Steady-state signatures of visual perceptual load, multimodal distractor filtering, and neural competition.
The perceptual load theory of attention posits that attentional selection occurs early in processing when a task is perceptually demanding but occurs late in processing otherwise. We used a frequency-tagged steady-state evoked potential paradigm to investigate the modality specificity of perceptual load-induced distractor filtering and the nature of neural-competitive interactions between task and distractor stimuli. EEG data were recorded while participants monitored a stream of stimuli occurring in rapid serial visual presentation (RSVP) for the appearance of previously assigned targets. Perceptual load was manipulated by assigning targets that were identifiable by color alone (low load) or by the conjunction of color and orientation (high load). The RSVP task was performed alone and in the presence of task-irrelevant visual and auditory distractors. The RSVP stimuli, visual distractors, and auditory distractors were "tagged" by modulating each at a unique frequency (2.5, 8.5, and 40.0 Hz, respectively), which allowed each to be analyzed separately in the frequency domain. We report three important findings regarding the neural mechanisms of perceptual load. First, we replicated previous findings of within-modality distractor filtering and demonstrated a reduction in visual distractor signals with high perceptual load. Second, auditory steady-state distractor signals were unaffected by manipulations of visual perceptual load, consistent with the idea that perceptual load-induced distractor filtering is modality specific. Third, analysis of task-related signals revealed that visual distractors competed with task stimuli for representation and that increased perceptual load appeared to resolve this competition in favor of the task stimulus.


Development and validation of the Molluscum Contagiosum Diagnostic Tool for Parents: diagnostic accuracy study in primary care.
Molluscum contagiosum (MC) is diagnosed by its distinct appearance. Parental diagnosis of MC may reduce anxiety and lead to reductions in healthcare consultations, and may be particularly useful in large-scale epidemiological studies. However, there are currently no published, validated tools allowing parental diagnosis of MC. To develop and validate a tool for parental diagnosis of MC. The Molluscum Contagiosum Diagnostic Tool for Parents (MCDTP) was developed and its diagnostic accuracy was compared with GP diagnosis in 12 GP surgeries in South Wales. Following development, which involved three phases with dermatologists, nurses, GPs, and parents, parents completed the MCDTP (index test) in the practice waiting room, and rated their confidence in their diagnosis. A GP then examined their child for MC (reference test). Test characteristics were calculated for all responders and for those who expressed being confident or very confident in their diagnosis. A total of 203 parents completed the MCDTP. The MCDTP showed a sensitivity of 91.5% (95% confidence intervals (CI) = 81.3 to 97.2) and a specificity of 88.2% (95% CI = 81.8 to 93.0) in all parents and a sensitivity of 95.8% (95% CI = 85.7 to 99.5) and a specificity of 90.9% (95% CI = 83.9 to 95.6) in parents who were confident or very confident in their diagnosis. The positive predictive value was 76.1% (95% CI = 64.5 to 85.4) and negative predictive value was 96.2% (95% CI = 91.4 to 98.8) for all parents. The MCDTP performed well compared with GP diagnosis and is suitable for clinical use by parents and in population-based studies.


The discriminative properties of erythrocyte anisocytosis in patients with resectable malignant pancreatic masses compared with an age and gender matched control group.
Red cell distribution width (RDW) is a parameter that reflects the heterogeneity in the size of the circulating erythrocytes. Elevated levels of RDW have been found related to various pathologic conditions including cancers. We hypothesized that elevated RDW levels might correspond to advanced stages of pancreatic cancer. The medical files and pathology reports of patients who underwent Whipple procedure were evaluated in a retrospective casecontrol study. The relationship of RDW to age, gender, cancer antigen 19-9 (CA 19-9), blood hemoglobin levels, stage of the tumor, tumor size, tumor grade, number of lymph nodes with metastasis, the status of lymphovascular and perineural invasion were investigated. A oneto-two, age- and- gender matched group of seemingly healthy patients was used to compare the levels of RDW between the patients of pancreatic head malignancy and healthy people. ROC (receiver operating characteristics) curves analysis was conducted to define a threshold to discriminate malignant pancreatic head tumors from healthy control subjects. Then, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated. The median age was 61 years (IRQ 54.75-69). The median RDWs were 15.20% (IQR 13.20-19.50) vs 13.00 (IQR 12.60-13.48) in the pancreas adenocancer and the control group, respectively, p=0.000). There was significant relationship between RDW and the grade of the tumor, p=0.026. An RDW level of 14% was obtained as a result of the ROC curves analysis and the positive predictivity about malignancy was 70.73% with a negative predictive rate of 89.95% compared with the healthy group of patients. The elevated levels of RDW in patients with a pancreatic mass may point to a possible malignancy; however, an elevated RDW in a patient with a malignant pancreatic head mass is related to the grade of the disease, not the stage.


Phage G Structure at 6.1 Å Resolution, Condensed DNA, and Host Identity Revision to a Lysinibacillus.
Phage G has the largest capsid and genome of any known propagated phage. Many aspects of its structure, assembly, and replication have not been elucidated. Herein, we present the dsDNA-packed and empty phage G capsid at 6.1 and 9 Å resolution, respectively, using cryo-EM for structure determination and mass spectrometry for protein identification. The major capsid protein, gp27, is identified and found to share the HK97-fold universally conserved in all previously solved dsDNA phages. Trimers of the decoration protein, gp26, sit on the 3-fold axes and are thought to enhance the interactions of the hexameric capsomeres of gp27, for other phages encoding decoration proteins. Phage G's decoration protein is longer than what has been reported in other phages, and we suspect the extra interaction surface area helps stabilize the capsid. We identified several additional capsid proteins, including a candidate for the prohead protease responsible for processing gp27. Furthermore, cryo-EM reveals a range of partially full, condensed DNA densities that appear to have no contact with capsid shell. Three analyses confirm that the phage G host is a Lysinibacillus, and not Bacillus megaterium: identity of host proteins in our mass spectrometry analyses, genome sequence of the phage G host, and host range of phage G.


Trends in injection risk behaviors in a sample of New York City injection drug users: 1992-1995.
This study assessed the relation between year of recruitment into an AIDS prevention project and likelihood of engaging (yes/no) in injection risk behaviors. In total, 834 injection drug users were recruited over a 44-month period (January 1992-August 1995) in New York City. Logistic regression was used to examine trends in three behaviors, across four successive annual cohorts: using needles/syringes that were previously used by another person, using injection supplies (e.g., cookers, cotton, rinse water) that had been previously used, and giving or lending of used needles/syringes to another person. Significant (p < .0001) decreasing trends occurred in two behaviors: giving or lending of used needles/syringes to another person and use of injection supplies that had been used by another person. Sample characteristics were generally consistent over time and did not obviate significant injection risk trends. Decreasing trends in injection risk behaviors could not be explained by changing sample characteristics. Even though some injectors report engaging in risky injection practices, the confluence of numerous AIDS prevention efforts in the 1990s has contributed to an overall reduction in the likelihood of such behaviors.


Phytosomal nanocarriers as platforms for improved delivery of natural antioxidant and photoprotective compounds in propolis: An approach for enhanced both dissolution behaviour in biorelevant media and skin retention profiles.
Propolis has been reported to possess rich content of antioxidant compounds and may provide health benefits through oxidative stress reduction. Presently, the formulation activities used to enhance the drug delivery have been hampered due to inherently low aqueous solubility and poor transdermal permeation of the bioactive phenols and flavonoids. Here, we show, the formulation of propolis extract (PE) into phytosome delivery systems. The optimum antioxidant activity was attained through extraction process using 75% v/v ethanol. The phytosome was prepared using thin-layer hydration technique with l-α-Phosphatidylcholine as a phospholipid. Fourier transform infrared (FTIR) was used to investigate the occurrence of molecular interactions between formulation components. This innovative approach could encapsulate >40% of bioactive compounds in PE, namely caffeic acid, quercetin, and kaempferol. FTIR spectroscopy indicated new hydrogen bond formation, supporting successful phytosome formulation. The phytosomes enhanced the dissolution up to 4-folds of bioactive compounds in bio-mimicked release media, as well as improved penetrability and skin retention up to 6-folds of the three main compounds of propolis, when compared to non-encapsulated PE formulation. Importantly, the hydrogel containing phytosome showed a potential for UVA and UVB radiation absorption, indicated by the SPF values of higher than 15. To conclude, this work shows promising novel delivery approaches for PE in the treatment of organ injured stress oxidative and skin aging.


UNC79 and UNC80, putative auxiliary subunits of the NARROW ABDOMEN ion channel, are indispensable for robust circadian locomotor rhythms in Drosophila.
In the fruit fly Drosophila melanogaster, a network of circadian pacemaker neurons drives daily rhythms in rest and activity. The ion channel NARROW ABDOMEN (NA), orthologous to the mammalian sodium leak channel NALCN, functions downstream of the molecular circadian clock in pacemaker neurons to promote behavioral rhythmicity. To better understand the function and regulation of the NA channel, we have characterized two putative auxiliary channel subunits in Drosophila, unc79 (aka dunc79) and unc80 (aka CG18437). We have generated novel unc79 and unc80 mutations that represent strong or complete loss-of-function alleles. These mutants display severe defects in circadian locomotor rhythmicity that are indistinguishable from na mutant phenotypes. Tissue-specific RNA interference and rescue analyses indicate that UNC79 and UNC80 likely function within pacemaker neurons, with similar anatomical requirements to NA. We observe an interdependent, post-transcriptional regulatory relationship among the three gene products, as loss of na, unc79, or unc80 gene function leads to decreased expression of all three proteins, with minimal effect on transcript levels. Yet despite this relationship, we find that the requirement for unc79 and unc80 in circadian rhythmicity cannot be bypassed by increasing NA protein expression, nor can these putative auxiliary subunits substitute for each other. These data indicate functional requirements for UNC79 and UNC80 beyond promoting channel subunit expression. Immunoprecipitation experiments also confirm that UNC79 and UNC80 form a complex with NA in the Drosophila brain. Taken together, these data suggest that Drosophila NA, UNC79, and UNC80 function together in circadian clock neurons to promote rhythmic behavior.


Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis.
Previous work identified an important role for hyperglycemia in diabetic nephropathy (The Diabetes Control and Complications Trial Research Group. N Engl J Med 329: 977-986, 1993; UK Prospective Diabetes Study Group. Lancet 352: 837-853, 1998), and increased glomerular GLUT1 has been implicated. However, the roles of GLUT1 and intracellular glucose have not been determined. Here, we developed transgenic GLUT1-overexpressing mice (GT1S) to characterize the roles of GLUT1 and intracellular glucose in the development of glomerular disease without diabetes. GLUT1 was overexpressed in glomerular mesangial cells (MC) of C57BL6 mice, a line relatively resistant to diabetic nephropathy. Blood pressure, blood glucose, glomerular morphometry, matrix proteins, cell signaling, transcription factors, and selected growth factors were examined. Kidneys of GT1S mice overexpressed GLUT1 in glomerular MCs and small vessels, rather than renal tubules. GT1S mice were neither diabetic nor hypertensive. Glomerular GLUT1, glucose uptake, mean capillary diameter, and mean glomerular volume were all increased in the GT1S mice. Moderately severe glomerulosclerosis (GS) was established by 26 wk of age in GT1S mice, with increased glomerular type IV collagen and fibronectin. Modest increases in glomerular basement membrane thickness and albuminuria were detected with podocyte foot processes largely preserved, in the absence of podocyte GLUT1 overexpression. Activation of glomerular PKC, along with increased transforming growth factor-beta1, VEGFR1, VEGFR2, and VEGF were all detected in glomeruli of GT1S mice, likely contributing to GS. The transcription factor NF-kappaB was also activated. Overexpression of glomerular GLUT1, mimicking the diabetic GLUT1 response, produced numerous features typical of diabetic glomerular disease, without diabetes or hypertension. This suggested GLUT1 may play an important role in the development of diabetic GS.


Diffraction efficiency gain, blazing, and apodizing of a symmetric square reflection grating in an étalon.
First-order diffraction efficiency of 50% into a single beam was obtained from a weak symmetric square metal diffraction grating operated in an étalon at the 632.8-nm He-Ne laser wavelength. Without the étalon the diffraction efficiency was just 2.7% in each of the two first-order beams. First-order diffraction efficiency gain as well as blazing and apodizing of the grating occur because of the resonant paraxial angular spectrum of the étalon.


Factors influencing quantitative liquid (scanning) transmission electron microscopy.
One of the experimental challenges in the study of nanomaterials in liquids in the (scanning) transmission electron microscope ((S)TEM) is gaining quantitative information. A successful experiment in the fluid stage will depend upon the ability to plan for sensitive factors such as the electron dose applied, imaging mode, acceleration voltage, beam-induced solution chemistry changes, and the specifics of solution reactivity. In this paper, we make use of a visual approach to show the extent of damage of different instrumental and experimental factors in liquid samples imaged in the (S)TEM. Previous results as well as new insights are presented to create an overview of beam-sample interactions identified for changing imaging and experimental conditions. This work establishes procedures to understand the effect of the electron beam on a solution, provides information to allow for a deliberate choice of the optimal experimental conditions to enable quantification, and identifies the experimental factors that require further analysis for achieving fully quantitative results in the liquid (S)TEM.


Preliminary evidence of transient fatigue and pacing during interchanges in rugby league.
This study aimed to quantify changes in heart rate (HR) and movement speeds in interchanged and whole-match players during 35 elite rugby league performances. Performances were separated into whole match, interchange bout 1, and interchange bout 2 and further subdivided into match quartiles. Mean percentages of peak HR (%HR(peak)) and total and high-intensity running (> 14 km/h) meters per minute (m/min) were recorded. For whole-match players, a decline in high-intensity m/min and %HR(peak) was observed between successive quartiles (P < .05). High-intensity m/min during interchange 1 also progressively declined, although initial m/min was higher than whole match (24.2 ± 7.9 m/min vs 18.3 ± 4.7 m/min, P = .018), and %HR(peak) did not change over match quartiles (P > .05). During interchange 2, there was a decline in high-intensity m/min from quartile 1 to quartile 3 (18 ± 4.1 vs 13.4 ± 5 m/min, P = .048) before increasing in quartile 4. Quartiles 1 and 2 also showed an increase in %HR(peak) (85.2 ± 6.5 vs 87.3 ± 4.2%, P = .022). Replacement players adopted a high initial intensity in their first match quartile before a severe decline thereafter. However, in a second bout, lower exercise intensity at the outset enabled a higher physiological exertion for later periods. These findings inform interchange strategy and conditioning for coaches while also providing preliminary evidence of pacing in team sport.


The use of monetary incentives in a community survey: impact on response rates, data quality, and cost.
To assess the effect of incentive size on response rates, data quality, and cost in a digestive health status mail survey of a community sample of health plan enrollees. The study population was selected from a database of enrollees in various health plans obligated to receive care at Park Nicollet Clinic-HealthSystem Minnesota, a large, multispecialty group in Minneapolis, Minnesota, and the nearby suburbs. A total of 1,800 HealthSystem Minnesota enrollees were randomly assigned to receive a survey with an incentive of $5 or $2. The response rates for each incentive level were determined. Data quality, as indicated by item nonresponse and scale scores, was measured. Total cost and cost per completed survey were calculated. The response rate among enrollees receiving $5 (74.3 percent) was significantly higher than among those receiving $2 (67.4 percent); differences were more pronounced in the first wave of data collection. Data quality did not differ between the two incentive groups. The total cost per completed survey was higher in the $5 condition than in the $2 condition. A $5 incentive resulted in a higher response rate among a community patient sample with one mailing than did a $2 incentive. However, the response rates in the $2 condition approached the level of the $5 incentive, and costs were significantly lower when the full follow-up protocol was completed. Response rates were marginally increased by follow-up phone calls. The incentive level did not influence data quality. The results suggest if a survey budget is limited and a timeline is not critical, a $2 incentive provides an affordable means of increasing participation.


Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function.
Anesthetic drugs cause brain cell death and long-term neurocognitive dysfunction in neonatal rats. Recently, human data also suggest that anesthesia early in life may cause cognitive impairment. The connection between cell death and neurocognitive decline is uncertain. It is conceivable that mechanisms other than brain cell death contribute to neurocognitive outcome of neonatal anesthesia. In a series of experiments, we demonstrate that isoflurane exposure causes significant hypercarbia in postnatal day 7 rats and that exposure to isoflurane or carbon dioxide for 4 h provoked brain cell death. However, 1 h of isoflurane exposure was not sufficient to cause brain cell death. Moreover, only 4 h of isoflurane exposure, but not 1 or 2 h of exposure or 4 h of carbon dioxide, led to impaired hippocampal function,questioning the association between anesthesia-induced brain cell death and neurocognitive dysfunction. Neurogenesis both in the developing and adult dentate gyrus is important for hippocampal function, specifically learning and memory. γ-Amino-butyric-acid regulates proliferation and neuronal differentiation both in the developing and the adult brain. Inhaled anesthetics are γ-amino-butyric-acid-ergic and may therefore affect neurogenesis, which could be an alternative mechanism mediating anesthesia-induced neurocognitive decline in immature rats. Understanding the mechanism will help guide clinical trials aiming to define the scope of the problem in humans and may lead to preventive and therapeutic strategies.


Decision-making for people with dementia and advanced kidney disease: a secondary qualitative analysis of interviews from the Conservative Kidney Management Assessment of Practice Patterns Study.
To explore dialysis decision-making for adults who lack capacity due to cognitive impairment, a common and under-recognised condition in those with advanced chronic kidney disease (CKD). Secondary analysis of qualitative data collected during the Conservative Kidney Management Assessment of Practice Patterns Study programme of research was performed. Sixty semistructured interviews were conducted with multiprofessional team members from UK renal centres. Staff were asked about local facilities, the value of conservative kidney management (CKM), when and with whom CKM was discussed and how CKM could be improved. Thematic analysis was employed to identify, characterise and report on themes that emerged from the data, focused on the specific issues experienced by people with dementia. A purposive sample of nine UK renal centres differing in the scale of their CKM programmes. Clinical directors of renal centres identified staff involved in CKM. Staff were asked to participate if they had experience of low clearance clinics or of caring for patients with advanced CKD (estimated glomerular filtration rate <20mL/min/1.732 or >65 years with end-stage kidney disease). Two overarching themes were identified: factors taken into consideration during decision-making, and the process of decision-making itself. Comorbidity, social support, quality of life and the feasibility of dialysis were reported as factors pertinent to clinicians' decisions regarding suitability. The majority of renal centres practised multidisciplinary 'best interests' decision-making for those without capacity. Attitudes to advance care planning were divided. In view of the prevalence of cognitive impairment among those with advanced CKD, we suggest consideration of routine assessment of cognition and capacity. In the UK, dialysis is initiated and continued for individuals with dementia and services should be adapted to meet the needs of this population.


Effectiveness of statins in reducing the rate of severe sepsis: a retrospective evaluation.
To determine whether use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is associated with a reduced rate of severe sepsis, and to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis. Retrospective cohort study. University-associated teaching hospital. Fifty-three patients admitted with sepsis; 16 were receiving statins and 37 were not receiving statins (controls) before admission. Patients were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patient demographics, vital signs, and laboratory values were collected from their electronic medical records. The primary end point was rate of severe sepsis, defined in accordance with guidelines from the American College of Chest Physicians and the Society of Critical Care Medicine. Secondary end points were in-hospital mortality rate and rate of five categories of organ dysfunction (cardiovascular, renal, pulmonary, hematologic, and metabolic). Preadmission statin therapy, compared with no statin therapy, was associated with a 30% lower rate of severe sepsis (56% vs 86%, p<0.02). In-hospital mortality was not significantly different between groups (38% vs 49%, p=0.33); however, the rate of cardiovascular dysfunction, defined as hypotension requiring vasopressor therapy, was significantly lower in the statin group (38% vs 73%, p<0.02). No significant differences in the other organ dysfunction categories were noted between groups. Statins appear to prevent sepsis from becoming severe, most notably through prevention of sepsis-induced hypotension. This potential role for statins in the prevention and treatment of severe sepsis should be further evaluated in a randomized controlled trial.


Effect of metoprolol on death and cardiac events during a 2-year period after coronary artery bypass grafting. The MACB Study Group.
To evaluate the effect of long-term treatment with metoprolol after coronary bypass grafting on death and cardiac events. Patients in western Sweden on whom coronary artery bypass grafting was performed between June 1988 and June 1991 were evaluated for inclusion during the first 3 weeks after surgery. Major exclusion criteria were age > 75 years, concomitant valve surgery, traditional contraindications to beta-blockers and unwillingness to participate. Patients were randomized in a double-blind fashion to 100 mg of metoprolol/placebo daily for 2 weeks and thereafter 200 mg daily for 2 years. Of 2365 patients who were operated on, 967 were randomized to either metoprolol (n = 480) or placebo (n = 487). Primary end points (death, non-fatal myocardial infarction, unstable angina pectoris, need for coronary artery bypass grafting or percutaneous transluminal angioplasty), were reached by 42 patients in the metoprolol group (8.8%), as compared with 39 in the placebo group (8.0%) (P = 0.73). Of all the patients randomized to metoprolol, 34% withdrew from blind treatment prematurely compared with 44% for placebo (P < 0.01). Prophylactic treatment with metoprolol over a 2-year period after coronary artery bypass grafting did not reduce death or the development of cardiac events. However, the 95% confidence limits ranged from the possibility of a 30% reduction in events to a 68% increase in events if patients were treated with metoprolol as compared with placebo.


Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice.
The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H(2)O(2)) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh. Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H(2)O(2) to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K(+) channel opener levcromakalim. Exogenous H(2)O(2) elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that the endothelium produced H(2)O(2) upon stimulation by ACh and that the H(2)O(2) production was markedly reduced in eNOS-KO mice. These results indicate that H(2)O(2) is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.


Progress towards eliminating Hib in Australia: an evaluation of Haemophilus influenzae type b prevention in Australia, 1 July 1993 to 30 June 2000.
The status of Haemophilus influenzae (Hib) disease and its prevention by vaccination was reviewed for the period 1997 to 2000. This forms the background to a change in national vaccine policy, from the use of two Hib vaccines to the use of PRP-OMP only throughout Australia from May 2000. Notifications of Hib in the 7-year period between 1993 and 2000 declined by 87 per cent among children 0-4 years of age; adjustment for likely under-reporting increase this to a 95 per cent reduction. Among age groups not included in the immunisation program, there was also a substantial decline in notified cases. Overall, a minimum 430 cases and 13 deaths were prevented by Hib immunisation annually in Australia. Enhanced Hib surveillance recorded 532 cases over seven years, with 353 in unvaccinated persons, 74 fulfilling criteria for true vaccine failure and 75 partially immunised. Of unvaccinated cases, 60 and 182 were eligible for routine and catch-up immunisation respectively. Although the overall incidence for 0-4 years of age declined from 15 to 1.2 cases per 100,000 population, the proportion of cases under six months of age increased from 11 per cent to 23 per cent. Overall vaccine effectiveness, estimated using data from the last five years of the program, was 83 per cent (95% CI 71-91%), increasing to 90 per cent (95% CI 83-94%) when adjusted for under-reporting to the Australian Childhood Immunisation Register. Among Aboriginal and Torres Strait Islander people, the incidence of invasive Hib disease fell from 4.6 cases per 100,000 population to 0.7 cases per 100,000 population but the proportion of cases now occurring among Aboriginal or Torres Strait Islander people increased significantly, from 7 to 15 per cent. The Hib immunisation program in Australia has been highly successful. Nevertheless, experience in Australia and elsewhere indicates that continued careful monitoring of Hib disease, with high quality laboratory surveillance, remains important.


TAT-based formal representation of medical guidelines: imatinib case-study.
Computer-based interpretation of medical guidelines (GLs) has drawn lots of attention in the past three decades. It is essential to use a formalism for GLs representation that would enable the validation of GLs structural properties, be able to map medical actions into the time scale and support the automatic formal verification of GLs without additional translation paths. In this paper we preset a novel approach based on Timed Automata extended with Tasks (TAT) for the medical protocol formal representation using the TIMES toolbox. We discuss the verification issues with the help of the Imatinib case study.


Relationships Between Periodontal Disease and Bacterial Pneumonia.
Bacterial pneumonia is a prevalent and costly infection that is a significant cause of morbidity and mortality in patients of all ages. The continuing emergence of antibiotic-resistant bacteria (e.g., penicillin-resistant pneumococci) suggests that bacterial pneumonia will assume increasing importance in the coming years. Thus, knowledge of the pathogenesis of, and risk factors for, bacterial pneumonia is critical to the development of strategies for prevention and treatment of these infections. Bacterial pneumonia in adults is the result of aspiration of oropharyngeal flora into the lower respiratory tract and failure of host defense mechanisms to eliminate the contaminating bacteria, which multiply in the lung and cause infection. It is recognized that community-acquired pneumonia and lung abscesses can be the result of infection by anaerobic bacteria; dental plaque would seem to be a logical source of these bacteria, especially in patients with periodontal disease. It is also possible that patients with high risk for pneumonia, such as hospitalized patients and nursing home residents, are likely to pay less attention to personal hygiene than healthy patients. One important dimension of this personal neglect may be diminished attention to oral hygiene. Poor oral hygiene and periodontal disease may promote oropharyngeal colonization by potential respiratory pathogens (PRPs) including Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli, Enterobacter species, etc.), Pseudomonas aeruginosa, and Staphylococcus aureus. This paper provides the rationale for the development of this hypothesis especially as it pertains to mechanically ventilated intensive care unit patients and nursing home residents, two patient groups with a high risk for bacterial pneumonia. J Periodontol 1996;67:1114-1122.


Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study.
Pulmonary embolism is incidentally diagnosed in up to 5% of patients with cancer on routine imaging scans. The clinical relevance and optimal therapy for incidental pulmonary embolism, particularly distal clots, is unclear. The aim of the current study was to assess current treatment strategies and the long-term clinical outcomes of incidentally detected pulmonary embolism in patients with cancer. We conducted an international, prospective, observational cohort study between October 22, 2012, and December 31, 2017. Unselected adults with active cancer and a recent diagnosis of incidental pulmonary embolism were eligible. Outcomes were recurrent venous thromboembolism, major bleeding, and all-cause mortality during 12 months of follow-up. Outcome events were centrally adjudicated. A total of 695 patients were included. Mean age was 66 years and 58% of patients were male. Most frequent cancer types were colorectal (21%) and lung cancer (15%). Anticoagulant therapy was initiated in 675 patients (97%), of whom 600 (89%) were treated with low-molecular-weight heparin. Recurrent venous thromboembolism occurred in 41 patients (12-month cumulative incidence, 6.0%; 95% CI, 4.4% to 8.1%), major bleeding in 39 patients (12-month cumulative incidence, 5.7%; 95% CI, 4.1% to 7.7%), and 283 patients died (12-month cumulative incidence, 43%; 95% CI, 39% to 46%). The 12-month incidence of recurrent venous thromboembolism was 6.4% in those with subsegmental pulmonary embolism compared with 6.0% in those with more proximal pulmonary embolism (subdistribution hazard ratio, 1.1; 95% CI, 0.37 to 2.9; P = .93). In patients with cancer with incidental pulmonary embolism, risk of recurrent venous thromboembolism is significant despite anticoagulant treatment. Patients with subsegmental pulmonary embolism seemed to have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots.


Glycosaminoglycan binding properties of natural venezuelan equine encephalitis virus isolates.
Equine-virulent, epidemic/epizootic strains of Venezuelan equine encephalitis (VEE) virus (VEEV) arise via mutation of progenitor enzootic strains that replicate poorly in equines. Sequencing studies have implicated positively charged amino acids on the surface of the E2 envelope glycoprotein in the acquisition of equine virulence and viremia potential, suggesting that changes in binding to cell surface glycosaminoglycans (GAGs) may mediate VEE emergence. Therefore, we evaluated the binding of natural enzootic and epizootic VEEV isolates to Chinese hamster ovary (CHO) cells expressing normal, high levels of GAGs as well as to mutant CHO cells lacking GAG expression. Binding to GAGs was not consistently associated with the epizootic phenotype, and cell culture passages resulted in increased GAG binding. The low levels of GAG binding exhibited by some low-passage, equine-virulent subtype IC VEEV strains indicate that the positive-charge E2 mutations implicated in VEE subtype IC emergence are not artifacts of laboratory passage and suggest that GAG binding does not play a major role in mediating VEE emergence. The increased GAG binding exhibited by VEEV strain CPA201 from the 1993 Mexican epizootic, when compared to that of closely related enzootic subtype IE strains, was shown to result from a Glu-to-Lys mutation at position 117 of the E2 envelope glycoprotein.


Anastrozole-associated sclerosing glomerulonephritis in a patient with breast cancer.
Anastrozole is a selective aromatase inhibitor and is used for the hormonal treatment of postmenopausal breast cancer. There are major side effects of anastrozole including decrease in both lumbar spine and total hip bone mineral density, increase in the incidence of all bone fractures (especially fractures of spine, hip and wrist), joint disorders and increase in the cholesterol level. We report a case of a 73-year-old postmenopausal woman with stage T2N0M0 breast cancer. Adjuvant chemotherapy was not indicated and anastrozole hormonotherapy was started. Diagnosis of sclerosing glomerulonephritis occurred in this patient during anastrozole use, suggesting a newly defined side effect of anastrozole. Renal elimination is not a significant pathway of elimination for anastrozole, clearance of anastrozole is unchanged even in severe renal impairment. Dosing adjustment in patients with renal dysfunction is not necessary for anastrozole. We believe that the acute renal failure in our patient was associated with anastrozole. Renal injury due to anastrozole has not been published in the English literature. Anastrozole may be the causative factor in patients with sclerosing glomerulonephritis.


Cyano-bridged Mn(III)3M(III) (M(III) = Fe, Cr) complexes: synthesis, structure, and magnetic properties.
Two cyano-bridged tetranuclear complexes composed of Mn(III) salen (salen = N,N'-ethylene bis(salicylideneiminate)) and hexacyanometalate(III) (M = Fe, Cr) in a stoichiometry of 3:1 have been selectively synthesized using {NH2(n-C12H25)2}3[M(III)(CN)6] (M(III) = Fe, Cr) starting materials: [{Mn(salen)(EtOH)}3{M(CN)6}] (M = Fe, 1; Cr, 2). Compounds 1 and 2 are isostructural with a T-shaped structure, in which [M(CN)6]3- assumes a meridional-tridentate building block to bind three [Mn(salen)(EtOH)]+ units. The strong frequency dependence and observation of hysteresis on the field dependence of the magnetization indicate that 1 is a single-molecule magnet.


Methods for Detecting Viruses in Foods: Background and General Principles 1.
Viruses are sometimes transmitted through foods. Hepatitis A (HA) and some viral gastroenteritides are the diseases now known to be spread most frequently in this way, but any virus from the human intestines probably could be. Bacterial indicators of fecal contamination show limited correlation with the incidence of viruses in foods, so tests to detect the viruses themselves are needed. The epidemiologic record has led to selection of shellfish (bivalve molluscs) and vegetables and fruits as foods for which test methods should be described, and ground beef and raw milk are also considered here because of the great interest they have attracted among research workers. Viruses in foods are presently detected on the basis of the infections they cause in cultured primate cells, but these cell culture methods do not permit detection of the HA virus nor the most important of the foodborne gastroenteritis viruses. Current methods of virus detection entail liquefaction of the food sample, clarification of the sample suspension, possibly concentration of the clarified food extract, and inoculation of cell cultures; a certain amount of specialized equipment is required for some of these procedures. The inclusion of the proper controls is critical to interpretation of results that are obtained.


Predictors and outcomes of viridans group streptococcal infections in pediatric acute myeloid leukemia: from the Canadian infections in AML research group.
Viridans group streptococci (VGS) cause significant morbidity in children treated for acute myeloid leukemia (AML). Our goals were to determine the occurrence and impact of these infections in children treated for AML and to understand the factors that increase the risk of VGS infections and viridans streptococcal shock syndrome (VSSS) in this population. We conducted a retrospective, population-based cohort study that included children ≤18 years of age with de novo AML treated at 15 Canadian centers. We evaluated factors related to VGS infection and VSSS. Among 341 children with AML, VGS occurred in 78 (22.9%) children over the entire course of therapy and 16 had recurrent episodes. VGS infection occurred in 97 of 1277 courses of chemotherapy (7.6%). VSSS occurred in 19.6% of these episodes and included 11 patients who required intensive care services with 2 VGS infections resulting in death. In multiple regression analysis, factors independently related to VGS included treatment on a Medical Research Council-based protocol (odds ratio (OR) 2.87, 95% confidence interval (CI) 1.53-5.39; P = 0.001), cytarabine dose per gram/m² (OR 1.04, 95% CI 1.01-1.07; P = 0.002) and prolonged neutropenia (OR 1.58, 95% CI: 0.97-2.56; P = 0.06). None of the evaluated factors were predictive of VSSS. VGS infections occur in 7.6% of chemotherapy courses and remain an important cause of morbidity and even mortality in children being treated for AML. Interventions to reduce VGS need to be identified.


Opinion piece: Australian residential aged care and the quality of nursing care provision.
The Australian government and aged care industry uphold the standard of care for persons who require high care and reside in residential aged care facilities. The residential aged care system is extremely complex and through research conducted at the micro level it is argued that the macro level of policy can be exposed for the effects on the ground. A case study methodology in the qualitative paradigm used a discourse analysis of the nursing care for three highly dependent residents in one accredited aged care facility. Detailed data were collected through interviews, non-participant observations and document analyses concerning the nursing care these residents received. A comparative analysis of the discourses revealed this facility to be functioning in an environment of neglect. Nursing care provision was rushed and untimely and the residents were at risk of unsafe practices and negligence. The documentation of nursing care was found to be fraudulent, demeaning and out of date. Environmental considerations, continence management and the social and activity needs of residents were contradictory to their quality of life. The autonomy of the residents and advocacy by relatives were misinterpreted and unethical discourses were apparent with relatives having to be constantly vigilant. The nursing care provided by nurses (and non-nurses) failed to meet professional nursing standards and competencies, which adversely affected the residents' health compromising their safety. This situation is attributed to residential aged care policies, whereby nurses and nursing practice have been silenced and made invisible resulting in a substandard level of nursing care provision in this accredited facility that may be transferable to other facilities.


Structures of apomyoglobin's various acid-destabilized forms.
The structures and the cold and hot melting thermodynamics of the acid- and salt-destabilized states of horse heart apomyoglobin (apoMb), including the E (extended) and various I forms, are studied using probes of tertiary structure (tryptophan fluorescence and FTIR spectroscopy) and secondary structure (far-UV CD and FTIR spectroscopy). These forms likely resemble early structures in the folding of the largely helical protein. Both the I and E forms retain the AGH core whereby the two ends of the protein are tied together with sufficient numbers of tertiary contacts, involving a number of hydrophobic residues, to show cooperative melting. The melting thermodynamics of E and I are distinctly different. E contains no other tertiary structure and probably little other secondary structure apart from the core. The more destabilized E form appears to contain "random" buried runs of polypeptide backbone which convert to alpha-helix in the I form(s). Most interestingly, E consists not of a single structure but is composed of a heterogeneous mixture of conformations, all showing corelike cooperative melting characteristics, and consisting presumably of varying contacts between the A portion of apomyoglobin and the G-H hairpin. These results bear on the energy landscape and structural features of the early part of apomyoglobin's folding pathway.


Institutional resources for communicable disease control in Europe: diversity across time and place.
This commentary discusses the causes and consequences of diversity in how European countries organize communicable disease control. Drawing on the historical record of the US Centers for Disease Control and Prevention, it first reviews the main explanations of that diversity, with a focus on the political dynamic of building institutional capacity in the field of public health. It then examines the significance of institutional diversity in the process of Europeanization, and closes with a few thoughts on factors that have shaped the development of communicable disease control capacities in the United States and the European Union.


Down-Regulation of MicroRNA-184 Is Associated With Corneal Neovascularization.
Although microRNA-184 (miR-184) is abundantly expressed in the corneas, the role of miR-184 in corneal neovascularization remains unknown. Here we investigated the association between miR-184 expression and corneal neovascularization. Quantitative real-time PCR assay was conducted to detect the expression of miR-184 and its potential target genes in the corneal epithelium of rats with corneal suture-induced neovascularization. MicroRNA-184 was also applied topically to the suture rats. Mimic and inhibitor of miR-184 were transfected into the cultured human umbilical vein endothelial cells (HUVECs), human corneal epithelial (HCE) cells, and simian choroidal endothelial cells (RF/6A). The following experiments were performed to evaluate the effects of miR-184 in these transfected cells: cell proliferation by cell viability assay, cell migration by a scratch wound test, VEGF-induced tube formation, and VEGF and β-catenin levels by Western blot analysis. The expression of miR-184 was significantly reduced, whereas the gene expression of frizzled-4, a receptor of the Wnt pathway, was up-regulated in the corneal epithelium of corneal suture rats. The corneal neovascularization induced by suture was ameliorated by topical administration of miR-184. In the cells transfected with mimic and inhibitor of miR-184, miR-184 significantly suppressed the cell proliferation and cell migration of HUVECs, miR-184 down-regulated VEGF, and β-catenin expression in HUVECs and HCE cells. Furthermore, miR-184 inhibited the tube formation of RF/6A cells. Down-regulation of miR-184 is associated with up-regulation of VEGF and Wnt/β-catenin expression as well as corneal neovascularization, indicating that miR-184 negatively regulates corneal neovascularization.


Clinical observations on acupuncture treatment of peripheral facial paralysis aided by infra-red thermography--a preliminary report.
We have carried out clinical observations on 34 patients with peripheral facial paralysis treated by acupuncture therapy prescribed according to selection of treatment regimen on the basis of facial thermogram and temperature. A comparison was made with a control group of 97 patients who received conventional acupuncture therapy only. It was found that 1) The cure rate in the group of selecting acupoints by thermogram (hereinafter referred to as the thermography--aided treatment group) was 67.65%, with a marked improvement rate of 26.40%; while the cure rate of the conventional acupuncture treatment group (hereinafter called the conventional treatment group) was 46.39%, the marked improvement rate being 29.90%, indicating a significant difference in therapeutic efficacy between the two groups (P less than 0.02). 2) The average duration of acupuncture therapy for the thermography aided treatment group was 6.02 weeks, whereas that for the conventional treatment group, 24 weeks. There was also a significant difference between the two groups (P less than 0.01). And 3) During the entire therapeutic course, 25.2 sessions of treatment were given on the average in the thermography--aided treatment group, and 78.8 sessions in the conventional treatment group, showing a very significant difference (P less than 0.001). The present thermography--aided method exhibits advantages over the conventional one in enhancing the cure rate and shortening the duration of treatment, which is worthy to be popularized in clinical practice. And it is also of certain significance in standardization and scientification of acupuncture therapy.


Shared Gene Expression Alterations in Nasal and Bronchial Epithelium for Lung Cancer Detection.
We previously derived and validated a bronchial epithelial gene expression biomarker to detect lung cancer in current and former smokers. Given that bronchial and nasal epithelial gene expression are similarly altered by cigarette smoke exposure, we sought to determine if cancer-associated gene expression might also be detectable in the more readily accessible nasal epithelium. Nasal epithelial brushings were prospectively collected from current and former smokers undergoing diagnostic evaluation for pulmonary lesions suspicious for lung cancer in the AEGIS-1 (n = 375) and AEGIS-2 (n = 130) clinical trials and gene expression profiled using microarrays. All statistical tests were two-sided. We identified 535 genes that were differentially expressed in the nasal epithelium of AEGIS-1 patients diagnosed with lung cancer vs those with benign disease after one year of follow-up ( P < .001). Using bronchial gene expression data from the AEGIS-1 patients, we found statistically significant concordant cancer-associated gene expression alterations between the two airway sites ( P < .001). Differentially expressed genes in the nose were enriched for genes associated with the regulation of apoptosis and immune system signaling. A nasal lung cancer classifier derived in the AEGIS-1 cohort that combined clinical factors (age, smoking status, time since quit, mass size) and nasal gene expression (30 genes) had statistically significantly higher area under the curve (0.81; 95% confidence interval [CI] = 0.74 to 0.89, P = .01) and sensitivity (0.91; 95% CI = 0.81 to 0.97, P = .03) than a clinical-factor only model in independent samples from the AEGIS-2 cohort. These results support that the airway epithelial field of lung cancer-associated injury in ever smokers extends to the nose and demonstrates the potential of using nasal gene expression as a noninvasive biomarker for lung cancer detection.


The Cdc2 protein kinase controls Cdc10/Sct1 complex formation.
In the fission yeast Schizosaccharomyces pombe, the execution of Start requires the activity of the Cdc2 protein kinase and the Cdc10/Sct1 transcription complex. The loss of any of these genes leads to G1 arrest and activation of the mating pathway under appropriate conditions. We have undertaken a genetic and biochemical analysis of these genes and their protein products to elucidate the molecular mechanism that governs the regulation of Start. We demonstrate that serine-196 of Cdc10 is phosphorylated in vivo and provide evidence that suggests that phosphorylation of this residue is required for Cdc10 function. Substitution of serine-196 of Cdc10 with alanine (Cdc10 S196A) leads to inactivation of Cdc10. We show that Cdc10 S196A is incapable of associating with Sct1 to form a heteromeric complex, whereas substitution of this serine with aspartic acid (S196D) restores DNA-binding activity by allowing Cdc10 to associate with Sct1. Furthermore, we demonstrate that Cdc2 activity is required for the formation of the heteromeric Sct1/Cdc10 transcription complex and that the Cdc10 S196D mutation alleviates this requirement. We thus provide biochemical evidence to demonstrate one mechanism by which the Cdc2 protein kinase may regulate Start in the fission yeast cell cycle.


Heat fixation of cancer cells ablated with high-intensity-focused ultrasound in patients with breast cancer.
High-intensity-focused ultrasound (HIFU) is a noninvasive thermal ablation technique. This study reports the use of histological techniques for the pathological assessment of HIFU effects in patients with breast cancer. Twenty-three patients with biopsy-proven breast cancer underwent HIFU treatment for primary breast lesion. Mastectomy was performed on all patients after HIFU. By using histological examinations, the surgical specimens were assessed to explore HIFU effects on breast cancer. Coagulation necrosis of targeted tumors was confirmed by microscopy in 23 patients. Tumor cells presented typical characteristics of coagulation necrosis in the peripheral region of the ablated tumor in all patients. However, in 11 of 23 patients, hematoxylin and eosin staining showed normal cellular structure in the central ablated tumor. By using electronic microscopy and nicotinamide adenine dinucleotide-diaphorase stain, those who had normal-appearing cancer cells were not viable. HIFU can cause the heat fixation of ablated tumor through thermal effect.


Left ventricular diastolic function after anthracycline chemotherapy in childhood: relation with systolic function, symptoms, and pathophysiology.
To examine left ventricular (LV) diastolic function in patients previously treated with anthracycline drugs for childhood malignancy. To consider clinical relevance, relations with systolic dysfunction, and the pathophysiology of anthracycline cardiotoxicity. Cross sectional echocardiographic study of LV function. Supraregional centre for paediatric cardiology, principal centre for the treatment of childhood malignancy in southwest England. 226 of 236 patients surviving between 6.5 months and 17 (median 5.3) years from initial anthracycline treatment for childhood malignancy attended for clinical and echocardiographic examination. Cumulative anthracycline doses were between 50 and 750 (median 300) mg/m2. 22 patients had also received cardiac irradiation. Detailed assessment of transmitral diastolic pulsed wave Doppler flow patterns along with LV dimensions and systolic function measured by M mode echocardiography. Peak early (E) and atrial (A) phase filling velocities and EA ratio, time and acceleration and deceleration to and from peak E velocity, velocity integrals and ratio, isovolumic relaxation time (IVRT), and heart rate were measured. Results were examined in relation to LV cavity and posterior wall dimensions and shortening fraction (SF), and compared with paired control data matched for body surface area. Eleven (5%) patients had abnormal effort tolerance. Fifty one (23%) had SF < 30% and SF was inversely correlated with cumulative dose and time from treatment. The relative risk of symptomatic cardiac failure was greatly increased by prior irradiation; > 60% of irradiated patients who received > 400 mg/m2 of anthracycline were symptomatic. Early diastolic filling was relatively normal or enhanced at low anthracycline doses or when SF was preserved, with a shorter IVRT and increased atrial phase filling. Early filling was reduced at higher doses or with reduced SF, with longer IVRT and a further increase in atrial phase filling. A more "restrictive" pattern of diastolic filling (with high E and low A velocities) was seen in some patients, particularly after cardiac irradiation. Significant abnormalities of diastolic function are associated with anthracycline induced cardiac damage. These are not linearly related to anthracycline dose but appear to reflect the underlying myocardial pathophysiology associated with anthracycline toxicity, which is not demonstrated by the standard M mode echocardiogram. Although the overall clinical significance of such diastolic dysfunction is uncertain, some individual abnormalities may have significant management and therapeutic implications.


Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis.
To investigate whether periosteal cells from adult humans have features of multipotent mesenchymal stem cells (MSCs) at the single-cell level. Cell populations were enzymatically released from the periosteum of the proximal tibia obtained from adult human donors and then expanded in monolayer. Single-cell-derived clonal populations were obtained by limiting dilution. Culture-expanded periosteal cell populations were tested for their growth potential and for expression of conventional markers of MSCs and were subjected to in vitro assays to investigate their multilineage potential. To assess their multipotency in vivo, periosteal cells were injected into a regenerating mouse tibialis anterior muscle for skeletal myogenesis or were either seeded into an osteoinductive matrix and implanted subcutaneously into nude mice for osteogenesis or implanted in a joint surface defect under a periosteal flap into goats for chondrogenesis. Cell phenotypes were analyzed by histochemistry and immunohistochemistry and by reverse transcription-polymerase chain reaction for the expression of lineage-related marker genes. Regardless of donor age, periosteal cells were clonogenic and could be expanded extensively in monolayer, maintaining linear growth curves over at least 30 population doublings. They displayed long telomeres and expressed markers of MSCs. Under specific conditions, both parental and single-cell-derived clonal cell populations differentiated to the chondrocyte, osteoblast, adipocyte, and skeletal myocyte lineages in vitro and in vivo. Our study demonstrates that, regardless of donor age, the adult human periosteum contains cells that, upon enzymatic release and culture expansion, are multipotent MSCs at the single-cell level.


Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome.
The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines' storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.


Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.


Liquisolid technique as a new approach to sustain propranolol hydrochloride release from tablet matrices.
It is suggested here that liquisolid technique has the potential to be optimized for the reduction of drug dissolution rate and thereby production of sustained release systems. In the present study, propranolol hydrochloride was dispersed in polysorbate 80 as the liquid vehicle. Then a binary mixture of carrier-coating materials (Eudragit RL or RS as the carrier and silica as the coating material) was added to the liquid medication under continuous mixing in a mortar. The final mixture was compressed using the manual tableting machine. The effect of drug concentration, loading factor, thermal treating and aging on release profile of propranolol hydrochloride from liquisolid compacts were investigated at two pH values (1.2 and 6.8). The release rate of propranolol HCl from liquisolid compacts was compared to the release of propranolol HCl from conventional tablets. X-ray crystallography and DSC were used to investigate the formation of any complex between drug and excipients or any crystallinity changes during the manufacturing process. Propranolol HCl tablets prepared by liquisolid technique showed greater retardation properties in comparison with conventional matrix tablets. This investigation provided evidence that polysorbate 80 (Tween 80) has important role in sustaining the release of drug from liquisolid matrices, and a reduction of T(g) of the polymer can be the reason for the release prolongation of liquisolid tablets. The results also showed that wet granulation had remarkable impact on release rate of propranolol HCl from liquisolid compacts, reducing the release rate of drug from liquisolid compacts. The results showed that aging (liquisolid tablets were kept at 25 degrees C/75% relative humidity for 6 months) had no effect on hardness and dissolution profile of drug. The kinetics studies revealed that most of the liquisolid formulations followed the zero-order release pattern. X-ray crystallography and DSC ruled out any changes in crystallinity or complex formation during the manufacturing process of liquisolid formulations.


Is image steganography natural?
Steganography is the art of secret communication. Its purpose is to hide the presence of information, using, for example, images as covers. We experimentally investigate if stego-images, bearing a secret message, are statistically "natural." For this purpose, we use recent results on the statistics of natural images and investigate the effect of some popular steganography techniques. We found that these fundamental statistics of natural images are, in fact, generally altered by the hidden "nonnatural" information. Frequently, the change is consistently biased in a given direction. However, for the class of natural images considered, the change generally falls within the intrinsic variability of the statistics, and, thus, does not allow for reliable detection, unless knowledge of the data hiding process is taken into account. In the latter case, significant levels of detection are demonstrated.


Microtubule behavior in the growth cones of living neurons during axon elongation.
To understand how microtubules are generated in the growth cone, we have imaged fluorescently tagged microtubules in living frog embryonic neurons. The neurons were labeled by injecting rhodamine-labeled tubulin into the fertilized egg and explanting the neurons from the neural tube. Microtubules extend deep into the growth cone periphery and adopt three characteristic distributions: (a) dispersed and splayed throughout much of the growth cone; (b) looped and apparently contorted by compression; and (c) bundled into tight arrays. These distributions interconvert on a time scale of several minutes and these interconversions are correlated with the behavior of the growth cone. We observed microtubule growth and shrinkage in growth cones, but are unable to determine their contribution to net assembly. However, translocation of polymer form the axon appears to be a major mechanism of generating new polymer in the growth cone, while bundling of microtubules in the growth cone appears to be the critical step in generating new axon. Neurons that were about to turn spontaneously generated microtubules in the future direction of growth, suggesting that orientation of microtubules might be an important early step in neuronal pathfinding.


Cordycepin (3'-deoxyadenosine), an inhibitor of mRNA polyadenylation, suppresses proliferation and activates apoptosis in human epithelial endometriotic cells in vitro.
Endometriosis is a benign but chronic disorder associated with pelvic pain and infertility. Enhanced proliferation and reduced apoptosis susceptibility are characteristics of endometriosis. Cordycepin is a poly(A) polymerase inhibitor. It induces shortening of poly(A) tails, leading to destabilization of mRNAs and finally to proliferation inhibition and cell death in normal and tumor cells. The potential of cordycepin to block proliferation and survival of 11z human immortalized epithelial endometriotic cells was determined. 11z cell cultures were treated with cordycepin. Cordycepin-induced inhibition of proliferation and alterations in protein expression and protein phosphorylation were determined by the methyl thiazolyl tetrazolium assay and immunoblot analysis, respectively. Cordycepin induced the rapid and significant upregulation of the cell cycle progression inhibitor p21 and the downregulation of the cell cycle progression promoter cyclin D(1), finally leading to the inhibition of the proliferation of 11z human epithelial endometriotic cells. Cordycepin reduced the phosphorylation of the p38 mitogen-activated protein kinase and the retinoblastoma protein. It also activated caspase-dependent, intrinsic apoptosis, as documented by the proteolytic cleavage of the caspase-9, caspase-3 and the poly(ADP ribose) polymerase 1 precursor. The mRNA polyadenylation inhibitor cordycepin inhibits proliferation and survival of endometriotic cells.


Replacement of vertebral lamina (laminoplasty) in surgery for lumbar isthmic spondylolisthesis. A prospective clinical study.
The use of lamina as a graft for fusion in isthmic lumbar spondylolisthesis (LIS) is not known. In the present prospective clinical study, we used the laminoplasty technique and reported on its outcomes. Twenty cases that have been operated in our clinic due to G1 and G2 ISL between February 2003 and December 2006 were clinically and radiologically examined. The clinical assessment of the patients was carried out with the Prolo Economic and Functional scale. Both interbody fusion and laminoplasty procedures concerning 88 pedicles in total were performed on 20 cases of which 10 were at the L4-5 level, whereas 6 were at the L5-S1 level and 2 were at the L3-4-5 level. Five (25%) cases also had coexisting spinal stenosis. 19 (95%) patients had solid fusion but one (5%) had no solid fusion formation while having posterior fusion along with a clinical neurological examination result similar to the one obtained during the preoperative period. In conclusion, the anterior fusion rate was 95%. The most remarkable finding among the patients was the recovery observed at the 2nd month. The Prolo scale results of the cases were good and the follow-up time was 23.5 months. The laminoplasty technique is a method which presents advantages in isthmic spondylolisthesis cases such as short duration of operation, absence of graft donor site complications, preservation of the osteoligamentous structures of the posterior column and a high probability of achievement of fusion through only a posterior approach at a single session; therefore, we believe it is an alternative surgical technique.


The Exosome - A Naturally Secreted Nanoparticle and its Application to Wound Healing.
Wound healing is a complex process and often delayed in patients with underlying chronic conditions. The cost of wound care is a significant burden to the society, warranting new techniques to prompt wound healing. Several studies have reported on the beneficial effects of mesenchymal stem cells (MSCs) function in recruiting host cells, releasing secretory factors and matrix proteins thereby increasing wound heal. These secrete bioactive trophic factors from MSCs also includes extracellular vesicles (EVs) or exosomes. Recent studies have shown that EVs are one of the key secretory products of MSCs mediating cell-to-cell communication to enhance wound healing. Current knowledge related to the potential use of EVs in wound healing is reviewed and the promising future for EVs - a naturally secreted nanoparticle - as an alternative to cell-based therapy is discussed.


Region-based line field design using harmonic functions.
Field design has wide applications in graphics and visualization. One of the main challenges in field design has been how to provide users with both intuitive control over the directions in the field on one hand and robust management of its topology on the other hand. In this paper, we present a design paradigm for line fields that addresses this challenge. Rather than asking users to input all singularities as in most methods that offer topology control, we let the user provide a partitioning of the domain and specify simple flow patterns within the partitions. Represented by a selected set of harmonic functions, the elementary fields within the partitions are then combined to form continuous fields with rich appearances and well-determined topology. Our method allows a user to conveniently design the flow patterns while having precise and robust control over the topological structure. Based on the method, we developed an interactive tool for designing line fields from images, and demonstrated the utility of the fields in image stylization.


Copy number polymorphism of glutathione-S-transferase genes (GSTM1 & GSTT1) in susceptibility to lung cancer in a high-risk population from north-east India.
Genetic polymorphisms in glutathione-S-transferase genes ( GSTM1 and GSTT1 ) have been studied intensively for their potential role in lung cancer susceptibility. However, most of the studies on association between the polymorphisms and lung cancer do not distinguish between genotypes with one or two copies of the genes. The present study investigates the gene dosage effects of GSTT1 and GSTM1 copy number and their environmental interactions to examine the association of lung cancer risk with trimodular genotypes of the GSTs in a high-risk population from north-east India. A total of 154 lung cancer cases and 154 age and sex matched controls from the high risk region of north-east India were analyzed by multiplex real-time PCR to determine the trimodal genotypes (+/+, +/- and -/-) in both the genes ( GSTM1 and GSTT1 ). No significant association and gene dosage effect of GSTM1 gene copy number with lung cancer risk ( P trend =0.13) were found. However, absence of GSTT1 conferred 68 per cent (OR=0.32;95%CI=0.15-0.71;P=0.005) reduced risk compared to the two copy number of the gene. t0 here was evidence of gene dosage effect of GSTT1 gene ( P trend =0.006). Tobacco smoking was a major environmental risk factor to lung cancer (OR=3.03;95%CI=1.73-5.31;P<0.001). However, its interaction with null genotype of GSTT1 conferred significant reduced risk to lung cancer (OR=0.30;95%CI=0.10-0.91;P=0.03). Further in only tobacco smokers, null genotype was associated with increased reduced risk [0.03(0.001-0.78)0.03; P trend =0.006]. No effect modification of GSTM1 was observed with lung cancer risk by environmental risk factors. The results suggest that absence of GSTT1 null genotype may be associated with a reduced risk of lung cancer and the effect remains unchanged after interaction with smoking.


The reconstitution of cell-mediated immunity in the cutaneous lesions of lepromatous leprosy by recombinant interleukin 2.
Human rIL-2 (10-30 micrograms) was injected intradermally into the skin of patients with lepromatous leprosy with high bacillary loads. All patients responded to the lymphokine with local areas of induration that peaked at 24 h and persisted for 4-7 d irrespective of whether the site was "normal skin" or a nodular lesion. Within 24 h there was an extensive emigration of T cells and monocytes into the site. The percentage of the dermis infiltrated by mononuclear cells increased by more than sevenfold, peaking at 4 d and persisting for greater than 15 d. Both CD4+ and CD8+ T cells entered the site. T cells of CD4+ phenotype predominated at 2-7 d but by 11 d, CD8+ cells were predominant. Considerable numbers of T6+ Langerhans' cells appeared in the dermis by 72 h and persisted for 3 wk. By 4 d the thickness of the overlying epidermis had increased twofold, and keratinocytes were expressing MHC class II antigen and the IFN-gamma-induced peptide IP-10. Starting at 48 h, there was an extensive destruction of mononuclear phagocytes that contained structurally intact or fragmented M. leprae observed at the electron microscope level. The organisms, either free or contained within endocytic vacuoles, were discharged into the extracellular space and then reingested by blood-borne monocytes. This was followed by marked reductions in the number of acid-fast organisms in the injected site, evident as early as 4-7 d and more marked at 2-3 wk after injection. 13 of 15 patients exhibited a disposal of acid-fast bacilli ranging from 5- to 1,000-fold with a mean value of approximately 100-fold. The administration of IL-2 leads to the generation of an effective cell-mediated immune response, recapitulating an antigen-driven event and leading to striking local reductions in M. leprae. In comparison with the purified protein derivative of tuberculin reaction, bacilli are cleared more promptly, although emigratory cells persist for a shorter time.


Lost and found in behavioral informatics.
From early anatomical lesion studies to the molecular and cellular methods of today, a wealth of technologies have provided increasingly sophisticated strategies for identifying and characterizing the biological basis of behaviors. Bioinformatics is a growing discipline that has emerged from the practical needs of modern biology, and the history of systematics and ontology in data integration and scientific knowledge construction. This revolution in biology has resulted in a capability to couple the rich molecular, anatomical, and psychological assays with advances in data dissemination and integration. However, behavioral science poses unique challenges for biology and medicine, and many unique resources have been developed to take advantage of the strategies and technologies of an informatics approach. The collective developments of this diverse and interdisciplinary field span the fundamentals of database development and data integration, ontology development, text mining, genetics, genomics, high-throughput analytics, image analysis and archiving, and numerous others. For the behavioral sciences, this provides a fundamental shift in our ability to associate and dissociate behavioral processes and relate biological and behavioral entities, thereby pinpointing the biological basis of behavior.


[Eating disorders risk among obese adolescents].
Preliminary research suggests that eating disorders (ED) are common among overweight teenagers. Missing the diagnosis is a poor prognostic factor. To quantify the risk of ED and the effects of age, sex and severity of obesity in obese adolescents. We studied 99 obese adolescents with a body mass index (BMI) > percentile 95 of CDC-NCHS, 51% females, aged between 11 and 19 years, attending an obesity clinic. The Eating Disorders Inventory-2 (EDI-2) was used to evaluate the risk of ED. A score equal or higher than 110, corresponding to the 85th percentile, was considered as risky. Sixteen percent of studied adolescents had EDI scores > 110. No statistically significant differences were observed by age, sex or severity of obesity. EDI-2 scores in participants with a BMI z score over and under 4 were 93.6 ± 33.9 and 78.2 ± 38.8 respectively (p = 0.02). A high percentage of participants had body dissatisfaction (BD) and drive for thinness. Bulimic symptoms, inefficacy, fear of maturity, and impulsivity scores were significantly higher among participants with a high risk of developing ED. Obese adolescents have a high risk for ED, regardless of their age and sex. The risk increases along with higher BMI. The routine use of screening tests is fundamental for an early detection of ED.


Comparison of conventional therapies for dentin hypersensitivity versus medical hypnosis.
This study compared the efficacy of conventional treatments for dentin hypersensitivity (DHS) and hypnotherapy. During a 1-month period at an urban practice in a service area of approximately 22,000 inhabitants, all patients were examined. A total of 102 individuals were included in the evaluation. Values of 186 teeth were analyzed. The comparison of the different treatment methods (desensitizer, fluoridation, and hypnotherapy) did not show significant differences in success rates. However, a noticeable difference was observed in terms of onset and duration of effect. For both desensitizer and hypnotherapy treatments, onset of effect was very rapid. Compared to the other methods studied, hypnotherapy effects had the longest duration. In conclusion, hypnotherapy was as effective as other methods in the treatment of DHS.


High-dose i.v. granisetron for the prevention of chemotherapy-induced emesis: cardiac safety and tolerability.
This phase II trial assessed the cardiovascular safety and tolerability of high-dose granisetron for the treatment of nausea and vomiting in cancer patients undergoing emetogenic chemotherapy. Forty-one patients were given 30-min infusions of granisetron, 40 or 120 microg/kg i.v., as either a single dose or as split doses, at 6-h intervals. Subsequently, patients had the option of the alternative dosing regimen or to return to conventional antiemetic therapy. Patients were monitored for 24 h following the first granisetron infusion. Electrocardiogram (ECG; lead II and Holter monitoring) measurements were made during the study and blood samples for pharmacokinetic analysis were taken at regular intervals for 48 h after the start of the first granisetron infusion. During the first chemotherapy session, granisetron was administered as: (i) bolus doses of 80 microg/kg (n=3) and 120 microg/kg (n=19) or (ii) split doses of 2x40 microg/kg (n=1) and 3x40 microg/kg (n=18). Crossover therapy was administered to 22 patients, with granisetron doses of 120 microg/kg (n=12), 2x40 microg/kg (n=1) and 3x40 microg/kg (n=9). We conclude that supra-therapeutic doses up to 120 microg/kg granisetron had no clinically significant effect on ECG, pulse rate or blood pressure. The treatment was well tolerated with no significant changes in biochemistry or hematological parameters.


Cardiovascular changes in calcium-deficient chick embryos.
We have developed an experimental system involving calcium-deficient chick embryos to examine the relationship between calcium homeostasis and cardiovascular activities. We have found that the calcium-deficient embryos, when compared with control animals, exhibit tachycardia and are significantly hypertensive. The effects are unlikely to be due to gross cardiac malformations or hypertrophy. The hypertensive condition appears to be a specific result of the systemic calcium deficiency since calcium supplementation to these embryos significantly restores the functions to normality.


Non-innocent adsorption of Co-pyrphyrin on rutile(110).
Solar-light driven water splitting is a promising way for the sustainable production of molecular hydrogen, the latter representing an efficient carrier for energy storage and conversion into common liquid fuels. In search of novel catalysts for high-performance water splitting devices, Co-pyrphyrin (CoPy) has been recently synthesized and successfully used as a homogeneous water reduction catalyst. We investigate the adsorption of this molecule on the rutile TiO2(110) surface as a possible first step towards the design of a heterogeneous water reduction system. We find that the adsorption of the molecule is stabilized by the interaction of the cyano groups with the under-coordinated Ti centers present at the surface. This interaction induces the rehybridization of the molecular orbitals localized on the cyano groups and the realignment of the lowest unoccupied molecular states. Moreover, the highest occupied molecular orbital of CoPy@rutile(110) is localized on CoPy and the energy gap turns out to be significantly smaller than the gap of pristine rutile(110). This implies that direct or indirect injection of electrons from CoPy to the rutile(110) surface is in principle possible upon the absorption of light in the visible range. On the other hand, the electronic properties of the Co(ii) center are not modified by the adsorption, which suggests that CoPy and its derivatives may be used in water electrolysis for hydrogen production also in the adsorbed state.


A Potential Outcomes Calculus for Identifying Conditional Path-Specific Effects.
The do-calculus is a well-known deductive system for deriving connections between interventional and observed distributions, and has been proven complete for a number of important identifiability problems in causal inference [1, 8, 18]. Nevertheless, as it is currently defined, the do-calculus is inapplicable to causal problems that involve complex nested counterfactuals which cannot be expressed in terms of the "do" operator. Such problems include analyses of path-specific effects and dynamic treatment regimes. In this paper we present the potential outcome calculus (po-calculus), a natural generalization of do-calculus for arbitrary potential outcomes. We thereby provide a bridge between identification approaches which have their origins in artificial intelligence and statistics, respectively. We use po-calculus to give a complete identification algorithm for conditional path-specific effects with applications to problems in mediation analysis and algorithmic fairness.


A Proteomic Approach Suggests Unbalanced Proteasome Functioning Induced by the Growth-Promoting Bacterium Kosakonia radicincitans in Arabidopsis.
Endophytic plant growth-promoting bacteria have significant impact on the plant physiology and understanding this interaction at the molecular level is of particular interest to support crop productivity and sustainable production systems. We used a proteomics approach to investigate the molecular mechanisms underlying plant growth promotion in the interaction of Kosakonia radicincitans DSM 16656 with Arabidopsis thaliana. Four weeks after the inoculation, the proteome of roots from inoculated and control plants was compared using two-dimensional gel electrophoresis and differentially abundant protein spots were identified by liquid chromatography tandem mass spectrometry. Twelve protein spots were responsive to the inoculation, with the majority of them being related to cellular stress reactions. The protein expression of 20S proteasome alpha-3 subunit was increased by the presence of K. radicincitans. Determination of proteasome activity and immuno blotting analysis for ubiquitinated proteins revealed that endophytic colonization interferes with ubiquitin-dependent protein degradation. Inoculation of rpn12a, defective in a 26S proteasome regulatory particle, enhanced the growth-promoting effect. This indicates that the plant proteasome, besides being a known target for plant pathogenic bacteria, is involved in the establishment of beneficial interactions of microorganisms with plants.


[Effect of resveratrol on myocardial fibrosis in mice with chronic viral myocarditis].
Some research has shown that resveratrol can ameliorate myocardial injury and improve cardiac function in mice with acute viral myocarditis (VMC), and can inhibit cardiac fibroblast proliferation and myofibroblast differentiation in vitro. This study was designed to investigate whether resveratrol has similar effects in the mouse model of chronic VMC. One hundred mice were inoculated with 0.3 mL of Coxsackievirus B3 1*106 TCID50. Thirty days later, the survivors (n=62) were used as a model of chronic VMC, and were randomly assigned to 4 groups: untreated VMC, and low- (10 mg/kg), middle- (100 mg/kg) and high-dose (1 000 mg/kg) resveratrol-treated VMC (once daily, for 30 days). Ten mice which received neither Coxsackievirus B3 nor resveratrol treatment served as the control group. After 30 days of resveratrol treatment, the mice were sacrificed. Serum concentrations of collagenous pre-peptides (PINP, PICP and PIIINP) were assessed using ELISA. Hematoxylin-eosin staining, picrosirius red staining and circularly polarized light were used to examine the histochemistry of myocardial collagen. The myocardial collagen volume fraction in the high-dose (0.74+/-0.19) and the middle-dose (1.07+/-0.12) resveratrol-treated VMC groups was significantly lower than that in the untreated VMC (2.33+/-0.18) and the low-dose resveratrol-treated VMC (2.17+/-0.19) groups (P<0.05). Compared with the untreated VMC group, serum concentrations of PICP and PIIINP in the high-dose and the middle-dose resveratrol-treated VMC groups were significantly reduced (P<0.05), while PINP concentrations increased significantly (P<0.05). Resveratrol can inhibit hyperplasia of myocardial collagen in the mouse model of chronic VMC, acting as an effective anti-fibrotic agent in the myocardium.


Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii.
Guanylate binding proteins (GBPs) are a family of large interferon-inducible GTPases that are transcriptionally upregulated upon infection with intracellular pathogens. Murine GBPs (mGBPs) including mGBP1 and 2 localize to and disrupt pathogen-containing vacuoles (PVs) resulting in the cell-autonomous clearing or innate immune detection of PV-resident pathogens. Human GBPs (hGBPs) are known to exert antiviral host defense and activate the NLRP3 inflammasome, but it is unclear whether hGBPs can directly recognize and control intravacuolar pathogens. Here, we report that endogenous or ectopically expressed hGBP1 fails to associate with PVs formed in human cells by the bacterial pathogens Chlamydia trachomatis or Salmonella typhimurium or the protozoan pathogen Toxoplasma gondii. While we find that hGBP1 expression has no discernible effect on intracellular replication of C. trachomatis and S. typhimurium, we observed enhanced early Toxoplasma replication in CRISPR hGBP1-deleted human epithelial cells. We thus identified a novel role for hGBP1 in cell-autonomous immunity that is independent of PV translocation, as observed for mGBPs. This study highlights fundamental differences between human and murine GBPs and underlines the need to study the functions of GBPs at cellular locations away from PVs.


Phosphatase inhibition prevents the activity-dependent trafficking of GABAA receptors during status epilepticus in the young animal.
To determine if the activity-dependent trafficking of γ2 subunit-containing γ-aminobutyric acid type A receptors (GABAA Rs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age-dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity-dependent plasticity of these receptors. The efficacy and potency of diazepam 0.2-10 mg/kg administered 3 or 60 min after the onset of a lithium/pilocarpine-induced seizure in postnatal day 15-16 rats was evaluated using video-electroencephalography (EEG) recordings. The surface expression of γ2 subunit-containing GABAA Rs was assessed using a biotinylation assay, and GABAA R-mediated miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch-clamp recording techniques from dentate granule cells in hippocampal slices acutely obtained 60 min after seizure onset (SE-treated). The effect of the protein phosphatase inhibitors FK506 and okadaic acid (OA) on the surface expression of these receptors was determined in organotypic slice cultures exposed to high potassium and N-methyl-d-aspartate (NMDA) or in SE-treated slices. Diazepam terminated seizures of 3 min but not 60 min duration, even at the highest dose. In the SE-treated slices, the surface expression of γ2 subunit-containing GABAA Rs was reduced and the amplitude of the mIPSCs was diminished. Inhibition of protein phosphatases prevented the activity-induced reduction of the γ2 subunit-containing GABAA Rs in organotypic slice cultures. Furthermore, treatment of SE-treated slices with FK506 or OA restored the surface expression of the γ2 subunit-containing GABAA Rs and the mIPSC amplitude. This study demonstrates that the plasticity of γ2 subunit-containing GABAA Rs associated with the development of benzodiazepine resistance in young and adult animals is similar. The findings of this study suggest that the mechanisms regulating the activity-dependent trafficking of GABAA Rs during SE can be targeted to develop novel adjunctive therapy for the treatment of benzodiazepine-refractory SE.


Interfacial and volumetric sensitivity of the dry sintering process of polymer colloidal crystals: a thermal transport and photonic bandgap study.
We introduce the in situ characterization of the dry sintering process of face-centred cubic colloidal crystals by two complementary techniques: thermal transport and photonic stopband characterization. Therefore, we employed time-dependent, isothermal laser flash analysis and specular reflectivity experiments close to the glass transition temperature of the colloidal crystal. Both methods yield distinctly different time constants of the film formation process. This discrepancy can be attributed to a volume- (photonic stopband) and interface-driven (thermal transport) sensitivity of the respective characterization method. Nevertheless, both methods yield comparable apparent activation energies. Finally, we extended the sintering process characterization to further polymer compositions, with vastly different glass transition temperatures. We could show that the film formation rate is governed by the viscoelastic properties of the polymers at the respective annealing temperature.


Multiple clinical episodes of Plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity.
Epidemiological studies indicate that some children experience many more episodes of clinical malaria than their age mates in a given location. Whether this is as a result of the micro-heterogeneity of malaria transmission with some children effectively getting more exposure to infectious mosquitoes than others, or reflects a failure in the acquisition of immunity needs to be elucidated. Here, we investigated the determinants of increased susceptibility to clinical malaria by comparing the intensity of exposure to Plasmodium falciparum and the acquisition of immunity in children at the extreme ends of the over-dispersed distribution of the incidence of clinical malaria. The study was nested within a larger cohort in an area where the intensity of malaria transmission was low. We identified children who over a five-year period experienced 5 to 16 clinical malaria episodes (children at the tail-end of the over-dispersed distribution, n = 35), remained malaria-free (n = 12) or had a single episode (n = 26). We quantified antibodies against seven Plasmodium falciparum merozoite antigens in plasma obtained at six cross-sectional surveys spanning these five years. We analyzed the antibody responses to identify temporal dynamics that associate with disease susceptibility. Children experiencing multiple episodes of malaria were more likely to be parasite positive by microscopy at cross-sectional surveys (X (2) test for trend 14.72 P = 0.001) and had a significantly higher malaria exposure index, than those in the malaria-free or single episode groups (Kruskal-Wallis test P = 0.009). In contrast, the five-year temporal dynamics of anti-merozoite antibodies were similar in the three groups. Importantly in all groups, antibody levels were below the threshold concentrations previously observed to be correlated with protective immunity. We conclude that in the context of a low malaria transmission setting, susceptibility to clinical malaria is not accounted for by anti-merozoite antibodies but appears to be a consequence of increased parasite exposure. We hypothesize that intensive exposure is a prerequisite for protective antibody concentrations, while little to modest exposure may manifest as multiple clinical infections with low levels of antibodies. These findings have implications for interventions that effectively lower malaria transmission intensity.


Differential diagnosis of Parkinson's disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: discriminant analysis of striatal 18F-dopa PET data.
Clinicopathological series indicate that the clinical diagnosis of Parkinson's disease is correct in only 80% of cases. Multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) comprise most of the misdiagnoses. By means of 18F-dopa PET the pattern of nigrostriatal dopaminergic dysfunction in 28 patients with clinically probable Parkinson's disease, 25 with MSA, and 10 patients with SRO, was assessed and compared with the pattern in 27 normal subjects. Discriminant function analysis was used to assess the ability of 18F-dopa PET to categorize individual parkinsonian patients on the basis of their caudate and putamen tracer uptake. Discriminant function analysis assigned all control subjects a normal category. One Parkinsonian patient out of 63 was classified as "normal" on the basis of PET findings, although this patient had significantly reduced putamen 18F-dopa uptake. Discriminant function analysis was less effective at distinguishing different categories of akinetic-rigid syndrome on the basis of their striatal 18F-dopa uptake, as judged against clinical criteria. Patients clinically labelled as having typical or atypical Parkinsonian syndromes were assigned the same category on PET criteria 64% and 69% of the time, respectively. When all three categories of Parkinson's disease, MSA, and SRO were considered together, clinical and 18F-dopa PET findings correlated in 64% of patients assigned a diagnosis of Parkinson's disease and 70% of those given a diagnosis of SRO; MSA was less readily discriminated, patients with MSA being assigned to MSA, Parkinson's disease, and SRO groups with equal frequency. The correlation between clinical and discriminant function analysis assignment improved when separate comparisons were made between Parkinson's disease and MSA, or Parkinson's disease and SRO groups. In these analyses, clinical and PET categorisation of MSA and Parkinson's disease agreed in 60% of cases, and of SRO and Parkinson's disease in 90% of cases. In summary, (18)F-dopa PET successfully discriminates normal subjects from parkinsonian patients, and patients with Parkinson's disease from patients with SRO, but is less reliable in distinguishing Parkinson's disease from MSA. The concomitant assessment of striatal neuronal function with additional PET tracers may be necessary to reliably differentiate typical and atypical parkinsonian syndromes.


Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability.
To determine whether fenofibric acid (FA) reduces high glucose (HG)-induced basement membrane component overexpression and hyperpermeability in human retinal pigment epithelial (RPE) cells. Retinal pigment epithelial cells (ARPE-19) were cultured for 18 days in normal glucose (5 mM) or HG (25 mM) medium and studied for the effects of FA on fibronectin (FN) and collagen IV (Coll IV) expression. During last 3 days of the experiment, 100 μM FA was added to cells grown in HG medium or in HG medium plus IL-1β (HG + IL-1β) to mimic, at least in part, the inflammatory aspect of the diabetic milieu. Real-time RT-PCR was performed to determine FN and Coll IV mRNA levels, whereas protein levels were assessed by Western blot analyses. Cell monolayer morphology and barrier function were analyzed by confocal microscopy using specific antibodies against tight junction proteins, ZO-1, and claudin-1 and by measuring apical-basolateral movements of FITC-dextran, respectively. FN and Coll IV expression were significantly increased in RPE cells grown in HG or HG + IL-1β medium compared with cells grown in normal medium. When cells grown in HG or HG + IL-1β medium were treated with FA, significant reductions in FN and Coll IV expression were observed. In addition, exposure to FA decreased excess permeability in a dose-dependent manner in cells grown in HG + IL-1β medium. This effect was unrelated to changes in tight junction protein content. Findings from this study suggest that the downregulation of basement membrane components by FA may have a protective effect against outer blood-retinal barrier leakage associated with diabetic retinopathy.