A modified dinucleotide for site-specific RNA-labelling by transcription priming and click chemistry.
An improved strategy for RNA labelling using an alkyne-carrying dinucleotide is reported. This involves near-quantitative priming by phage RNA-polymerases followed by conjugation of different labels using click chemistry. Moreover, these transcripts bear a ligation compatible 5'-end, and thus through ligation the terminal label can be transformed to an internal one.


Fas ligand-Fas signaling participates in light-induced apoptotic death in photoreceptor cells.
We investigated the function of Fas in photoreceptors. Postmortem human eyes and mouse-derived photoreceptor cells (661W) were examined for Fas expression by in situ hybridization and immunofluorescence. 661W cells were treated with FasL or Fas agonistic antibody, or exposed to light with/without pharmacological manipulation of Fas signaling, followed by apoptosis detection by TUNEL, immunofluorescence and fluorescence activated cell scanning (FACS). Fractionated cellular extracts were used to detect protein expression or protein phosphorylation after immunoprecipitation by Western blot. Fas was expressed in the photoreceptor layer of human retina. Fas and a cleaved form of FasL were found on the cell surface of 661W cells. Treatment with FasL or Fas agonistic antibody induced apoptosis in 661W cells. Blocking the activity of FasL or administration of caspase-8 inhibitor z-IETD inhibited light-induced apoptosis. However, it simultaneously caused induction of necroptosis, which could be blocked by the receptor-interacting protein 1 (RIP1) inhibitor, necrostatin-1. Light exposure in the presence of z-IETD caused hyper-phosphorylation of RIP1. Light exposure did not elevate the expression of Fas, FasL, or the Fas-associated death domain adaptor protein (FADD). Cells or conditioned medium after light exposure induced apoptosis in dark-adapted cells, which could be attenuated by blockade of Fas. Fas has a pro-apoptotic role in photoreceptors. Under light stress, soluble and membrane-bound FasL can bind to Fas, inducing apoptosis via a paracrine mechanism. Although blocking Fas signaling inhibits apoptosis, it does not improve the overall photoreceptor survival due to a compensatory activation of necroptosis. Hence, prevention of photoreceptor loss from retinal photo-oxidative stress should target Fas and RIP1.


Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy.
Preemptive analgesia is currently in use in the management of postoperative pain and no more under search. The administration of ketamine as intraoperative analgesic agent is well-known since a long time; the analgesic properties of this drug are related to its actions as a non-competitive N-methyl-D-aspartate receptors antagonist; these receptors present an excitatory function on pain transmission and this binding seems to prevent or reverse the central sensitisation of every kind of pain, including postoperative pain. In literature, the use of this anesthetic for the preemptive analgesia in the management of postoperative pain is controversial; for this reason the aim of our study was the clinical evaluation of preemptive perioperative analgesia with low-doses ketamine. This trial involved 40 patients undergoing laparoscopic cholecystectomy, with the same surgical operator; postoperative analgesia was performed with the intraoperative administration of ketamine (0.7 mg/kg) or tramadol (15 mg/kg). A randomized, double-blind study was performed; after an inhalatory/analgesic general anesthesia (sevofluorane + remifentanyl) the postoperative-pain control was clinically evaluated through algometric measurements (Visual Analog Scale, Verbal Rating Scale, Pain Intensity Difference); supplemental doses of tramadol were administered if required, also to quantify the adequacy of analgesia, and adverse effects were evaluated. The results show that preemptive intraoperative analgesia with ketamine produces a good analgesia at the awakening, despite low duration (approximately 1 hour), and upgrades the analgesic effect of tramadol in the postoperative period. Among the adverse effects, some (for example nausea) were related to the administration of both analgesics and to the kind of surgery, others (hallucinosis, nystagmus, photophobia, psychomotor excitation, psychotic symptoms) were due to ketamine, and others (respiratory depression and hypotension) could be related to tramadol. Although the adverse effects due to ketamine are more numerous than those related to tramadol, the second could potentially be more dangerous. Our study suggests that preemptive low-doses ketamine is able to produce an adequate postoperative analgesia and increases the analgesic effect of tramadol; furthermore, ketamine adverse effects could be reduced by intraoperative administration of benzodiazepines and/or antiemetic drugs, or by the association of ketamine and a peripheral analgesic (ketorolac).


Aspirin potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer by targeting GRP78 activity.
Aspirin has recently emerged as an anticancer drug, but its therapeutic effect on lung cancer has been rarely reported, and the mechanism of action is still unclear. Long-term use of celecoxib in large doses causes serious side effects, and it is necessary to explore better ways to achieve curative effects. In this study, we evaluated the synergistic anticancer effects of celecoxib and aspirin in non-small cell lung cancer (NSCLC) cells. In vitro, we evaluated the combined effects of celecoxib (40 μM) and aspirin (8 mM) on cell apoptosis, cell cycle distribution, cell proliferation, cell migration and signaling pathways. Furthermore, the effect of aspirin (100 mg/kg body weight) and celecoxib (50 mg/kg body weight) on the growth of xenograft tumors was explored in vivo. Our data suggest that cancer sensitivity to combined therapy using low concentrations of celecoxib and aspirin was higher than that of celecoxib or aspirin alone. Further research showed that the anti-tumor effect of celecoxib combined with aspirin was mainly produced by activating caspase-9/caspase-3, arresting cell cycle and inhibiting the ERK-MAPK signaling pathway. In addition, celecoxib alone or in combination with aspirin inhibited the migration and invasion of NSCLC cells by inhibiting MMP-9 and MMP-2 activity levels. Moreover, we identified GRP78 as a target protein of aspirin in NSCLC cells. Aspirin induced an endoplasmic reticulum stress response by inhibiting GRP78 activity. Furthermore, combination therapy also exhibited a better inhibitory effect on tumor growth in vivo. Our study provides a rationale for further detailed preclinical and potential clinical studies of the combination of celecoxib and aspirin for NSCLC therapy.


Diaphragm disease compared with cryptogenic multifocal ulcerous stenosing enteritis.
As the use of drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) increases, so too do gastrointestinal ulcers, bleeding, perforation and obstruction. Diaphragm disease of the small intestine is formed by submucosal fibrosis and destruction of lamina muscularis due to chronic ulceration, which corresponds to the most severe stage of NSAID enteropathy. It may lead to stricture of the small intestine. If such ulcerations and strictures in the small intestine are multiple, differential diagnosis is between diaphragm disease and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), because the gross findings of diaphragm disease are similar to those of CMUSE. We report a rare case of diaphragm disease caused by NSAID. It has been finally confirmed by capsule endoscopy and the origin of chronic obscure gastrointestinal bleeding was found to be multiple ulcers and strictures in the small intestine. After operation, we diagnosed the patient with diaphragm disease rather than CMUSE.


Synthesis and Bergman cyclization of a beta-extended porphyrenediyne.
Condensation of a porphyrin-2,3-dione with a 1,2-diaminoarenediyne affords a [small beta]-extended porphyrinic-enediyne: upon thermal Bergman cyclization the quinoxaline spacer positioned between the macrocycle and the enediyne prevents tandem radical cyclization to a picenoporphyrin.


[The effect of vibration on brain GABA metabolism in rats with hypo- and hypercalcemia].
The horizontal vibration (30 min, 20 Hz, A = 0.4 mm) has been studied for its influence on the level of GABA components and dicarbonic acids in brain tissues of adult male rats with hypo- and hypercalcemia. It is assumed, that hypercalcemia vibration situation prevents excessive stress agent, thus leading to a decrease in the level of GABA and activity of glutamate decarboxylase in various structures of the brain.


[The effect of systemic thrombolytic therapy on left ventricular contractile function and on the tolerance for physical loading in patients with an acute myocardial infarct].
36 patients with macrofocal myocardial infarction (MI) underwent systemic thrombolytic therapy with avelysin (500,000-750,000 U) within the disease first 6 hours. By the results of the treatment 2 groups were identified: patients with thrombolysis and myocardial reperfusion (n = 20), patients free of reperfusion manifestations (n = 16). The patients were examined in hospital and outside 10 months after MI development: myocardial contractility and hemodynamics were assessed at echocardiography and radiocardiography, exercise tolerance, coronary and myocardial cardiac reserves using bicycle ergometry. Better exercise tolerance and myocardial contractility were shown both in hospital and in follow-up by patients with myocardial reperfusion. According to the follow-up findings, myocardial contractility was such the same as that on postinfarction week 4, exercise tolerance was much higher than at the first examination. Thus, myocardial reperfusion affects positively the parameters studied in MI patients.


Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Aberrant expression of Jab1/CSN5, a negative regulator of the cell-cycle inhibitor p27, is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional relationship between Jab1 and p27 protein expression in NPC. Immunohistochemical analysis showed an inverse association between Jab1 and p27 in NPC tissue samples, and overexpression of Jab1 correlated with poor survival in patients with NPC. Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome-dependent manner. Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability. Jab1 depletion also enhanced the antitumor effects of cisplatin in NPC cells. Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1-mediated p27 degradation. Jab1 therefore represents a novel diagnostic marker and therapeutic target in patients with NPC.


Serum estradiol is associated with volumetric BMD and modulates the impact of physical activity on bone size at the age of peak bone mass: a study in healthy male siblings.
This study investigates determinants of peak bone mass (PBM) in healthy men, focusing on effects and interactions of parameters reflecting mechanical loading and sex steroids. Healthy male siblings (n = 677; 25-45 yr) were recruited in a cross-sectional, population-based study. Physical activity score was assessed by a self-reported questionnaire. Cross-sectional muscle area (CSMA) and bone parameters of radius (4% and 66% site) and tibia (66% site) were assessed using pQCT. Peak torque of biceps and quadriceps muscles was assessed by isokinetic dynamometry. Serum testosterone (T) and estradiol (E(2)) levels were measured using immunoassays; free hormone fractions were calculated. Relations between indices of bone strength, CSMA, muscle strength, and sex steroids were studied using linear mixed-effects modeling. Physical activity, CSMA, and muscle strength were positively associated with indices of bone strength, except for volumetric BMD (vBMD). After controlling for age, weight, and height, free E(2) levels were positively associated with trabecular and cortical vBMD, negatively associated with endosteal circumference at the radius, and positively associated with cortical vBMD at the tibia. In addition, positive interactions between physical activity and serum E(2) concentrations were observed for bone size at the tibia. No associations between free T levels and pQCT bone parameters were found. In this population of healthy men at the age of PBM, parameters reflecting mechanical loading are confirmed as important determinants of bone size. E(2), but not T, levels are positively associated with vBMD and modulate the impact of physical activity on bone size at the tibia.


[Use of muramyl peptides in viral vaccines].
Discusses the selective activation of HIV replication under the effect of various muramylpeptides with immunostimulating effect. Emphasizes the significance of selecting adjuvants inducing no HIV activation, particularly in cases when the vaccines are intended for seropositive subjects.


[Information on parity in the medical registry of births of the National Board of Health. Validation with the help of a new fertility database in Danish Statistics].
Information on parity from the Medical Register of Births kept by The Danish National Board of Health was compared with a parity value calculated with the aid of a new, individual-based Fertility Database compiled by the Danmarks Statistik. The parity information contained in the Medical Register of Births is recorded by the midwife at each birth, where the woman's number of previous live-births is noted. The Register on Population Statistics records live-born infants with reference to their mother, and parity is calculated in the Fertility Database on the basis of these records. The results show a very high degree of accordance between the two measures of parity. More than 99.5% of women with parity one who have given birth since 1978 are classified as such by both systems. Due to an ambiguity in the midwife's birth notification form there has previously been uncertainty regarding the classification of first-time mothers based on the information contained in the Medical Register of Births. This evaluation shows that this information can be regarded as valid.


Autoimmune diseases in pregnancy.
Autoimmune diseases are a significant problem in women of reproductive age. This article reviews some of the more common autoimmune disorders and discusses their diagnosis and management during pregnancy. The effects of the autoimmune disorder on pregnancy and the effects of pregnancy on the course of the autoimmune disorder are also discussed with an emphasis on the implications for clinical management.


[Forensic-medical assessment of terroristic chemical attacks].
By potential damage, chemical terroristic attacks are much more dangerous than terroristic bombing. To fight chemical terrorism it is necessary to create the system of medical-environmental defense of the population. In line with emergency medicine, forensic medical service is a very important element of the antiterroristic defense. The activity of forensic-medical experts in the field of terroristic chemical attack is analysed.


Recovery and repair issues after stroke from the scientific perspective.
Animal and human studies have shown that motor and somatosensory cortex are capable of reorganization throughout adult life. Cortical reorganization has been associated with functional recovery in experimental and human stroke. Retraining after experimental cortical infarction has been shown to extend cortical representation of the infarcted area and improve skilled motor performance.


Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model.
Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay (®) (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-β-glucuronide (E17βG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and interesting research lines in biology and human physiology with the potential for significant benefits for both space and terrestrial medicine.


[Safety criteria in the problem of protection for the pilot's head against impact].
In order to determine man's tolerance, clinical symptoms of craniocerebral injuries were compared with physical characteristics of impacts. A ranking scheme of clinical manifestations of craniocerebral injuries as applied to specific flight conditions was developed. With respect to the craniocerebral injury biomechanics, clinical data were taken under statistical study, which helped to evaluate impact critical parameters and to propose a graphic scheme that can be used to describe in detail the accident and to estimate the probability of injuries of various degree over the entire range encountered in aviation and clinical practice.


Characteristics of Patients with Nonvariceal Upper Gastrointestinal Bleeding - Are We Underestimating Gastroprotection during NSAIDs Therapy?
The aim of our study was to determine the etiological factors, treatment and outcome of patients with non-variceal bleeding from upper gastrointestinal tract. This study enrolled 200 patients admitted to Sarajevo University Clinical Center with signs and symptoms of upper gastrointestinal bleeding, from January 2019 to July 2020. All patients had undergone gastroscopy, confirming the cause of gastrointestinal bleeding. Clinical and laboratory data were collected retrospectively, including previous non-steroid antiinflammatory drugs (NSAIDs) and anticoagulant therapy, comorbidities, risk factors, as well as endoscopic findings, laboratory findings, treatment and clinical follow-up. The majority of patients were men (59%) with an average age of 53±6 years. Duodenal and gastric ulcers were the most common cause, followed by other etiologies. In our study, previous NSAIDs therapy had been registered in 29.5% of patients, anticoagulants in 8%, and proton pump inhibitors (PPI) in 2.9% of patients. Endoscopic intervention was required in 34% of patients. The need for transfusion occurred in 44.5% of cases. Rebleeding during hospitalization was observed in 7.5% of patients, mortality in 1.5% and surgery in 3% of patients. The patients admitted to our hospital with symptoms of acute nonvariceal upper gastrointestinal bleeding were elderly, predominantly males, with significant comorbidities and a higher incidence of NSAID use. Gastroprotection is underutilized during NSAID treatment in patients with other coexisting risk factors, with a low rate of concomitant use of PPI during NSAIDs therapy. Endoscopic therapy, together with PPI, significantly reduces rebleeding rates, mortality and the number of emergency surgical interventions.


Three dimensional porous SiC for lithium polysulfide trapping.
One of the key issues in lithium sulfur batteries is the fast capacity fade induced by the lithium polysulfide (LiPS) migration. Hence, a series of three-dimensional (3D) porous SiC materials with active sp2 Si atoms have been designed for lithium polysulfide entrapping in Li-S batteries. The ZGM-SiC-1 and AGM-SiC-3 have been confirmed to be thermodynamically and dynamically stable from the formation energy and phonon dispersion spectrum, meanwhile showing good mechanical properties. The moderate band gaps suggest fast electron transport during the charge-discharge cycles of the Li-S batteries, especially in ZGM-SiC-1. The 3D porous ZGM-SiC-1 and AGM-SiC-3 display strong affinity to S8 and LiPS with the direct Si-S and Li-C interactions, which are comparable to the case of the N doped carbon host. As compared to the 3D pristine graphene monoliths and two dimensional SiC nanosheet, the entrapping of LiPS in the 3D porous SiC host is much stronger (ca. 2.5 eV to 3.5 eV), which is effective in inhibiting the shutter effect in Li-S batteries. Most interestingly, the extraordinarily strong adsorption of the S8 molecule indicates high sulfur loading in the 3D porous SiC host.


Clinical, genetic and regulatory consequences of exposure to mutagens.
Not a single agent is known to cause an increase of genetic disorders in humans. Even studies on large numbers of children born to parents after exposure to ionizing radiation or DNA alkylating agents failed to detect significant genetic consequences. This is in contrast to effects observed in human somatic cells or germ cells, and to various investigations with laboratory animals. A definite explanation of these discrepancies does not exist. Nevertheless, on the basis of the currently available human data it cannot be justified to advise a previously exposed person against having children, if this individual is otherwise healthy. There are obvious incongruencies between the potency of an agent to cause mutations at all, and to induce genetic effects in the offspring. It should therefore be emphasized that a regulatory classification of agents according to a potential genetic hazard in man must not solely be based on in vitro mutagenicity data.


Partial sequence of human platelet heparitinase and evidence of its ability to polymerize.
Heparitinase cleaves heparan sulfate, a glycosaminoglycan associated with all nucleated mammalian cells and extracellular matrices. Despite the important physiologic role heparitinase is postulated to play in such processes as tumor metastasis and inflammation, the identity of the enzyme remains a matter of controversy and there is a question of whether heparitinase is CTAP III. We report a 900,000-fold purification of heparitinase from human platelets. A multi-step procedure utilizing chromatography on heparin, DEAE, hydroxyapatite and size exclusion matrices was employed and yielded a single protein as judged by Coomassie staining of protein separated by SDS-PAGE. The purified protein had an apparent molecular mass of 35 kDa by size exclusion chromatography and 55 kDa by SDS-PAGE. During purification, heparitinase activity co-eluted from the hydroxyapatite and size exclusion columns with the 35-55 kDa protein, confirming that the purified protein was indeed heparitinase. The 35-55 kDa protein reacted strongly with concanavalin A, a lectin known to bind to heparitinase, further confirming that the protein was heparitinase. Platelet heparitinase formed dimers and tetramers upon storage in a purified form, possibly accounting for the various molecular weights previously reported for the enzyme. A partial amino acid sequence of the protein revealed that heparitinase has not been previously sequenced.


Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice.
Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice (Scn5a(+/ΔKPQ)). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a(+/ΔKPQ) mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a(+/ΔKPQ) mice, light phase-restricted feeding shifted the RR and QT rhythms ~12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ~10%. In contrast to WT mice, the QTc interval in Scn5a(+/ΔKPQ) mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a(+/ΔKPQ) mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.


Optical-Fiber Microsphere-Based Temperature Sensors with ZnO ALD Coating-Comparative Study.
This study presents the microsphere-based fiber-optic sensor with the ZnO Atomic Layer Deposition coating thickness of 100 nm and 200 nm for temperature measurements. Metrological properties of the sensor were investigated over the temperature range from 100 °C to 300 °C, with a 10 °C step. The interferometric signal was used to monitor the integrity of the microsphere and its attachment to the connecting fiber. For the sensor with a 100 nm coating, a spectrum shift of the reflected signal and the optical power of the reflected signal were used to measure temperature, while only the optical power of the reflected signal was used in the sensor with a 200 nm coating. The R2 coefficient of the discussed sensors indicates a linear fit of over 0.99 to the obtained data. The sensitivity of the sensors, investigated in this study, equals 103.5 nW/°C and 19 pm/°C or 11.4 nW/°C for ZnO thickness of 200 nm and 100 nm, respectively.


Precise instrumental conditioned reflexes and the role of different sensory modalities in their execution in dogs.
Elaboration of an instrumental reaction involving conditioned rearrangement of innate motor coordination takes a long time to attain in dogs. Particular difficulties are encountered in the execution of conditioned movement when painful stimulation evokes an inborn response opposite to the conditioned one. Exclusion of visual control of performance selectively impairs the phase of searching for the "safety zone" by the animal, whereas the ability to maintain the limb in a constant position for a long time and to carry out its correct readjustments was not affected. Exclusion of afferents from the joint led to profound and irreversible motor disturbances: along with considerable impairment of the ability to maintain the limb at a given height. Also affected were searching for the "safety zone" and the ability to carry out prompt and correct adjustments upon exposure to painful stimuli. As a result, motor reactions were accompanied by a large number of shocks when the "safety zone" was wide and could not be carried out at all when it was narrow. Forcing the animals into the unusual posture strongly disrupted the elaborated reactions: the animals were no longer able to find the "safety zone" either during the isolated action of the signal or during painful stimulation. The observed disturbances tended to progress and gradually led to the derangement of the motor habit, up to complete dropping out of the conditioned reflex component.


Support Seeking in the Postpartum Period: Content Analysis of Posts in Web-Based Parenting Discussion Groups.
The transition from pregnancy to motherhood is a major developmental phase that can be challenging for both women and their families. For new mothers, the postpartum period is recognized as a critical period for increased risk of both physical and mental health concerns. For this reason, it is imperative that women receive accurate, evidence-based information during this time. This study aims to explore the conversations of new mothers on a web-based parenting forum to investigate what topics or concerns are being discussed. A leading Australian web-based support forum for women before and after birth was used to obtain a sample of posts from the mothers of infants aged 0-12 months. Quantitative data (word frequencies and sentiment analysis) and qualitative data (post content) were extracted from discussion threads and examined to determine sentiments and theoretical storylines. In total, 260 posts were sampled. Infant care was the most prominent overarching topic discussed, with feeding and sleep being the most discussed subtopics. Discussions about maternal care were much less frequent but included questions about birth recovery, breastfeeding concerns, and interconception. A pattern of behavior emerged within the posts. This pattern resembled a cycle of learning across five phases: help seeking, solution ideation, testing and skill development, consolidation, and empowerment and improved mental well-being. A dynamic interplay was observed as mothers navigated new concerns or developmental changes. Engagement in web-based forums to seek help and support during the postpartum period was common, with infant health and well-being being the primary concerns for new mothers during this time. The identification of a maternal learning cycle within the forum underscores the contributory role of web-based communities in maternal peer social support, information seeking, and early parenting practices.


[Analysis of variables related with dementia mortality trend. Andalusia, Spain].
The dementias are a cause of mortality have increased over the last years. Therefore is important to analyze the variables more related to its development in Andalusia between 1999 and 2010. With the deaths of 60 and over by dementia from Andalusia Statistical Institute and the populations from corresponding years, are estimated crude mortality rates, standardized and age-specific; by joinpoint regression was calculated percentages annual change; and also, with the population estimates by marital status and deaths was calculated crude rates and standardized for age, sex and marital status. The standardized mortality rates increased from 124.8 to 161.0 deaths per 100,000 in women and 110.3 to 147.7 in men, the annual increase was 4.2% and 3.8% in women and men. The women died more than men with a standardized rate ratio between 1.08 and 1.29. Age was the variable that determined mortality. Mortality from dementia in Andalusia has increased over the past 12 years and will continue to increase with the consequent social and health impacts posed by these diseases, configured as a major health problem.


The efficacy of biodiversity and ecosystem assessment approaches for informing a regenerative approach to built development.
The built environment, even at its "greenest," inevitably entails changing ecosystem structure and function. Multiple sustainable development tools and approaches are available to reduce environmental harm from built development. However, the reality that society exists within fully integrated socioecological systems, wholly interdependent on supporting ecosystems, is not yet adequately represented in regulation or supporting tools. Regenerative development seeks to address this interdependence in part by improving the health of supporting socioecological systems through the development process. We demonstrate the relevance of a series of approaches-Local Nature-Related Planning Policy (LNRPP), Biodiversity Net Gain (BNG), the Environmental Benefits from Nature Tool (EBN Tool), Nature Assessment Tool for Urban and Rural Environments (NATURE Tool), and Rapid Assessment of Wetland Ecosystem Services+ (RAWES+)-for their ability to meet their stated aims and objectives and how these relate to wider regenerative themes. A comparative analysis of the five approaches is done by applying them to a practical case study site, resulting in policy- and practice-relevant learning and recommendations. The research reveals current gaps in methodology, which can lead to adverse outcomes for sustainability. This is particularly clear for the spatial and temporal scales across which each approach operates. In addition, this research discusses the inherent limitations of taking a reductionist approach to examining complex systems. Integr Environ Assess Manag 2023;00:1-15. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Phylogenomic Analyses of Non-Dikarya Fungi Supports Horizontal Gene Transfer Driving Diversification of Secondary Metabolism in the Amphibian Gastrointestinal Symbiont, Basidiobolus.
Research into secondary metabolism (SM) production by fungi has resulted in the discovery of diverse, biologically active compounds with significant medicinal applications. The fungi rich in SM production are taxonomically concentrated in the subkingdom Dikarya, which comprises the phyla Ascomycota and Basidiomycota. Here, we explore the potential for SM production in Mucoromycota and Zoopagomycota, two phyla of nonflagellated fungi that are not members of Dikarya, by predicting and identifying core genes and gene clusters involved in SM. The majority of non-Dikarya have few genes and gene clusters involved in SM production except for the amphibian gut symbionts in the genus BasidiobolusBasidiobolus genomes exhibit an enrichment of SM genes involved in siderophore, surfactin-like, and terpene cyclase production, all these with evidence of constitutive gene expression. Gene expression and chemical assays also confirm that Basidiobolus has significant siderophore activity. The expansion of SMs in Basidiobolus are partially due to horizontal gene transfer from bacteria, likely as a consequence of its ecology as an amphibian gut endosymbiont.


Beyond the tip of the iceberg: A narrative review to identify research gaps on comorbid psychiatric disorders in adolescents with methamphetamine use disorder or chronic methamphetamine use.
Methamphetamine use disorder (MUD) frequently begins in adolescence, often accompanied by other psychiatric or mental disorders. Up to now, no comprehensive review about MUD and comorbid disorders in adolescents is available. We thus aimed to review the literature on comorbid mental disorders and MUD in adolescents in order to identify future research topics. Method: A PubMed search was conducted in July 2019. Relevant comorbidities were defined as attention-deficit disorder with/without hyperactivity, anxiety disorders, depression, eating disorders, post-traumatic stress disorder, psychosis, borderline personality disorder, conduct disorder and antisocial personality disorder, as well as other substance use disorders. For each comorbidity, we summarized prevalence rates, findings on comorbidity mechanisms, and recommended treatment options, if applicable. Results: Few articles focused on MUD in adolescents. Prevalence rates differed largely between comorbid disorders, with tobacco use disorder, conduct disorder, post-traumatic stress disorder, anxiety disorders, and attention-deficit disorders being the most prevalent comorbidities while eating disorders were rare. Examined onset patterns and comorbidity mechanisms indicated three groups of comorbidities: preexisting disorders self-medicated with methamphetamine, disorders induced by chronic methamphetamine use, and disorders arising due to risk factors shared with MUD. Reviewed comorbidities were frequently associated with worse treatment outcomes. Conclusions: The limited evidence is in stark contrast to the presumably high prevalence and relevance of comorbid mental disorders in adolescents with MUD. Suggestions for future research topics, informed by adult findings, include genetic vulnerabilities, biological changes, and consequences of different use patterns. Surprisingly few MUD treatment programs explicitly integrate comorbid mental disorder modules.


Insight into a strategy for attenuating AmpC-mediated beta-lactam resistance: structural basis for selective inhibition of the glycoside hydrolase NagZ.
NagZ is an exo-N-acetyl-beta-glucosaminidase, found within Gram-negative bacteria, that acts in the peptidoglycan recycling pathway to cleave N-acetylglucosamine residues off peptidoglycan fragments. This activity is required for resistance to cephalosporins mediated by inducible AmpC beta-lactamase. NagZ uses a catalytic mechanism involving a covalent glycosyl enzyme intermediate, unlike that of the human exo-N-acetyl-beta-glucosaminidases: O-GlcNAcase and the beta-hexosaminidase isoenzymes. These latter enzymes, which remove GlcNAc from glycoconjugates, use a neighboring-group catalytic mechanism that proceeds through an oxazoline intermediate. Exploiting these mechanistic differences we previously developed 2-N-acyl derivatives of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), which selectively inhibits NagZ over the functionally related human enzymes and attenuate antibiotic resistance in Gram-negatives that harbor inducible AmpC. To understand the structural basis for the selectivity of these inhibitors for NagZ, we have determined its crystallographic structure in complex with N-valeryl-PUGNAc, the most selective known inhibitor of NagZ over both the human beta-hexosaminidases and O-GlcNAcase. The selectivity stems from the five-carbon acyl chain of N-valeryl-PUGNAc, which we found ordered within the enzyme active site. In contrast, a structure determination of a human O-GlcNAcase homologue bound to a related inhibitor N-butyryl-PUGNAc, which bears a four-carbon chain and is selective for both NagZ and O-GlcNAcase over the human beta-hexosamnidases, reveals that this inhibitor induces several conformational changes in the active site of this O-GlcNAcase homologue. A comparison of these complexes, and with the human beta-hexosaminidases, reveals how selectivity for NagZ can be engineered by altering the 2-N-acyl substituent of PUGNAc to develop inhibitors that repress AmpC mediated beta-lactam resistance.


Students aggress against professors in reaction to receiving poor grades: an effect moderated by student narcissism and self-esteem.
Laboratory evidence about whether students' evaluations of teaching (SETs) are valid is lacking. Results from three (3) independent studies strongly confirm that "professors" who were generous with their grades were rewarded for their favor with higher SETs, while professors who were frugal were punished with lower SETs (Study 1, d = 1.51; Study 2, d = 1.59; Study 3, partial η(2) = .26). This result was found even when the feedback was manipulated to be more or less insulting (Study 3). Consistent with laboratory findings on direct aggression, results also indicated that, when participants were given a poorer feedback, higher self-esteem (Study 1 and Study 2) and higher narcissism (Study 1) were associated with them giving lower (more aggressive) evaluations of the "professor." Moreover, consistent with findings on self-serving biases, participants higher in self-esteem who were in the positive grade/feedback condition exhibited a self-enhancing bias by giving their "professor" higher evaluations (Study 1 and Study 2). The aforementioned relationships were not moderated by the professor's sex or rank (teaching assistant vs.professor). Results provide evidence that (1) students do aggress against professors through poor teaching evaluations, (2) threatened egotism among individuals with high self-esteem is associated with more aggression, especially when coupled with high narcissism, and (3) self-enhancing biases are robust among those with high self-esteem.


Altered nuclear factor-kappaB inducing kinase expression in insulin-resistant mice.
Insulin resistance is an underlying feature of both type 2 diabetes and metabolic syndrome. Currently, it is unclear whether nuclear factor (NF)-κB inducing kinase (NIK) plays a role in the development of insulin resistance. The present in vivo study investigated the roles of NIK and IκB kinase α (IKKα) in obesity-induced insulin resistance using animal models. NIK expression was evaluated by Western blotting in male Lep(ob) mice and C57BL/6J mice fed a high-fat diet (HFD) (45% fat). After metformin and sulfasalazine treatment, NIK expression was investigated during the improvement of insulin resistance. NIK was increased by about 1-fold in the renal tissues of Lep(ob) mice and C57BL/6J mice fed a HFD for 12 weeks. After 1 and 3 weeks of high-fat feeding, we observed an almost 50% decrease in NIK and IKKα expression in the liver and renal tissues of C57BL/6J mice. NIK expression was significantly lower in the liver and renal tissues of HFD-fed mice that were treated with insulin sensitizers, metformin and sulfasalazine. However, IKKα expression was increased after metformin treatment in both tissues. These results suggest a possible role of NIK in the liver and renal tissues of insulin-resistant mice.


Long-term effect of yogic practices on diurnal metabolic rates of healthy subjects.
The metabolic rate is an indicator of autonomic activity. Reduced sympathetic arousal probably resulting in hypometabolic states has been reported in several yogic studies. The main objective of this study was to assess the effect of yoga training on diurnal metabolic rates in yoga practitioners at two different times of the day (at 6 a.m. and 9 p.m.). Eighty eight healthy volunteers were selected and their metabolic rates assessed at 6 a.m. and 9 p.m. using an indirect calorimeter at a yoga school in Bangalore, India. The results show that the average metabolic rate of the yoga group was 12% lower than that of the non-yoga group (P < 0.001) measured at 9 p.m. and 16% lower at 6 a.m. (P < 0.001). The 9 p.m. metabolic rates of the yoga group were almost equal to their predicted basal metabolic rates (BMRs) whereas the metabolic rate was significantly higher than the predicted BMR for the non-yoga group. The 6 a.m. metabolic rate was comparable to their predicted BMR in the non-yoga group whereas it was much lower in the yoga group (P < 0.001). The lower metabolic rates in the yoga group at 6 a.m. and 9 p.m. may be due to coping strategies for day-to-day stress, decreased sympathetic nervous system activity and probably, a stable autonomic nervous system response (to different stressors) achieved due to training in yoga.


LINC01116 promotes proliferation, invasion and migration of osteosarcoma cells by silencing p53 and EZH2.
The aim of this study was to elucidate the expression pattern and potential function of LINC01116 in regulating the progression of osteosarcoma. Expression levels of LINC01116 in osteosarcoma tissues (n=52) and adjacent normal tissues (n=52) were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). Survival analysis and univariate analysis were performed in osteosarcoma patients based on the relative expression levels of LINC01116 and clinical data. Overexpression or silence of LINC01116 in osteosarcoma cells was achieved by transfection of plasmid complementary deoxyribonucleic acid (pcDNA)-LINC01116 or si-LINC01116, respectively. Subsequently, the regulatory effects of LINC01116 on cellular behaviors of osteosarcoma cells were examined by cell counting kit-8 (CCK-8), transwell and flow cytometry. Meanwhile, the potential mechanism of LINC01116 in regulating the progression of osteosarcoma was explored by RNA binding protein immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and Western blot. Potential target genes in osteosarcoma were searched, and their functions were clarified through a series of rescue experiments. LINC01116 expression in osteosarcoma tissues was significantly higher than adjacent normal tissues. The expression of LINC01116 was negatively correlated with overall survival, whereas positively correlated with tumor size and clinical grade of osteosarcoma patients. Transfection of pcDNA-LINC01116 significantly enhanced proliferative, migratory and invasive abilities of U2OS cells, shortened G0/G1 phase period, and inhibited cell apoptosis. However, transfection of si-LINC01116 in MG63 cells obtained the opposite trends in the above-mentioned cellular behaviors. Furthermore, RIP assay confirmed the binding of enhancer of zeste homolog 2 (EZH2) to LINC01116. Knockdown of LINC01116 significantly up-regulated the expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. Moreover, EZH2 knockdown could reverse the inhibitory effect of LINC01116 on carcinogenesis of osteosarcoma. LINC01116 is highly expressed in osteosarcoma. Up-regulated LINC01116 can promote cell proliferation, invasion and cell cycle progression, while inhibiting the apoptosis of osteosarcoma cells. Furthermore, LINC01116 is involved in the development of osteosarcoma by binding to EZH2 to regulate expressions of PTEN and p53.


Acupuncture for 'frequent attenders' with medically unexplained symptoms: a randomised controlled trial (CACTUS study).
Medically unexplained physical symptoms (MUPS) are common and difficult to treat. To investigate the effectiveness of adding five-element acupuncture to usual care in 'frequent attenders' with MUPS. Randomised controlled trial in four London general practices. Participants were 80 adults with MUPS, consulting GPs ≥8 times/year. The intervention was individualised five-element acupuncture, ≥12 sessions, immediately (acupuncture group) and after 26 weeks (control group). The primary outcome was 26-week Measure Yourself Medical Outcome Profile (MYMOP); secondary outcomes were wellbeing (W-BQ12), EQ-5D, and GP consultation rate. Intention-to-treat analysis was used, adjusting for baseline outcomes. Participants (80% female, mean age 50 years, mixed ethnicity) had high health-resource use. Problems were 59% musculoskeletal; 65% >1 year duration. The 26-week questionnaire response rate was 89%. Compared to baseline, the mean 26-week MYMOP improved by 1.0 (95% confidence interval [CI] = 0.4 to 1.5) in the acupuncture group and 0.6 (95% CI = 0.3 to 0.9) in the control group (adjusted mean difference: acupuncture versus control -0.6 [95% CI = -1.1 to 0] P = 0.05). Other between-group adjusted mean differences were: W-BQ12 4.4 (95% CI = 1.6 to 7.2) P = 0.002; EQ-5D index 0.03 (95% CI = -0.11 to 0.16) P = 0.70; consultation rate ratio 0.90 (95% CI = 0.70 to 1.15) P = 0.4; and number of medications 0.56 (95% CI = 0.47 to 1.6) P = 0.28. All differences favoured the acupuncture group. Imputation for missing values reduced the MYMOP adjusted mean difference to -0.4 (95% CI = -0.9 to 0.1) P = 0.12. Improvements in MYMOP and W-BQ12 were maintained at 52 weeks. The addition of 12 sessions of five-element acupuncture to usual care resulted in improved health status and wellbeing that was sustained for 12 months.


Review of smartphone mobile applications for skin cancer detection: what are the changes in availability, functionality, and costs to users over time?
Smartphone applications (apps) are available to consumers for skin cancer prevention and early detection. This study aims to review changes over time in the skin cancer apps available to consumers as well as their functionality and costs. Apps for the prevention of skin cancer were searched on two major smartphone app stores (Android and iOS) in June 2019. The number, functionality, ratings, and price of the apps were described and compared to similar reviews of the skin cancer app market from 2014 to 2017. Overall, the June 2019 search identified 66 apps. Of 39 apps found in 2014, 30 were no longer available in 2019 representing an attrition rate of 77%; of 43 apps available in 2017, attrition was 46.5%. In 2019, 63.6% (n = 42/66) of apps were free to download compared to 53.5% (n = 23/43) in 2017. Input from clinician/professional bodies was evident for 47.0% (n = 31/66) of the apps in 2019 compared to 34.9% (15/43) in 2017. The most common app functionality offered in 2019 was monitoring/tracking of lesions at 48.5% (n = 32/66). Since 2014, there has been a steady increase in the number of apps available for the general public to support the prevention or early detection of skin cancers. There continues to be a high turnover of apps, and many apps still appear to lack clinician input and/or evidence for their safety and value.


Nonspecific Binding of Complement by Digestion Fragments from Antiviral Gamma Globulin.
The nonspecificity of rabbit gamma-globulin (antibody) to western equine encephalitis virus and the non-specificity of normal rabbit gamma-globulin in complement-fixation tests with anti-gens prepared from chick-embryo cells infected with this virus and normal chick-embryo cells resided primarily in Porter's fragment III. Addition of complement to fragment III from the anti-body globulin, followed by inactivation of the added complement, abolished the complement-fixing ability of fragment III with both specific and nonspecific antigens. Similar treatment of the undigested antibody abolished its complement-fixing ability with nonspecific antigen only.


Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates.
Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.


Use of octreotide in the treatment of chylothorax and chyloperitoneum.
Report of three cases of chylothorax and one case of chylous ascites in children who had undergone cardiac surgery with no response to routine clinical treatment, based on fasting and long-term parenteral nutrition. Treatment with octreotide at an initial dose of 1.0 mcg/kg/h was chosen, with a gradual increase of 1.0 mcg/kg/hr/day until a maximum dose of 4.0 mcg/kg/h. All cases had a favorable response, with gradual reduction of drainage output until prognosis improvement with no significant side effects.


Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition.
There is strong interest in the characterisation of gene fusions and their use to enhance clinical practices in prostate cancer (PrCa). Significantly, ~50% of prostate tumours harbour a gene fusion. Inherited factors are thought to predispose to these events but, to date, only one study has investigated gene fusions in a familial context. Here, we examined the prevalence and diversity of gene fusions in 14 tumours from a single large PrCa family, PcTas9, using the TruSight® RNA Fusion Panel and Sanger sequencing validation. These fusions were then explored in The Cancer Genome Atlas (TCGA) PrCa data set (n = 494). Overall, 64.3% of PcTas9 tumours harboured a gene fusion, including known erythroblast transformation-specific (ETS) fusions involving ERG and ETV1, and two novel gene fusions, C19orf48:ETV4 and RYBP:FOXP1. Although 3' ETS genes were overexpressed in PcTas9 and TCGA tumour samples, 3' fusion of FOXP1 did not appear to alter its expression. In addition, PcTas9 fusion carriers were more likely to have lower-grade disease than noncarriers (p = 0.02). Likewise, TCGA tumours with high-grade disease were less likely to harbour fusions (p = 0.03). Our study further implicates an inherited predisposition to PrCa gene fusion events, which are associated with less aggressive tumours. This knowledge could lead to clinical strategies to predict men at risk for fusion-positive PrCa and, thus, identify patients who are more or less at risk of aggressive disease and/or responsive to particular therapies.


The changing profile of obstructive sleep apnea: long term trends in characteristics of patients presenting for diagnostic polysomnography.
We aimed to analyze long-term trends in characteristics of patients undergoing diagnostic polysomnography (PSG) and subsequently diagnosed with obstructive sleep apnea (OSA) to inform delivery of sleep services. We studied 24,510 consecutive patients undergoing PSG at a tertiary-care sleep service between 1989 and 2013. OSA was defined by an apnea hypopnea index (AHI)≥ 5 events/hour. Changes to hypopnea definition and flow sensing techniques in 2002 created two distinct AHI scoring periods: American Sleep Disorders Association (ASDA) 1989 - July 2002 and American Academy of Sleep Medicine (Chicago) from August 2002. Over 23.5 years there was a steady increase in proportion of females (15% to 45%), small increases in average age and BMI, and a small decline in socioeconomic status in the overall group. AHI varied between scoring periods both overall [ASDA 10.8/h (3.2-29.6), Chicago 24.3/h (11.8-48.1)] and in the large subgroup (80.7%) diagnosed with OSA [ASDA 20.7/h (10.6-44.1), Chicago 27.4/h (14.8-51.5)]. OSA diagnosis rates increased in the Chicago period (ASDA 66%, Chicago 91%). Increases in AHI and proportion diagnosed appeared better explained by changes in scoring methods than key OSA risk factors. Temporal increases in proportion of females and decreases in socioeconomic status of people undergoing PSG may reflect greater community awareness of sleep disorders. Temporal increases in age and obesity are consistent with secular trends. Changes in scoring methods have major impacts on OSA diagnosis and judgement of disease severity, with important implications for contemporary resourcing of sleep services and interpretation of historical OSA data.


Use of hypertonic saline-dextran solution to resuscitate hypovolemic calves with diarrhea.
To determine effectiveness of a new and practical method for fluid resuscitation of dehydrated diarrheic calves. Animals randomly allocated to 4 groups with appropriate controls. 16 healthy male dairy calves, 3 to 6 days old. After instrumentation and recording baseline data, diarrhea and hypovolemia were induced by administering milk replacer (33 ml/kg of body weight) and isotonic sucrose solution (2 g of sucrose in 19.5 ml of water/kg, PO) every 8 hours, and furosemide (2 mg/kg, IM) every 4 to 8 hours. Administration of milk replacer and furosemide was discontinued when calves became 6% dehydrated. Calves were then randomly allocated as: control (no treatment); hypertonic saline-dextran (HSD) solution (4 ml/kg, 2,400 mOsm/L NaCl in 6% dextran-70, administered once over 4 minutes, IV); isotonic alkalinizing oral electrolyte solution (55 ml/kg, PO, q 8 h); and HSD-oral electrolyte solution (combination of HSD and oral treatments). Calves were monitored for 24 hours after treatment. Significant changes included moderate dehydration (8% body weight), marked lethargy, decreased cardiac output and plasma volume, and increased blood lactate concentration, hematocrit, and serum concentrations of albumin, creatinine, sodium, and phosphate. Control calves continued to be lethargic and dehydrated, with significant increases in hematocrit and serum creatinine concentration. Increase in cardiac output and plasma volume was transient in the HSD group and waned by 2 to 8 hours after treatment. Oral electrolyte fluid administration caused slow and sustained increase in cardiac output and plasma volume, and decrease in heart rate, blood lactate concentration, and hematocrit. Combined administration of HSD-oral electrolyte solution caused immediate and sustained increase in cardiac output and plasma volume, and decrease in heart rate, blood lactate concentration, and hematocrit. Treatment of hypovolemic diarrheic calves with IV HSD and oral electrolyte solution is superior to administration of either solution alone.


Mother's CD4+ count moderates the risk associated with higher parity for late postnatal HIV-free survival of breastfed children: an individual patient data meta-analysis of randomized controlled trials.
Risk association studies of late postnatal outcomes for children breastfed by HIV-1 positive mothers have had inconsistent findings and have not explored interactions among risk factors. This study addresses these limitations through an individual patient data (IPD) meta-analysis of HIV-free survival outcomes of nine randomized controlled trials to prevent early mother-to-child transmission of HIV-1. The pooled sample consisted of 3,324 African children in resource-limited settings who survived to age 28 days and were at-risk of acquiring HIV through breast milk. Based on a proportional hazards mixed effects meta-analysis, the composite endpoint of HIV-1 infection and all-cause mortality was found to be significantly associated with maternal immune status (CD4(+) ≥350 cells/mm(3), HR 0.59 95% CI (0.39, 0.87)), infant preterm delivery (gestational age <37 weeks, 1.40 (1.03, 1.89)), infant oral candidiasis infection (1.87, (1.53, 2.29)), and occurrence of breast abnormality before breastfeeding cessation (2.56 (1.90, 3.46)). A significant interaction between mother's parity (any previous pregnancy) and CD4(+) count ≥350 (HR 0.63 (0.40, 0.99), P-value = 0.045) suggested that higher CD4(+) count offsets the risk associated with higher parity. Further research is needed to elucidate the moderating effect of immune status on the risk associated with high parity and adverse late postnatal outcomes for infants breastfed by HIV-infected mothers in the absence of antiretroviral treatment.


Association of California Mastitis Test Scores with Intramammary Infection Status in Lactating Dairy Cows Admitted to a Veterinary Teaching Hospital.
Subclinical mastitis is of concern in veterinary hospitals because contagious mastitis pathogens might be unknowingly transmitted to susceptible cows and then back to their farm of origin. To evaluate the California mastitis test (CMT) as an indicator of intramammary infection (IMI) in lactating dairy cows admitted to a veterinary hospital. A total of 139 admissions of 128 lactating dairy cows admitted to the University of Illinois Veterinary Teaching Hospital over a 2-year period. A retrospective study with a convenience sample was conducted. Medical records of cows with CMT results and milk culture results for the day of admission were reviewed. Breed, age, season, maximum CMT score for the 4 quarters, maximum CMT score difference, and clinical diagnosis were evaluated as predictors of IMI by the chi-square test and stepwise logistic regression. An IMI was identified in 51% of quarters. For cows admitted without evidence of clinical mastitis, the sensitivity of a CMT score ≥trace in predicting an IMI on a quarter or cow basis was 0.45 and 0.68, respectively. The distributions of maximal quarter CMT score and the maximum difference in quarter CMT score for cows without evidence of clinical mastitis did not differ (P = 0.28, P = 0.84, respectively) for cows with and without IMI. Stepwise logistic regression did not identify significant predictors of IMI in cows without clinical mastitis. Lactating dairy cattle admitted to a veterinary hospital should be managed as if they have an IMI, even in the absence of clinical mastitis.


Systematic identification of hypothetical bacteriophage proteins targeting key protein complexes of Pseudomonas aeruginosa.
Addressing the functionality of predicted genes remains an enormous challenge in the postgenomic era. A prime example of genes lacking functional assignments are the poorly conserved, early expressed genes of lytic bacteriophages, whose products are involved in the subversion of the host metabolism. In this study, we focused on the composition of important macromolecular complexes of Pseudomonas aeruginosa involved in transcription, DNA replication, fatty acid biosynthesis, RNA regulation, energy metabolism, and cell division during infection with members of seven distinct clades of lytic phages. Using affinity purifications of these host protein complexes coupled to mass spectrometric analyses, 37 host complex-associated phage proteins could be identified. Importantly, eight of these show an inhibitory effect on bacterial growth upon episomal expression, suggesting that these phage proteins are potentially involved in hijacking the host complexes. Using complementary protein-protein interaction assays, we further mapped the inhibitory interaction of gp12 of phage 14-1 to the α subunit of the RNA polymerase. Together, our data demonstrate the powerful use of interactomics to unravel the biological role of hypothetical phage proteins, which constitute an enormous untapped source of novel antibacterial proteins. (Data are available via ProteomeXchange with identifier PXD001199.).


Lysis of T4 phage by the specific lipocarbohydrate of phase II Shigella sonnei.
When the specific lipocarbohydrate of Phase II Sh. sonnei and T(4) phage react in vitro, the virus is rapidly inactivated and the content of the viral membrane is released into the surrounding medium. The reaction between phage and lipocarbohydrate proceeds only in the presence of a lipide constituent which can be extracted from the polysaccharide, rendering the latter inactive, and which can be replaced by certain fatty acids. It has been suggested that the lipocarbohydrate is the receptor substance of the Phase II bacillus which specifically combines with and brings about disintegration of the virus when the latter infects the host cell.


Electrophoretic separation of influenza virus ribonucleoproteins.
A new procedure for the separation of influenza virus particle ribonucleoproteins (RNPs) by electrophoresis on a slab of polyacrylamide gel resolves five discrete bands. The largest is a triplet containing the three largest RNAs (1 to 3), the intermediate sized RNP is a doublet containing RNAs 5 and 6 and the others each contain a single RNA. In addition, each RNP is composed of NP protein and an amount of M which is independent of the size of the RNP. This suggests that some virus particle M is specifically associated with influenza ribonucleoprotein.


Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension.
The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter. Multicenter retrospective study. Three European university hospitals. Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival. At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively. Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.


Grid Cells, Border Cells and Discrete Complex Analysis.
We propose a mechanism enabling the appearance of border cells-neurons firing at the boundaries of the navigated enclosures. The approach is based on the recent discovery of discrete complex analysis on a triangular lattice, which allows constructing discrete epitomes of complex-analytic functions and making use of their inherent ability to attain maximal values at the boundaries of generic lattice domains. As it turns out, certain elements of the discrete-complex framework readily appear in the oscillatory models of grid cells. We demonstrate that these models can extend further, producing cells that increase their activity towards the frontiers of the navigated environments. We also construct a network model of neurons with border-bound firing that conforms with the oscillatory models.


Graves ophthalmopathy. Results of transantral orbital decompression performed primarily for cosmetic indications.
Transantral orbital decompression is effective treatment for excessive proptosis and optic neuropathy due to Graves ophthalmopathy. In these sight-threatening circumstances, patients willingly accept the side effects of orbital decompression. When transantral orbital decompression is performed for cosmetic indications, patients' acceptance of side effects may be different. This study reports detailed results of transantral decompression for 34 patients in whom the indications were primarily cosmetic. The medical records of 34 patients with Graves ophthalmopathy who had transantral orbital decompression primarily for cosmetic indications were reviewed. Preoperative and postoperative physical features of the eyes were compared. Long-term assessment was formulated from follow-up examination and a follow-up questionnaire. The most notable improvement was in the reduction of proptosis (mean decrease, 5.2 mm). The frequency of asymmetry of proptosis, however, did not improve. Asymmetry was more than 1 mm in 44% of patients preoperatively and in 54% postoperatively. Although the palpebral fissure was decreased by an average of 2.7 mm, upper lid retraction became worse in 12 (43%) of 28 eyes. Of 15 patients who had no diplopia preoperatively, continuous diplopia developed postoperatively in 73%. The patients underwent a total of 37 eye muscle operations and 31 eyelid operations after decompression. Of 29 patients who responded to a long-term follow-up questionnaire, 69% were satisfied with the appearance of the eyes and 31% found it acceptable. No patient was dissatisfied. Symptomatic diplopia was present in 6.9% of patients at the time of the follow-up questionnaire. Transantral orbital decompression performed for cosmetic indications in Graves ophthalmopathy may need to be followed by eye muscle and lid operations. These procedures result in a high degree of patient satisfaction. However, a small percentage of patients experience persistent diplopia, despite multiple eye muscle procedures.


Developments in clinical cell therapy.
Immunotherapy has become an important part of hematopoietic stem cell (HSC) transplantation and cancer therapy. Regenerative and reparative properties of somatic cell-based therapies hold tremendous promise for repairing injured tissue, preventing and reversing damage to organs, and restoring balance to compromised immune systems. The principles and practices of the diverse aspects of immune therapy for cancer, HSC transplantation and regenerative medicine have many commonalities. This meeting report summarizes a workshop sponsored by the National Heart, Lung and Blood Institute (NHLBI) and Production Assistance for Cellular Therapies (PACT), held on 23-24 April 2009 at the National Institutes of Health (NIH, USA). A series of scientific sessions and speakers highlighted key aspects of the latest scientific, clinical and technologic developments in cell therapy, involving a unique set of cell products with a special emphasis on converging concepts in these fields.


Leishmaniasis: prevention, parasite detection and treatment.
Leishmaniasis remains a public health problem worldwide, affecting approximately 12 million people in 88 countries; 50 000 die of it each year. The disease is caused by Leishmania, obligate intracellular vector-borne parasites. In spite of its huge health impact on the populations in vast areas, leishmaniasis is one of the most neglected diseases. No safe and effective vaccine currently exists against any form of human leishmaniasis. The spectrum and efficacy of available antileishmanial drugs are also limited. First part of this review discusses the approaches used for the vaccination against leishmaniasis that are based on the pathogen and includes virulent or attenuated parasites, parasites of related nonpathogenic species, whole killed parasites, parasites' subunits, DNA vaccines, and vaccines based on the saliva or saliva components of transmitting phlebotomine vector. Second part describes parasite detection and quantification using microscopy assays, cell cultures, immunodetection, and DNA-based methods, and shows a progress in the development and application of these techniques. In the third part, first-line and alternative drugs used to treat leishmaniasis are characterized, and pre-clinical research of a range of natural and synthetic compounds studied for the leishmanicidal activity is described. The review also suggests that the application of novel strategies based on advances in genetics, genomics, advanced delivery systems, and high throughput screenings for leishmanicidal compounds would lead to improvement of prevention and treatment of this disease.


The association between pulse wave velocity and cognitive function: the Sydney Memory and Ageing Study.
Pulse wave velocity (PWV) is a measure of arterial stiffness and its increase with ageing has been associated with damage to cerebral microvessels and cognitive impairment. This study examined the relationship between carotid-femoral PWV and specific domains of cognitive function in a non-demented elderly sample. Data were drawn from the Sydney Memory and Ageing Study, a cohort study of non-demented community-dwelling individuals aged 70-90 years, assessed in successive waves two years apart. In Wave 2, PWV and cognitive function were measured in 319 participants. Linear regression was used to analyse the cross-sectional relationship between arterial stiffness and cognitive function in the whole sample, and separately for men and women. Analysis of covariance was used to assess potential differences in cognition between subjects with PWV measurements in the top and bottom tertiles of the cohort. Covariates were age, education, body mass index, pulse rate, systolic blood pressure, cholesterol, depression, alcohol, smoking, hormone replacement therapy, apolipoprotein E ε4 genotype, use of anti-hypertensive medications, history of stroke, transient ischemic attack, myocardial infarction, angina, diabetes, and also sex for the whole sample analyses. There was no association between PWV and cognition after Bonferroni correction for multiple testing. When examining this association for males and females separately, an association was found in males, with higher PWV being associated with lower global cognition and memory, however, a significant difference between PWV and cognition between males and females was not found. A higher level of PWV was not associated with lower cognitive function in the whole sample.


Regular Use of VKA Prior to COVID-19 Associated with Lower 7-Day Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Cohort Study.
Vitamin K concentrations are inversely associated with the clinical severity of COVID-19. The objective of this cohort study was to determine whether the regular use of vitamin K antagonist (VKA) prior to COVID-19 was associated with short-term mortality in frail older adults hospitalized for COVID-19. Eighty-two patients consecutively hospitalized for COVID-19 in a geriatric acute care unit were included. The association of the regular use of VKA prior to COVID-19 with survival after 7 days of COVID-19 was examined using a propensity-score-weighted Cox proportional-hazards model accounting for age, sex, severe undernutrition, diabetes mellitus, hypertension, prior myocardial infarction, congestive heart failure, prior stroke and/or transient ischemic attack, CHA2DS2-VASc score, HAS-BLED score, and eGFR. Among 82 patients (mean ± SD age 88.8 ± 4.5 years; 48% women), 73 survived COVID-19 at day 7 while 9 died. There was no between-group difference at baseline, despite a trend for more frequent use of VKA in those who did not survive on day 7 (33.3% versus 8.2%, p = 0.056). While considering "using no VKA" as the reference (hazard ratio (HR) = 1), the HR for 7-day mortality in those regularly using VKA was 5.68 [95% CI: 1.17; 27.53]. Consistently, COVID-19 patients using VKA on a regular basis had shorter survival times than the others (p = 0.031). Regular use of VKA was associated with increased mortality at day 7 in hospitalized frail elderly patients with COVID-19.


MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.
Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38α is involved in resistance of colon cancer cells to camptothecin-related drugs. Here we further investigated the cellular mechanisms involved in such drug resistance and showed that, in HCT116 human colorectal adenocarcinoma cells in which TP53 was genetically ablated (HCT116-TP53KO), overexpression of constitutively active MAPK14/p38α decreases cell sensitivity to SN-38 (the active metabolite of irinotecan), inhibits cell proliferation and induces survival-autophagy. Since autophagy is known to facilitate cancer cell resistance to chemotherapy and radiation treatment, we then investigated the relationship between MAPK14/p38α, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38α activation. Finally, we showed that inhibition of MAPK14/p38α or autophagy both sensitizes HCT116-TP53KO cells to drug therapy. Our data proved that the two effects are interrelated, since the role of autophagy in drug resistance required the MAPK14/p38α. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38α is activated and triggers survival-promoting autophagy to protect tumor cells against the cytotoxic effects of the drug. Colon cancer cells could thus be sensitized to drug therapy by inhibiting either MAPK14/p38 or autophagy.


[Several aspects of formation of occupational recommendations for health examinations and employment of the disabled].
The article analyzed medical examination of 100 patients observed as disabled in 1993. The authors revealed notable drawbacks in occupational rehabilitation of the patients and the disabled individuals by Commissions of occupational medical examination and medical consultation, so inadequate occupational placement was given. Analysis of the data helped to determine the guidelines for better occupational rehabilitation of disabled people. Those guidelines are: professional training and informational supplies for Commission of occupational medical examination, use of up-to-date scientific methods to organize placement for disabled people.


A short and scalable route to orthogonally O-protected 2-deoxystreptamine.
A seven-step synthesis of orthogonally O-protected 2-deoxy-streptamine has been developed from readily available neomycin, with an overall yield of 28%. Key chemical transformations include a chemoselective glycosidic bond hydrolysis and two regioselective protective group manipulations involving acetylation and deacetylation. The synthetic route is amenable to scale-up for the production of multigram quantities of enantiopure and orthogonally O-protected 2-deoxystreptamine, a versatile scaffold for the generation of libraries of RNA-targeting ligands.


Evaluation of a commercial gene probe for identification of Legionella cultures.
Confirmation of a culture as Legionella when it is unreactive with available serologic reagents involves tests that are impractical in most clinical laboratories. A nucleic acid probe that hybridizes only to members of the genus Legionella was recently prepared for marketing by Gen-Probe, Inc., San Diego, Calif. We tested 215 Legionella strains, representing 22 species, and 84 non-Legionella strains, representing 17 bacterial genera, with the Gen-Probe kit. All but four Legionella strains (L. bozemanii, less than 2% of total) and no heterologous strains gave positive test results. We conclude that the Legionella gene probe is a valuable addition to existing diagnostic tests for Legionella organisms.


Stem cell culture engineering - process scale up and beyond.
Advances in stem cell research and recent work on clinical trials employing stem cells have heightened the prospect of stem cell applications in regenerative medicine. The eventual clinical application of stem cells will require transforming cell production from laboratory practices to robust processes. Most stem cell applications will require extensive ex vivo handling of cells, from isolation, cultivation, and directed differentiation to product cell separation, cell derivation, and final formulation. Some applications require large quantities of cells in each defined batch for clinical use in multiple patients; others may be for autologous use and require only small-scale operations. All share a common requirement: the production must be robust and generate cell products of consistent quality. Unlike the established manufacturing process of recombinant protein biologics, stem cell applications will likely see greater variability in their cell source and more fluctuations in product quality. Nevertheless, in devising stem cell-based bioprocesses, much insight could be gained from the manufacturing of biological materials, including recombinant proteins and anti-viral vaccines. The key to process robustness is thus not only the control of traditional process chemical and physical variables, but also the sustenance of cells in the desired potency or differentiation state through controlling non-traditional variables, such as signaling pathway modulators.


Motor consequences of experimentally induced limb pain: a systematic review.
Compelling evidence exists that pain may affect the motor system, but it is unclear if different sources of peripheral limb pain exert selective effects on motor control. This systematic review evaluates the effects of experimental (sub)cutaneous pain, joint pain, muscle pain and tendon pain on the motor system in healthy humans. The results show that pain affects many components of motor processing at various levels of the nervous system, but that the effects of pain are largely irrespective of its source. Pain is associated with inhibition of muscle activity in the (painful) agonist and its non-painful antagonists and synergists, especially at higher intensities of muscle contraction. Despite the influence of pain on muscle activation, only subtle alterations were found in movement kinetics and kinematics. The performance of various motor tasks mostly remained unimpaired, presumably as a result of a redistribution of muscle activity, both within the (painful) agonist and among muscles involved in the task. At the most basic level of motor control, cutaneous pain caused amplification of the nociceptive withdrawal reflex, whereas insufficient evidence was found for systematic modulation of other spinal reflexes. At higher levels of motor control, pain was associated with decreased corticospinal excitability. Collectively, the findings show that short-lasting experimentally induced limb pain may induce immediate changes at all levels of motor control, irrespective of the source of pain. These changes facilitate protective and compensatory motor behaviour, and are discussed with regard to pertinent models on the effects of pain on motor control.


An evaluation of closed reduction techniques for femoral neck fractures.
Seven different reduction techniques have been tested in the treatment of displaced femoral neck fractures using the fracture table. Wellmerling's technique is preferred because of its utility, predictable results, and flexibility in treatment alternatives.


Reduction of renal triglyceride accumulation: effects on proximal tubule Na+/H+ exchange and urinary acidification.
One main pathophysiological mechanism underlying the increased risk for uric acid nephrolithiasis in humans with the metabolic syndrome is the excretion of unduly acidic urine, in part because of reduced excretion of the main urinary buffer, ammonium. The Zucker diabetic fatty (ZDF) rat, an established rodent model of the metabolic syndrome, has similar urinary abnormalities, attributed in part to lower expression and activity of the principal mediator of proximal tubule ammonium excretion, brush-border membrane Na+/H+ exchanger 3 (NHE3). These defects are associated with renal tubular steatosis in ZDF rats, but the causal relationship between renal steatosis and defective urinary acidification has not been investigated in vivo. We hypothesized that reduction of renal steatosis would commensurately normalize urinary acidification parameters. We treated ZDF rats with thiazolidinediones to reduce nonadipose tissue steatosis. Four weeks of treatment reduced renal triglyceride accumulation and restored urinary acidification parameters in ZDF rats to levels comparable to their lean littermates; urinary acidification was not affected by treatment in lean rats. To further document the direct effects of fat, we showed that functional abnormalities induced by fat loading in a cell culture model of proximal tubule steatosis and lipotoxicity can be reversed by fat removal but not by thiazolidinediones alone. Together, these findings support the causative role of renal steatosis in the pathogenesis of urinary acidification defects, demonstrate reversibility upon lipid removal, and highlight a potential therapeutic strategy for renal abnormalities in the metabolic syndrome.


Contribution of conserved ATP-dependent proteases of Campylobacter jejuni to stress tolerance and virulence.
In prokaryotic cells the ATP-dependent proteases Lon and ClpP (Clp proteolytic subunit) are involved in the turnover of misfolded proteins and the degradation of regulatory proteins, and depending on the organism, these proteases contribute variably to stress tolerance. We constructed mutants in the lon and clpP genes of the food-borne human pathogen Campylobacter jejuni and found that the growth of both mutants was impaired at high temperature, a condition known to increase the level of misfolded protein. Moreover, the amounts of misfolded protein aggregates were increased when both proteases were absent, and we propose that both ClpP and Lon are involved in eliminating misfolded proteins in C. jejuni. In order to bind misfolded protein, ClpP has to associate with one of several Clp ATPases. Following inactivation of the ATPase genes clpA and clpX, only the clpX mutant displayed the same heat sensitivity as the clpP mutant, indicating that the ClpXP proteolytic complex is responsible for the degradation of heat-damaged proteins in C. jejuni. Notably, ClpP and ClpX are required for growth at 42 degrees C, which is the temperature of the intestinal tract of poultry, one of the primary carriers of C. jejuni. Thus, ClpP and ClpX may be suitable targets of new intervention strategies aimed at reducing C. jejuni in poultry production. Further characterization of the clpP and lon mutants revealed other altered phenotypes, such as reduced motility, less autoagglutination, and lower levels of invasion of INT407 epithelial cells, suggesting that the proteases may contribute to the virulence of C. jejuni.


Io volcanism seen by new horizons: a major eruption of the Tvashtar volcano.
Jupiter's moon Io is known to host active volcanoes. In February and March 2007, the New Horizons spacecraft obtained a global snapshot of Io's volcanism. A 350-kilometer-high volcanic plume was seen to emanate from the Tvashtar volcano (62 degrees N, 122 degrees W), and its motion was observed. The plume's morphology and dynamics support nonballistic models of large Io plumes and also suggest that most visible plume particles condensed within the plume rather than being ejected from the source. In images taken in Jupiter eclipse, nonthermal visible-wavelength emission was seen from individual volcanoes near Io's sub-Jupiter and anti-Jupiter points. Near-infrared emission from the brightest volcanoes indicates minimum magma temperatures in the 1150- to 1335-kelvin range, consistent with basaltic composition.


Lymphocyte and macrophage function.
The aim of this article is to review the tests available for assessing lymphocyte and monocyte function and to discuss their usefulness in the diagnosis and monitoring of primary and secondary immunodeficiency.


Cyberknife hypofractionated stereotactic radiosurgery (HSRS) of resection cavity after excision of large cerebral metastasis: efficacy and safety of an 800 cGy × 3 daily fractions regimen.
Development of hypofractionated stereotactic radiosurgery (HSRS) has expanded the size of lesion that can be safely treated by focused radiation in a limited number of treatment sessions. However, clinical data regarding the efficacy and morbidity of HSRS in the treatment of cerebral metastasis is lacking. Here, we review our experience with CyberKnife(®) HSRS for this indication. From 2005 to 2010, we identified 37 patients with large (>3 cm in diameter) cerebral metastases resection cavity that was treated with HSRS. This constituted approximately 8% of all treated resection cavities. We reviewed dose regimens, local control, distal control, and treatment associated morbidities. Primary sites for the metastatic lesions included: lung (n = 10), melanoma (n = 12), breast (n = 9), kidney (n = 4), and colon (n = 2). All patients underwent resection of the cerebral metastasis and received 800 cGy × 3 daily fractions to the resection cavity. Of the 37 patients treated, one-year follow-up data was available for 35 patients. The median survival was 5.5 months. Actuarial local control rate at 6 months was 80%. Local failures did not correlate with prior WBRT, or tumor histology. Distant recurrence occurred in 7 of the 35 patients. Morbidities associated with HSRS totaled 9%, including radiation necrosis (n = 1, 2.9%), prolonged steroid use (n = 1, 2.9%), and new-onset seizures (n = 1, 2.9%). This study demonstrates the safety and efficacy of an 800 cGy × 3 daily fractions CyberKnife(®) HSRS regimen for irradiation of large resection cavity. The efficacy compares favorably to historical data derived from patients undergoing WBRT, SRS, or brachytherapy.


Inhibition of platelet prostaglandin synthetase by oral aspirin.
Aspirin inhibits platelet function by permanently acetylating the cyclooxygenase that forms prostaglandins. We determined the sensitivity of platelets to aspirin in normal subjects by measuring [3H-acetyl]aspirin-susceptible cyclooxygenase in washed platelets obtained at various times after aspirin ingestion. A single 325-mg aspirin dose inactivated 89% of platelet cyclooxygenase. The inhibition persisted for 2 days suggesting that oral aspirin also inactivated megakaryocyte cyclooxygenase. Thereafter, active enzyme returned with a time-course reflecting platelet turnover (life-span 8.2+/-2 days). Single doses of 20-650 mg aspirin resulted in 34- greater than 95% inhibition after 24 h. Daily doses of 20-325 mg aspirin for brief periods produced 61- greater than 95% inactivation when measured 24 h after cessation of the drug. Platelet cyclooxygenase is more sensitive to inactivation by aspirin than enzyme in sheep seminal vesicles.


Inhibition of rheumatoid synovial fibroblast proliferation by antisense oligonucleotides targeting proliferating cell nuclear antigen messenger RNA.
To evaluate the feasibility of antisense oligonucleotides as therapeutic agents to inhibit synovial cell growth in rheumatoid arthritis (RA). Fibroblast-like cells established from RA synovium were stimulated with interleukin-1beta (IL-1beta) and treated with antisense or sense oligonucleotides targeting proliferating cell nuclear antigen (PCNA) messenger RNA (mRNA). Proliferation of these cells was determined by 3H-thymidine incorporation. Effects of antisense oligonucleotides on the expression of mRNA and protein were evaluated by reverse transcriptase-polymerase chain reaction and immunohistochemical staining, respectively. Antisense oligonucleotides targeting PCNA inhibited IL-1-stimulated fibroblast proliferation, whereas sense oligonucleotides had no effect. Both mRNA and protein levels of PCNA were suppressed in the cells treated with antisense oligonucleotides, indicating that the antiproliferative effect was occurring through an antisense mechanism. These results suggest that antisense strategies designed to suppress PCNA expression have potential use as therapeutic agents for RA.


Three-level fiber laser amplifier: a theoretical model.
A theoretical analysis of a three-level fiber laser amplifier in the small-signal regime is presented in which the effects of the transverse variation of the pump and signal mode intensities, the transverse variation of the density of the lasing species, and excited-state absorption of pump photons are included. Guidelines for the design of an optimum fiber are given.


Oxygenation of 4-alkoxyl groups in alkoxybenzoic acids by Polyporus dichrous.
The degradation of several alkyl ethers of vanillic acid, of 3-ethoxy-4-hydroxybenzoic acid, and of syringic acid, by the lignin-decomposing fungus Polyporus dichrous included (i) 4-dealkylation (e.g., 3-ethoxy-4-isopropoxybenzoic acid was in part dealkylated to 3-ethoxy-4-hydroxybenzoic acid), (ii) hydroxylation of the 4-alkoxyl groups (e.g., 3-ethoxy-4-isopropoxybenzoic acid was oxidized in part to 2-[4-carboxy-2-ethoxyphenoxy]-propane-1-ol), and (iii) reduction of carboxyl groups (older cultures) (e.g., 3-ethoxy-4-isopropoxybenzoic acid was reduced to 3-ethoxy-4-isopropoxybenzaldehyde and 3-ethoxy-4-isopropoxybenzyl alcohol). Some ethers (e.g., tri-O-methyl gallic acid and glycerol-beta-[4-carboxy-2-ethoxyphenyl]-ether) were not affected. The dealkylations and hydroxylations indicate that the fungus has a relatively nonspecific mechanism for oxygenating various 4-alkoxyl groups of alkoxybenzoic acids; no evidence for oxygenation of 3-alkoxyl groups was obtained. Hydroxylation products were generally degraded further, probably via dealkylation. The vanillic acid and 3-ethoxy-4-hydroxybenzoic acid formed by dealkylations were readily metabolized. Although the isopropyl ether of syringic acid was hydroxylated to 2-(4-carboxy-2, 6-dimethoxyphenoxy)-propane-1-ol, neither this compound nor the parent isopropyl ether was dealkylated; syringic acid itself was only slowly and incompletely metabolized. The relationship of these results to lignin degradation is discussed.


Macrophages in immunity to syphilis: suppressive effect of concurrent infection with Mycobacterium bovis BCG on the development of syphilitic lesions and growth of Treponema pallidum in tuberculin-positive rabbits.
Paired groups of male rabbits were challenged with Treponema pallidum and Mycobacterium bovis BCG. One group had been sensitized to BCG by inoculation 3 weeks before challenge. All animals were challenged intradermally at multiple sites with T. pallidum alone, BCG alone, and both organisms into the same sites. The resulting lesions were followed clinically and histologically. BCG lesions enlarged more rapidly in sensitized rabbits, but they were otherwise no different from those in the controls. T. pallidum lesions enlarged and regressed simultaneously in both groups, but in the BCG-sensitized animals they became twice as large as those in the unsensitized rabbits. Mixed BCG-T. pallidum lesions showed the greatest differences in the two groups of animals. Like the pure BCG lesions, they enlarged more rapidly in the sensitized rabbits but began to recede after 1 week. The corresponding lesions in the controls enlarged more slowly and reached their maximum size after 3 weeks when the receding lesions in the sensitized animals were much smaller. The most marked histological-histochemical difference between the two groups of animals was in the number and activation of macrophages. These cells were more numerous in the mixed lesions of BCG-sensitized animals than in similar lesions of the controls and more activated as determined by beta-galactosidase staining. Although sparsely distributed, activated macrophages were more numerous in the pur T. pallidum lesions of sensitized animals than in those of control animals. Silver-stained sections revealed fewer treponemes in mixed lesions of sensitized animals than in the mixed lesions of control animals. Quantitation of treponemes in pure T. pallidum versus mixed lesions was determined in two groups of rabbits challenged intratesticularly. The total number of treponemes per testis in the mixed lesions of BCG-sensitized rabbits was significantly less than the number in the mixed lesions of control animals, and also less than the number in pure T. pallidum lesions of both groups of animals.


Parental functioning in families of children with ADHD: evidence for behavioral parent training and importance of clinically meaningful change.
Statistically significant and clinically meaningful effects of behavioral parent training on parental functioning were examined for 20 children with ADHD and their parents who had successfully completed a psychosocial treatment for ADHD. Findings suggest that behavioral parent training resulted in statistically significant improvements in some domains of parenting behavior for both mothers and fathers and in reductions in most domains of parenting stress for mothers. Importantly, clinically meaningful change also was noted for these parental functioning areas, as well as for other domains of parental functioning that did not result in statistically significant findings. Clinical implications are discussed.


Aquatic insect community structure revealed by eDNA metabarcoding derives indices for environmental assessment.
Environmental DNA (eDNA) analysis provides an efficient and objective approach for monitoring and assessing ecological status; however, studies on the eDNA of aquatic insects, such as Ephemeroptera, Plecoptera, and Trichoptera (EPT), are limited despite its potential as a useful indicator of river health. Here, we investigated the community structures of aquatic insects using eDNA and evaluated the applicability of eDNA data for calculating assessment indices. Field surveys were conducted to sample river water for eDNA at six locations from upstream to downstream of two rivers in Japan in July and November 2016. Simultaneously, aquatic insects were collected using the traditional Surber net survey method. The communities of aquatic insects were revealed using eDNA by targeting the cytochrome oxidase subunit I gene in mitochondrial DNA via metabarcoding analyses. As a result, the eDNA revealed 63 families and 75 genera of aquatic insects, which was double than that detected by the Surber net survey (especially for families in Diptera and Hemiptera). The seasonal differences of communities were distinguished by both the eDNA and Surber net survey data. Furthermore, the total nitrogen concentration, a surrogate of organic pollution, showed positive correlations with biotic environmental assessment indices (i.e., EPT index and Chironomidae index) calculated using eDNA at the genus-level resolution but the indices calculated using the Surber net survey data. Our results demonstrated that eDNA analysis with higher taxonomic resolution can provide as a more sensitive environmental assessment index than the traditional method that requires biotic samples.


Intramuscular granular cell tumor in the sternocleidomastoid muscle: A case report and literature review.
Granular cell tumor (GCT) is a rare soft-tissue neoplasm that originates from Schwann cells. Most cases occur in the subcutaneous or submucosal regions, and intramuscular GCT is even more uncommon. Herein, we describe an atypical GCT growing in the sternocleidomastoid muscle. A 41-year-old Chinese man was admitted to our hospital for a right neck mass. In magnetic resonance images, the mass showed higher signal intensity than the adjacent normal muscle on T2-weighted images and intermediate signal intensity on T1-weighted images. Slightly enhanced and higher signal intensity was observed in the peripheral rim on contrast-enhanced fat-sat T1-weighted images, and the "stripe sign" was evident. The tumor was completely resected, and pathological examination indicated an atypical GCT. The patient tolerated the procedure well. This is a rare case report of an intramuscular GCT from diagnosis to treatment. Magnetic resonance imaging might help diagnose such tumors, and we review different magnetic resonance imaging characteristics of intramuscular GCTs at other sites.