Comparison of methods for detection of norovirus in oysters.
In the absence of culture methods for noroviruses, detection in foods relies on molecular techniques such as Reverse Transcription-Polymerase Chain Reaction (RT-PCR) on extracted viral RNA followed by PCR product confirmation by hybridisation and/or sequencing. However, in order to obtain a successful detection it is of great importance to remove the tissue inhibitors during the viral RNA extraction. To select the most efficient extraction procedure of oysters we have compared four protocols. A pool of digestive gland material from oyster samples was divided into 1.5 g portions and spiked with 10-fold dilutions of human faecal samples containing norovirus genogroup II. The samples were tested on three different occasions using four different sample treatment protocols. The protocols were assessed with regard to their ability to recover viral RNA and detect norovirus in spiked oysters and for their in-house reproducibility. One method using viral elution by a Mixer Mill Cell Disrupter resulted in a 10-fold better recovery than the other three protocols when an RT-seminested PCR (G2SKR/COG2F and G2SKR/G2SKF) detection approach was applied. Although less distinctive this was also the case when NoV was detected by a single round RT-PCR approach using the primers JV13i and JV12y. The second most efficient method was a method using chloroform extraction and polyethylene precipitation.


Safety of calcium fructoborate as a novel food pursuant to Regulation (EU) 2015/2283.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on calcium fructoborate as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF, produced by chemical synthesis, contains a maximum of 2.9% of boron and on average 4.7% calcium and 84.2% fructose. It is intended to be marketed as food supplements targeting the general adult population, excluding pregnant and lactating women, at a maximum level of 220 mg/day (maximum boron intake of 6.4 mg per day). The combined intake of boron from the background diet and the NF is in the range of 9.6-9.9 mg/day (corresponding to up to 0.14 mg/kg body weight (bw) per day given a default bw of 70 kg). This is in the range of the acceptable daily intake (ADI) of 0.16 mg/kg bw per day. Under conditions mimicking the gastrointestinal (GI) environment, the NF is fully hydrolysed and the Panel considered boron toxicity relevant for the safety assessment. The Panel considers that there is no concern with respect to genotoxicity of the NF. The effect induced by the NF in a 13-week rat study is consistent with toxicological findings induced by treatment with boron compounds in animal studies. Epididymides-to-brain weight ratio was identified as the most relevant endpoint and the reference point derived was the lowest model averaged BMDL10 value of 529 mg/kg bw per day. This corresponds to 14.8 mg/kg bw per day of boron, which is higher than the critical no observed adverse effect level (NOAEL) (9.6 mg boron/kg bw per day) used for establishing the ADI of 0.16 mg/kg bw per day for boron. The Panel therefore applied the present ADI for boron in the assessment of the NF. The Panel concludes that the NF, calcium fructoborate, is safe under the proposed uses and use levels.


Age Patterns of Mortality During the Black Death in London, A.D. 1349-1350.
This paper examines adult age-specific mortality patterns of one of the most devastating epidemics in recorded history, the Black Death of A.D. 1347-351. The goal was to determine whether the epidemic affected all ages equally or if it targeted certain age groups. Analyses were done using a sample of 337 individuals excavated from the East Smithfield cemetery in London, which contains only individuals who died during the Black Death in London in 1349-1350. The age patterns from East Smithfield were compared to a sample of 207 individuals who died from non-epidemic causes of mortality. Ages were estimated using the method of transition analysis, and age-specific mortality was evaluated using a hazards model. The results indicate that the risk of mortality during the Black Death increased with adult age, and therefore that age had an effect on risk of death during the epidemic. The age patterns in the Black Death cemetery were similar to those from the non-epidemic mortality sample. The results from this study are consistent with previous findings suggesting that despite the devastating nature of the Black Death, the 14(th)-century disease had general patterns of selectivity that were similar to those associated with normal medieval mortality.


Preclinical evaluation of Millipede 088 intracranial aspiration catheter in cadaver and in vitro thrombectomy models.
Larger bore aspiration catheters are expected to significantly improve the speed and completeness of acute stroke revascularization. To evaluate the navigability and clot retrieval performance of a novel 8Fr aspiration catheter, Millipede 088 (Perfuze Ltd), using fresh-frozen cadavers and an in vitro thrombectomy model, respectively. Cadaveric study: Transfemoral catheterization of the intracranial arteries was performed in six cadavers, allowing evaluation of navigation to 12 middle cerebral arteries (MCAs) and six basilar arteries. Commercially available 6Fr aspiration catheters (SOFIA Plus, Microvention) were used as controls. In vitro study: Three human blood clot phenotypes were created; red blood cell-rich, mixed, and fibrin/platelets-rich. Two clot sizes, resulting in occlusion of the internal carotid artery (ICA) and MCA-M1 were investigated. Endpoints were first-pass effect (FPE), first-pass complete ingestion, and second-pass recanalization. Cadaveric study: Both the Millipede 088 and SOFIA Plus devices reached the distal MCA-M1 and the basilar artery in 10/12 and 2/2 of the navigation attempts, respectively. In the two instances of unsuccessful navigation, neither device was able to cross the ophthalmic artery. In vitro study: In 10 mm long M1 occlusions, Millipede 088 achieved 100% FPE versus 40% for 6Fr devices (p>0.001). In 20 mm long ICA occlusions, Millipede 088 achieved 100% removal success within two passes in each clot phenotype compared with an average of 27% for 6Fr devices (p>0.001). Navigation of the Millipede 088 catheter to the MCA-M1 and basilar artery is feasible in a cadaver model. Millipede 088 demonstrates superiority over 6Fr aspiration catheters for three representative clot phenotypes at the most common sites of occlusion in an in vitro vasculature model.


Dermatomal somatosensory evoked potentials in unilateral lumbosacral radiculopathy.
We examined scalp-recorded somatosensory evoked potentials (SSEPs) to electrical stimulation of the peroneal nerves and to stimulation in the L5 and S1 dermatomes in 19 patients with unilateral radiculopathies involving these segments. For the dermatomal studies at least two trials of 512 responses were recorded from the vertex with reference to both the midfrontal and contralateral parietal electrodes, using an averaging technique. Findings on the symptomatic and asymptomatic sides were compared in each patient. We found that peroneal SSEPs were normal in all patients. Dermatomal SSEPs correctly identified the lesion in 5 patients. In 1 patient dermatomal SSEPs lateralized the lesion correctly but localized it to the adjacent root. In 10 cases dermatomal SSEPs gave misleading information, indicating an abnormality on the asymptomatic side in 1 patient and no abnormality in 9. In the remaining 3 patients, both SSEPs and radiological contrast studies failed to identify any lesion, although the radiculopathy was confirmed by electromyography. These findings raise doubt about the ultimate utility of these evoked potential techniques in the evaluation of patients with suspected radiculopathies.


Coffee berry borer (Hypothenemus hampei) (Coleoptera: Curculionidae) development across an elevational gradient on Hawai'i Island: Applying laboratory degree-day predictions to natural field populations.
Coffee berry borer (CBB, Hypothenemus hampei) (Coleoptera: Curculionidae: Scolytinae) is the most destructive pest of coffee worldwide. Information on CBB development times can be used to predict the initiation of new infestation cycles early in the coffee-growing season and thus inform the timing of insecticide applications. While laboratory estimates of CBB development under constant conditions exist, they have not been applied under the heterogeneous environmental conditions that characterize many coffee-growing regions. We measured CBB development times and abundance in commercial coffee farms across an elevational gradient on Hawai'i Island and applied thermal accumulation models from previous laboratory studies to test their fit to field data. Artificial lures were used to infest coffee berries at five farms ranging in elevation from 279-792 m, and weather variables were monitored at macro (farm-level) and micro (branch-level) scales. CBB development was followed in the field from the time of initial berry infestation by the founding female through the development of F1 mature adults. Mean development time from egg to adult across all sites was 38.5 ± 3.46 days, while the mean time required for the completion of a full life cycle (from time of infestation to presence of mature F1 females) was 50.9 ± 3.35 days. Development time increased with increasing elevation and decreasing temperature. Using macro-scale temperature data and two different estimates for the lower temperature threshold (14.9°C and 13.9°C), we estimated a mean requirement of 332 ± 14 degree-days and 386 ± 16 degree-days, respectively, from the time of berry infestation to the initiation of a new reproductive cycle in mature coffee berries. Similar estimates were obtained using micro-scale temperature data, indicating that macro-scale temperature monitoring is sufficient for life-cycle prediction. We also present a model relating elevation to number of CBB generations per month. Our findings suggest that CBB development times from laboratory studies are generally applicable to field conditions on Hawai'i Island and can be used as a decision support tool to improve IPM strategies for this worldwide pest of coffee.


Should implants be considered for patients with periodontal disease?
Dental implants are seen as a good option for replacing missing teeth. The success and survival rates for implants are very high. Concerns are developing about the problem of peri-implantitis. The reports of its prevalence vary but it is noted that the presence of periodontal disease is a risk factor. The issue of peri-implantitis was raised in the House of Lords in 2014. Complaints relating to implants is on the rise with the General Dental Council. Placement of implants in patients with periodontal disease is not a treatment that should be done without a full periodontal assessment and stabilisation of periodontal disease first. This review considers the risk of placing implants in patients with aggressive and chronic periodontitis.


Progression of pathogenic events in cynomolgus macaques infected with variola virus.
Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections - an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions.


Action of the fungal compound citrinin, a bioherbicide candidate, on photosystem II.
Bioherbicides are becoming more attractive as safe weed control tools towards sustainable agriculture. Natural products constitute an important source chemicals and chemical leads for discovery and development of novel pesticide target sites. Citrinin is a bioactive compound produced by fungi of the genera Penicillium and Aspergillus. However, its physiological-biochemical mechanism as a phytotoxin remains unclear. Citrinin causes visible leaf lesions on Ageratina adenophora similar to those produced by the commercial herbicide bromoxynil. Phytotoxicity bioassay tests using 24 plant species confirmed that citrinin has a broad activity spectrum and therefore has potential as a bioherbicide. Based on chlorophyll fluorescence studies, citrinin mainly blocks PSII electron flow beyond plastoquinone QA at the acceptor side, resulting in the inactivation of PSII reaction centers. Furthermore, molecular modeling of citrinin docking to the A. adenophora D1 protein suggests that it binds to the plastoquinone QB site by a hydrogen bond between the O1 hydroxy oxygen atom of citrinin and the histidine 215 of the D1 protein, the same way as classical phenolic PSII herbicides do. Finally, 32 new citrinin derivatives were designed and sorted according to free energies on the basis of the molecular model of an interaction between the citrinin molecule and the D1 protein. Five of the modeled compounds had much higher ligand binding affinity within the D1 protein compared with lead compound citrinin. Citrinin is a novel natural PSII inhibitor that has the potential to be developed into a bioherbicide or utilized as a lead compound for discovery of new derivatives with high herbicidal potency. © 2023 Society of Chemical Industry.


Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity.
Amyotrophic lateral sclerosis is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of amyotrophic lateral sclerosis. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report the inhibition of NMD by arginine-rich dipeptide repeats derived from C9orf72 hexanucleotide repeat expansion, the most common cause of familial amyotrophic lateral sclerosis. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons specifically from amyotrophic lateral sclerosis patients carrying C9orf72 hexanucleotide repeat expansion, suggesting the suppression of NMD pathway in these patients. Using Drosophila as a model, we have validated that the C9orf72 hexanucleotide repeat expansion products could lead to the accumulation of the NMD substrates and identified arginine-rich dipeptide repeats, including poly glycine-arginine and poly proline-arginine, as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of glycine-arginine with 36 repeats (GR36) was sufficient to cause NMD inhibition. In cells expressing GR36, stress granule accumulation was accompanied by decreased processing body formation, which contributed to the inhibition of NMD. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich dipeptide repeats in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in dipeptide repeat-expressing flies, indicating that genetically reactivating the NMD pathway could suppress dipeptide repeat toxicity. Finally, after validating tranilast as an NMD-activating drug, we demonstrated the therapeutic potential of this asthma drug in cellular and Drosophila models of C9orf72 dipeptide repeat neurotoxicity. Therefore, our study has revealed a cellular mechanism whereby arginine-rich C9orf72 dipeptide repeats could inhibit NMD activities by reducing the abundance of processing bodies. Furthermore, our results suggested that activation of the NMD pathway could be a potential therapeutic strategy for amyotrophic lateral sclerosis with defective RNA metabolism.


Pregnancy in mixed connective tissue disease: comparison with systemic lupus erythematosus.
The risk of pregnancy was evaluated in 31 patients with mixed connective tissue disease (MCTD), 31 patients with systemic lupus erythematosus (SLE) and 51 controls. The fertility rates in MCTD and SLE were unaltered by disease; however, parity was decreased and fetal wastage was increased both before and even more so after onset. It is our observation that pregnancy carries the same risks in MCTD as it does in SLE.


Evolution and development of the tetrapod auditory system: an organ of Corti-centric perspective.
The tetrapod auditory system transmits sound through the outer and middle ear to the organ of Corti or other sound pressure receivers of the inner ear where specialized hair cells translate vibrations of the basilar membrane into electrical potential changes that are conducted by the spiral ganglion neurons to the auditory nuclei. In other systems, notably the vertebrate limb, a detailed connection between the evolutionary variations in adaptive morphology and the underlying alterations in the genetic basis of development has been partially elucidated. In this review, we attempt to correlate evolutionary and partially characterized molecular data into a cohesive perspective of the evolution of the mammalian organ of Corti out of the tetrapod basilar papilla. We propose a stepwise, molecularly partially characterized transformation of the ancestral, vestibular developmental program of the vertebrate ear. This review provides a framework to decipher both discrete steps in development and the evolution of unique functional adaptations of the auditory system. The combined analysis of evolution and development establishes a powerful cross-correlation where conclusions derived from either approach become more meaningful in a larger context which is not possible through exclusively evolution or development centered perspectives. Selection may explain the survival of the fittest auditory system, but only developmental genetics can explain the arrival of the fittest auditory system. [Modified after (Wagner 2011)].


Determination of the Maillard product oxalic acidmonolysinylamide (OMA) in heated milk products by ELISA.
Oxalic acid monolysinylamide (OMA), a Maillard product which had initially been identified as a reaction product of L-ascorbic acid, was formed, dependent on the reaction conditions, also from other carbohydrate sources. At elevated temperatures and in the presence of oxygen, the reaction of lactose with proteins resulted in the formation of relatively high amounts of OMA. Using a polyclonal antibody, which bound with high specificity and affinity to OMA-modified proteins, a competitive enzyme linked immunosorbent assay (ELISA) was developed to measure OMA formation in heat-treated milk products. The assay performance was characterized for OMA-modified beta-lactoglobulin diluted in buffer or pasteurized milk. For the latter, the least detectable dose was determined as 1.4 ng/ml with a linear range for quantification between 2 ng/ml and 200 ng/ml. For some samples intra- and interassay variation were determined. The ELISA was used to measure OMA-formation in heated milk and commercially available infant formula.


Left Atrial Appendage Exclusion in Atrial Fibrillation Radiofrequency Ablation during Mitral Valve Surgery: A Single-Center Experience.
Atrial fibrillation surgical radiofrequency ablation (AFSA) during mitral valve surgery (MVS) has almost completely superseded the Cox-Maze procedure for the treatment of atrial fibrillation. We retrospectively analyzed 100 patients who underwent MVS + AFSA in our institution from January 2008 to June 2017. We compared the effectiveness of AFSA in patients who underwent LAA exclusion to those who did not. Moreover, we analyzed the role of preoperative AF duration (≤ or >1 year) and medial-lateral left atrial dimensions (ML-LAD) (≤ or >6 cm). The efficacy endpoint was freedom from AF at discharge and at 2-year follow-up. The safety endpoints were need of a permanent pacemaker (PMK), surgical re-exploration, occurrence of stroke, and left circumflex artery or esophageal lesions. Overall, the rate of AF freedom was 69% at discharge and 80% at 2-year follow-up. LAA exclusion did not influence AF freedom at 2-year follow-up, and 84.6% of patients who underwent LAA exclusion were in the sinus rythm (SR) at 2 year compared to 75% of those who did not receive LAA exclusion free from AF as well (p=0.230). AF duration ≤1 or >1 year did not influence sinus rhythm (SR) maintenance (85.7% vs. 75.8%; p=0.224), and in these two groups, LAA exclusion did not change the efficacy of AFSA. ML-LAD ≤ 6 cm was associated with better results in terms of SR maintenance. A statistically significant association between LAA exclusion and SR maintenance at 2-year follow-up (p=0.017) was found among patients with ML-LAD ≤ 6 cm. Complications included 7 cases of PMK implantation, 2 cases of surgical re-exploration, and 1 case of stroke. No circumflex artery or esophageal lesions occurred after surgical procedures. In our experience, AFSA during isolated MVS resulted in good outcomes in terms of SR maintenance and incidence of complications. AF duration ≤ 1 year did not influence results, while patients with ML-LAD ≤ 6 cm had significantly better results regarding SR at follow-up. In patients with ML-LAD ≤ 6 cm, LAA exclusion significantly increased the success rate of SR maintenance at 2-year follow-up.


[Alpha-2-globulins of blood in experimental burns].
Complex physico-chemical procedures for separation and analysis of protein composition during the separation steps showed that alpha-2-globulins from blood serum of rats with thermic burns differed from the globulins of normal blood serum either in absolute and relative increase in their content or qualitative features: increase in electrophoretic mobility, conformational changes leading to increase in compactness at the slightly acid pH, increase in affinity to anion exchange resin, atypical reactions with a precipitant (rivanol), increase in the rate of dissociation into subunits. The major part of alpha-2-globulins in burns constituted alpha-2-lipoprotein and alpha-2-macroglobulin which were separated with minimal cross-contamination.


Urinary pH Levels are Strongly Associated with Bladder Recurrence After Nephroureterectomy in Upper Tract Urothelial Carcinoma Patients with a Smoking History.
Aromatic amines, well-known bladder carcinogens, derived from cigarette smoke are activated by acidic urine. We herein determined whether urinary pH levels are associated with bladder recurrence in upper tract urothelial carcinoma patients with a positive smoking history. A total of 256 upper tract urothelial carcinoma patients who were surgically treated at our institution between 1990 and 2013 were included. Urinary pH levels were defined as the median of at least two consecutive measurements within 1 month of surgery. Ninety-six patients (37.5 %) had pH <5.5 and 160 (62.5 %) had pH ≥5.5, and urinary pH levels were identified as one of the significant predictors for bladder recurrence in univariate but not multivariate Cox regression analysis in overall. In patients with a positive smoking history among those without a history of bladder tumor (N = 110), the 5-year bladder recurrence-free survival rate was 52.5 % in patients with pH ≥5.5, which was significantly higher than that in those with pH <5.5 (25.9 %, p = 0.032). In the multivariate analysis, urinary pH <5.5 (p = 0.022, HR; 1.86) was independently associated with bladder recurrence. No significant difference for bladder recurrence was observed between these two groups in patients with no smoking history among them. Urinary pH <5.5 is associated with an increased risk of bladder recurrence in upper tract urothelial carcinoma patients with a positive smoking history among those without a history of bladder tumor. Modifications to pH for urine alkalization may prevent bladder recurrence.


Nothing Personal: What Psychologists Get Wrong about Identity.
What makes someone the same person over time? There is a growing body of research exploring how people ordinarily think about personal identity. We argue here that many of the experiments in this domain fail to properly distinguish similarity from personal identity, and therefore certain conclusions regarding commonsense intuitions about identity are not supported.


Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization.
Chronic hypoxia is associated with both blunted agonist-induced and myogenic vascular reactivity and is possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the mechanism of endogenous CO-meditated vasodilation remains unclear. Isolated pressurized mesenteric arterioles from chronically hypoxic rats were administered the HO substrate heme-l-lysinate (HLL) in the presence or absence of iberiotoxin, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), ryanodine, or free radical spin traps (N-tert-butyl-alpha-phenylnitrone and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL administration on vascular smooth muscle (VSM) membrane potential were assessed in superior mesenteric artery strips in the presence and absence of zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL administration produced a dose-dependent vasodilatory response that was nearly eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor ryanodine altered the vasodilatory response to HLL, although ODQ abolished the vasodilatory response to S-nitroso-N-acetyl-penicillamine. HLL administration produced a zinc protoporphyrin IX- and iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory response to endogenous CO involves cGMP-independent activation of VSM large-conductance Ca2+-activated K+ channels and does not likely involve the formation of Ca2+ sparks emanating from ryanodine-sensitive stores.


DO THE RADIOLOGICAL CRITERIA WITH THE USE OF RISK FACTORS IMPACT THE FORECASTING OF ABDOMINAL NEUROBLASTIC TUMOR RESECTION IN CHILDREN?
The treatment of neuroblastoma is dependent on exquisite staging; is performed postoperatively and is dependent on the surgeon's expertise. The use of risk factors through imaging on diagnosis appears as predictive of resectability, complications and homogeneity in staging. To evaluate the traditional resectability criteria with the risk factors for resectability, through the radiological images, in two moments: on diagnosis and in pre-surgical phase. Were analyzed the resectability, surgical complications and relapse rate. Retrospective study of 27 children with abdominal and pelvic neuroblastoma stage 3 and 4, with tomography and/or resonance on the diagnosis and pre-surgical, identifying the presence of risk factors. The mean age of the children was 2.5 years at diagnosis, where 55.6% were older than 18 months, 51.9% were girls and 66.7% were in stage 4. There was concordance on resectability of the tumor by both methods (INSS and IDRFs) at both moments of the evaluation, at diagnosis (p=0.007) and post-chemotherapy (p=0.019); In this way, all resectable patients by IDRFs in the post-chemotherapy had complete resection, and the unresectable ones, 87.5% incomplete. There was remission in 77.8%, 18.5% relapsed and 33.3% died. Resectability was similar in both methods at both pre-surgical and preoperative chemotherapy; preoperative chemotherapy increased resectability and decreased number of risk factors, where the presence of at least one IDRF was associated with incomplete resections and surgical complications; relapses were irrelevant.


Rapid myocardial perfusion imaging with 99Tcm-teboroxime and a three-headed SPECT system: a comparative study with 201Tl.
99Tcm-teboroxime is a new myocardial perfusion agent with a high first pass extraction and rapid myocardial washout. The usefulness of 99Tcm-teboroxime was evaluated for detection of myocardial ischaemia using a three-headed single photon emission tomography (SPECT) system which allows for rapid data acquisition. The subjects consisted of 14 patients, including seven with ischaemic heart disease, four with cardiomyopathy and three others. After the 99Tcm-teboroxime injection, dynamic data was collected every minute for 15 min with continuous rotation. High-quality SPECT images could be obtained by reconstructing the serial scans from 2 to 8 min. The sensitivity, specificity and accuracy of the 99Tcm-teboroxime study for the detection of the ischaemic region were not significantly different from those of the 201Tl study. Myocardial clearance was slow in the ischaemic lesion and in the myocardium of cardiomyopathy patients, while the coronary angiograms did not show any abnormality. These results therefore indicate that the rapid SPECT imaging and myocardial clearance of 99Tcm-teboroxime obtained with a three-headed SPECT system were useful for the detection of myocardial ischaemia.


Outbreak of bullous impetigo caused by Staphylococcus aureus strains of phage type 3C/71 in a maternity ward linked to nasal carriage of a healthcare worker.
We describe an outbreak of bullous impetigo (BI) that occurred in a maternity unit and show phenotypic and genotypic properties and relatedness of isolated Staphylococcus aureus strains. Clinical material was obtained from 11 affected neonates. Additionally, nasal swabs from 67 healthy care workers (HCWs) as well as 107 environmental swabs were investigated. All isolates were screened for exfoliative toxin genes (eta, etb), antibiotic susceptibility and phage typed. Chromosomal DNA was genotyped by MLVF method and PCR/RFLP of coagulase gene were tested. Affected neonates were infected by two clusters of eta-positive S. aureus of phage type 3C/71: (1) MLVF type A isolates resistant only to penicillin, and (2) MLVF type B isolates resistant to penicillin and erythromycin/clindamycin. All isolates were susceptible to methicillin. We found 19 of 67 HCWs to be S. aureus nasal carriers. Two nasal isolates from HCWs were related to the outbreak on the basis of phage typing, PCR detection of eta/etb genes, antibiotyping and genotyping. Additionally, environmental swabs from the maternity unit revealed a 3C/71 S. aureus in the mattress of a baby bed. This is the first documented case of an outbreak of BI caused by phage type 3C/71 eta-positive strain of S. aureus.


Density-dependent liquid nitromethane decomposition: molecular dynamics simulations based on ReaxFF.
The decomposition mechanism of hot liquid nitromethane at various compressions was studied using reactive force field (ReaxFF) molecular dynamics simulations. A competition between two different initial thermal decomposition schemes is observed, depending on compression. At low densities, unimolecular C-N bond cleavage is the dominant route, producing CH(3) and NO(2) fragments. As density and pressure rise approaching the Chapman-Jouget detonation conditions (∼30% compression, >2500 K) the dominant mechanism switches to the formation of the CH(3)NO fragment via H-transfer and/or N-O bond rupture. The change in the decomposition mechanism of hot liquid NM leads to a different kinetic and energetic behavior, as well as products distribution. The calculated density dependence of the enthalpy change correlates with the change in initial decomposition reaction mechanism. It can be used as a convenient and useful global parameter for the detection of reaction dynamics. Atomic averaged local diffusion coefficients are shown to be sensitive to the reactions dynamics, and can be used to distinguish between time periods where chemical reactions occur and diffusion-dominated, nonreactive time periods.


Expression of recombinant aequorin as an intracellular calcium reporter in the phytopathogenic fungus Phyllosticta ampelicida.
Conidia of Phyllosticta ampelicida germinate only after they have made contact with a substratum. Previous work has shown that external free calcium must be available to the spore for germination to be initiated. Transgenic strains of P. ampelicida expressing apo-aequorin, a calcium-sensitive luminescent protein, were developed to monitor cytoplasmic free Ca(2+) ([Ca(2+)]c). Transformants were verified by PCR and Southern hybridization. Apo-aequorin production was quantified for each of 21 transformants. The transformant that emitted the most light per unit of protein was found to contain 0.59 mg apo-aequorin/g total protein. To ascertain the feasibility of aequorin-based [Ca(2+)]c quantification, [Ca(2+)]c changes were measured in mycelia during various physiologically perturbing treatments: exposure to high concentrations of external Ca(2+), hypoosmotic shock, and mechanical perturbation. This is the first report of a plant pathogenic fungus for which aequorin-based Ca(2+) measurement protocols have been developed.


First Report of Leaf Spot of Spinach Caused by Pleospora betae in Spain.
The production of spinach (Spinacia oleracea L.) in Spain has increased 50% since 2009, mainly due to the commercialization of fresh-cut spinach leaves packaged in modified atmosphere containers. In October 2012, light brown leaf spots 1 to 2 cm in diameter with dark concentric rings were observed in a commercial spinach production area in Valencia Province, Spain. The initial outbreak comprised an area of about 3 ha with a 20% disease incidence. Symptomatic leaves from spinach cv. Apollo were collected in the affected area and were surface disinfected with 0.5% NaOCl for 2 min. Small fragments from lesions were placed onto potato dextrose agar (PDA) amended with 0.5 g streptomycin sulfate/liter. Fungal colonies developed after 3 days of incubation at 23°C from about 90% of the infected tissues plated. Isolates were transferred to oatmeal agar (OA) (1) and water agar (WA) amended with autoclaved pea seeds (2). Plates were incubated for 30 days at 24°C with 13 h of fluorescent light and 11 h of dark for morphological examination. Colonies were olivaceous grey in OA and pycnidia developed in WA were globose to subglobose, olivaceous black, and 100 to 200 μm in diameter. Conidia were globose to ellipsoidal, hyaline, aseptate, and 3.8 to 7.7 × 2.4 to 3.9 μm. Swollen cells were observed. Isolates showed a positive reaction to NaOH (1). Partial 18S, ITS1, 5.8S, ITS2, and partial 28S ribosomal RNA (rRNA) regions were amplified using the primers ITS1 and ITS4 (4) and sequenced from DNA extracted from the isolate designated as IVIA-V004 (GenBank Accession No. KF321782). The sequence had 100% identity (e-value 0.0) with that of Pleospora betae (Berl.) Nevod. (syn. Phoma betae A.B. Frank) representative strain CBS 523.66 (1). Pathogenicity tests were performed twice by inoculating 4-month-old plants of spinach cv. Apollo, table beet (Beta vulgaris L.) cv. Detroit, and Swiss chard (B. vulgaris subsp. cicla) cv. Verde de Penca Blanca. Plants were inoculated by spraying a conidial suspension of isolate IVIA-V004 (10 ml/plant, 105 conidia/ml water) using a manual pressure sprayer. Plants were immediately covered with black plastic bags and incubated in a growth chamber at 23°C. In each experiment, four plants of each host were inoculated with the fungus and four additional plants sprayed with sterile distilled water were used as controls. Plastic bags were removed after 48 h and leaf spots similar to those observed in affected spinach plants in the field were visible on all spinach, table beets, and Swiss chard plants 3 to 5 days after inoculation. No symptoms were observed on control plants. Fungal colonies morphologically identified as P. betae were re-isolated from leaf lesions on inoculated plants, but not from asymptomatic leaves of control plants. To our knowledge, this is the first report of leaf spot caused by P. betae on spinach in Spain, where it was previously described affecting sugar beet (3). The disease reduces the quality of spinach leaves and proper control measures should be implemented. References: (1) G. H. Boerema et al. Phoma Identification Manual, Differentiation of Specific and Infra-Specific Taxa in Culture. CABI Publishing, Wallingford, UK, 2004. (2) O. D. Dhingra and J. B. Sinclair. Basic Plant Pathology Methods, 2nd ed. CRC Press, Boca Raton, FL, 1995. (3) P. Melgarejo et al. Patógenos de Plantas Descritos en España. MARM-SEF, Madrid, 2010. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990.


Prevalence and Persistence of Multidrug-Resistant Yersinia enterocolitica 4/O:3 in Tonsils of Slaughter Pigs from Different Housing Systems in Croatia.
Yersinia enterocolitica is one of the priority biological hazards in pork inspection. Persistence of the pathogen, including strains resistant to antimicrobials, should be evaluated in pigs from different housing systems for risk ranking of farms. In this 2019 study, tonsils were collected from 234 pigs, of which 69 (29.5%) were fattened on 3 big integrated farms, 130 (55.5%) on 10 medium-sized farms, and 35 (15%) on 13 small family farms. In addition, 92 pork cuts and minced meat samples from the same farms were tested for the presence of Y. enterocolitica using the culture method. Phenotypic and genetic characteristics of the isolates were compared with previously collected isolates from 2014. The overall prevalence of Y. enterocolitica in pig tonsils was 43% [95% CI 36.7−49.7]. In pigs from big integrated, medium-sized, and small family farms, the prevalence was 29%, 52%, and 40%, respectively. All retail samples of portioned and minced pork tested negative for pathogenic Y. enterocolitica, likely due to high hygienic standards in slaughterhouses/cutting meat or low sensitivity of culture methods in these matrices. The highest recovery rate of the pathogen from tonsils was found when alkali-treated PSB and CIN agar were combined. The biosecurity category of integrated and medium farms did not affect the differences in prevalence of Y. enterocolitica (p > 0.05), in contrast to family farms. Pathogenic ail-positive Y. enterocolitica biotype 4 serotype O:3 persisted in the tonsils of pigs regardless of the type of farm, slaughterhouse, and year of isolation 2014 and 2019. PFGE typing revealed the high genetic concordance (80.6 to 100%) of all the Y. enterocolitica 4/O:3 isolates. A statistically significant higher prevalence of multidrug-resistant Y. enterocolitica 4/O:3 isolates was detected in the tonsils of pigs from big integrated farms compared to the other farm types (p < 0.05), with predominant and increasing resistance to nalidixic acid, chloramphenicol, and streptomycin. This study demonstrated multidrug resistance of the pathogen in pigs likely due to more antimicrobial pressure on big farms, with intriguing resistance to some clinically relevant antimicrobials used in the treatment of yersiniosis in humans.


Growth factor modulation of p53-mediated growth arrest versus apoptosis.
Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of interlekin-3 (IL-3) induces G1 arrest, and irradiation in the absence of IL-3 results in rapid apoptotic cell death. Both of these end points are dependent on p53. Transient removal of IL-3 at the time of irradiation results in decreased clonogenic survival of irradiated cells. The removal of IL-3 results in a failure of the irradiated cells to arrest at the G1 checkpoint, despite induction of p53 and p21WAF1/CIP1, and then the cells enter S-phase where they undergo apoptosis. There are no cytokine-related changes in Bcl-2, Bax, or Bcl-x protein levels that could account for the modulation of G1 arrest versus apoptosis by growth factors. In contrast, rapid p53-independent alterations of basal levels of gadd45 and p21WAF1/CIP1 expression are linked to IL-3 withdrawal, suggesting a potential mechanism for this modulation. Constitutive activation of cytokine-like pathways with induced expression of v-Src or activated c-Raf inhibits the radiation-induced apoptosis and the alterations in p21WAF1/CIP1 and gadd45 expression. These observations suggest additional molecular mechanisms that can contribute to the development of radioresistance and resistance to apoptosis during tumorigenesis and provide an explanation for the observed lack of p53 mutations in some tumor types. In addition, these data suggest that oncogenic changes occurring during multistep tumorigenesis could be classified as those that either enhance or decrease apoptosis tendencies.


Personalized Medicine in Ovarian Cancer: A Perspective From Mexico.
Ovarian cancer (OC) represents a serious health problem worldwide. In Mexico, most OC patients are detected at late stages, consequently making OC one of the leading causes of death in women after reaching puberty. Personalized medicine (PM) provides an individualized therapeutic opportunity for treating each patient relying on "omic" tools to match the correct drug with the specific pathogenic genomic signature. PM can help predict the best therapeutic option for each affected woman suffering from OC. In recent years, Mexico has made contributions to the PM of OC; however, it still has a long way to go for its full implementation in the country's health system.


[Diagnosis and treatment of giant air cysts of the lung].
Giant air cysts of the lung were found in 6 of 180 patients admitted to the hospital with spontaneous pneumothorax. The preoperative diagnosis was established in all the patients on the basis of their past history, clinical course, X-ray examination and puncture of the pleural cavity. The operative treatment of cysts of the lung is recommended. All the 6 patients were operated upon with good results (in 3 patients--lobectomy, cysts were removed in 3 patients).


An increase in fetal plasma cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes.
The role of steroid hormones in the control of human parturition has been a subject of debate. Activation of the fetal hypothalamic-pituitary-adrenal axis leading to an increase in plasma cortisol is followed by the onset of parturition in sheep. In contrast, androgens, specifically, dehydroepiandrosterone sulfate, have been implicated in the control of parturition in nonhuman primates. The purpose of this study was to determine the relationship between human fetal plasma cortisol and dehydroepiandrosterone sulfate and the onset of preterm labor in patients with preterm premature rupture of the membranes. Fetal blood sampling was performed in 51 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for aerobic and anaerobic bacteria and mycoplasmas. Corticosteroids had not been administered before fetal blood sampling. Cortisol and dehydroepiandrosterone sulfate were measured with sensitive and specific immunoassays. Analysis was conducted with nonparametric statistics and survival analysis. (1) Patients who went into spontaneous labor and delivered within 7 days of cordocentesis had a significantly higher median level of fetal plasma cortisol but not of dehydroepiandrosterone sulfate than those delivered after 7 days (for fetal plasma cortisol: median 8.35 [4.7 to 12.4] micrograms/dL vs median 4.75 [3.0 to 10.4] micrograms/dL, P <.0001; for fetal plasma dehydroepiandrosterone sulfate: median 154.4 [8.6 to 333.8] micrograms/dL vs median 194.6 [96.7 to 402.5] micrograms/dL, P =.09). (2) The cordocentesis-to-delivery interval was significantly shorter in patients with a fetal plasma cortisol value of >/=7 micrograms/dL (derived by receiver-operating characteristic curve analysis) than in those with fetal cortisol <7 micrograms/dL (median 49 [4 to 1849] hours vs median 325 [11 to 2590] hours, P <.001). (3) Fetal plasma cortisol, but not maternal cortisol, was an independent predictor of the duration of pregnancy after we adjusted for gestational age and the results of amniotic fluid culture (hazards ratio 2.9, P <.05). (4) There was a significant correlation between fetal plasma cortisol and fetal plasma interleukin-6 (r = 0.3, P <.05). (5) A strong relationship was found between the fetal plasma cortisol/dehydroepiandrosterone sulfate ratio and the interval to delivery (P <.005). An elevation in fetal plasma cortisol but not dehydroepiandrosterone sulfate was followed by the onset of spontaneous preterm labor in patients with preterm premature rupture of the membranes.


Bird-inspired dynamic grasping and perching in arboreal environments.
Birds take off and land on a wide range of complex surfaces. In contrast, current robots are limited in their ability to dynamically grasp irregular objects. Leveraging recent findings on how birds take off, land, and grasp, we developed a biomimetic robot that can dynamically perch on complex surfaces and grasp irregular objects. To accommodate high-speed collisions, the robot's two legs passively transform impact energy into grasp force, while the underactuated grasping mechanism wraps around irregularly shaped objects in less than 50 milliseconds. To determine the range of hardware design, kinematic, behavior, and perch parameters that are sufficient for perching success, we launched the robot at tree branches. The results corroborate our mathematical model, which shows that larger isometrically scaled animals and robots must accommodate disproportionately larger angular momenta, relative to their mass, to achieve similar landing performance. We find that closed-loop balance control serves an important role in maximizing the range of parameters sufficient for perching. The performance of the robot's biomimetic features attests to the functionality of their avian counterparts, and the robot enables us to study aspects of bird legs in ways that are infeasible in vivo. Our data show that pronounced differences in modern avian toe arrangements do not yield large changes in perching performance, suggesting that arboreal perching does not represent a strong selection pressure among common bird toe topographies. These findings advance our understanding of the avian perching apparatus and highlight design concepts that enable robots to perch on natural surfaces for environmental monitoring.


The cerrado of Goiás in the literature of Bernardo Élis, from a viewpoint of environmental history.
This article analyzes the representations of nature in the literature of Bernardo Élis based on the theoretical and methodological assumptions of environmental history. Élis was part of a group of intellectuals whose literature presented the living conditions in the frontier of Goiás and the human relationships occurring in these landscapes. In these scrublands, the dramas of their characters are mixed with the physical environment of the cerrado region in a realistic narrative denouncing the living conditions in this isolated frontier area. In their dialog with literature, the fundamentals of this field of historiographic research can be adopted as analytical instruments, combined with concepts related to the integration between society and nature, such as the frontier and wilderness.


Electrically tunable Yb-doped fiber laser based on a liquid crystal photonic bandgap fiber device.
We demonstrate electrical tunability of a fiber laser using a liquid crystal photonic bandgap fiber. Tuning of the laser is achieved by combining the wavelength filtering effect of a tunable liquid crystal photonic bandgap fiber device with an ytterbium-doped photonic crystal fiber. We fabricate an all-spliced laser cavity based on the liquid crystal photonic bandgap fiber mounted on a silicon assembly, a pump/signal combiner with single-mode signal feed-through and an ytterbium-doped photonic crystal fiber. The laser cavity produces a single-mode output and is tuned in the range 1040-1065 nm by applying an electric field to the silicon assembly.


Dysregulation of serum prolactin links the hypothalamus with female nociceptors to promote migraine.
Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms. A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats-Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats-Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice. Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.


New pimarane diterpenes and other antimycobacterial metabolites from Anisochilus verticillatus.
Phytochemical investigation of the acetone extract of the aerial parts of Anisochilus verticillatus afforded a new 8,9-secopimarane diterpene (1), two new isopimarane diterpenes (2, 3) and the known ursolic acid (4), α-amyrin (5), β-amyrin (6), stigmast-5-en-3-one (7) and hydroxychavicol (8). Structures of the new compounds were elucidated with the help of 1D and 2D nuclear magnetic resonance spectroscopic data, and single crystal X-ray crystallography of compound 3. Compounds 2 and 8 inhibited Mycobacterium tuberculosis H37Ra with an IC50 of 11.3 (IC90 of 20.0 μg/mL) and 12.5 μg/mL, respectively. Correspondingly, molecular docking studies with Extra Precision Glide revealed a correlation between score and biological activity for these compounds to describe the molecular basis for the most significant SAR results.


VESTIBULAR NUCLEI: ACTIVITY OF SINGLE NEURONS DURING NATURAL SLEEP AND WAKEFULNESS.
The rate of spontaneous discharge of second-order vestibular neurons is higher during wakefulness than during drowsiness and synchronized sleep. The activity of units recorded from the lateral (and superior) vestibular nucleus remains unmodified or is slightly increased during desynchronized sleep, in spite of the complete disappearance of the postural tonus. Units in medial and descending vestibular nuclei show bursts of rapid discharge associated with the eye movements characteristic of desynchronized sleep.


[Anesthesia of the cervical plexus in surgical interventions on the neck and its organs].
The author proposes a new method for anesthesia of neck plexus, which is seen to be more safe, has reliable points of reference, and is administered by "one-touch" injection. The article gives a description of this method, results of its clinical application, indications and counter-indications. The anesthesia of neck plexus was applied on 71 patients. No complications were marked. This method makes it possible to produce an adequate anesthesia in vast operations on neck and its organs.


Ultrasound-guided dry needling of masticatory muscles in trigeminal neuralgia - A case series of 35 patients.
Trigeminal neuralgia (TGN) is considered a sensory neuropathy. However, reports of pain on chewing/speaking suggest a masticatory myofascial involvement. To examine the effect of ultrasound-guided dry needling (USGDN), which deactivates myofascial trigger points in masticatory, neck, and facial muscles on TGN symptoms. Charts of 35 patients treated for TGN were retrospectively reviewed. Treatment was USGDN alone or combined with trigeminal ganglion/mandibular nerve pulsed radiofrequency (PRF), followed by yoga mudras to stretch masticatory and facial muscles. Patients were followed for 1-8 years. Outcome parameters were reduction of medications with reduction in neuralgic attack frequency and Numeric Rating Scale (NRS) score. 23 patients (65.7%) received USGDN alone, 12 patients (34.3%) received PRF treatment before USGDN. A significant reduction in the mean (SD) NRS (5.7 [1.2] vs 8.8 [1.6]; P < .001) and neuralgic attack frequency (47 [27] vs 118 [70] attacks/day; P < .001) was seen after PRF compared with baseline, respectively. Following USGDN, the mean (SD) NRS further decreased significantly to 1.0 (0.9) (P < .001). USGDN alone produced a similar improvement in the NRS (8.9 [1.5] at baseline reduced to 0.6 [0.7] post-USGDN; P < .001). Patients in both groups reported a cessation in neuralgic attacks after USGDN. Post-USGDN, 18/27 patients completely discontinued medication, with the mean (SD) carbamazepine dose significantly reducing from 716.7 (260.9) mg/day at baseline to 113.0 (250.2) mg/day post-USGDN (P < .001). Decisive relief of TGN by USGDN suggests neuromyalgia involving masticatory muscles. Prospective, controlled studies could confirm these findings.


Thermodynamic susceptibility as a measure of cooperative behavior in social dilemmas.
The emergence of cooperation in the thermodynamic limit of social dilemmas is an emerging field of research. While numerical approaches (using replicator dynamics) are dime a dozen, analytical approaches are rare. A particularly useful analytical approach is to utilize a mapping between the spin-1/2 Ising model in 1D and the social dilemma game and calculate the magnetization, which is the net difference between the fraction of cooperators and defectors in a social dilemma. In this paper, we look at the susceptibility, which probes the net change in the fraction of players adopting a certain strategy, for both classical and quantum social dilemmas. The reason being, in statistical mechanics problems, the thermodynamic susceptibility as compared to magnetization is a more sensitive probe for microscopic behavior, e.g., observing small changes in a population adopting a certain strategy. In this paper, we find the thermodynamic susceptibility for reward, sucker's payoff, and temptation in classical Prisoner's Dilemma to be positive, implying that the turnover from defect to cooperate is greater than vice versa, although the Nash equilibrium for the two-player game is to defect. In the classical hawk-dove game, the thermodynamic susceptibility for resource suggests that the number of players switching to hawk from dove strategy is dominant. Entanglement in Quantum Prisoner's Dilemma has a non-trivial role in determining the behavior of thermodynamic susceptibility. At maximal entanglement, we find that sucker's payoff and temptation increase the number of players switching to defect. In the zero-temperature limit, we find that there are two second-order phase transitions in the game, marked by a divergence in the susceptibility. This behavior is similar to that seen in type-II superconductors wherein also two second-order phase transitions are seen.


Evaluation of Patients with Vaccine Allergies Prior to mRNA-Based COVID-19 Vaccination.
During the initial rollout of coronavirus disease 2019 (COVID-19) vaccination in Singapore, the Ministry of Health (MOH) issued a recommendation that patients with a history of any previous vaccine allergy be referred to an allergist for further review of their suitability to proceed with mRNA-based COVID-19 vaccines. Patients fulfilling the above criterion were divided into three groups: immediate reaction (Group A), delayed reaction (Group B) and no/irrelevant reaction (Group C). They were subjected to either a skin prick test (SPT) and intradermal test (IDT) with polyethylene glycol (PEG) or polysorbate-containing products; direct injection with the Pfizer BNT162b2 vaccine in the allergy clinic; or injection at community vaccination centres, respectively. Groups A and B were also invited to complete a questionnaire survey on post-vaccination reactions, and blood sampling pre-vaccination and 1 h after the first dose of the BNT162b2 vaccine to measure immunoglobulin (Ig) G, IgM and IgE antibodies to the Pfizer BNT162b2 vaccine via ELISA assays immobilised with the BNT162b2 vaccine, as well as levels of allergic cytokines interleukin (IL)-4 and IL-33, complement C5a and the endothelial activation marker intercellular adhesion molecule-1 (ICAM-1). Groups A and B comprised 62 (20.5%) patients each. In Group A, two subjects (3.2%) with equivocal IDT results tolerated both doses of the BNT162b2 vaccine without major allergic reactions. The remaining 60 (96.8%) in Group A and 62 (100%) in Group B completed both doses of BNT162b2 vaccination without major adverse reactions. Among the 99 who completed the questionnaire survey, 13 (13%) patients reported mild allergic reactions after the first dose of the vaccine. Immunoglobulin (Ig) G and M antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine were detected in 67 subjects prior to vaccination. The presence of anti-Pfizer BNT162b2 IgG and IgM prior to vaccination did not result in major allergic reactions nor increases in Th2-related cytokines (IL-4, IL-33), complement activation products (C5a) or endothelial activation (ICAM-1). The majority of those with suspected reactions to non-COVID-19 polysorbate-containing vaccines tolerated the BNT162b2 vaccine. Excipient skin tests for PEG and polysorbate prior to vaccination are unnecessary.


The effect of posterior fossa decompression surgery on brainstem and cervical spinal cord dimensions in adults with Chiari malformation type 1.
Posterior fossa decompression (PFD) surgery creates more space at the skull base, reduces the resistance to the cerebrospinal fluid (CSF) motion, and alters craniocervical biomechanics. In this paper, we retrospectively examined the changes in neural tissue dimensions following PFD surgery on Chiari malformation type 1 adults (CMI). Measurements were performed on T2-weighted brain magnetic resonance images acquired before and four months after surgery. Measurements were conducted for neural tissue volume and spinal cord/brainstem width at four different locations; two width measurements were made on the brainstem and two on the spinal cord in the midsagittal plane. Cerebellar tonsillar position (CTP) was also measured before and after surgery. Twenty-five adult patients, with a mean age of 38.9 ± 8.8 years, were included in the study. The cervical cord volume increased by an average of 2.3±3.3% (p=0.002). The width at the pontomedullary junction increased by 2.2±3.5% (p<0.01), while the width 10 mm caudal to this junction increased by 4.2±3.9% (p<0.0001). The spinal cord width at the base of C2 and C3 did not significantly change after surgery. The cerebellar tonsillar position decreased by 60±37% (p<0.0001) after surgery, but no correlation was found between CTP change and dimension change. The brainstem width and cervical cord volume showed a modest increase after PFD surgery, although standard deviations were large. A reduction in compression after PFD surgery may allow for an increase in neural tissue dimension. However, clinical relevance is unclear and should be assessed in future studies with high-resolution imaging.


Ini1/hSNF5 is dispensable for retrovirus-induced cytoplasmic accumulation of PML and does not interfere with integration.
Retroviral infection triggers the cytoplasmic translocation of two Crm1-dependent shuttle factors, namely the Ini1 (integrase interactor 1, hSNF5) and the promyelocytic leukemia (PML) protein. Blocking nuclear export of shuttle factors by leptomycin B increases the efficiency of retroviral integration, suggesting that some may mediate antiviral activity. While PML was shown to counteract proviral establishment, it remained unclear whether Ini1, a protein implicated in various processes during human immunodeficiency virus replication, has the same potential. Employing RNA interference-mediated knock-down of Ini1, we show here that the simultaneous accumulation of both proteins in the cytoplasm likely reflects two non-interdependent phenomena. Furthermore, Ini1 does not interfere with retroviral integration, as cells lacking Ini1 show no increased infection susceptibility.


Preparing for prescriptive privileges: a CNS-physician collaborative model. Expanding the scope of the psychiatric-mental health clinical nurse specialist.
Advanced practice nurses throughout the United States have been successful in securing prescriptive privileges and the related accountability for independent practice. As their authority for the medication management of patients increases, opportunities for practice in expanded nursing roles also increase. When the clinical nurse specialist (CNS) is able to undertake medication management of patients in addition to providing specialized nursing care, continuity is enhanced and cost is reduced. Assuring that the CNS is prepared to provide comprehensive patient services and has the competence to efficiently assess the need for medication, prescribe specific drugs, implement patient teaching, and monitor patients' responses to the medication regimen are key factors if this extended role is to be successful. This article focuses on the CNS in psychiatric mental health nursing. It outlines a collaborative CNS-physician model that addresses the challenges of developing the necessary knowledge and skills to manage patients' medication.


[Breast cancer in women with prior malignant tumors].
Indices have been studied for a relative risk of development of subsequent metachronic breast cancer (BC) in 15627 sick female subjects presenting with different localizations of primary malignant tumours. The risk for development of BC in those women presenting with cancer of chief localizations exceeds the populational morbidity probability up to 30-fold. It is the female patients having cancer of the other mammary gland, endometrium, thyroid gland, lung, and skin who demonstrated the highest risk for development of BC. Such a polyneoplasia was recorded in 150 female subjects out of the 191 ones (78.6%). The risk for BC development in those female patients with cancer of the ovaries, cervical cancer, stomach, and melanosis cutis appeared to be insignificant. Metachronic BC in cancer patients depending on the site of the primary tumour can be a sequel of different pathogenetic mechanisms, of which hormonal-and-metabolic disturbances are the chief ones together with the genetical factor, and exposure to prior methods of antitumour chemoradiation therapy as well.


Clotrimazole/betamethasone diproprionate: a review of costs and complications in the treatment of common cutaneous fungal infections.
The use of antifungal/corticosteroid combinations as topical therapy for dermatophytoses has been criticized as being less effective, more expensive, and the cause of more adverse cutaneous reactions than antifungal monotherapy. The combination of clotrimazole and betamethasone diproprionate (Lotrisone) is a mix of an azole antifungal and a high-potency corticosteroid, and is one of the most widely prescribed of these combinations. Our objective was to describe the beneficial and deleterious effects of Lotrisone in the treatment of common cutaneous fungal infections and its relative cost-effectiveness. We did a literature review documenting clinical trial data and adverse reactions to Lotrisone and collected a cost analysis of topical antifungal prescribing data over a 2-month period from a large midwestern staff-model health maintenance organization (HMO). Lotrisone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of tinea pedis, tinea cruris, and tinea corporis in adults and children more than 12 years of age. Treatment is limited to 2 weeks in the groin area and 4 weeks on the feet. The most concerning adverse effects of Lotrisone were reported in children and included treatment failure, striae distensae, hirsuitism, and growth retardation. This combination was also reported to have decreased efficacy in clearing candidal and Trichophyton infections as compared to single-agent antifungals. Lotrisone was considerably more expensive than clotrimazole alone and was found to account for more than 50% of topical antifungal expenditures as prescribed by primary care physicians, but only 7% of topical antifungals prescribed by dermatologists. We found that Lotrisone was shown to have the potential to induce many steroid-related side effects and to be less cost effective than antifungal monotherapy. This combination should be used judiciously in the treatment of cutaneous fungal infections and may not be appropriate for use in children.


Validation of discrete time-to-event prediction models in the presence of competing risks.
Clinical prediction models play a key role in risk stratification, therapy assignment and many other fields of medical decision making. Before they can enter clinical practice, their usefulness has to be demonstrated using systematic validation. Methods to assess their predictive performance have been proposed for continuous, binary, and time-to-event outcomes, but the literature on validation methods for discrete time-to-event models with competing risks is sparse. The present paper tries to fill this gap and proposes new methodology to quantify discrimination, calibration, and prediction error (PE) for discrete time-to-event outcomes in the presence of competing risks. In our case study, the goal was to predict the risk of ventilator-associated pneumonia (VAP) attributed to Pseudomonas aeruginosa in intensive care units (ICUs). Competing events are extubation, death, and VAP due to other bacteria. The aim of this application is to validate complex prediction models developed in previous work on more recently available validation data.


Women's HIV risk reduction efforts and traditional models of health behavior: a review and critique.
This article reviews the empirical literature on women and HIV prevention and evaluates the predictive utility of prevailing models of health behavior change. The review focuses on three constructs that are central to the health belief model, protection motivation theory, and the theories of reasoned action and planned behavior: perceived vulnerability to HIV risk, outcome expectancies related to HIV preventive behaviors, and self-efficacy to reduce risk. The critical review pays particular attention to methodological and conceptual problems that may arise in applications of these models to the specific circumstances of HIV and AIDS and the specific experiences of women. Last, the ways in which these models should be adapted and expanded to adequately explain extra-individual influences on women's preventive behavior are discussed.


Family background, sociometric peer nominations, and perceived control as predictors of academic achievement.
This study investigated relationships between measures of family background, sociometric nominations, perceptions of control, and academic achievement in a sample of Turkish children. The analyses indicated that sociometric measures explained a substantial amount of variation in academic achievement. Perceptions of control emerged as significant predictors of popularity, but not of rejection measures. Parental educational background emerged as a significant predictor of perceptions of control. Both parental educational background and perceptions of control seemed to exert direct and indirect effects on children's grade point averages. The results partially support contextual explanations of academic achievement.


Carpal Tunnel Syndrome: Evaluation of the Effects of Low-Level Laser Therapy With Ultrasound Strain Imaging.
To evaluate the efficacy of low-level laser therapy on median nerve stiffness by using strain elastography in carpal tunnel syndrome (CTS). This study included 37 wrists of 34 patients with mild or moderate CTS between January 2016 and August 2016. The control group comprised 17 patients (18 wrists) with CTS who were treated with wrist splinting for 3 weeks. The low-level laser therapy group included 17 patients (19 wrists) with CTS who were treated with a combination of splinting and low-level laser therapy, which was applied 5 times per week for 3 weeks. Clinical assessment scales, including the Symptom Severity Scale (SSS) and Functional Status Score (FSS), were obtained from our database. The cross-sectional area by ultrasound and strain ratio by elastography were studied. The differences in the strain ratio, cross-sectional area, SSS, and FSS between pretreatment and posttreatment periods in the groups were compared by the paired-sample t test. The correlations between changes in the strain ratio and the cross-sectional area, SSS, and FSS were analyzed by Pearson correlation coefficients. The control group included 13 women and 4 men, and the therapy group included 14 women and 3 men. In the therapy group, the mean values of the strain ratio, cross-sectional area, SSS, and FSS decreased significantly after laser therapy (P < .001) in contrast to the control group. No significant correlation was observed between the decreasing degree of the strain ratio and the cross-sectional area, SSS, and FSS after laser therapy. The strain ratio and cross-sectional area of the median nerve decrease after low-level laser therapy. These changes may be related to the therapeutic effects of low-level laser therapy, such as nerve regeneration and improvement of the vascular supply.


Simplification of the diagnostic management of suspected deep vein thrombosis.
The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose. At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses. We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral. It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.


[Clinico-roentgenological signs of myelodysplasia in adults and their value for expert opinion].
The results of clinico-retgenological investigations of 12 patients (7 males and 5 females) aged 26 to 57 years with concealed myelodysplasy were analyzed. Initial clinical signs are considered with neurological disorders and rentgenological signs of changes in bones and joints. The latters were characterized as: 1, secondary neurodystrophic lesions; 2, congenital malformations with frequent large and several segments-long spina bifida posterior in lumbosecral region; 3, degenerative-dystrophic lesions. Labor ability of myelodysplasy patients was determined by the degree and extent of neurodystrophic disorders, skeleton anomalies, nervous dysfunction, the course of pathology with due account of the character of the job and wording conditions.


Sustained, synchronous oscillations in discharge of sustaining fibers of crayfish optic nerve.
1. The regularity of the sustaining fiber (SF) steady-state discharge increases with the intensity of a uniform field of illumination. 2. In a high levels of illumination SFs exhibit a highly periodic or rhythmically bursting steady-state discharge. 3. The period of the burst cycle is independent of the light intensity and the mean firing rate. 4. Multimodal interspike-interval histograms in which successive modes decline exponentially suggest that the discharge arises from a regular input. 5. In conditions of uniform illumination, the regular input must be common to all or several SFs since the period of the burst cycle of simultaneously monitored SFs are the same and cross-correlations indicate that the SFs burst in approximate synchrony. 6. It is proposed that the common, regular input is a network of presynaptic elements exhibiting recurrent lateral inhibition. Evidence supporting this hypothesis is that following a brief light pulse to the inhibitory surround, SFs exhibit cycles of silence and bursting, phase-locked to the stimulus but with a period equal to the steady-state burst-cycle period. 7. Furthermore, lateral inhibitory influences are common to several or all SFs as indicated by the close similarity in response time course of two SFs subjected to a common inhibitory stimulus. 8. The response of the lateral pathways to sinusoidally modulated illumination is highly selective to frequencies near the burst-repetition rate. The excitatory pathways exhibit frequency modulation or entrainment over a wide range of input frequencies. 9. The intersustaining burst cycle phase is under partial visual stimulus control (position and intensity) and the possibility of phase coding in the SF ensemble is discussed.


Surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts.
The objective of this study was to review the outcome of surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts. Twenty-seven patients (13 female, 14 male) with 4 bilateral and 23 unilateral alveolar clefts who were treated in our clinic during the period between 2002 and 2009 were included in the study. All the patients had oronasal fistulas, and all of them were closed successfully except one. Recurrence of the oronasal fistula was seen in 1 patient. Alar base was supported by onlay cortical bone in most of the patients. Eleven of the canines at the cleft site erupted after the operation in to the grafted area. Seventy-six percent (n = 16) of the 21 patients could be assigned to the successful groups 1 and 2, whereas 24% (n = 5) were assigned to the unfavorable group. There was not any insufficient result. Bone graft placed along the piriform margin and alar wings during alveolar bone grafting improves the results of nasal correction. Late grafting should be performed at least to support the alar base for nasal symmetry.


Copper deficiency decreases plasma homocysteine in rats.
The purpose of this study was to determine the effects of copper deficiency on key aspects of homocysteine metabolism that involve methionine recycling and transsulfuration. Male weanling Sprague-Dawley rats were fed AIN-93G-based diets containing <1 or approximately 6 mg Cu/kg. After 6 wk (Expt. 1) and 4 wk (Expt. 2) we found that plasma homocysteine was significantly decreased, and plasma glutathione significantly increased, in rats fed the low-Cu diet. Real-time RT-PCR was used to determine the expression of the subunits of glutamate-cysteine ligase (Gcl) in liver that catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of Gcl, was upregulated by Cu deficiency; Gclm, the modifier subunit, was not affected. Hepatic betaine-homocysteine methyltransferase (Bhmt), which catalyzes one of the two ways that homocysteine can be remethylated to methionine, was downregulated by Cu deficiency. Because Cu deficiency results in upregulation of Gclc and an increase in the biosynthesis of glutathione, it is plausible that the net flux of homocysteine through the transsulfuration pathway is increased. Furthermore, if Bhmt is downregulated, less homocysteine is available for remethylation (methionine recycling) and more is then available to irreversibly enter the transsulfuration pathway where it is lost. The net effect of increased Gclc and decreased Bhmt would be a decrease in homocysteine as a result of Cu deficiency.


Whole-Blood Mitochondrial DNA Copies Are Associated With the Prognosis of Acute Respiratory Distress Syndrome After Sepsis.
Acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs that develops primarily in response to pulmonary or systemic sepsis, resulting in a disproportionate death toll in intensive care units (ICUs). Given its role as a critical activator of the inflammatory and innate immune responses, previous studies have reported that an increase of circulating cell-free mitochondrial DNA (mtDNA) is a biomarker for fatal outcome in the ICU. Here we analyzed the association of whole-blood mtDNA (wb-mtDNA) copies with 28-day survival from sepsis and sepsis-associated ARDS. We analyzed mtDNA data from 687 peripheral whole-blood samples within 24 h of sepsis diagnosis from unrelated Spanish patients with sepsis (264 with ARDS) included in the GEN-SEP study. The wb-mtDNA copies were obtained from the array intensities of selected probes, with 100% identity with mtDNA and with the largest number of mismatches with the nuclear sequences, and normalized across the individual-probe intensities. We used Cox regression models for testing the association with 28-day survival. We observed that wb-mtDNA copies were significantly associated with 28-day survival in ARDS patients (hazard ratio = 3.65, 95% confidence interval = 1.39-9.59, p = 0.009) but not in non-ARDS patients. Our findings support that wb-mtDNA copies at sepsis diagnosis could be considered an early prognostic biomarker in sepsis-associated ARDS patients. Future studies will be needed to evaluate the mechanistic links of this observation with the pathogenesis of ARDS.


Epidemiology of chronic venous ulcers.
A metropolitan population of 238,000 in Perth, Western Australia, was screened for chronic ulceration of the leg. Patients with a chronic leg ulcer and a venous abnormality comprised 57 per cent of all patients with a chronic leg ulcer, giving a prevalence of 0.62 per 1000 population. There was an increasing prevalence with age; 90 per cent of patients were 60 years and older. This group comprised 16.7 per cent of the population, and had a prevalence of 3.3 per 1000. Although chronic venous ulcers were more common in women there was no difference in age related prevalence. In 36 per cent of patients with a venous abnormality, there was at least one other aetiological factor contributing to chronic ulceration of the leg; 96 per cent had either a history of deep venous thrombosis or a condition known to predispose to deep venous thrombosis.


Targeted next-generation sequencing of sputum for diagnosis of drug-resistant TB: results of a national survey in Democratic Republic of the Congo.
The surveillance of drug resistance among tuberculosis (TB) patients is central to preventing the spread of antimicrobial resistance. The Democratic Republic of the Congo (DR Congo) is classified by the World Health Organization (WHO) as a country with a high burden of TB and multidrug-resistant TB (MDR-TB), but there are no nationally representative data on drug resistance. In 2016-2017, a national survey of TB patients was conducted in 108 microscopy centres across all 11 provinces of the country using innovative molecular approaches. Sputum samples were collected from 1,545 new and 163 previously treated patients. These were tested by the Xpert MTB/RIF assay, followed by targeted next-generation sequencing performed directly on sputum. The prevalence of rifampicin resistance was low, at 1.8% (95% CI: 1.0-3.2) among new and 17.3% (95% CI: 11.9-24.4) among previously treated patients. Resistance to pyrazinamide, fluoroquinolones and second-line injectables was also low. The prevalence of resistance to isoniazid among rifampicin-susceptible patients was higher, at 6.6% (95% CI: 4.4-9.8) among new and 8.7% (95% : 3.2-21.2) among previously treated patients. Diagnosing and treating isoniazid-resistant patients remains a challenge, given that many will be missed by the current national diagnostic algorithm that is driven by detecting rifampicin resistance by Xpert MTB/RIF. This is the first nationwide survey incorporating targeted sequencing directly on sputum. It serves as a proof-of-concept for other settings that do yet have rapid specimen transport networks or capacity to conduct culture.


Dictyostelium discoideum contains a single-copy gene encoding a unique subtype of histone H1.
A Dictyostelium discoideum genomic library was screened using a degenerate oligodeoxyribonucleotide derived from the peptide, GPKAPT, obtained from the N terminus of purified histone H1. Two identical H1 clones were isolated. Comparative sequence data reveal a typical H1 three-domain structure with considerable homology to the globular domain of higher eukaryotic H1 histones, especially to plant H1 histones. Southern blot analysis shows that this gene is probably a single-copy gene, and suggests that any other H1 gene(s), if present, must be very different in sequence. Amino acid (aa) sequence comparison of the globular core of D. discoideum H1 to the consensus globular core reveals the absence of a 6-aa motif, GXGXXG, from D. discoideum. This motif matches the consensus for a putative nucleotide-binding loop, which is also absent in plant H1 histones like Arabidopsis thaliana, pea and wheat.


A new constructive algorithm for architectural and functional adaptation of artificial neural networks.
The generalization ability of artificial neural networks (ANNs) is greatly dependent on their architectures. Constructive algorithms provide an attractive automatic way of determining a near-optimal ANN architecture for a given problem. Several such algorithms have been proposed in the literature and shown their effectiveness. This paper presents a new constructive algorithm (NCA) in automatically determining ANN architectures. Unlike most previous studies on determining ANN architectures, NCA puts emphasis on architectural adaptation and functional adaptation in its architecture determination process. It uses a constructive approach to determine the number of hidden layers in an ANN and of neurons in each hidden layer. To achieve functional adaptation, NCA trains hidden neurons in the ANN by using different training sets that were created by employing a similar concept used in the boosting algorithm. The purpose of using different training sets is to encourage hidden neurons to learn different parts or aspects of the training data so that the ANN can learn the whole training data in a better way. In this paper, the convergence and computational issues of NCA are analytically studied. The computational complexity of NCA is found to be O(W xP(t) xtau), where W is the number of weights in the ANN, P(t) is the number of training examples, and tau is the number of training epochs. This complexity has the same order as what the backpropagation learning algorithm requires for training a fixed ANN architecture. A set of eight classification and two approximation benchmark problems was used to evaluate the performance of NCA. The experimental results show that NCA can produce ANN architectures with fewer hidden neurons and better generalization ability compared to existing constructive and nonconstructive algorithms.


The clinical educator and complexity: a review.
Complexity science perspectives have helped in examining fundamental assumptions about learning and teaching in the health professions. The implications of complexity thinking for how we understand the role and development of the clinical educator is less well articulated. This review article outlines: the key principles of complexity science; a conceptual model that situates the clinical educator in a complex system; and the implications for the individual, organisation and the system. Our conceptual model situates the clinical educator at the centre of a complex and dynamic system spanning four domains and multiple levels. The four domains are: personal (encompassing personal/professional needs and expectations); health services (health agencies and their consumers); educational (educational institutions and their health students); and societal (local community/region and government). The system also comprises: micro or individual, meso or organisational, and macro or socio-political levels. Our model highlights that clinical educators are situated within a complex system comprising different agents and connections. It emphasises that individuals, teams and organisations need to recognise and be responsive to the unpredictability, interconnectedness and evolving nature of this system. Importantly, our article also calls for an epistemological shift from faculty development to capacity building in health professions education, aimed at developing individual, team, organisational and system capabilities to work with(in) complexity. Clinical educators are situated within a complex system comprising different agents and connections.


Equating scores of the University of Pennsylvania Smell Identification Test and Sniffin' Sticks test in patients with Parkinson's disease.
Impaired olfaction is an important feature in Parkinson's disease (PD) and other neurological diseases. A variety of smell identification tests exist such as "Sniffin' Sticks" and the University of Pennsylvania Smell Identification Test (UPSIT). An important part of research is being able to replicate findings or combining studies in a meta-analysis. This is difficult if olfaction has been measured using different metrics. We present conversion methods between the: UPSIT, Sniffin' 16, and Brief-SIT (B-SIT); and Sniffin' 12 and Sniffin' 16 odour identification tests. We used two incident cohorts of patients with PD who were tested with either the Sniffin' 16 (n = 1131) or UPSIT (n = 980) and a validation dataset of 128 individuals who took both tests. We used the equipercentile and Item Response Theory (IRT) methods to equate the olfaction scales. The equipercentile conversion suggested some bias between UPSIT and Sniffin' 16 tests across the two groups. The IRT method shows very good characteristics between the true and converted Sniffin' 16 (delta mean = 0.14, median = 0) based on UPSIT. The equipercentile conversion between the Sniffin' 12 and 16 item worked well (delta mean = 0.01, median = 0). The UPSIT to B-SIT conversion showed evidence of bias but amongst PD cases worked well (mean delta = -0.08, median = 0). We have demonstrated that one can convert UPSIT to B-SIT or Sniffin' 16, and Sniffin' 12 to 16 scores in a valid way. This can facilitate direct comparison between tests aiding future collaborative analyses and evidence synthesis.


Neuroanesthesia for the pregnant woman.
Neuroanesthesia for the pregnant patient is required infrequently, and evidence-based recommendations for neuroanesthetic management are sparse. We present a framework for a practical approach to anesthesia of the pregnant patient with subarachnoid or intracerebral hemorrhage, intracranial tumor, traumatic brain injury, spinal tumor, or spinal injury. The importance of a team-approach is emphasized. The anesthesiologist may have to anesthetize the pregnant patient for neurosurgery well before delivery, for cesarean delivery at the time of the neurosurgical procedure, or for delivery after neurosurgery. These scenarios are discussed along with fetal safety and anesthetic considerations for interventional neuroradiology.


Comparison of the seasonal variations of Synechococcus assemblage structures in estuarine waters and coastal waters of Hong Kong.
Seasonal variation in the phylogenetic composition of Synechococcus assemblages in estuarine and coastal waters of Hong Kong was examined through pyrosequencing of the rpoC1 gene. Sixteen samples were collected in 2009 from two stations representing estuarine and ocean-influenced coastal waters, respectively. Synechococcus abundance in coastal waters gradually increased from 3.6 × 10(3) cells ml(-1) in March, reaching a peak value of 5.7 × 10(5) cells ml(-1) in July, and then gradually decreased to 9.3 × 10(3) cells ml(-1) in December. The changes in Synechococcus abundance in estuarine waters followed a pattern similar to that in coastal waters, whereas its composition shifted from being dominated by phycoerythrin-rich (PE-type) strains in winter to phycocyanin-only (PC-type) strains in summer owing to the increase in freshwater discharge from the Pearl River and higher water temperature. The high abundance of PC-type Synechococcus was composed of subcluster 5.2 marine Synechococcus, freshwater Synechococcus (F-PC), and Cyanobium. The Synechococcus assemblage in the coastal waters, on the other hand, was dominated by marine PE-type Synechococcus, with subcluster 5.1 clades II and VI as the major lineages from April to September, when the summer monsoon prevailed. Besides these two clades, clade III cooccurred with clade V at relatively high abundance in summer. During winter, the Synechococcus assemblage compositions at the two sites were similar and were dominated by subcluster 5.1 clades II and IX and an undescribed clade (represented by Synechococcus sp. strain miyav). Clade IX Synechococcus was a relatively ubiquitous PE-type Synechococcus found at both sites, and our study demonstrates that some strains of the clade have the ability to deal with large variation of salinity in subtropical estuarine environments. Our study suggests that changes in seawater temperature and salinity caused by the seasonal variation of monsoonal forcing are two major determinants of the community composition and abundance of Synechococcus assemblages in Hong Kong waters.


Learn, see, practice, prove, do, maintain: an evidence-based pedagogical framework for procedural skill training in medicine.
Acquisition of competency in procedural skills is a fundamental goal of medical training. In this Perspective, the authors propose an evidence-based pedagogical framework for procedural skill training. The framework was developed based on a review of the literature using a critical synthesis approach and builds on earlier models of procedural skill training in medicine. The authors begin by describing the fundamentals of procedural skill development. Then, a six-step pedagogical framework for procedural skills training is presented: Learn, See, Practice, Prove, Do, and Maintain. In this framework, procedural skill training begins with the learner acquiring requisite cognitive knowledge through didactic education (Learn) and observation of the procedure (See). The learner then progresses to the stage of psychomotor skill acquisition and is allowed to deliberately practice the procedure on a simulator (Practice). Simulation-based mastery learning is employed to allow the trainee to prove competency prior to performing the procedure on a patient (Prove). Once competency is demonstrated on a simulator, the trainee is allowed to perform the procedure on patients with direct supervision, until he or she can be entrusted to perform the procedure independently (Do). Maintenance of the skill is ensured through continued clinical practice, supplemented by simulation-based training as needed (Maintain). Evidence in support of each component of the framework is presented. Implementation of the proposed framework presents a paradigm shift in procedural skill training. However, the authors believe that adoption of the framework will improve procedural skill training and patient safety.


Mixed ion pair liquid chromatography method for the simultaneous assay of ascorbic acid, caffeine, chlorpheniramine maleate, dextromethorphan HBr monohydrate and paracetamol in Frenadol sachets.
The five active drug substances and two of the excipients present in Frenadol, a cold medication, were separated. The active drug components dextromethorphan HBr monohydrate, ascorbic acid, caffeine, paracetamol and chlorpheniramine maleate were quantitatively assayed by a mixed ion pair LC method. The excipients separated were citric acid and maleic acid. The HPLC assay included dual-wavelength detection to simultaneously quantify the large concentration of paracetamol and the much lower concentration of chlorpheniramine and dextromethorphan. Both tetrabutylammonium hydrogen sulphate (TBA) and pentane sulphonic acid (PSA) were necessary for resolution of the seven compounds. The TBA was necessary to lessen peak tailing for dextromethorphan and chlorpheniramine, to retain ascorbic acid and to shorten assay time. The pentane sulphonic acid enhanced peak shape for dextromethorphan and chlorpheniramine. The assay of the active drug substances was validated for use in quality control applications. Validation studies demonstrated that the procedure was accurate, linear, precise, reproducible and rugged. The method conformed to both USP and EC validation guidelines.


Drp1-dependent mitochondrial fission in cardiovascular disease.
Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as 'mitochondrial dynamics'. Dynamin-related protein 1 (Drp1) is known as the major pro-fission protein whose activity is tightly regulated to clear the damaged mitochondria via mitophagy, ensuring a strict control over the intricate process of cellular and organ dynamics in heart. Various posttranslational modifications (PTMs) of Drp1 have been identified including phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation, which implicate a role in the regulation of mitochondrial dynamics. An intact mitochondrial homeostasis is critical for heart to fuel contractile function and cardiomyocyte metabolism, while defects in mitochondrial dynamics constitute an essential part of the pathophysiology underlying various cardiovascular diseases (CVDs). In this review, we summarize current knowledge on the critical role of Drp1 in the pathogenesis of CVDs including endothelial dysfunction, smooth muscle remodeling, cardiac hypertrophy, pulmonary arterial hypertension, myocardial ischemia-reperfusion, and myocardial infarction. We also highlight how the targeting of Drp1 could potentially contribute to CVDs treatments.