenously administered 16,16-dimethyl prostaglandin E2 (5 and 500 micrograms/kg), high-dose LiCl (30, 60, or 90 mg/kg) resulted in significantly more protection against ethanol-induced injury (p less than 0.001). In contrast, when both nonantisecretory doses were compared, 16,16-dimethyl prostaglandin E2 (5 micrograms/kg) gave significantly better protection than LiCl (3 mg/kg). These data indicate that LiCl is a potent gastric antisecretory and protective agent. The protective properties of LiCl appear to be related to acid inhibition and be independent of endogenous prostaglandins, although other protective mechanisms may be present at higher LiCl doses. Additionally, this study indicates that LiCl may have clinical application in protecting the gastric mucosa against hemorrhagic gastritis.


Tobramycin in renal impairment.
Calculated elimination rate constants of tobramycin were correlated with endogenous creatinine clearances in 128 normal subjects or patients with various degrees of renal impairment. A similar correlation was made with serum creatinine concentration in 85 subjects. Superimposition of these regression lines permitted calculation of daily maintenance dosage ranges for tobramycin in patients with all degrees of impairment of renal function as determined by either creatinine clearances or serum creatinine concentrations. These maintenance dosage ranges are presented in a simplified figure.


Purine deoxynucleoside toxicity in nondividing human lymphoid cells.
Cultured leukemic T-lymphoblasts, incubated in the presence of inhibitors of adenosine deaminase, are exquisitely sensitive to growth inhibition by deoxyadenosine. An analogy between this phenomenon and human combined immunodeficiency disease associated with inborn adenosine deaminase deficiency and the use of inhibitors of adenosine deaminase in the management of T-cell acute lymphoblastic leukemia has been noted. These phenomena are believed to reflect accumulation of high intracellular concentrations of deoxyadenosine triphosphate (dATP) following phosphorylation of deoxyadenosine, inhibiting replicating T-cells. In an attempt to extend these observations to noncultured, nonleukemic T-cells, we studied deoxyadenosine metabolism in human thymocytes. Human thymuses were separated into large replicating and small nondividing cell types by centrifugal elutriation. Both thymocyte subpopulations elevated in their dATP pools on incubation with microM concentrations of deoxyadenosine in the presence of erythro-9-[3-(2-hydroxynonyl)]adenosine, an inhibitor of adenosine deaminase. These dATP pool rises were similar in extent to those found in cultured leukemic T-lymphoblasts. However, the finding that small nonreplicating thymocytes elevate their dATP pool was unexpected. This prompted study of unstimulated peripheral blood lymphocytes. These cells (T and non-T) showed a similar elevation of their dATP pool on incubation with deoxyadenosine. Furthermore, these nondividing peripheral blood lymphocytes were killed by microM concentrations of deoxyadenosine in the presence of an inhibitor of adenosine deaminase. The biochemical mechanism of this G0-phase cell death is not known. These findings provide impetus for the investigation of adenosine deaminase inhibitors as lympholytic immunosuppressants or as agents to noncycling malignant lymphoid cells.


Patterns and processes of brain diversification within esociform teleosts.
The richness of nervous systems represented by extant fishes has not yet been fully determined; the brain morphology of many groups remains undescribed. For this reason we have begun to examine the brains of esociforms, a group representing basal euteleosts, focusing here on three goals: 1) to provide the first general descriptions of the brains of two esociform teleosts, Esox masquinongy (muskellunges) and Esox lucius (northern pikes); 2) to describe the neuronal development of E. masquinongy; and 3) to compare the differences in neuronal features between E. masquinongy and E. lucius with reference to the ontogeny of E. masquinongy. We demonstrate that relative to the brains of E. lucius and other basal euteleosts, the brains of E. masquinongy exhibit several paedomorphic features involving the position and morphology of nuclei present throughout the brain. This heterochronic shift parallels differences in nonneural morphological features described between these two species. We conclude that at finer taxonomic levels in some groups such as esocids, aspects of neuronal diversification may be explained by evolutionary transformations involving all body systems. © 1996 Wiley-Liss, Inc.


The Implementation of Targeted Temperature Management: An Evidence-Based Guideline from the Neurocritical Care Society.
Targeted temperature management (TTM) is often used in neurocritical care to minimize secondary neurologic injury and improve outcomes. TTM encompasses therapeutic hypothermia, controlled normothermia, and treatment of fever. TTM is best supported by evidence from neonatal hypoxic-ischemic encephalopathy and out-of-hospital cardiac arrest, although it has also been explored in ischemic stroke, traumatic brain injury, and intracranial hemorrhage patients. Critical care clinicians using TTM must select appropriate cooling techniques, provide a reasonable rate of cooling, manage shivering, and ensure adequate patient monitoring among other challenges. The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacotherapy to form a writing Committee in 2015. The group generated a set of 16 clinical questions relevant to TTM using the PICO format. With the assistance of a research librarian, the Committee undertook a comprehensive literature search with no back date through November 2016 with additional references up to March 2017. The Committee utilized GRADE methodology to adjudicate the quality of evidence as high, moderate, low, or very low based on their confidence that the estimate of effect approximated the true effect. They generated recommendations regarding the implementation of TTM based on this systematic review only after considering the quality of evidence, relative risks and benefits, patient values and preferences, and resource allocation. This guideline is intended for neurocritical care clinicians who have chosen to use TTM in patient care; it is not meant to provide guidance regarding the clinical indications for TTM itself. While there are areas of TTM practice where clear evidence guides strong recommendations, many of the recommendations are conditional, and must be contextualized to individual patient and system needs.


Fins as Mechanosensors for Movement and Touch-Related Behaviors.
Mechanosensation is a universal feature of animals that is essential for behavior, allowing detection of animals' own body movement and position as well as physical characteristics of the environment. The extraordinary morphological and behavioral diversity that exists across fish species provide rich opportunities for comparative mechanosensory studies in fins. The fins of fishes have been found to function as proprioceptors, by providing feedback on fin ray position and movement, and as tactile sensors, by encoding pressures applied to the fin surface. Across fish species, and among fins, the afferent response is remarkably consistent, suggesting that the ability of fin rays and membrane to sense deformation is a fundamental feature of fish fins. While fin mechanosensation has been known in select, often highly specialized, species for decades, only in the last decade have we explored mechanosensation in typical propulsive fins and considered its role in behavior, particularly locomotion. In this paper, we synthesize the current understanding of the anatomy and physiology of fin mechanosensation, looking toward key directions for research. We argue that a mechanosensory perspective informs studies of fin-based propulsion and other fin-driven behaviors and should be considered in the interpretation of fin morphology and behavior. In addition, we compare the mechanosensory system innervating the fins of fishes to the systems innervating the limbs of mammals and wings of insects in order to identify shared mechanosensory strategies and how different organisms have evolved to meet similar functional challenges. Finally, we discuss how understanding the biological organization and function of fin sensors can inform the design of control systems for engineered fins and fin-driven robotics.


Mouse mononuclear cell chemotaxis: description of system.
The mononuclear cell chemotaxis assay was adapted for use with normal mouse peritoneal cells. Mouse peritoneal macrophages responded well to endotoxinactivated mouse serum and to chemotactic factors produced by mouse spleen cell cultures stimulated with mitogens or specific antigen. The assay was quantitative, reproducible, and applicable to several mouse strains.


Auxin acts independently of DELLA proteins in regulating gibberellin levels.
Shoot elongation is a vital process for plant development and productivity, in both ecological and economic contexts. Auxin and bioactive gibberellins (GAs), such as GA1, play critical roles in the control of elongation, along with environmental and endogenous factors, including other hormones such as the brassinosteroids. The effect of auxins, such as indole-3-acetic acid (IAA), is at least in part mediated by its effect on GA metabolism, since auxin up-regulates biosynthesis genes such as GA 3-oxidase and GA 20-oxidase and down regulates GA catabolism genes such as GA 2-oxidases, leading to elevated levels of bioactive GA 1. In our recent paper, we have provided evidence that this action of IAA is largely independent of DELLA proteins, the negative regulators of GA action, since the auxin effects are still present in the DELLA-deficient la cry-s genotype of pea. This was a crucial issue to resolve, since like auxin, the DELLAs also promote GA 1 synthesis and inhibit its deactivation. DELLAs are deactivated by GA, and thereby mediate a feedback system by which bioactive GA regulates its own level. However, our recent results, in themselves, do not show the generality of the auxin-GA relationship across species and phylogenetic groups or across different tissue types and responses. Further, they do not touch on the ecological benefits of the auxin-GA interaction. These issues are discussed below as well as the need for the development of suitable experimental systems to allow this process to be examined.


State legislative approaches to regulating coverage for experimental procedures.
As addressed in past issues of the Newsletter, the Employment Retirement Income Security Act ("ERISA"), 29 U.S.C. sections 1001 et seq., limits the ability of states to regulate the terms and conditions of group health plans. See Newsletters, Vol. 8, No. 6, June 1993, at 6 and 23; Vol. 8, No. 1, January 1993, at 7; Vol. 7, No. 2, February 1992, at 13; Vol. 6, No. 11, November 1991, at 3. Under ERISA, states cannot mandate that self-insured group health plans or employers provide specific types of coverage. Metropolitan Life Ins. Co. v. Massachusetts, 471 U.S. 724, 105 S.Ct. 2380 (1985). Such mandates are enforceable only as to insurance companies and HMOs, and only to the extent that they are deemed to "regulate insurance." Id. As a result, state legislative attempts to regulate experimental treatment insurance coverage have largely been limited to health plans that are not self insured. Given the inconsistent handling of experimental treatment insurance coverage by both insurance companies and courts across the nation, state legislatures have demonstrated that they are ready to address this matter themselves. However, unless ERISA is amended to afford employees with self-insured plans the same protections as those with insured plans, such state efforts will not be able to resolve the problem for all citizens.


[Recurrent multicystic peritoneal mesothelioma in endometriosis of the pelvis].
In the case of a 21-year old woman, who complained of chronic pelvic pain and where cystic structures in the adnexal region had been diagnosed ultrasonically and by laparoscopy, a tumour made up of many small cysts was discovered in the pouch of Douglas next to a typical endometrial cyst. Both the endometrial cyst and the cystic tumour were excised by laparotomy. Histology established the tumour as a multicystic peritoneal mesothelioma. Postoperative recurrence was noticed by ultrasound less than one year later. Laparotomy revealed a 5 cm serous cyst of the right ovary and again countless liquid-filled grape-like small cysts in the pouch of Douglas. Histology revealed a multicystic peritoneal mesothelioma identical to the previously excised tumour. Multicystic peritoneal mesothelioma is a rare soft tissue tumour noted for its frequent recurrences. Most authors agree, that it belongs to the morphological spectrum of reactive mesothelial proliferative lesions and not the neoplastic spectrum. It appears mostly in women, often concomitant with endometriosis and pelvic inflammatory disease and frequently in women, who had previous surgical interventions in the abdominal region.


A Novel Experimental Dental Implant Permits Quantitative Grading of Surface-Property Effects on Osseointegration.
To test the hypothesis if a novel single-chamber experimental dental implant allows in vivo the quantitative assessment of osseointegration over time and as a function of different surface properties (physical, chemical, geometric, biologic [osteoconductive or osteoinductive]) in a biologically unfavorable environment (local osteoporosis). Three prototypes of a novel experimental implant with different chamber sizes (small, medium, and large) were compared with each other to find out the minimum size of bone chambers needed to allow a discriminative quantification of osseointegration over time. For the comparison of low and high surface osteoconductivity properties, conventional sandblasted, acid-etched chamber surfaces (low surface osteoconductivity) were compared with biomimetically (calcium phosphate) coated ones (high surface osteoconductivity). The implants (4 implants per animal; 88 implants per time point) were inserted into the edentulous maxillae of a total of 66 adult goats with a physiologically osteoporotic masticatory apparatus. Two, 4, and 8 weeks later, they were excised and prepared for a histomorphometric analysis of the volume of neoformed bone within the chamber space and of the bone-to-implant contact (BIC) area. The implants with small chambers did not show significant differences in bone coverage (BIC) nor bone volume (relative and absolute volume), neither as a function of time nor as of implant surface property (low versus high surface osteoconductivity). However, medium and large chambers revealed significant differences respecting both of these parameters over the 8-week postoperative time period. The new implant model permits a discriminative quantification of osseointegration in vivo in an osteoporotic bone environment for implants with medium-sized and large-sized chambers. Quantitative assessment of osseointegration is possible, both over time and as a function of low and high surface osteoconductivity properties.


Coherence of the Surface EMG and Common Synaptic Input to Motor Neurons.
Coherence between electromyographic (EMG) signals is often used to infer the common synaptic input to populations of motor neurons. This analysis, however, may be limited due to the filtering effect of the motor unit action potential waveforms. This study investigated the ability of surface EMG-EMG coherence to predict common synaptic input to motor neurons. Surface and intramuscular EMG were recorded from two locations of the tibialis anterior muscle during steady ankle dorsiflexions at 5 and 10% of the maximal force in 10 healthy individuals. The intramuscular EMG signals were decomposed to identify single motor unit spike trains. For each trial, the strength of the common input in different frequency bands was estimated from the coherence between two cumulative spike trains, generated from sets of single motor unit spike trains (reference measure). These coherence values were compared with those obtained from the coherence between the surface EMG signals (raw, rectified, and high-passed filtered at 250 Hz before rectification) using linear regression. Overall, the high-pass filtering of the EMG prior to rectification did not substantially change the results with respect to rectification only. For both signals, the correlation of EMG coherence with motor unit coherence was strong at 5% MVC (r2 > 0.8; p < 0.01), but only for frequencies > 5 Hz. At 10% MVC, the correlation between EMG and motor unit coherence was only significant for frequencies > 15 Hz (r2 > 0.8; p < 0.01). However, when using raw EMG for coherence analysis, the only significant relation with motor unit coherence was observed for the bandwidth 5-15 Hz (r2 > 0.68; p = 0.04). In all cases, there was no association between motor unit and EMG coherence for frequencies < 5 Hz (r2 ≤ 0.2; p ≥ 0.51). In addition, a substantial error in the best linear fit between motor unit and EMG coherence was always present. In conclusion, high-frequency (>5 Hz) common synaptic inputs to motor neurons can partly be estimated from the rectified surface EMG at low-level steady contractions. The results, however, suggest that this association is weakened with increasing contraction intensity and that input at lower frequencies during steady isometric contractions cannot be detected accurately by surface EMG coherence.