Implicit and explicit appraisals of the importance of intrusive thoughts.
To evaluate cognitive theories of obsessions, the current study experimentally manipulated appraisals of the importance of intrusive thoughts. Undergraduate students (N = 156) completed measures of obsessive-compulsive disorder (OCD) symptoms and beliefs and were primed with a list of commonly reported unwanted thoughts. Participants were then informed that unwanted thoughts are either (1) significant and indicative of their personal values, or (2) meaningless, or participants (3) received no instructions about unwanted thoughts. Participants then completed implicit and explicit measures of self-evaluation and interpretations of their unwanted thoughts. Results indicated that the manipulation shifted implicit appraisals of unwanted thoughts in the expected direction, but not self-evaluations of morality or dangerousness. Interestingly, explicit self-esteem and beliefs about the significance of unwanted thoughts were associated with measures of OCD beliefs, whereas implicit self-evaluations of dangerousness were better predicted by the interaction of pre-existing OCD beliefs with the manipulation. Results are discussed in terms of divergent predictors of implicit and explicit responses to unwanted thoughts.


Geometry and structural plasticity of synaptic connectivity.
Changes in synaptic connectivity patterns through the formation and elimination of dendritic spines may contribute to structural plasticity in the brain. We characterize this contribution quantitatively by estimating the number of different synaptic connectivity patterns attainable without major arbor remodeling. This number depends on the ratio of the synapses on a dendrite to the axons that pass within a spine length of that dendrite. We call this ratio the filling fraction and calculate it from geometrical analysis and anatomical data. The filling fraction is 0.26 in mouse neocortex, 0.22-0.34 in rat hippocampus. In the macaque visual cortex, the filling fraction increases by a factor of 1.6-1.8 from area V1 to areas V2, V4, and 7a. Since the filling fraction is much smaller than 1, spine remodeling can make a large contribution to structural plasticity.


[Pathophysiology of overactive bladder].
The pathophysiology knowledge of the overactive bladder syndrome has evolved considerably over the past 20 years. The objective of this work was, from a review of the literature, to synthesize current knowledge on the pathophysiology of the overactive bladder syndrome. A systematic review based on Pubmed, Embase, Google Scholar, was conducted in February 2020 using the keywords "overactive bladder" and "pathophysiology". Four pathophysiological mechanisms involved in the overactive bladder syndrome development can be described. They include the detrusor muscle dysfunction, an urothelial or sub-urothelial origin, a neurological origin and a change in the urinary microbiome. At the same time, it should be noted that all of the pathophysiological mechanisms described above are favored by different clinical conditions such as aging, ischemia, metabolic syndrome, menopause and the dysfunction of other abdominopelvic systems. The pathophysiology of the overactive bladder syndrome is complex and includes several mechanisms most often associated.


Site-selective serotonin agonists as discriminative stimuli.
Various direct- and indirect-acting serotonin (5-HT) agonists serve as training drugs in tests of stimulus control of behavior; such agents include: 5-hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine, and fenfluramine. However, with the recent discovery of multiple populations of central 5-HT binding sites, the concept of site-selective serotonergic agents needs to be addressed. Certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes such as DOM (4-methyl), DOB (4-bromo), and DOI (4-iodo) appear to be 5-HT2-selective agonists and serve as effective training drugs in rats. Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)]. 8-OH DPAT and TFMPP also serve as training drugs; the 8-OH DPAT-stimulus generalizes to other 5-HT1A agonists, but not to 5-HT1B or 5-HT2 agonists, whereas the TFMPP-stimulus generalizes to other 5-HT1B agonists, but not to 5-HT1A or 5-HT2 agonists. Classical serotonin antagonists, most of which are rather selective for 5-HT2 sites, and 5-HT2-selective antagonists are able to block the stimulus effects of DOM, DOB, and DOI, but not those of 8-OH DPAT or TFMPP. The results of such studies reveal that, in rats, site-selective 5-HT agonists produce stimulus effects that are also selective; although generalization may occur with nonselective 5-HT agonists, animals trained to discriminate site-selective 5-HT agonists apparently do not recognize other 5-HT agonists that are selective for a different site. Animals trained to discriminate such agents from saline might be useful for the identification and/or investigation of novel site-selective agonists and antagonists (for example, the 8-OH DPAT-stimulus generalizes to members of a new class of anxiolytics that display high affinity for 5-HT1A binding sites), and might also aid in the overall understanding of central serotonergic mechanisms.


Pragmatic Randomised Controlled Trials for Complex Therapies.
In order to be able to 'predict' the extent or likelihood of success of an intervention, it is essential to know that exposure and effect are causally related. The randomised controlled clinical trial (RCT) is commonly referred to as the golden standard to establish causality. Apart from ethical constraints or rare diseases it is rarely impossible to do an RCT. Sometimes, however, RCTs may not be feasible (at least at first glance) due to e. g. patients' or therapists' reluctance to participate, lack of funding, organisational limitations, or because technical skills to deliver a therapy are not available. A variety of design alternatives have been proposed to overcome these problems, e. g. clinician-preferred treatment, single consent design, double consent randomised design, prerandomisation, cluster randomisation, and response-adaptive designs ('play the winner'). For complex ('combined modality') therapies it seems reasonable to study the effect of the whole treatment package on the patient rather than the value of individual components. Change to open label or optional cross-over allow 'individualized treatment' as well as 'individualized outcome' within the framework of the RCT. For clinicians and researchers it seems wise to put more emphasis on the search for a suitable and appropriate de-sign for their current problem rather than to artificially tailor their study to an awkward standard design (or even abandon the idea to seek an answer to an open question): Much more alternatives exist than one would imagine.


Fetal liver disease may precede extrahepatic siderosis in neonatal hemochromatosis.
Three children of a mother with biopsy-confirmed posttransfusional hepatitis of undetermined etiology (non-A, non-B hepatitis) died in utero or in infancy. All had liver disease of intrauterine onset. The two liveborn children died of the consequences of severe hepatic insufficiency manifest at birth and met clinicopathologic criteria for neonatal hemochromatosis. Although hepatic architecture in the stillborn fetus was markedly disordered, with hepatocyte giant cell transformation, extrahepatic siderosis was not present and hepatic siderosis was minimal. These findings indicate that in some cases of neonatal hemochromatosis, extrahepatic siderosis may be caused by hepatic injury rather than primarily due to excessive transport of iron from mother to fetus and support speculation that in some instances an infective agent may be responsible.


Spinal anaesthesia in children: A narrative review.
Spinal anaesthesia is an established and frequently used anaesthetic technique in adults. However, this versatile regional anaesthetic technique is less frequently used in paediatric anaesthesia even though it can be used for minor (e.g. inguinal hernia repair) and major (e.g. cardiac surgery) surgical procedures. The aim of this narrative review was to summarize the current literature with regard to technical aspects, surgical context, choice of drugs, potential complications, as well as the effects of the neuroendocrine surgical stress response and potential long-term effects of anaesthesia during infancy. In summary, spinal anaesthesia represents a valid alternative in the paediatric anaesthesia setting also.


Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway.
Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.


Mitochondrial and ion channel gene alterations in autism.
To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).


Membrane action of ethmozin on normoxic and hypoxic canine Purkinje fibers.
Transmembrane potentials were recorded from canine Purkinje fiber preparations before and after perfusion with ethmozin (0.05, 0.2, and 1.0 microgram/ml). Under normal oxygenation (95% O2 + 5% CO2; n = 9), ethmozin at 0.05 microgram/ml significantly (p less than 0.05) reduced maximal rate of depolarization (MRD), from 750 +/- 61 to 709 +/- 58 V/s, without affecting other parameters. MRD was further decreased to 647 +/- 53 and 540 +/- 78 V/s at 0.2 and 1.0 microgram/ml of this agent. Reduction of maximal diastolic potential, from -86.1 +/- 6.0 to -84.6 +/- 5.9 mV, occurred only at 1.0 microgram/ml, suggesting that the decrease in MRD is not voltage dependent. Ethmozin significantly shortened the action potential duration at 50 (APD50) and 90% (APD90) repolarization, from 231 +/- 16 and 306 +/- 18 to 199 +/- 26 and 279 +/- 14 ms, respectively. At 1.0 microgram/ml, these values were further reduced. The effective refractory period also showed a concentration-dependent shortening, but the ratio of the refractory period to APD90 was increased. The membrane responsiveness curve was shifted by ethmozin to more negative potentials. The h infinity (inactivation of the fast Na+ current) curve was shifted by 3.8 mV to more negative values by 1.0 microgram/ml ethmozin. "Slow response" produced by high K+ + isoproterenol (0.025 microgram/ml) was not affected by ethmozin (1.0 and 5.0 microgram/ml). Ethmozin exaggerated the electrophysiologic effects of hypoxia (95% N2 + 5% CO2; n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)


A novel bioelectrochemical system for chemical-free permanent treatment of acid mine drainage.
The mining sector is currently under unprecedented pressure due to stringent environmental regulations. As a consequence, a permanent acid mine drainage (AMD) treatment is increasingly being regarded as a desirable target with direct benefits for the environment and the operational and economic viability of the resources sector. In this study we demonstrate that a novel bioelectrochemical system (BES) can deliver permanent treatment of acid mine drainage without chemical dosing. The technology consists of a two-cell bioelectrochemical setup to enable the removal of sulfate from the ongoing reduction-oxidation sulfur cycle to less than 550 mg L-1 (85 ± 2% removal from a real AMD of an abandoned silver mine), thereby also reducing salinity at an electrical energy requirement of 10 ± 0.3 kWh kg-1 of SO42--S removed. In addition, the BES operation drove the removal and recovery of the main cations Al, Fe, Mg, Zn at rates of 151 ± 0 g Al m-3 d-1, 179 ± 1 g Fe m-3 d-1, 172 ± 1 g Mg m-3 d-1 and 46 ± 0 g Zn m-3 d-1 into a concentrate stream containing 263 ± 2 mg Al, 279 ± 2 mg Fe, 152 ± 0 mg Mg and 90 ± 0 mg Zn per gram of solid precipitated after BES fed-rate control treatment. The solid metal-sludge was twice less voluminous and 9 times more readily settleable than metal-sludge precipitated using NaOH. The continuous BES treatment also demonstrated the concomitant precipitation of rare earth elements together with yttrium (REY), with up to 498 ± 70 μg Y, 166 ± 27 μg Nd, 155 ± 14 μg Gd per gram of solid, among other high-value metals. The high-REY precipitates could be used to offset the treatment costs.


Judicial outcomes of child abuse homicide.
To determine whether convictions and sentencing differ between child abuse homicide cases and adult homicide cases and to identify characteristics of the victim, suspect, or crime that influence conviction and sentencing results. Retrospective case review. Homicide data abstracted from the National Violent Death Reporting System in Utah. All deaths classified as homicide in Utah between January 1, 2002, and December 31, 2007. Judicial processing of homicide cases for conviction and sentencing results. Conviction rate, level of felony conviction, and severity of sentencing for suspects of child abuse homicide vs adult homicide. Utah had 373 homicide victims during the study period; 52 cases were child abuse homicide. Among 211 homicide cases with an identified suspect, conviction rates for child abuse homicide (88.2%) and adult homicide (83.0%) were similar (risk ratio, 1.0; 95% confidence interval [CI], 0.8-1.4). There were no significant differences in level of felony conviction (adjusted risk ratio, 0.8; 95% CI, 0.4-1.3) or severity of sentencing (adjusted risk ratio, 0.8; 95% CI, 0.5-1.5) for suspects of child abuse homicide vs adult homicide. Among child abuse homicide cases, no demographic factor was significantly associated with felony conviction results. Suspects of child abuse homicide are convicted at a rate similar to that of suspects of adult homicide and receive similar levels of felony conviction and severity of sentencing.


The difference in activity between (+)- and (-)-methadone is intrinsic and not due to a difference in metabolism.
The disposition and metabolism of (+)- and (-)-methadone has been compared in rats. At equal molecular doses, somewhat higher plasma levels of (-)-isomer were observed. At equal analgesic doses, brain and plasma concentrations of (+)-methadone were at least 25 times greater than those of (-)-methadone. No qualitative differences were observed between isomers with respect to in vivo metabolic pattern or in vitro N-demethylation rates. The results strongly support the conclusion that the large differences in analgesic potency between the isomers is due to an intrinsic difference in pharmacologic properties and is not related to a difference in disposition or metabolism.


Work-related musculoskeletal disorders in vulnerable populations: what are the most common body parts affected?
Studies investigating vulnerable populations have shown that work-related musculoskeletal disorders have a negative impact on quality of life. However, no study has examined the body regions commonly affected by work-related musculoskeletal disorders in vulnerable populations. To describe the body regions commonly affected by work-related musculoskeletal disorders in vulnerable populations. Cross-sectional study. We used the ABEP questionnaire, the World Health Organization Quality of Life, the Nordic Musculoskeletal Disorders Questionnaire, the Perceived Stress Scale, and a self-report questionnaire to determine morning-evening in human circadian rhythms (chronotype assessment). To reduce the possibility of information bias, we provided prior training in the use of the instruments and created an electronic database that was filled out in duplicate (in cases of disagreement, a third researcher was consulted). We tested the normality of the data using the Shapiro-Wilk test. The sample consisted of 132 participants, but there was a sample loss of 41.6% (final sample n = 77). We observed the predominance of those who worked from 6 to 8 h/day, rest of 1 h during the working day, from 1 to 10 years of service and only 1 employment relationship. Regarding the quality of life, we observed a worse result in the domain related to the environment, as well as a stress level of 15.43 (± 7.52) with a maximum of 30. Finally, we observed the presence of pain self-reported by the artisanal fishermen in several regions of the body, lumbar being the most mentioned. The neck, shoulders, arms, elbows, forearms, wrists, back, lumbar spine, and lower limbs are the most common parts of the body affected by work-related musculoskeletal disorders in artisanal fishermen.


The roles of RelA/(p)ppGpp in glucose-starvation induced adaptive response in the zoonotic Streptococcus suis.
The (p)ppGpp signal molecules play a central role in the stringent response (SR) to adapt to nutrient starvation in bacteria, yet the carbohydrate starvation induced adaptive response and the roles of SR in this response is not well characterized, especially in Gram-positives. Here, two (p)ppGpp synthetases RelA and RelQ are identified in Streptococcus suis, an important emerging zoonotic Gram-positive bacterium, while only RelA is functional under glucose starvation. To characterize the roles of RelA/(p)ppGpp in glucose starvation response in S. suis, the growth curves and transcriptional profiles were compared between the mutant strain ΔrelA [a (p)ppGpp(0) strain under glucose starvation] and its parental strain SC-19 [(p)ppGpp(+)]. The results showed great difference between SC-19 and ΔrelA on adaptive responses when suffering glucose starvation, and demonstrated that RelA/(p)ppGpp plays important roles in adaptation to glucose starvation. Besides the classic SR including inhibition of growth and related macromolecular synthesis, the extended adaptive response also includes inhibited glycolysis, and carbon catabolite repression (CCR)-mediated carbohydrate-dependent metabolic switches. Collectively, the pheno- and genotypic characterization of the glucose starvation induced adaptive response in S. suis makes a great contribution to understanding better the mechanism of SR.


Effect of Moringa oleifera leaf extract on exercise and dexamethasone-induced functional impairment in skeletal muscles.
Chronic administration of steroids like dexamethasone produces symptoms including weight loss and skeletal muscle dysfunction. Similar events are reported in chronic or high-intensity exercises, that can lead to fatigue and muscle damage. In the present study, the effect of Moringa oleifera leaf extract was evaluated against dexamethasone (Dex) and exercise (Exe)-induced muscle changes in rats. Six groups each containing 6 rats, namely normal, Dex control, Exe Control, Dex + M. oleifera leaf extract (300mg/kgp.o.), Dex + Exe, Dex + Exe + M. oleifera leaf extract were assessed in the study. Dex was administered at 0.6 mg/kg i.p. daily for 7 days. Exercise was given for a total of 10 days after 30 minutes of dosing using treadmill equipment for 900 seconds at speed 18 m/min. Animals were assessed for variation in body weight, muscular endurance using treadmill, locomotor activity using actophotometer, motor coordination using rotarod on day zero, and day seven. Hemidiaphragm of rats were isolated and used for evaluation of the glucose uptake. Gastrocnemius muscle was isolated and subjected to hematoxylin and eosin staining. Dex and Exe control animals showed a significant decrease in skeletal muscle activity when compared to normal control animals in the actophotometer test. Improvement in endurance were seen in Dex + M. oleifera leaf extract, and Dex + exercise + M. oleifera leaf extract groups compared to Dex control group. Improvement in locomotor activity was seen in Dex group subjected to exercise and was significant when treated with M. oleifera leaf extract. Histology reports were in accordance with the functional parameters. M. oleifera leaf extract supplemented with exercise showed a reversal in the dexamethasone-induced functional impairment in skeletal muscles.


A novel 5x multiplex immunohistochemical staining reveals PSMA as a helpful marker in prostate cancer with low p504s expression.
The ability to combine multiple immunohistochemical (IHC) markers within a single tissue section facilitates the evaluation and detection of co-expressions, while saving tissue. A newly developed 5x multiplex (MPX) IHC staining of five different IHC markers (Basal cell cocktail (34βE12 + p63), p504s (SP116), ERG (EPR3864), Ki-67 (30-9), PSMA (EP192)) was applied on whole sections of n = 37 radical prostatectomies (RPE) including normal and cancerous tissue. Four different colors including brown, magenta, yellow and teal coded for different stainings, whereas magenta was used twice for nuclear Ki-67 and cytosolic / membranous PSMA. The staining of multiplex IHC was compared to single stains of ERG, PSMA and p504s. The proper staining of the basal cell cocktail and Ki-67 could be assessed by internal positive controls in the multiplex staining. The proportion of PSMA and p504s expression revealed a significant correlation between multiplex and single stains (p < 0.01) as well as a concordant staining pattern for ERG (n = 14 prostate cancers were identified ERG positive with both methods). Our proof of concept study demonstrates a robust staining pattern of all five different antibodies with this newly developed 5x MPX IHC. This approach facilitates the recognition of prostate cancer, in particular by adding PSMA in cases with low p504s expression.


Genetic alterations of the APC gene in familial adenomatous polyposis patients of the hellenic group for the study of colorectal cancer.
Familial Adenomatous Polyposis (FAP)-a premalignant clinical entity inherited as an autosomal dominant trait-is characterized by the development of hundreds to thousands of adenomatous polyps of the colorectum during the second and third decade of life. Approximately 80% of the FAP patients harbour truncating germ-line mutations in the APC tumor suppressor gene (Adenomatous Polyposis Coli). We tested 48 members from 9 families. Two novel truncating mutations were identified-2601delGA, R923X--and five already known mutations R564X, R876X, Q1045X, 3927-3931delAAAGA and D1822V were found. Our method for testing was PCR amplification from genomic DNA extracted from whole blood, followed by automated DNA sequencing.


Scleromyxedema with corneal deposits.
Scleromyxedema (Arndt-Gottron syndrome) is a rare cutaneous disease in which hyaluronic acid is deposited in the dermis. The authors describe a patient with scleromyxedema and corneal deposits. A corneal biopsy demonstrated hyaluronic acid deposition in the corneal stroma and amyloid P component in Bowman's membrane. This is the first report of scleromyxedema involving the cornea. It is also the first report of amyloid P component deposition in the cornea occurring independent of corneal amyloid deposits.


Pro-necrotic Activity of Cationic Mastoparan Peptides in Human Glioblastoma Multiforme Cells Via Membranolytic Action.
Glioblastoma multiforme is the most common and lethal malignant brain tumor. Because of its complexity and heterogeneity, this tumor has become resistant to conventional therapies and the available treatment produces multiple side effects. Here, using multiple experimental approaches, we demonstrate that three mastoparan peptides-Polybia-MP1, Mastoparan X, and HR1-from solitary wasp venom exhibit potent anticancer activity toward human glioblastoma multiforme cells. Importantly, the antiglioblastoma action of mastoparan peptides occurs by membranolytic activity, leading to necrosis. Our data also suggest a direct relation between mastoparan membranolytic potency and the presence of negatively charged phospholipids like phosphatidylserine. Collectively, these data may warrant additional studies for mastoparan peptides as new agents for the treatment of glioblastoma multiforme brain tumor.


Gene editing in T cell therapy.
The adoptive transfer of engineered T cells for the treatment of cancer, autoimmunity, and infectious disease is a rapidly growing field that has shown great promise. Gene editing holds tremendous potential for further improvements of T cell therapy. Here we review the applications of gene editing in various T cell therapies, focusing on antiviral strategies and cancer immunotherapies, and discuss the challenges and future prospects.


Erratum: Establishing apoptosis resistant cell lines for improving protein productivity of cell culture.
Cytotechnology 23 : 55-59, 1997.The correct version of authors list should read: Eiji Suzuki(1)-, Satoshi Terada(1), Hiroshi Ueda(1), Tetsuo Fujita(1), Tomoaki Komatsu(1), Yon Hui Kim(1), Shinichi Takayama(2), and John C. Reed(2).


Morphological and molecular characterisation of Diaporthe species associated with grapevine trunk disease in China.
Trunk diseases in grapevine (Vitis spp.) are major problems in the wine and table-grape industries reducing the productivity, quality and longevity of vineyards. Species of Diaporthe are important fungal pathogens of grapevine trunk disease worldwide. A survey of 14 grape vineyards located in different provinces of China was yielded Diaporthe isolates associated with symptomatic grapevine wood. These isolates were identified based on morphology and a combined data matrix of rDNA ITS, partial sequences of translation elongation factor 1-α (EF 1-α), β-tubulin (TUB) and calmodulin (CAL) gene regions. Four species of Diaporthe were identified, which included Diaporthe eres, Diaporthe hongkongensis, Diaporthe phaseolorum and Diaporthe sojae. All isolates of Diaporthe caused disease on detached grape shoots in pathogenicity experiments but differed in virulence. The incidence in local vineyards and the pathogenicity results indicate that D. eres is an important pathogen of grapevine in Chinese vineyards, where it may significantly limit grape production. This is the first detailed report of Diaporthe species associated with grapevine trunk diseases in China with morphology, pathogenicity and molecular data.


[Idiopathic blepharospasm. Clinical and electrophysiological investigations in 27 patients (author's transl)].
Idiopathic blepharospasm is reexamined and the differential diagnosis discussed on the basis of the signs and symptoms of 27 unpublished cases. As in tardive dyskinesia, middle-aged and elderly women are mostly affected. Contrary to general opinion, spontaneous improvement occurred in about one-fifth of the patients. The habituation of the orbicularis oculi reflexes (investigated electromyographically) was diminished in 52% of the patients. These and other symptoms indicate an organic cerebral lesion as the main cause of the disease. Similarities existing between blepharospasm and torticollis spasticus are discussed.


[Changes in the contractile activity of the rat portal vein induced by parathyroid hormone].
Comparative study performed in Wistar and Wistar-Kyoto rats, revealed the effect of parathyroid hormone on the phasic and tonic components of contractile activity of the portal vein smooth muscle cells. The hormone reduced the tonic tension of vessels. The autorhythmic activity frequency was decreased under the effect of the hormone which was followed by increased amplitudes of phasic contractions in the Wistar rats.


Site-Specific Amino Acid Distributions Follow a Universal Shape.
In many applications of evolutionary inference, a model of protein evolution needs to be fitted to the amino acid variation at individual sites in a multiple sequence alignment. Most existing models fall into one of two extremes: Either they provide a coarse-grained description that lacks biophysical realism (e.g., dN/dS models), or they require a large number of parameters to be fitted (e.g., mutation-selection models). Here, we ask whether a middle ground is possible: Can we obtain a realistic description of site-specific amino acid frequencies while severely restricting the number of free parameters in the model? We show that a distribution with a single free parameter can accurately capture the variation in amino acid frequency at most sites in an alignment, as long as we are willing to restrict our analysis to predicting amino acid frequencies by rank rather than by amino acid identity. This result holds equally well both in alignments of empirical protein sequences and of sequences evolved under a biophysically realistic all-atom force field. Our analysis reveals a near universal shape of the frequency distributions of amino acids. This insight has the potential to lead to new models of evolution that have both increased realism and a limited number of free parameters.


Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review.
Choice of urine sampling technique in urinary tract infection may impact diagnostic accuracy and thus lead to possible over- or undertreatment. Currently no evidencebased consensus exists regarding correct sampling technique of urine from women with symptoms of urinary tract infection in primary care. The aim of this study was to determine the accuracy of urine culture from different sampling-techniques in symptomatic non-pregnant women in primary care. A systematic review was conducted by searching Medline and Embase for clinical studies conducted in primary care using a randomized or paired design to compare the result of urine culture obtained with two or more collection techniques in adult, female, non-pregnant patients with symptoms of urinary tract infection. We evaluated quality of the studies and compared accuracy based on dichotomized outcomes. We included seven studies investigating urine sampling technique in 1062 symptomatic patients in primary care. Mid-stream-clean-catch had a positive predictive value of 0.79 to 0.95 and a negative predictive value close to 1 compared to sterile techniques. Two randomized controlled trials found no difference in infection rate between mid-stream-clean-catch, mid-stream-urine and random samples. At present, no evidence suggests that sampling technique affects the accuracy of the microbiological diagnosis in non-pregnant women with symptoms of urinary tract infection in primary care. However, the evidence presented is in-direct and the difference between mid-stream-clean-catch, mid-stream-urine and random samples remains to be investigated in a paired design to verify the present findings.


Peak intensity prediction in MALDI-TOF mass spectrometry: a machine learning study to support quantitative proteomics.
Mass spectrometry is a key technique in proteomics and can be used to analyze complex samples quickly. One key problem with the mass spectrometric analysis of peptides and proteins, however, is the fact that absolute quantification is severely hampered by the unclear relationship between the observed peak intensity and the peptide concentration in the sample. While there are numerous approaches to circumvent this problem experimentally (e.g. labeling techniques), reliable prediction of the peak intensities from peptide sequences could provide a peptide-specific correction factor. Thus, it would be a valuable tool towards label-free absolute quantification. In this work we present machine learning techniques for peak intensity prediction for MALDI mass spectra. Features encoding the peptides' physico-chemical properties as well as string-based features were extracted. A feature subset was obtained from multiple forward feature selections on the extracted features. Based on these features, two advanced machine learning methods (support vector regression and local linear maps) are shown to yield good results for this problem (Pearson correlation of 0.68 in a ten-fold cross validation). The techniques presented here are a useful first step going beyond the binary prediction of proteotypic peptides towards a more quantitative prediction of peak intensities. These predictions in turn will turn out to be beneficial for mass spectrometry-based quantitative proteomics.


[Electrocardiogram analysis in high risk population of unexplained sudden death in Yunnan province].
The purpose of this study was to analyze the electrocardiographic features of the people living in the area with high incidence of unexplained sudden deaths in Yunnan province. The electrocardiograms of 338 residents from three villages (Dayao, Ninglang, Heqing) with high incidence of unexplained sudden deaths and one control village (Dali) were analyzed [averaged age was (33.4 +/- 11.7) years, 175 men and 163 women]. The incidence of cardiac arrhythmias was similar low in all groups. The left ventricular hypertrophy was observed in 34.6% of residents from Dayao. QTc significantly prolonged in the residents from all 3 high incidence areas compare the control area of Dali [control (386.8 +/- 27.22) ms, Ninglang (428.92 +/- 25.71) ms, Heqing (440.67 +/- 28.03) ms, Dayao (417.7 +/- 24.00) ms, P < 0.05 vs. control]. Incidence of U wave was significantly higher in Heqing village than that in control village (P < 0.05). The QUc of these 3 villages was: (613.67 +/- 37.34) ms, (597.19 +/- 46.47) ms, (608.59 +/- 39.59) ms respectively, and also significantly longer than the control village of Dali (589.33 +/- 41.27) ms (P < 0.05). The typical pattern of U wave presents as enlarged U wave and apparent T-U complex. In the 7 residents who have the family history of unexplained sudden death, 6 residents have U wave, and 4 of them present typical U wave pattern. The significant ECG changes in villages with high incidence of unexplained sudden death in Yunnan province were prolonged QTc, enlarged U wave and apparent T-U complex and these ECG features suggested the repolarization abnormalities of the heart in these subjects.


Assessment of the lower limb biomechanics in patients after tibiofibular syndesmosis injury treatment.
There is no consensus as to the number of bone cortices engaged in tibiofibular syndesmosis treatment. The purpose of our study was to assess the weight distribution on the lower limbs after tricortical or quadricortical syndesmosis fixation and different timing of screw removal. A total of 55 patients who underwent treatment for acute tibiofibular syndesmosis injury were analyzed in this study. The Zebris pedobarographic platform was used to measure the distribution of body weight on the lower limbs. The study population was stratified by the time to syndesmotic screw removal (8-15 weeks versus 16-22 weeks) and the number of bone cortices involved in fixation (three [tricortical fixation] versus four [quadricortical fixation]). The weight distribution on the operated and healthy limbs in patients with tricortical syndesmosis fixation was asymmetrical, with the mean load on the operated and healthy limbs of 48.38% and 51.62%, respectively. The patients who underwent quadricortical syndesmosis fixation exhibited a symmetrical distribution of weight on the operated and healthy limb. There was a symmetrical distribution of the load of body weight on the operated and healthy limbs both in the group with different times to syndesmotic screw removal. Tricortical syndesmosis fixation is associated with an asymmetrical weight distribution on the operated and healthy limbs. In treating tibiofibular syndesmosis injuries, based on our pedobarographic research, quadricortical syndesmosis fixation and leaving the syndesmotic screw in place for up to 15 weeks, seems more beneficial to the patient.


No Evidence of Antibodies against GAD65 and Other Specific Antigens in Children with Autism.
The presence of autoantibodies has been proposed as evidence for a role of autoimmunity in autism. This report investigates the prevalence of autoantibodies in children with autism using the luciferase immunoprecipitation systems (LIPS) immunoassay technology. A panel of autoantibody targets against several known and candidate neurological autoantigens, autoimmune-associated autoantigens and viruses was employed. Serological analysis was performed on typically developing children (n = 55), developmentally delayed children without autism (n = 24) and children diagnosed with autism (n=104). Autoantibodies were measured against glutamic acid decarboxylase-65 (GAD65), a CNS autoantigen proposed to be associated with autism and against Ro52, glial fibrillary acidic protein, tyrosine hydroxylase, aquaporin-4, and gamma-enolase, the mouse mammary tumor virus and the xenotropic murine leukemia virus. Antibody levels and seropositivity prevalence were analyzed for statistically significant differences between the three groups. The majority of the children (98%) were seronegative for all targets in the antigen panel. No GAD65 seropositive children were detected in the cohort. Several low level seropositive sera against several of the protein targets were identified in isolated children in each of the three groups, but there was no difference in prevalence. Using this panel of antigens and a sensitive, robust assay, no evidence of unusual immunoreactivity was detected in children with autism, providing evidence against a role of autoimmunity against several previously implicated proteins in autism spectrum disorder pathogenesis. The idea that autoantibodies represent an underlying cause or are biomarkers for autism pathophysiology is not supported by this report.


Coenzyme binding ability of homologs of M4-lactate dehydrogenase in temperature adaptation.
Temperature effects on dissociation constants (Kd), binding enthalpies and apparent Michaelis constants (Km) for NADH, plus Arrhenius activation energies (Ea), substrate turnover numbers (kcat), and NADH 'on' constants (k1) were measured or calculated for M4-lactate dehydrogenase homologs from deep-sea, midwater, shallow-water temperate, and shallow-water tropical teleost fishes, and a mammal. At any single measurement temperature, Km and kcat values were significantly higher for groups adapted to lower temperatures. This pattern of Km values and temperature illustrates a strong evolutionary conservation of Km of NADH. When determined at the average body temperature of each species, the Km values are very similar, resulting in the preservation of the catalytic capacity and regulatory properties of these enzyme homologs at their in situ temperatures. In contrast, Kd values, while varying considerably among species, are not significantly different among the different groups at any one temperature. The ratio of Km to Kd tends to follow a phylogenetic pattern rather than a pattern of environmental adaptation. Thus, evolutionary adjustments in Km are not directly the result of changes in cofactor binding. All the rate constants involved in determining the Km and Kd of NADH (kcat, k1 and k-1) can be modified.


Antigen presentation in the rat: role of a nonadherent, nonphagocytic, W3/13, OX-6 positive T cell in the presentation of antigen to primed T lymphocytes.
The nature of accessory cells in rat lymph nodes which can present antigen to primed T cells was investigated. Removal of adherent, phagocytic cells from antigen-primed lymph node cells by passage over glass-bead and nylon wool columns followed by treatment with carbonyl iron did not abrogate the antigen-specific proliferative response to keyhole limpet hemocyanin (KLH) or to the synthetic polypeptide L-glutamic acid-L-alanine-L-tyrosine (GAT). This T cell-enriched population was free of contaminating macrophages as determined by latex bead ingestion and morphological criteria during a 4-day culture period. Treatment of the T cell preparation with rabbit anti-rat IgG and complement or rosetting with IgG-coated sheep erythrocytes to remove any remaining B cells or macrophages did not significantly affect the proliferative response to antigen. Analysis of the T cell preparation by panning techniques with monoclonal antibodies to T cell surface markers suggested that both the responding T cell and the antigen-presenting cell were positive for the rat T cell marker, W3/13. The KLH-primed LN T cell-enriched fraction contained two distinct cell populations that were separable on the basis of their reactivity to OX-6 antibody. Two populations, an OX-6+ and an OX-6-, interacted synergistically in a KLH-dependent in vitro proliferative response. The cells within the T cell-enriched fraction that were positive for the OX-6 marker functioned primarily as the APCs, while the OX-6- cell fraction contained cells that proliferated to antigen when OX-6+ cells from either the T cell fraction or the adherent fraction were present. The implications of these findings are discussed.


The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis--impact on disease phenotype.
The JAK2 V617F tyrosine kinase mutation is present in the great majority of patients with polycythemia vera (PV), and approximately half of the patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The three distinct disease entities may be considered as three phenotypic presentations of the same JAK2 V617F positive chronic myeloproliferative disorder. Together with physiological and genetic modifiers the phenotype may be determined by the JAK2 V617F allele burden. In the present study, we aimed to asses the JAK2 mutational load and its impact on phenotype. A highly sensitive real-time quantitative PCR (qPCR) assay was used for quantification of the JAK2 V617F mutational load in 165 patients with Philadelphia chromosome negative chronic myeloproliferative disorders (ET = 40, PV = 95, PMF = 30). We provide evidence of increasing JAK2 V617F allele burden from ET, over PV to PMF (P = 0.001 and P < 0.00001 respectively). The present data suggests the JAK2 V617F allele burden as a key determinant of the degree of myeloproliferation and myeloid metaplasia reflected by significantly higher levels of white blood cell counts (WBC) (P = 0.03), CD34 counts (P = 0.03), lactate dehydrogenase and Polycythemia Rubra Vera gene 1 levels (P = 0.03 and P < 0.00001 respectively), as well as lower platelet counts (P = 0.02) and more cases of splenomegaly (P = 0.001) in homozygous PV patients compared to their heterozygous counterparts. The present study support the concept of the JAK2 V617F positive chronic myeloproliferative disorders as a biological continuum with phenotypic presentation in part influenced by JAK2 V617F mutational load.


Computational prediction of amphioxus microRNA genes and their targets.
Using a homology search based on genomic survey sequence analysis and microRNA (miRNA) secondary structure, a total of 51 miRNA genes encoding 30 amphioxus miRNAs were identified. These amphioxus miRNAs belong to 27 miRNA families. Many miRNA genes were found in multiple locations and in more than one genomic context. Analysis of amphioxus miRNA genes revealed nearly 50% miRNA genes identified positioning within introns of protein-coding genes. MicroRNA genes were also positioned intergenically between known protein-coding genes. MicroRNA genes were also clustered throughout the genome, indicating the potential for the cotranscription and coordinate expression of miRNAs located in a given cluster. Cross-species comparison indicates that of the 27 miRNA families, 17 families are shared by both protostomia and deuterostomia, and 2, 3 and 5 families are protostome-specific, deuterostome invertebrate-specific and chordate-specific, respectively. Computational predictions of amphioxus miRNA targets, taking into account the relationship between miRNA target genes and their host genes/neighboring genes, show that 49 target sites for 34 potential target genes were complementary to 19 miRNAs. For the intronic miRNA genes co-expressed with the host gene, they may not be involved in the regulation of the host gene expression. However, some intergenic miRNAs could participate in the modulation of their neighboring gene expression.


Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing.
Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk .


Thyroid hormone upregulates ecto-5'-nucleotidase/CD73 in C6 rat glioma cells.
Thyroid hormones have profound effects on the central nervous system, such as proliferation, secretion of growth factors and gene expression regulation. Ecto-NTPDases and ecto-5'-nucleotidase can control the extracellular ATP/adenosine levels, which have been described as proliferation factors. Here, we investigated the influence of T(3) on the enzyme cascade which catalyzes interconversion of purine nucleotides in rat C6 glioma cells. Exposure of C6 cells to T(3) caused a dose dependent increase of 30% in the AMP hydrolysis up to 0.25 nM, which was suppressed by actinomycin. No significant alteration was observed on ATP/ADP hydrolysis and T(4) at higher concentrations (10-1000 nM) promoted an increase in AMP hydrolysis that was not dose dependent. T(3) treatment also increased the expression of CD73 mRNA. Besides the importance of the ecto-5'-NT in the cell proliferation and differentiation, its overexpression can enhance extracellular adenosine levels, which could also be an important proliferation signal.


Avian Biotechnology.
Primordial germ cells (PGCs) generate new individuals through differentiation, maturation and fertilization. This means that the manipulation of PGCs is directly linked to the manipulation of individuals, making PGCs attractive target cells in the animal biotechnology field. A unique biological property of avian PGCs is that they circulate temporarily in the vasculature during early development, and this allows us to access and manipulate avian germ lines. Following the development of a technique for transplantation, PGCs have become central to avian biotechnology, in contrast to the use of embryo manipulation and subsequent transfer to foster mothers, as in mammalian biotechnology. Today, avian PGC transplantation combined with recent advanced manipulation techniques, including cell purification, cryopreservation, depletion, and long-term culture in vitro, have enabled the establishment of genetically modified poultry lines and ex-situ conservation of poultry genetic resources. This chapter introduces the principles, history, and procedures of producing avian germline chimeras by transplantation of PGCs, and the current status of avian germline modification as well as germplasm cryopreservation. Other fundamental avian reproductive technologies are described, including artificial insemination and embryo culture, and perspectives of industrial applications in agriculture and pharmacy are considered, including poultry productivity improvement, egg modification, disease resistance impairment and poultry gene "pharming" as well as gene banking.


High-risk research in schizophrenia: a summary of what has been learned.
High-risk research on schizophrenia has been concerned chiefly with two types of issues: (1) description of background factors in the early lives of high-risk subjects; and (2) identification of biological variables that may be markers of the genetic liability to schizophrenic disorders. It is concluded that efforts to describe background factors have led to some conflicting results, have shown little evidence of specificity of the factors under study to risk for schizophrenia, and may not be generalizable to most individuals who develop schizophrenia. Results of research focusing on biological variables are summarized under the headings of attention and information processing (AIP), smooth pursuit eye movement (SPEM), neurological signs, electrodermal responding, event related potentials, and ventricular size. Of these, certain AIP and SPEM dysfunctions show substantial evidence of serving as biological markers, certain other AIP impairments are promising in this regard, electrodermal responsivity is not, and the other three categories present uncertain or conflicting results. Several methodological issues that have hampered the first generation of high-risk research are discussed.


Matching familiar figures test: a unidimensional measure of reflection-impulsivity?
In an initial factor-analytic study using preschool children (41 girls, 44 boys), the errors and latencies on the Matching Familiar Figures Test saturated different factors. A second study (47 boys, 39 girls), employing the Kansas Reflection Impulsivity Scale for Preschoolers, replicated this finding. In addition, the error (but not the latency) was associated with measures of gross-motor, fine-motor, and perceptual-motor coordination. The results suggest that error measures a maturational dimension of task-oriented attention for this age group.


A not-so-silent cry for help. Older female cancer caregivers' need for information.
Cancer family caregivers face uncertainty every day. The holistic health care practitioner is in a unique position to alleviate some of this uncertainty by providing information. Although this may appear to be straightforward, unfortunately, more often than not, information is not provided or is provided in such a way that it is more harmful than helpful. This article presents findings from a qualitative study conducted with 21 older female caregivers of persons with advanced-stage cancer. Six areas of concern or need arose from the data and are presented with caregiver narrative examples. This article's purpose is not to be prescriptive (e.g., telling holistic health care practitioners what to say and how to say it). Instead, the purpose is to highlight the need for holistic health care practitioners to evaluate their caregivers' individual needs for information and to attempt to provide this information in a sensitive yet factually accurate manner.


The best utilization of D. zingiberensis C.H. Wright by an eco-friendly process.
An eco-friendly process for the best utilization of D. zingiberensis C.H. Wright tubers was developed. In the first stage, cellulose and ethanol were recovered by physical separation, multi-enzymes hydrolysis with yeast fermentation, and in the second stage diosgenin was separated using ethanol-modified supercritical carbon dioxide extraction. The new approach could not only recover 95% of diosgenin production, 95% of ethanol and 75% of cellulose, but also efficiently reduce 88% of COD in wastewater compared with the conventional method, which only extract diosgenin with discharging 80,000mg/l of COD into public sewers. The research indicates that the proposed system could be a clean and technological-efficient alternative to conventional processing of D. zingiberensis C.H. Wright tubers in industry.


Postoperative complications and pelvic organ prolapse recurrence following combined pelvic organ prolapse and rectal prolapse surgery compared with pelvic organ prolapse only surgery.
There is a growing interest in combined pelvic organ prolapse and rectal prolapse surgery for concomitant pelvic floor prolapse despite a paucity of data regarding complications and clinical outcomes of combined repair. The primary objective of this study was to compare the <30-day postoperative complication rate in women undergoing combined POP + RP surgery with that of women undergoing pelvic organ prolapse-only surgery. The secondary objectives were to describe the <30-day postoperative complications, compare the pelvic organ prolapse recurrence between the 2 groups, and determine the preoperative predictors of <30-day postoperative complications and predictors of pelvic organ prolapse recurrence. This was a multicenter, retrospective cohort study at 5 academic hospitals. Patients undergoing combined pelvic organ prolapse and rectal prolapse surgery were matched by age, pelvic organ prolapse stage by leading compartment, and pelvic organ prolapse procedure compared with those undergoing pelvic organ prolapse-only surgery from March 2003 to March 2020. The primary outcome measure was <30-day complications separated into Clavien-Dindo classes. The secondary outcome measures were (1) subsequent pelvic organ prolapse surgeries and (2) pelvic organ prolapse recurrence, defined as patients who complained of vaginal bulge symptoms postoperatively. Overall, 204 women underwent combined surgery for pelvic organ prolapse and rectal prolapse, and 204 women underwent surgery for pelvic organ prolapse only. The average age (59.3±1.0 vs 59.0±1.0) and mean parity (2.3±1.5 vs 2.6±1.8) were similar in each group. Of note, 109 (26.7%) patients had at least one <30-day postoperative complication. The proportion of patients who had a complication in the combined surgery group and pelvic organ prolapse-only surgery group was similar (27.5% vs 26.0%; P=.82). The Clavien-Dindo scores were similar between the groups (grade I, 10.3% vs 9.3%; grade II, 11.8% vs 12.3%; grade III, 3.9% vs 4.4%; grade IV, 1.0% vs 0%; grade V, 0.5% vs 0%). Patients undergoing combined surgery were less likely to develop postoperative urinary tract infections and urinary retention but were more likely to be treated for wound infections and pelvic abscesses than patients undergoing pelvic organ prolapse-only surgery. After adjusting for combined surgery vs pelvic organ prolapse-only surgery and parity, patients who had anti-incontinence procedures (adjusted odds ratio, 1.85; 95% confidence interval, 1.16-2.94; P=.02) and perineorrhaphies (adjusted odds ratio, 1.68; 95% confidence interval, 1.05-2.70; P=.02) were more likely to have <30-day postoperative complications. Of note, 12 patients in the combined surgery group and 15 patients in the pelvic organ prolapse-only surgery group had subsequent pelvic organ prolapse repairs (5.9% vs 7.4%; P=.26). In the combined surgery group, 10 patients (4.9%) underwent 1 repair, and 2 patients (1.0%) underwent 2 repairs. All patients who had recurrent pelvic organ prolapse surgery in the pelvic organ prolapse-only surgery group had 1 subsequent pelvic organ prolapse repair. Of note, 21 patients in the combined surgery group and 28 patients in the pelvic organ prolapse-only surgery group reported recurrent pelvic organ prolapse (10.3% vs 13.7%; P=.26). On multivariable analysis adjusted for number of previous pelvic organ prolapse repairs, combined surgery vs pelvic organ prolapse-only surgery, and perineorrhaphy at the time of surgery, patients were more likely to have a subsequent pelvic organ prolapse surgery if they had had ≥2 previous pelvic organ prolapse repairs (adjusted odds ratio, 6.06; 95% confidence interval, 2.10-17.5; P=.01). The average follow-up times were 307.2±31.5 days for the combined surgery cohort and 487.7±49.9 days for the pelvic organ prolapse-only surgery cohort. Survival curves indicated that the median time to recurrence was not statistically significant (log-rank, P=.265) between the combined surgery group (4.2±0.4 years) and the pelvic organ prolapse-only surgery group (5.6±0.4 years). In this retrospective cohort study, patients undergoing combined pelvic organ prolapse and rectal prolapse surgery had a similar risk of <30-day postoperative complications compared with patients undergoing pelvic organ prolapse-only surgery. Furthermore, patients who underwent combined surgery had a similar risk of recurrent pelvic organ prolapse and subsequent pelvic organ prolapse surgery compared with patients who underwent pelvic organ prolapse-only surgery.


Poly(vinylpyrrolidone-co-dimethyl maleic acid) as a novel renal targeting carrier.
Poly(vinylpyrrolidone-co-dimethyl maleic acid) (PVD) was found to have high renal-targeting capability and safety as a drug carrier. To optimize the renal drug delivery system using PVD, the relationship between the molecular weight of PVD and its renal accumulation were evaluated in mice by their intravenous injection. It was found that the molecular size of 6-8 kDa was associated with the highest renal accumulation. The specific bioactivity of PVD-conjugated superoxide dismutase (SOD) relative to that of unmodified SOD gradually decreased with an increase in the degree of modification to SOD with PVD6K. The conjugated SOD (L-PVD-SOD) with the molecular size of 73 kDa, which had comparable specific bioactivity with native SOD, showed longer plasma half-life than native SOD. About sixfold more L-PVD-SOD was distributed to the kidneys than native SOD 3 h after intravenous injection, whereas extensive PVD modification did not enhance the renal accumulation of SOD. This L-PVD-SOD effectively accelerated recovery from mercuric chloride-induced acute renal failure in vivo. These results suggest that L-PVD-SOD may be the optimal derivative as a potential therapeutic agent to various renal diseases.


Various hydrogen bonds make different fates of pharmaceutical contaminants on oxygen-rich nanomaterials.
Various hydrogen bonds, especially charge-assisted hydrogen bond (CAHB), is considered as one of vital mechanisms affecting the environmental behavior and risk of pharmaceutical contaminants (PCs). Herein the sorption/desorption of three PCs including clofibric acid (CA), acetaminophen (ACT), and sulfamerazine (SMZ) on three Oxygen-rich (O-rich) nanoparticles (nano-silica: Nano-SiO2, nano-alumina: Nano-Al2O3, and oxidized carbon nanotubes: O-CNTs) were investigated to explore the effect of various hydrogen bonds with different strengths on environmental behaviors of PCs. The results indicated that although solvent-assisted CAHB, solvent-uninvolved CAHB, and ordinary hydrogen bond (OHB) all played a crucial role in sorption of PCs on three O-rich nanomaterials, they showed significantly different effects on the desorption behaviors of PCs from three sorbents. Compared with OHB (hysteresis index ≤0.0766), the stronger CAHB (hysteresis index ≥0.1981) between PCs and O-rich nanoparticles having comparable pKa with PCs, caused obvious desorption hysteresis of PCs, resulting in their better immobilization on O-rich nanomaterials. The FTIR characterization found that both solvent-assisted and solvent-uninvolved CAHB formation resulted in a new characteristic peak appeared in the high frequency (3660 cm-1 for Nano-SiO2, 3730 cm-1 for Nano-Al2O3, and 3780 cm-1 for O-CNTs). Also, density functional theory (DFT) calculation verified that the smaller |ΔpKa| between PCs and O-rich sorbents, the shorter bond length, and the larger bond angle resulted in the stronger hydrogen bond formed, thereby leading to the greater immobilization of PCs. These results provide in-depth understanding of the environmental behavior and risk of PCs, and light new idea for designed materials to control PCs pollution in the environment.


Reassessing Impacts of Extended Daily Exposure to Low Level Solar UV Radiation.
Currently, health agencies recommend that no sun-protection is required when the UV Index (UVI) is less than 3. We use high-quality data from spectroradiometers and model calculations to demonstrate that this simplification is seriously flawed, particularly for mid-latitude conditions. For days when the peak UVI is below the threshold for advising protection, the daily dose of sun-burning UV available frequently far exceeds the threshold for damage to fair skin. This may have important health consequences, as populations at mid latitudes include a significant proportion with fair skin that is susceptible to damage.


The thrifty genotype in type 2 diabetes: an unfinished symphony moving to its finale?
The basic premise of the thrifty gene hypothesis is that certain populations may have genes that determine increased fat storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and type 2 diabetes. The concept finds support in a unique animal model (Psammomys obesus) as well as among high type 2 diabetes susceptibility populations, such as North American Indians and South Pacific islanders. However, in some developing communities (e.g., Black South Africans) the thrifty phenotype hypothesis of perinatal malnutrition causing beta-cell dysfunction seems a better explanation, but this remains a contentious issue. Several genes have already been identified as candidates for the thrifty genotype, including those encoding proteins of the insulin-signaling and leptin pathways, as well as intermediary fat metabolism. Particular interest lies in the peroxisome-proliferator activated receptors. An innovative approach might be to focus on the "mirror image" of the thrifty genotype-congenital lipoatrophic diabetes mellitus, whose molecular defect remains enigmatic. We conclude that the genetic basis of the thrifty genotype probably derives from the multiplicative effects of polymorphisms at several sites mentioned above, rather than a single regulatory abnormality.


Benzo(a)pyrene metabolism by lymphocytes from normal individuals and individuals carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase.
In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects (Mediterranean variant), show a sharp decrease in this enzymatic activity and in NADPH:NADP+ ratio. These cells are less able than controls to hydroxylate benzo(a)pyrene (BaP) when tested in the absence of an exogenous NADPH-generating system. They exhibit great resistance to the toxic effect of BaP. G6PD-deficient fibroblasts are less prone than controls to in vitro transformation by BaP. To investigate whether this depends on a decreased production of active BaP metabolites and BaP:DNA adducts by G6PD-deficient cells, BaP metabolism was studied in G6PD-deficient HL cultured in vitro in the presence of mitogens and treated with BaP for 24 hr. HPLC profiles of organo- and water-soluble metabolites revealed that both types of benzo(a)anthracene (BaA)-induced HL produced: 4,5-, 7,8-, 9,10-diols, 1,3-, 3,6-quinones, 3-, 9-hydroxy and 2 peaks of more polar metabolites. There was a 25-76% decrease of organo- and water-soluble metabolites in the G6PD-deficient cells. When HL were incubated with 7,8-diol, the formation of metabolites mutagenic for Salmonella typhimurium (His-) was very low in G6PD-deficient cells. BaP:deoxyadenosine (dAde) and BaP:deoxyguanosine (dGua) adducts were identified after incubation of both types of HL with BaP. There was a 31-79% fall in adduct formation by G6PD-deficient cells. Our results indicate that G6PD-deficient human lymphocytes are less able to metabolize BaP than normal lymphocytes. We suggest that the NADPH pool is inadequate, in deficient cells, for active BaP metabolism.


Cardiorespiratory fitness as a feature of metabolic syndrome in older men and women: the Dose-Responses to Exercise Training study (DR's EXTRA).
We studied the associations of cardiorespiratory fitness with metabolic syndrome in older men and women, because such data are limited in representative population samples. We studied a population sample of 671 men and 676 women aged 57-79 years at baseline of a randomized controlled intervention study. We assessed maximal oxygen uptake (Vo(2max)) by respiratory gas analysis during a maximal bicycle exercise test. Vo(2max) had a strong, inverse, and graded association with the risk of having metabolic syndrome as defined by the National Cholesterol Education Program criteria. Men and women in the lowest third of Vo(2max) had 10.2- and 10.8-fold higher risks and those in the middle third had 2.9- and 4.7-fold higher risks (P < 0.001 all) of metabolic syndrome than those with the highest Vo(2max) after multivariable adjustments. Factor analysis generated a principal factor that was strongly loaded by the main components of metabolic syndrome and Vo(2max) (-0.68 in men and -0.70 in women). Low cardiorespiratory fitness is associated with metabolic syndrome in older men and women. Our findings suggest that low cardiorespiratory fitness could be considered a feature of metabolic syndrome.


Effect of different DOM components on arsenate complexation in natural water.
Dissolved organic matter (DOM) and dissolved ions are two integral parameters to affect the environmental fate of As in different ways. Numerous studies chose surrogate of DOM, humic substances (HSs), to investigate the As complexation behavior. However, microbial secretion (protein and polysaccharide) was also considered for a great proportion in surface aquatic system, and its effect was still not fully understood. The present research distinguished the As complexation behavior with different DOM components (HSs, protein, polysaccharide and synthetic organic matter) in natural and simulated water samples. The results indicated that different DOM components exhibited various binding capacities for As. HSs showed the strongest affinity for As, followed by long-chain compounds (polysaccharide and synthetic organic matter) and proteins. In water source, HSs were probably the primary parameter for As complexation. In eutrophic water system, however, polysaccharide maybe the main DOM component to bind As. Cationic bridge function was prone to occur in the presence of HSs, but not observed in the presence of protein. PO43- competed for binding sites with As, consequently decreasing the As complexation with all the DOM components. The research implied that a comprehensive and meticulous analyses of DOM fractions and coexist ions are the prerequisite to understanding the behavior of As (or other pollutants) in different natural aquatic systems.


Appropriateness of leaving emergency medical service treated hypoglycemic patients at home: a retrospective study.
Hypoglycemic patients treated by the emergency medical service (EMS) system are commonly left home. The criteria for leaving hypoglycemic patients at home and the appropriateness of the procedure remains, however, unvalidated. The present retrospective article addresses these questions. The Copenhagen physician-based mobile intensive care unit (MICU) responds to emergency calls in a two-tier rendezvous system. Its prehospital data from 1995 to 1998 were retrospectively incorporated into a clinical database and cross-referenced with clinical information from three Danish national registries, enabling identification of criteria for transportation of the patients to the hospital, and a detailed 72-h follow up on patients left at home. The MICU treated 1148 hypoglycemic patients within the period, of which 84% were released at home. Treatment or no treatment before arrival of the MICU and level of consciousness following MICU treatment, were found to be strong predictors of a need for transportation to hospital; although other factors were implicated. Within the 72-h following MICU treatment less than 8% of the patients left at home needed secondary MICU or hospital treatment because of glucose regulatory problems, and less than 5% experienced secondary hypoglycemia. Less than 1% was admitted to hospital beds with recurrent hypoglycemia within 24 h. Poor compliance with the diabetic treatment instructions often appeared to be involved in cases of recurrent hypoglycemia. A delay in admission was not to blame for a serious secondary patient course in any of the cases. The majority of patients with prehospital hypoglycemia may safely be treated and released at home in a physician-based EMS area.


Acid Gastroesophageal Reflux Disease and Apparent Life-Threatening Events: Simultaneous pH-metry and Cardiorespiratory Monitoring.
To investigate the prevalence and the characteristics of gastroesophageal reflux disease (GERD) in infants with apparent life threatening events (ALTE). Infants with at least one episode of ALTE in absence of predisposing factors were included. All infants underwent a cardiorespiratory recording with simultaneous 24-hour pH-monitoring. Patients were divided into 3 groups according to the severity of GERD: A. Reflux Index (RI) <3%, B. RI = 3-7%, C. RI >7%. Monthly evaluations were performed and the anti-reflux therapy was maintained till normalization of monitoring and clinic. 41 infants were enrolled. GERD was found in 80% of patients (moderate in 54%, severe in 27%). A normalization of the cardiorespiratory tracks was recorded on average after 1 month for group A, 7 months for the group B and 9.5 months for group C. A significant difference was registered between group A and both group B and C (P < 0.0001), as well as between the group B and C (P < 0.05). GERD influences significantly the time of normalization of the cardiorespiratory monitoring in infants with ALTE. GERD diagnosis and treatment are mandatory in these patients.


Pathophysiology of Leishmania Infection during Pregnancy.
The pathological processes resulting from parasitic infection are known to have important impacts on the mother child dyad during pregnancy. The roles of parasite transmission and the maternal immune response have been described in diseases such as malaria, toxoplasmosis, and trypanosomiasis. However, the impact of parasites of the genus Leishmania, etiological agents of the neglected tropical diseases tegumentary leishmaniasis (TL) and visceral leishmaniasis (VL), is comparatively less well known, though it is an increasingly recognized concern for infected mothers and their fetuses. In this review, we first consider the pathophysiology of placental infection and transplacental transmission of this parasite, and then discuss the role and mechanisms of the maternal immune system in simultaneously mediating maternal-fetal infection and adverse pregnancy outcomes.


Reversible control of enzymatic transglycosylations in supercritical fluoroform using a lipid-coated beta-D-galactosidase.
The transgalactosylation rate catalyzed by the lipid-coated beta-d-galactosidase in supercritical fluoroform (scCHF3) can be reversibly controlled by changing temperature or pressure (reflecting polarity changes) without damaging enzymes.


Plant and soil nitrogen dynamics in mediterranean grasslands: a comparison of annual and perennial grasses.
The predominance of annual species in the rangelands of southwestern Spain is not due only to climatic factors but is also strongly influenced by grazing management. Manipulating the grazing system in an experimental plot gave a vegetation structure with patches of annual grasses (mainly Vulpia ssp. and Bromus hordeaceus) and patches of perennial grasses (mainly Phalaris aquatica). This vegetation change allowed us to test the hypothesis that life-cycle differences between annual and perennial grasses affect soil nitrogen availability and plant uptake. Nitrogen availability, measured by in situ incubation, and nitrogen uptake were measured through the growing period (October to June). Amounts of in situ mineralized nitrogen over the whole growth phase were more important for soils supporting perennials (37 ppm) than for soils supporting annuals (27 ppm). The difference between the mineral nitrogen produced in situ and the mineral nitrogen accumulated during the same time in the soil allowed an estimation of the maximum mineral nitrogen quantity which can be taken up by the vegetation during each incubation period. The quantities accumulated over the year were 47 and 38 ppm (or 103 and 83 kg/ha) for soils supporting perennials and annuals respectively. For the same period, amounts of nitrogen immobilized in biomass production were 90 and 70 kg/ha for perennials and annuals respectively. During the autumn, a large proportion of mineral nitrogen was leached from soils supporting annual plants which had only just commenced germination. By contrast, the ability to use mineral nitrogen as soon as autumn rains occurred gave a competitive advantage to the perennial species, but only if they were protected from grazing during this period. The higher mineralization and use of this nitrogen reserve by perennials indicates that they made more efficient use of nitrogen resources than annuals, and validate the initial hypothesis.


SUMO1-dependent modulation of SERCA2a in heart failure.
The calcium-transporting ATPase ATP2A2, also known as SERCA2a, is a critical ATPase responsible for Ca(2+) re-uptake during excitation-contraction coupling. Impaired Ca(2+) uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, and is involved in many cellular processes. Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca(2+) decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA (shRNA) accelerated pressure-overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure.


In vivo test system for tumor production by cell lines derived from lower vertebrates.
The immune suppressed lizard, Anolis carolinensis, can be used to test for in vivo tumor production by cell lines derived from a variety of ectothermic vertebrates. Cell lines tested for tumor production were also assessed for loss of attachment-dependent proliferation and contact inhibition of cell overlap. The results demonstrate that the criteria standardly used to assess transformation and neoplastic change in cultured mammalian cells apply equally well to cultured cells from ectotherms.


Association Between the Anti-Aging Protein Klotho and Sleep Duration in General Population.
Sleep duration is associated with aging. However, the relationship between sleep duration and the concentration of the protein klotho in the serum remains unknown in the general population of the United States. Hence, this study aimed at exploring the association between them. Participants whose data included klotho protein and sleep duration variables in the National Health and Nutrition Examination Survey data from 2007 to 2016 were utilized for this analysis. Sleep duration was non-linearly associated with the level of klotho protein in the serum, with a negative association between sleep duration and serum klotho concentration after adjusting for confounding variables (β = -7.6; 95% CI: -11.3, -4.0; P < 0.001). The conversion of the sleep duration from a continuous variable to a categorical variable (tertile: T1: <5.5 hours; T2: 5.5-7.5 hours; T3: >7.5 hours) revealed that the serum klotho of the participants in the highest tertile (>7.5 hours) was 21.9 pg/mL lower (95% CI: -38.6, -5.2; P = 0.01) than those in the lowest tertile (<5.5 hours). Our results revealed that people who sleep more than 7.5 hours per night have decreased levels of the anti-aging protein klotho in their serum, thus being more at risk of aging-related syndromes.


Atlanto-axial dislocation complicating a type II odontoid fracture. Reduction and final fixation.
A case of traumatic posterolateral C1-C2 dislocation associated with odontoid fracture is reported. This is a rare case of traumatic posterolateral C1-C2 dislocation associated with odontoid fracture. Its management is discussed. A traumatic dislocation of atlanto-axial joint associated with an odontoid fracture remains a rare injury. No case of posterior dislocation has been reported so far in the literature with this type of management. The case is of a 25 year-old-man with a primary atlanto-axial posterolateral dislocation associated with a type II displaced odontoid fracture without any neurological complication. The patient underwent gentle traction during 24 hours with a halo frame. An incomplete reduction was achieved. Two days later, a complete reduction was obtained thanks to a preoperative manual traction maintained by a Mayfield (R) modified skull clamp. Anterior C1-C2 fixation was performed according to Vaccaro's technique. The patient wore a cervical collar and underwent physiotherapy during three months. To our best knowledge, this case represents the first traumatic atlanto-axial dislocation associated with an odontoid fracture which was treated through retropaharyngeal approach. This had been rendered possible thanks to the final reduction maneuver in extension.


Effects of subchronic exposure to Caramel Colour III on the immune system in mice.
Administration of Caramel Colour III is associated with lymphopenia in laboratory animals, especially if the animals are fed a vitamin B6-deficient diet. Recently, functional immunological alterations in rats exposed to Caramel Colour III have been reported. The component of Caramel Colour III that is responsible for the immunological effects has been shown to be 2-acetyl-4-tetrahydroxybutyl imidazole (THI). In the present study, female Balb/c mice fed a diet with a relatively high vitamin B6 content were exposed to 2 or 10% of a commercial Caramel Colour III preparation with a low THI content (less than 25 ppm) in the drinking water for 9 wk. Although this treatment did not induce a lymphopenia in the exposed mice, flow cytometric analysis of lymphocyte subpopulations demonstrated reductions in the CD4+ and CD8+ cell populations. In addition, the proliferative response of spleen cells to B and T cell mitogens was significantly reduced in the mice exposed to 2% Caramel Colour III. No changes were observed in natural killer cell activity or in the humoral antibody response to a viral antigen. The results indicate that Caramel Colour III that meets the specified limit of less than 25 mg THI/kg may, nevertheless, interfere with the lymphoid system in mice with an adequate vitamin B6 status.


The Clinical Kinase Index: A Method to Prioritize Understudied Kinases as Drug Targets for the Treatment of Cancer.
The approval of the first kinase inhibitor, Gleevec, ushered in a paradigm shift for oncological treatment-the use of genomic data for targeted, efficacious therapies. Since then, over 48 additional small-molecule kinase inhibitors have been approved, solidifying the case for kinases as a highly druggable and attractive target class. Despite the role deregulated kinase activity plays in cancer, only 8% of the kinome has been effectively "drugged." Moreover, 24% of the 634 human kinases are understudied. We have developed a comprehensive scoring system that utilizes differential gene expression, pathological parameters, overall survival, and mutational hotspot analysis to rank and prioritize clinically relevant kinases across 17 solid tumor cancers from The Cancer Genome Atlas. We have developed the clinical kinase index (CKI) app (http://cki.ccs.miami.edu) to facilitate interactive analysis of all kinases in each cancer. Collectively, we report that understudied kinases have potential clinical value as biomarkers or drug targets that warrant further study.


Postoperative delirium after cholecystectomy in older patients: A retrospective study.
Postoperative delirium (POD) is a common complication that increases mortality and morbidity in older patients. This study aimed to evaluate the clinical significance of post-cholecystectomy delirium in older patients. This retrospective study included 201 patients aged > 75 years who underwent cholecystectomy for acute or chronic cholecystitis between January 2016 and December 2019. Patients were divided into the POD (n = 21) and non-POD (n = 180) groups, and their demographic features and clinical results were compared. The mean patient age was 78.88 years; the female/male ratio was 44.8%/55.2%. Laparoscopic surgery was performed in 93.5% of patients. The univariate analysis showed that lower body mass index (BMI), immobilized admission status, neuropsychiatric disease history, preoperative intervention (percutaneous drainage), high C-reactive protein, hypoalbuminemia, neutrophilia, hypo-/hyperkalemia, and longer operative time were more frequently observed in the POD group. The multivariate analysis showed that lower BMI (odds ratio [OR], 2.796; p = 0.024), neuropsychiatric disease history (OR, 3.019; p = 0.049), hyperkalemia (OR, 5.972; p = 0.007), and longer operative time (OR, 1.011; p = 0.013) were significant risk factors for POD. POD was associated with inflammation degree, general condition, poor nutritional status, electrolyte imbalance, and stressful conditions. Recognizing risk factors requiring multidisciplinary team approaches is important to prevent and treat POD.


Osteogenic properties of bioactive titanium in inflammatory environment.
It is very important that the effects of surface modified titanium on osteogenic differentiation of bone marrow mesenchymal stem cells in the process of bone regeneration. The bio-function of modified titanium could be affected by the inflammatory micro-environment. The aim of this study was to investigate the effects of modified titanium on osteogenic differentiation in the inflammatory conditions and the osteogenic properties of the modified titanium dental implant in vivo. The medical pure titanium metals (PT-Ti) subjected to Anodic Oxidation (AO-Ti), Sand Blasting/acid etching (SLA-Ti) and Plasma-sprayed HA coating (HA coating-Ti) were used for regulating the osteogenic properties of MSCs in the normal and inflammatory conditions. The amount of the MSCs in the inflammatory environment were more similar to that in the non-inflammatory environment after cultured on AO-Ti samples for 7D. However, the proliferation of the MSCs was obviously inhibited on the other groups in the inflammatory condition. The morphology of MSC cells on the modified titanium surface was affected in the inflammatory conditions and the AO-Ti was more conducive to maintain the skeletal morphology of MSCs. The results of osteogenic related proteins expression showed that the amount of BMP-2 on AO-Ti group was the highest in the inflammatory conditions, and followed the order of AO-Ti > HA coating-Ti > SLA-Ti > PT-Ti. What's more, the AO-Ti samples were more beneficial to promote the expression of osteogenic genes ALP, OCN, COL-I and Runx2 in the inflammatory conditions. The results of osteogenic properties in vivo showed that the gingival depth of the AO-Ti group was smaller than that on the other groups. Some new bone could be observed around the AO-Ti implant at two weeks. The bone binding rates on AO-Ti group was the highest of 81.3% after implanted for one year. The AO-Ti was beneficial to osteogenic differentiation than other modified titanium metals in inflammatory condition. The anodic oxidation is an effective surface modification method on titanium to promote bone regeneration.


Willi Hennig's dichotomization of nature.
Two formal assumptions implied in Willi Hennig's "phylogenetic systematics" were repeatedly criticized for not being biologically grounded. The first is that speciation is always dichotomous; the second is that the stem-species always goes extinct when its lineage splits into two daughter species. This paper traces the theoretical roots of Hennig's "principle of dichotomy". While often considered merely a methodological principle, Hennig's realist perspective required him to ground the "principle of dichotomy" ontologically in speciation. As a methodological principle, the adherence to a strictly dichotomously structured phylogenetic system allowed Hennig to be unequivocal in character analysis and precise in the rendition of phylogenetic relationships. The ontological grounding of the "principle of dichotomy" in speciation remains controversial, however. This has implications for the application of techniques of phylogeny reconstruction to populations of bisexually reproducing organisms (phylogeography). Beyond that, the "principle of dichotomy" has triggered an intensive debate with respect to phylogeny reconstruction at the prokaryote level. © The Willi Hennig Society 2010.


Intelligence and epilepsy: The early era.
This contribution to the commemoration of the 20th anniversary of Epilepsy & Behavior addresses the topic of epilepsy and intelligence, an early focus of interest in the history of the neuropsychology of epilepsy. The path through which the earliest measures of intelligence found their way to epilepsy research is reviewed followed by an overview of the subsequent themes of research, points of disagreement, advances in research using measures of intelligence, and developing awareness of the limitations associated with reliance on intelligence tests. Special Issue: Epilepsy & Behavior's 20th Anniversary.


Efficacy of discontinuing the use of low-dose aspirin at 28 weeks of gestation for preventing preeclampsia.
Low-dose aspirin (LDA) has been shown to reduce the incidence of preeclampsia (PE). Previous studies have focused on the timing of LDA initiation, but no study to date has assessed the timing of LDA discontinuation. This study aimed to evaluate the effect of LDA when LDA is initiated between 12 and 16 weeks of gestation and continued until 28 weeks of gestation. This prospective cohort study with historical controls investigated singleton pregnancies that were at a high risk for PE. High-risk factors were defined as a history of hypertensive disorders of pregnancy, chronic hypertension, diabetes mellitus, autoimmune disease, obesity, and high normal blood pressure in the first trimester. We performed adjustments using propensity score matching (PSM) for each indication of LDA, maternal age, primiparity, and assisted reproductive technology. The primary outcome was the incidence of PE. Secondary outcomes were the incidence of preterm PE, fetal growth restriction (FGR), preterm birth, fetal malformation, and maternal postpartum hemorrhage (PPH). A total of 203 and 543 participants were assigned to the LDA and control group, respectively. After PSM, there was no significant difference in the incidence of PE (22.0% vs. 16.8%; p = 0.20), preterm PE (12.0% vs. 13.1%; p = 0.76), FGR (7.9% vs. 12.0%; p = 0.17), or preterm birth (17.3% vs. 15.7%; p = 0.68). There was also no significant increase in maternal PPH or in the incidence of fetal malformations. Discontinuing the use of LDA at 28 weeks of gestation did not result in a lower incidence of PE and FGR.


A hold-and-feed mechanism drives directional DNA loop extrusion by condensin.
Structural maintenance of chromosomes (SMC) protein complexes structure genomes by extruding DNA loops, but the molecular mechanism that underlies their activity has remained unknown. We show that the active condensin complex entraps the bases of a DNA loop transiently in two separate chambers. Single-molecule imaging and cryo-electron microscopy suggest a putative power-stroke movement at the first chamber that feeds DNA into the SMC-kleisin ring upon adenosine triphosphate binding, whereas the second chamber holds on upstream of the same DNA double helix. Unlocking the strict separation of "motor" and "anchor" chambers turns condensin from a one-sided into a bidirectional DNA loop extruder. We conclude that the orientation of two topologically bound DNA segments during the SMC reaction cycle determines the directionality of DNA loop extrusion.


Effects of branched-chain amino acids on postprandial 3-OH butyrate and glucagon in the baboon.
Although chronic postprandial elevation of branched-chain amino acids (BCAAs) occurs in diabetic subjects and in subjects consuming high-protein diets, the metabolic effects of simultaneously increasing levels of these three amino acids are unclear. In this study, a mixture of the BCAAs was infused intravenously into baboons, beginning 30 minutes after the daily meal and continuing for 200 minutes on four consecutive days. Blood samples were collected on the last day of treatment. Infusion of the BCAAs into fed baboons promoted an increase in peak levels of glucagon, a decrease in postprandial levels of seven amino acids, and an increase in plasma levels of 3-OH butyrate. The ketone body response occurred despite an increase in the plasma ratio of insulin/glucagon in four of the five animals and was not associated with a change in the rate of lipolysis as indicated by plasma glycerol measurements. These findings raise the possibility that ketone bodies are one of the metabolic products of BCAA metabolism induced by high concentrations of leucine or ketoisocaproate. The observation that chronic elevation of BCAAs augments glucagon secretion may explain the parallel increases in plasma glucagon and plasma BCAAs observed in subjects fed high protein diets.


New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets.
The recent identification of a cellular balance between ceramide and sphingosine 1-phosphate (S1P) as a critical regulator of cell growth and death has stimulated increasing research effort to clarify the role of ceramide and S1P in various diseases associated with dysregulated cell proliferation and apoptosis. S1P acts mainly, but not exclusively, by binding to and activating specific cell surface receptors, the so-called S1P receptors. These receptors belong to the class of G protein-coupled receptors that constitute five subtypes, denoted as S1P(1)-S1P(5), and represent attractive pharmacological targets to interfere with S1P action. Whereas classical receptor antagonists will directly block S1P action, S1P receptor agonists have also proven useful, as recently shown for the sphingolipid-like immunomodulatory substance FTY720. When phosphorylated by sphingosine kinase to yield FTY720 phosphate, it acutely acts as an agonist at S1P receptors, but upon prolonged presence, it displays antagonistic activity by specifically desensitizing the S1P(1) receptor subtype. This commentary will cover the most recent developments in the field of S1P receptor pharmacology and highlights the potential therapeutic benefit that can be expected from these novel drug targets in the future.


Evaluation of mild periorbital cellulitis and home-based therapy in children-EPOCH study: A prospective single centre cohort study.
Paediatric periorbital cellulitis is a common eye condition and warrants prompt management for the prevention of complications. International consensus on the approach to optimal management of children with mild periorbital cellulitis including ambulatory management is lacking. We aimed to prospectively investigate the safety and effectiveness of ambulatory management of children with mild periorbital cellulitis. Over a 23-month period, we prospectively enrolled 70 children aged between 2 and 16 years who presented to the emergency department with mild periorbital cellulitis. Demographic and clinical data were collected. Eligible children were commenced on oral antibiotics and were discharged home with close outpatient ambulatory care and ophthalmology follow up. We used descriptive statistics for data presentation. Of the 70 children with mild periorbital cellulitis, 30 (43%) had unknown aetiology. Sixty-five (92%) children received a structured ambulatory follow up. Five children (7%) received inpatient parenteral antibiotics for worsening of local symptoms within 24 h of initial presentation. One child developed orbital cellulitis at follow up. There was no mortality or significant morbidity noted in this group and none of the children needed surgical intervention. Ambulatory care for children with mild periorbital cellulitis is an effective and safe management strategy. This might prevent hospitalisation, reduce the burden on hospital bed occupancy and promote patient care in the community.


DelIrium VULnerability in GEriatrics (DIVULGE) study: a protocol for a prospective observational study of electroencephalogram associations with incident postoperative delirium.
Delirium is a neurocognitive disorder common in older adults in acute care settings. Those who develop delirium are at an increased risk of dementia, cognitive decline and death. Electroencephalography (EEG) during delirium in older adults is characterised by slowing and reduced functional connectivity, but markers of vulnerability are poorly described. We aim to identify EEG spectral power and event-related potential (ERP) markers of incident delirium in older adults to understand neural mechanisms of delirium vulnerability. Characterising delirium vulnerability will provide substantial theoretical advances and outcomes have the potential to be translated into delirium risk assessment tools. We will record EEG in 90 participants over 65 years of age prior to elective coronary artery bypass grafting (CABG) or transcatheter aortic valve implantation (TAVI). We will record 4-minutes of resting state (eyes open and eyes closed) and a 5-minute frequency auditory oddball paradigm. Outcome measures will include frequency band power, 1/f offset and slope, and ERP amplitude measures. Participants will undergo cognitive and EEG testing before their elective procedures and daily postoperative delirium assessments. Group allocation will be done retrospectively by linking preoperative EEG data according to postoperative delirium status (presence, severity, duration and subtype). This study is approved by the Human Research Ethics Committee of the Royal Adelaide Hospital, Central Adelaide Local Health Network and the University of South Australia Human Ethics Committee. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences. ACTRN12618001114235 and ACTRN12618000799257.


Actin-Associated Gene Expression is Associated with Early Regional Metastasis of Tongue Cancer.
We aimed to analyze gene expression profile of tongue cancer associated with early lymph node metastasis using the cancer genome atlas (TCGA) data. Basic research. A total of 515 patients with matched RNAseq data of primary tumor and clinical data from TCGA data were extracted. To compare gene expression profile between early T-stage tongue cancer with cervical lymph node metastasis and late T-stage tongue cancer without cervical metastasis, genomic data of following two groups was assessed; 1) group 1: T1/2 and N2/3 (n = 41), 2) group 2: T4 and N0 (n = 65). Using R and limma package in bioconductor program, differentially expressed genes (DEGs) were extracted. Gene ontology and pathway enrichment analysis were performed using the DAVID online tool. FFPE tissue of 285 patients were evaluated for the validation of relevant genes by imunofluorescence (IF) and immunohistochemical (IHC) stain. A total of 225 DEGs were found, and 50 genes were highly significant with absolute fold change over eight. Gene ontology and pathway enrichment analysis revealed that most of the upregulated genes were associated with actin cytoskeleton and included following genes: ANKRD23, NO3, PDLIM3, MUSTN1, TNNT3, MYBPC1, MB, MYH3, TTN, ACTA1, and ACTC1. When comparing tongue cancer with cN0pN0 vs. pN0pN+ using the total tongue cancer cohort of TCGA, ACTA1 was the only parameter which was associated with hidden lymph node metastasis in T1/2 (P = .019). Perineural invasion was significantly associated with high expression of ACTA1 (P < .001). IF and IHC analysis revealed that actin was overexpressed, while E-cadherin and N-cadherin were not significantly different. Actin associated genes, especially overexpression of ACTA1 may be associated with early regional metastasis of tongue cancer. 3 Laryngoscope, 131:813-819, 2021.