Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation.
Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.


Cochlear implant failure: diagnosis and treatment of soft failures.
Early diagnosis of cochlear implant failures (CIF) is a critical part of post-implantation follow-up. Diagnosis is challenging and time consuming. Our study aimed to describe diagnoses of CIF with emphasis on soft failures (SF), focusing on symptoms, time from symptoms to replacement, and differences between SF and hard failures (HF). A retrospective review of medical records in a tertiary care referral paediatric medical centre including all patients who experienced CIF during 2000-2020. Of 1004 CI surgeries, 72 (7.2%) cases of CIF were included, of which 60 CIF were in children (mean age 3.1 years). Twenty-five cases were due to HF, 26 SF, and 21 due to medical reasons. Patients with SF were more likely to present with headache, dizziness, or tinnitus compared with those with HF. Facial stimulation and disconnections were more common in implants from Advanced Bionics, dizziness and tinnitus in Cochlear, and poor progression in Med-El. Mean time from symptoms to implant replacement surgery was longer in cases with SF compared to HF. SF poses a diagnostic challenge. Symptoms such as headache, dizziness, and tinnitus are common. Diagnosis of failure should often be based on assessments of the implant and rehabilitation teams.


Cingulo-hippocampal effective connectivity positively correlates with drug-cue attentional bias in opioid use disorder.
Individuals with opioid use disorder (OUD) often relapse when exposed to opioid-related cues. Previous functional magnetic resonance imaging (fMRI) studies have identified neuronal corticolimbic changes related to drug cue reactivity in OUD. However, the corresponding manner in which brain regions interact is still unclear. Effective (directional) connectivity was analyzed using dynamic causal modeling of fMRI data acquired from 27 OUD participants (13 with OUD and 14 with OUD and cocaine use disorder [OUD+CUD]), while performing an opioid-word Stroop task. Participants were shown opioid and neutral words presented in different colors and were instructed to indicate word color but ignore word meaning. The effects of opioid words relative to neutral words on effective connectivity and on behavioral reaction time were defined as modulatory change and attentional bias, respectively. For all the 27 participants, left anterior cingulate cortex (ACC) to right hippocampus effective connectivity exhibited the largest modulatory change, which was positively correlated with attentional bias. The findings for the ACC to hippocampus EC were consistent across OUD and CUD found in a previous study.


Dog intestinal mucosa contains two vitamin D-stimulating calcium binding proteins.
Dog intestinal mucosa has been found to contain more than one vitamin D-responsive calcium-binding protein (CaBP). Duodenal and upper jejunal mucosa contains a protein that has a mol wt of 19,000 and a Kd of 1.2 microM, and that increases in activity over twofold after administration of 1,25 (OH)2 vitamin D3. This protein could not be demonstrated in ileal tissue. In ileal mucosa all the calcium binding activity resides in fractions that elute from Sephadex G200 with a mol wt of about 57,000. Calcium-binding activity was demonstrated in gel electrophoresis corresponding to a protein with an Rf of about 0.5, unlike the small CaBP, which has an Rf of 1.0. The calcium-binding activity from the ileum was demonstrated to coincide with a protein band on acrylamide gel electrophoresis, and to be destroyed by pronase. This large CaBP responded to 1,25 (OH02 vitamin D3 by increasing activity by about 50%, and was inhibited similarly to the small protein by Sr, Ba, and Mg. Neither fresh tissue homogenates, nor explants cultured up to 20 hr showed any evidence of the small CaBP on disc gel acrylamide electrophoresis. The small CaBP could be demonstrated on gel electrophoresis only in tissue that was partially autolyzed or was treated with a 10% (milligrams per milligram) solution of trypsin. The small CaBP was relatively resistant to trypsin. It is suggested that the small CaBP may be derived at least in part from the large protein.


Ethical considerations in pandemic influenza planning.
Although the timing and severity of the next influenza pandemic is impossible to predict, there is broad agreement that one will occur. Preparation is vital to mitigating its effects. A severe influenza pandemic like that which began in 1918 would be unlike other disasters in nature, scale, and duration. It could cripple normal business operations and disrupt global distribution of essential goods and services. It could force ethical decisions that many in a country accustomed to relative abundance are poorly prepared to make. Although sound evidence and clinical and public health expertise are needed to make informed decisions, so is an understanding of our common and diverse values. This article outlines some of the challenges the state would face during a pandemic, especially concerning the rationing of resources and care. It also describes a process currently underway to develop guidelines for how the state should approach the ethical questions that would arise.


[Juvenile primary fibromyalgia syndrome--review].
Fibromyalgia syndrome is known to cause significant morbidity among adults characterised by widespread musculoskeletal pain, stiffness, fatigue, non-restorative sleep, cognitive dysfunction and diminished physical function. Although well-recognised in adults, the impact of the syndrome in the paediatric population has only recently been addressed. The estimated prevalence of juvenile primary fibromyalgia syndrome (JPFS) is 1.2%-6.2%. Prevalence is higher in girls than boys, and peaks at the time of puberty. JPFS is of unknown aetiology, characterised by numerous symptoms that mimic the symptoms of adult fibromyalgia syndrome, the most prevalent being sleep disturbance, widespread persistent musculoskeletal pain and fatigue. JPFS has a major influence on health, physical function and quality of life. The diagnosis of JPFS is based on the criteria defined by Yunus and Masi (1985), which include generalised musculoskeletal aching at three or more regions for at least three months and at least five of eighteen typical tender points. The precise cause of JPFS is unknown, but there is an emerging understanding that the development of this syndrome is related to many factors, such as genetic and anatomic factors, disordered sleep and psychological distress. According to emerging studies, a multidisciplinary treatment may be helpful in treating JPFS. Multicomponent treatment that includes attendance by patient and parents, sleep hygiene with or without medication, physical training and cognitive behavioural therapy, is advocated.


Visualizing sphingolipid biosynthesis in cells.
Biosynthetic pathways play a fundamental role in the building and operation of the cell by synthesizing the constituents by which the cell is constructed, and by producing signalling intermediates that play a key role in cell regulation. While a lot is known about the metabolite profile of the cells and about the biochemical pathways through which these metabolites are produced, the cellular localization of the biosynthetic machineries and the importance of this localization to the regulation of the metabolism has often been given less attention. This derives from the fact that, for several of these pathways, the enzymes involved are found colocalized in one compartment where their specific localization is unlikely to influence their function. The sphingolipid (SL) metabolic pathway is a notable exception to this as SL synthetic enzymes are laid out on a specific pattern across the secretory compartments. Such compartmentalized organization of the SL synthesis has functional implications as it makes the fine-tuned regulation of the process possible by allowing cells to regulate specific segments of the pathway in response to stimuli and for adaptation. The organization, dynamics, and regulation of the SLs and their biosynthetic machinery have been investigated using imaging-based methods. Here we provide a brief introduction to the techniques that have been or that could be employed to visualize the SL biosynthetic machinery and SLs themselves and discuss the insights provided by these studies in understanding this metabolism.


Comparative efficacy and safety of cefprozil and cefaclor in the treatment of acute uncomplicated urinary tract infections.
Cefprozil is a new oral semi-synthetic cephalosporin with broad antibacterial spectrum and prolonged serum elimination half-life. In vitro, cefprozil demonstrates excellent activity against common urinary tract pathogens such as Escherichia coli and Klebsiella pneumoniae. Cefprozil, 500 mg once a day, was compared to cefaclor, 250 mg three times a day, in an open, randomized, comparative, clinical trial for the treatment of acute, uncomplicated, urinary tract infection. One hundred and two adult patients were eligible for safety evaluation; four patients were excluded due to side-effects (abdominal discomfort, nausea and vomiting). Ninety-eight patients were eligible for evaluation of efficacy. Clinical and bacteriological responses were comparable for both antibiotics. Leucopenia, nausea, and vaginal yeast infections were slightly more common in the cefprozil group. Cefprozil, 500 mg once daily, appears to be an appropriate alternative for the treatment of acute, uncomplicated urinary tract infections.


Separation of morphine analgesia from physical dependence.
Intravenous infusion of morphine sulfate in rats for 24 hours produced marked opioid dependence, manifested by a series of well-documented signs appearing after injection of the opiate antagonist naloxone. Treatment of rats with naloxonazine significantly reduced the analgesia associated with the morphine infusions for more than 24 hours. Furthermore, 14 of 16 withdrawal signs observed in naloxonazine-treated rats were virtually identical to those in rats that received morphine alone. These results raise the possibility that different receptor mechanisms mediate morphine analgesia and many of the withdrawal signs associated with morphine dependence.


Independent origin of sex chromosomes in two species of the genus Silene.
Here we introduce a new model species, Silene colpophylla, that could facilitate research of sex chromosome evolution and sex-determining systems. This species is related to the well-established dioecious plant model Silene latifolia. Our results show that S. colpophylla is, similarly to S. latifolia, a male heterogametic species, but its sex chromosomes have evolved from a different pair of autosomes than in S. latifolia. The results of our phylogenetic study and mapping of homologs of S. latifolia X-linked genes indicate that the sex determination system in S. colpophylla evolved independently from that in S. latifolia. We assert that this model species pair will make it possible to study two independent patterns of sex chromosome evolution in related species.


Multilocus DNA sequence analysis shows that Penicillium biourgeianum is a distinct species closely related to P. brevicompactum and P. olsonii.
Penicillium brevicompactum and other isolates with the compact, complex conidiogenous apparatus typical of the species were sequenced in one ribosomal and two protein coding regions. The aligned DNA sequences were analyzed by maximum parsimony and the data from different loci were tested for compatibility using the partition homogeneity test. Analysis of each of the three loci revealed three clades corresponding to P. brevicompactum, P. olsonii and P. biourgeianum. Using the phylogenetic species concept and the genetic isolation of the clades, P. hagemi, P. patrismei, P. stoloniferum, and P. griseobrunneum are all synonyms of P. brevicompactum. P. volgaense is a synonym of Penicillium olsonii, while P. biourgeianum is a distinct species closely related to P. brevicompactum and P. olsonii. Phenotypic distinctions between the species are mostly based on colony characteristics such as colour. P. bialowiezenze, often treated as a synonym of P. brevicompactum, is most closely related to P. polonicum.


Long-term follow-up clinics after hematopoietic cell transplantation: its needs and challenges in Japan.
With a growing number of transplant survivors, long-term survivorship care has received more attention. In long-term survivors, mortality remains higher than that of the general population, and they are prone to a unique set of late complications. The common late effects are as follows: chronic graft-versus-host disease, organ failure, endocrine complication, secondary cancer, mental health problem, and financial burden due to factors including unemployment. Long-term follow-up (LTFU) clinic plays an important role in the screening and early intervention for late effects and in informing and supporting patients to improve their quality of life. The importance of LTFU has been recognized, and the guidelines for screening and preventive practices for long-term survivors after transplantation were first published in 2006 and updated in 2012 based on a consensus opinion of the international working group. The guidelines for LTFU have been recently published by the Japan society for hematopoietic cell transplantation; they highlight the recommended screening and intervention available in our country, utilizing the evidence on the late effects reported from our country and overseas. In this review, I would like to illustrate the background of the need for LTFU and discuss the challenges in operating an LTFU clinic to effectively provide physical, mental, and social care to transplant survivors.


Absence of rickets in infants with fatal abusive head trauma and classic metaphyseal lesions.
To determine if rickets is present in cases of infant homicide with classic metaphyseal lesions (CMLs) and other skeletal injuries. This study was exempt from the institutional human subjects board review because all infants were deceased. An archival review (1984-2012) was performed of the radiologic and histopathologic findings of 46 consecutive infant fatalities referred from the state medical examiner's office for the evaluation of possible child abuse. Thirty infants with distal femoral histologic material were identified. Additional inclusion criteria were as follows: (a) The medical examiner determined that the infant had sustained a head injury and that the manner of death was a homicide, (b) at least one CML was evident at skeletal survey, (c) CMLs were confirmed at autopsy, and (d) non-CML fractures were also present. Nine infants (mean age, 3.9 months; age range, 1-9 months) were identified. Two pediatric radiologists independently reviewed the skeletal surveys for rachitic changes at the wrists and knees. A bone and soft tissue pathologist reviewed the distal femoral histologic slices for rickets. There were no radiographic or pathologic features of rickets in the cohort. The findings provide no support for the view that the CML is due to rickets. Rather, they strengthen a robust literature that states that the CML is a traumatic injury commonly encountered in physically abused infants.


[Syndrome of high-altitude hypertrophic cardiomyopathy].
The authors report the clinical, ECG, PCG and echocardiography data obtained in mountaineers suffering from associated essential hypertension and high-altitude pulmonary hypertension. Demonstrate the advisability of distinguishing the high-altitude hypertrophic cardiomyopathy syndrome (HHCS) in part of mountaineers with essential hypertension living permanently at an altitude of 3600-4200 m over the sea level. The HHCS is marked by a lot of the clinical and echocardiographic signs which are regarded as characteristic of hypertrophic cardiomyopathy, particularly by appreciable asymmetrical hypertrophy of the interventricular septum. Criteria for the differential diagnosis between the HHCS and idiopathic hypertrophic subaortic stenosis are suggested. The possible mechanisms by which the HHCS develops in part of mountaineers are discussed.


Heat-Processed Scutellariae Radix Enhances Anti-Inflammatory Effect against Lipopolysaccharide-Induced Acute Lung Injury in Mice via NF- κ B Signaling.
The present study was conducted to examine whether heat-processed Scutellariae Radix has an ameliorative effect on lipopolysaccharide- (LPS-) induced acute lung injury in mice. The effects of Scutellariae Radix heat-processed at 160°C (HSR) were compared with those of nonheat-processed Scutellariae Radix (NSR). The LPS-treated group displayed a markedly decreased body weight and significantly increased lung weight; however, the administration of NSR or HSR improved both the body and lung weights. The increased oxidative stress and inflammatory biomarker levels in the serum and lung were reduced significantly with HSR. The reduced superoxide dismutase and catalase increased significantly by both NSR and HSR. Also, the dysregulated oxidative stress and inflammation were significantly ameliorated by NSR and HSR. The expression of inflammatory mediators and cytokines by nuclear factor-kappa B activation was modulated through inhibition of a nuclear factor kappa Bα degradation. Also, lung histological change was markedly suppressed by HSR rather than NSR. Overall, the ameliorative effects of HSR were superior to those when being nonheat-processed. The representative flavonoid contents of Scutellariae Radix that include baicalin, baicalein, and wogonin were greater by heat process. These data reveal heat-processed Scutellariae Radix may be a critical factor involved in the improvement of lung disorders caused by LPS.


Disruption of functional connectivity of the default-mode network in alcoholism.
The default mode network (DMN) comprises brain structures maximally active at rest. Disturbance of network nodes or their connections occurs with some neuropsychiatric conditions and may underlie associated dysfunction. DMN connectivity has not been examined in alcoholism, which is marked by compromised DMN nodes and impaired spatial working memory. To test whether performance would be related to DMN integrity, we examined DMN functional connectivity using functional magnetic resonance imaging (fMRI) data and graph theory analysis. We assumed that disruption of short paths between network nodes would attenuate processing efficiency. Alcoholics and controls were scanned at rest and during a spatial working memory task. At rest, the spontaneous slow fluctuations of fMRI signals in the posterior cingulate and cerebellar regions in alcoholics were less synchronized than in controls, indicative of compromised functional connectivity. Graph theory analysis indicated that during rest, alcoholics had significantly lower efficiency indices than controls between the posterior cingulate seed and multiple cerebellar sites. Greater efficiency in several connections correlated with longer sobriety in alcoholics. During the task, on which alcoholics performed on par with controls, connectivity between the left posterior cingulate seed and left cerebellar regions was more robust in alcoholics than controls and suggests compensatory networking to achieve normal performance.


Exploring parental risk perception regarding childhood unintentional home injuries: A cross-sectional study.
While previous studies on childhood injury focused mainly on the relationship between parents' preventive behavior and its determinants, knowledge about parental risk perception that can help to develop, implement, and evaluate successful interventions to prevent childhood unintentional home injuries is still limited. The aim of this study was to gain a deeper understanding of parental risk perception regarding unintentional home injuries of children under six years of age. A convenience sample of 469 parents, residing in Germany, completed a web-based questionnaire assessing factors potentially associated with parental risk perception on the child, parental, and environmental level. Descriptive statistics, p for trend, and Spearman's Rho correlation coefficients were calculated. Key factors influencing parental risk perception included children's sex, age, migrant status, emotionality, and injury risk as well as parents' parenting style and external locus of control. While parental risk perception was positively associated with children's injury risk, the analyses showed no associations between parental risk perception and parents' preventive behavior. Our findings add to a better understanding of parental risk perception, provide practical implications for injury prevention, and indicate that the relationship between parental risk perception and parents' preventive behavior is based on a complex mechanism which is possibly moderated by parents' locus of control. The identified key factors help to assess parental risk perception more accurately. Therefore, they should be considered in the development of tailored interventions to prevent unintentional home injuries of children, for instance, by targeting specific groups of parental risk perception.


Generalized multi-organ autoimmunity in CCR7-deficient mice.
Development of autoimmunity is a multi-factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7-deficient mice are prone to develop generalized multi-organ autoimmunity. The autoimmune phenotype of CCR7-/- mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue-specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7-deficient mice show increased susceptibility to streptozotocin-induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity.


A Markov analysis of DNA sequences.
We present a model by which we look at the DNA sequence as a Markov process. It has been suggested by several workers that some basic biological or chemical features of nucleic acids stand behind the frequencies of dinucleotides (doublets) in these chains. Comparing patterns of doublet frequencies in DNA of different organisms was shown to be a fruitful approach to some phylogenetic questions (Russel & Subak-Sharpe, 1977). Grantham (1978) formulated mRNA sequence indices, some of which involve certain doublet frequencies. He suggested that using these indices may provide indications of the molecular constraints existing during gene evolution. Nussinov (1981) has shown that a set of dinucleotide preference rules holds consistently for eukaryotes, and suggested a strong correlation between these rules and degenerate codon usage. Gruenbaum, Cedar & Razin (1982) found that methylation in eukaryotic DNA occurs exclusively at C-G sites. Important biological information thus seems to be contained in the doublet frequencies. One of the basic questions to be asked (the "correlation question") is to what extent are the 64 trinucleotide (triplet) frequencies measured in a sequence determined by the 16 doublet frequencies in the same sequence. The DNA is described here as a Markov process, with the nucleotides being outcomes of a sequence generator. Answering the correlation question mentioned above means finding the order of the Markov process. The difficulty is that natural sequences are of finite length, and statistical noise is quite strong. We show that even for a 16000 nucleotide long sequence (like that of the human mitochondrial genome) the finite length effect cannot be neglected. Using the Markov chain model, the correlation between doublet and triplet frequencies can, however, be determined even for finite sequences, taking proper account of the finite length. Two natural DNA sequences, the human mitochondrial genome and the SV40 DNA, are analysed as examples of the method.


2,6-Diarylnaphtho[1,8-bc:5,4-b'c']dithiophenes as new high-performance semiconductors for organic field-effect transistors.
A series of 2,6-diaryl-substituted naphtho[1,8-bc:5,4-b'c']dithiophene derivatives 2-6, whose aryl groups include 5-hexyl-2-thienyl, 2,2'-bithiophen-5-yl, phenyl, 2-naphthyl, and 4-biphenylyl, was synthesized by the palladium-catalyzed Suzuki-Miyaura coupling and utilized as active layers of organic field-effect transistors (OFETs). All devices fabricated using vapor-deposited thin films of these compounds showed typical p-type FET characteristics. The mobilities are relatively good and widely range from 10(-4) to 10(-1) cm2 V(-1) s(-1), depending on the substituent groups. Among them, the mobilities of the devices using films of 3-5 tend to increase with the increasing temperature of the Si/SiO2 substrate during film deposition. In particular, the device based on the naphthyl derivative 5, when fabricated at 140 degrees C, marked a high mobility of 0.11 cm2 V(-1) s(-1) with an on/off ratio of 10(5), which is a top class of performance among organic thin-film transistors. Studies of X-ray diffractograms (XRDs) have revealed that the film of 4 and 5 is composed of two kinds of crystal grains with different phases, so-called "single-crystal phase" and "thin film phase", and that the proportion of the thin film phase increases with an increase of the substrate temperature. In the thin film phase the assembled molecules stand nearly upright on the substrate in such a way as to be favorable to carrier migration.


Insight toward epithelial Na+ channel mechanism revealed by the acid-sensing ion channel 1 structure.
The epithelial Na(+) channel/degenerin (ENaC/DEG) protein family includes a diverse group of ion channels, including nonvoltage-gated Na(+) channels of epithelia and neurons, and the acid-sensing ion channel 1 (ASIC1). In mammalian epithelia, ENaC helps regulate Na(+) and associated water transport, making it a critical determinant of systemic blood pressure and pulmonary mucosal fluidity. In the nervous system, ENaC/DEG proteins are related to sensory transduction. While the importance and physiological function of these ion channels are established, less is known about their structure. One hallmark of the ENaC/DEG channel family is that each channel subunit has only two transmembrane domains connected by an exceedingly large extracellular loop. This subunit structure was recently confirmed when Jasti and colleagues determined the crystal structure of chicken ASIC1, a neuronal acid-sensing ENaC/DEG channel. By mapping ENaC to the structural coordinates of cASIC1, as we do here, we hope to provide insight toward ENaC structure. ENaC, like ASIC1, appears to be a trimeric channel containing 1alpha, 1beta, and 1gamma subunit. Heterotrimeric ENaC and monomeric ENaC subunits within the trimer possibly contain many of the major secondary, tertiary, and quaternary features identified in cASIC1 with a few subtle but critical differences. These differences are expected to have profound effects on channel behavior. In particular, they may contribute to ENaC insensitivity to acid and to its constitutive activity in the absence of time- and ligand-dependent inactivation. Experiments resulting from this comparison of cASIC1 and ENaC may help clarify unresolved issues related to ENaC architecture, and may help identify secondary structures and residues critical to ENaC function.


Use of multiple fasciocutaneous flaps for the management of extensive hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a relapsing nature that has a significant impact on the patient's quality of life. The clinical presentation of the disease includes deep dermal abscesses and sinus tracts. Long-term affliction of the disease may lead to contractures, scars and fibrosis. Management is still challenging and varies from medical to surgical options. We report the following case of a man in his 30s who presented with severe HS in the axillae, groins, perineum and lower sacral region. The patient has been treated by excision of the whole lesions followed by using multiple fasciocutaneous flaps as a reconstructive method.


Surgeon training and complications in total ankle arthroplasty.
This study assessed the problems with initial use of ankle arthroplasty by surgeons who were trained by observing the surgeon/inventor (group I), who have completed a structured, hands-on surgical training course (group II), or who were trained during a 1-year foot and ankle fellowship (group III). The perioperative records of the first 10 cases of nine surgeons were reviewed. We evaluated the 6-month-postoperative standing mortise and lateral radiographs for evidence of syndesmosis union and accuracy of tibial component implantation. Three surgeons were each in group I, group II, and group III. Average patient age at time of surgery was similar. Ankle arthritis was classified as rheumatoid arthritis (RA) or osteoarthritis (OA) as follows: group I (7 RA, 23 OA), group II (7 RA, 23 OA), and group III (3 RA, 27 OA). In group I, there were nine intraoperative complications, four postoperative wound dehiscences, and three postoperative deep infections. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 10/26 (38%) had a delayed union of the syndesmosis. In group II, there were six intraoperative complications and two postoperative wound problems: an early anterior wound problem and a delayed lateral wound breakdown. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 13/26 (50%) had a delayed union of the syndesmosis. In group III, there were four intraoperative complications and four postoperative wound problems--all healed with local supportive care with one requiring lateral hardware removal. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 5/30 (17%) had a delayed union of the syndesmosis. The initial series from these three groups are statistically indistinguishable with respect to rates of complications, revisions, or malalignment. No identified training method had a statistically demonstrable positive impact on preparing surgeons for performing total ankle replacement. Some of these findings are likely generic for total ankle replacements and not restricted to any class or design of implant. Surgeon initial use of total ankle replacement needs to be done with caution and serious consideration.


Filarial-specific IgG4 response correlates with active Wuchereria bancrofti infection.
The filarial-specific humoral immune response of adult residents of two areas of Papua New Guinea, differing in transmission of Wuchereria bancrofti infection was compared. The majority of residents of the village of Bonahoi, in an area where transmission of filariasis had been interrupted by a 20-year insecticide spray program to control malaria, showed no parasitologic signs of active W. bancrofti infection and were negative for both circulating phosphorylcholine Ag and peripheral blood microfilariae. In contrast, adult residents of the village of Nanaha were in an area exposed to infection, and were phosphorylcholine-Ag- and microfilariae-positive. The antibody response of these two groups to both adult worm excretory/secretory (ES) Ag and somatic antigen extract was examined to determine which components of the filarial-specific immune response were dependent on active infection. Identification of these immune responses may point to immunologic methods to evaluate control programs for lymphatic filariasis. Adults from Bonahoi were found to have significant immune responses to [35S] methionine-labeled ES Ag by immunoprecipitation and to adult somatic antigen extracts by ELISA and by immunoblotting. This result is consistent with the fact that these individuals were previously exposed to and/or infected with W. bancrofti. Similarly, residents of the endemic village had detectable immune responses to these Ag irrespective of if they were microfilaremic. The most striking immunologic difference observed between the two groups was that residents of Bonahoi had a dramatically reduced filarial-specific IgG4 antibody response to both adult somatic Ag and adult ES Ag. These data suggest that longitudinal measurement of filarial-specific IgG4 levels may be a useful seroepidemiologic indicator of changes in W. bancrofti infection status.


Conical Intersections at the Nanoscale: Molecular Ideas for Materials.
The ability to predict and describe nonradiative processes in molecules via the identification and characterization of conical intersections is one of the greatest recent successes of theoretical chemistry. Only recently, however, has this concept been extended to materials science, where nonradiative recombination limits the efficiencies of materials for various optoelectronic applications. In this review, we present recent advances in the theoretical study of conical intersections in semiconductor nanomaterials. After briefly introducing conical intersections, we argue that specific defects in materials can induce conical intersections between the ground and first excited electronic states, thus introducing pathways for nonradiative recombination. We present recent developments in theoretical methods, computational tools, and chemical intuition for the prediction of such defect-induced conical intersections. Through examples in various nanomaterials, we illustrate the significance of conical intersections for nanoscience. We also discuss challenges facing research in this area and opportunities for progress.


An etiologic basis for congestive heart failure on the molecular level.
It is here proposed that disordered redox balance leads to congestive heart failure in a variety of diverse clinical situations. These conditions include those associated with an excess of reducing agents, such as catecholamines and thyroid hormone, or impaired oxidant defenses, such as in selenium deficiency. The clinical situations include hypertension, hyperthyroidism, progressive congestive heart failure, amphetamine overdose and hemochromatosis. The molecular damage to the cardiac muscle is postulated to be mediated via reaction oxygen radicals.


Medical Management of COVID-19: Evidence and Experience.
Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and this infectious disease is termed COVID-19 in short. On a global scale, as of June 1, 2020, the World Health Organization (WHO) published statistics of 6,057,853 infected patients and 371,166 deaths worldwide. Despite reported observational data about the experimental use of certain drugs, there is no conclusively proven curative therapy for COVID-19 as of now; however, remdesivir received emergency use authorization (EUA) by the Food and Drug Administration (FDA) recently for use in patients hospitalized with COVID-19. There are several ongoing clinical trials related to the pharmacological choices of therapy for COVID-19 patients; however, drug trials related to observational studies so far have yielded mixed results and therefore have created a sense of confusion among healthcare professionals (HCPs). In this review article, we seek to collate and provide a summary of treatment strategies for COVID-19 patients with a variable degree of illness and discuss pharmacologic and other therapies intended to be used either as experimental medicine/therapy or as part of supportive care in complicated cases of COVID-19.


Impact of dose calculation accuracy during optimization on lung IMRT plan quality.
The purpose of this study was to evaluate the effect of dose calculation accuracy and the use of an intermediate dose calculation step during the optimization of intensity-modulated radiation therapy (IMRT) planning on the final plan quality for lung cancer patients. This study included replanning for 11 randomly selected free-breathing lung IMRT plans. The original plans were optimized using a fast pencil beam convolution algorithm. After optimization, the final dose calculation was performed using the analytical anisotropic algorithm (AAA). The Varian Treatment Planning System (TPS) Eclipse v11, includes an option to perform intermediate dose calculation during optimization using the AAA. The new plans were created using this intermediate dose calculation during optimization with the same planning objectives and dose constraints as in the original plan. Differences in dosimetric parameters for the planning target volume (PTV) dose coverage, organs-at-risk (OARs) dose sparing, and the number of monitor units (MU) between the original and new plans were analyzed. Statistical significance was determined with a p-value of less than 0.05. All plans were normalized to cover 95% of the PTV with the prescription dose. Compared with the original plans, the PTV in the new plans had on average a lower maximum dose (69.45 vs. 71.96Gy, p = 0.005), a better homogeneity index (HI) (0.08 vs. 0.12, p = 0.002), and a better conformity index (CI) (0.69 vs. 0.59, p = 0.003). In the new plans, lung sparing was increased as the volumes receiving 5, 10, and 30 Gy were reduced when compared to the original plans (40.39% vs. 42.73%, p = 0.005; 28.93% vs. 30.40%, p = 0.001; 14.11%vs. 14.84%, p = 0.031). The volume receiving 20 Gy was not significantly lower (19.60% vs. 20.38%, p = 0.052). Further, the mean dose to the lung was reduced in the new plans (11.55 vs. 12.12 Gy, p = 0.024). For the esophagus, the mean dose, the maximum dose, and the volumes receiving 20 and 60 Gy were lower in the new plans than in the original plans (17.91 vs. 19.24 Gy, p = 0.004; 57.32vs. 59.81 Gy, p = 0.020; 39.34% vs. 41.59%, p = 0.097; 12.56%vs. 15.35%, p = 0.101). For the heart, the mean dose, the maximum dose, and the volume receiving 40 Gy were also lower in new plans (11.07 vs. 12.04 Gy, p = 0.007; 56.41 vs. 57.7 Gy, p = 0.027; 7.16% vs. 9.37%, p= 0.012). The maximum dose to the spinal cord in the new plans was significantly lower than in the original IMRT plans (29.1 vs. 31.39Gy, p = 0.014). Difference in MU between the IMRT plans was not significant (1216.90 vs. 1198.91, p = 0.328). In comparison to the original plans, the number of iterations needed to meet the optimization objectives in the new plans was reduced by a factor of 2 (2-3 vs. 5-6 iterations). Further, optimization was 30% faster corresponding to an average time savings of 10-15 min for the reoptimized plans. Accuracy of the dose calculation algorithm during optimization has an impact on planning efficiency, as well as on the final plan dosimetric quality. For lung IMRT treatment planning, utilizing the intermediate dose calculation during optimization is feasible for dose homogeneity improvement of the PTV and for improvement of optimization efficiency.


Investigating malignancy-dependent mechanical properties of breast cancer cells.
Cancer invasiveness significantly impacts cellular mechanical properties which regulate cell motility and, subsequently, cell metastatic potential. Understanding the adhesion forces and stiffness/rigidity of cancer cells can provide better insights into their mechanical adaptability related to their degree of invasiveness. Here, we used single-cell force spectroscopy in conjunction with quartz crystal microbalance-with dissipation measurements to compare the mechanical properties of mammary epithelial cancer cells with different metastatic potentials, namely MCF-7 (non-invasive) and MDA-MB-231 (aggressive and highly invasive). Our results showed that MCF-7 exhibits larger adhesion forces, stronger intercellular forces, and a considerably stiff/rigid phenotype, contrary to MDA-MB-231. The biomechanical properties obtained are associated with the malignant potential of these cells such that the forces of adhesion and viscoelasticity are inversely proportional to cell invasiveness. This study integrates a new quantitative tool with real-time measurements to provide better insights into the mechanics of cancer cells across metastatic stages.


AMA's Todd pushes for reform--cautiously. Interview by Richard L. Clark.
James S. Todd, MD, executive vice president, American Medical Association (AMA), believes there are only two ways to make sure all Americans are covered by health insurance--raise taxes or decrease benefits. In an interview with Richard L. Clarke, FHFMA, president, Healthcare Financial Management Association, Todd discusses the AMA's national healthcare reform plan and the AMA's outlook on global budgets, managed competition, and physician-hospital relationships.


Influence of food availability, plant productivity, and indigenous forest use on ranging behavior of the endangered samango monkey (Cercopithecus albogularis schwarzi), in the Soutpansberg Mountains, South Africa.
Understanding the determinants of ranging patterns in species susceptible to habitat fragmentation is fundamental for assessing their long-term adaptability to an increasingly human-dominated landscape. The aim of this study was to determine and compare the influence of ground-based food availability, remotely sensed plant productivity, and indigenous forest use on the ranging patterns of the endangered samango monkey (Cercopithecus albogularis schwarzi). We collected monthly ranging data on two habituated samango monkey groups, from February 2012 to December 2016, from our field site in the Soutpansberg Mountains, South Africa. We used linear mixed models to explore how food availability, plant productivity, and indigenous forest use influenced monthly ranging patterns, while controlling for group size, number of sample days and day length. We found that as more areas of high plant productivity (derived from remotely sensed EVI) were incorporated into the ranging area, both total and core monthly ranging areas decreased. In addition, both total ranging area and mean monthly daily path length decreased as more indigenous forest was incorporated into the ranging area. However, we found no effect of either ground-based food availability or remotely sensed plant productivity on ranging patterns. Our findings demonstrate the behavioral flexibility in samango monkey ranging, as samangos can utilize matrix habitat during periods of low productivity but are ultimately dependent on access to indigenous forest patches. In addition, we highlight the potential of using remotely sensed areas of high plant productivity to predict ranging patterns in a small ranging, forest-dwelling guenon, over ground-based estimates of food availability.


Endoplasmic reticulum membrane isolated from small-intestinal epithelial cells: enzyme and protein components.
Endoplasmic reticulum membrane-rich fraction was obtained by subfractionation of the light microsomes from mouse jejunal mucosal epithelial cells. It was marked by high glucose-6-phosphatase, NADPH-cytochrome c reductase, and NADH-cytochrome c reductase activities and low Na+,K+-ATPase activity. The enrichment of Na+,K+-ATPase was 180-fold higher in the basolateral membranes than in the endoplasmic reticulum membrane-rich fraction relative to glucose-6-phosphatase. The protein peak that was phosphorylated in a Na-dependent manner was prominent in the basolateral membranes while it was a minor peak in the endoplasmic reticulum membrane-rich fraction. Under the electron microscope the fraction was seen to be composed of homogeneous small vesicles with thin smooth membranes.


Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects.
BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality-adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-years (QALY) gained for TAC versus FAC was calculated. For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy.


Association of Physical Activity or Fitness With Incident Heart Failure: A Systematic Review and Meta-Analysis.
Previous studies have shown that high levels of physical activity are associated with lower risk of risk factors for heart failure (HF), such as coronary heart disease, hypertension, and diabetes mellitus. However, the effects of physical activity or fitness on the incidence of HF remain unclear. MEDLINE and EMBASE were systematically searched until November 30, 2014. Prospective cohort studies reporting measures of the association of physical activity (n=10) or fitness (n=2) with incident HF were included. Extracted effect estimates from the eligible studies were pooled using a random-effects model meta-analysis, with heterogeneity assessed with the I(2) statistic. Ten cohort studies on physical activity eligible for meta-analysis included a total of 282 889 participants followed for 7 to 30 years. For the physical activity studies, maximum versus minimal amount of physical activity groups were used for analyses; with a total number of participants (n=165 695). The pooled relative risk (95% confidence interval [CI]) for HF among those with a regular exercise pattern was 0.72 (95% CI, 0.67-0.79). Findings were similar for men (0.71 [95% CI, 0.61-0.83]) and women (0.72 [95% CI, 0.67-0.77]) and by type of exercise. There was no evidence of publication bias (P value for Egger test=0.34). The pooled associated effect of physical fitness on incident HF was 0.79 (95% CI, 0.75-0.83) for each unit increase in metabolic equivalent of oxygen consumption. Published literature support a significant association between increased physical activity or fitness and decreased incidence of HF.


[Challenges for healthcare coordination: strategies for integrating levels of care in large cities].
This article analyzes the development of instruments for coordination between the Family Health Strategy and other levels in the health system, with a focus on measures to promote coordination linked to the 'integration among levels of care'. The results of case studies in four large cities indicate the presence of mechanism for integration among levels of care, suggesting concern with guaranteeing comprehensive care. The principal strategies identified here were: creation and strengthening of regulatory structures in the Municipal Health Secretariats and family health units with decentralization of roles to the local level, organization of flows, electronic patient charts, and expansion in the supply of specialized services at the municipal level. However, lack of integration among different providers, insufficient formal flows for hospital care, and absence of policies for medium complexity care were detected as barriers to the guarantee of comprehensive care, making the network's integration incomplete.


Quantitative diffusion-weighted MRI parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.
Patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas have a better survival rate than those with human papillomavirus-negative oropharyngeal squamous cell carcinomas. DWI characterizes biologically relevant tumor features, and the generated ADC may also provide prognostic information. We explored whether human papillomavirus status and ADC values are independent tumor characteristics. Forty-four patients with oropharyngeal squamous cell carcinomas underwent pretreatment DWI. ADC values for the primary tumors were determined by using 3 b-values in an ROI containing the largest area of solid tumor on a single section of an axial DWI image. Human papillomavirus status was determined with p16 immunostaining, followed by high-risk human papillomavirus DNA detection on the p16-positive cases. Twenty-two patients were human papillomavirus-positive (50.0%). ADC values were not significantly different between human papillomavirus-negative (ADC(mean) = 1.56 [1.18-2.18] × 10(3) mm(2)/s) and human papillomavirus-positive tumors (ADC(mean) = 1.46 [1.07-2.16] × 10(3) mm(2)/s). No significant association between ADC and human papillomavirus status was found in oropharyngeal squamous cell carcinomas. In our study population, differences in genetic and histologic features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas did not translate into different ADC values. Long-term follow-up studies are needed to establish whether ADC has prognostic value and whether this is independent of the human papillomavirus status.


On choosing the number of interim analyses in clinical trials.
Small but important therapeutic effects of new treatments can be most efficiently detected through the study of large randomized prospective series of patients. Such large scale clinical trials are nowadays commonplace. The alternative is years of polemic and debate surrounding several trials each too small to detect plausible differences with any certainty. Such trials produce equivocal and contradictory results, which could be predicted from power calculations based upon sensible pre-trial estimates of treatment differences. Unfortunately such calculations often lead to sample sizes of several thousands. It is not surprising that investigators tend to be over-optimistic in their estimation of treatment effects (which are necessarily uncertain) especially when the sample size requirements are so stark. In this paper a method is outlined for incorporating into the sample size calculations the uncertainty of the estimate made at the design stage of a clinical trial. In particular a formal scheme is described for deciding how many interim analyses should be performed to satisfy ethical and pragmatic requirements of large clinical trial design. Although the argument will be 'Bayesian', the criteria for assessment and comparison will be strictly of a Neyman-Pearson (i.e. significance testing) kind.


Impact of Work Organization on Technology Use: The Case of Hydration Process with a Smart Drinking Glass.
This paper presents preliminary results from a larger project led with the French company Auxivia. The latter offers a smart drinking glass (SDG), supporting monitoring daily water intakes of elderly people and helping identify residents to encourage. Contexts and work organizations can deeply differ from a nursing home to another and can impact the use of the SDG. Based on a comparison between two nursing homes, we unveil the impact of both work organizations on the integration of technology requirements. We discuss the results by providing recommendations to improve the integration of SDGs in various work organizations.


Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity.
Neurotrophins, secreted in an activity-dependent manner, are thought to be involved in the activity-dependent refinement of synaptic connections. Here we demonstrate that in hippocampal neurons and the rat pheochromocytoma cell line PC12 application of exogenous neurotrophins induces secretion of neurotrophins, an effect that is mediated by the activation of tyrosine kinase neurotrophin receptors (Trks). Like activity-dependent secretion of neurotrophins, neurotrophin-induced neurotrophin secretion requires mobilization of calcium from intracellular stores. Because neurotrophins are likely to be released from both dendrites and axons, neurotrophin-induced neurotrophin release represents a potential positive feedback mechanism, contributing to the reinforcement and stabilization of synaptic connections.


Biochemical Analysis of Pleural Fluid and Ascites.
Biochemical testing of peritoneal and pleural fluids is carried out widely, although the range of tests likely to be useful is limited in comparison to the repertoire of tests available in a modern biochemistry laboratory. Fluids accumulate when pathological processes cause an imbalance between hydrostatic pressure gradients, capillary membrane permeability and lymphatic capacity, resulting in protein-poor transudates or inflammatory exudates. In peritoneal fluid, albumin is the most useful test, for the calculation of the serum-ascites albumin gradient; protein and LDH have a role regarding risk and diagnosis of spontaneous bacterial peritonitis and amylase may be useful in diagnosing fluid accumulation due to pancreatitis. Peritoneal fluid pH and glucose are not indicated analyses. For pleural fluid, protein and LDH are important in distinguishing between transudate and exudate using Light's criteria; albumin and the serum-effusion albumin gradient may have a complementary role in patients already on diuretics. Pleural fluid pH is the most useful marker of infection although LDH and glucose are also used. Pleural fluid amylase is often measured but, if raised, is more likely to reflect a malignant process than pancreatic disease as the former is much more prevalent. Tumour markers in both peritoneal and pleural fluids generally have limited diagnostic accuracy for detecting local malignancy. Limited studies validating standard serum test methods for use with pleural and peritoneal fluids have been published but work is progressing in this area both in Australasia and overseas and opportunities exist for contributing to this effort.


Detection of Pentosidine Cross-Links in Cell-Secreted Decellularized Matrices Using Time Resolved Fluorescence Spectroscopy.
Hyperglycemia-mediated, nonenzymatic collagen cross-links such as pentosidine (PENT) can have deleterious effects on cellular interactions with the extracellular matrix (ECM). Present techniques to quantify PENT are limited, motivating the need for improved methods to study the accumulation and contribution of PENT toward diabetic clinical challenges such as impaired bone healing. Current methods for studying PENT are destructive, laborious, and frequently employ oversimplified collagen films that lack the complexity of the native ECM. The primary goal of this study was to evaluate the capacity of time-resolved fluorescence spectroscopy (TRFS) to detect PENT in cell-secreted ECMs possessing enhanced compositional complexity. To demonstrate an application of this method, we assessed the response of human mesenchymal stem cells (MSCs) to cross-linked substrates to explore the role of detected PENT on osteogenic differentiation. We exposed MSC-secreted decellularized matrices (DMs) to 0.66 M ribose for 2 weeks and used TRFS to detect the accumulation of PENT. Ribose treatment resulted in a 30 nm blue shift in peak fluorescence emission and a significant decrease in average lifetime compared to that of control DMs (4.4 ± 0.3 ns vs 3.5 ± 0.09 ns). Evaluation of samples with high performance liquid chromatography (HPLC) confirmed that changes in observed fluorescence were due to PENT accumulation. A strong correlation was found between TRFS parameters and the HPLC measurement of PENT, validating the use of TRFS as an alternative method of PENT detection. Osteoblastic gene expression was significantly reduced in MSCs seeded on ribose DMs at days 7 and 14. However, no significant differences in calcium deposition were detected between control and ribose DMs. These data demonstrate the efficacy of nondestructive fluorescence spectroscopy to examine the formation of nonenzymatic collagen cross-links within biomimetic culture platforms and showcase one example where an improved biomimetic substrate can be used to probe cell-ECM interactions in the presence of collagen cross-links.


[The immediate and late results of protecting the patient's normal tissues by using the gas hypoxic mixture GHM-10 in the radiation therapy of breast cancer].
The effect of inhalation of gaseous hypoxic mixture GHM-10 (oxygen--10 +/- 1.0 and nitrogen--90.0 +/- 1.0%) on radiation response of normal tissues was studied in 184 breast cancer patients. The mixture was administered to 120 patients while 74 controls received a standard course of radiotherapy. Administration of the mixture improved normal tissue resistance to radiotherapy for breast cancer and was followed by lower incidence of long-term radiation injury, lower frequency and shorter duration of general vegetative reactions to radiation.


Fungi-based treatment of real brewery waste streams and its effects on water quality.
Nutrient-rich liquid waste streams generated during the beer brewing were treated by submerged fungal growth. Among five filamentous fungal strains tested, Pleurotus ostreatus and Trichoderma harzianum were selected for treatment of run-off from spent grain and hot trub, respectively. In both waste streams, nitrogen was well removed by fungal treatment, with a maximum reduction of 91.5 ± 0.5% of total nitrogen in run-off from spent grain treated with P. ostreatus and 77.0 ± 3.1% in hot trub treated with T. harzianum. Removal of phosphorus was considerably lower, with maximum removal of total phosphorus of 30.8 ± 11.1% for the P. ostreatus treatment and 16.6 ± 7.8% for the T. harzianum treatment. Considering the high concentration of phosphorus in the waste sources (320-600 mg L-1), additional techniques for its removal are needed. In the P. ostreatus treatment, a total amount of 13.2 ± 2.2 g L-1 dwt of biomass with a protein concentration of 11.6 ± 2.1% was produced.


Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism.
Anticonvulsant mood stabilizers, e.g., valproic acid and carbamazepine, and atypical antipsychotic drugs (APDs), e.g., clozapine, quetiapine, olanzapine, risperidone, and ziprasidone, have been reported to preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect partially or fully inhibited by WAY100635, a selective 5-HT(1A) antagonist. These atypical APDs have themselves been reported to be effective mood stabilizers, although the importance of increased cortical DA release to mood stabilization has not been established. The purpose of the present study was to determine whether zonisamide, another anticonvulsant mood stabilizer, as well as lithium, a mood stabilizer without anticonvulsant properties, also increases prefrontal cortical DA release and, if so, whether this release is also inhibited by 5-HT(1A) antagonism. As with valproic acid and carbamazepine, zonisamide (12.5 and 25 mg/kg) increased DA release in the mPFC, but not the NAC, an increase abolished by WAY100635 (0.2 mg/kg). However, lithium (100 and 250 mg/kg) decreased DA release in the NAC, an effect also attenuated by WAY100635 (0.2 mg/kg). Lithium itself had no effect in the mPFC but the combination of WAY100635 (0.2 mg/kg) and lithium (100 and 250 mg/kg) markedly increased DA release in the mPFC. Furthermore, M100907 (0.1 mg/kg), a selective 5-HT(2A) antagonist, abolished this increase in DA release in the mPFC. These results indicate that not all mood-stabilizing agents but only those, which have anticonvulsant mood-stabilizing properties, increase DA release in the cortex, and that the effect is dependent upon 5-HT(1A) receptor stimulation. However, the combination of lithium and 5-HT(1A) blockade may result in excessive 5-HT(2A) receptor stimulation, relative to 5-HT(1A) receptor stimulation, both of which can increase prefrontal cortical DA release.


α7 nicotinic acetylcholine receptor agonist attenuates the cerebral injury in a rat model of cardiopulmonary bypass by activating the Akt/GSK3β pathway.
α7 nicotinic acetylcholine receptor (α7nAchR) agonist treatment may provide a promising therapeutic effect for cerebral injuries. However, it is unclear whether the activation of α7nAchR agonist may reduce cerebral injuries induced by cardiopulmonary bypass (CPB). A total of 96 male Sprague‑Dawley rats were randomly divided into four groups (n=24/group): i) Sham operation group; ii) CPB group; iii) CPB + α7nAchR agonist group; and iv) CPB + α7nAchR agonist + α7nAchR antagonist group. Following treatment, 24 rats from each group were sacrificed and the serum and hippocampal tissues were collected. The serum expression levels of S100β, interleukin 6 and tumor necrosis factor α were evaluated by ELISA, hippocampal tissues were analyzed by histopathological examination using hematoxylin & eosin and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick‑end labeling (TUNEL) staining and Caspase 3 expression in the hippocampal tissues was evaluated by immunohistochemistry. In addition, Caspase 3, Akt and glycogen synthase kinase 3β (GSK3β), as well as phosphorylated (p)‑Akt and (p)‑GSK3β were examined by western blot assay. The present study demonstrated that α7nAchR agonist treatment was able to alleviate pathological damage and inhibit hippocampal cell apoptosis and inflammatory response. α7nAchR agonist treatment also increased the expression levels of p‑Akt and p‑GSK3β, which indicated an upregulation in Akt/GSK3β signaling. These data suggested that α7nAchR agonist may provide a promising new therapeutic approach for cerebral injury caused by CPB.


Clinical variables associated with failure of retinal detachment repair: the European vitreo-retinal society retinal detachment study report number 4.
To identify risk factors associated with failure of anatomic reattachment in primary rhegmatogenous retinal detachment repair. Nonrandomized, multicenter, collaborative study. Primary procedures for 7678 rhegmatogenous retinal detachments reported by 176 surgeons from 48 countries. We recorded specific preoperative clinical findings, repair method, and outcome after intervention. We performed univariate, bivariate, and multivariate analyses to identify variables associated with surgical failure. Final failure of retinal detachment repair (level 1), remaining silicone oil at study conclusion (level 2), and need for additional procedures to repair the detachment (level 3). We analyzed 7678 cases of rhegmatogenous retinal detachment repair. Presence of choroidal detachment or significant hypotony was associated with significantly higher level 1 failure rates when grade 0 or B proliferative vitreoretinopathy (PVR) was present and higher level 2 failure rates, regardless of PVR status (P<0.05). Excluding cases with choroidal detachment or hypotony, increasing PVR was associated with increasing level 1 failure rates. The difference between grade B and C-1 PVR was significant (P = 2 × 10(-6)). No difference was observed in level 1 failure rates when operated eyes were phakic versus pseudophakic. Level 1 failure was significantly higher when all 4 quadrants of retina (4.4%) were detached than when only 1 quadrant (0.8%) had subretinal fluid. With grade B or C-1 PVR, cases with large or giant tears had significantly higher level 1 failure rates. No association was observed between number of retinal breaks and failure rates. Multivariate analysis showed grade C-1 PVR, 4 detached quadrants, and presence of choroidal detachment or significant hypotony were independently linked with a greater level 1 failure rate; the presence of a smaller retinal break was associated with a lesser level 1 failure rate. Choroidal detachment, significant hypotony, grade C-1 PVR, 4 detached quadrants, and large or giant retinal breaks were independent explanatory variables of retinal detachment repair failure. In contrast to earlier studies, the significance of phakic versus pseudophakic status was not confirmed.


A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19.
The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.


The non-association of Panton-Valentine leukocidin and mecA genes in the genome of Staphylococcus aureus from hospitals in South Western Nigeria.
Virulence genes play important roles in pathogenesis of infections caused by S. aureus. The aim of this study was to determine the prevalence of PVL, eta and mecA genes in S. aureus isolated from patients in South-Western Nigeria. In this study, a total of 116 S. aureus isolates from the clinical specimens submitted to laboratories in tertiary hospitals in the South Western Nigeria were used. Antibiotic susceptibility test was carried out to determine the susceptibility pattern of the isolates using multiple antibiotics disc. Minimum inhibitory concentration (MIC) was also carried out to determine the degree of resistant of the isolates to methicillin. PCR was used to screen for the presence of PVL, eta, and mecAgenes. mecA gene was detected in 48 (41.4%) of 116 strains of S. aureus. The MIC 50 and MIC 90 for mecA negative strains were 1 and 8 μg/ml, respectively while the MIC 50 and MIC 90 for mecA positive were >256 μg/ml. Twenty eight (24.1%) of 116 isolates were PVL gene positive with none of them mecA+. The prevalence of community acquired MRSA (CA-MRSA) was estimated to be 6.9% using molecular techniques. No localization of mecA gene and PVL gene on the genome of the entire S. aureus strains studied. Site of isolation of organism /specimen type was found to be associated with the prevalence of PVL+ and mecA+ S. aureus (P< 0.01). This study concludes that the PVL+ MRSA is rare and the prevalence of CA-MRSA is low in South-Western, Nigeria.


The formation of glucosides of isoflavones and of some other phenols by rabbit liver microsomal fractions.
1. Rabbit liver microsomal fractions in vitro effected the transfer of glucuronic acid from UDP-glucuronic acid to biochanin A, formononetin, daidzein, genistein and equol. Only monoglucuronides were formed. 2. The same isoflavones were converted into monoglucosides when UDP-[6-(3)H]glucose was substituted for UDP-glucuronic acid in the incubation medium in vitro. The glucosides were formed in much lesser yield than were the glucuronides. 3. The glucoside of genistein was identified as genistin (genistein 7-glucoside) by Sephadex chromatography and reverse isotope dilution. 4. The specificity of the glucuronyl- and glucosyl-transfer mechanisms was compared for a series of steroids and other phenols in addition to the isoflavones. It was concluded that separate transferases were responsible for the formation of the two types of glycosides.


Systematic review of home telemonitoring for chronic diseases: the evidence base.
Home telemonitoring represents a patient management approach combining various information technologies for monitoring patients at distance. This study presents a systematic review of the nature and magnitude of outcomes associated with telemonitoring of four types of chronic illnesses: pulmonary conditions, diabetes, hypertension, and cardiovascular diseases. A comprehensive literature search was conducted on Medline and the Cochrane Library to identify relevant articles published between 1990 and 2006. A total of 65 empirical studies were obtained (18 pulmonary conditions, 17 diabetes, 16 cardiac diseases, 14 hypertension) mostly conducted in the United States and Europe. The magnitude and significance of the telemonitoring effects on patients' conditions (e.g., early detection of symptoms, decrease in blood pressure, adequate medication, reduced mortality) still remain inconclusive for all four chronic illnesses. However, the results of this study suggest that regardless of their nationality, socioeconomic status, or age, patients comply with telemonitoring programs and the use of technologies. Importantly, the telemonitoring effects on clinical effectiveness outcomes (e.g., decrease in the emergency visits, hospital admissions, average hospital length of stay) are more consistent in pulmonary and cardiac studies than diabetes and hypertension. Lastly, economic viability of telemonitoring was observed in very few studies and, in most cases, no in-depth cost-minimization analyses were performed. Home telemonitoring of chronic diseases seems to be a promising patient management approach that produces accurate and reliable data, empowers patients, influences their attitudes and behaviors, and potentially improves their medical conditions. Future studies need to build evidence related to its clinical effects, cost effectiveness, impacts on services utilization, and acceptance by health care providers.


Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.
Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.


Comparison of Quality of Life, Productivity, Functioning and Self-Esteem in Adults Diagnosed With ADHD and With Symptomatic ADHD.
Objective: Investigate the association between diagnosis and outcomes in adults with symptoms of ADHD. Method: The Validate Attitudes and Lifestyle Issues in Depression, ADHD and Troubles with Eating (VALIDATE) study collected sociodemographic and clinical characteristics data, and responses from validated questionnaires on health-related quality of life (HRQoL), work productivity, functioning, and self-esteem. ADHD-diagnosed respondents (n = 444) were matched with respondents with symptomatic ADHD (n = 1,055) within the same sex-by-age group using propensity score matching. Effects of ADHD diagnosis on each outcome were adjusted for covariates that remained imbalanced after matching, using generalized mixed models. Results: After matching, symptomatic respondents (n = 867) had worse outcomes than ADHD-diagnosed respondents (n = 436), as measured by the Work Productivity and Activity Impairment: General Health questionnaire and Sheehan Disability Scale (p < .001). ADHD-diagnosed respondents had better mean EuroQol five-dimensional five-level (EQ-5D-5L) scores and Rosenberg Self-Esteem Scale scores than symptomatic respondents (p < .001). Conclusion: ADHD-diagnosed individuals are more likely to experience better functional performance, work-related productivity, HRQoL, and self-esteem than individuals with symptomatic ADHD.


Effect of ramadan fasting on glycemic control and other essential variables in diabetic patients.
Fasting during the holy month of Ramadan is a religious obligation for all Muslims who represent 1.8 billion of the world population (24%). This study explores the effect of Ramadan fasting on the blood glucose, glycated hemoglobin (HbA1c), lipid profile, sleeping quality, and essential lifestyle parameters and also explores the safety of fasting for a whole month among diabetic patients. The aim of the present study was to assess the impact of Ramadan fasting on the blood glucose, HbA1c, lipid profile, sleeping quality, and lifestyle parameters among patients with type 2 diabetes mellitus (T2DM) in Turkey. A total of 1780 diabetic patients were approached, and 1246 (70%) participated in this cross-sectional study carried out during the period from May 27, 2017, to June 24, 2017. Data analysis comprised sociodemographic features, lifestyle habits, blood pressure measurements, serum lipid profiles, serum calcium, Vitamin D 25-hydroxy, uric acid, and HbA1c at before 4 weeks and after 12 weeks from Ramadan. Out of 1246 patients, 593 (47.6%) were male and 653 (52.4%) were female. The mean ± standard deviation age of the patients was 50.39 ± 15.3 years. Males were significantly older than females (51.53 ± 12.56 vs. 49.26 ± 14.4; P = 0.003, respectively). Significant differences were found in Vitamin D, blood glucose, HbA1c level, creatinine, bilirubin, albumin, total cholesterol, triglycerides, high-density lipoprotein-cholesterol (female), low-density lipoprotein-cholesterol (male), uric acid, and systolic and diastolic blood pressure after and before the holy month of Ramadan (P < 0.05 for each). HbA1c (P < 0.001), physical activity (P < 0.001), hours of sleeping (P < 0.001), systolic blood pressure (BP) (mmHg) (P = 0.007), BMI (P = 0.016), diastolic BP (mmHg) (P = 0.018), family history (P = 0.021), and smoking (P = 0.045) were identified as significantly associated with Ramadan fasting as contributing factors. In one of the largest studies of its kind, we show that Ramadan fasting has positive effects on T2DM patients as it reduces their blood pressure, blood glucose, HbA1C, and BMI. Furthermore, there are improvements in the duration of sleep and physical activity, the role of Ramadan fasting in diabetes therapy has been confirmed.


Correlation between the oscillatory and adhesion activities in erythroid cells.
The attachment kinetics of erythroid cells, such as human erythrocytes, their saponin ghosts, and erythroleukemic cells K562 to a glass surface has been studied in the presence of substances inhibiting spontaneous fluctuations of cell membranes. It has been shown that wheat germ agglutinin (WGA) slows down the attachment kinetics of K562 cells, as is the case in intact erythrocytes. Concanavalin A (Con A), which inhibits the attachment of erythrocytes to glass does not affect the adhesion of K562 cells to glass due to the absence of band 3 proteins in the membranes of K562 cells. Both lectins slow down the adhesion rate of saponin ghosts of human erythrocytes, as it takes place in intact erythrocytes. Suramin and the anionic dye ANS bind specifically to the actin protofilaments of the erythrocyte skeleton and also inhibit cell adhesion to glass. At the same time, these substances do not affect the oscillatory and adhesion activities of intact erythrocytes due to the impermeability of erythrocyte membranes for these drugs. The results obtained allow the conclusion that inhibition of erythrocyte adhesion by lectins is due to lectin binding to different constituents of the erythrocyte membrane--sialic acid moieties of glycophorin in the case of WGA and band 3 proteins in the case of Con A. The most probable mechanism of erythrocyte and K562 cell attachment to glass is the formation of the so-called local contacts between cells and the glass surface. It is also suggested that the cell surface oscillations facilitate the formation of cell contacts.


Modulation, individual variation and the role of lingual sensory afferents in the control of prey transport in the lizard Pogona vitticeps.
Most organisms feed on a variety of food items that may differ dramatically in their physical and behavioural characteristics (e.g. mobility, mass, texture, etc.). Thus the ability to modulate prey transport behaviour in accordance with the characteristics of the food appears crucial. Consequently, prey reduction and transport movements must be adjusted to the natural variation in material properties of the food, between and within feeding sequences and transport cycles. Here we describe an investigation of (1) the ability of the agamid lizard Pogona vitticeps to modulate prey transport kinematics when feeding on a range of food items differing in their physical characteristics and (2) the role of sensory feedback in controlling jaw and tongue movements by bilateral transection of the lingual trigeminal sensory afferents. Our findings demonstrate that P. vitticeps modulates the kinematics of its feeding behaviour in response to the mechanical demands imposed by different food types. In addition, transection of the trigeminal sensory afferents has an effect on the movements of jaws and tongue during transport, and increases the duration of transport cycles needed to process a given food type. However, after transection, transport cycles were still different for different food types suggesting that other sources of sensory information are also used to modulate prey transport in the lizard P. vitticeps.


The chromosomal arsenic resistance genes of Thiobacillus ferrooxidans have an unusual arrangement and confer increased arsenic and antimony resistance to Escherichia coli.
The chromosomal arsenic resistance genes of the acidophilic, chemolithoautotrophic, biomining bacterium Thiobacillus ferrooxidans were cloned and sequenced. Homologues of four arsenic resistance genes, arsB, arsC, arsH, and a putative arsR gene, were identified. The T. ferrooxidans arsB (arsenite export) and arsC (arsenate reductase) gene products were functional when they were cloned in an Escherichia coli ars deletion mutant and conferred increased resistance to arsenite, arsenate, and antimony. Therefore, despite the fact that the ars genes originated from an obligately acidophilic bacterium, they were functional in E. coli. Although T. ferrooxidans is gram negative, its ArsC was more closely related to the ArsC molecules of gram-positive bacteria. Furthermore, a functional trxA (thioredoxin) gene was required for ArsC-mediated arsenate resistance in E. coli; this finding confirmed the gram-positive ArsC-like status of this resistance and indicated that the division of ArsC molecules based on Gram staining results is artificial. Although arsH was expressed in an E. coli-derived in vitro transcription-translation system, ArsH was not required for and did not enhance arsenic resistance in E. coli. The T. ferrooxidans ars genes were arranged in an unusual manner, and the putative arsR and arsC genes and the arsBH genes were translated in opposite directions. This divergent orientation was conserved in the four T. ferrooxidans strains investigated.


In situ filamentous communities from the Ediacaran (approx. 563 Ma) of Brazil.
Precambrian filamentous microfossils are common and diverse. Nevertheless, their taxonomic assignment can be difficult owing to their overall simple shapes typically lacking in diagnostic features. Here, we report in situ communities of well-preserved, large filamentous impressions from the Ediacaran Itajaí Basin (ca 563 Ma) of Brazil. The filaments are uniserial (unbranched) and can reach up to 200 µm in width and up to 44 mm in length. They occur as both densely packed or sparsely populated surfaces, and typically show a consistent orientation. Although simple in shape, their preferred orientation suggests they were tethered to the seafloor, and their overall flexibility (e.g. bent, folded and twisted) supports a biological (rather than sedimentary) affinity. Biometric comparisons with modern filamentous groups further support their biological affinity, suggesting links with either large sulfide-oxidizing bacteria (SOB) or eukaryotes. Other morphological and palaeoecological characteristics further corroborates their similarities with modern large filamentous SOB. Their widespread occurrence and association with complex Ediacaran macrobiota (e.g. frondose organisms, Palaeopascichnus) suggest that they probably played an important role in the ecological dynamics of these early benthic communities by providing firm substrates for metazoans to inhabit. It is further hypothesized that the dynamic redox condition in the latest Ediacaran, with the non-continuous rise in oxygen concentration and periods of hypoxia, may have created ideal conditions for SOB to thrive.


Cyclic nucleotides in glutamate chemosensory signal transduction of Paramecium.
Glutamate is an attractant stimulus to Paramecium tetraurelia. It causes a hyperpolarization of the cell and smooth, relatively fast swimming that is characteristic of hyperpolarizing stimuli. We show here that by 1-30 seconds of stimulation, glutamate increases intracellular cAMP. Interestingly, other attractant stimuli, such as acetate and NH4Cl, that similarly hyperpolarize the cell do not induce an increase in cyclic AMP observable at 30 seconds. In order to determine whether the changes in cyclic AMP could be rapid enough to participate in stimulation as compared to slower processes such as adaptation, rapid kinetic measurements of cyclic AMP were made on whole cells by quenched-flow. We found that, in cells stimulated with glutamate, intracellular cyclic AMP increases by 30 mseconds and peaks at about sevenfold over basal levels by 200 mseconds. Cyclic GMP does not change relative to basal levels over rapid or slower time courses of glutamate stimulation. An antagonist of glutamate, IMP, depolarizes the cells and decreases intracellular cyclic AMP by approx. 50% and slightly increases cyclic GMP. Results of behavioral tests of cells treated with protein kinase inhibitors also suggest that cyclic AMP is part of the signal transduction pathway for glutamate, but not for other attractant stimuli. These studies are the first demonstration of a possible role for cyclic nucleotide second messengers in an attractant chemosensory transduction pathway in Paramecium.


Collagenase is a major gene product of induced rabbit synovial fibroblasts.
We have investigated the effects of the tumor-promoting phorbol diester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on rabbit synovial fibroblasts, and found that this agent induced a major switch in gene expression in these cells that was marked by the specific induction of the neutral proteinase, collagenase, and was always accompanied by alterations in cell morphology. Procollagenase synthesis and secretion was first observed 6-12 h after the addition of TPA. The rate of collagenase production (1-5 U, or approximately 0.2-1 micrograms secreted procollagenase protein per 10(5) cells per 24 h) depended on the TPA concentration (1-400 ng/ml) and time of exposure (1-72 h). Procollagenase was the most prominent protein visible by direct silver staining or by autoradiography after SDS PAGE of [35S]methionine-labeled proteins. The two procollagenase bands of Mr 53,000 and 57,000, which migrated as a family of spots on two-dimensional gels and were immunoprecipitated by antibodies to purified rabbit collagenase, accounted for 23% of the newly synthesized, secreted protein in TPA-treated cells. Cell-free translation of mRNA from TPA-treated cells in rabbit reticulocyte lysate produced a single band of immunoprecipitable preprocollagenase (Mr 55,000) as a major product (5% of total) that migrated as a single spot on two-dimensional gels. Secreted procollagenase, preprocollagenase , and active collagenase (purified to homogeneity; specific activity 1.2 X 10(4) U/mg protein) had related peptide maps. Two other major secreted proteins, a neutral metalloproteinase of Mr 51,000 and a polypeptide of Mr 47,000, were also induced by TPA. In contrast to the induction of these four polypeptides, TPA decreased synthesis and secretion of a number of proteins, including collagen and fibronectin. Thus, collagenase is a convenient marker for major alterations in the pattern of protein synthesis and secretion by rabbit synovial fibroblasts treated with TPA.


The Effects of VR-based Wii Fit Yoga on Physical Function in Middle-aged Female LBP Patients.
[Purpose] The purpose of this research was to determine the effects of a virtual reality-based yoga program on middle-aged female low back pain patients. [Subjects and Methods] Thirty middle-aged female patients who suffered from low back pain were assigned to either a physical therapy program or a virtual reality-based yoga program for a period of four weeks. Participants could check their posture and weight bearing on a monitor as they shifted their weight or changed their postures on a Wii balance board. There were a total of seven exercise programs. A 30-minute, three times per week, virtual reality-based Wii Fit yoga program or trunk stabilizing exercise was performed, respectively. [Results] Repeated-measures analysis of covariance revealed significant differences in between pre- and post-training VAS, algometer, Oswestry low-back pain disability index (ODI), Roland Morris disability questionnaire (RMDQ), and fear avoidance beliefs questionnaire (FBQ) scores. The VAS, algometer, ODI, RMDQ, and FBQ scores showed significant differences in groups. Regarding the effect of time-by-group interaction, there were significant differences in VAS, ODI, ODI, and FBQ scores. [Conclusion] In conclusion, for middle-aged female patients who have low back pain, a virtual reality-based yoga program was shown to have positive effects on physical improvements, and this program can be employed as a therapeutic medium for prevention and cure of low back pain.


How does hospitalization affect continuity of drug therapy: an exploratory study.
Transitions between different levels of health care, such as hospital admission and discharge, pose a significant threat to the quality and continuity of medication therapy. This study aims to explore the role of hospitalization on medication changes as patients are transferred from and back to ambulatory care. Secondary analysis of claims data from Swiss residents with basic health insurance at the Helsana Group was performed. We evaluated medication invoices of patients who were hospitalized in a Swiss private hospital group in the year 2013. Medication changes were defined as discontinuation, new prescription, or change in the Anatomical Therapeutic Chemical (ATC) Classification System level 4, which is equivalent to a change in the chemical/therapeutic/pharmacological subgroup. Multiple Poisson regression analysis was applied to evaluate whether medication change was predicted by socioeconomic or clinical patient characteristics or by a system factor (physician dispensing of medication allowed in canton of residence). We investigated a total of 10,123 hospitalized patients, among whom a mean number of 3.85 (median 3.00) changes were identified. Change most frequently affected antihypertensives, analgesics, and antirheumatics. If patients were enrolled in a managed care plan, they were less likely to undergo changes. If a patient resided in a canton, in which physicians were allowed to dispense medication directly, the patient was more likely to experience change. There is considerable change in medication when patients shift between ambulatory and inpatient health care levels. This interruption of medication continuity is in part desirable as it responds to clinical needs. However, we hypothesize that there is also a significant proportion of change due to unwarranted factors such as financial incentives for change of products.


Improved Xylose Metabolism by a CYC8 Mutant of Saccharomyces cerevisiae.
Engineering Saccharomyces cerevisiae for the utilization of pentose sugars is an important goal for the production of second-generation bioethanol and biochemicals. However, S. cerevisiae lacks specific pentose transporters, and in the presence of glucose, pentoses enter the cell inefficiently via endogenous hexose transporters (HXTs). By means of in vivo engineering, we have developed a quadruple hexokinase deletion mutant of S. cerevisiae that evolved into a strain that efficiently utilizes d-xylose in the presence of high d-glucose concentrations. A genome sequence analysis revealed a mutation (Y353C) in the general corepressor CYC8, or SSN6, which was found to be responsible for the phenotype when introduced individually in the nonevolved strain. A transcriptome analysis revealed altered expression of 95 genes in total, including genes involved in (i) hexose transport, (ii) maltose metabolism, (iii) cell wall function (mannoprotein family), and (iv) unknown functions (seripauperin multigene family). Of the 18 known HXTs, genes for 9 were upregulated, especially the low or nonexpressed HXT10, HXT13, HXT15, and HXT16 Mutant cells showed increased uptake rates of d-xylose in the presence of d-glucose, as well as elevated maximum rates of metabolism (Vmax) for both d-glucose and d-xylose transport. The data suggest that the increased expression of multiple hexose transporters renders d-xylose metabolism less sensitive to d-glucose inhibition due to an elevated transport rate of d-xylose into the cell.IMPORTANCE The yeast Saccharomyces cerevisiae is used for second-generation bioethanol formation. However, growth on xylose is limited by pentose transport through the endogenous hexose transporters (HXTs), as uptake is outcompeted by the preferred substrate, glucose. Mutant strains were obtained with improved growth characteristics on xylose in the presence of glucose, and the mutations mapped to the regulator Cyc8. The inactivation of Cyc8 caused increased expression of HXTs, thereby providing more capacity for the transport of xylose, presenting a further step toward a more robust process of industrial fermentation of lignocellulosic biomass using yeast.


A population of comets in the main asteroid belt.
Comets are icy bodies that sublimate and become active when close to the Sun. They are believed to originate in two cold reservoirs beyond the orbit of Neptune: the Kuiper Belt (equilibrium temperatures of approximately 40 kelvin) and the Oort Cloud (approximately 10 kelvin). We present optical data showing the existence of a population of comets originating in a third reservoir: the main asteroid belt. The main-belt comets are unlike the Kuiper Belt and Oort Cloud comets in that they likely formed where they currently reside and may be collisionally activated. The existence of the main-belt comets lends new support to the idea that main-belt objects could be a major source of terrestrial water.


Comparative study using scanning electron techniques for imaging of micro-architecture and antigen appearance.
We have used various scanning electron microscopy technologies for the analysis of structures and the appearance of antigen on eukaryotic cells. Various scanning electron microscopy including conventional scanning electron microscopy, high-resolution scanning electron microscopy and environmental scanning electron microscopy applied for cell surface analysis allow obtaining sub-micrometre surface features on cell membranes. We used cell systems for imaging along with molecular localization of a cell surface antigen, SVEP1 protein. SVEP1 was studied using the immuno-gold technique for the identification of cell surface features and protein localization. We used an antibody to SVEP1 molecule that was labelled with secondary antibody conjugated with gold particles. The comparison between scanning electron methods enabled the visualization of surface structures and the molecular imaging for the distribution of SVEP1.


The phylogenetic potential of entire 26S rDNA sequences in plants.
18S ribosomal RNA genes are the most widely used nuclear sequences for phylogeny reconstruction at higher taxonomic levels in plants. However, due to a conservative rate of evolution, 18S rDNA alone sometimes provides too few phylogenetically informative characters to resolve relationships adequately. Previous studies using partial sequences have suggested the potential of 26S or large-subunit (LSU) rDNA for phylogeny retrieval at taxonomic levels comparable to those investigated with 18S rDNA. Here we explore the patterns of molecular evolution of entire 26S rDNA sequences and their impact on phylogeny retrieval. We present a protocol for PCR amplification and sequencing of entire (approximately 3.4 kb) 26S rDNA sequences as single amplicons, as well as primers that can be used for amplification and sequencing. These primers proved useful in angiosperms and Gnetales and likely have broader applicability. With these protocols and primers, entire 26S rDNA sequences were generated for a diverse array of 15 seed plants, including basal eudicots, monocots, and higher eudicots, plus two representatives of Gnetales. Comparisons of sequence dissimilarity indicate that expansion segments (or divergence domains) evolve 6.4 to 10.2 times as fast as conserved core regions of 26S rDNA sequences in plants. Additional comparisons indicate that 26S rDNA evolves 1.6 to 2.2 times as fast as and provides 3.3 times as many phylogenetically informative characters as 18S rDNA; compared to the chloroplast gene rbcL, 26S rDNA evolves at 0.44 to 1.0 times its rate and provides 2.0 times as many phylogenetically informative characters. Expansion segment sequences analyzed here evolve 1.2 to 3.0 times faster than rbcL, providing 1.5 times the number of informative characters. Plant expansion segments have a pattern of evolution distinct from that found in animals, exhibiting less cryptic sequence simplicity, a lower frequency of insertion and deletion, and greater phylogenetic potential.