BiCyCLE NMES-neuromuscular electrical stimulation in the perioperative treatment of sarcopenia and myosteatosis in advanced rectal cancer patients: design and methodology of a phase II randomised controlled trial.
Colorectal cancer is associated with secondary sarcopenia (muscle loss) and myosteatosis (fatty infiltration of muscle) and patients who exhibit these host characteristics have poorer outcomes following surgery. Furthermore, patients, who undergo curative advanced rectal cancer surgery such as pelvic exenteration, are at risk of skeletal muscle loss due to immobility, malnutrition and a post-surgical catabolic state. Neuromuscular electrical stimulation (NMES) may be a feasible adjunctive treatment to help ameliorate these adverse side-effects. Hence, the purpose of this study is to investigate NMES as an adjunctive pre- and post-operative treatment for rectal cancer patients in the radical pelvic surgery setting and to provide early indicative evidence of efficacy in relation to key health outcomes. In a phase II, double-blind, randomised controlled study, 58 patients will be recruited and randomised (1:1) to either a treatment (NMES plus standard care) or placebo (sham-NMES plus standard care) group. The intervention will begin 2 weeks pre-operatively and continue for 8 weeks after exenterative surgery. The primary outcome will be change in mean skeletal muscle attenuation, a surrogate marker of myosteatosis. Sarcopenia, quality of life, inflammatory status and cancer specific outcomes will also be assessed. This phase II randomised controlled trial will provide important preliminary evidence of the potential for this adjunctive treatment. It will provide guidance on subsequent development of phase 3 studies on the clinical benefit of NMES for rectal cancer patients in the radical pelvic surgery setting. Protocol version 6.0; 05/06/20. ClinicalTrials.gov NCT04065984 . Registered on 22 August 2019; recruiting.


Complex brain networks: graph theoretical analysis of structural and functional systems.
Recent developments in the quantitative analysis of complex networks, based largely on graph theory, have been rapidly translated to studies of brain network organization. The brain's structural and functional systems have features of complex networks--such as small-world topology, highly connected hubs and modularity--both at the whole-brain scale of human neuroimaging and at a cellular scale in non-human animals. In this article, we review studies investigating complex brain networks in diverse experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans) and provide an accessible introduction to the basic principles of graph theory. We also highlight some of the technical challenges and key questions to be addressed by future developments in this rapidly moving field.


Refreshment need metrics for improved shape and texture object-based resilient video coding.
Video encoders may use several techniques to improve error resilience. In particular, for video encoders that rely on predictive (inter) coding to remove temporal redundancy, intra coding refreshment is especially useful to stop error propagation when errors occur in the transmission or storage of the coded streams, which can cause the decoded quality to decay very rapidly. In the context of object-based video coding, the video encoder can apply intra coding refreshment to both the shape and the texture data. In this paper, shape refreshment need and texture refreshment need metrics are proposed which can be used by object-based video encoders, notably MPEG-4 video encoders, to determine when the shape and the texture of the various video objects in the scene should be refreshed in order to improve the decoded video quality, e.g., for a given bitrate.


Mineralocorticoid and glucocorticoid effects on 31,000- and 29,000-dalton proopiomelanocortin in rat anterior pituitary and neurointermediate lobe.
The effects of adrenal steroids on proopiomelanocortin (POMC) levels in rat pituitary have been studied by two-dimensional gel electrophoresis. In intact rats the relative abundance of POMC was much higher in the neurointermediate lobe (N-IL) than in anterior pituitary (AP); in both tissues the predominant species appeared to be of 29,000-dalton (29K) molecular mass, with lesser amounts of a 31K form. In both tissues, the 31K and 29K forms showed multiple spots, consistent with different degrees of sialoglycosylation. Adrenalectomy was followed by a marked increase in AP levels of POMC, and a marked decrease in N-IL levels. In adrenalectomized rats, dexamethasone administration did not affect N-IL levels of POMC, but suppressed 35S incorporation into POMC in AP in a dose-related manner; deoxycorticosterone showed minimal effects on AP levels of POMC, but progressively elevated N-IL levels; 9 alpha fluorocortisol (9 alpha fF) progressively both suppressed AP levels, and raised N-IL levels of POMC. Estimation of immunoreactive (ir) ACTH and ir-beta-endorphin in parallel samples showed an elevation of N-IL levels in response to mineralocorticoids (deoxycorticosterone, 9 alpha fF), and a paradoxical elevation of AP levels in response to glucocorticoids (dexamethasone, 9 alpha fF) compared with oil-injected adrenalectomized controls. We conclude (a) that glucocorticoids suppress the secretion of ir-ACTH and ir-beta-endorphin to a greater extent than they inhibit the synthesis of POMC; (b) that mineralocorticoids specifically elevate the N-IL levels of both POMC and its immunoreactive product (beta-endorphin).


[Ultrastructure of nerve endings of varying function in the wall of the frog urinary bladder].
Sensory and effector nerve endings were presented at ultrastructural level. Four morphological types of receptor terminals were identified that vary in peculiarities of neurilemma, organelle composition, matrix structure etc. These types were suggested to be ultrastructural equivalents for different functional states. Several types of myoneural and neuro-neural synapses and their morphological peculiarities were described. The endings explored are a part of apparatus of nervous regulation of complicated and variable functions of an organ with relatively simple structure.


Bidirectional iterative parcellation of diffusion weighted imaging data: separating cortical regions connected by the arcuate fasciculus and extreme capsule.
This paper introduces a Bidirectional Iterative Parcellation (BIP) procedure designed to identify the location and size of connected cortical regions (parcellations) at both ends of a white matter tract in diffusion weighted images. The procedure applies the FSL option "probabilistic tracking with classification targets" in a bidirectional and iterative manner. To assess the utility of BIP, we applied the procedure to the problem of parcellating a limited set of well-established gray matter seed regions associated with the dorsal (arcuate fasciculus/superior longitudinal fasciculus) and ventral (extreme capsule fiber system) white matter tracts in the language networks of 97 participants. These left hemisphere seed regions and the two white matter tracts, along with their right hemisphere homologues, provided an excellent test case for BIP because the resulting parcellations overlap and their connectivity via the arcuate fasciculi and extreme capsule fiber systems are well studied. The procedure yielded both confirmatory and novel findings. Specifically, BIP confirmed that each tract connects within the seed regions in unique, but expected ways. Novel findings included increasingly left-lateralized parcellations associated with the arcuate fasciculus/superior longitudinal fasciculus as a function of age and education. These results demonstrate that BIP is an easily implemented technique that successfully confirmed cortical connectivity patterns predicted in the literature, and has the potential to provide new insights regarding the architecture of the brain.


Empirical therapy for neonatal candidemia in very low birth weight infants.
Neonatal candidemia is often fatal. Empirical antifungal therapy is associated with improved survival in neonates and patients with fever and neutropenia. Although guidelines for empirical therapy exist for patients with fever and neutropenia, these do not exist for neonates. A multicenter, retrospective, cohort study was conducted of neonatal intensive care unit patients (N = 6172) who had a blood culture (N = 21,233) after day of life 3 and whose birth weight was <or=1250 g. We performed multivariable conditional logistic regression of risk factors for candidemia. From the regression modeling coefficients, we developed a candidemia score. In multivariable modeling, thrombocytopenia (odds ratio [OR]: 3.56; 95% confidence interval [CI]: 2.68-4.74) and cephalosporin or carbapenem use in the 7 days before obtaining the blood culture (OR: 1.77; 95% CI: 1.33-2.29) were risk factors for subsequent candidemia. Children who were 25 to 27 weeks' estimated gestational age (OR: 2.02; 95% CI: 1.52-3.05) and children who were born at <25 weeks (OR: 4.15; 95% CI: 3.12-6.29) were at higher risk of developing candidemia than were children who were born at >or=28 weeks. We developed a candidemia score on the basis of the ORs from the multivariable model. Children with a candidemia score >or=2 points were classified as having a "positive" score, and a score of >or=2 points had a sensitivity of 85% and a specificity of 47%. We developed a clinical predictive model for neonatal candidemia with high sensitivity and moderate specificity for candidemia. On the basis of our model, when a physician obtains a blood culture, the physician should consider providing antifungal therapy to neonates who are <25 weeks' estimated gestational age and to neonates who have thrombocytopenia at the time of blood culture. In addition, if a physician obtains a blood culture from a child who is 25 to 27 weeks' estimated gestational age and is not thrombocytopenic but has a history of third-generation cephalosporin or carbapenem exposure in the 7 days before the blood culture, then the physician should consider administration of empirical antifungal therapy.


Signal Reconstruction of Pulmonary Vein Recordings Using a Phenomenological Mathematical Model: Application to Pulmonary Vein Isolation Therapy.
Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is commonly initiated by ectopic beats originating from a small myocardial sleeve extending over the pulmonary veins. Pulmonary vein isolation therapy attempts to isolate the pulmonary veins from the left atrium by ablating tissue, commonly by using radiofrequency ablation. During this procedure, the cardiologist records electrical activity using a lasso catheter, and the activation pattern recorded is used as a guide toward which regions to ablate. However, poor contact between electrode and tissue can lead to important regions of electrical activity not being recorded in clinic. We reproduce these signals through the use of a phenomenological model of the cardiac action potential on a cylinder, which we fit to post-AF atrial cells, and model the bipolar electrodes of the lasso catheter by an approximation of the surface potential. The resulting activation pattern is validated by direct comparison with those of clinical recordings. A potential application of the model is to reconstruct the missing electrical activity, minimizing the impact of the information loss on the clinical procedure, and we present results to demonstrate this.


[Diurnal rhythm of sensitivity of nerve cell genome activity to changed motor regime].
Diurnal variations in the incorporation of labelled precursors of RNA and proteins into the spinal, stem, and cerebral cell populations of the rat nervous system were studied on surviving brain slices under standard conditions and during exercise by swimming. Cosinor analysis of the relative level of 3H-uridine incorporation into spinal ganglia L5, superior cervical ganglia, spinal cord L5, hypothalamic suprachiasmatic nuclei and cerebellar cortex revealed that the arrangement of the calculated acrophases of these organs in the dark period of a day. The acrophases of visual and somatosensory cortical cells were observed in the light period of a day. The calculated maximum values of the rate of 3H-leucine incorporation into nerve cell proteins (the internal acrophases ranged from 3 to 9 hours) were seen at certain intervals. Thus, the processes providing the function of a protein-synthesizing apparatus of nerve cells are characterized by a definite time organization and these processes vary significantly in their activity during a diurnal cycle. Depending on the time of a day when exercise was performed, there were differences in the changing activity of genetic and protein-synthesizing apparatuses during nerve cell reactions. This is associated with the different time of the onset of a reaction, passage of its some stages, with the rate of processes, and with the periods of normalization. The curves of a phasic response are discussed.


Effect of age and caloric restriction on bleomycin-chelatable and nonheme iron in different tissues of C57BL/6 mice.
The objective of this study was to test the hypothesis that the widely observed age-associated increase in the amounts of macromolecular oxidative damage is due to an elevation in the availability of redox-active iron, that is believed to catalyze the scission of H2O2 to generate the highly reactive hydroxyl radical. Concentrations of bleomycin-chelatable iron and nonheme iron were measured in various tissues and different regions of the brain of mice fed on ad libitum (AL) or a calorically restricted (to 60% of AL) diet at different ages. The concentrations of these two pools of iron varied markedly as a function of tissue, age, and caloric intake. There was no consistent ratio between the amounts of nonheme and the bleomycin-chelatable iron pools across these conditions. Nonheme iron concentration increased with age in the liver, kidney, heart, striatum, hippocampus, midbrain and cerebellum of AL animals, whereas bleomycin-chelatable iron increased significantly with age only in the liver. Amounts of both nonheme and bleomycin-chelatable iron remained unaltered during aging in the cerebral cortex and hindbrain of AL mice. Caloric restriction had no effect on iron concentration in the brain or heart, but caused a marked increase in the concentration of both bleomycin-chelatable and nonheme iron in the liver and the kidney. The results do not support the hypothesis that accumulation of oxidative damage with age, or its attenuation by CR, are associated with corresponding variations in redox-active iron.


Effects of low-level light therapy on hepatic antioxidant defense in acute and chronic diabetic rats.
Diabetes causes oxidative stress in the liver and other tissues prone to complications. Photobiomodulation by near infrared light (670 nm) has been shown to accelerate diabetic wound healing, improve recovery from oxidative injury in the kidney, and attenuate degeneration in retina and optic nerve. The present study tested the hypothesis that 670 nm photobiomodulation, a low-level light therapy, would attenuate oxidative stress and enhance the antioxidant protection system in the liver of a model of type I diabetes. Male Wistar rats were made diabetic with streptozotocin (50 mg/kg, ip) then exposed to 670 nm light (9 J/cm(2)) once per day for 18 days (acute) or 14 weeks (chronic). Livers were harvested, flash frozen, and then assayed for markers of oxidative stress. Light treatment was ineffective as an antioxidant therapy in chronic diabetes, but light treatment for 18 days in acutely diabetic rats resulted in the normalization of hepatic glutathione reductase and superoxide dismutase activities and a significant increase in glutathione peroxidase and glutathione-S transferase activities. The results of this study suggest that 670 nm photobiomodulation may reduce, at least in part, acute hepatic oxidative stress by enhancing the antioxidant defense system in the diabetic rat model.


Habitat mediates coevolved but not novel species interactions.
Ongoing recovery of native predators has the potential to alter species interactions, with community and ecosystem wide implications. We estimated the co-occurrence of three species of conservation and management interest from a multi-species citizen science camera trap survey. We demonstrate fundamental differences in novel and coevolved predator-prey interactions that are mediated by habitat. Specifically, we demonstrate that anthropogenic habitat modification had no influence on the expansion of the recovering native pine marten in Ireland, nor does it affect the predator's suppressive influence on an invasive prey species, the grey squirrel. By contrast, the direction of the interaction between the pine marten and a native prey species, the red squirrel, is dependent on habitat. Pine martens had a positive influence on red squirrel occurrence at a landscape scale, especially in native broadleaf woodlands. However, in areas dominated by non-native conifer plantations, the pine marten reduced red squirrel occurrence. These findings suggest that following the recovery of a native predator, the benefits of competitive release are spatially structured and habitat-specific. The potential for past and future landscape modification to alter established interactions between predators and prey has global implications in the context of the ongoing recovery of predator populations in human-modified landscapes.


Measuring dental students' ethical sensitivity.
This paper describes the development of stimulus materials and scoring procedures to measure an individual's ability to recognize the ethical issues often hidden within the dentist's professional problems. The importance of this ability is discussed as it relates to other abilities thought to be necessary conditions for ethical or moral behavior. Dental students completed the ethical sensitivity test and Rest's test of moral reasoning. The sensitivity test requires transcribing verbal responses to audio dramas, a technique that: (1) elicits sufficient data for making inferences about ethical sensitivity, (2) produces good interjudge agreement and interrater reliability, and (3) measures variability in student performance. Data indicate high internal consistency compared with previous efforts to measure components of sensitivity (e.g., empathy), acceptable test-retest reliability for a subsample. and the distinctiveness of sensitivity and reasoning scores. The results have broad application for the teaching of ethics and suggest new directions for the study of professional socialization.


Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y⁺LAT2 Carrier-Mediated Loss.
Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y⁺LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y⁺LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y⁺LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y⁺LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y⁺LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.


Nutritionally Enriched Muffins from Roselle Calyx Extract Using Response Surface Methodology.
Hibiscus sabdariffa, often called Roselle, is a flowering plant with a variety of traditional medicinal uses. Its calyx, with a bright and attractive red color, produces a tart and pleasant acidic taste. The purpose of this study was to develop a Roselle muffin and assess the acceptability, nutrition, and shelf life of the muffin using its ingredients. The muffin was developed using different formulations in different proportions resulting from Response Surface Methodology (RSM). Sensory parameters were used to assess the muffin's acceptability. According to the findings, the combination of extract volume 45.37 mL, citric acid 1.11 g, and sodium bicarbonate 1.67 g produces the best muffin, with the panelist's sensory scores reaching up to 84%. The outcome of the study suggests muffins baked with the Roselle calyx extract have high antioxidant (12.53 ± 0.13)%, anthocyanin (126.63 ± 1.96) mg Cyn-3-glu/100 g, phenolic (12.91 ± 0.69) mg GAE/100 g, and ascorbic acid (12.10 ± 0.89) mg/100 g contents. The microbial shelf life of the developed muffin is estimated to be 6 days at room temperature. The study findings can therefore be utilized in the development of foods containing Roselle calyx extract.


Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression.
One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune tolerant microenvironment. To determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1), NeuT/ATTAC mice, a conditional model of mammary fibrosis that we recently developed, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab, and drug response was monitored by tumor development, imaging mass cytometry, immunohistochemistry and tumor gene expression by RNAseq. Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1 and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors.


Towards an inhalative in vivo application of immunomodulating gelatin nanoparticles in horse-related preformulation studies.
Delivering active ingredients using biocompatible and biodegradable carriers such as gelatin nanoparticles (GNPs) to the lung constitutes a promising non-invasive route of administration. However, the pulmonary delivery of nanoparticle-based immunotherapy is still a field that requires more clarification. In this study, GNPs loaded with cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODN)-loaded and plain GNPs were aerosolised either by a conventional pressured metered dose inhaler (pMDI) or by active or passive vibrating-mesh (VM) nebulisers. GNP sizes after nebulisation by active and passive VM nebulisers were 248.2 ± 7.34 and 222.3 ± 1.42 nm, respectively. GNP concentrations after aerosolisation were found consistent and second-stage particle deposition in an impinger was up to 65.68 ± 11.2% of the nebulised dose. VM nebulisers produced high fine particle fractions, while pMDIs did not. Nebulised CpG-ODN-loaded GNPs remained capable to stimulate IL-10 release (225.2 ± 56.3 pg/ml) in vitro from equine alveolar lymphocytes. Thus, a novel system for pulmonary GNP-mediated immunotherapy in vivo was established.


A Review of Scabies: An Infestation More than Skin Deep.
Human scabies, a common infestation, has a worldwide distribution with a variable impact and presentation depending on the clinical situation. In developed, high-income settings, health institution and residential home outbreaks challenge health and social care services. In resource-poor settings, it is the downstream sequelae of staphylococcal and streptococcal bacteraemia, induced by scratching, which have a significant impact on the long-term health of communities. Over the past decade scabies has been recognised as a "neglected tropical disease" (NTD) by the World Health Organisation, has an accepted practical system of global diagnostic criteria and is being adopted into integrated programmes of mass drug administration for NTDs in field settings. This review seeks to summarise the recent advances in the understanding of scabies and highlight the advocacy and research headlines with their implication for diagnosis and management of outbreaks and individuals. In addition, it will indicate the priorities and questions that remain.


The LNK Gene Family: At the Crossroad between Light Signaling and the Circadian Clock.
Light signaling pathways interact with the circadian clock to help organisms synchronize physiological and developmental processes to periodic environmental cycles. The plant photoreceptors responsible for clock resetting have been characterized, but signaling components that link the photoreceptors to the clock remain to be identified. Members of the family of NIGHT LIGHT⁻INDUCIBLE AND CLOCK-REGULATED (LNK) genes play key roles linking light regulation of gene expression to the control of daily and seasonal rhythms in Arabidopsis thaliana. Particularly, LNK1 and LNK2 were shown to control circadian rhythms, photomorphogenic responses, and photoperiod-dependent flowering time. Here we analyze the role of the four members of the LNK family in Arabidopsis in these processes. We found that depletion of the closely related LNK3 and LNK4 in a lnk1;lnk2 mutant background affects circadian rhythms, but not other clock-regulated processes such as flowering time and seedling photomorphogenesis. Nevertheless, plants defective in all LNK genes (lnkQ quadruple mutants) display developmental alterations that lead to increased rosette size, biomass, and enhanced phototropic responses. Our work indicates that members of the LNK family have both distinctive and partially overlapping functions, and are an essential link to orchestrate light-regulated developmental processes.


Barriers to dental care for children with special needs: General dentists' perception in Kerala, India.
Special children are among the underserved dental patient groups around the globe. Oral health care for disabled children remain an unmet challenge. One out of two persons with a significant disability cannot find a professional resource to provide appropriate dental care. Identification of barriers can be the first step in addressing the deficiencies in dental care for such patients. To investigate the perception of dental practitioners in Kerala, India regarding the hurdles faced by them in providing dental care to Special Needs Children including the challenges faced by them. 149 dental professionals were interviewed through a questionnaire for their perceived barriers to provide oral health care for children with special needs. The data was obtained and Chi-square test, Pearson correlation coefficient and logistic regression model were assessed using the SPSS version 20.0. All analyses were performed using a level of 0.05 for statistical significance. Greatest barriers as perceived by the practitioners were their level of training and lack of motivation of caretakers. Significant association was found between experience of the dentist with the frequency with which they reported seeing children with special needs (pConclusion: Findings from this study provide a valid picture of barriers to access for children with special needs within general dental private practice system. Recommendations for amendment of undergraduate dental curriculum is made in order to equip future graduates to deal with this group of children better.


Loop-anchor purse-string closure of gastrotomy in NOTES(R) procedures: survival studies in a porcine model.
Transgastric NOTES(®) procedures remain without a simple method to close the gastrotomy. In four survival swine studies, we have tested a novel gastric closure device: the loop-anchor purse-string (LAPS) closure system. In four anesthetized pigs, an endoscopic gastrotomy was performed. Four loop anchors were arrayed in a 2-cm square pattern around the gastrotomy. The endoscope was passed into the abdominal cavity, and the gastrotomy was cinched closed. Procedure times ranged from 50-180 minutes. Three pigs survived 14 days. One animal was sacrificed early due to signs of sepsis. Another animal developed fevers and was treated with antibiotics. At necropsy, there were no abscesses, including in the septic animal. Histologic examination revealed evidence of healing in all animals. The LAPS system holds promise with early success in an animal model. Future human studies are needed to determine viability as a human visceral closure device.


Enhanced stimulus-induced gamma activity in humans during propofol-induced sedation.
Stimulus-induced gamma oscillations in the 30-80 Hz range have been implicated in a wide number of functions including visual processing, memory and attention. While occipital gamma-band oscillations can be pharmacologically modified in animal preparations, pharmacological modulation of stimulus-induced visual gamma oscillations has yet to be demonstrated in non-invasive human recordings. Here, in fifteen healthy humans volunteers, we probed the effects of the GABAA agonist and sedative propofol on stimulus-related gamma activity recorded with magnetoencephalography, using a simple visual grating stimulus designed to elicit gamma oscillations in the primary visual cortex. During propofol sedation as compared to the normal awake state, a significant 60% increase in stimulus-induced gamma amplitude was seen together with a 94% enhancement of stimulus-induced alpha suppression and a simultaneous reduction in the amplitude of the pattern-onset evoked response. These data demonstrate, that propofol-induced sedation is accompanied by increased stimulus-induced gamma activity providing a potential window into mechanisms of gamma-oscillation generation in humans.


Rapid palliation of symptoms with platinum-based chemotherapy plus cetuximab in recurrent oral cancer: a case report.
Symptom control is an important consideration in the choice of treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients who demonstrate objective tumour responses to platinum-based chemotherapy are more likely to have symptom relief than those who do not have such responses. A phase III trial (EXTREME) showed that adding the epidermal growth factor receptor (EGFR)-targeting IgG1 monoclonal antibody cetuximab to first-line platinum-based chemotherapy significantly prolongs progression-free and overall survival and increases response rate compared with platinum-based chemotherapy alone. We report here the case of a 60-year old female with recurrent squamous cell carcinoma of the gum who had rapid palliation of symptoms and reduction of facial disease mass following treatment with a combination of carboplatin/5-fluorouracil (5-FU) and cetuximab. The patient was diagnosed with T4N0 M0 disease of the oral cavity in November 2006 and underwent surgery, with R0 resection, followed by adjuvant radiotherapy and concomitant cisplatin chemotherapy. Around 3 months later, the disease recurred and the patient had severe pain (9/10 on a visual pain scale), marked facial oedema and a palpable facial mass of 89 mm. The patient received 4 21-day cycles of carboplatin (AUC 5), 5-FU (1,000 mg/m2/day for 4 days) and cetuximab (400 mg/m2 initial dose followed by subsequently weekly doses of 250 mg/m2), with continuation of cetuximab monotherapy at the end of this time, and pain relief with topical fentanyl and oral morphine. After 7 days of treatment, pain had reduced to 2/10, with discontinuation of morphine after 4 days, and the facial mass had reduced to 70 mm. After 2 cycles of treatment, the facial mass had decreased to 40 mm. After 3 cycles of treatment, pain and facial oedema had resolved completely and a cervical computed tomography scan showed a marked reduction in tumour mass. Cetuximab monotherapy was continued uninterrupted for 7 months. This case illustrates the rapid reduction of tumour mass and disease-associated pain and oedema that can be achieved with a combination of platinum-based chemotherapy and cetuximab in recurrent and/or metastatic SCCHN.


Possible complications of subclavian crush syndrome.
A 70-year-old woman with symptomatic Mobitz type II atrioventricular block underwent implantation of a dual-chamber pacemaker 11 years ago. The leads were inserted through a percutaneous puncture of the right subclavian vein, using standard techniques. Both leads were passive fixation leads. Due to battery failure and end of life criteria, the pulse generator (PG) had been routinely replaced six years previously. Predischarge pacemaker control revealed normal pacing, sensing thresholds and impedance for both leads. Because of a syncopal attack subsequent to lead fractures, most likely secondary to right subclavian crush syndrome (SCS) of both leads, she underwent a double lead re-implantation one year after PG replacement by access via left subclavian vein puncture. After a symptom-free period of few years she was re-analysed because of palpitations, dizziness, angina pectoris and tiredness. Pulmonary embolisation and myocardial perfusion defects were detected utilising scintigraphic techniques. Chest X-ray revealed the crushed atrial lead dislocated from the right subclavian region and lodged into the right ventricle towards the inferior septum. Because she was symptomatic, a retrieval technique was applied and the crushed atrial lead was pulled back from the right ventricle and securely fixed to its former position. On maintenance medical treatment, she remains well.


Bottleneck-mediated quasispecies restriction during spread of an RNA virus from inoculation site to brain.
The amplification of RNA viruses such as poliovirus is associated with high error rates, and the resulting diversity likely facilitates viral survival within an infected host. However, within individual tissues of infected hosts, there may be barriers to viral spread that limit genome sampling. We tested whether poliovirus population diversity was maintained during viral spread to the brain of poliovirus receptor-expressing mice. Each of four restriction enzyme site-tagged viruses was shown to be able to replicate in the mouse brain. However, when infection was initiated by i.m., i.v., or i.p. routes, only a subset of the members of the injected pool was detectable in the brain. This jackpot effect was the result of a bottleneck in viral transit from the inoculation site to the brain. The bottleneck was difficult to overcome, requiring a 10(7) increase in viral inoculum to allow representation of all or most members of the infecting pool. Therefore, the bottleneck is not likely to be a physical barrier but an antiviral state induced by a founder virus. We suggest that the innate immune response can limit viral pathogenicity by limiting the number and therefore the diversity of viruses during spread to vulnerable tissues.


Dynamical heterogeneity of suprachiasmatic nucleus neurons based on regularity and determinism.
The suprachiasmatic nucleus (SCN) is known to be the master biological clock in mammals. Despite the periodic mean firing rate, interspike interval (ISI) patterns of SCN neurons are quite complex and irregular. The aim of the present study was to investigate the existence of nonlinear determinism in the complex ISI patterns of SCN neurons. ISI sequences were recorded from 173 neurons in rat hypothalamic slice preparations using a cell-attached patch recording technique. Their correlation dimensions (D2) were estimated, and were then compared with those of the randomly-shuffled surrogate data. We found that only 16 neurons (16/173) exhibited deterministic ISI patterns of spikes. In addition, clustering analysis revealed that SCN neurons could be divided into two subgroups of neurons each having distinct values of coefficient of variation (CV) and skewness (SK). Interestingly, most deterministic SCN neurons (14/16) belonged to the group of irregularly spiking neurons having large CV and SK values. To see if the neuronal coupling mediated by the gamma-aminobutyric acid (GABA), the major neurotransmitter in the SCN, contributed to the deterministic nature, we examined the effect of the GABAA receptor antagonist bicuculline on D2 values of 56 SCN neurons. 8 SCN neurons which were originally stochastic became to exhibit deterministic characteristics after the bicuculline application. This result suggests that the deterministic nature of the SCN neurons arises not from GABAergic synaptic interactions, but likely from properties inherent to neurons themselves.


Inactivation of G(i) proteins by pertussis toxin diminishes the effectiveness of adrenergic stimuli in conduit arteries from spontaneously hypertensive rats.
Treatment with pertussis toxin (PTX) which eliminates the activity of G(i) proteins effectively reduces blood pressure (BP) and vascular resistance in spontaneously hypertensive rats (SHR). In this study we have compared the functional characteristics of isolated arteries from SHR with and without PTX-treatment (10 microg/kg i.v., 48 h before the experiment). Rings of thoracic aorta, superior mesenteric artery and main pulmonary artery were studied under isometric conditions to measure the reactivity of these vessels to receptor agonists and to transmural electrical stimuli. We have found that the treatment of SHR with PTX had no effect on endothelium-dependent relaxation of thoracic aorta induced by acetylcholine. In PTX-treated SHR, the maximum contraction of mesenteric artery to exogenous noradrenaline was reduced and the dose-response curve to cumulative concentration of noradrenaline was shifted to the right. Similarly, a reduction in the magnitude of neurogenic contractions elicited by electrical stimulation of perivascular nerves was observed in the mesenteric artery from PTX-treated SHR. PTX treatment of SHR also abolished the potentiating effect of angiotensin II on neurogenic contractions of the main pulmonary artery. These results indicate that PTX treatment markedly diminishes the effectiveness of adrenergic stimuli in vasculature of SHR. This could importantly affect BP regulation in genetic hypertension.


Action by the Customs Co-operation Council to combat illicit drug trafficking.
Since its establishment in 1953, the Customs Co-operation Council (CCC) has been actively involved in combating illicit drug trafficking. CCC has adopted legal measures designed to meet the requirements of member States in their efforts to promote the prevention, investigation and repression of customs offences, including drug smuggling. CCC studies patterns and trends in drug trafficking and promotes ways and means of detecting drug smuggling and financial transactions related to such smuggling. CCC publishes studies and handbooks that serve as practical guides to national customs administrations of member States. In its work to combat drug trafficking, the CCC co-operates with the United Nations bodies concerned with drug control and the International Criminal Police Organizations (ICPO/Interpol).


The development of the experience and anticipation of regret.
Although recent studies have established that children experience regret from around 6 years, we do not yet know when the ability to anticipate this emotion emerges, despite the importance of the anticipation of regret in decision-making. We examined whether children will anticipate they will feel regret if they were to find out in a box-choosing game that, had they made a different choice, they would have obtained a better prize. Experiment 1 replicated Guttentag and Ferrell's study in which children were asked what they hoped was in a non-chosen box. Even 8- to 9-year olds find this question difficult. However, when asked what might make them feel sadder, 7- to 8-year olds (but not younger children) predicted that finding the larger prize in the unchosen box would make them feel this way. In Experiments 2 and 3, children predicted how they would feel if the unchosen box contained either a larger or smaller prize, in order to examine anticipation of both regret and of relief. Although 6- to 7-year olds do experience regret when they find out they could have won a better prize, they do not correctly anticipate feeling this way. By around 8 years, the majority of children are able to anticipate both regret and relief.


A case-control study of Creutzfeldt-Jakob disease in Japan: transplantation of cadaveric dura mater was a risk factor.
A case-control study was conducted to reveal the relative risk of cadaveric dura mater graft transplantation for Creutzfeldt-Jakob disease. Fifty-two cases with Creutzfeldt-Jakob disease that were reported to the surveillance of the disease, and 102 age- and sex-matched hospital controls were selected. Information on family history, occupations, and medical history was collected. Eight cases and no control had a history of cadaveric dura mater graft transplantation. Surgical operations without the dura mater graft, blood transfusion, and acupuncture did not elevate the risk.


Door-to-balloon times for patients with ST-segment elevation myocardial infarction requiring interhospital transfer for primary percutaneous coronary intervention: a report from the national cardiovascular data registry.
national initiatives have reduced door-to-balloon (DTB) times for direct-arrival ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). However, STEMI patients requiring interhospital transfer for primary PCI are often excluded from public performance assessments of this quality metric. we compared DTB time improvements between 2005 and 2007 for 29,248 transfer (25%) and 86,382 direct-arrival STEMI patients treated with primary PCI at 790 hospitals in the National Cardiovascular Data Catheterization PCI Registry. Among the 165 hospitals that submitted data for ≥10 patients per year, we examined the correlation between hospital-level changes in transfer and direct-arrival DTB times. although DTB times decreased significantly over time for both groups, transfer STEMI patients had longer DTB times (median 149 vs 79 minutes, P < .0001), few received PCI ≤90 minutes (10% vs 63%, P < .0001), and the adjusted rate of DTB time improvement was slower (5% vs 9% relative decrease per year, P < .001) compared with direct-arrival patients. Larger annual transfer volume (not necessarily for primary PCI) was associated with greater improvement in transfer DTB times. However, there was no correlation between hospitals that improved direct-arrival DTB times and those that improved transfer DTB times (r = 0.094, P = .23). although there has been modest temporal improvement in DTB times, transfer patients still rarely achieve benchmark standards. Hospitals that had greater improvements in direct-arrival DTB times were not necessarily those with greater improvements in transfer DTB times. These results highlight the need for targeted system and policy approaches to improve DTB time for transferred primary PCI patients.


Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse.
A number of calcium buffers were examined for their ability to reduce evoked transmitter release when injected into the presynaptic terminal of the squid giant synapse. Injection of EGTA was virtually ineffective at reducing transmitter release, even at estimated intracellular concentrations up to 80 mM. Conversely, the buffer 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), which has an equilibrium affinity for calcium similar to that of EGTA at pH 7.2, produced a substantial reduction in transmitter release when injected presynaptically. This effect of BAPTA was reversible, presumably because the buffer diffused out of the terminal and into uninjected regions of the presynaptic axon. BAPTA derivatives with estimated intracellular calcium dissociation constants (Kd) ranging from 0.18 to 4.9 microM were effective at reducing transmitter release at similar estimated concentrations. A BAPTA derivative with an estimated intracellular Kd of 31 mM was less effective. BAPTA did not affect presynaptic action potentials or calcium spikes in ways that could explain its ability to reduce transmitter release. The relative effects of presynaptic injections of BAPTA and derivatives are consistent with the calcium-buffering capability of these compounds if the presynaptic calcium transient that triggers release is hundreds of microM or larger. The superior potency of BAPTA compared to EGTA apparently results from the faster calcium-binding kinetics of BAPTA and suggests that the calcium-binding molecule that triggers release binds calcium in considerably less than 200 microsec and is located very close to calcium channels.


Symmetric myositis and fasciitis: a complication of sickle cell anemia during vasoocclusion.
Repeated episodes of symmetric myositis and fasciitis occurred in 2 males with sickle cell anemia after prolonged painful crises. Drugs and infection could not be implicated as a cause. Histologically and therapeutically these cases differ from all other known types of myositis/fasciitis. Microscopic evidence of vasoocclusion compels consideration of an ischemic basis for this previously undescribed entity.


Prevalence of low back pain in the elderly population: a systematic review.
The aim of this study was to estimate the prevalence of low-back pain (LBP) and to identify the level of functional disability in elderly individuals in different populations. From January 1985 to October 2018, a search was performed using the following databases: Embase, LILACS, SciELO, Scopus, Medline, and the Web of Science. The descriptors were low-back pain, back pain, lower-back pain, prevalence, and elderly in Portuguese and English. Two independent reviewers conducted a search for studies and evaluated their methodological quality. The search strategy returned 2186 titles, and 35 were included in this review. The studies evaluated 135,059 elderly individuals aged between 60 and 102 years, and the prevalence of LBP ranged from 21% to 75%. The levels of functional disability, as well as functional difficulties, activities of daily living, and physical capacity, were identified in 60% of the studies. This review indicated a high prevalence of LBP in elderly individuals and functional disability that affects factors important for independence. However, the studies used different methodologies, suggesting that more studies be conducted with scientific accuracy, methodological quality, and low risk of bias to contribute to the proposal of preventive actions for elderly populations.


Plutonium Partitioning Behavior to Humic Acids from Widely Varying Soils Is Related to Carboxyl-Containing Organic Compounds.
In order to examine the influence of the HA molecular composition on the partitioning of Pu, ten different kinds of humic acids (HAs) of contrasting chemical composition, collected and extracted from different soil types around the world were equilibrated with groundwater at low Pu concentrations (10-14 M). Under mildly acidic conditions (pH ∼ 5.5), 29 ± 24% of the HAs were released as colloidal organic matter (>3 kDa to <0.45 μm), yet this HA fraction accounted for a vast majority of the bound Pu, 76 ± 13% on average. In comparison, the particulate HA fraction bound only 8 ± 4% on average of the added Pu. The truly dissolved Pu fraction was typically <1%. Pu binding was strongly and positively correlated with the concentrations of organic nitrogen in both particulate (>0.45 μm) and colloidal phases in terms of activity percentage and partitioning coefficient values (logKd). Based on molecular characterization of the HAs by solid state 13C nuclear magnetic resonance (NMR) and elemental analysis, Pu binding was correlated to the concentration of carboxylate functionalities and nitrogen groups in the particulate and colloidal phases. The much greater tendency of Pu to bind to colloidal HAs than to particulate HA has implications on whether NOM acts as a Pu source or sink during natural or man-induced episodic flooding.


Environment of care: vertical evacuation concerns for acutely ill patients and others with restricted mobility.
This perspective paper was intended to raise awareness and the urgency of needing additional evacuation-related, hospital building design policies. We addressed the challenges to maintain the integrity of exits and inadequate hospital design considerations for individuals with restricted mobility. Hospitals are occupied by people who may have restricted mobility and visitors who are likely unfamiliar with their surroundings. A hospital fire threatens all people in the building, but especially patients in the intensive care unit who are frail and have limited mobility. Evacuating immobile patients is complex, involving horizontal and vertical evacuation approaches. Hospital design must consider the needs of individuals with restricted mobility, who are the most vulnerable in case of a hospital fire. Consequently, we urge that acutely ill patients and others with restricted mobility should occupy units located on the ground floor or Level 2. In addition, when configuring the physical environment of hospitals, providing step-free ground floor access (indoor or outdoor ramps) and evacuation aids for vertical evacuation is crucial. Step-free ground floor access between Level 2 and the ground floor should be wide enough to allow transporting patients on their beds. A standard revision to include these recommendations is desperately needed.


Otolithic membranes of the saccule and utricle in man.
The otolithic membranes of the human saccule and utricle can be prepared as whole mounts or surface specimens for microscopic examination. They are not simple, homogeneous, gelatinous structures as heretofore described. Instead, each shows a definite and characteristic fibrillar design, which appears to be correlated with the known cytoarchitectural pattern of the underlying neuroepithelium.


[Problem-oriented pharmacotherapeutical education].
Teaching pharmacotherapy to students of medicine is concerned with knowledge and understanding, skills and attitudes. These elements can be communicated by using a problem-oriented decision-making process. Learning the logical steps from problem to diagnosis, treatment and result and the feedback to the diagnosis, improves the future capacity of adequately solving the individual patient's problems.


Localization and characterization of adrenergic receptors on frog skin melanophores.
The functional location of adrenergic binding sites was studied in frog skin melanophores by injecting norepinephrine (NE) outside and inside a melanophore. In 49 groups of cells (75% of the fields tested) iontophoretic injection of NE outside the cell caused melanosome aggregation in the target cell and/or in the field. In six cells in which a resting membrane potential was measured before and after intracellular injection (10-90 nA), NE elicited no change in melanosome configuration. Once the receptors were localized, the effect of temperature on these receptors was determined by measuring the reflectance of skins (an indication of melanosome aggregation or dispersion) in two populations of frogs treated with NE, Rana pipiens pipiens (with dominant alpha-receptors) and Rana berlandieri forreri (with dominant beta-receptors). NE (0.1 mM) caused melanosome aggregation in the former and dispersion in the latter tested at 12, 22, and 40 degrees C. The iontophoretic and reflectance results suggest that the binding site of the adrenergic receptor is located on the outer surface of the plasma membrane of melanophores and that alpha- and beta-receptors evoke aggregation and dispersion, respectively, within the temperature range of these experiments.


Medication errors with electronic prescribing (eP): Two views of the same picture.
Quantitative prospective methods are widely used to evaluate the impact of new technologies such as electronic prescribing (eP) on medication errors. However, they are labour-intensive and it is not always feasible to obtain pre-intervention data. Our objective was to compare the eP medication error picture obtained with retrospective quantitative and qualitative methods. The study was carried out at one English district general hospital approximately two years after implementation of an integrated electronic prescribing, administration and records system. QUANTITATIVE: A structured retrospective analysis was carried out of clinical records and medication orders for 75 randomly selected patients admitted to three wards (medicine, surgery and paediatrics) six months after eP implementation. QUALITATIVE: Eight doctors, 6 nurses, 8 pharmacy staff and 4 other staff at senior, middle and junior grades, and 19 adult patients on acute surgical and medical wards were interviewed. Staff interviews explored experiences of developing and working with the system; patient interviews focused on experiences of medicine prescribing and administration on the ward. Interview transcripts were searched systematically for accounts of medication incidents. A classification scheme was developed and applied to the errors identified in the records review. The two approaches produced similar pictures of the drug use process. Interviews identified types of error identified in the retrospective notes review plus two eP-specific errors which were not detected by record review. Interview data took less time to collect than record review, and provided rich data on the prescribing process, and reasons for delays or non-administration of medicines, including "once only" orders and "as required" medicines. The qualitative approach provided more understanding of processes, and some insights into why medication errors can happen. The method is cost-effective and could be used to supplement information from anonymous error reporting schemes.


Serum lipids and lipoproteins in insulin-dependent diabetic subjects during high-carbohydrate, high-fiber diet.
The response of blood glucose and serum lipids and lipoproteins to a high-carbohydrate, high-fiber, low-fat diet was assessed in 10 insulin-dependent diabetic subjects. The diet contained approximately 60% of calories as carbohydrate (CHO) and 20% as fat. The patients were followed for 2 wk in a metabolic ward and subsequently for 4 wk at home without changing insulin dosage. During this 6-wk period, the fasting blood glucose fell from 10.6 +/- 1.1 to 8.9 +/- 1.3 mmol/L (NS); HbA1 fell from 11.7 +/- 0.5 to 11.0 +/- 0.7% (P less than 0.05). Serum total triglyceride and very-low-density lipoprotein levels remained unchanged. After 2 wk in the ward on a high-CHO diet, total cholesterol fell by 15% (P less than 0.01), LDL cholesterol by 16% (P less than 0.001), and HDL cholesterol by 10% (P less than 0.05). The fall of HDL cholesterol was due to a decrease of HDL3 cholesterol only. After the 4-wk home period on a high-CHO diet, the observed lipoprotein changes were reversed. Heparin-releasable adipose tissue LPL activity was not influenced by a high-CHO diet. In conclusion, a high-carbohydrate, high-fiber, low-fat diet did not deteriorate the diabetic control, and it had no unfavorable effects on serum lipids or lipoproteins.


MORBIDITY, COMORBIDITY AND MULTIMORBIDITY AS PORTALS FOR SUBJECTIVE WELL-BEING AMONG OLDER PERSONS IN A RURAL NIGERIAN ENVIRONMENT: A CROSS-SECTIONAL HOSPITAL-BASED STUDY.
Subjective well-being (SWB) has been described as a new vital sign that predicts the overall health and future health status of individuals. Despite the process of natural ageing, older persons in addition suffer morbid, comorbid and multimorbid medical conditions that affect their SWB. The aim of the study was to determine the morbidity, comorbidity and multimorbidity as predictors of SWB among older persons in a rural environment of Nigeria. This was a cross-sectional study that was carried out on 214 older persons from January to December 2022 in Nigeria. Data collection was done using structured, pretested and interviewer guided questionnaire. Subjective well-being was assessed with self-rated health status questionnaire. Morbidity was determined by self-reported health problems, clinical, laboratory and radio-diagnostic methods. Co-morbidity was assessed using Self-Reported Comorbidity Questionnaire (SCQ) while multimorbidity was evaluated using multimorbidity Assessment Questionnaire for Primary Care (MAQ-PC). The study participants were aged 60-99 years with mean age of 68±4.5 years. There were 123(57.5%) females. Ninety-three(43.5%) of the study participants had good SWB. The three most common morbidities were malaria(97.2%), hypertension(69.2%) and musculo-skeletal disorders(67.8%). The commonest cardiovascular comorbidity was musculoskeletal disorders(56.1%) and one hundred and five(49.1%) of the study participants had three co-morbid chronic conditions. The prevalence of multimorbidity was 45.3%. The independent predictors of poor SWB were age≥75 years(ORs=2.103; 95%CI(1.215-4.214), P=.026); poor healthseeking behaviour(ORs=2.005; 95%CI(1.351-5.090), P=.041); presence of ≥ 3 comorbidities(ORs=3.111; 95%CI(1.465-6.910); P=.019) and presence of ≥ 3 multimorbidities(ORs=3.309; 95%CI(1.899- 7.921); P= .001). The study has shown the overall SWB of the study participants. The independent predictors of poor SWB were age ≥ 75 years, poor health seeking behaviour, presence of ≥ 3 comorbidities and multimorbidities. Health-seeking behaviours, comorbidities and multimorbidities should be explored during clinical consultations with older persons with poor SWB.


Personalizing Behavioral Interventions Through Single-Patient (N-of-1) Trials.
Behavioral interventions are typically studied with the use of a conventional between-subject randomized controlled trial (RCT) design. In this design, the effect of an intervention on one group of patients is compared with the effect of a control condition on another group of patients, such that a between-subject change is tested. A between-subject design has an underlying assumption that there is a homogenous treatment effect for a behavioral intervention, drug or psychotherapy, and that the way the intervention operates in the study that will tend to operate in the same way in many other patients. We review some of the philosophical and practical problems with the use of this design when a clinician is attempting to decide on a course of behavioral treatment aimed at within-subject change in patients who are likely to have heterogeneous or unique responses to behavioral treatment. We also review the biases inherent in our current clinical practice model, which does not use any empirical data collection or design for testing if a treatment is useful, and also in the conventional between-subject personalized medicine RCT designs. We propose increased use of single-patient (also known as N-of-1) trials that employ within-subject designs, in cases where treatment response is heterogeneous-as is the case for most psychological and behavioral treatments. Limitations of such designs include that they can only be used when the treatment is potentially reversible, the patient can act as their own control, and the outcome can be measured repeatedly. Increased use of within-subject trials may address in many more instances the more clinically relevant question of how a specific patient will respond to a specific treatment, and could introduce a more harmonious scientific approach into the way we treat our patients. We have incorporated a case presentation that illustrates the complexities of applying evidence drawn from these different designs to selecting and evaluating treatments for the behavioral issues commonly faced by clinicians and patients.


Tunable photonic crystal lens with high sensitivity of refractive index.
We design a photonic crystal (PhC) lens whose focal length is highly tunable based on the frequency sensitive super-collimation (FSSC) phenomenon. Theoretically, an analytic expression of the focal length in PhCs is derived. The diffraction could be dramatically changed by modest change in refractive index of the dielectric rods in PhCs, because the sensitivity of the equi-frequency-contours around FSSC to refractive index is several orders larger than that in common bulk material. Numerically, we demonstrate that focal length can be nearly one order larger with only 0.2% refractive index change, from 28a (a is lattice constant) to 240a. With its micro-size, high sensitivity and feasibility by on-chip technology, such tunable lens has great potentials in modern optical systems.


Morus alba L. Diminishes visceral adiposity, insulin resistance, behavioral alterations via regulation of gene expression of leptin, resistin and adiponectin in rats fed a high-cholesterol diet.
Ethanolic extract of leaves of Morus alba L. (M. alba), known as white mulberry, was orally administered (100 mg/kg b.wt) for 8 weeks to female Wistar rats that were fed a high-cholesterol diet (HCD), to investigate the potential of M. alba leaves in attenuation of obesity, dyslipidemia, insulin resistance, and deficits in mood, cognitive as well as motor activity that are linked to the adipokines secretions of visceral adipose tissue. Results showed that M. alba diminished body weight gain, hypercholesterolemia, hypertriglyceridemia, atherogenic (AI) & coronary artery indices (CRI), and ameliorated glucose level and insulin resistance index in rats on HCD, compared with untreated HCD rats. Moreover, M. alba administration significantly decreased serum leptin and resistin contents as well as their mRNA expression in visceral adipose tissue, but significantly increased serum adiponectin level, and its mRNA expression in visceral adipose tissue in rats fed on HCD, compared to those in untreated HCD group. Regarding behavioral alterations, M. alba attenuated motor deficit, declined memory, depression and anxiety-like behavior, as well in rats on HCD, compared to that noticed in untreated HCD rats. The current data showed that serum leptin and resistin showed a positive correlation with and body weight gain, triglycerides (TG), AI as well as CRI, but showed a negative correlation with exploration, declined memory, depression- and anxiety-like behavior. Conversely, serum adiponectin showed a negative correlation with and body weight gain, TG, AI as well as CRI, but showed a positive correlation with locomotor activity, exploration, declined memory, and depression- and anxiety-like behavior. In conclusion, M. alba leaves supplementation could attenuate adiposity, insulin resistance behavioral deficits via down-regulation of regulation of gene expression of leptin, resistin, but up-regulation of adiponectin gene expression in the visceral adipose tissue of rats fed a high-cholesterol diet.


Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.
Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.


Isolated familial plasminogen deficiency may not be a risk factor for thrombosis.
Despite many reports of individuals with congenital plasminogen deficiency and thrombosis, there is still uncertainty whether heterozygous deficiency represents a real thrombophilic risk factor or simply a coincidental finding. We have addressed this issue by testing for plasminogen deficiency in a cohort of 9611 blood donors. Out of 66 donors with reduced plasminogen activity on two occasions 28 were shown to have a familial deficiency state (including 3 with dysplasminogenaemia). Our observed prevalence rate for familial plasminogen deficiency, calculated at 2.9/1000 (95% CI = 1.9-4.2 per 1000), was not significantly different from that calculated from published reports of congenital plasminogen deficiency in thrombotic cohorts (5.4/1000). Furthermore, with only two exceptions, all 80 donors and relatives with familial deficiency were asymptomatic with regard to thrombosis-including a 29 year old donor with suspected compound heterozygous hypoplasminogenaemia. These findings add further weight to the argument that familial heterozygous plasminogen deficiency, at least in isolation, does not constitute a significant thrombotic risk factor. However, it remains uncertain whether plasminogen deficiency, when combined with other thrombophilic conditions, may become more clinically important.


Genetic variation and origin of parthenogenesis in the Aspidoscelis cozumela complex: evidence from mitochondrial genes.
Parthenogenesis is a form of clonal reproduction. Eggs develop in the absence of sperm and offspring are genetically identical to their mother. Although common in invertebrates, it occurs in only a few species of squamate reptiles. Parthenogenetic reptiles have their origin in interspecific hybridization, and their populations are exclusively female. Because of its high mutation rate and maternal inheritance, mitochondrial DNA sequence data can evaluate the origin and evolution of all-female vertebrates. Partial sequences from two mitochondrial genes, Cytb and ND4, were analyzed to investigate questions about the origin of parthenogenesis in the Aspidoscelis cozumela complex, which includes A. cozumela, A. maslini and A. rodecki. Low levels of divergence were detected among parthenogenetic species, and between them and A. angusticeps, confirming it as the maternal species of the parthenoforms. A gene tree was constructed using sequences from three populations of A. angusticeps and nine of its unisexual daughter species. The phylogeny suggests that two independent hybridization events between A. angusticeps and A. deppii formed three unisexual species. One hybridization resulted in A. rodecki and the other formed A. maslini and A. cozumela. Although A. cozumela has the haplotype characteristic of A. maslini from Puerto Morelos, it is considered to be a different species based on karyological and morphological characteristics and its geographical isolation.


Surface softening in palladium nanoparticles: effects of a capping agent on vibrational properties.
The presence of a capping agent (CTAB) on Pd nanoparticles produces a strong static disorder in the surface region. This results in a surface softening, which contributes to an overall increase in the Debye-Waller coefficient measured by X-ray powder diffraction. Molecular dynamics and density functional theory simulations show that the adsorption-induced surface disorder is strong enough to overcome the effects of nanoparticle size and shape.


Does Humeral Component Version Affect Range of Motion and Clinical Outcomes in Reverse Total Shoulder Arthroplasty? A Systematic Review.
Prosthesis selection, design, and placement in reverse total shoulder arthroplasty (RTSA) affect post-operative results. The aim of this systematic review was to evaluate the influence of the humeral stem version and prosthesis design (inlay vs. onlay) on shoulder function following RTSA. A systematic review of the literature on post-operative range of motion (ROM) and functional scores following RTSA with specifically known humeral stem implantations was performed using MEDLINE, Pubmed, and Embase databases, and the Cochrane Library. Functional scores included were Constant scores (CSs) and/or American Shoulder and Elbow Surgeons (ASES) scores. The patients were organised into three separate groups based on the implanted version of their humeral stem: (1) less than 20° of retroversion, (2) 20° of retroversion, and (3) greater than 20° of retroversion. Data from 14 studies and a total of 1221 shoulders were eligible for analysis. Patients with a humeral stem implanted at 20° of retroversion had similar post-operative mean ASES (75.8 points) and absolute CS (68.1 points) compared to the group with humeral stems implanted at less than 20° of retroversion (76 points and 62.5 points; p = 0.956 and p = 0.153) and those implanted at more than 20° of retroversion (73.3 points; p = 0.682). Subjects with humeral stem retroversion at greater than 20° tended towards greater active forward elevation and external rotation compared with the group at 20° of retroversion (p = 0.462) and those with less than 20° of retroversion (p = 0.192). Patients with an onlay-type RTSA showed statistically significantly higher mean post-operative internal rotation compared to patients with inlay-type RTSA designs (p = 0.048). Other functional scores and forward elevation results favoured the onlay-types, but greater external rotation was seen in inlay-type RTSA designs (p = 0.382). Humeral stem implantation in RTSA at 20° of retroversion and greater appears to be associated with higher post-operative outcome scores and a greater range of motion when compared with a retroversion of less than 20°. Within these studies, onlay-type RTSA designs were associated with greater forward elevation but less external rotation when compared to inlay-type designs. However, none of the differences in outcome scores and range of motion between the humeral version groups were statistically significant.


An observational study of Yasmin in the management of women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is the commonest endocrine disturbance affecting women in the reproductive age group and encompasses signs of hyperandrogenism, menstrual cycle disturbances and obesity. Some of the symptoms of PCOS may be ameliorated by the combined oral contraceptive pill (COCP). A pilot observational study was carried out in a university teaching hospital setting to determine whether the clinical and biochemical features of PCOS are ameliorated by a new COCP, Yasmin, which contains a new progestogen, drosperinone. Treatment with Yasmin was given for 6 months to 17 patients. Thirteen patients (76%) completed 6 months of therapy. Good cycle control was achieved in all patients. Percentage body fat increased, with no overall change in body mass index. Fasting insulin and triglyceride concentrations rose significantly. Serum total testosterone concentrations fell with a concomitant rise in sex hormone binding globulin levels. Hirsutism scores did not change significantly in the 12 women who were clinically hirsute. There was, however, a significant improvement in the acne scores. Four of the 17 patients dropped out of the trial between Cycles 3 and 5 due to side effects. Yasmin provides good cycle control for women with PCOS, with an improvement in acne over 6 months but not in other symptoms of the syndrome.


Robust Epileptic Seizure Detection Using Long Short-Term Memory and Feature Fusion of Compressed Time-Frequency EEG Images.
Epilepsy is a prevalent neurological disorder with considerable risks, including physical impairment and irreversible brain damage from seizures. Given these challenges, the urgency for prompt and accurate seizure detection cannot be overstated. Traditionally, experts have relied on manual EEG signal analyses for seizure detection, which is labor-intensive and prone to human error. Recognizing this limitation, the rise in deep learning methods has been heralded as a promising avenue, offering more refined diagnostic precision. On the other hand, the prevailing challenge in many models is their constrained emphasis on specific domains, potentially diminishing their robustness and precision in complex real-world environments. This paper presents a novel model that seamlessly integrates the salient features from the time-frequency domain along with pivotal statistical attributes derived from EEG signals. This fusion process involves the integration of essential statistics, including the mean, median, and variance, combined with the rich data from compressed time-frequency (CWT) images processed using autoencoders. This multidimensional feature set provides a robust foundation for subsequent analytic steps. A long short-term memory (LSTM) network, meticulously optimized for the renowned Bonn Epilepsy dataset, was used to enhance the capability of the proposed model. Preliminary evaluations underscore the prowess of the proposed model: a remarkable 100% accuracy in most of the binary classifications, exceeding 95% accuracy in three-class and four-class challenges, and a commendable rate, exceeding 93.5% for the five-class classification.


An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.
RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1-ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3΄ site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping.


A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS.
Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.


The interactions between integrin α5β1 of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis.
Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α5β1 from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α5β1, which greatly promoted cell growth in 3D microstructures. Integrin-α5 was more sensitive and specific than integrin-β1 in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α5β1 dependent manner. Furthermore, fibronectin, integrin-α5, and integrin-β1 were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α5, and integrin-β1 as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment.


Appearance of new phage types and new lysogenic strains after adaptation of lysogenic B. megatherium to ammonium sulfate culture medium.
1. Lysogenic B. megatherium 899a was adapted to growth in a minimal ammonium sulfate medium (ASCM). 2. Adaptation took place slowly and the following changes in the culture occurred: (a) The growth rate increased from 0.5 to 1.5-2.0/hr. (b) The culture changed from diffuse to mucoid. (c) The total phage titer, and the gelatinase concentration decreased to 1/100 or less. (d) The types of phage produced changed from >99 per cent T (wild type) to 30 to 60 per cent miscellaneous clear types. The original T phage was replaced by a different smaller t, never observed in the original 899a culture. (e) Several new colony types also appeared, but the colony morphology was not correlated with the phage types produced. None of the colony types was stable on repeated transfer either in peptone or ASCM, but continued to disassociate into different colony types (cf. Ivánovics, 1955). 3. Control experiments showed that these changes in phage production and colony types could not be brought about by growing sensitive B. megatherium in the presence of the various new phages, in ASCM. It is therefore unlikely that the changes observed in adapted culture were due to infection of a sensitive cell with phage. 4. Continued growth of the ASCM-adapted strain in peptone resulted in increasing the total phage titer, and also the gelatinase concentration. The growth rate returned to its original value and the ability to grow rapidly in ASCM was soon lost. The phage types, however, remained the same as in the ASCM. 5. An improved cell for steady state growth is described.


Randomized study of etirinotecan pegol versus irinotecan as second-line treatment for metastatic colorectal cancer.
Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC). Patients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1). The study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40-1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56-1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively. EP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC.


Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.
On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol.


Ultrastructural Immunocytochemical Abnormalities of Peripheral Myelin Proteins in Hereditary Sensory-Motor Neuropathies: 12 cases.
Hereditary sensorimotor neuropathies form a heterogeneous group of genetically determined diseases, of which Charcot-Marie-Tooth (CMT) disease is the most common. In order to establish relations between genotype and the expression of peripheral myelin proteins, we carried out a quantitative study by ultrastructural immunocytochemistry of several myelin proteins (PMP22, P0, MBP) on sural nerve biopsy samples from 12 unrelated CMT patients. The diagnosis of CMT was based on the clinical, electrophysiological, and histological findings along with those of molecular biological studies. CMT X diagnoses were not included in this study. The expression of myelin proteins was well correlated with the molecular biological findings in these patients. The results also provided evidence for interference between different myelin proteins. Our findings are in line with the results from animal studies (trembler and knock-out mice), which may provide insights into the pathogenesis of these human conditions.


Studies on the induction of tolerance to alloantigens. III. Induction of antibodies directed against alloantigen-specific delayed-type hypersensitivity T cells by a single injection of allogeneic lymphocytes via portal venous route.
BALB/c mice were inoculated with normal C3H/He spleen cells via the portal venous (p.v.) route. Intravenous injection of serum from these BALB/c mice into naive syngeneic mice resulted in almost complete abrogation of their ability to generate anti-C3H/He delayed-type hypersensitivity (DTH) responses as induced by s.c. immunization with C3H/He cells. Since a portion of the same serum did not inhibit the development of anti-C57BL/6 DTH responses, the suppressive effect of the transferred serum was alloantigen-specific. Such serum factor(s) was produced in normal but not in nude mice and the suppressive activity was transferred in H-2- or immunoglobulin allotype-incompatible combinations. Immunochemical analyses of this serum suppressive factor have revealed that its m.w. was approximately 150,000, corresponding to the size of immunoglobulin (Ig)G, and that the activity was trapped by protein A or by an anti-immunoglobulin column. Although the absorption of the serum from anti-C3H/He-tolerant BALB/c mice with C3H/He target spleen cells did not abrogate the suppressive activity, the additional absorption with spleen cells from anti-C3H/He hyperimmune BALB/c mice almost completely eliminated the suppressive potential. Moreover, pretreatment of BALB/c anti-C3H/He DTH effector spleen cells with the above serum from tolerant mice induced the inhibition of anti-C3H/He DTH responses. Taken together, these results indicate that a single injection of allogeneic cells via the p.v. route results in the production of antibody capable of inhibiting the capacity of DTH effector cells specific for alloantigens used for the p.v. presensitization.


Bilayers connected by threadlike micelles in amphiphilic mixtures: a self-consistent field theory study.
Binary mixtures of amphiphiles in solution can self-assemble into a wide range of structures when the two species individually form aggregates of different curvatures. A specific example of this is seen in solutions of lipid mixtures where the two species form lamellar structures and spherical micelles, respectively. Here, vesicles connected by threadlike micelles can form in a narrow concentration range of the sphere-forming lipid. We present a study of these structures based on self-consistent field theory (SCFT), a coarse-grained model of amphiphiles. First, we show that the addition of sphere-forming lipid to a solution of lamella-former can lower the free energy of cylindrical, threadlike micelles and hence encourage their formation. Next, we demonstrate the coupling between composition and curvature; specifically, that increasing the concentration of sphere-former in a system of two bilayers connected by a thread leads to a transfer of amphiphile to the thread. We further show that the two species are segregated within the structure, with the concentration of sphere-former being significantly higher in the thread. Finally, the addition of larger amounts of sphere-former is found to destabilize the junctions linking the bilayers to the cylindrical micelle, leading to a breakdown of the connected structures. The degree of segregation of the amphiphiles and the amount of sphere-former required to destabilize the junctions is shown to be sensitive to the length of the hydrophilic block of the sphere-forming amphiphiles.


Maize from an adena mound in athens county, ohio.
The discovery of a carbonized ear of maize in an Adena burial mound at Athens, Athens County, Ohio, is the first indisputable evidence of Adena maize horticulture. The mound contained typical middle Adena features, including a bark prepared burial, and has yielded charcoal radiocarbon dated at 280 B.C. +/- 140 years.


[Machina Machinarum. The clock as a concept and metaphor between 1450 and 1750].
The changing use of the clock metaphor serves as a helpful contrast medium to highlight the different concepts of the body-soul-system between 1450 and 1750. This article first relates to the social, political and philosophical functions of the horologium. Then it outlines the different fields of discourse, in which the clock metaphor was mainly invoked. Finally, it examines the writings of a number of significant authors (Cusanus, Ficino, Descartes, Leibniz, Wolff, La Mettrie) with an eye to the evolution of the clock metaphor in various theological, metaphysical and physiological contexts. Surprisingly enough, the clock (or watch) initially represented the life-giving soul and human consciousness, before turning into the well-known symbol for the body-machine, and in particular for its neurophysiological operations.


The effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract NPDR and its effect on fundus microcirculation and blood ICAM-1, MCP-1 and MIF levels.
To explore the effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract complicated with non-proliferative diabetic retinopathy (NPDR) and its effects on fundus microcirculation, intercellular adhesion molecule 1 (ICAM-1), mono - cyte chemoattractant protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). From March 2019 to January 2021, a total of 114 patients with cataract and NPDR were included, and the patients were assigned into the control and the observation groups by random number table method, with 57 cases/group. The control was given hypoglycemic drugs, and the observation was given calcium dobesilate combined therapy. The therapeutic efficacy, blood glucose and blood lipid levels, fluorescein fundus angiography results, fundus microcirculation indexes, retinal neovascularizationrelated factors, and ICAM-1, MCP-1, and MIF levels before and after treatment were compared between the two groups. The total effective rate of treatment in the observation was higher vs. the control (P < 0.05); Fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) in the observation after treatment were reduced vs. the control (P < 0.05); The number of micro-hemangiomas in the observation after treatment was less vs. the control, and the area of hemorrhage, the area of exudation and the thickness of the yellow plate were smaller vs. the control (P < 0.05); The resistance index (RI) value of the observation after treatment was lower than the control, and the end-diastolic blood flow velocity (EDV) and the peak systolic blood flow velocity (PSV) of the observation were higher vs. the control (P < 0.05). ICAM-1, MCP-1, MIF, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1) in the observation after treatment were reduced vs. the control, but pigment epithelium-derived factor (PEDF) were higher vs. the control (P < 0.05); one case of gastrointestinal reaction took place in the observation, but no adverse reaction occurred in the control, and no clear difference exhibited in the incidence of adverse reactions between the two groups (P > 0.05). Calcium dobesilate combined with hypoglycemic drugs has good clinical efficacy in the treatment of cataract complicated with NPDR, which can effectively reduce the level of blood glucose and blood lipids, reduce inflammation, and mitigate the microcirculation of branch retinal vein occlusion lesions.


A novel computational strategy for defining the minimal protein molecular surface representation.
Most proteins perform their biological function by interacting with one or more molecular partners. In this respect, characterizing local features of the molecular surface, that can potentially be involved in the interaction with other molecules, represents a step forward in the investigation of the mechanisms of recognition and binding between molecules. Predictive methods often rely on extensive samplings of molecular patches with the aim to identify hot spots on the surface. In this framework, analysis of large proteins and/or many molecular dynamics frames is often unfeasible due to the high computational cost. Thus, finding optimal ways to reduce the number of points to be sampled maintaining the biological information (including the surface shape) carried by the molecular surface is pivotal. In this perspective, we here present a new theoretical and computational algorithm with the aim of defining a set of molecular surfaces composed of points not uniformly distributed in space, in such a way as to maximize the information of the overall shape of the molecule by minimizing the number of total points. We test our procedure's ability in recognizing hot-spots by describing the local shape properties of portions of molecular surfaces through a recently developed method based on the formalism of 2D Zernike polynomials. The results of this work show the ability of the proposed algorithm to preserve the key information of the molecular surface using a reduced number of points compared to the complete surface, where all points of the surface are used for the description. In fact, the methodology shows a significant gain of the information stored in the sampling procedure compared to uniform random sampling.


The Impact of Land Use Transformations on Zooplankton Communities in a Small Mountain River (The Corgo River, Northern Portugal).
Transformation of the river catchment and the river bed cause significant changes in the functioning of river ecosystems. The main effects of anthropogenic transformations are hydrological changes, such as lower current velocity or an increase of nutrient content, and higher temperature. Zooplankton reacts rapidly to the new environmental conditions in rivers, increasing its richness and abundance. We tried to answer two questions: what type of catchment use has a greater influence on the zooplankton communities in a river and how do dam impoundments influence the zooplankton communities downstream? The study was conducted in the Corgo river (drainage of the Douro river, Northern Portugal) at 17 sampling sites in the lotic, free-flowing sections. Crustaceans present in the Corgo can attain relatively high densities in the rural section, which offers them better trophic conditions. The urban catchment use and the presence of dams have a greater impact on the rotifer density and the increase of zooplankton density downstream. The results of this study confirm that zooplankton properties allow for the evaluation of the degree of river-bed transformation.


Women's health: where are nurse practitioner programs headed?
Until quite recently, the discipline of women's health has been restricted to reproductive health. While graduate nurse practitioner (NP) programs have included issues across the life cycle and health promotion in their curricula, there is growing emphasis on primary care of women. Graduate nursing programs that offer women's health and obstetric/gynecologic NP tracks were surveyed in 1996 to elicit content in the curriculum and to ascertain whether changes in requirements for certification were impacting programs. Programs listed in the 1994 National Organization of Nurse Practitioner Faculties directory (NONPF) were surveyed. Twenty-eight of 31 programs responded; results were tallied by frequency distribution. Results documented differences in programs, suggesting that a clear definition of women's health advanced practice is needed. The author recommends a national dialog to explore advanced practice in women's health and asks if there should be two types of NP programs--primary care of women (a generalist NP) and reproductive health (a specialist NP)--and how NP programs and credentialing bodies should differentiate graduate programs as well as content for certification exams.