Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe.
Unmet needs exist in actinic keratosis (AK) treatment. Daylight photodynamic therapy (DL-PDT) has shown good efficacy and safety results compared to conventional PDT (c-PDT) in a recent Phase III multi-centre randomised controlled trial in Australia among 100 subjects with AKs. Demonstrate non-inferior efficacy and superior safety of DL-PDT compared to c-PDT in treating multiple mild and/or moderate facial/scalp AKs. Phase III, 12 week, multi-centre, randomised, investigator-blinded, controlled, intra-individual study conducted at different latitudes in Europe. AKs of adult subjects were treated once with methyl aminolevulinate (MAL) DL-PDT on one side of the face and MAL c-PDT contralaterally. Endpoints for DL-PDT concerned efficacy (non-inferiority regarding complete lesion response at week 12) and safety (superiority regarding subject's assessment of pain after treatment, on an 11-point numeric rating scale). Safety evaluation also included incidence of adverse events. Subject satisfaction was described using a questionnaire at baseline and last visit. At week 12, the total lesion complete response rate with DL-PDT was similar (non-inferior) to c-PDT (70% vs. 74%, respectively; 95% CI [-9.5; 2.4] in PP analysis, confirmed in ITT analysis). In addition, efficacy of DL-PDT was demonstrated regardless of weather conditions (sunny or cloudy). DL-PDT was nearly painless compared to c-PDT (0.7 vs. 4.4, respectively; P < 0.001), better tolerated and resulted in higher subject satisfaction. DL-PDT in comparison with c-PDT was as effective, better tolerated and nearly painless with high patient satisfaction, and may be considered a treatment of choice to meet needs of patients with mild or moderate facial/scalp AKs.


Indomethacin restricts cerebral blood flow during pressure ventilation of newborn pigs.
Unanesthetized newborn pigs were studied to evaluate the immediate (10 min) and delayed (45 min) effects of increased ventilation pressure coupled with cyclooxygenase inhibition. Cardiac output and cerebral blood flow were measured at a low (5 cm H2O) and high (30 cm H2O) mean airway pressure (Paw) before and 45 min after 5 mg/kg of indomethacin. In a second group, these parameters were also measured 10 min after indomethacin was given during ventilation at a Paw of 30 cm H2O. Before treatment with indomethacin, increasing Paw decreased cardiac output without affecting cerebral blood flow. Baseline (Paw = 5 cm H2O) cerebral blood flow decreased 40% 45 min after indomethacin treatment. Adding the stress of a ventilation-induced drop in cardiac output did not further depress cerebral blood flow. When indomethacin was administered during high Paw, cerebral blood flow decreased markedly within 10 min. Cerebral oxygen consumption was maintained by increasing oxygen extraction. Therefore, indomethacin decreases cerebral blood flow at a high Paw. The fall in cerebral blood flow decreases brain oxygen delivery. However, cerebral oxygen consumption is maintained by an increase in oxygen extraction.


Therapeutic preferences and outcomes in newly diagnosed patients with Crohn's diseases in the biological era in Hungary: a nationwide study based on the National Health Insurance Fund database.
Accelerated treatment strategy, including tight disease control and early aggressive therapy with immunosuppressives (IS) and biological agents have become increasingly common in inflammatory bowel disease (IBD). The aim of the present study was to estimate the early treatment strategy and outcomes in newly diagnosed patients with Crohn's disease (CD) between 2004 and 2008 and 2009-2015 in the whole IBD population in Hungary based on the administrative database of the National Health Insurance Fund (OEP). We used the administrative database of the OEP, the only nationwide state-owned health insurance provider in Hungary. Patients were identified through previously reported algorithms using the ICD-10 codes for CD in the out-, inpatient (medical, surgical) non-primary care records and drug prescription databases between 2004 and 2015. Patients were stratified according to the year of diagnosis and maximum treatment steps during the first 3 years after diagnosis. A total of 6173 (male/female: 46.12%/53.87%) newly diagnosed CD patients with physician-diagnosed IBD were found in the period of 2004-2015. The use of 5-ASA and steroids remained common in the biological era, while immunosuppressives and biologicals were started earlier and became more frequent among patients diagnosed after 2009. The probability of biological therapy was 2.9%/6.4% and 8.4%/13.7% after 1 and 3 years in patients diagnosed in 2004-2008/2009-2015. The probability of hospitalization in the first 3 years after diagnosis was different before and after 2009, according to the maximal treatment step (overall 55.7%vs. 47.4% (p = 0.001), anti-TNF: 73%vs. 66.7% (p = 0.103), IS: 64.6% vs. 56.1% (p = 0.001), steroid: 44.2%vs. 36.8% (p < 0.007), 5-ASA: 32.6% vs. 26.7% p = 0.157)). In contrast, surgery rates were not significantly different in patients diagnosed before and after 2009 according to the maximum treatment step (overall 16.0%vs.15.3%(p = 0.672) anti-TNF 26.7%vs.27.2% (p = 0.993), IS: 24.1%vs22.2% (p = 0.565), steroid 8.1%vs.7.9% (p = 0.896), 5-ASA 10%vs. 11% (p = 0.816)). IS and biological exposure became more frequent, while hospitalization decreased and surgery remained low but constant during the observation period. Use of steroids and 5-ASA remained high after 2009. The association between the maximal treatment step and hospitalization/surgery rates suggests that maximal treatment step can be regarded as proxy severity marker in patients with IBD.


Membrane association and dimerization of a cysteine-rich, 16-kilodalton polypeptide released from the C-terminal region of the coronavirus infectious bronchitis virus 1a polyprotein.
More than 10 mature proteins processed from coronavirus gene 1-encoded polyproteins have been identified in virus-infected cells. Here, we report the identification of the most C-terminal cleavage product of the 1a polyprotein as a 16-kDa protein in infectious bronchitis virus-infected Vero cells. Indirect immunofluorescence demonstrated that the protein exhibits a distinct perinuclear punctate staining pattern, suggesting that it is associated with cellular membranes. Positive staining observed on nonpermeabilized cells indicates that the protein may get transported to the cell surface, but no secretion of the protein out of the cells was observed. Treatment of the membrane fraction prepared from cells expressing the 16-kDa protein with Triton X-100, a high pH, and a high concentration of salts showed that the protein may be tightly associated with intracellular membranes. Dual-labeling experiments demonstrated that the 16-kDa protein colocalized with the 5'-bromouridine 5'-triphosphate-labeled viral RNA, suggesting that it may be associated with the viral replication machinery. Sequence comparison of the 16-kDa protein with the equivalent products of other coronaviruses showed multiple conserved cysteine residues, and site-directed mutagenesis studies revealed that these conserved residues may contribute to dimerization of the 16-kDa protein. Furthermore, increased accumulation of the 16-kDa protein upon stimulation with epidermal growth factor was observed, providing preliminary evidence that the protein might be involved in the growth factor signaling pathway.


[Bone repair in pseudarthrosis after arthrodesis of the upper ankle joint].
Delayed union or non-union of ankle arthrodesis is a common problem and revision arthrodesis is necessary in those difficult cases. Three cases are presented, in which a non-union after tibiotalar or tibiacalcanear fusion could be treated effectively with a bone graft taken from the anterior cortex of the distal tibia or from the anterior iliacal spine. The bone graft was fixed proximally with a screw. Distally the graft was inserted in an slot gouged into the talus or the calcaneus respectively with or without screw fixation. Postoperative care included short-time external fixation and immobilisation with a shortleg weight bearing cast. We conclude that the technique of a sliding tibiotalar graft can be used for effective treatment of non-union following ankle arthrodesis.


The presence of sperm-specific surface isoantigens on the egg following fertilization.
Sperm surface isoantigens can be detected on the surface of fertilized eggs by using cytotoxic (complement dependent) sperm-specific isoantisera. These isoantigens cannot be detected on unfertilized eggs. This may indicate their transfer from sperm to egg during fertilization.


[Blood glucose and immunoreactive insulin in children with diabetic siblings and diabetic mothers (author's transl)].
The study was designed to examine the behaviour of blood glucose (BG), serum immunoreactive insulin (IRI) and of the insulinogenic index after an oral glucose load in children with a history of familial diabetes mellitus (D.m). Oral glucose tolerance tests (50 g/m2) were performed both without (OGTT) and after pretreatment with 2 times 5 mg Prednisolon within 12 hrs (CGTT) in 25 children with diabetic siblings (group I) and in 13 children with diabetic mothers (group II). Subjects fitting the criteria for An normal OGTT as established by Fajans and Conn and 5 children with clinical D.m. served as controls. Seventeen children of group I had a normal OGTT, 8 (32%) presented with either latent (N = 4) or asymptomatic (N =4) D.m. Six children (46%) with diabetic mothers (group II) had a normal OGTT, 7 (54%) presented with either latent (N = 4) or asymptomatic (N = 3) Dm. Children of ideal weight and with latent D.m. responded to an OGTT with an either normal or an elevated insulin release, and showed during the CGTT a distinctly increased insulin release when compared with healthy subjects. Insulin secretion in children with asymptomatic D.m. was smaller both upon OGTT and CGTT than that of children with latent D.m. but not significantly different from that of healthy subjects. The insulinogenic index was maximal in healthy obese children, it was normal in latent and in asymptomatic, and lowest in clinical diabetics. In conclusion it appears that in children the initial stage of D.m. (i.e. latent and subclinical D.m.) is not necessarily linked to hypoinsulinemia.


Cost and co-morbidities associated with hypoglycemic inpatients in Belgium.
Little is known about the economic burden of hypoglycemia in Belgium, or its related co-morbidities. This study aimed at estimating the cost and length of stay associated with hypoglycemia-related hospitalizations in diabetic patients in Belgium and the association between hypoglycemia and in-hospital all-cause mortality, incidence of traumatic fractures, depression, and cardiovascular diseases (myocardial infarction or unstable angina), using retrospective data from 2011. Patient data were retrieved from the IMS Hospital Disease Database, including longitudinal (per calendar year) information on diagnoses, procedures, and drugs prescribed in ∼20% of all Belgian hospital beds. The eligible population included all adult (<19 year) diabetic (both types) patients, further split between those with/without a history of hypoglycemia-related hospitalizations. Diabetes, hypoglycemia, and co-morbidities of interest were identified based on International Classification of Diseases and Related Health Problems Version 9 (ICD-9) diagnosis codes. All costs were extrapolated to 2014 using progression in hospitalization costs since 2001. A total of 43,410 diabetes-related hospitalizations were retrieved, corresponding to 30,710 distinct patients. The average hospitalization cost was €10,258 when hypoglycemia was documented (n = 2625), vs €7173 in other diabetic hospitalized patients (n = 40,785). When controlling for age and sex, a higher mortality risk (OR = 1.59; p-value <0.001), a higher incidence of traumatic fractures (OR = 1.25; p-value = 0.009), and a higher probability of depression-related hospitalizations (OR = 1.90; p-value <0.001) were observed in hypoglycemic patients. A similar risk of cardiovascular event was observed in both groups, but hypoglycemic patients were more at risk of experiencing multiple events. Hospitalizations for hypoglycemia are expensive and associated with an increased risk of depression and traumatic fractures as well as increased in-hospital mortality. Interventions that can help reduce the risk of hypoglycemia, and consequently the burden on hospitals and society, without compromising glycemic control, will help to further improve diabetes management.


Inoculation with Bartonella henselae followed by feline herpesvirus 1 fails to activate ocular toxoplasmosis in chronically infected cats.
Infection by Toxoplasma gondii is very common in cats although most remain disease free. The factors that trigger development of uveitis in some cats infected with T gondii have not been elucidated, but infection by more than one organism may be contributory. In this study, cats chronically infected with T gondii were inoculated with Bartonella henselae followed by FHV-1 to test the hypothesis that immune stimulation by multiple infections will reactivate ocular toxoplasmosis. Anterior uveitis and chorioretinitis were not detected in the cats with chronic T gondii infection thus allowing rejection of the hypothesis using this experimental design.


[Celioscopic gastrostomies and jejunostomies].
The authors describe a technique of laparoscopic gastrostomy and jejunostomy, which has been used in 23 patients between May 1991 and August 1992: 13 laparoscopic gastrostomies (LG) and 10 laparoscopic jejunostomies (LJ), all performed under general anaesthesia. There were no operative deaths, one intraoperative complication and 3 postoperative complications. Twelve patients had died by the end of the study, 7 patients were still using their feeding tube and 4 patients ate normally. The mean duration of use of the feeding tubes was 4 months for LG and 43 days for LJ. The secondary complications consisted of 3 tube obstructions and one case of pyloric obstruction. Laparoscopic gastrostomy and jejunostomy, performed according to the method described, constitute an effective and reliable alternative to open operations. They can be performed in cases in which endoscopic gastrostomy is impossible. Due to its technical simplicity, laparoscopic jejunostomy should be preferred to gastrostomy whenever there is a risk of inhalation.


Enhanced antimicrobial activity of essential oil components immobilized on silica particles.
The antimicrobial activity of essential oils components (EOCs) is well-known. However, their high volatility and powerful aroma limit their application in the formulation of a wide range of food products. In this context, the antimicrobial activity of carvacrol, eugenol, thymol and vanillin grafted onto the surface of three silica supports with different morphologies, textural properties and chemical reactivities (fumed silica, amorphous silica and MCM-41) was evaluated herein. Materials characterization revealed a good immobilization yield and all the devices showed a micro-scale particle size. Sensory evaluation revealed that sensory perception of EOCs decreases after covalent immobilization. Moreover, immobilization greatly enhanced the antimicrobial activity of the essential oil components against Listeria innocua and Escherichia coli compared to free components. The incorporation of EOCs immobilized on silica particles into pasteurized milk inoculated with L. innocua demonstrated their effectiveness not only for in vitro conditions, but also in a real food system.


Modulatory effect of lycopene against carbofuran toxicity in African catfish, Clarias gariepinus.
In the current study, African catfish, Clarias gariepinus, was exposed to a sublethal concentration of carbofuran (CF) to investigate its negative effects on biochemical and oxidative stress biomarkers. Also, the putative role of lycopene (LYC) administration in alleviating these negative effects was evaluated. Fish were divided into six groups in triplicates as follows: group I was without treatment, group II was orally administered corn oil, group III was orally administered 18 mg LYC/kg body weight, group IV was exposed to 0.121 mg CF/L, group V was orally administered 9 mg LYC/kg body weight and exposed to 0.121 mg CF/L, and group VI was orally administered 18 mg LYC/kg body weight and exposed to 0.121 mg CF/L for 4 weeks. At the end of this period, blood and tissue (liver and kidney) samples were collected and biochemical and oxidative stress biomarkers were analysed. Also, histopathological changes were determined. Carbofuran caused significant increments of glucose, cortisol, aspartic amino transferase, alanine amino transferase, cholesterol, urea, and creatinine; meanwhile, serum acetylcholinesterase, total protein, albumin, and total lipids were significantly reduced. Significant increments in hepatic and renal malondialdehyde (MDA) and superoxide dismutase (SOD) levels and marked reduction in hepatic and renal catalase (CAT), glutathione (GSH), and total antioxidant capacity (TAC) levels were observed in CF-exposed fish comparing to the control group. Treatment with LYC attenuated the CF-induced oxidative stress, and this improvement was more pronounced in fish received the high LYC dose (18 mg/kg body weight). Further, congestion of the central vein with infiltration of mononuclear inflammatory cells, vacuolar necrosis, and haemorrhage was observed in the livers of CF-exposed fish. Oral administration of LYC reduced behavioural changes and histopathological alterations. All the altered biochemical parameters and antioxidant biomarkers were also restored to be near the normal levels. The obtained results evoked that LYC administration alleviated the destructive effects of carbofuran and reduced its toxicity effect on African catfish.


Fear of re-injury in people who have returned to sport following anterior cruciate ligament reconstruction surgery.
To examine fear of re-injury in athletes who had returned to regular sports participation following anterior cruciate ligament reconstruction surgery. Cross-sectional case series. A self-report questionnaire was used to collect data 2-7 years following surgery. Key inclusion criteria were regular participation in sport prior to injury and participation in sport at the time of the study. A sample of 209 (88 females, 121 males) at a mean of 39.6 ± 13.8 months post surgery participated. Overall, participants did not express fear of re-injury, scoring >6/10 (where 10 was the most positive response) on all questions. In terms of the total score and for six out of eight questions, participants who returned to their pre-injury sports level had significantly less fear of re-injury than those who had not returned to their pre-injury level. Females had significantly more concern than males about the environmental conditions experienced while playing (mean 6.1 compared to 7.5). On three out of eight questions, individuals who had surgery more than 3 months after injury had a greater fear of re-injury than those who had their surgery closer to the time of injury. Athletes participating in sport 2-7 years following their anterior cruciate ligament reconstruction generally appear to do so without fear of re-injury. However, gender, the timing of surgery following injury and the level of sport the athletes returned to may be associated with fear of re-injury following surgery.


Liposomal vaccines--targeting the delivery of antigen.
Vaccines that can prime the adaptive immune system for a quick and effective response against a pathogen or tumor cells, require the generation of antigen (Ag)-specific memory T and B cells. The unique ability of dendritic cells (DCs) to activate naïve T cells, implies a key role for DCs in this process. The generation of tumor-specific CD8(+) cytotoxic T cells (CTLs) is dependent on both T cell stimulation with Ag (peptide-MHC-complexes) and costimulation. Interestingly, tumor cells that lack expression of T cell costimulatory molecules become highly immunogenic when transfected to express such molecules on their surface. Adoptive immunotherapy with Ag-pulsed DCs also is a strategy showing promise as a treatment for cancer. The use of such cell-based vaccines, however, is cumbersome and expensive to use clinically, and/or may carry risks due to genetic manipulations. Liposomes are particulate vesicular lipid structures that can incorporate Ag, immunomodulatory factors and targeting molecules, and hence can serve as potent vaccines. Similarly, Ag-containing plasma membrane vesicles (PMV) derived from tumor cells can be modified to incorporate a T cell costimulatory molecule to provide both TCR stimulation, and costimulation. PMVs also can be modified to contain IFN-gamma and molecules for targeting DCs, permitting delivery of both Ag and a DC maturation signal for initiating an effective immune response. Our results show that use of such agents as vaccines can induce potent anti-tumor immune responses and immunotherapeutic effects in tumor models, and provide a strategy for the development of effective vaccines and immunotherapies for cancer and infectious diseases.


Migrating and circulating breast carcinoma cells are within active phases of the cell cycle.
The emergence of blood-borne epithelial-derived tumour cells in breast cancer patients is generally supposed to be an indicator of cancer cell spread but only a very small percentage of these cells ultimately initiate metastases. In this study, we investigated the presence of the cell cycle marker Ki-67 in mammary tumour cells isolated from patients' blood and SKBR3 breast carcinoma cells by confocal laser scanning microscopy. We also compared the immunostaining patterns for Ki-67 of blood-borne tumour cells from the patients with actively migrating cells within a collagen matrix. Both circulating tumour cells and migrating SKBR3 cells were found to be in G1- or S-phase. These findings will have impact on adjuvant chemotherapy as circulating tumour cells that are within the active part of the cell cycle are highly susceptible to chemotherapeutic agents and therefore can be killed while they migrate to distant organs to build a metastasis.


Economic comparison of nutritional management strategies for Venezuelan dual-purpose cattle systems.
Objectives of this study were to compare three nutritional management strategies for dual-purpose herds in Venezuela in 1987 using a deterministic, multiperiod linear programming model of a representative farm. The model maximized discounted net margin (total revenues minus variable costs) from the herd for a 3-yr cow replacement cycle partitioned into six periods. The periods accounted for seasonal variation in forage availability and quality, and the model provided information about optimal animal inventories, animal sales, land in forage, and feed supplements. We compared current nutritional management practices and alternatives allowing optimal supplementation with commercial concentrate, molasses, cassava root, and urea. Iteration between the programming model and results from the Cornell Net Carbohydrate and Protein System assured technical coefficients consistent with predicted animal performance. Compared with management practices relying on commercial concentrate, optimal use of molasses and urea permitted increases in the stocking rate. Productivity and profit were restricted primarily by energy intake, which was constrained by intakes of NDF and DM. Alternative management strategies changed the relative importance of nutrient requirements and feed intake constraints. Thus, optimal interventions to alleviate nutritional constraints will vary with current management. Mobilizing adipose and protein tissues during lactation was optimal for most strategies. Supplementing with molasses and urea instead of commercial concentrate was the most profitable strategy, increasing herd net margin by 16% compared to the predominant feeding strategy in the late 1980s.


Distributed and polarimetric pressure sensitivity in spun highly birefringent optical fibers.
We examine experimentally the influence of the fiber inelastic twist on polarimetric sensitivity to hydrostatic pressure and pressure sensitivity in a Rayleigh-scattering-based optical frequency-domain reflectometer (OFDR) for highly birefringent side-hole fibers. The fibers were drawn from the same preform with different spin pitches varying from 5 mm to 200 mm. We also demonstrate that the sensitivities of spun fiber can be estimated analytically based on its spin pitch, measured birefringence, and the sensitivity of the corresponding non-twisted fiber, showing good agreement with the experimental results. We proved that polarimetric sensitivity to pressure decreases with the shorter spin pitches, while distributed pressure sensitivity decreases for the one polarization eigenmode and increases for the second polarization eigenmode. Therefore, the spun-fibers can operate well as the polarimetric sensors of other physical parameters inducing circular birefringence even under varying pressure. Moreover, they can be used to obtain the desired difference between sensitivities for both polarization eigenmodes.


General synthesis of substituted 1,2-dihydropyridines.
A general and practical metal-free protocol for the synthesis of 1,2-dihydropyridines with wide structural/functional diversity at the ring and featuring mono, double, or spiro substitution at the sp(3) position is described. The protocol entails a microwave-assisted domino reaction of a propargyl vinyl ether (secondary or tertiary) and a primary amine (aliphatic or aromatic) in toluene or methanol.


Enhancement of the Hydrogen-Bonding Network of Water Confined in a Polyelectrolyte Brush.
Water existing in the vicinity of polyelectrolytes exhibits unique structural properties, which demonstrate key roles in chemistry, biology, and geoscience. In this study, X-ray absorption and emission spectroscopy was employed to observe the local hydrogen-bonding structure of water confined in a charged polyelectrolyte brush. Even at room temperature, a majority of the water molecules confined in the polyelectrolyte brush exhibited one type of hydrogen-bonding configuration: a slightly distorted, albeit ordered, configuration. The findings from this study provide new insight in terms of the correlation between the function and local structure of water at the interface of biological materials under physiological conditions.


Historical processes constrain patterns in global diatom diversity.
There is a long-standing belief that microbial organisms have unlimited dispersal capabilities, are therefore ubiquitous, and show weak or absent latitudinal diversity gradients. In contrast, using a global freshwater diatom data set, we show that latitudinal gradients in local and regional genus richness are present and highly asymmetric between both hemispheres. Patterns in regional richness are explained by the degree of isolation of lake districts, while the number of locally coexisting diatom genera is highly constrained by the size of the regional diatom pool, habitat availability, and the connectivity between habitats within lake districts. At regional to global scales, historical factors explain significantly more of the observed geographic patterns in genus richness than do contemporary environmental conditions. Together, these results stress the importance of dispersal and migration in structuring diatom communities at regional to global scales. Our results are consistent with predictions from the theory of island biogeography and metacommunity concepts and likely underlie the strong provinciality and endemism observed in the relatively isolated diatom floras in the Southern Hemisphere.


Ticks infesting animals in the Sudan and Southern Sudan: past and current status.
In this review, we collate information about ticks identified in different parts of the Sudan and South Sudan since 1956 in order to identify gaps in tick prevalence and create a map of tick distribution. This will avail basic data for further research on ticks and policies for the control of tick-borne diseases. In this review, we discuss the situation in the Republic of South Sudan as well as Sudan. For this purpose we have divided Sudan into four regions, namely northern Sudan (Northern and River Nile states), central Sudan (Khartoum, Gazera, White Nile, Blue Nile and Sennar states), western Sudan (North and South Kordofan and North, South and West Darfour states) and eastern Sudan (Red Sea, Kassala and Gadarif states).


Atligator Web: A Graphical User Interface for Analysis and Design of Protein-Peptide Interactions.
A key functionality of proteins is based on their ability to form interactions with other proteins or peptides. These interactions are neither easily described nor fully understood, which is why the design of specific protein-protein interaction interfaces remains a challenge for protein engineering. We recently developed the software ATLIGATOR to extract common interaction patterns between different types of amino acids and store them in a database. The tool enables the user to better understand frequent interaction patterns and find groups of interactions. Furthermore, frequent motifs can be directly transferred from the database to a user-defined scaffold as a starting point for the engineering of new binding capabilities. Since three-dimensional visualization is a crucial part of ATLIGATOR, we created ATLIGATOR web-a web server offering an intuitive graphical user interface (GUI) available at https://atligator.uni-bayreuth.de. This new interface empowers users to apply ATLIGATOR by providing easy access with having all parts directly connected. Moreover, we extended the web by a design functionality so that, overall, ATLIGATOR web facilitates the use of ATLIGATOR with a more intuitive UI and advanced design options.


Critical ACE2 Determinants of SARS-CoV-2 and Group 2B Coronavirus Infection and Replication.
The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARS-CoV-2 and emerging coronavirus animal model development.IMPORTANCE SARS-CoV-2 (the causative agent of COVID-19) is a major public health threat and one of two related coronaviruses that have caused epidemics in modern history. A method of screening potential infectible hosts for preemergent and future emergent coronaviruses would aid in mounting rapid response and intervention strategies during future emergence events. Here, we evaluated determinants of SARS-CoV-2 receptor interactions, identifying key changes that enable or prevent infection. The analysis detailed in this study will aid in the development of model systems to screen emergent coronaviruses as well as treatments to counteract infections.


Determination of tRNA aminoacylation levels by high-throughput sequencing.
Transfer RNA (tRNA) decodes mRNA codons when aminoacylated (charged) with an amino acid at its 3' end. Charged tRNAs turn over rapidly in cells, and variations in charged tRNA fractions are known to be a useful parameter in cellular responses to stress. tRNA charging fractions can be measured for individual tRNA species using acid denaturing gels, or comparatively at the genome level using microarrays. These hybridization-based approaches cannot be used for high resolution analysis of mammalian tRNAs due to their large sequence diversity. Here we develop a high-throughput sequencing method that enables accurate determination of charged tRNA fractions at single-base resolution (Charged DM-tRNA-seq). Our method takes advantage of the recently developed DM-tRNA-seq method, but includes additional chemical steps that specifically remove the 3'A residue in uncharged tRNA. Charging fraction is obtained by counting the fraction of A-ending reads versus A+C-ending reads for each tRNA species in the same sequencing reaction. In HEK293T cells, most cytosolic tRNAs are charged at >80% levels, whereas tRNASer and tRNAThr are charged at lower levels. These low charging levels were validated using acid denaturing gels. Our method should be widely applicable for investigations of tRNA charging as a parameter in biological regulation.


Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine.
A growing body of evidence suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may relieve symptoms of migraineurs. Frequency is one of the key stimulation parameters. The aim of this study is to investigate the modulation effect of taVNS frequency on the descending pain modulation system (DPMS) in patients with migraine. Twenty-four episodic migraineurs without aura (21 females) were recruited for the single-blind, crossover, functional magnetic resonance imaging (fMRI) study. Each participant attended two separate fMRI scan sessions, one for 1 Hz and another for 20 Hz taVNS, in a random order. Seed-based functional connectivity analysis was applied using the ventrolateral periaqueductal gray (PAG) as the region of interest. Compared with the pre-taVNS resting state, continuous 1 Hz taVNS (during) produced a significant increase in functional connectivity between the PAG and the bilateral middle cingulate cortex (MCC), right precuneus, left middle frontal gyrus (MFG), and left cuneus. Compared with 20 Hz taVNS, 1 Hz taVNS produced greater PAG connectivity increases with the MCC, right precuneus/posterior cingulate cortex, left insula, and anterior cingulate cortex (ACC). A significant negative correlation was observed between the number of migraine attacks in the previous 4 weeks and the PAG-MCC functional connectivity in the pre-taVNS resting-state before 1 Hz taVNS. Our findings suggest that taVNS with different frequencies may produce different modulation effects on the descending pain modulation system, demonstrating the important role of stimulation frequency in taVNS treatment.


Computed tomography of the hindfoot.
This investigation used computed tomography (CT) to study the normal anatomy of the hindfoot and to demonstrate abnormalities in patients with rheumatoid arthritis, pes planovalgus , old trauma, and soft-tissue masses. The hindfeet of 10 normal volunteers and 17 patients were scanned in the coronal and axial transverse planes. The articular surfaces of the tibia, talus, and calcaneus were assessed, as were the relationships of each bone to the others. Normal subjects had markedly symmetrical hindfeet . The "heel valgus angle" (relating the calcaneus to the tibia) was 5.2 +/- 1.6 degrees (mean +/- standard error of the mean). The "sustentacular angle" (indicating the angle of elevation of the sustentaculum tali at the midsubtalar joint) was 18.3 +/- 1.3 degrees. The "medial offset" of the talar head with respect to the calcaneus (measured at the anterior subtalar joint) averaged 5.2 +/- 1.8 mm. Patients with rheumatoid arthritis had erosions involving both sides of the subtalar joint, leading to talocalcaneal alignment abnormalities. In patients with pes planovalgus the heel valgus angle was greater and the elevation of sustentaculum tali lower in the foot that was most severely affected. Bony talocalcaneal fusions, fractures, and the erosions of pigmented villonodular synovitis were detected on CT. The pattern of postoperative bone healing after attempted subtalar fusion could be demonstrated. We conclude that CT is a useful tool for pre- and postoperative evaluation of the hindfoot.


Interactions between sulfated polysaccharides from sea brown algae and Toll-like receptors on HEK293 eukaryotic cells in vitro.
We studied the interactions between sulfated polysaccharides, fucoidans from sea brown algae Laminaria japonica, Laminaria cichorioides, and Fucus evanescens, with human Toll-like receptors (TLR) expressed on membranes of cultured human embryonic kidney cells (HEK293-null, HEK293-TLR2/CD14, HEK293-hTLR4/CD14-MD2, and HEK293-hTLR5). Fucoidans interacted with TLR-2 and TLR-4, but not with TLR-5, and were nontoxic for the cell cultures. L. japonica fucoidan (1 mg/ml), L. cichorioides fucoidan (100 μg/ml and 1 mg/ml), and F. evanescens fucoidan (10 μg/ml-1 mg/ml) activated transcription nuclear factor NF-ϰB by binding specifically to TLR-2. L. japonica fucoidan (100 μg/ml and 1 mg/ml), L. cichorioides fucoidan (10 μg/ml-1 mg/ml), and F. evanescens fucoidan (1 μg/ml-1 mg/ml) activated NF-ϰB via binding to TLR-4. These results indicated that fucoidans could induce in vivo defense from pathogenic microorganisms of various classes.


XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.
X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations.


Reliability and Technical Error of Calf Circumference and Mid-half Arm Span Measurements for Nutritional Status Assessment of Elderly Persons in Malaysia.
This study sought to examine the reliability of two measurements; Calf Circumference (CC) and Mid-half Arm Span (MHAS). A sample of 130 elderly persons aged 60 years and above seen consecutively in the Kuala Lumpur Hospital outpatient clinic during the period of December 2005 to January 2006, upon consent, were recruited to the study. There was a high degree of reliability for both inter- and intra-examiner (r close to 1). For inter-examiner, on average the CC measurements taken by the first examiner were 0.3 cm lower than that of the second examiner. The upper and lower limit of the differences were +0.4 to -0.9 cm respectively. Inter-examiner MHAS measurements on average by the first examiner were 0.2 cm lower than that of the second examiner. The limits were +1.7 to -2.1 cm. By comparison, the inter-examiner CC measurements were more reliable than the MHAS measurements. For intra-examiner, on average the CC measurements at Time 1 were consistent with Time 2 (mean difference=0) with limits of the difference at + 0.5 cm. MHAS measurements at Time 1 were on average 0.1 cm less than at Time 2 with limits at +1.7 and -1.8 cm. The technical error of measurement (TEM) and coefficient of variation of CC and MHAS for both interexaminer and intra-examiner measurements were within acceptable limits with the exception of MHAS TEM. This study suggests that CC and MHAS measured in elderly persons 60 years and above, using Seca Circumference Tape ® 206, Germany (0.05 cm) are reliable and can be used in a community survey.


[Immune response against modified low-density lipoproteins in patients with non-insulin-dependent diabetes mellitus].
Diabetes mellitus is a risk factor for atherosclerosis. Low density lipoproteins are considered a key factor in the formation of atheroma and the immune system has an important contribution to this process. To quantify the immune response against modified low density lipoproteins in patients with non insulin dependent diabetes mellitus. LDLs obtained from blood of healthy subjects, were glycated or altered with malondialdehyde and used as antigens. Serum autoantibodies against these LDLs were measured by ELISA in 22 patients with non insulin dependent diabetes mellitus aged 46 to 67 years old and 13 healthy controls aged 41 to 65 years old. Basal and LDL stimulated tumor necrosis factor a production in vitro, by peripheral leukocytes of diabetics and controls was also measured. The ratio of glycated LDL/native LDL antibodies was higher in diabetics than in controls (9.37 +/- 2.72 and 0.41 +/- 0.11 respectively p < 0.05) and the ratio of MDA modified LDL/native LDL antibodies was not significantly different (8.64 +/- 3.83 and 2.14 +/- 1.26 respectively, NS). Tumor necrosis or production by leukocytes was higher in diabetics than in controls in basal conditions (53.3 +/- 15.3 and 26.9 +/- 14.7 arbitrary units (a.u.) respectively), when stimulated with native LDL (46.5 +/- 5 and 24.3 +/- 9.4 a.u. respectively), when stimulated with malondialdehyde modified LDL (50 +/- 16.2 and 24.4 +/- 7.7 a.u. respectively) or when stimulated with glycated LDL (38.3 +/- 8.8 and 14.4 +/- 7.5 a.u. respectively). Diabetic patients have an enhanced immune response against low density lipoproteins, factor that could contribute to the accelerated atherogenesis of this disease.


Ligasure versus diathermy scissors tonsillectomy: A controlled randomized study.
Ligasure tonsillectomies took longer than bipolar diathermy scissors tonsillectomies. Peroperative haemostasis was comparable in the two groups. Postoperative haemorrhage was higher than expected, which needs to be further investigated. A new handpiece, specifically designed for tonsillectomy, could probably improve surgical performance regarding operative time. To compare tonsillectomy using Ligasure with bipolar diathermy scissors with regard to operative time, blood loss and complications. This was a prospective study; 150 patients (> 15 years of age) undergoing tonsillectomy were randomized to tonsillectomy using either Ligasure or bipolar diathermy scissors. Operative time, peroperative blood loss, postoperative pain and complications were recorded and evaluated. A total of 149 cases were included, 75 randomized to Ligasure tonsillectomy and 74 to bipolar diathermy scissors tonsillectomy. Peroperative blood loss was similar in both groups. On average the operative time was 8 min longer in the Ligasure group. Postoperative pain was similar in the two groups. Twenty patients (13%) experienced postoperative haemorrhage, which is higher than our previous material. Slightly fewer patients experienced postoperative haemorrhage in the Ligasure group compared with the diathermy scissors group but the difference was not significant. Two of the 20 patients that experienced postoperative haemorrhage required a return to theatre to stop the bleeding, fewer than previously observed. No other complications were seen.


Identification of SPPL2a Inhibitors by Multiparametric Analysis of a High-Content Ultra-High-Throughput Screen.
The intramembrane protease signal peptide peptidase-like 2a (SPPL2a) is a potential drug target for the treatment of autoimmune diseases due to an essential role in B cells and dendritic cells. To screen a library of 1.4 million compounds for inhibitors of SPPL2a, we developed an imaging assay detecting nuclear translocation of the proteolytically released cytosolic substrate fragment. The state-of-the-art hit calling approach based on nuclear translocation resulted in numerous false-positive hits, mainly interrupting intracellular protein trafficking. To filter the false positives, we extracted 340 image-based readouts and developed a novel multiparametric analysis method that successfully triaged the primary hit list. The identified scaffolds were validated by demonstrating activity on endogenous SPPL2a and substrate CD74/p8 in B cells. The multiparametric analysis discovered diverse cellular phenotypes and provided profiles for the whole library. The principle of the presented imaging assay, the screening strategy, and multiparametric analysis are potentially applicable in future screening campaigns.


Microplastics in Sediment Cores from Asia and Africa as Indicators of Temporal Trends in Plastic Pollution.
Microplastics (<5 mm) were extracted from sediment cores collected in Japan, Thailand, Malaysia, and South Africa by density separation after hydrogen peroxide treatment to remove biofilms were and identified using FTIR. Carbonyl and vinyl indices were used to avoid counting biopolymers as plastics. Microplastics composed of variety of polymers, including polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethyleneterphthalates (PET), polyethylene-polypropylene copolymer (PEP), and polyacrylates (PAK), were identified in the sediment. We measured microplastics between 315 µm and 5 mm, most of which were in the range 315 µm-1 mm. The abundance of microplastics in surface sediment varied from 100 pieces/kg-dry sediment in a core collected in the Gulf of Thailand to 1900 pieces/kg-dry sediment in a core collected in a canal in Tokyo Bay. A far higher stock of PE and PP composed microplastics in sediment compared with surface water samples collected in a canal in Tokyo Bay suggests that sediment is an important sink for microplastics. In dated sediment cores from Japan, microplastic pollution started in 1950s, and their abundance increased markedly toward the surface layer (i.e., 2000s). In all sediment cores from Japan, Thailand, Malaysia, and South Africa, the abundance of microplastics increased toward the surface, suggesting the global occurrence of and an increase in microplastic pollution over time.


Pooches on a platform: Text mining twitter for sector perceptions of dogs during a global pandemic.
Businesses commonly text mine Twitter data to identify patterns and extract valuable information. However, this method is rarely applied to the animal welfare sector. Here, we describe Twitter conversations regarding dogs during a global pandemic, assess the evolution of sentiment, and examine the dynamics of sector influence. Between March and August 2020, we gathered 61,088 unique tweets from the United Kingdom and Republic of Ireland, relating to COVID-19 and dogs. Tweets were assigned to one of four pandemic phases and active accounts were assigned to a sector: Personal (i.e., UK and ROI public), Press (i.e., mass media), State (i.e., Government, Police, and NHS), and Other (i.e., welfare organizations, social enterprises, research organizations, charity, and business). Word frequency and sentiment analysis between phases and sectors were assessed, and cross correlation functions and lagged regressions were used to evaluate sector influence. Topical foci of conversations included: meat trade, separation anxiety and dog theft. Sentiment score remained stable until the last phase where sentiment decreased (F 3, 78, 508 = 44.4, p < 0.001), representing an increased use of negative language. Sentiment differed between the four sectors (F 3, 11, 794 = 52.2, p < 0.001), with Personal and Press accounts presenting the greatest use of negative language. Personal accounts were initially partly influenced by State accounts (R = -0.26; p = 0.05), however this altered to Press accounts by the last phase (R = -0.31; p = 0.02). Our findings highlight that whilst Personal accounts may affect sector-specific messaging online, perhaps more importantly: language used, and sentiment expressed by Press, State and Other accounts may influence public perception. This draws attention to the importance of sector responsibility regarding accurate and appropriate messaging, as irresponsible/ill-considered comments or campaigns may impact future human-animal interaction.


A method-comparison study regarding the validity and reliability of the Lactate Plus analyzer.
The aims of this study were to: (1) determine the validity and reliability of the Nova Biomedical Lactate Plus portable analyzer, and quantify any fixed or proportional bias; (2) determine the effect of any bias on the determination of the lactate threshold and (3) determine the effect that blood sampling methods have on validity and reliability. In this method comparison study we compared blood lactate concentration measured using the Lactate Plus portable analyzer to lactate concentration measured by a reference analyzer, the YSI 2300. University campus in the USA. Fifteen active men and women performed a discontinuous graded exercise test to volitional exhaustion on a motorised treadmill. Blood samples were taken via finger prick and collected in microcapillary tubes for analysis by the reference instrument at the end of each stage. Duplicate samples for the portable analyzer were either taken directly from the finger or from the micro capillary tubes. PRIMARY OUTCOME MEASUREMENTS: Ordinary least products regressions were used to assess validity, reliability and bias in the portable analyzer. Lactate threshold was determined by visual inspection. Though measurements from both instruments were correlated (r=0.91), the differences between instruments had large variability (SD=1.45 mM/l) when blood was sampled directly from finger. This variability was reduced by ∼95% when both instruments measured blood collected in the capillary tubes. As the proportional and fixed bias between instruments was small, there was no difference in estimates of the lactate threshold between instruments. Reliability for the portable instrument was strong (r=0.99, p<0.05) with no proportional bias (slope=1.02) and small fixed bias (-0.19 mM/l). The Lactate Plus analyzer provides accurate and reproducible measurements of blood lactate concentration that can be used to estimate workloads corresponding to blood lactate transitions or any absolute lactate concentrations.


Quality Oncology Practice Initiative Can Guide and Improve Oncology Providers' Training in Brazil.
It has become crucial to translate scientific findings and to find ways by which to mobilize local resources to improve the quality and accessibility of cancer care in developing countries. This study seeks to provide insight into challenge through examining differences in clinician documentation of patients with cancer treated at a Brazilian Public University Hospital. ASCO Quality Oncology Practice Initiative (QOPI) measures were used to examine the care provided in the departments of breast, colorectal, lymphoma, gynecology, and lung cancers. For this study, data from a representative sample of patients receiving chemotherapy in the previous month were extracted and quality of cancer care indicators examined. Certain elements of medical care were consistently and appropriately documented, including cancer diagnosis and stage, chemotherapy planning, administration, and summary. In general, considering the specific cancer management measures, patients received recommended care in accordance with recognized guidelines. Despite this, a number of important gaps in care were identified, including the assessment and treatment of pain, documentation of chemotherapy intention, symptom and toxicity management, patients' psychosocial status, and provision of a treatment summary at care completion. These findings are encouraging in terms of adherence to core treatment guidelines in cancer care in Brazil. However, results suggest important opportunities for improving care across a number of domains, many of which represent a challenge throughout both developing and developed countries. This study may also provide preliminary guidance for enhancing educational and training programs for professionals and students alike, to implement high-quality, comprehensive cancer care.


The upper Miocene chitons of northwest France (Mollusca: Polyplacophora).
This study describes the chiton fauna (Mollusca, Polyplacophora) from the upper Miocene Tortonian deposits of northwest France previously known as the 'Redonian'. Twenty-two species were identified (represented by 9,380 valves), of which seven were already known, one is assigned at generic level (Leptochiton sp.) and 14 are described as new (Lepidopleurus pseudobenoisti sp. nov., L. gallicus sp. nov., Leptochiton parvus sp. nov., Leptochiton lateropustulosus sp. nov., Leptochiton renauleauensis sp. nov., Hanleya sancticlementensis sp. nov., H. sossoi sp. nov., Ischnochiton nitidum sp. nov., Callochiton pouweri sp. nov., Rhyssoplax assurrectum sp. nov., Tonicella redoniensis sp. nov., Acanthochitona globosa sp. nov., A. andegavensis sp. nov. and A. chauvereauensis sp. nov.). Regarding the stratigraphic distribution of the 21 taxa identified, 15 are restricted to the Miocene, the remaining six are extant and are distributed in the Atlantic and Mediterranean (Lepidopleurus cajetanus, Leptochiton algesirensis, Hanleya hanleyi, Ischnochiton rissoi, Callochiton doriae and Rhyssoplax corallinus. The number of new species is high (14 out of 22), possibly explained in part by the fact that this is the first description of the northwestern French upper Miocene chiton fauna - true endemicity is less likely in the light of scarce sampling.


Identification of an hexapeptide that binds to a surface pocket in cyclin A and inhibits the catalytic activity of the complex cyclin-dependent kinase 2-cyclin A.
The protein-protein complexes formed between different cyclins and cyclin-dependent kinases (CDKs) are central to cell cycle regulation. These complexes represent interesting points of chemical intervention for the development of antineoplastic molecules. Here we describe the identification of an all d-amino acid hexapeptide, termed NBI1, that inhibits the kinase activity of the cyclin-dependent kinase 2 (cdk2)-cyclin A complex through selective binding to cyclin A. The mechanism of inhibition is non-competitive for ATP and non-competitive for protein substrates. In contrast to the existing CDKs peptide inhibitors, the hexapeptide NBI1 interferes with the formation of the cdk2-cyclin A complex. Furthermore, a cell-permeable derivative of NBI1 induces apoptosis and inhibits proliferation of tumor cell lines. Thus, the NBI1-binding site on cyclin A may represent a new target site for the selective inhibition of activity cdk2-cyclin A complex.


Mode-coupling behavior of a Lennard-Jones binary mixture upon increasing confinement.
Molecular dynamics simulations are performed on a Lennard Jones binary mixture confined in off lattice matrices of soft spheres with increasing radius. We focus on dynamics upon supercooling and in particular on testing the mode coupling theory properties of the confined mixture. Parameters of mode coupling theory in going from bulk to weak confinement, and from weak to strong confinement are extracted from simulations and analyzed. We focus on the study of the behavior of the single particle density correlators. We find that the mode coupling theory retains its validity also in the case of strong confinement, with a reduction of range of validity. The role of hopping is discussed in relation with the differences between the results obtained from the diffusion coefficients and the mode coupling theory predictions.


Surgical issues in the management of melanoma.
The mainstay of treatment of cutaneous melanoma is surgical excision. Excision of the primary disease, lymph node metastases, and in some instances, distant metastases is the only therapeutic strategy that leads to long-term disease-free survival with rare exceptions. Surgical treatment of melanoma can be divided into therapy of the primary lesion, treatment of the lymph nodes, treatment of distant metastases, and treatment of in-transit disease by regional administration of intravascular chemotherapeutics. The current recommendations for each of these four areas is discussed in this review.


Radiotherapy with neoadjuvant chemotherapy versus concurrent chemoradiotherapy for ascending-type nasopharyngeal carcinoma: a retrospective comparison of toxicity and prognosis.
In the era of intensity-modulated radiotherapy (IMRT), the role of neoadjuvant chemotherapy (NACT) in treating ascending-type nasopharyngeal carcinoma (NPC) is under-evaluated. This study was to compare the efficacy of NACT followed by IMRT (NACT + RT) with the efficacy of concurrent chemoradiotherapy (CCRT) on ascending-type NPC. Clinical data of 214 patients with ascending-type NPC treated with NACT + RT or CCRT between December 2009 and July 2011 were analyzed. Of the 214 patients, 98 were treated with NACT followed by IMRT, and 116 were treated with CCRT. The survival rates were assessed using Kaplan-Meier analysis, and the survival curves were compared using a log-rank test. The 4-year overall survival, locoregional failure-free survival, distant failure-free survival, and failure-free survival rates were not significantly different between the two groups (all P > 0.05). However, patients in the CCRT group exhibited more severe acute adverse events than did patients in the NACT + RT group during radiotherapy, including leukopenia (30.2% vs. 15.3%, P = 0.016), neutropenia (25.9% vs. 11.2%, P = 0.011), and mucositis (57.8% vs. 40.8%, P = 0.028). After radiotherapy, patients in the CCRT group exhibited significantly higher rates of xerostomia (21.6% vs. 10.2%, P = 0.041) and hearing loss (17.2% vs. 6.1%, P = 0.023). The treatment outcomes of the NACT + RT and CCRT groups were similar; however, CCRT led to higher rates of acute and late toxicities. NACT + RT may therefore be a better treatment strategy for ascending-type NPC.


Bis-clickable Mesoporous Silica Nanoparticles: Straightforward Preparation of Light-Actuated Nanomachines for Controlled Drug Delivery with Active Targeting.
Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co-condensation of TEOS with variable amounts (2-5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on-demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans-to-cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on-command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin-loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.


Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model.
Understanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification of Escherichia coli bacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate was E. coli ATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility.


Diabetes and the direct secondary use of electronic health records: Using routinely collected and stored data to drive research and understanding.
Electronic health records provide an unparalleled opportunity for the use of patient data that is routinely collected and stored, in order to drive research and develop an epidemiological understanding of disease. Diabetes, in particular, stands to benefit, being a data-rich, chronic-disease state. This article aims to provide an understanding of the extent to which the healthcare sector is using routinely collected and stored data to inform research and epidemiological understanding of diabetes mellitus. Narrative literature review of articles, published in both the medical- and engineering-based informatics literature. There has been a significant increase in the number of papers published, which utilise electronic health records as a direct data source for diabetes research. These articles consider a diverse range of research questions. Internationally, the secondary use of electronic health records, as a research tool, is most prominent in the USA. The barriers most commonly described in research studies include missing values and misclassification, alongside challenges of establishing the generalisability of results. Electronic health record research is an important and expanding area of healthcare research. Much of the research output remains in the form of conference abstracts and proceedings, rather than journal articles. There is enormous opportunity within the United Kingdom to develop these research methodologies, due to national patient identifiers. Such a healthcare context may enable UK researchers to overcome many of the barriers encountered elsewhere and thus to truly unlock the potential of electronic health records.


Nontraumatic Subarachnoid Hemorrhage and Ruptured Intracranial Aneurysm: Recognition and Evaluation.
Subarachnoid hemorrhage caused by a ruptured intracranial aneurysm is a neurosurgical emergency with a mortality rate of approximately 50%. Prompt identification and treatment of aneurysmal subarachnoid hemorrhage are paramount to reduce mortality, long-term morbidity, and health care burden for survivors. The prevalence of intracranial aneurysms is 2% to 6% of the global population, many of which are found incidentally during workup for an unrelated condition. Screening is not recommended for the general population and should be reserved for patients who have at least one family member with a history of intracranial aneurysm or subarachnoid hemorrhage or when there is a high index of suspicion for those with certain medical conditions associated with an increased incidence of intracranial aneurysms. Physicians who treat patients with headache should be aware of the spectrum of clinical presentation of aneurysmal subarachnoid hemorrhage because not all patients present with the classic thunderclap headache. The Ottawa Subarachnoid Hemorrhage Rule is a validated clinical decision tool to help determine which patients with a sudden, acute headache require imaging with noncontrast computed tomography. Based on the results of initial computed tomography and duration of symptoms, the patient may require a lumbar puncture or additional imaging to confirm the diagnosis. Prompt diagnosis of an aneurysmal subarachnoid hemorrhage is essential to patients receiving definitive treatment.


OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR.
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which DEPTOR stability is regulated are still elusive. Here, we report that OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR in a deubiquitination assay. We found that OTUB1 directly interacted with DEPTOR via its N-terminal domain, deubiquitinated DEPTOR, and thereby stabilized DEPTOR in a Cys-91-independent but Asp-88-dependent manner, suggesting that OTUB1 targets DEPTOR for deubiquitination via a deubiquitinase activity-independent non-canonical mechanism. The interaction between OTUB1 and DEPTOR was enhanced when the cells were treated with amino acids. Moreover, OTUB1 suppressed amino acid-induced activation of mTORC1 in a DEPTOR-dependent manner and thereby ultimately controlled cellular autophagy, cell proliferation, and size. Our findings reveal a mechanism that stabilizes the mTORC1 inhibitor DEPTOR via OTUB1's deubiquitinase activity. Our insights may inform research into various mTOR activity-related diseases, such as cancer, and may contribute to the identification of new diagnostic markers and therapeutic strategies for cancer treatments.


Motor priming in neurorehabilitation.
Priming is a type of implicit learning wherein a stimulus prompts a change in behavior. Priming has been long studied in the field of psychology. More recently, rehabilitation researchers have studied motor priming as a possible way to facilitate motor learning. For example, priming of the motor cortex is associated with changes in neuroplasticity that are associated with improvements in motor performance. Of the numerous motor priming paradigms under investigation, only a few are practical for the current clinical environment, and the optimal priming modalities for specific clinical presentations are not known. Accordingly, developing an understanding of the various types of motor priming paradigms and their underlying neural mechanisms is an important step for therapists in neurorehabilitation. Most importantly, an understanding of the methods and their underlying mechanisms is essential for optimizing rehabilitation outcomes. The future of neurorehabilitation is likely to include these priming methods, which are delivered prior to or in conjunction with primary neurorehabilitation therapies. In this Special Interest article, we discuss those priming paradigms that are supported by the greatest amount of evidence, including (i) stimulation-based priming, (ii) motor imagery and action observation, (iii) sensory priming, (iv) movement-based priming, and (v) pharmacological priming.Video Abstract available. (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A86) for more insights from the authors.


Use of indomethacin to demonstrate enterotoxic activity in extracts of Entamoeba histolytica trophozoites.
The present study was designed to develop and characterize animal models for the assay of enterotoxic activity in extracts of Entamoeba histolytica trophozoites. Marked water and electrolyte secretion occurred in both in vivo rabbit ileal loops and rat colon loops exposed to clarified sonic fluids of E. histolytica strain HM-1 trophozoites (10(6)/ml) when the animals were first administered indomethacin (0.1 mg/kg). No effect on intestinal absorption was observed in animals exposed to Entamoeba extracts alone or after administration of a lower (0.01 mg/kg). No effect on intestinal absorption was observed in animals exposed to Entamoeba extracts alone or after administration of a lower (0.01 mg/kg) dose of indomethacin. Higher doses (greater than or equal to 1 mg/kg) of indomethacin inhibited extract-induced secretion. No enterotoxic activity was detected with or without indomethacin, using extracts from the nonpathogenic E. histolytica-like Laredo strain, even at 10-fold-higher cell concentrations. The HM-1 enterotoxic activity was heat labile. Prior exposure of the loop lumen to fetuin (100 micrograms/ml) blocked the secretory response to subsequent HM-1 extract exposure, but postexposure of the loop to fetuin did not block secretion that had already been established by the amoeba extract. No histological changes were seen associated with the amoeba extract-induced secretion. The data suggest that E. histolytica HM-1 strain elaborates an enterotoxic activity capable of causing consistent secretion in the mammalian intestine that has had its mucosal cytoprotection impaired by indomethacin.


Spontaneous improvement of tardive dystonia during mania.
Two cases of bipolar affective disorder with tardive dystonic symptoms seemed to improve only with mood elevation, whether the latter occurred spontaneously or was 'induced' pharmacologically. Such cases could prove an interesting locus for the investigation of both affective disorders and tardive dyskinesias.


Manual ventilation to prevent hypoxaemia during endotracheal intubation of critically ill adults: protocol and statistical analysis plan for a multicentre randomised trial.
Hypoxaemia is the most common complication during endotracheal intubation of critically ill adults, and it increases the risk of cardiac arrest and death. Manual ventilation between induction and intubation has been hypothesised to decrease the incidence of hypoxaemia, but efficacy and safety data are lacking. The Preventing Hypoxemia with Manual Ventilation during Endotracheal Intubation trial is a prospective, multicentre, non-blinded randomised clinical trial being conducted in seven intensive care units in the USA. A total of 400 critically ill adults undergoing endotracheal intubation will be randomised 1:1 to receive prophylactic manual ventilation between induction and endotracheal intubation using a bag-valve-mask device or no prophylactic ventilation. The primary outcome is the lowest arterial oxygen saturation between induction and 2 min after successful endotracheal intubation, which will be analysed as an unadjusted, intention-to-treat comparison of patients randomised to prophylactic ventilation versus patients randomised to no prophylactic ventilation. The secondary outcome is the incidence of severe hypoxaemia, defined as any arterial oxygen saturation of less than 80% between induction and 2 min after endotracheal intubation. Enrolment began on 2 February 2017 and is expected to be complete in May 2018. The trial was approved by the institutional review boards or designees of all participating centres. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. NCT03026322; Pre-results.


Use of Tendon Allograft for Recurrent Extensor Carpi Ulnaris Instability in Ehlers-Danlos Syndrome: A Case Report.
Background Subluxation of the extensor carpi ulnaris (ECU) tendon can be a challenging problem to the surgeon, with no options described for failure following autologous reconstruction. It is our intention to provide guidance on technique by describing our experience in a 20-year-old male with Ehlers-Danlos syndrome. Case Description The patient presented with pain and snapping of the ECU tendon, and failed both immobilization and ECU reconstruction with autologous extensor retinaculum. A gracilis tendon allograft was used to reconstruct the ECU sheath, in addition to ulnar groove deepening. At 1-year follow-up, the patient had no pain and the ECU was stable without recurrent subluxation. Literature Review To the authors' knowledge, the use of tendon allograft for stabilization of recurrent ECU subluxation following surgical repair or reconstruction has not been previously described in the medical literature. Clinical Relevance Utilization of tendon allograft is a viable technique to stabilize the ECU tendon while minimizing the risk in relying on compromised autologous tissue. This report represents the first account of successful reconstruction following failed autologous reconstruction.


Exercise-induced alterations in muscle lipid metabolism improve insulin sensitivity.
Exercise is a key component for the successful management of many obesity-related metabolic complications, including insulin resistance. This review addresses the effect of chronic and acute endurance exercise on insulin action in obesity and the role of exercise-induced alterations in fatty acid partitioning within the muscle cell on insulin sensitivity.


Excitotoxic mechanisms, and age-related susceptibility to brain damage in ischemia, hypoglycemia and toxic mussel poisoning.
Initial research by Olney, investigating the toxicity of glutamate as a food additive, demonstrated that irreversible (necrotic) changes could be produced in the CNS by glutamate. Subsequently, it became clear that the release of excitatory amino acids into the extracellular space of nervous tissue may play a role in CNS ischemia, and, later hypoglycemia. Experiments utilizing excitatory amino acid antagonists at the N-methyl-d-aspartate and other subtypes of excitatory receptor have shown neuronal protection, in both ischemia and hypoglycemia. The protection is robust enough to produce a detectable improvement in neurologic deficit on neurobehavioral testing, in addition to significantly reducing the number of necrotic cells in the brain. A third condition where excitotoxicity plays a role is toxic mussel poisoning. In contrast to ischemia and hypoglycemia, an excitotoxin which is exogenous to the brain plays a role. Domoic acid is contained in mussels which have filter-fed large quantities of domoate-rich phytoplankton, and when contaminated mussels are ingested in large quantities, serious and irreversible CNS effects, accompanied by necrosis, may result. In contrast to ischemia and hypoglycemia, however, damage is mediated at a different excitatory CNS receptor, namely the kainate receptor. In all three conditions, a constant aspect of the excitotoxic pathology is an increased susceptibility to excitotoxic damage with increasing age. This may be due to the dendritic location of excitatory receptors, and the richer branching of neuronal dendritic trees in aged animals, leading to enhanced susceptibility of the neuron to excitotoxic necrosis with age.


Barriers and facilitators for consumer adherence to the dietary guidelines for Americans: the HEALTH study.
The majority of the US population does not meet recommendations for consumption of milk, whole grains, fruit, and vegetables. The goal of our study was to understand barriers and facilitators to adherence to the Dietary Guidelines for Americans for four nutrient-rich food groups in fifth-grade children and unrelated adult caregivers across six sites in a multistate study. A total of 281 unrelated adult caregivers (32% African American, 33% European American, and 35% Hispanic American) and 321 children (33% African American, 33% European American, and 34% Hispanic American) participated in 97 Nominal Group Technique sessions. Nominal Group Technique is a qualitative method of data collection that enables a group to generate and prioritize a large number of issues within a structure that gives everyone an equal voice. The core barriers specific to unrelated adult caregivers were lack of meal preparation skills or recipes (whole grains, fruit, vegetables); difficulty in changing eating habits (whole grains, fruit, vegetables), cost (milk, whole grains, fruit, vegetables), lack of knowledge of recommendation/portion/health benefits (milk, vegetables), and taste (milk, whole grains, vegetables). Specific to children, the core barriers were competing foods (ie, soda, junk foods, sugary foods [whole grains, milk, fruit, vegetables]), health concerns (ie, milk allergy/upset stomach [milk]), taste/flavor/smell (milk, whole grains, fruit, vegetables), forget to eat them (vegetables, fruit), and hard to consume or figure out the recommended amount (milk, fruit). For both unrelated adult caregivers and children, reported facilitators closely coincided with the barriers, highlighting modifiable conditions that could help individuals to meet the Dietary Guidelines for Americans.


Efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with radiofrequency ablation versus DEB-TACE alone in Chinese hepatocellular carcinoma patients.
To compare the efficacy of drug-eluting bead transarterial chemoembolization combined with radiofrequency ablation (DEB-TACE+RFA) versus DEB-TACE alone in Chinese hepatocellular carcinoma (HCC) patients.The 28 patients receiving DEB-TACE+RFA and 74 HCC patients receiving DEB-TACE were recruited in this study. Treatment responses, progression-free survival (PFS), and overall survival (OS) were evaluated.One to 3 months after treatments, the proportion of patients achieving complete response (CR) (78.6% vs 33.8%, P <.001) and objective response rate (ORR) (92.9% vs 78.4%, P =.010) were elevated in DEB-TACE+RFA group compared with DEB-TACE group. Multivariate logistic regression displayed that DEB-TACE+RFA was an independently predicting factor for better CR (P = .006). Subgroup analysis of CR achievement illuminated that DEB-TACE+RFA disclosed better CR achievement in patients with history of cirrhosis (P <.001), tumor located in right liver (P = .003), bilobar disease (P = .013), tumor size <3.3 cm (P = .001), no portal vein invasion (P = .001), no hepatic vein invasion (P <.001), Child-pugh stage A (P <.001), Barcelona Clinic Liver Cancer (BCLC) stage 0, A-B (P <.001), abnormal alpha-fetoprotein (AFP) (P = .001) and normal AFP (P = .016). The PFSs were similar between 2 groups (P = .112), however, the OS was more prolonged in DEB-TACE+RFA group (P = .025) compared with DEB-TACE group. And subgroup analysis displayed that PFS of patients with largest nodule size >3.3 cm (P = .025) was longer and patients with unilobar disease (P = .009), and patients with no hepatic invasion (P = .019) and Child-pugh stage A (P = .037) had more favorable OS in DEB-TACE+RFA group compared with DEB-TACE group.DEB-TACE+RFA achieved better treatment responses and OS compared with DEB-TACE alone in Chinese HCC patients.


Acupuncture Attenuates Blood Pressure via Inducing the Expression of nNOS.
Sympathetic activation leads to elevated blood pressure. Neuronal nitric oxide synthase (nNOS) inhibits sympathetic nervous system activity, thereby decreasing blood pressure (BP). nNOS is highly expressed in the arcuate nucleus (ARC) and ventrolateral periaqueductal gray (vlPAG), which play essential roles in the regulation of the cardiovascular and sympathetic nervous systems. This study was designed to verify the hypothesis that acupuncture exerts an antihypertensive effect via increasing the expression of nNOS in ARC and vlPAG of spontaneously hypertensive (SHR) rats. Rats without anesthesia were subject to daily acupuncture for 2 weeks. BP was monitored by the tail-cuff method. nNOS expressions in the ARC and vlPAG were detected by western blot and immunofluorescence. BP was measured after 7-Nitroindazole (7-NI), a specific nNOS inhibitor, was microinjected into ARC or vlPAG in SHR rats treated with acupuncture. Acupuncture for 14 days significantly attenuated BP, and the Taichong (LR3) acupoint was superior to Zusanli (ST36) and Fengchi (GB20) in lowering BP. In addition, acupuncture at Taichong (LR3) induced an increase of nNOS expression in ARC and vlPAG, whereas microinjection of 7-NI into ARC or vlPAG reversed the antihypertensive effect of acupuncture. This study indicates that acupuncture at Taichong (LR3) induces a better antihypertensive effect than at Zusanli (ST36) or at Fengchi (GB20) in SHR rats, and enhancement of nNOS in ARC and vlPAG probably contributes to the antihypertensive effect of acupuncture.


Chemical Constituents of Coreopsis lanceolata Stems and Their Antitermitic Activity Against the Subterranean Termite Coptotermes curvignathus.
Coreopsis lanceolata is an Asteraceous plant known to contain semiochemicals active against nematodes and leukemic agents. The objective of the study was to discover termite resistant constituents from C. lanceolata stems. Five compounds were isolated from C. lanceolata stems. These compounds were identified as 5-phenyl-2-(1-propynyl)-thiophene (1), 1-phenylhepta-1,3,5-tryne (2), β-sitosterol (3), succinic acid (4), and protocatechuic acid (5), respectively; they were confirmed by spectroscopic analysis. Their antitermitic effects were evaluated with the no-choice feeding test against Coptotermes curvignathus. Of the isolates, 5-phenyl-2-(1-propynyl)-thiophene (1) and 1-phenylhepta-1,3,5-tryne (2) showed strong potent antitermitic activity. Our findings suggested that compounds 1 and 2 isolated from C. lanceolata stems appears to be the active ingredients.


Cognitive Speed of Processing Training Can Promote Community Mobility among Older Adults: A Brief Review.
Background. Community mobility is crucial for maintaining independent functioning and quality of life for older adults. Purpose. The present paper describes the relationship of cognition, particularly speed of processing as measured by the Useful Field of View Test, to mobility as indicated by driving behaviors, life space, and falls among healthy older adults. Research examining the impact of cognitive speed of processing training (SOPT) on older adults' community mobility (i.e., driving behaviors) is also summarized. Key Issues. Even slight cognitive declines can place older adults at risk for mobility limitations. However, cognitive interventions like SOPT can mitigate declines in driving mobility. Implications. The potential of SOPT to sustain community mobility among older adults is discussed.


Cardiopulmonary effects of mechanical distension of the rumen in nonanesthetized sheep.
The cardiopulmonary effects of mechanical distension of the rumen were studied in nonanesthetized sheep. Results in group I ewes indicated that simply increasing intraruminal pressure by compressed air insufflation did not seriously affect cardiopulmonary hemodynamics. Changes were more serious in group II ewes when water injection was followed by ruminal insufflation with compressed air. Heart rate, total peripheral resistance, and total pulmonary resistance increased, with a concommitant increase in arterial and pulmonary blood pressure and decrease in stroke volume. Infusion of water alone increased heart rate and cardiac output. The blood gas data indicated a definite arterial hypoxemia and hypercapnia, suggesting impaired ventilation during ruminal distension. The increase in total pulmonary resistance was thought to be due to alveolar hypoxia caused by a significant decrease in ventilation.


Experimental Study on the Cement-Based Materials Used in Coal Mine Gas Extraction for Hole Sealing.
Gas drainage is an important method to prevent and control gas disasters. Sealing materials have an important impact on the gas drainage effect. To improve the extraction rate, the configuration and related characteristics of sealing materials were studied in this study. It was found that the fluidity increased gradually with the increase of the dosage of the suspension concentrate (SC). The water-cement ratio was directly proportional to the setting time of the slurry. Also, the mixing amount of the special cement was inversely proportional to the setting time of the slurry. The influence of the amount of foaming agent, special cement, and suspending agent on the expansion rate of the slurry was positive, and the influence gradually weakened. When the water-cement ratio of cement-based materials was 0.6, the special cement content percentage was 6, the suspension agent content percentage was 3, the plasticizer content percentage was 0.7, the early strength agent content percentage was 1.2, and the foaming agent content percentage was 0.2, the sealing effect was the best. The research results suggest that the porosity and pore length of the cement-based material are smaller than those of polyurethane, and its sealing property was better. This could further increase the sealing effect of the gas borehole, thereby facilitating gas extraction.


Cobalt-Catalyzed Tandem Radical Cyclization/C-C Coupling Initiated by Directed C-H Activation.
A cobalt-N-heterocyclic carbene catalyst promotes a tandem radical cyclization/C-C coupling reaction between tosylamide-tethered bromo-alkenes and aryl N-H imines initiated by chelation-assisted arene C-H activation, affording 3-(arylmethyl)pyrrolidine derivatives in moderate to good yields. The reaction tolerates a variety of substituents on the aryl imine as well as various modifications on the bromo-alkene substrate.


Glycothiohexides, novel antibiotics produced by "Sebekia" sp. LL-14E605. I. Taxonomy, fermentation and biological evaluation.
The new glycothiohexide antibiotics, which are related to nosiheptide, were identified in fermentations of an actinomycete belonging to the genus "Sebekia". Strain LL-14E605 was classified as a "Sebekia" based on the presence of both mesodiaminopimelic acid and madurose in the cell wall and the presence of pseudosporangia encasing the spores. Culture LL-14E605 was successfully fermented in 10 to 3,000 liters of a complex medium. Antibiotic activity closely followed cell mass accumulation and usually peaked after 4 to 5 days of incubation. Glycothiohexide alpha demonstrated excellent in vitro activity against Gram-positive bacteria with MICs of 0.03 to 0.06 microgram/ml against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. However, glycothiohexide alpha failed to protect mice against a lethal challenge with Staphylococcus aureus Smith unless it was administered prior to challenge.


Odors Associated With Autobiographical Memory Induce Visual Imagination of Emotional Scenes as Well as Orbitofrontal-Fusiform Activation.
Specific odors can induce memories of the past, especially those associated with autobiographical and episodic memory. Odors associated with autobiographical memories have been found to elicit stronger activation in the orbitofrontal cortex, hippocampus, and parahippocampus compared with odors not linked to personal memories. Here, we examined whether continuous odor stimuli associated with autobiographical memories could activate the above olfactory areas in older adults and speculated regarding whether this odor stimulation could have a protective effect against age-related cognitive decline. Specifically, we used functional magnetic resonance imaging to investigate the relationship between blood oxygen levels in olfactory regions and odor-induced subjective memory retrieval and emotions associated with autobiographical memory in older adults. In our group of healthy older adults, the tested odors induced autobiographical memories that were accompanied by increasing levels of retrieval and the feeling of being "brought back in time." The strength of the subjective feelings, including vividness of the memory and degree of comfort, impacted activation of the left fusiform gyrus and left posterior orbitofrontal cortex. Further, our path model suggested that the strength of memory retrieval and of the emotions induced by odor-evoked autobiographical memories directly influenced neural changes in the left fusiform gyrus, and impacted left posterior orbitofrontal cortex activation through the left fusiform response.


Characteristics of diffuse muscular coactivation (DMC) in persons with fibromyalgia -- part 2.
This study examined the electrical characteristics (Root Mean Square -- RMS and median frequency) of Diffuse Muscular Coactivation (DMC) associated with the tender points of fibromyalgia. DMC is defined as an increase from resting levels (tonus) in the electrical activity of any muscle during a movement which does not involve that muscle and is not part of the agonist -- antagonist unit. The results show an increase in RMS in fibromyalgia sufferers as compared to controls. Coactivation was stronger proximal to the neck and decreased in intensity as the area recorded moved distally. Median frequency changed over time but not significantly between groups. Possible neurological mechanisms are discussed.


Involvement of FtsZ protein in shift-up-induced division delay in Escherichia coli.
A nutritional shift-up from glucose minimal medium to LB broth was previously shown to cause a division delay of about 20 min in synchronized cultures of Escherichia coli, and a similar delay was observed after a nutritional pulse (a shift-up followed rapidly by a return to glucose minimal medium). Using synchronized cultures, we show here that the pulse-induced division delay does not require protein synthesis during the period in LB broth, suggesting that a nonprotein signal is generated by the shift-up and transmitted to the cell division machinery. The cell division protein FtsZ, target of the SOS-associated division inhibitor SfiA (or SulA), seems to be involved in the postshift division delay. Mutants in which the FtsZ-SfiA interaction is reduced, either sfiA (loss of SfiA) or ftsZ(SfiB) (modification of FtsZ), have a 50- to 60-min division delay after a shift-up. Furthermore, after a nutritional pulse, the ftsZ(SfiB) mutant had only a 10- to 16-min delay. These results suggest that the FtsZ protein is the target element of the cell division machinery to which the shift-up signal is transmitted.


Cerebrospinal fluid leak and meningitis associated with nasal continuous positive airway pressure therapy.
Clear rhinorrhea is a common symptom in patients with obstructive sleep apnea (OSA) and may worsen with continuous positive airway pressure therapy. Clear rhinorrhea can also be the presenting symptom of cerebrospinal fluid (CSF) leak, which is evidence of a communication between the subarachnoid space and the nasal cavity or sinuses. While CSF leak has been reported to occur with nasal continuous positive airway pressure (nCPAP) therapy following trauma to the skull base, its association with OSA and nCPAP therapy in the absence of trauma has not been previously described. We report two patients with OSA in whom CSF leak developed following the institution of nCPAP therapy. In one patient, the rhinorrhea was complicated by meningitis. Both patients underwent successful repair of their defects. One patient successfully restarted nCPAP therapy, while the other refused it.


[Shoulder instability. Classification and treatment].
Shoulder instability includes different degrees of instability from painful hyperlaxity to subluxation to dislocation. Different classifications of shoulder instability have been created in order to facilitate decision making for treatment. None of these, however, has gained acceptance. Subject to the indications, shoulder instability can be treated conservatively or surgically after repositioning the acute dislocation. A survey of arthroscopic and open stabilization procedures and their results are given in relation to the indications.


The contraction phase of virus-specific CD8+ T cells is unaffected by a pan-caspase inhibitor.
The effectiveness of protection conferred by CD8(+) memory T cells is determined by both their quality and their quantity, which suggests that vaccine efficacy might be improved if it were possible to increase the size of the memory pool. Approximately 90% of virus-specific CD8(+) T cells die during the contraction phase and, herein, we have attempted to increase the memory pool by reducing CD8(+) T cell death. CD8(+) T cell contraction has been attributed to apoptosis, or programmed cell death (PCD), which, classically, is dependent on caspases. Caspase-dependent PCD can be prevented by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (zVAD), and here we evaluate the effect of this compound on virus-specific T cell responses in mice. zVAD prevented caspase-dependent PCD of freshly isolated virus-specific T cells in tissue culture, and a fluorescent analog, FITC-VAD, entered CD8(+) T cells following in vivo injection. However, despite using 11 different regimens of zVAD administration in vivo, no significant effects on CD8(+) or CD4(+) memory T cell numbers were observed. Furthermore, the CD8(+) memory T cell responses to secondary virus infection were indistinguishable, both qualitatively and quantitatively, in zVAD-treated and normal mice. The absence of effect cannot be attributed to a technical flaw, because identical doses of zVAD were able to rescue mice from hepatocyte apoptosis and lethal intrahepatic hemorrhage, induced by inoculation of anti-Fas Ab. We conclude that the contraction phase of the virus-specific T cell response is unlikely to require caspase-dependent PCD. We propose that contraction can be mediated by an alternative, caspase-independent pathway(s).


Sex Differences in High School Athletes' Knowledge of Sport-Related Concussion Symptoms and Reporting Behaviors.
Recent researchers have reported that athletes' knowledge of sport-related concussion (SRC) has increased but that athletes still lack knowledge of all the signs and symptoms of SRC. Understanding the signs and symptoms of SRC and the dangers of playing while symptomatic are critical to reporting behaviors in high school athletes. To examine sex differences in knowledge of SRC symptoms and reasons for not reporting a suspected SRC to an authoritative figure in high school athletes. Cross-sectional study. Survey. A total of 288 athletes across 7 sports (198 males [68.8%] and 90 females [31.2%]). A validated knowledge-of-SRC survey consisted of demographic questions, a list of 21 signs and symptoms of SRC, and reasons why athletes would not report their SRC. The independent variable was sex. Athlete knowledge of SRC symptoms was assessed by having participants identify the signs and symptoms of SRC from a list of 21 symptoms. Knowledge scores were calculated by summing the number of correct answers; scores ranged from 0 to 21, with a score closer to 21 representing greater knowledge. Reporting-behavior questions asked athletes to choose reasons why they decided not to report any possible SRC signs and symptoms to an authoritative figure. A sex difference in total SRC symptom knowledge was found (F286 = 4.97, P = .03, d = 0.26). Female high school athletes had more total SRC symptom knowledge (mean ± standard deviation = 15.06 ± 2.63; 95% confidence interval = 14.54, 15.57) than males (14.36 ± 2.76; 95% confidence interval = 13.97, 14.74). Chi-square tests identified significant relationships between sex and 8 different reasons for not reporting an SRC. High school males and females had similar SRC symptom knowledge; however, female athletes were more likely to report their concussive symptoms to an authoritative figure.


Short- and long-term results of stapedotomy and stapedectomy with a teflon-wire piston prosthesis.
We analyzed the results of 604 cases of primary stapes surgery performed between 1974 and 1997 with replacement of the stapes by a 0.6- or 0.8-mm Schuknecht Teflon-wire piston. At long-term follow-up (1 to 21 years; mean, 7 years), the residual air-bone gap was 10 dB or less in 79% of the cases. The hearing results and postoperative complications were comparable to those reported by authors who used the same evaluation criteria. Although the aim of the surgery was to perform a small stapedotomy with a narrow footplate perforation (0.8 mm), a large stapedotomy or a stapedectomy was performed in 134 cases (22.2%) because of surgical or anatomic conditions. Our results show that the larger footplate perforations allowed a better correction of the air-bone gap at the lower frequencies. The ears with larger perforations did not show a higher incidence of sensorineural hearing loss.


Communicating non-targeted effects of ionizing radiation to achieve adaptive homeostasis in tissues.
Non-targeted effects, i.e., those responses in cells or tissues that were not subject to energy deposition events after localized exposure to ionizing radiation, are well established. While they are not a universal phenotype, when they do occur they can be associated with subsequent tissue or whole body responses. Here it is argued that non-targeted effects are a tissue level response to restore equilibrium within an organ system, and thus restore tissue homeostasis. This "adaptive homeostasis" has evolved in response to a variety of environmental and other such stresses an individual is exposed to in their lifetime. These non-targeted effects are not likely to impact significantly on estimates of potential risks associated with radiation exposure because they are presumably "built into" current risk estimates. However, they could have implications for radiation carcinogenesis, by driving processes in targeted and non-targeted cells that could eliminate transformed cells or transform cells from a normal phenotype to a phenotype associated with malignancy within a tissue.