Cystoid maculopathy in diabetics.
Three patients with long-standing diabetes manifested reduced visual acuity and notable bilateral symmetrical cystoid maculopathy, with no other sign of meaningful background diabetic retinopathy, eg, minimal to no microaneurysms, hemorrhages, or exudates. Results of fluorescein angiography showed that the entire retinal capillary bed in the macula was dilated and leaked fluorescein diffusely and profusely, but also showed that there was excellent capillary perfusion. Argonlaser photocoagulation was applied to one eye of each patient in an attempt to resolve the cystoid maculopathy. The laser treatment effectively resolved the edema in the specific areas of treatment, but the foveal and perifoveal areas, which were not treated, showed no areas of resolution of the cystoid edema in two cases and no improvement (and no decrease) in visual acuity in all three cases.


Management of the soybean cyst nematode Heterodera glycines with combinations of different rhizobacterial strains on soybean.
Soybean cyst nematode (SCN) is the most damaging soybean pest worldwide. To improve soybean resistance to SCN, we employed a soybean seed-coating strategy through combination of three rhizobacterial strains, including Bacillus simple, B. megaterium and Sinarhizobium fredii at various ratios. We found seed coating by such rhizobacterial strains at a ratio of 3:1:1 (thereafter called SN101) produced the highest germination rate and the mortality of J2 of nematodes. Then, the role of soybean seed coating by SN101 in nematode control was evaluated under both greenhouse and two field conditions in Northeast China in 2013 and 2014. Our results showed that SN101 treatment greatly reduced SCN reproduction and significantly promoted plant growth and yield production in both greenhouse and field trials, suggesting that SN101 is a promising seed-coating agent that may be used as an alternative bio-nematicide for controlling SCN in soybean fields. Our findings also demonstrate that combination of multiple rhizobacterial strains needs to be considered in the seed coating for better management of plant nematodes.


Drug interaction between clopidogrel and proton pump inhibitors.
Proton pump inhibitors (PPIs) have been recommended for reducing the risk of gastrointestinal bleeding associated with dual antiplatelet therapy (aspirin plus clopidogrel). However, studies have found decreased efficacy of clopidogrel when concurrently administered with a PPI. To determine the mechanism of and evidence for the potential interaction between clopidogrel and PPIs, along with the clinical implications of this drug interaction, we reviewed recently published reports of trials that examined the interaction. A MEDLINE database search (1966-September 2009) for English-language reports of clinical trials in human subjects was performed, supplemented by a manual search of reference lists. Four trials that examined surrogate outcomes and eight trials that examined clinical outcomes were included in this review. Two surrogate outcome studies showed that PPIs negatively affected clopidogrel response and increased platelet aggregation, whereas the other two did not find a significant difference between groups receiving PPIs and not receiving PPIs. Three of four published clinical outcomes studies and three of four unpublished clinical outcomes studies available as abstracts found a significant association between PPI use and rates of acute myocardial infarction, rehospitalization, death, or stroke. Most of the currently available data, primarily from observational studies, show that some PPIs may decrease clopidogrel's antiplatelet effectiveness, with increased cardiac adverse outcomes when clopidogrel is combined with PPIs. Although current data do not show causation of adverse outcomes with PPI use because the available data are conflicting, this topic is still controversial. Careful risk-benefit assessment is required before prescribing PPIs for individual patients taking dual antiplatelet therapy. More evidence from randomized controlled trials is needed to clarify this drug interaction dilemma.


[Pathogenicity of Burkholderia pseudomallei: extracellular and surface antigen functions].
The data of literature and the results of investigations carried out by the authors on the analysis of B. pseudomallei pathogenicity factors. They include mucoid, endotoxin, lecithinase, proteases, hemolysins, etc. In addition to fimbriae and pili, the adhesive properties of B. pseudomallei are supposed to be associated with surface capsule-like structures whose composition includes Ag8. The characterization of exoproteases, hemolysins and lethal toxins is given. The virulence and immunogenicity of B. pseudomallei were shown to be linked with the components of surface glycoprotein Ag8. The conclusion has been made that the analyzed pathogenicity factors are of importance for deciphering the pathogenesis of melioidosis.


Community-based surveillance of infectious diseases: a systematic review of drivers of success.
Community-based surveillance may improve early detection and response to disease outbreaks by leveraging the capacity of community members to carry out surveillance activities within their communities. In 2021, the WHO published a report detailing the evidence gaps and research priorities around community-centred approaches to health emergencies. In response, we carried out a systematic review and narrative synthesis of the evidence describing the drivers of success of community-based surveillance systems. We included grey literature and peer-reviewed sources presenting empirical findings of the drivers of success of community-based surveillance systems for the detection and reporting of infectious disease-related events. We searched for peer-reviewed literature via MEDLINE, EMBASE, Global Health, SCOPUS and ReliefWeb. We carried out grey literature searches using Google Search and DuckDuckGo. We used an evaluation quality checklist to assess quality. Nineteen sources (17 peer-reviewed and 2 grey literature) met our inclusion criteria. Included sources reported on community-based surveillance for the detection and reporting of a variety of diseases in 15 countries (including three conflict settings). The drivers of success were grouped based on factors relating to: (1) surveillance workers, (2) the community, (3) case detection and reporting, (4) and integration. The drivers of success were found to map closely to principles of participatory community engagement with success factors reflecting high levels of acceptability, collaboration, communication, local ownership, and trust. Other factors included: strong supervision and training, a strong sense of responsibility for community health, effective engagement of community informants, close proximity of surveillance workers to communities, the use of simple and adaptable case definitions, quality assurance, effective use of technology, and the use of data for real-time decision-making. Our findings highlight strategies for improving the design and implementation of community-based surveillance. We suggest that investment in participatory community engagement more broadly may be a key surveillance preparedness activity. CRD42022303971.


Two roles for CD4 cells in the control of the generation of cytotoxic T lymphocytes.
The generation of CTL against Qa-1 Ag in C57BL/6 (B6) (Qa-1b) and B6.Tlaa (Qa-1a) congenic strains requires in vivo priming with the Qa-1 alloantigen together with a helper Ag, such as H-Y. The primed precursors obtained from these female mice generate Qa-1-specific CTL activity upon culture in vitro. Although the presence of the H-Y helper Ag is not required for the in vitro sensitization, no response occurs in the absence of CD4 cells. Addition of unprimed B6.Tlaa CD4 cells from Qa-1 incompatible radiation bone marrow chimeras (B6.Tlaa----B6), that are presumably tolerant to Qa-1b, provide helper activity for Qa-1b-specific CTL. This indicates that although CD4 cells are obligatory for the Qa-1 response, they need not be specific for alloantigens on the APC to generate helper activity in in vitro cultures. Addition of unirradiated B6 CD8-depleted spleen cells to CD4-depleted B6.Tlaa anti-B6 cultures in the presence of either B6.Tlaa CD4 cells or rIL-2 prevents the generation of Qa-1 specific CTL. This inhibition is not due to an anti-idiotypic Ts cell since B6.Tlaa----B6 chimeric cells do not suppress an anti-Qa-1b response. Rather, this finding is consistent with that of a veto cell mechanism. To determine whether CD4 cells themselves exhibit veto activity, highly purified CD4 populations were tested for their ability to inhibit the generation of Qa-1-specific CTL. CD4 cells precultured for 2 to 3 days with Con A and rIL-2 specifically inhibit CTL activity whereas resting cells do not, similar to that noted for CD8 veto cells. The relative efficiency of activated CD4 cells is greater than that of resting NK cells but is less than that of activated CD8 or NK cells. Thus, CD4 cells not only provide helper activity for CTL precursors, but also act as veto cells to prevent the generation of CTL activity.


β‑glucan vaccine adjuvant approach for cancer treatment through immune enhancement (B‑VACCIEN) in specific immunocompromised populations (Review).
The incidence of cancer, which is the second leading cause of mortality globally, continues to increase, although continued efforts are being made to identify effective treatments with fewer side‑effects. Previous studies have reported that chronic microinflammation, which occurs in diseases, including diabetes, along with weakened immune systems, may ultimately lead to cancer development. Chemotherapy, radiotherapy and surgery are the mainstream approaches to treatment; however, they all lead to immune system weakness, which in turn increases the metastatic spread. The aim of the present review was to provide evidence of a biological response modifier β‑glucan [β‑glucan vaccine adjuvant approach to treating cancer via immune enhancement (B‑VACCIEN)] and its beneficial effects, including vaccine‑adjuvant potential, balancing metabolic parameters (including blood glucose and lipid levels), increasing peripheral blood cell cytotoxicity against cancer and alleviating chemotherapy side effects in animal models. This suggests its value as a potential strategy to provide long‑term prophylaxis in immunocompromised individuals or genetically prone to cancer.


The effects of acetamiprid multigeneration stress on metabolism and physiology of Aphis glycines Matsumura (Hemiptera: Aphididae).
Aphis glycines Matsumura (Hemiptera: Aphididae) is a major soybean pest that often poses a serious threat to soybean production. In this study, we checked the effects of acetamiprid on redox, energy metabolism, and hormone expression in A. glycines. The LC50 and LC30 of acetamiprid were used to treat the fourth instar nymphs in each generation from F0 to F4 to measure the activity of peroxidase, pyruvate kinase, and trehalase using a microassays approach. The peroxidase activity was significantly higher than control when treated with the LC30 of acetamiprid in F2-F5 generations. The activity of pyruvate kinase was significantly higher, while trehalase activity was substantially lower than control in each generation. Besides, we monitored molting and juvenile hormone expression in soybean aphids using enzyme-linked immunosorbent assay. The juvenile hormone titer of third instar nymphs was significantly higher in the treatment group (F1, F2, F4, and F5), while no effects were noted in the F3 generation. Taken together, the activity of peroxidase and pyruvate kinase in soybean aphid first increased to the peak and then decreased, while the trehalase activity continuously decreased in all generations following exposure to acetamiprid. The juvenile hormone titer was significantly higher, while the molting hormone titer was significantly lower in LC50 -treated aphids than in control. Moreover, the LC30 of acetamiprid increased the molting hormone expression in soybean aphids. These findings indicated a baseline for the effective use of acetamiprid in controlling soybean aphids.


EnILs: A General Ensemble Computational Approach for Predicting Inducing Peptides of Multiple Interleukins.
Interleukins (ILs) are a group of multifunctional cytokines, which play important roles in immune regulations and inflammatory responses. Recently, IL-6 has been found to affect the development of COVID-19, and significantly elevated levels of IL-6 cytokines have been reported in patients with severe COVID-19. IL-10 and IL-17 are anti-inflammatory and proinflammatory cytokines, respectively, which play multiple protective roles in host defense against pathogens. At present, a number of machine learning methods have been proposed to predict ILs inducing peptides, but their predictive performance needs to be further improved, and the inducing peptides of different ILs are predicted separately, rather than using a general approach. In our work, we combine the statistical features of peptide sequence with word embedding to design a general ensemble model named EnILs to predict inducing peptides of different ILs, in which the predictive probabilities of random forest, eXtreme Gradient Boosting and neural network are integrated in an average way. Compared with the state-of-the-art machine learning methods, EnILs shows considerable performance in the prediction of IL-6, IL-10, and IL-17 inducing peptides. In addition, we predict the most promising IL-6 inducing peptides in Severe Acute Respiratory Syndrome Coronavirus 2 spike protein in the case study for further experimental verification.


Percutaneous transtracheal jet ventilation for cardiopulmonary resuscitation: evaluation of a new jet ventilator.
This study compared percutaneous transtracheal jet ventilation (PTJV) at a frequency (f) of 20/min, with high-frequency positive-pressure ventilation (HFPPV) at f of 60/min, and endotracheal intubation and intermittent positive-pressure ventilation (ET IPPV) at f of 10/min in apneic dogs. Fifty-four emergency medicine trainees (EMTs) attempted PTJV via a 14-gauge Angiocath attached to a hand-held jet ventilator, f of 20/min, and ET IPPV using an Ambu bag, f of 10/min. Twenty-nine other EMTs attempted cricothyrotomy using a prototype nonkinkable catheter (Arrow) and a new jet ventilator, Bronchovent, f of 60/min, equipped with a pressure sensor which stops ventilation at pressures greater than 20 cm H2O. Adequate oxygenation was achieved by all 3 groups, but only the HFPPV group avoided respiratory alkalosis. There was a higher equipment failure rate (catheter kinking and dislodgment) in the PTJV group. In the HFPPV group, the Bronchovent's pressure-limiting sensor stopped ventilation when the catheter was kinked or out of position, reducing the extent of subcutaneous emphysema and barotrauma. With further catheter improvements, HFPPV Bronchovent may offer a safe and reliable method of ventilating patients during CPR in the field.


Median fin function in bluegill sunfish Lepomis macrochirus: streamwise vortex structure during steady swimming.
Fishes have an enormous diversity of body shapes and fin morphologies. From a hydrodynamic standpoint, the functional significance of this diversity is poorly understood, largely because the three-dimensional flow around swimming fish is almost completely unknown. Fully three-dimensional volumetric flow measurements are not currently feasible, but measurements in multiple transverse planes along the body can illuminate many of the important flow features. In this study, I analyze flow in the transverse plane at a range of positions around bluegill sunfish Lepomis macrochirus, from the trailing edges of the dorsal and anal fins to the near wake. Simultaneous particle image velocimetry and kinematic measurements were performed during swimming at 1.2 body lengths s(-1) to describe the streamwise vortex structure, to quantify the contributions of each fin to the vortex wake, and to assess the importance of three-dimensional flow effects in swimming. Sunfish produce streamwise vortices from at least eight distinct places, including both the dorsal and ventral margins of the soft dorsal and anal fins, and the tips and central notched region of the caudal fin. I propose a three-dimensional structure of the vortex wake in which these vortices from the caudal notch are elongated by the dorso-ventral cupping motion of the tail, producing a structure like a hairpin vortex in the caudal fin vortex ring. Vortices from the dorsal and anal fin persist into the wake, probably linking up with the caudal fin vortices. These dorsal and anal fin vortices do not differ significantly in circulation from the two caudal fin tip vortices. Because the circulations are equal and the length of the trailing edge of the caudal fin is approximately equal to the combined trailing edge length of the dorsal and anal fins, I argue that the two anterior median fins produce a total force that is comparable to that of the caudal fin. To provide additional detail on how different positions contribute to total force along the posterior body, the change in vortex circulation as flow passes down the body is also analyzed. The posterior half of the caudal fin and the dorsal and anal fins add vortex circulation to the flow, but circulation appears to decrease around the peduncle and anterior caudal fin. Kinematic measurements indicate that the tail is angled correctly to enhance thrust through this interaction. Finally, the degree to which the caudal fin acts like a idealized two-dimensional plate is examined: approximately 25% of the flow near the tail is accelerated up and down, rather than laterally, producing wasted momentum, a loss not present in ideal two-dimensional theories.


[Introduction of studies by the German Breast Center Study Group (GBSG)].
The GBSG is actually running two studies on breast cancer therapy: GBSG-5 addresses the necessity of radiotherapy following tumor removal, in breast preserving treatment of pT1N0M0 G1 breast cancer. The other question to be answered in a randomised 2- by 2-design is related to the replacement of radiotherapy by a 5-year treatment with tamoxifen. Up till now, 341 patients have been randomised. 200 more patients are needed for a valid study evaluation. GBSG-6 will be activated in fall of this year. It should answer the question whether the addition of systemic therapy to the local treatment of isolated locoregional recurrence will prolong time to further relapse as well as overall survival. According to a prognostic profile derived drom previous studies patients will be randomly allocated to more or less intensive treatment with chemo- and/or hormone therapy.


Phenoptosis, another specialized neologism, or the mark of a widespread revolution?
The classical approach of evolutionism is based on the concept of the survival of the fittest individuals. More and more data indicate that natural selection often acts with supra-individual mechanisms favoring genes and actions harmful for the individual. The most striking type of cases is when an individual kills himself or his offspring by actions genetically determined or favored. The neologism "phenoptosis" describes these events and implicates that they are not evolutionary anomalies but physiological phenomena determined by natural selection. The most important and familiar kind of phenoptosis, the "slow phenoptosis" or aging, which is currently considered an inevitable and scarcely changeable event, is transformed by this different interpretation into a function, in principle modifiable and manageable. Perhaps, the neologism "phenoptosis" will represent, together with the term supra-individual selection, the mark of a vital enrichment of evolutionism, conceived in broader terms of which the individual selection is just a particular case, and will be referred to as the brand and the standard for the start of a new era.


Activation of intracellular metabotropic glutamate receptor 5 in striatal neurons leads to up-regulation of genes associated with sustained synaptic transmission including Arc/Arg3.1 protein.
The G-protein coupled receptor, metabotropic glutamate receptor 5 (mGluR5), is expressed on both cell surface and intracellular membranes in striatal neurons. Using pharmacological tools to differentiate membrane responses, we previously demonstrated that cell surface mGluR5 triggers rapid, transient cytoplasmic Ca(2+) rises, resulting in c-Jun N-terminal kinase, Ca(2+)/calmodulin-dependent protein kinase, and cyclic adenosine 3',5'-monophosphate-responsive element-binding protein (CREB) phosphorylation, whereas stimulation of intracellular mGluR5 induces long, sustained Ca(2+) responses leading to the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Elk-1 (Jong, Y. J., Kumar, V., and O'Malley, K. L. (2009) J. Biol. Chem. 284, 35827-35838). Using pharmacological, genetic, and bioinformatics approaches, the current findings show that both receptor populations up-regulate many immediate early genes involved in growth and differentiation. Activation of intracellular mGluR5 also up-regulates genes involved in synaptic plasticity including activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mechanistically, intracellular mGluR5-mediated Arc induction is dependent upon extracellular and intracellular Ca(2+) and ERK1/2 as well as calmodulin-dependent kinases as known chelators, inhibitors, and a dominant negative Ca(2+)/calmodulin-dependent protein kinase II construct block Arc increases. Moreover, intracellular mGluR5-induced Arc expression requires the serum response transcription factor (SRF) as wild type but not SRF-deficient neurons show this response. Finally, increased Arc levels due to high K(+) depolarization is significantly reduced in response to a permeable but not an impermeable mGluR5 antagonist. Taken together, these data highlight the importance of intracellular mGluR5 in the cascade of events associated with sustained synaptic transmission.


Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease.
Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.


Hemidiaphragmatic paralysis following subclavian vein catheterization.
The right subclavian artery was inadvertently punctured during attempted preoperative insertion of a right subclavian venous catheter in a 59-yr-old woman undergoing radical hysterectomy. Large supraclavicular swelling became apparent soon after the arterial puncture. The postoperative chest X-ray obtained approximately 24 h after the catheterization revealed significant elevation of the right hemidiaphragm, which was further augmented on the 2nd to 4th postoperative days; oxygenation was concurrently impaired during these days. It was clinically judged that the hemidiaphragmatic paralysis was responsible for the elevated diaphragm. Both chest roentogenogram and arterial blood gas analyses started to improve on the 5th day, finally returning to normal on the 6th day. It is unlikely that the surgical procedure caused the paralysis, because it dealt only with the lower abdomen. Rather, the attempts at the subclavian venous catheterization probably caused the phrenic nerve paralysis, because the phrenic nerve travels very close to the subclavian vessels. Both the large haematoma formation following the arterial puncture and the time course of the paralysis suggest that compression of the right phrenic nerve by the haematoma, rather than needle trauma, was responsible for the paralysis.


Association of Adequacy of Broadband Internet Service With Access to Primary Care in the Veterans Health Administration Before and During the COVID-19 Pandemic.
Although telemedicine expanded rapidly during the COVID-19 pandemic and is widely available for primary care, required broadband internet speeds may limit access. To identify disparities in primary care access in the Veterans Health Administration based on the association between broadband availability and primary care visit modality. This cohort study used administrative data on veterans enrolled in Veterans Health Administration primary care to identify visits at 937 primary care clinics providing telemedicine and in-person clinical visits before the COVID-19 pandemic (October 1, 2016, to February 28, 2020) and after the onset of the pandemic (March 1, 2020, to June 30, 2021). Federal Communications Commission-reported broadband availability was classified as inadequate (download speed, ≤25 MB/s; upload speed, ≤3 MB/s), adequate (download speed, ≥25 <100 MB/s; upload speed, ≥5 and <100 MB/s), or optimal (download and upload speeds, ≥100 MB/s) based on data reported at the census block by internet providers and was spatially merged to the latitude and longitude of each veteran's home address using US Census Bureau shapefiles. All visits were coded as in-person or virtual (ie, telephone or video) and counted for each patient, quarterly by visit modality. Poisson models with Huber-White robust errors clustered at the census block estimated the association between a patient's broadband availability category and the quarterly primary care visit count by visit type, adjusted for covariates. In primary care, 6 995 545 veterans (91.8% men; mean [SD] age, 63.9 [17.2] years; 71.9% White; and 63.0% residing in an urban area) were seen. Adjusted regression analyses estimated the change after the onset of the pandemic vs before the pandemic in patients' quarterly primary care visit count; patients living in census blocks with optimal vs inadequate broadband had increased video visit use (incidence rate ratio [IRR], 1.33; 95% CI, 1.21-1.46; P < .001) and decreased in-person visits (IRR, 0.84; 95% CI, 0.84-0.84; P < .001). The increase in the rate of video visits before vs after the onset of the pandemic was greatest among patients in the lowest Area Deprivation Index category (indicating least social disadvantage) with availability of optimal vs inadequate broadband (IRR, 1.73; 95% CI, 1.42-2.09). This cohort study found that patients with optimal vs inadequate broadband availability had more video-based primary care visits and fewer in-person primary care visits after the onset of the COVID-19 pandemic, suggesting that broadband availability was associated with video-based telemedicine use. Future work should assess the association of telemedicine access with clinical outcomes.


A multicentre study of meticillin-resistant Staphylococcus aureus in acute bacterial skin and skin-structure infections in China: susceptibility to ceftaroline and molecular epidemiology.
Ceftaroline is a novel cephalosporin with activity against Gram-positive organisms, including meticillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to investigate the susceptibility to ceftaroline of hospital-associated MRSA (HA-MRSA) isolates causing acute bacterial skin and skin-structure infections (ABSSSIs) in China and to examine their relationship by genotyping. A total of 251 HA-MRSA isolates causing ABSSSIs were collected from a multicentre study involving 56 hospitals in 38 large cities across 26 provinces in mainland China. All isolates were characterised by multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) typing, spa typing and detection of the Panton-Valentine leukocidin locus (lukS-PV and lukF-PV). Minimum inhibitory concentrations (MICs) of 14 antimicrobial agents, including ceftaroline, were determined by broth microdilution and were interpreted using Clinical and Laboratory Standards Institute breakpoints. The ceftaroline MIC50 and MIC90 values (MICs that inhibit 50% and 90% of the isolates, respectively) were 1 μg/mL and 2 μg/mL, respectively; 33.5% (n=84) of the isolates studied were ceftaroline-non-susceptible, with MICs of 2 μg/mL, but no isolate exhibited ceftaroline resistance (MIC>2 μg/mL). All of the ceftaroline-non-susceptible isolates belonged to the predominant HA-MRSA clones: 95.2% (n=80) from MLST clonal complex 8 (CC8), with the remaining 4.8% (n=4) from CC5. The high rate of non-susceptibility to ceftaroline amongst HA-MRSA causing ABSSSIs in China is concerning.


Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.
Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.


Deployable, Variable Stiffness, Cable Driven Robot for Minimally Invasive Surgery.
Minimally Invasive Surgery (MIS) imposes a trade-off between non-invasive access and surgical capability. Treatment of early gastric cancers over 20 mm in diameter can be achieved by performing Endoscopic Submucosal Dissection (ESD) with a flexible endoscope; however, this procedure is technically challenging, suffers from extended operation times and requires extensive training. To facilitate the ESD procedure, we have created a deployable cable driven robot that increases the surgical capabilities of the flexible endoscope while attempting to minimize the impact on the access that they offer. Using a low-profile inflatable support structure in the shape of a hollow hexagonal prism, our robot can fold around the flexible endoscope and, when the target site has been reached, achieve a 73.16% increase in volume and increase its radial stiffness. A sheath around the variable stiffness structure delivers a series of force transmission cables that connect to two independent tubular end-effectors through which standard flexible endoscopic instruments can pass and be anchored. Using a simple control scheme based on the length of each cable, the pose of the two instruments can be controlled by haptic controllers in each hand of the user. The forces exerted by a single instrument were measured, and a maximum magnitude of 8.29 N observed along a single axis. The working channels and tip control of the flexible endoscope remain in use in conjunction with our robot and were used during a procedure imitating the demands of ESD was successfully carried out by a novice user. Not only does this robot facilitate difficult surgical techniques, but it can be easily customized and rapidly produced at low cost due to a programmatic design approach.


C2 and Greater Occipital Nerve: The Anatomic and Functional Implications in Spinal Surgery.
Posterior C1-C2 fusion is a highly successful treatment for atlantoaxial instability and other pathologies of the cervical spine, with fusion rates approaching 95%-100%. However, poor visualization of the lateral masses of C1 secondary to the course of the C2 nerve root along with blood loss from the venous plexus and compression of the C2 nerve from lateral mass screws are technical obstacles that can arise during surgery. Thus, sacrifice of the C2 nerve root has long since been debated in fusions involving the C1 and C2 vertebral bodies. Cadaveric dissections on four adult specimens were performed. Both intradural and extradural courses of C2 were studied in detail. The tentative site of C2 nerve root compression during placement of C1 lateral mass screws was studied in detail. Both the indication as well as the ease of C2 neurectomy were studied in relation to postoperative compression and entrapment. Four-six dorsal rootlets of C2 nerve were observed while studying the intradural course. The extradural course was studied with respect to the lateral mass of C1. The greater occipital nerve (GON) course was fairly consistent in all specimens. Transection of C2 around its ganglion would allow for proper C1 lateral mass screw placement as the course of C2 nerve interferes with proper placement of instrumentation. C2 nerve root transection is associated with occipital numbness but this often has no effect on health-related quality of life (HRQOL). The C2 nerve root preservation is often associated with entrapment neuropathy or occipital neuralgia, which greatly affects HRQOL. The C2 nerve root transection helps in better visualization, aids in optimal placement of C1 lateral mass screws, minimizes estimated blood loss and improves surgical outcome with successful fusion.


Brain-Penetrating Peptide Shuttles across the Blood-Brain Barrier and Extracellular-like Space.
Systemic delivery of therapeutics into the brain is greatly impaired by multiple biological barriers─the blood-brain barrier (BBB) and the extracellular matrix (ECM) of the extracellular space. To address this problem, we developed a combinatorial approach to identify peptides that can shuttle and transport across both barriers. A cysteine-constrained heptapeptide M13 phage display library was iteratively panned against an established BBB model for three rounds to select for peptides that can transport across the barrier. Using next-generation DNA sequencing and in silico analysis, we identified peptides that were selectively enriched from successive rounds of panning for functional validation in vitro and in vivo. Select peptide-presenting phages exhibited efficient shuttling across the in vitro BBB model. Two clones, Pep-3 and Pep-9, exhibited higher specificity and efficiency of transcytosis than controls. We confirmed that peptides Pep-3 and Pep-9 demonstrated better diffusive transport through the extracellular matrix than gold standard nona-arginine and clinically trialed angiopep-2 peptides. In in vivo studies, we demonstrated that systemically administered Pep-3 and Pep-9 peptide-presenting phages penetrate the BBB and distribute into the brain parenchyma. In addition, free peptides Pep-3 and Pep-9 achieved higher accumulation in the brain than free angiopep-2 and may exhibit brain targeting. In summary, these in vitro and in vivo studies highlight that combinatorial phage display with a designed selection strategy can identify peptides as promising carriers, which are able to overcome the multiple biological barriers of the brain and shuttle different-sized molecules from small fluorophores to large macromolecules for improved delivery into the brain.


Why business office consolidations can fail.
Because of a maze of organizational and resource issues, healthcare systems planning to consolidate the business operations of member facilities should proceed carefully. A central business office can lead to increased cash flow but also can exaggerate problems existing at individual hospitals. Before moving ahead, hospital systems should consider their objectives, evaluate existing support systems, set up accountability procedures, and take other steps.


Restraint and Seclusion Practices and Policies in U.S. Forensic Psychiatric Hospitals.
Over the last 30 years, there have been significant efforts to reduce the use of restraint and seclusion in psychiatric hospitals. Although authors have previously described restraint policies and practices in general psychiatry settings across the United States, this study is the first to attempt to describe policies regarding those practices in forensic hospital settings. We review the history of restraint and seclusion use in the United States, placing it within an international context. We then describe the results of a national survey of state forensic services directors regarding restraint modalities and policies in forensic hospital facilities. Twenty-nine respondents representing 25 states completed the survey. The results indicate that physical holds are the most frequently available method of restraint and that restraint chairs are the least frequently available. Most respondents reported having a policy regulating the use of restraint in their facilities, most commonly at the institutional level.


Healthcare employment as a risk factor for functional neurological disorder: A case-control study.
Female gender, younger age and stressful life events are known predisposing factors for functional neurological disorders (FNDs). Employment in a healthcare profession has also been suggested to be a predisposing factor. We set out to conduct a large-scale case-control study to estimate the rate employment in a healthcare profession among people with FND. We included 200 consecutive patients with a confirmed diagnosis of FND, referred to our clinic at University Hospital Bern Switzerland between October 1, 2016, and August 1, 2019. In addition, we included a control group of 200 patients with a confirmed neurological disorder, matched for age and gender, seen during the same period. The primary endpoint was to compare the prevalence of healthcare professionals between the groups. We also describe the clinical manifestations and concomitant psychiatric diagnoses in the FND cohort. Female gender was predominant (70%), and the participants' mean age was 37 years. The proportion of healthcare professionals in the FND patients was 18% (33/186), which was significantly higher than in the control group, in which it was 10.6% (17/189; p = 0.019, 95% confidence interval odds ratio 1.168-4.074). Most healthcare professionals in both cohorts were nurses (21/33 among FND patients, 10/17 among controls). Among FND patients, 140 (70%) had motor symptoms and 65 (32.5%) had a concomitant psychiatric diagnosis. This case-control study confirmed a higher rate of employment in healthcare professions in patients with FND, suggesting two potential mechanisms of FND: exposure to models/specific knowledge about neurological symptoms or stress-related professional factors. This warrants further studies on underlying mechanisms and prevention.


Toxicity and mutagenicity of 2,4,-6-trinitrotoluene and its microbial metabolites.
TNT (2,4,6-trinitrotoluene) of explosive grade is highly toxic to marine forms that included fresh water unicellular green algae (Selenastrum capricornutum), tidepool copepods (Tigriopus californicus), and oyster larvae (Crassostrea gigas), and mutagenic to Salmonella typhimurium. On the basis of mutagenic assays carried out with a set of histidine-requiring strains of the bacterium, TNT was detected as a frameshift mutagen that significantly accelerates the reversion rate of a frameshift tester, TA-98. In contrast, the major microbial metabolites of TNT appeared to be nontoxic and nonmutagenic.


Spatial and temporal patterns of phytoplankton community succession and characteristics of realized niches in Lake Taihu, China.
Understanding the dynamics and succession of phytoplankton in large lakes can help inform future lake management. The study analyzed phytoplankton community variations in Lake Taihu over a 21-year period, focusing on realized niches and their impact on successions. The study developed a niche periodic table with 32 niche dimensions, revealing responses to environmental factors and the optimal number of niches. Results showed that the phytoplankton in Lake Taihu showed significant spatial and temporal heterogeneity, with biomass decreasing as one moved from the northwest to the southeast and expanding towards central lake area, and towards autumn and winter. Different phytoplankton groups in Lake Taihu occupy realized niches shaped by temperature, nitrate, and phosphate. To predict the response of eutrophic freshwater lake ecosystems to human activities and climate change, it is critical to interpret the law of phytoplankton bloom and niche succession.


Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry.
Increasing evidence supports transcellular propagation of toxic protein aggregates, or proteopathic seeds, as a mechanism for the initiation and progression of pathology in several neurodegenerative diseases, including Alzheimer's disease and the related tauopathies. The potentially critical role of tau seeds in disease progression strongly supports the need for a sensitive assay that readily detects seeding activity in biological samples. By combining the specificity of fluorescence resonance energy transfer (FRET), the sensitivity of flow cytometry, and the stability of a monoclonal cell line, an ultra-sensitive seeding assay has been engineered and is compatible with seed detection from recombinant or biological samples, including human and mouse brain homogenates. The assay employs monoclonal HEK 293T cells that stably express the aggregation-prone repeat domain (RD) of tau harboring the disease-associated P301S mutation fused to either CFP or YFP, which produce a FRET signal upon protein aggregation. The uptake of proteopathic tau seeds (but not other proteins) into the biosensor cells stimulates aggregation of RD-CFP and RD-YFP, and flow cytometry sensitively and quantitatively monitors this aggregation-induced FRET. The assay detects femtomolar concentrations (monomer equivalent) of recombinant tau seeds, has a dynamic range spanning three orders of magnitude, and is compatible with brain homogenates from tauopathy transgenic mice and human tauopathy subjects. With slight modifications, the assay can also detect seeding activity of other proteopathic seeds, such as α-synuclein, and is also compatible with primary neuronal cultures. The ease, sensitivity, and broad applicability of FRET flow cytometry makes it useful to study a wide range of protein aggregation disorders.


Clinical and Genetic Spectrum of Bartter Syndrome Type 3.
Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.


Effects of antimony on rats following 90-day exposure via drinking water.
The subchronic toxicity of antimony in drinking water was studied in the rat. Male and female Sprague-Dawley rats (127-135 g body weight, 15 animals per group) were exposed to a soluble trivalent antimony salt, potassium antimony tartrate, in drinking water at concentrations of 0.5, 5, 50 and 500 ppm for 13 wk. Control rats received tap water as drinking water. An additional 10 male and 10 female rats were included in each of the control and 500 ppm groups and were given tap water for a further 4-wk recovery period after the 13-week treatment period. During treatment, the highest dose animals of both sexes consumed significantly less water and showed suppressed body weight gain. During recovery, water intake was quickly restored to that of the control groups and body weight gain was accelerated. At termination, one highest dose male had a cirrhotic liver, and three highest dose males exhibited gross haematuria. Female rats showed a dose-related decrease in serum glucose starting at 5 ppm, and rats of both sexes in the highest dose group had slightly decreased alkaline phosphatase activity and creatinine. The highest dose males had decreased red blood cell and platelet counts and increased mean corpuscular volume. Hepatic glutathione S-transferase activity was increased in the highest dose males and females and ethoxyresorufin-O-deethylase activity was increased in the highest dose males. In the highest dose groups, mild adaptive histological changes were observed in the thyroid, liver and pituitary gland of both sexes, and in the spleen of male rats and thymus of female rats. After a 4-wk recovery period, the pituitary gland of both sexes appeared normal and the changes in the liver and thyroid of both sexes became less severe. On the other hand, minimal changes persisted in the spleen of both sexes and in the thymus of males. Tissue antimony levels were dose-related and follow the order: red blood cells > > spleen, liver > kidney > brain, fat > serum. After the recovery period, antimony level in the highest dose animals decreased for all tissues except the spleen, which remained the same as before recovery. A NOAEL of 0.5 ppm antimony in drinking water, equivalent to an average intake of 0.06 mg/kg body weight/day, was established on the basis of the histological and biochemical changes observed at 5.0 ppm.


Histidine deficiency has a negative effect on lactational performance of dairy cows.
A 10-wk randomized complete block design experiment with 24 Holstein cows was conducted to investigate the long-term effects of feeding a His-deficient diet on lactational performance of dairy cows. Cows were blocked by days in milk, milk yield, and parity, and randomly assigned to 1 of the following 2 treatments: (1) His-adequate diet [HAD; providing +166 g/d over metabolizable protein (MP) requirements, according to the National Research Council (2001) and digestible His (dHis) supply of 68 g/d, or 2.5% of MP requirements] and (2) His-deficient diet (HDD; +37 g/d over MP requirements and dHis supply of 49 g/d, or 1.9% of MP requirements). Both HAD and HDD were supplemented with rumen-protected (RP) Met and Lys supplying digestible Met and digestible Lys at 2.4 and 2.4% and 7.2 and 7.1% of MP requirements, respectively. At the end of the 10-wk experiment, HDD was supplemented with RPHis (HDD+RPHis; total dHis supply of 61 g/d, or 2.4% of MP requirements) for an additional 9 d. Dry matter intake (DMI; 25.4 and 27.1 kg/d, standard error of the mean = 0.41), yields of milk (37.6 and 40.5 kg/d, standard error of the mean = 0.62), protein and lactose, energy-corrected milk, and milk and plasma urea-N were decreased by HDD compared with HAD. Feed and energy-corrected milk feed efficiencies, milk fat, protein and lactose concentrations, body weight, and body condition score of the cows were not affected by treatment. Apparent total-tract digestibility of dry and organic matter, crude protein, and neutral detergent fiber, and excretion of urinary N and urea-N were decreased by HDD compared with HAD. Concentration of plasma leptin tended to be decreased for HDD compared with HAD. Plasma concentrations of EAA (His, Leu, Lys, Val) and carnosine decreased and total EAA tended to be decreased in cows fed HDD compared with HAD. Muscle concentrations of free His, Leu, and Val decreased and Gly and β-alanine tended to be increased by HDD compared with HAD. Cows fed HDD had a lower blood hemoglobin concentration than cows fed HAD. At the end of the 10-wk study, the 9-d supplementation of HDD with RPHis (i.e., HDD+RPHis) increased DMI and plasma His, and tended to increase energy-corrected milk yield and plasma carnosine, compared with HDD. In conclusion, feeding a diet deficient in dHis supplying adequate MP, digestible Met, and digestible Lys affected negatively lactational performance of dairy cows. These results confirm our previous findings that low dietary His supply can impair DMI, yields of milk and milk protein, and blood hemoglobin in dairy cows.


The transcriptome of the colonial marine hydroid Hydractinia echinata.
An increasing amount of expressed sequence tag (EST) and genomic data, predominantly for the cnidarians Acropora, Hydra and Nematostella, reveals that cnidarians have a high genomic complexity, despite being one of the morphologically simplest multicellular animals. Considering the diversity of cnidarians, we performed an EST project on the hydroid Hydractinia echinata, to contribute towards a broader coverage of this phylum. After random sequencing of almost 9000 clones, EST characterization revealed a broad diversity in gene content. Corroborating observations in other cnidarians, Hydractinia sequences exhibited a higher sequence similarity to vertebrates than to ecdysozoan invertebrates. A significant number of sequences were hitherto undescribed in metazoans, suggesting that these may be either cnidarian innovations or ancient genes lost in the bilaterian genomes analysed so far. However, we cannot rule out some degree of contamination from commensal bacteria. The identification of unique Hydractinia sequences emphasizes that the acquired genomic information generated so far is not large enough to be representative of the highly diverse cnidarian phylum. Finally, a database was created to store all the acquired information (http://www.mchips.org/hydractinia_echinata.html).


Differential responses of disease-related GRIN variants located in pore-forming M2 domain of N-methyl-D-aspartate receptor to FDA-approved inhibitors.
N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg2+ inhibition. Voltage-dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3-dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA-approved NMDAR drugs-memantine, dextromethorphan, and ketamine-were chosen based on their ability to bind near the M2 re-entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage-dependent Mg2+ block. These results provide insight of structural determinants of FDA-approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology.


Enhanced Adherence in Patients Using an Automated Home Medication Dispenser.
Many factors contribute to medication nonadherence including psychological and memory disorders, aging, and pill burden. The Automated Home Medication Dispenser (AHMD) is a medication management system intended to help solve unintentional medication nonadherence. The purpose of this study was to determine if use of the AHMD improved medication adherence. We conducted a 6-month prospective, feasibility study assessing use of the AHMD in 21 patient-caregiver dyads. Patients were referred by their physician because of poor medication adherence and included if they resided in Rochester, NY and on at least two medications in pill form. Pill counts were performed at baseline to assess previous adherence. Prospective medication adherence was assessed using AHMD recorded dosing information. A paired t-test was used to compare previous and prospective adherence. The mean age of patients was 75.1 years. Fifteen patients (71.4%) and eight caregivers (38.1%) were women; half (47.6%) of caregivers lived with the patient. The most common patient comorbidities were hypertension (76.2%) and memory disorder (61.9%). Mean adherence increased from 49.0% at baseline to 96.8% after 6 months of AHMD use (p < .001). In a cohort of unintentionally nonadherent patients, use of the AHMD for 6 months significantly improved medication adherence.


Ultra-rapid access to words in the brain.
Rapid information processing in the human brain is vital to survival in a highly dynamic environment. The key tool humans use to exchange information is spoken language, but the exact speed of the neuronal mechanisms underpinning speech comprehension is still unknown. Here we investigate the time course of neuro-lexical processing by analyzing neuromagnetic brain activity elicited in response to psycholinguistically and acoustically matched groups of words and pseudowords. We show an ultra-early dissociation in cortical activation elicited by these stimulus types, emerging ∼50 ms after acoustic information required for word identification first becomes available. This dissociation is the earliest brain signature of lexical processing of words so far reported, and may help explain the evolutionary advantage of human spoken language.


The discrete single-entity electrochemistry of Pickering emulsions.
Single-entity analysis is an important research topic in electrochemistry. To date, electrode collisions and subsequent electrode-particle interactions have been studied for many types of nano-objects, including metals, polymers, and micelles. Here we extend this nano-object electrochemistry analysis to Pickering emulsions for the first time. The electrochemistry of Pickering emulsions is important because the internal space of a Pickering emulsion can serve as a reactor or template; this leads to myriad possible applications, all the while maintaining mechanical stability far superior to what is exhibited by conventional emulsions. This work showed that Pickering emulsions exhibit similar hydrodynamic behavior to other nano-objects, despite the complex structure involving hard nanoparticle surfactants, and the electron-transport mechanism into the internal volume of Pickering emulsions was elucidated. The Pickering emulsion electrochemistry platform developed here can be applied to electrochemical nanomaterial synthesis, surmounting the challenges faced by conventional synthetic strategies involving normal emulsions.


A history of why fathers' RNA matters.
Having been debated for many years, the presence and role of spermatozoal RNAs is resolving, and their contribution to development is now appreciated. Data from different species continue show that sperm contain a complex suite of coding and noncoding RNAs that play a role in an individual's life course. Mature sperm RNAs provide a retrospective of spermatogenesis, with their presence and abundance reflecting sperm maturation, fertility potential, and the paternal contribution to the developmental path the offspring may follow.Sperm RNAs delivered upon fertilization provide some of the initial contacts with the oocyte, directly confront the maternal with the paternal contribution as a prelude to genome consolidation. Following syngamy, early embryo development may in part be modulated by paternal RNAs that can include epidydimal passengers. This provides a direct path to relay an experience and then initiate a paternal response to the environment to the oocyte and beyond. Their epigenetic impact is likely felt prior to embryonic genome activation when the population of sperm delivered transcripts markedly changes. Here, we review the insights gained from sperm RNAs over the years, the subtypes, and the caveats of the RNAs described. We discuss the role of sperm RNAs in fertilization and embryo development, and their possible mechanism(s) influencing offspring phenotype. Approaches to meet the future challenges as the study of sperm RNAs continues, include, elucidating the potential mechanisms underlying how paternal allostatic load, the constant adaptation of health to external conditions, may be relayed by sperm RNAs to affect future generations.


[Formaldehyde determination in tobacco smoke--studies under experimental and actual conditions].
The estimation of an external exposure to formaldehyde in tobacco smoke requires a reliable analytical method. The gas chromatographic determination of formaldehyde shows in comparison to photometric methods a higher sensitivity and specificity. In the main stream smoke of various kinds of cigarettes the amount of formaldehyde vary between 3.4 micrograms to 8.8 micrograms/cigarette, this is equal to concentration between 2.3 to 6.1 ppm. In the air of lounges in hospitals formaldehyde concentrations up to 0.19 ppm can be detected after smoking of 15 cigarettes over a period of 1.5 h. In kindergartens without tobacco smoke the formaldehyde concentrations in air range from 0.005 to 0.01 ppm. The smoking of 30 cigarettes and one pipe in a non ventilated room over 1.5 h exceeded formaldehyde concentrations between 0.21 to 0.45 ppm. The concentration declines to 0.08 ppm within 2h after termination of smoking. The MAK-value of 0.5 ppm is not exceeded; in contrast to this the indoor limit of 0.1 ppm recommended by the German Bundesgesundheitsamt is exceeded in the vicinity of the smoker. The formaldehyde concentrations in tobacco smoke reported in the older literature can not be confirmed; this is due to the nonspecificity of the photometric methods. On the basis of our results can be concluded that the irritating effects of tobacco smoke to the mucous membranes are the result of the sum of irritating effects caused by several compounds and particles in the smoke and not only the impact of formaldehyde.


Assessment of central venous catheterization and complications in a tertiary pediatric intensive care unit.
Tolunay İ, Yıldızdaş RD, Elçi H, Alabaz D. Assessment of central venous catheterization and complications in a tertiary pediatric intensive care unit. Turk J Pediatr 2018; 60: 63-69. In catheter-using units as pediatric intensive care, it is important to know the complications that may occur during the insertion and use of central venous catheterization (CVC), and to take appropriate measures in order to reduce the mortality and morbidity of critical patients. The aim of this study was to evaluate CVC and catheter related complications in our tertiary pediatric intensive care unit. For this prospective study, 155 central venous catheters and/or hemodialysis catheters used with 106 patients, between August 2014 and August 2015 were evaluated. Demographic information about patients, catheter insertion procedure and catheter related complications were recorded. Sixty-two (58.5%) male and forty-four (41.5%) female patients were evaluated in this study. The median age was 67.5 months (1-212). The mean dwell time of catheters was 10.54±8 days. Twenty-two (14.2%) catheters were removed from patients because of catheter related complications. The mean dwell time of complicated catheters was 10.6±8.5 days and there was no statistically significant difference between complicated and non-complicated catheters. Catheter related blood stream infections was diagnosed in 5.1% (8/155) patients and these catheters were removed from patients. Including these patients, positive blood culture was found to be at 14.2% (22/155). The mean dwell time of catheters with positive blood culture was 14.25±7.3 days. The mean dwell time of catheters with positive blood culture was statistically significantly longer than catheters with negative blood culture. In the 3 patients who developed catheter thrombosis, 2 patients were followed up because of infection/sepsis and 1 patient had a neurological disease. Catheter thrombosis developed in 1 femoral vein and 2 internal jugular veins. The development of central venous catheter complications depends on many different factors and it is possible to reduce the complications with precautions taken during replacement and daily use.


Association between daily use of social media and behavioral lifestyles in the Saudi community: a cross-sectional study.
This study aimed to investigate the association between nine social media platforms use and health-related behavior, including fruit and vegetable intake, physical activity, tobacco use, and risk factors including depression and obesity. A cross-sectional study was conducted using secondary data from the Sharik Health Indicators Surveillance System (SHISS). Participants 18 years and older were recruited via phone-interviews. The nine social media platform use [Twitter-(X), Facebook, Instagram, WhatsApp, LinkedIn, Snapchat, TikTok, Telegram, and YouTube] were assessed using self-reported use. Health-related variables include behavioral factors including diet, physical activity, and tobacco use including (cigarettes, waterpipes, and e-cigarettes), risk of depression and obesity. Logistic regression analysis was performed to explore the association between social media use and health-related variables. The study indicated that daily Snapchat users had a lower healthy diet (fruit and vegetable intake), whereas daily LinkedIn and WhatsApp users were positively associated with a healthier diet, relative to those with infrequent social media use. Furthermore, daily interaction with Instagram, TikTok, Telegram, and YouTube was significantly associated with increased depression risk. Conversely, Snapchat and WhatsApp usage was significantly linked to a decreased depression risk. Tobacco-smoking behaviors were associated with specific social media platforms: cigarette smoking was associated with Snapchat, TikTok, and YouTube; e-cigarette with Facebook, LinkedIn, Snapchat, and TikTok; and waterpipe smoking with Facebook and TikTok. Interestingly, some platforms, such as Instagram, were associated with reduced cigarette smoking. The relationship between social media activity and health-related outcomes remained significant after adjusting for age and gender. This study highlights the potential negative impact of particular daily social media use on health-related variables, including dietary habits, tobacco use, and depression. Nevertheless, particular daily social media use of some platforms was associated with a potential positive impact on the health-related variables. Social media platforms are tools that can be used to achieve both a positive and negative effect. By knowing which demographic segments have a greater presence on one platform, we are creating opportunities to understand the social phenomena and at the same time use it to reach those segments and communicate with them, because each social media platform has its unique way and framework of user communication.


Epilepsies and neuronal plasticity: for better or for worse?
Extensive experimental investigations have confirmed that "seizures beget seizures." Thus, in adults, limbic seizures lead to cell loss, followed by the formation of novel excitatory synapses that contribute to generating further seizures. The triggering signal is an enhancement of synaptic efficacy, followed by a molecular cascade that triggers axonal sprouting. New synapses are aberrant, since they are formed in regions in which they are not present in controls. They also involve receptors that are not present in controls, and this facilitates the generation of seizures. Therefore, an aberrant form of reactive neuronal plasticity provides a substrate for the long-lasting sequelae of seizures. Since these events take place in brain structures involved in integrative and mnemonic functions, they will have an important impact. Reactive plasticity is documented for other insults and disorders, and may be the basis for the long-term progression of neurodegenerative disorders.


Status of the cattle genome map.
During the last 30 years, the cattle genome map has been expanded from 4 genes linked on chromosome X to over 22,000 genes identified in the cattle genome sequence assembly. This progress has been achieved due to numerous projects on linkage and physical mapping of the cattle genome driven by its agricultural and scientific significance. Indeed, the high-resolution mapping and functional analysis of the genome led to the discovery of major quantitative trait loci (QTL) regions and several quantitative trait nucleotides (QTNs), as well as some disease genes in the cow population. In addition, a comparison of the cattle genome to the genomes of other mammals has revealed its unique features gained during the speciation and adaptation. With the development of non-expensive sequencing techniques, the analysis of the cattle genome will shift towards the identification of differences between breeds or individuals within breeds that account for the unique features of each breed. This approach holds promise for the development of effective tools for the marker assistant selection and disease diagnostics in cattle.


[Acute abdomen in renal transplant recipients. Epidemiology and treatment in not referral transplantation centers].
The incidence of gastrointestinal complications in renal transplant recipients is relatively high while about 10% is related to acute abdomen. Data concerning gastrointestinal (GI) complications were reported in literature mainly from referral center studies. A multicenter retrospectively survey was performed in Lazio, Italy, in order to evaluate the incidence of acute abdomen in renal transplant recipients observed to the emergency departments of not referral transplantation centers. Clinical and demographic findings regarding 14 patients who experienced acute abdomen between February 2005 and Dicember 2008 have been collected. The following data was investigated: etiology, diagnostic workup, duration of symptoms, elapsed time between admission and emergency operation if performed, morbility and mortality. The severity of disease at presentation was assessed by mean of the Acute Physiology and Chronic Health Evaluation score (APACHE II). Acute abdomen was due to pancreatitis in three patients (23.1%); to cholecystitis in three (23.1%); to acute diverticolitis with colon perforation in two patients (15.4%); to acute appendicitis in two (15.4%) and to intestinal obstruction in 2 patients (15.4%). Small bowel perforation was observed in two patients (15.4%) which one case, upon pathological examination, showed malignant lymphoma. The mean APACHE II score was 14.0 ± 5.9. Ten patients (71.4%) were submitted to surgery. Overall mortality and morbidity were 35% and 42% respectively. Statistical analysis showed admission APACHE II score (p<0.01), duration of symptoms (p<0.05), and total time elapsed between the onset of symptoms and treatment (p<0.04) as factors significantly related to mortality.


Boosting Mitochondrial Biogenesis Diminishes Foam Cell Formation in the Post-Stroke Brain.
Following ischemic stroke, the degradation of myelin and other cellular membranes surpasses the lipid-processing capabilities of resident microglia and infiltrating macrophages. This imbalance leads to foam cell formation in the infarct and areas of secondary neurodegeneration, instigating sustained inflammation and furthering neurological damage. Given that mitochondria are the primary sites of fatty acid metabolism, augmenting mitochondrial biogenesis (MB) may enhance lipid processing, curtailing foam cell formation and post-stroke chronic inflammation. Previous studies have shown that the pharmacological activation of the β2-adrenergic receptor (β2-AR) stimulates MB. Consequently, our study sought to discern the effects of intensified β2-AR signaling on MB, the processing of brain lipid debris, and neurological outcome using a mouse stroke model. To achieve this goal, aged mice were treated with formoterol, a long-acting β2-AR agonist, daily for two and eight weeks following stroke. Formoterol increased MB in the infarct region, modified fatty acid metabolism, and reduced foam cell formation. However, it did not reduce markers of post-stroke neurodegeneration or improve recovery. Although our findings indicate that enhancing MB in myeloid cells can aid in the processing of brain lipid debris after stroke, it is important to note that boosting MB alone may not be sufficient to significantly impact stroke recovery.


Enhancing Annular Fissures and High-Intensity Zones: Pain, Internal Derangement, and Anesthetic Response at Provocation Lumbar Discography.
A high-intensity zone identified on preprocedural MR imaging is known to correlate with pain at provocation lumbar discography. The correlation between enhancing annular fissures and pain at provocation lumbar discography has not been comprehensively evaluated. The purpose of this study was to assess the pain response and imaging features at enhancing annular fissure nonoperated disc levels identified on preprocedural MR imaging with comparison with the high-intensity zone and nonenhancing disc levels in patients referred for provocation lumbar discography. One-hundred nonoperated discs in 44 patients were retrospectively evaluated for an enhancing annular fissure on sagittal postcontrast T1-weighted pre-discogram MR imaging. Enhancing annular fissure discs were graded on the sagittal T2-weighted sequence (Grade 4: like CSF to Grade 1: negative/barely visible) for high-intensity-zone conspicuity. High-intensity-zone detection was performed independently. In the primary assessment, enhancing annular fissure and high-intensity zones were associated with pain response at provocation lumbar discography. Additional analysis included intradiscal anesthetic response and postdiscogram CT appearance. Thirty-nine discs demonstrated an enhancing annular fissure, with 23/39 demonstrating a high-intensity zone. The presence of a high-intensity zone predicted severe pain (concordant + nonconcordant; P = .005, sensitivity of 40%, specificity of 94%) and concordant pain (P = .007, sensitivity of 39%, specificity of 86%) at provocation lumbar discography. Enhancing annular fissures without a detected high-intensity zone were more frequently observed among severely painful (50%) and concordant (36%) discs than among discs negative for pain (9%; P = .01). This finding resulted in a substantially greater overall sensitivity of enhancing annular fissures for severe (P < .001, 64%) and concordant pain (P = .008, 61%), significantly improving the overall predictive ability of a high-intensity zone alone. A high-intensity zone went undetected in 9/11 Grade 1 disc levels with concordant pain present in 7/9. Consideration of enhancing annular fissures on preprocedural MR imaging substantially improves the prediction of severe/concordant pain in provocation lumbar discography.


[Argyrophilic proteins in the regions of nucleolar organizers are markers of cell proliferation rate].
The paper reviews the literature on the role of the above proteins in the mechanisms of cell cycle regulation and presents data on changes in protein expression in dynamics of cell cycle. The significance of studies dealing with the expression of these proteins, which, along with the assessment of a cell population growth fraction, allow one to characterize the rate of cell proliferation that under malignant growth is the determinant of cell proliferative status, which has a great impact on tumor progression, is discussed. The data on the diagnostic value of these proteins as an independent predictor for a broad spectrum of tumors are considered.


[Structure of interstitial nephritis in children].
The authors provide the data on 24 cases of interstitial nephritis in children treated at the Nephrological Center of the city of Kuibyshev in 1986-1990. Describe the etiological structure of interstitial nephritis using the classification developed by N. A. Korovina and coworkers (1982), randomization according to the age, sex, and the disease course. Demonstrate the predominance of the postviral and toxicoallergic disease patterns in children of the early, preschool and junior school age. Estimate the importance of the types of urine proteinograms in the diagnosis of interstitial nephritis.


The last battle of Anne of Brittany: Solving mass grave through an interdisciplinary approach (paleopathology, biological anthropology, history, multiple isotopes and radiocarbon dating).
Mass graves are usually key historical markers with strong incentive for archeological investigations. The identification of individuals buried in mass graves has long benefitted from traditional historical, archaeological, anthropological and paleopathological techniques. The addition of novel methods including genetic, genomic and isotopic geochemistry have renewed interest in solving unidentified mass graves. In this study, we demonstrate that the combined use of these techniques allows the identification of the individuals found in two Breton historical mass graves, where one method alone would not have revealed the importance of this discovery. The skeletons likely belong to soldiers from the two enemy armies who fought during a major event of Breton history: the siege of Rennes in 1491, which ended by the wedding of the Duchess of Brittany with the King of France and signaled the end of the independence of the region. Our study highlights the value of interdisciplinary approaches with a particular emphasis on increasingly accurate isotopic markers. The development of the sulfur isoscape and testing of the triple isotope geographic assignment are detailed in a companion paper [13].


Measuring low vision service outcomes: Rasch analysis of the seven-item National Eye Institute Visual Function Questionnaire.
To describe a short, functional visual disability instrument capable of measuring the outcomes of a government funded country-wide multicenter low vision service in Wales and to determine if postal implementation might lead to response bias. Seven items from the National Eye Institute Visual Function Questionnaire (NEI VFQ), which have previously been shown to be responsive to low vision service intervention, were incorporated into a postal questionnaire which was given to patients before they attended the all Wales Low Vision Service. Rasch analysis was used to describe the instrument's psychometric properties. Rasch analysis of 490 completed questionnaires showed that all seven questions worked together to form a unidimensional scale. By combining the first two response categories, category utilization and targeting was improved. There were no significant differences in the age (p = 0.29), gender (p = 0.75), distance binocular Visual Acuity (VA; p = 0.86), living situation (p = 0.34) or prevalence of macular degeneration (p = 0.31) between those who returned a completed questionnaire and those who did not. The seven-item National Eye Institute Visual Function Questionnaire is an appropriate and precise outcome measure that is acceptable to patients and easy to administer. It measures aspects of near, reading, and distance visual disability that have been shown to be amenable to low vision service provision and, therefore, it should be highly responsive to this intervention and facilitate inter-service assessment. We found no evidence to suggest that postal implementation results in response bias. The instrument is an appropriate measure of patient based outcomes for a large-scale, multicenter low vision service.


Nitric oxide and NO-synthases in mammals in different functional states.
This review deals with the physical and chemical properties of nitric oxide as well as with the mechanisms and enzymes synthesizing this compound in animals including humans. The cytotoxic, vasodilatory, neuromediatory, and other properties of NO are analyzed. Polyfunctionality of NO in the norm and in pathologies of different genesis is shown. It is suggested that the analysis of the mechanisms of cyclic conversion of nitric oxide and the elucidation of the role of all NO metabolism products in living organisms would allow us to approach a more profound understanding of the NO problem in biology and medicine. It is reasonable to think the knowledge obtained in the course of the studies will permit an elaboration of the strategy and tactics of medical treatment of many diseases occurring on the background of disturbance in the mechanisms of formation and utilization of this compound.


Characterization of a novel sphingosine 1-phosphate receptor, Edg-8.
Three G protein-coupled receptors (Edg-1, Edg-3, and Edg-5) for the lysolipid phosphoric acid mediator sphingosine 1-phosphate have been described by molecular cloning. Using a similar sequence that we found in the expressed sequence tag data base, we cloned and characterized of a fourth, high affinity, rat brain sphingosine 1-phosphate receptor, Edg-8. When HEK293T cells were co-transfected with Edg-8 and G protein DNAs, prepared membranes showed sphingosine 1- phosphate-dependent increases in [(35)S]guanosine 5'-(3-O-thio)triphosphate binding with an EC(50) of 90 nm. In a rat hepatoma Rh7777 cell line that exhibits modest endogenous responses to sphingosine 1-phosphate, this lipid mediator inhibited forskolin-driven rises in cAMP by greater than 90% when the cells were transfected with Edg-8 DNA (IC(50) 0.7 nm). This response is blocked fully by prior treatment of cultures with pertussis toxin, thus implicating signaling through G(i/o)alpha proteins. Furthermore, Xenopus oocytes exhibit a calcium response to sphingosine 1-phosphate after injection of Edg-8 mRNA, but only when oocytes are co-injected with chimeric G(q/i)alpha protein mRNA. Membranes from HEK293T and Rh7777 cell cultures expressing Edg-8 exhibited high affinity (K(D) = 2 nm) binding for radiolabeled sphingosine 1-phosphate. Rat Edg-8 RNA is expressed in spleen and throughout adult rat brain where in situ hybridization revealed it to be associated with white matter. Together our data demonstrate that Edg-8 is a high affinity sphingosine 1-phosphate receptor that couples to G(i/o)alpha proteins and is expressed predominantly by oligodendrocytes and/or fibrous astrocytes in the rat brain.


Acupuncture for ankle sprain: systematic review and meta-analysis.
Ankle sprain is one of the most frequently encountered musculoskeletal injuries; however, the efficacy of acupuncture in treating ankle sprains remains uncertain. We therefore performed a systematic review to evaluate the evidence regarding acupuncture for ankle sprains. We searched 15 data sources and two trial registries up to February 2012. Randomized controlled trials of acupuncture were included if they involved patients with ankle sprains and reported outcomes of symptom improvement, including pain. A Cochrane risk of bias assessment tool was used. Risk ratio (RR) or mean difference (MD) was calculated with 95% confidence intervals (CIs) in a random effects model. Subgroup analyses were performed based on acupuncture type, grade of sprain, and control type. Sensitivity analyses were also performed with respect to risk of bias, sample size, and outcomes reported. Seventeen trials involving 1820 participants were included. Trial quality was generally poor, with just three reporting adequate methods of randomization and only one a method of allocation concealment. Significantly more participants in acupuncture groups reported global symptom improvement compared with no acupuncture groups (RR of symptoms persisting with acupuncture = 0.56, 95% CI 0.42-0.77). However, this is probably an overestimate due to the heterogeneity (I2 = 51%) and high risk of bias of the included studies. Acupuncture as an add-on treatment also improved global symptoms compared with other treatments only, without significant variability (RR 0.61, 95% CI 0.51-0.73, I2 = 1%). The benefit of acupuncture remained significant when the analysis was limited to two studies with a low risk of bias. Acupuncture was more effective than various controls in relieving pain, facilitating return to normal activity, and promoting quality of life, but these analyses were based on only a small number of studies. Acupuncture did not appear to be associated with adverse events. Given methodological shortcomings and the small number of high-quality primary studies, the available evidence is insufficient to recommend acupuncture as an evidence-based treatment option. This calls for further rigorous investigations.


Induction of cellular transcription factors in trigeminal ganglia of mice by corneal scarification, herpes simplex virus type 1 infection, and explantation of trigeminal ganglia.
In a mouse model for herpes simplex virus type 1 (HSV-1) latency in which the virus was inoculated via the eye after corneal scarification, HSV-1 replicated in corneal epithelial cells and infected the nerve cell endings. HSV-1 reached the trigeminal ganglia by fast axonal transport between 2 and 10 days postinfection (p.i.) and established a latent infection in neuronal cells or replicated and spread to nonneuronal cells. By using in situ hybridization, we showed that cellular transcription factors are stimulated by HSV-1 infection in trigeminal ganglia. This stimulation is biphasic, peaking at 1 and 3 to 4 days p.i. The first peak involves c-jun and oct-1 expression in neurons, and the second involves c-jun, c-fos, and oct-1 expression in neurons and nonneuronal cells. Corneal scarification, alone or followed by infection with UV-inactivated HSV-1, induced monophasic c-jun and oct-1 expression in some neurons of the trigeminal ganglia, with a peak at 1 day p.i. Corneal infection without prior scarification induced c-jun, c-fos, and oct-1 expression in some neuronal and nonneuronal cells of the trigeminal ganglia 2 to 9 days p.i. Explanation of ganglia from latently infected animals resulted in reactivation of the latent virus. Independently of the presence of latent HSV-1 in explanted ganglia, expression of c-fos, c-jun, and oct-1 was induced first in nonneuronal cells, peaking 6 to 10 h postexplantation, and then in neuronal cells, with a peak at 24 h after explantation when expression of viral replicative genes was first detectable. Since ocular HSV-1 infection, corneal scarification, and explantation of trigeminal ganglia all resulted in induction of expression of cellular transcription factors in ganglia, these factors may play a critical role in the permissiveness of cells for HSV-1 replication during acute infection, latency, and reactivation.


Current Treatment of Laryngopharyngeal Reflux.
Objectives: Laryngopharyngeal reflux (LPR) is a complex syndrome characterized by the reflux of gastroduodenal contents into the pharynx or larynx, resulting in a range of symptoms, including chronic cough, throat clearing, pain, dysphagia, hoarseness, and dysphonia. Despite the lack of a gold standard for diagnosis or treatment, various strategies have been proposed to manage LPR. However, the effectiveness of these treatments is compromised by the lack of a uniform treatment protocol, which places a burden on patients, physicians, and the healthcare system. This study aims to systematically review the treatments of LPR and provide updated and useful clinical information to clinical physicians. Methods: The literature with an emphasis on LPR and related keywords is searched and reviewed in PubMed. Results: Treatment of LPR includes health education, lifestyle modification, dietary changes, medications, and surgery, as well as the emergence of a novel treatment method involving external upper esophageal sphincter compression devices. Conclusions: Currently, medication is the main treatment, supplemented with lifestyle and dietary changes, but there is still a lack of effective means for patients with drug-resistant or intolerant LPR. More high-quality and rigorous trials must continue to be conducted to determine the best treatment options and find novel treatments. Taking into account the complexity of LPR, this study proposes a simple algorithm to help clinicians with the initial management of this disease.


The unclosing premature mortality gap in gout: a general population-based study.
Gout, the most common inflammatory arthritis, is associated with premature mortality. Whether this mortality gap has improved over time, as observed in rheumatoid arthritis (RA), is unknown. Using an electronic medical record database representative of the UK general population, we identified incident gout cases and controls between 1999 and 2014. The gout cohort was divided based on year of diagnosis into early (1999-2006) and late (2007-2014) cohorts. We compared the mortality rates and HRs, adjusting for potential confounders between the cohorts. We conducted sensitivity analyses among patients with gout who received at least one prescription for urate-lowering therapy, which has been found to have a validity of 90%. In both cohorts, patients with gout showed similar levels of excess mortality compared with their corresponding comparison cohort (ie, 29.1 vs 23.5 deaths/1000 person-years and 23.0 vs 18.8 deaths/1000 person-years in the early and late cohorts, respectively). The corresponding mortality HRs were 1.25 (95% CI 1.21 to 1.30) and 1.24 (95% CI 1.20 to 1.29), and the multivariable HRs were 1.10 (95% CI 1.06 to 1.15) and 1.09 (95% CI 1.05 to 1.13), respectively (both p values for interaction >0.72). Our sensitivity analyses showed similar findings (both p values for interaction >0.88). This general population-based cohort study indicates that the level of premature mortality among patients with gout remains unimproved over the past 16 years, unlike RA during the same period. This unclosing premature mortality gap calls for improved management of gout and its comorbidities.


[Effect of immunomodulators on liver regeneration].
The directed influence of immunomodulators on various chains of the immune system makes possible the control over liver restoration processes, as demonstrated on the model of hepatic resection. It is established that macrophages together with T-lymphocytes play a very important role in the process of liver regeneration.


Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.
Mitochondria are involved in many cellular processes; mitochondrial dysfunctions have been associated with apoptosis, aging, and a number of pathological conditions, including osteoarthritis (OA). Mitochondrial proteins are attractive targets for the study of metabolism of the chondrocyte, the unique cell type present in mature cartilage, and its role in tissue degradation. Using a proteomics approach based on two-dimensional DIGE and MALDI-TOF/TOF mass spectrometric identification of mitochondria- enriched protein fractions from human articular chondrocytes, we analyzed mitochondrial protein changes that are characteristic of OA chondrocytes. A total of 73 protein forms were unambiguously identified as significantly altered in OA; 23 of them have been previously described as mitochondrial. An extensive statistical and cluster analysis of the data revealed a mitochondrial protein profile characteristic for OA. This pattern includes alterations in energy production, maintenance of mitochondrial membrane integrity, and free radical detoxification. Real time PCR, Western blot, and immunohistofluorescence assays confirmed a significant decrease of the major mitochondrial antioxidant protein manganese-superoxide dismutase (SOD2) in the superficial layer of OA cartilage. As possible outputs for this antioxidant deficiency, we found an increase of intracellular reactive oxygen species generation in OA chondrocytes and also verified an OA-dependent increase in the mitochondrial tumor necrosis factor-alpha receptor-associated protein 1 (TRAP1), a chaperone with a reported reactive oxygen species antagonist role. Our results describe the differences between the mitochondrial protein profiles of normal and OA chondrocytes, demonstrating that mitochondrial dysregulation occurs in cartilage cells during OA and highlighting redox imbalance as a key factor in OA pathogenesis.


Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team.
Amprenavir is a human immunodeficiency virus (HIV) protease inhibitor with a favorable pharmacokinetic profile and good in vitro activity. Ninety-two lamivudine- and protease inhibitor-naive individuals with >/=50 CD4 cells/mm3 and >/=5000 HIV RNA copies/mL were assigned amprenavir (1200 mg) alone or with zidovudine (300 mg) plus lamivudine (150 mg), all given every 12 h. After a median follow-up of 88 days, the findings of a planned interim review resulted in termination of the amprenavir monotherapy arm. Among 85 subjects with confirmed plasma HIV RNA determination, 15 of 42 monotherapy versus 1 of 43 triple-therapy subjects had an HIV RNA increase above baseline or 1 log10 above nadir (P=.0001). For subjects taking triple therapy at 24 weeks, the median decrease in HIV RNA was 2.04 log10 copies/mL, and 17 (63%) of 27 evaluable subjects had <500 HIV RNA copies/mL. Treatment with amprenavir, zidovudine, and lamivudine together reduced the levels of HIV RNA significantly more than did amprenavir monotherapy.


Urticaria: evaluation and treatment.
Urticaria involves intensely pruritic, raised wheals, with or without edema of the deeper cutis. It is usually a self-limited, benign reaction, but can be chronic. Rarely, it may represent serious systemic disease or a life-threatening allergic reaction. Urticaria has a lifetime prevalence of approximately 20 percent in the general population. It is caused by immunoglobulin E- and nonimmunoglobulin E-mediated mast cell and basophil release of histamine and other inflammatory mediators. Diagnosis is made clinically. Chronic urticaria is usually idiopathic and requires only a simple laboratory workup unless elements of the history or physical examination suggest specific underlying conditions. Treatment includes avoidance of triggers, although these can be identified in only 10 to 20 percent of patients with chronic urticaria. First-line pharmacotherapy for acute and chronic urticaria is nonsedating second-generation antihistamines (histamine H1 blockers), which can be titrated to larger than standard doses. First-generation antihistamines, histamine H2 blockers, leukotriene receptor antagonists, and brief corticosteroid bursts may be used as adjunctive treatment. More than one-half of patients with chronic urticaria will have resolution or improvement of symptoms within one year.


Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials.
Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD. We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model. Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported. Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.


Ocular VEMPs indicate repositioning of otoconia to the utricle after successful liberatory maneuvers in benign paroxysmal positioning vertigo.
This study showed a transient increase of ocular vestibular evoked myogenic potential (oVEMP) amplitudes in the affected ear after successful liberatory maneuvers and no changes in cervical VEMP (cVEMP) amplitudes. These findings support the hypothesis that successful liberatory maneuvers can lead to a repositioning of otoconia to the utricle. To evaluate whether oVEMP amplitudes increase after successful liberatory maneuvers in patients with posterior semicircular canal benign paroxysmal positioning vertigo (pc-BPPV), while cVEMP amplitudes do not change. These findings may indicate a successful repositioning of dislodged otoconia to the utricular macula, but not to the saccular macula. Thirty patients with unilateral pc-BPPV were prospectively examined with bone-conducted oVEMP and air-conducted cVEMP at four time points: before, after, 1 week after, and 1 month after the liberatory maneuvers (Sémont maneuvers). At the 1-week follow-up, 20 of 30 patients were asymptomatic (responders); BPPV could still be induced in the other 10 (non-responders). In responders the mean n10 amplitude on the affected side increased from 12 ± 6.5 µV at baseline (before the treatment) to 15.9 ± 7.1 µV at 1 week after treatment; this increase was significantly (p = 0.001) higher in responders than in non-responders. cVEMP did not differ significantly.