Characterization of human foetal intestinal alkaline phosphatase. Comparison with the isoenzymes from the adult intestine and human tumour cell lines.
The molecular structure of human foetal intestinal alkaline phosphatase was defined by high-resolution two-dimensional polyacrylamide-gel electrophoresis and amino acid inhibition studies. Comparison was made with the adult form of intestinal alkaline phosphatase, as well as with alkaline phosphatases isolated from cultured foetal amnion cells (FL) and a human tumour cell line (KB). Two non-identical subunits were isolated from the foetal intestinal isoenzyme, one having same molecular weight and isoelectric point as placental alkaline phosphatase, and the other corresponding to a glycosylated subunit of the adult intestinal enzyme. The FL-cell and KB-cell alkaline phosphatases were also found to contain two subunits similar to those of the foetal intestinal isoenzyme. Characterization of neuraminidase digests of the non-placental subunit showed it to be indistinguishable from the subunits of the adult intestinal isoenzyme. This implies that no new phosphatase structural gene is involved in the transition from the expression of foetal to adult intestinal alkaline phosphatase, but that the molecular changes involve suppression of the placental subunit and loss of neuraminic acid from the non-placental subunit. Enzyme-inhibition studies demonstrated an intermediate response to the inhibitors tested for the foetal intestinal, FL-cell and KB-cell isoenzymes when compared with the placental, adult intestinal and liver forms. This result is consistent with the mixed-subunit structure observed for the former set of isoenzymes. In summary, this study has defined the molecular subunit structure of the foetal intestinal form of alkaline phosphatase and has demonstrated its expression in a human tumour cell line.


Serum of obstructive sleep apnea patients impairs human coronary endothelial cell migration.
Endothelial cell migration and proliferation play an important role in the growth and development of new blood vessels and endothelium healing. This process occurs in response to injury, inflammation and immune reactions. Dysfunction of the endothelium may play a significant role in development and progression of cardiovascular disease related to sleep-disordered breathing. The aim of our study was to evaluate the chemo-attractant activity of serum from obstructive sleep apnea (OSA) and normal subjects on coronary artery endothelial cell migration. We studied 12 severe OSA patients, free of other co-morbidities and on no treatment, along with 12 age-, body mass index, and gender matched healthy controls. Blood was collected at three time points: at 21:00 before sleep, at 6:00 after waking from sleep, and at 11:00 (after 5 h of normal daytime activity). Serum chemo-attractant activity for human coronary endothelial cells was assessed using a colorimetric cell migration assay kit. In healthy subjects, serum chemo-attractant activity peaked in the morning after waking from sleep (p = 0.02). This early morning increase was blunted in severe OSA subjects, in whom chemo-attractant activity was weaker than in normal controls (p = 0.02), and did not change significantly at the different time-points (p < 0.001 vs. controls). Chemo-attractant activity of the serum from OSA patients is lower compared to serum from healthy subjects, especially in the morning. Altered chemo-attractant serum activity may conceivably contribute to the impairment of endothelial function in obstructive sleep apnea patients.


Tension of Agricultural Land and Water Use in China's Trade: Tele-Connections, Hidden Drivers and Potential Solutions.
Interregional trade can potentially extend the management of scarce resources beyond a region's territory along supply chains. Here we combined the multiregional input-output model with structural decomposition analysis to reveal the distant connections of agricultural land and water use as well as the drivers behind their variations in China. Our results show that trade-embodied agricultural land use increase by 2.3-fold and 2.5-fold for virtual agricultural water use flows from 2002 to 2012. The water-starved northern China with abundant agricultural land is the main exporter of virtual (also called trade-embodied) agricultural land and water. Moreover, the role of the virtual water use importers and exporters were determined by the availability of land, rather than water resources. Based on scenario analysis, we found that if agricultural water use efficiency of north China reached the world's top-level but agricultural land use efficiency remained unchanged, the virtual water flows would be reduced by 32% and only water resources, not agricultural land, would be able to sustain future economic development. Our findings may provide significant information for potential solutions to China's regional water shortage from a land-water nexus perspective.


[Ablation of ventricular tachycardia in a patient with a left ventricular assist device].
The use of a left ventricular assist device (LVAD) as a bridge to heart transplantation (HTx) or as a destination therapy in patients with a contraindication for HTx is increasing. However, nearly half of the patients with LVAD support experience a ventricular arrhythmia (VA) in the first year. The history of a pre-LVAD VA is one of the most powerful predictors of VA after LVAD implantation. The clinical experience and data about ablation of a VA in patients with an LVAD are limited. There are important issues to be considered before and during the procedure in LVAD patients compared to other VA ablation patients. This is a report of ablation of intractable ventricular tachycardia in a patient with a LVAD.


Quantitative in situ hybridization for peptide mRNAs in mouse brain.
The objective was to determine the feasibility of using a radioactive capture method (Fuji FLA 2000) and image analysis system for the measurement of peptide mRNA levels in specific brain regions in mice. As a test mRNA, we chose vasopressin (VP) and oxytocin (OT) because they are expressed in abundance in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). A comparison was made between free-floating and slide-mounted sections to determine which method yielded better results. Mouse brains were fixed in 4% paraformaldehyde (PFA) and processed for in situ hybridization using 35S-oligonucleotide probes for VP and OT. After overnight hybridization and high stringency washes, 25-microm brain sections and 14C standards were exposed to a BAS-IIIs Fuji imaging film over a range of times (4 h-6 days). Results showed that there was an intense hybridization reaction in the PVN and SON, making it possible to distinguish the specific brain regions. Using Image Gauge Software, the signal was quantified in PVN and SON. A comparison of the different exposure times showed that the signal could be measured after as little as 4 h. The intensity readings increased over time while the calculated radioactivity remained constant. The free-floating method was superior to the slide-based system, providing a lower background and a higher signal. The data illustrates the applicability of the phosphor imaging system for the reproducible measurement of mRNA levels in discrete regions of the mouse brain.


Pulmonary arterial stent implantation in an adult with Williams syndrome.
We report a 38-year-old patient who presented with pulmonary hypertension and right ventricular dysfunction due to pulmonary artery stenoses as a manifestation of Williams syndrome, mimicking chronic thromboembolic pulmonary hypertension. The patient was treated with balloon angioplasty and stent implantation. Short-term follow-up showed a good clinical result with excellent patency of the stents but early restenosis of the segments in which only balloon angioplasty was performed. These stenoses were subsequently also treated successfully by stent implantation. Stent patency was observed 3 years after the first procedure.


Characteristics of calcium transport and binding by rat myometrium plasma membrane subfractions.
A gradient has been designed to yield two subfractions of plasma membrane vesicles from rat myometrium, a low buoyant density (8-24% sucrose) fraction N1 richer in 5'-nucleotidase and a higher buoyant density (24-30% sucrose) fraction N2, instead of a previously described fraction F1. Both N1 and N2 had very low activities of NADPH-cytochrome c reductase and succinate-cytochrome c reductase. Electron micrographs of thin sections of N1 showed clear vesicles, whereas N2 consisted of vesicles with electron-dense bodies attached to them. These plasma membrane vesicles can actively take up Ca. The active uptake of Ca was potentiated by oxalate and phosphate and abolished by the Ca ionophore A23187. Dilution of actively loaded vesicles in isotonic media containing EGTA led to loss of a small proportion of the stored Ca instantaneously and the remainder more slowly in a biphasic manner. Dilution in hypotonic media with EGTA led to a release of a much larger proportion of the accumulated Ca. A23187 at high concentrations (10 microM) caused a release of all the sequestered Ca whether the active Ca uptake had been carried out in the presence or in the absence of oxalate. A23187, 0.5 microM, released all the sequestered Ca from the vesicles that were actively loaded in the absence of oxalate, but only 37% when the vesicles were actively loaded with Ca in the presence of oxalate. Comparison of the composite plasma membrane fraction F1 (8-30% sucrose) and the subfractions N1 and N2 showed that they had different capacities for Ca uptake in the presence and absence of ATP. An attempt has been made to analyze the active Ca-uptake data in terms of various Ca pools.


Prevalence and Risk Factors of Voice Problems Among Primary School Teachers in India.
Teachers are more prone to develop voice problems (VPs) when compared with other professional voice users. The aim of present study was to investigate the prevalence and risk factors of VPs among primary school teachers in India. Epidemiological cross-sectional survey. Self-reporting questionnaire data were collected from 1082 teachers. Out of 1082 teachers who participated in the present study, 188 teachers reported VPs that account for a prevalence rate of 17.4%. Tired voice after long hours of talking was the most frequently reported symptom, followed by sore/dry throat, strain in voice, neck muscle tension, and difficulty in projecting voice. The adjusted odds ratio values showed number of years of teaching, high background noise levels in the classroom, experiencing psychological stress while teaching classes, improper breath management (holding breath while speaking), poor focus of the tone (clenching jaw/teeth while speaking), upper respiratory tract infection, thyroid problems, and acid reflux as significant risk factors for the development of VPs in the current cohort of teachers. Current results suggest that teachers develop VPs due to multiple risk factors. These factors may be either biological, psychomotor, or environment-related factors. A holistic approach (which could include educating teachers about voice care during their training, and if they develop VP during their career, then managing the VP by taking into consideration different risk factors) addressing all these factors needs to be adopted to prevent VPs in primary school teachers.


Physical environment and life expectancy at birth in Mexico: an eco-epidemiological study.
The objective of this ecological study was to ascertain the effects of physical environment on life expectancy at birth, using data from all 32 Mexican states. 50 environmental indicators with information about demography, housing, poverty, water, soils, biodiversity, forestry resources, and residues were included in exploratory factor analysis. Four factors were extracted: population vulnerability/susceptibility, and biodiversity (FC1), urbanization, industrialization, and environmental sustainability (FC2), ecological resilience (FC3), and free-plague environments (FC4). Using OLS regressions, FC2, FC3, and FC4 were found to be positively associated with life expectancy at birth, while FC1 was negatively associated. This study suggests that physical environment is an important macro-determinant of the health of the Mexican population, and highlights the usefulness of ecological concepts in epidemiological studies.


Right ventricular septal pacing as alternative for failed left ventricular lead implantation in cardiac resynchronization therapy candidates.
To compare the effects on left ventricular (LV) function of right ventricular (RV) septal pacing vs. cardiac resynchronization therapy (CRT) in patients with an indication for the latter. Cardiac resynchronization therapy is an effective therapy in patients with drug-refractory heart failure. Despite advances in implantation techniques, LV lead placement can be impossible in up to 10% of cases. We, therefore, assessed the effects of RV septal pacing from mid septum (RVmIVS) and outflow tract (RVOT) on cardiac performance, in comparison with CRT. Twenty-two patients scheduled for CRT underwent dual-chamber temporary pacing. The ventricular lead was placed at the RV apex (RVA), RVmIVS, and RVOT in random order. Comprehensive echocardiography was performed in a baseline AAI mode and then at each RV position in dual chamber pacemaker function (D pacing, D sensing, D dual responses) mode and repeated on the next day following CRT implantation. Right ventricular apex pacing did not change any of the assessed echocardiography parameters. Both RVmIVS and RVOT pacing increased LV ejection fraction (EF): 29 ± 7% at baseline vs. 32 ± 6% (P = 0.02) and 32 ± 5% (P = 0.04) with RVmIVS and RVOT pacing, respectively. Similarly, the dyssynchrony index (Ts-SD) decreased: 50 ± 19 ms at baseline vs. 39 ± 17 ms (P = 0.04) and 37 ± 17 ms (P = 0.006) with RVmIVS and RVOT pacing, respectively. Cardiac resynchronization therapy further improved LVEF and Ts-SD to 36 ± 7% and 34 ± 15 ms, respectively, however, only LVEF was significantly higher compared with RVmIVS and RVOT pacing (P = 0.03 and P = 0.01 respectively). There were no significant differences in either LVEF or Ts-SD between RVmIVS and RVOT. Right ventricular septal pacing from mid septum or RVOT pacing improves LVEF and LV synchrony in CRT candidates. Further improvement in LVEF was achieved by CRT, which remains the 'gold standard' therapy in these patients. However, RV septal pacing is worthy of further study as an alternative strategy when LV lead implantation fails.


Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group.
The efficacy of two doses of zidovudine was examined for the treatment of the acquired immunodeficiency syndrome (AIDS) dementia complex in a randomized, double-blinded, placebo-controlled trial conducted at nine study centers. For the initial 16 weeks, 40 subjects with mild to moderate AIDS dementia complex were randomized to one of three treatment arms: 400 mg of zidovudine five times daily, 200 mg of zidovudine five times daily, or placebo five times daily. After week 16, patients initially randomized to the placebo group were rerandomized to one of the two zidovudine treatment arms. The primary efficacy end point was improvement in performance on a battery of seven neuropsychological tests; the secondary end point was improvement on a protocol neurological evaluation directed at the cardinal features of the AIDS dementia complex. For the initial 16-week period, average z scores based on the neuropsychological test battery revealed a significant improvement in the combined treatment groups compared to the placebo group; however, when the two treatment groups were compared separately to the placebo group, only the group receiving the higher zidovudine dose exhibited significant improvement. After rerandomization of the placebo patients to one of the two treatment arms at week 16, this group also showed significant improvement in the average neuropsychological z score by week 32. These results extend previous observations that indicate a therapeutic benefit of zidovudine for the treatment of AIDS dementia complex.


Emerging of antimicrobial resistance in staphylococci isolated from clinical and food samples in Algeria.
The antimicrobial resistance of staphylococci rose worldwide. In total, 96 Staphylococcus isolates from food and clinical samples were collected from two provinces in Algeria. The antimicrobial susceptibility testing was performed and resistance-associated genes were detected. Fifty-one strains were isolated from food samples and differentiated into 33 Staphylococcus aureus and 18 coagulase-negative staphylococci. Forty-five staphylococci were collected from hospital and community-acquired infection cases. All S. aureus isolated from food were resistant to penicillin and 45.5% were resistant to tetracycline. The resistance rates of 45 clinical Staphylococcus isolates were 86.7%, 48.9%, 37.8% and 20.0% to penicillin, tetracycline, erythromycin and kanamycin, respectively. Nine isolates were confirmed as MRSA from food and clinical isolates. One S. aureus originated from food was confirmed as vancomycin-resistant. Multidrug-resistance was observed among 25.5% and 53.3% of food and clinical staphylococci, respectively. The tetM/K, blaZ, aacA-aphD, ermC and mecA genes were detected in food and clinical isolates. ermA gene was not found. This study provided insight into the status of antimicrobial resistance of staphylococci isolated from food and clinical samples in Algeria. Further investigations and surveillance programmes are mandatory.


Power and cost containment in a Danish public hospital.
The assumption that hospital decision-making is hierarchical in character underpins the policy formulation process in public as well as pluralist national health care systems. This article's analysis of decision-making in a Danish public hospital reinforces the contrary assertion: that effective authority in acute-care hospitals rests in an amorphous power relationship among the hospital's several occupational groups, in which physicians clearly have the upper hand. After a brief introduction to this Danish hospital, the article develops a detailed portrait of its informal power structure and of the different occupational groups' permanent power-maximizing strategies. Subsequently, the article assesses the impact of these strategies upon two recent efforts to contain the hospital's costs: a decision to close an expensive specialty clinic, and an attempt to shrink the hospital's size by transferring less sick elderly patients to a newly created rehabilitation facility. The study's findings suggest that efforts to impose hospital cost containment by exclusively political means are unlikely to succeed.


PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.
PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.


An evaluation of crude palm oil (CPO) and tocotrienol rich fraction (TRF) of palm oil as percutaneous permeation enhancers using full-thickness human skin.
The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.


The Lγ Phase of Pulmonary Surfactant.
To determine how different components affect the structure of pulmonary surfactant, we measured X-ray scattering by samples derived from calf surfactant. The surfactant phospholipids demonstrated the essential characteristics of the Lγ phase: a unit cell with a lattice constant appropriate for two bilayers, and crystalline chains detected by wide-angle X-ray scattering (WAXS). The electron density profile, obtained from scattering by oriented films at different relative humidities (70-97%), showed that the two bilayers, arranged as mirror images, each contain two distinct leaflets with different thicknesses and profiles. The detailed structures suggest one ordered leaflet that would contain crystalline chains and one disordered monolayer likely to contain the anionic compounds, which constitute ∼10% of the surfactant phospholipids. The spacing and temperature dependence detected by WAXS fit with an ordered leaflet composed of dipalmitoyl phosphatidylcholine. Physiological levels of cholesterol had no effect on this structure. Removing the anionic phospholipids prevented formation of the Lγ phase. The cationic surfactant proteins inhibited Lγ structures, but at levels unlikely related to charge. Because the Lγ phase, if arranged properly, could produce a self-assembled ordered interfacial monolayer, the structure could have important functional consequences. Physiological levels of the proteins, however, inhibit formation of the Lγ structures at high relative humidities, making their physiological significance uncertain.


Gender and international clinician educators.
To describe gender differences of international clinician educators (CEs) and leaders, and CEs' perceptions by gender of preparation, roles, rewards and factors affecting job satisfaction and retention in emerging international competency-based residency programmes. Cross-sectional surveys of CEs and leadership were conductedJune 2013-June 2014 at institutions that had adopted competency-based graduate medical education and were accredited by the Accreditation Council for Graduate Medical Education-International. 274 (76.3%) of 359 eligible participants responded; 69 (25.2%) were female. Two (18%) of 11 chief executive officers and 1 (9%) of 11 chief medical officers were women. Female CEs were younger, more likely to be single and childless. They were less likely to hold academic appointments, despite no gender differences in length of time at current institution or in current position. A greater proportion of female CEs felt they were 'never' rewarded by academic promotion. Satisfaction rates were similar between the genders. Single female CEs were five times as likely to report being 'extremely likely' to stay in the country. Female CEs with children <21 were less likely to report high likelihood of staying in academia. Marital status and children were not associated with outcomes for male CEs. In the international academic medicine programmes studied, there were fewer female CEs in the pipeline and they perceived a gender gap in appointment and advancement. Stakeholders at international programmes need to develop contextualised strategies to expand entry and decrease attrition of women into CE tracks, and promote gender equity.


Left atrial hypertension causes pleural effusion formation in unanesthetized sheep.
We studied the effect of left atrial pressure (LAP) elevation on the formation of pleural effusion in unanesthetized sheep. We prepared the animals by placing catheters in the left atrium, pulmonary artery, femoral artery, and vein. We also placed a balloon catheter in the left atrium. After a recovery period of at least 1 wk, we measured LAP, pulmonary artery pressure (PAP), systemic arterial pressure, systemic venous pressure, cardiac output, plasma protein concentration, and plasma colloid osmotic pressure (pi c). We calculated capillary pressure (Pc) as 0.5(PAP - LAP). We then elevated LAP such that Pc-pi c was between -10 and 19.5 mmHg for 6-24 h. At the end of the experiment, we killed the sheep and measured the volume and protein concentration of the right pleural effusion. We also determined the extravascular fluid to blood free dry weight of the right lung. We found that pleural effusions and pulmonary edema formed when Pc-pi c greater than 5 mmHg. We also found that the pleural effusion volume correlated with the amount of pulmonary edema. Our data show that elevated LAP may cause pleural effusions, but only after pulmonary edema has developed.


Reproducibility of ambulatory gastric pH recordings in the corpus and antrum. Effect of food, time, and electrode position.
The reproducibility of simultaneous, long-term, ambulatory gastric pH recordings in the antrum and corpus was investigated in nine healthy subjects who underwent three separate, 27-h gastric double pH-metries. Intraindividual reproducibility for the entire 27-h recording period was good in the corpus (Kendall's concordance coefficient, W' = 0.6393, p less than 0.025) but not in the antrum (W' = 0.4806, NS). Analysis of predefined time periods showed that non-meal daytime pH was reproducible in the corpus (W' = 0.6531, p less than 0.025) but not in the antrum (W' = 0.3395, NS), whereas mealtime pH was reproducible in the antrum (W' = 0.7159, p less than 0.005) but not in the corpus (W' = 0.4954, NS); nocturnal pH was not reproducible in either the antrum or the corpus. These results reflect the functional separation of corpus and antrum and their differing responses to food. Thus, studies of gastric acidity over long periods should be conducted in the corpus, whereas studies of gastric acidity over shorter, meal-related periods should be conducted with a second electrode in the antrum.


Behavioural oscillations in visual orientation discrimination reveal distinct modulation rates for both sensitivity and response bias.
Perception is modulated by ongoing brain oscillations. Psychophysical studies show a voluntary action can synchronize oscillations, producing rhythmical fluctuations of visual contrast sensitivity. We used signal detection to examine whether voluntary action could also synchronize oscillations in decision criterion, and whether that was due to the oscillations of perceptual bias or of motor bias. Trials started with a voluntary button-press. After variable time lags, a grating at threshold contrast was presented briefly and participants discriminated its orientation (45° or -45°) with a mouse-click. Two groups of participants completed the experiment with opposite mappings between grating orientations and response buttons. We calculated sensitivity and criterion in the 800 ms period following the button press. To test for oscillations, we fitted first-order Fourier series to these time series. Alpha oscillations occurred in both sensitivity and criterion at different frequencies: ~8 Hz (sensitivity) and ~10 Hz (criterion). Sensitivity oscillations had the same phase for both stimulus-response mappings. Criterion oscillations, however, showed a strong anti-phase relationship when the two groups were compared, suggesting a motor bias rather than perceptual bias. Our findings suggest two roles for alpha oscillations: in sensitivity, reflecting rhythmic attentional inhibition, and in criterion, indicating dynamic motor-related anticipation or preparation.


Symptomatic treatment of the cough in whooping cough.
The worldwide incidence of whooping cough (pertussis) has been estimated at 48.5 million cases and nearly 295,000 deaths per year. In low-income countries, the case-fatality rate among infants may be as high as 4%. Much of the morbidity of whooping cough in children and adults is due to the effects of the paroxysmal cough. Cough treatments proposed include corticosteroids, beta 2-adrenergic agonists, pertussis-specific immunoglobulin, antihistamines and possibly leukotriene receptor antagonists (LTRAs). To assess the effectiveness and safety of interventions to reduce the severity of paroxysmal cough in whooping cough in children and adults. We updated searches of the Cochrane Central Register of Controlled Trials (CENTRAL Issue 2, 2012), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, the Database of Abstracts of Reviews of Effects (DARE Issue 2, 2012) accessed from The Cochrane Library, MEDLINE (1950 to January 2012), EMBASE (1980 to January 2012), AMED (1985 to January 2012), CINAHL (1980 to January 2012) and LILACS (January 2012). We searched Current Controlled Trials to identify trials in progress. We selected randomised controlled trials (RCTs) and quasi-RCTs of any intervention (excluding antibiotics and vaccines) to suppress the cough in whooping cough. Two review authors (SB, MT) independently selected trials, extracted data and assessed the quality of each trial for this review in 2009. Two review authors (SB, KW) independently reviewed additional studies identified by the updated search in 2012. The primary outcome was frequency of paroxysms of coughing. Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis (turning blue), development of serious complications, mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay. Ten trials were included of varying sample sizes (N = 9 to 135) from high-income countries. Study quality was generally poor. Included studies did not show a statistically significant benefit for any of the interventions. Only six trials including a total of 196 participants reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) - 4.7 to 8.5. One study on pertussis immunoglobulin reported a possible mean reduction of -3.1 whoops per 24 hours (95% CI -6.2 to 0.02) but no change in hospital stay (MD -0.7 days; 95% CI -3.8 to 2.4). Dexamethasone did not show a clear decrease in length of hospital stay (MD -3.5 days; 95% CI -15.3 to 8.4) and salbutamol showed no change in coughing paroxysms per 24 hours (MD -0.2; 95% CI -4.1 to 3.7). Only one trial comparing pertussis immunoglobulin versus placebo reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site). There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough.


Neuroimaging in aphasia treatment research: quantifying brain lesions after stroke.
New structural and functional neuroimaging methods continue to rapidly develop, offering promising tools for cognitive neuroscientists. In the last 20 years, advanced magnetic resonance imaging (MRI) techniques have provided invaluable insights into how language is represented and processed in the brain and how it can be disrupted by damage to, or dysfunction of, various parts of the brain. Current functional MRI (fMRI) approaches have also allowed researchers to purposefully investigate how individuals recover language after stroke. This paper presents recommendations for quantification of brain lesions derived from discussions among international researchers at the Neuroimaging in Aphasia Treatment Research Workshop held at Northwestern University (Evanston, Illinois, USA). Methods for detailing and characterizing the brain damage that can influence results of fMRI studies in chronic aphasic stroke patients are discussed. Moreover, we aimed to provide the reader with a set of general practical guidelines and references to facilitate choosing adequate structural imaging strategies that facilitate fMRI studies in aphasia treatment research.


A novel non-ataxic guinea pig strain with cerebrocortical and cerebellar abnormalities.
This is the first description of GS guinea pigs, a partially inbred, non-ataxic, albino Peruvian (long-hair) strain with abnormal motor behavior and seizures. GS guinea pigs show gross and microscopic cerebellar and microscopic cerebrocortical abnormalities compared to Hartley strain animals. There is little difference between GS and short-hair guinea pig strains in Purkinje cell function, electrically evoked Ca2+ transients or immune responsiveness. The GS strain may prove useful in studying altered functions of the cerebellum in human disease.


Physiological noise in brainstem FMRI.
The brainstem is directly involved in controlling blood pressure, respiration, sleep/wake cycles, pain modulation, motor, and cardiac output. As such it is of significant basic science and clinical interest. However, the brainstem's location close to major arteries and adjacent pulsatile cerebrospinal fluid filled spaces, means that it is difficult to reliably record functional magnetic resonance imaging (fMRI) data from. These physiological sources of noise generate time varying signals in fMRI data, which if left uncorrected can obscure signals of interest. In this Methods Article we will provide a practical introduction to the techniques used to correct for the presence of physiological noise in time series fMRI data. Techniques based on independent measurement of the cardiac and respiratory cycles, such as retrospective image correction (RETROICOR, Glover et al., 2000), will be described and their application and limitations discussed. The impact of a physiological noise model, implemented in the framework of the general linear model, on resting fMRI data acquired at 3 and 7 T is presented. Data driven approaches based such as independent component analysis (ICA) are described. MR acquisition strategies that attempt to either minimize the influence of physiological fluctuations on recorded fMRI data, or provide additional information to correct for their presence, will be mentioned. General advice on modeling noise sources, and its effect on statistical inference via loss of degrees of freedom, and non-orthogonality of regressors, is given. Lastly, different strategies for assessing the benefit of different approaches to physiological noise modeling are presented.


Full and surface tibial cementation in total knee arthroplasty: a biomechanical investigation of stress distribution and remodeling in the tibia.
Aseptic tibial component loosening remains a major cause of total knee arthroplasty failure. The cementation technique used to achieve fixation may play a major role in loosening. Despite this, the optimum technique remains unanswered. This study aims to investigate stress and strain distributions in the proximal tibia for full cementation and surface cementation of the Genesis II tibial component. Principal cortical bone strains were measured experimentally in intact, surface cemented and fully cemented synthetic tibiae using strain gauges. Both axial and 15° flexion loading were considered. Finite element models were used to assess both cortical and cancellous bone stresses and strains. Using a bone remodeling algorithm potential sites of bone formation and resorption were identified post-implantation. Principal cortical bone strain results demonstrate strong correlations between the experimental and finite element analyses (R(2)≥0.81, RMSE(%)≤17.5%). Higher cortical strains are measured for surface cementation, as full cementation creates a stiffer proximal tibial structure. Simulations reveal that both cementation techniques result in lower cancellous stresses under the baseplate compared to the intact tibia, with greater reductions being computed for full cementation. The surface cementation model displays the closest cancellous stress distribution to the intact model. In addition, bone remodeling simulations predict more extensive bone resorption under the baseplate for full cementation (43%) than for surface cementation (29%). Full cementation results in greater stress reduction under the tibial baseplate than surface cementation, suggesting that surface cementation will result in less proximal bone resorption, thus reducing the possibility of aseptic loosening.


Fabrication of Hierarchical Porous Carbon Nanoflakes for High-Performance Supercapacitors.
In the current work, the carbon nanoflakes (CNs-Fe/KOH) and porous carbon (PC-Ni/KOH) have been produced by using Fe(NO3)3/KOH and Ni(NO3)2/KOH as the cographitization/activation catalysts to treat the natural plane tree fluff, respectively. The as-prepared carbon materials show different morphologies when treated with different metal ions. Compared with PC-Ni/KOH, the CNs-Fe/KOH have both high graphitization degree (IG/ID = 1.53) and large SBET (1416 m2/g). In a three-electrode setup, the CNs-Fe/KOH electrode shows a high specific capacitance of 253 F/g at 10 A/g, with a capacitance retention of 92.64% after 10000 cycles in 2 M H2SO4 aqueous solution, which is far better than the sample without Fe3+ addition. In 1 M LiPF6 in ethylene carbonate/diethyl carbonate organic solution, CNs-Fe/KOH-based symmetric supercapacitor also presents an excellent specific capacitance of 32.2 F/g at 1 A/g. In addition, an energy density of 39.98 W h/kg can be achieved at the power density of 1.49 kW/kg. Influence of metal ions on the morphology and structure as well as electrochemical performance of the carbon materials are further analyzed in detail. The current work provides a novel path for design and fabrication of supercapacitor electrode materials with promising electrochemical performances.


Highly Activated Ex Vivo-expanded Natural Killer Cells in Patients With Solid Tumors in a Phase I/IIa Clinical Study.
We previously developed a novel technique for expanding highly activated and purified natural killer (NK) cells able to maximize the theoretical activation potential of NK cells; thus, we named this cell population zenithal-NK (ZNK). To evaluate the safety, feasibility, and preliminary efficacy of autologous ZNK cells in patients with different types of advanced cancer with measurable solid lesions. In this phase I/IIb first-in-human, open-label, dose-escalation study (trial registration ID: UMIN-000011555), eligible patients received ZNK cells intravenously starting from 106 to 108 cells/patient/dose at 2-week dosing intervals. A maximum of six cycles were allowed. Safety and survival analyses were also carried out for cases that were excluded and never administered ZNK cells. As of April 20, 2017, a total of nine patients were enrolled in this study, with one recruited twice. Overall, neither grade 2 or higher toxicities (Common Terminology Criteria for Adverse Events v5.0) caused by cell administration, nor adverse events causing discontinuation of protocol treatment were found. In four cases, the number of administered ZNK cells was increased to 108 cells/body/dose without any serious dose-limiting toxicity; the maximally tolerated dose was therefore considered to be at least 108 cells. The overall response rate was 40.0% in 10 net cases, one of partial response and three of stable disease, and the patient with partial response is still alive after 4 year's observation. These results demonstrate that autologous ZNK cells are safe and well-tolerated in patients with different types of advanced solid tumors. Clinical studies using similarly active ZNK cells from human leukocyte antigen/killer cell immunoglobulin-like receptor-mismatched healthy donors under Good Manufacturing Practice-compliant manufacturing, and with modified treatment regimen, i.e. doses and frequencies, are warranted for further investigation to show the potential of ZNK cells in such patients.


Prenatal and childhood influences on osteoporosis.
Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, in both genders there is a dissociation between the peak velocities for height gain and bone mineral accrual. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status and sporadic risk factors such as cigarette smoking. Measures for maximizing bone mineral acquisition, particularly through encouraging physical activity and adequate dietary calcium intake, are likely to affect the risk of fracture in later generations. In addition to these modifiable factors during childhood, evidence has also accrued that the risk of fracture might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the hypothalamic - pitutiary - adrenal (HPA) and growth hormone/insulin-like growth factor I (GH/IGF-I) axes. Maternal smoking, diet and physical activity levels appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.


Family-centered care for US children with special health care needs: who gets it and why?
The goal was to examine racial/ethnic and language disparities in family-centered care (FCC) and in FCC components for children with special health care needs (CSHCN). Bivariate and multivariate logistic regression analyses of data from the 2005-2006 National Survey of CSHCN were performed. A total of 66% of CSHCN with a health visit in the past year received FCC. In adjusted analyses, we found lower odds of FCC for Latino (odds ratio: 0.53 [95% confidence interval: 0.45-0.63]), African-American (odds ratio: 0.60 [95% confidence interval: 0.52-0.69]), and other (odds ratio: 0.58 [95% confidence interval: 0.43-0.78]) children, compared with white children, and for children in households with a non-English primary language (odds ratio: 0.48 [95% confidence interval: 0.36-0.64]), compared with those in households with English as the primary language. These disparities persisted after adjustment for child health (condition severity and emotional, behavioral, and developmental needs), socioeconomic (poverty level, parental education, household composition, and residing in a metropolitan statistical area), and access (insurance type, usual source of care, and having a personal physician) factors. Of these factors, only condition severity was significantly associated with the racial/ethnic disparities; none was significantly associated with the language disparities. Disparities were found for Latino and African-American children and children in households with a non-English primary language for the FCC components of time spent with the provider and sensitivity to the family's values and customs. Robust FCC racial/ethnic and language disparities exist for CSHCN; initial efforts to address these disparities should focus on increasing provider time and cultural sensitivity.


Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study.
Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.


Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis.
Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.


Pancytopenia and atrial fibrillation associated with chronic hepatitis C infection and presumed hepatocellular carcinoma: a case report.
Pancytopenia secondary to hepatitis viral infection is a rare but noted clinical entity. An acute aplastic crisis usually occurs shortly after viral infection, however, viral serologies are usually negative and the pancytopenia is often fatal if left untreated. A 66-year-old woman presented to the emergency department with shortness of breath and palpitations. She was found to have pulmonary edema secondary to a newly diagnosed atrial fibrillation and was treated with rate control and anticoagulation. She was found to have an anemia that was reported to be longstanding and that was apparently being investigated by a hematologist, although no diagnosis had yet been achieved. Her blood work also revealed a mild leucopenia and pronounced thrombocytopenia. The patient was admitted to ensure appropriate rate control of her atrial fibrillation and for work-up of her pancytopenia. Review of the bone marrow biopsy performed by the hematologist revealed a normal marrow with no infiltrative process. The results of the patient's blood tests ruled out a hemolytic process. There was also no evidence of infection, toxin ingestion, or recent medication that could be associated with pancytopenia. An abdominal ultrasound was ordered to rule out enlargement of the spleen and a possible consumptive coagulopathy. The spleen was mildly enlarged with a diameter of 13 cm. The liver, however, was mildly cirrhotic and a small solitary liver lesion was seen. A magnetic resonance imaging scan of the liver confirmed a single solitary solid mass and the alpha-fetal protein level in the serum was elevated. The patient's preliminary viral serologies were positive for hepatitis C. The patient was diagnosed with presumed hepatocellular carcinoma and referred to a hepatic surgeon for evaluation of treatment options. Hepatitis associated aplastic anemia is an acute condition while milder more chronic presentations, such as this case, likely result from increased portal pressure generated from the resulting cirrhosis, which leads to a relative hypersplenism.


A non-targeted metabolite profiling pilot study suggests that tryptophan and lipid metabolisms are linked with ADHD-like behaviours in dogs.
Attention deficit hyperactivity disorder (ADHD) is a prevalent and multifactorial neuropsychiatric disorder in the human population worldwide. Complex etiology and clinical heterogeneity have challenged the research, diagnostics and treatment of the disease. Hyperactive and impulsive behaviour has also been observed in dogs, and they could offer a physiologically relevant model for human ADHD. As a part of our ongoing study to understand the molecular etiology of canine anxiety traits, this study was aimed to pilot an approach to identify metabolic biomarkers in canine ADHD-like behaviours for research, diagnostics and treatment purposes. We collected fresh plasma samples from 22 German Shepherds with varying ADHD-like behaviours. All dogs were on the same controlled diet for 2 weeks prior to sampling. A liquid chromatography combined with mass spectrometry (LC-MS)-based non-targeted metabolite profiling was performed to identify plasma metabolites correlating with the ADHD-like behaviour of the dogs. 649 molecular features correlated with ADHD-like behavioural scores (praw < 0.05), and three of them [sn-1 LysoPC(18:3), PC(18:3/18:2) and sn-1 LysoPE(18:2)] had significant correlations also after FDR correction (pFDR < 0.05). Phospholipids were found to negatively correlate with ADHD-like behavioural scores, whereas tryptophan metabolites 3-indolepropionic acid (IPA) and kynurenic acid (KYNA) had negative and positive correlations with ADHD-like behavioural scores, respectively. Our study identified associations between canine ADHD-like behaviours and metabolites that are involved in lipid and tryptophan metabolisms. The identified metabolites share similarity with earlier findings in human and rodent ADHD models. However, a larger replication study is warranted to validate the discoveries prior to further studies to understand the biological role of the identified metabolites in canine ADHD-like behaviours.


Spinal cord herniation after stabbing injury.
A 19-year-old man presented with delayed paraplegia on the second day after a stab injury of the spine. Magnetic resonance imaging showed herniation of the spinal cord through the dural defect. After emergency surgery, his paraplegia recovered leaving a Brown-Sequard syndrome immediate after injury. Spinal cord herniation should be considered as one of the possible factors in patients developing neurological deterioration after a stab injury of the spine. The possible pathogenesis of symptomatic non-spontaneous spinal cord herniation is discussed.


Cathepsin C is a tissue-specific regulator of squamous carcinogenesis.
Serine and cysteine cathepsin (Cts) proteases are an important class of intracellular and pericellular enzymes mediating multiple aspects of tumor development. Emblematic of these is CtsB, reported to play functionally significant roles during pancreatic islet and mammary carcinogenesis. CtsC, on the other hand, while up-regulated during pancreatic islet carcinogenesis, lacks functional significance in mediating neoplastic progression in that organ. Given that protein expression and enzymatic activity of both CtsB and CtsC are increased in numerous tumors, we sought to understand how tissue specificity might factor into their functional significance. Thus, whereas others have reported that CtsB regulates metastasis of mammary carcinomas, we found that development of squamous carcinomas occurs independently of CtsB. In contrast to these findings, our studies found no significant role for CtsC during mammary carcinogenesis but revealed squamous carcinogenesis to be functionally dependent on CtsC. In this context, dermal/stromal fibroblasts and bone marrow-derived cells expressed increased levels of enzymatically active CtsC that regulated the complexity of infiltrating immune cells in neoplastic skin, development of angiogenic vasculature, and overt squamous cell carcinoma growth. These studies highlight the important contribution of tissue/microenvironment context to solid tumor development and indicate that tissue specificity defines functional significance for these two members of the cysteine protease family.


Sequential morphometric evaluation at UnicCa® and SLActive® implant surfaces. An experimental study in the dog.
To study sequential osseointegration around implants with nano-technologically modified surfaces at different periods of healing. After 3 months, two different implant systems with different nano-technologically modified surfaces were randomly installed in the edentulous molar regions of the mandible of 12 dogs. One surface was acid-etched surface, and subsequently modified with calcium ions (UnicCa® ), while the other was a hydrophilic sandblasted with large grit and acid-etched (SLActive® ) surface. The implants were fully submerged, and biopsies were obtained representing the healing after 1, 2, 4 and 8 weeks (n = 6 per period). A morphometric evaluation of densities of new soft tissues (provisional matrix and immature bone marrow), new and old bone, mature bone marrow, vessels and other tissues (bone debris/particles and clot) was performed in the spongiosa compartment of the sites of implantation. After 1 week of healing, the soft tissues, mainly composed of provisional matrix, were present at 41.5 ± 23.9% and 30.1 ± 20.0% at the UnicCa® and SLActive surfaces, respectively. These percentages were >40% at both surfaces after 2 weeks of healing, presenting greater amount of immature bone marrow. Subsequently, these percentages decreased up to disappear after 8 weeks of healing. New bone increased progressively between 1 and 8 weeks of healing from 8.2 ± 3.0% to 77.1 ± 6.4% and from 6.8 ± 2.8% to 67.9 ± 6.8% at the UnicCa® and SLActive® , respectively. Old bone decreased progressively over time. The patterns of healing at highly hydrophilic surfaces occurred through the early formation of a provisional matrix followed by the formation of new bone and marrow at various stages of maturation. The healing was similar to those described in different animal models, anatomical sites and surgical procedures.


Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders.
To determine seroprevalence of neuromyelitis optica (NMO)-IgG in childhood CNS inflammatory demyelinating disorders. We analyzed demographic, clinical, and radiologic data in a blinded fashion and assessed serum NMO-IgG status for 87 children: 41 with relapsing-remitting multiple sclerosis (RRMS), 17 with NMO, 13 with monophasic/recurrent optic neuritis (ON), 13 with transverse myelitis, of whom 10 were longitudinally extensive on MRI spine (LETM), and another 3 with LETM in the context of acute disseminated encephalomyelitis (ADEM). Ten of the 87 children (11%) were seropositive. Eight of 17 with NMO (47%) were seropositive (7 of 9 with relapsing NMO [78%], 1 of 8 with monophasic NMO [12.5%]). Two other children were seropositive: 1 of 5 with recurrent ON and one child with recurrent LETM. No seropositive case was identified among 41 with RRMS (14% of whom had LETM at some point in their clinical course), 8 with monophasic ON, 9 with monophasic LETM, or 3 with LETM in the context of ADEM. The similar frequency of neuromyelitis optica (NMO)-IgG in both childhood and adult cases of NMO, and its rarity in relapsing-remitting multiple sclerosis, supports the concept that these diseases have a similar pathogenesis in childhood and adulthood. It is noteworthy that none of nine children with monophasic longitudinally extensive transverse myelitis (LETM) was NMO-IgG-seropositive. Furthermore, LETM does not appear to be as predictive of an NMO spectrum disorder in children as it is in adults. Longitudinal studies of larger pediatric LETM cohorts are required to ascertain whether the absence of NMO-IgG is a negative predictor for relapse in this childhood entity.


The effects of diffraction on the field of view of an optical instrument.
Exact formulas are derived for the field of view of an optical instrument with rectangular primary and secondary apertures and a rectangular field stop. The formulas derived include the effects of diffraction at the primary and secondary apertures. Numerical results are presented for an instrument with square optics, viewing a uniform monochromatic source. Similar calculations have been done for optical instruments with circular apertures by Goldberg and McCulloch [Appl. Opt. 8, 1451 (1969)]. The calculations for an instrument with square optics without a secondary aperture show that if the angle theta(f) subtended by the geometrically determined field of view is 35 times as large as the ratio of wavelength to aperture size, then less than 5% of the energy collected at the detector will be from areas of the source outside the geometrical field of view. Using these formulas, an expression has been derived for the field of view of the same type of instrument viewing an infinite monochromatic source having two uniform brightness levels separated by a straight edge. Numerical results are presented for an instrument with square optics. If theta(f) is at least ten times as large as the ratio of wavelength to aperture size, than 90% of the instrument's response to the step change in brightness occurs while the step is crossing the geometrically determined field of view.


Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats.
Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which is associated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), a CYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A single intraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis. CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNA adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis were examined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-κB protein and TNF-α expression, which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced by ethanol feeding were significantly inhibited by the one month CMZ treatment. At 10-months of treatment, hepatocellular adenomas were detected in ethanol-fed rats only, but neither in control rats nor in animals receiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoic acid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment. These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-α expression, NF-κB activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats.


Quantitative atomic force microscopy provides new insight into matrix vesicle mineralization.
Matrix vesicles (MVs) are a class of extracellular vesicles that initiate mineralization in cartilage, bone, and other vertebrate tissues by accumulating calcium ions (Ca2+) and inorganic phosphate (Pi) within their lumen and forming a nucleation core (NC). After further sequestration of Ca2+ and Pi, the NC transforms into crystalline complexes. Direct evidence of the existence of the NC and its maturation have been provided solely by analyses of dried samples. We isolated MVs from chicken embryo cartilage and used atomic force microscopy peak force quantitative nanomechanical property mapping (AFM-PFQNM) to measure the nanomechanical and morphological properties of individual MVs under both mineralizing (+Ca2+) and non-mineralizing (-Ca2+) fluid conditions. The elastic modulus of MVs significantly increased by 4-fold after incubation in mineralization buffer. From AFM mapping data, we inferred the morphological changes of MVs as mineralization progresses: prior to mineralization, a punctate feature, the NC, is present within MVs and this feature grows and stiffens during mineralization until it occupies most of the MV lumen. Dynamic light scattering showed a significant increase in hydrodynamic diameter and no change in the zeta potential of hydrated MVs after incubation with Ca2+. This validates that crystalline complexes, which are strongly negative relative to MVs, were forming within the lumen of MVs. These data were substantiated by transmission electron microscopy energy dispersive X-ray and Fourier transform infrared spectroscopic analyses of dried MVs, which provide evidence that the complexes increased in size, crystallinity, and Ca/P ratio within MVs during the mineralization process.


Biomonitoring human exposure to environmental carcinogenic chemicals.
A coordinated study was carried out on the development, evaluation and application of biomonitoring procedures for populations exposed to environmental genotoxic pollutants. The procedures used involved both direct measurement of DNA or protein damage (adducts) and assessment of second biological effects (mutation and cytogenetic damage). Adduct detection at the level of DNA or protein (haemoglobin) was carried out by 32P-postlabelling, immunochemical, HPLC or mass spectrometric methods. Urinary excretion products resulting from DNA damage were also estimated (immunochemical assay, mass spectrometry). The measurement of adducts was focused on those from genotoxicants that result from petrochemical combustion or processing, e.g. low-molecular-weight alkylating agents, PAHs and compounds that cause oxidative DNA damage. Cytogenetic analysis of lymphocytes was undertaken (micronuclei, chromosome aberrations and sister chromatid exchanges) and mutation frequency was estimated at a number of loci including the hprt gene and genes involving in cancer development. Blood and urine samples from individuals exposed to urban pollution were collected. Populations exposed through occupational or medical sources to larger amounts of some of the genotoxic compounds present in the environmental samples were used as positive controls for the environmentally exposed population. Samples from rural areas were used as negative controls. The project has led to new, more sensitive and more selective approaches for detecting carcinogen-induced damage to DNA and proteins, and subsequent biological effects. These methods were validated with the occupational exposures, which showed evidence of DNA and/or protein and/or chromosome damage in workers in a coke oven plant, garage workers exposed to diesel exhaust and workers exposed to ethylene oxide in a sterilization plant. Dose reponse and adduct repair were studied for methylated adducts in patients treated with methylating cytostatic drugs. The biomonitoring methods have also demonstrated their potential for detecting environmental exposure to genotoxic compounds in nine groups of non-smoking individuals, 32P-postlabelling of DNA adducts being shown to have the greatest sensitivity.


Maintaining empathy in medical school: it is possible.
Empathy is an indispensable skill in medicine and is an integral part of 'professionalism'. Yet, there is still increasing concern among medical educators and medical professionals regarding the decline in medical students' empathy during medical education. This article aims at comparing the levels of empathy in medical school students across the different years of undergraduate medical education. It also aims at examining differences in empathy in relation to gender, year of study, cultural and religious backgrounds, previous tertiary education and certain programmes within the curriculum. The Jefferson Scale of Physician Empathy, Student version (JSPE-S) was employed to measure empathy levels in medical students (years one to five) in a cross-sectional study. Attached to the scale was a survey containing questions on demographics, stage of medical education, previous education, and level of completion of particular programmes that aim at promoting personal and professional development (PPD). Four hundred and four students participated in the study. The scores of the JSPE-S ranged from 34 to 135 with a mean score of 109.07 ± 14.937. Female medical students had significantly higher empathy scores than male medical students (111 vs. 106, p < 0.001) across all five years of the medical course. There was no significant difference in the total empathy scores in relation to year of medical education. Yet, the highest means were scored by year five students who had completed personal and professional development courses. Our findings suggest that there is a gender difference in the levels of empathy, favouring female medical students. They also suggest that, despite prior evidence of a decline, empathy may be preserved in medical school by careful student selection and/or personal and professional development courses.


Primary cutaneous cryptococcosis.
Cryptococcal infections in immuno-compromised patients are of major importance. Current opinion holds that cutaneous cryptococcal infections in these patients indicate disseminated disease. In our renal transplant patient with primary cutaneous cryptococcosis, intravenously administered antifungal chemotherapy resulted in resolution of the disease and appears to have prevented disseminated infection.


Optimization of enhanced absorption in 3D-woodpile metallic photonic crystals.
We present a detailed theoretical analysis which reveals a useful insight to understand the resonant dissipative behavior of 3D woodpile metallic photonic crystals in the spectral response. We observe that a small amount of structural parameter modifications can induce great flexibility to alter the properties of the absorption resonance with even an extremely narrow band width of ~13 nm. Analyzing the dispersive properties of the 3D woodpile metallic photonic crystals and performing thorough numerical simulations for the finite number of layers we found that the magnitude, band width, and tunability of enhanced absorption can be easily optimized, which can be of significance to design an efficient photonic crystal thermal emitter.


Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States.
From October 4 to November 2, 2001, the first 10 confirmed cases of inhalational anthrax caused by intentional release of Bacillus anthracis were identified in the United States. Epidemiologic investigation indicated that the outbreak, in the District of Columbia, Florida, New Jersey, and New York, resulted from intentional delivery of B. anthracis spores through mailed letters or packages. We describe the clinical presentation and course of these cases of bioterrorism-related inhalational anthrax. The median age of patients was 56 years (range 43 to 73 years), 70% were male, and except for one, all were known or believed to have processed, handled, or received letters containing B. anthracis spores. The median incubation period from the time of exposure to onset of symptoms, when known (n=6), was 4 days (range 4 to 6 days). Symptoms at initial presentation included fever or chills (n=10), sweats (n=7), fatigue or malaise (n=10), minimal or nonproductive cough (n=9), dyspnea (n=8), and nausea or vomiting (n=9). The median white blood cell count was 9.8 X 10(3)/mm(3) (range 7.5 to 13.3), often with increased neutrophils and band forms. Nine patients had elevated serum transaminase levels, and six were hypoxic. All 10 patients had abnormal chest X-rays; abnormalities included infiltrates (n=7), pleural effusion (n=8), and mediastinal widening (seven patients). Computed tomography of the chest was performed on eight patients, and mediastinal lymphadenopathy was present in seven. With multidrug antibiotic regimens and supportive care, survival of patients (60%) was markedly higher (<15%) than previously reported.


Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism.
Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.


Production of bioethanol using agricultural waste: banana pseudo stem.
India is amongst the largest banana (Musa acuminata) producing countries and thus banana pseudo stem is commonly available agricultural waste to be used as lignocellulosic substrate. Present study focuses on exploitation of banana pseudo stem as a source for bioethanol production from the sugars released due to different chemical and biological pretreatments. Two fungal strains Aspergillus ellipticus and Aspergillus fumigatus reported to be producing cellulolytic enzymes on sugarcane bagasse were used under co-culture fermentation on banana pseudo stem to degrade holocellulose and facilitate maximum release of reducing sugars. The hydrolysate obtained after alkali and microbial treatments was fermented by Saccharomyces cerevisiae NCIM 3570 to produce ethanol. Fermentation of cellulosic hydrolysate (4.1 g%) gave maximum ethanol (17.1 g/L) with yield (84%) and productivity (0.024 g%/h) after 72 h. Some critical aspects of fungal pretreatment for saccharification of cellulosic substrate using A. ellipticus and A. fumigatus for ethanol production by S. cerevisiae NCIM 3570 have been explored in this study. It was observed that pretreated banana pseudo stem can be economically utilized as a cheaper substrate for ethanol production.


Evaluation of watershed-derived mass loads to prioritize TMDL decision-making.
A total maximum daily load (TMDL) for oxygen demanding substances is being implemented in the San Joaquin River (SJR) in California (USA) due to frequently occurring low dissolved oxygen conditions. The SJR is a eutrophic river, heavily impacted by agriculture. A mass balance was developed to identify the sources of oxygen-demanding substances and nutrients to the river with the objective of providing a scientific basis for management actions needed to meet TMDL requirements. Data were collected for flow and water quality and mass loads calculated for sites within the main stem of the SJR, river inputs (tributaries), and diversions in the study area. Using a quadrant analysis, tributary flows and loads are ranked to identify targets for water quality improvement efforts. Additionally, all mass loads were summed (inputs minus diversions) and compared with observed loads at the downstream limit of the study area. The mass balance analysis identifies major contributors of mass loads and mass balance closure is assessed for each constituent. These analysis methods inform the TMDL process which includes a load allocation, and is useful for determining locations for implementation of improvement projects needed to improve the health of the river.


Objective physical activity of filipino youth stratified for commuting mode to school.
The Cebu Longitudinal Health and Nutrition Survey included self-report measures and objective measures (Caltrac accelerometer) of Filipino adolescent (ages 14-16) physical activity (PA) in 1998-99. The purpose of this subanalysis was to compare objectively monitored PA of adolescents who differed by their self-reported habitual commuting mode to school, specifically commuting by walking, motorized transport, or a combination of the two. Descriptive analysis included the proportion of adolescents who reported commuting to school by the different modes, participating in sport/exercise during or after school, or currently working. ANCOVA was used to estimate and compare adjusted mean Caltrac-derived energy expenditure (kcal.d ) by commuting mode for each gender. Covariates were age, weight, and height. The analysis sample of 1518 Filipino adolescents included 691 male (BMI = 18.5 +/- 2.5) and 827 female subjects (BMI = 18.7 +/- 2.3). A total of 323 male subjects (46.8% of all male subjects) walked to school, 160 (23.2%) took motorized transport, and 208 (30.0%) used a combination of the two modes. The corresponding values for female subjects were 303 (36.6%), 177 (21.4%), and 347 (42.0%). The absolute difference in Caltrac-derived energy expenditure that appeared to be due to active commuting was 44.2 kcal.d for Filipino male adolescents and 33.2 kcal.d for female adolescents. These differences between commuting modes could not be explained by participation in sport/exercise or by current employment. Assuming 200 school days in a year, the difference in energy expended due to active commuting translates to a 8840 kcal and 6640 kcal in male and female subjects, respectively. For those youth who commute to school by motorized transport a yearly positive energy balance (i.e., weight gain) of 2-3 lb would be anticipated, all other things being held constant.


Macrophage inflammatory protein derivative ECI301 enhances the alarmin-associated abscopal benefits of tumor radiotherapy.
Radiotherapy can produce antitumor benefits beyond the local site of irradiation, an immune-based phenomenon known as the abscopal effect, but the mechanisms underlying these benefits are poorly understood. Preclinical studies of ECI301, a mutant derivative of macrophage inhibitory protein-1α, have shown that its administration can improve the antitumor effects of radiotherapy in a manner associated with a tumor-independent abscopal effect. In this article, we report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by intratumoral injection [corrected] of the alarmins HSP70 or HMGB1, but not HSP60, and i.v. administration [corrected] of ECI301 + HSP70 were sufficient to inhibit tumor growth. Although i.v. administration [corrected] of ECI301 + HMGB1 did not inhibit tumor growth, we found that administration of a neutralizing HMGB1 antibody neutralized the cooperative effects of ECI301 on tumor irradiation. Moreover, mice genetically deficient in TLR4, an immune pattern receptor that binds alarmins, including HMGB1 and HSP70, did not exhibit antitumor responses to irradiation with ECI301 administration. Although ECI301 was cleared rapidly from peripheral blood, it was found to bind avidly to HSP70 and HMGB1 in vitro. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4(+) and CD8(+) T cells against tumor cells that may evade irradiation. Cancer Res; 74(18); 5070-8. ©2014 AACR.


Drinking to their health: social analysis of a micronutrient-fortified beverage field trial.
Anthropologic research was conducted among pregnant and lactating women in rural Tanzania in conjunction with clinical trials of a micronutrient-fortified beverage. Use of the beverage was examined through interviews and ethnographic observation in clinics and at home. Women liked the taste of the beverage, considered it beneficial to their health, preferred it to pills or injections, and most were willing and able to use it according to instructions. Most consumed the beverage according to schedule in the hope of improving pregnancy outcomes. However, public health facilities in Tanzania are not currently equipped to ensure regular delivery of micronutrient supplements, and many of the women with the worst nutrition profiles are also those who would be least able to purchase supplements on the open market. Successful distribution of micronutrient supplements in forms that appeal to consumers, such as a fortified beverage, will require programmatic attention to locally appropriate social marketing and to the challenges of reaching those with extremely low incomes.


Chemical inhibitors of monogalactosyldiacylglycerol synthases in Arabidopsis thaliana.
Monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the main lipids in photosynthetic membranes in plant cells. They are synthesized in the envelope surrounding plastids by MGD and DGD galactosyltransferases. These galactolipids are critical for the biogenesis of photosynthetic membranes, and they act as a source of polyunsaturated fatty acids for the whole cell and as phospholipid surrogates in phosphate shortage. Based on a high-throughput chemical screen, we have characterized a new compound, galvestine-1, that inhibits MGDs in vitro by competing with diacylglycerol binding. Consistent effects of galvestine-1 on Arabidopsis thaliana include root uptake, circulation in the xylem and mesophyll, inhibition of MGDs in vivo causing a reduction of MGDG content and impairment of chloroplast development. The effects on pollen germination shed light on the contribution of galactolipids to pollen-tube elongation. The whole-genome transcriptional response of Arabidopsis points to the potential benefits of galvestine-1 as a unique tool to study lipid homeostasis in plants.


N-terminal pro-B-type natriuretic peptide-ratio predicts mortality after transcatheter aortic valve replacement.
We studied the prognostic value of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP)-ratio, which is independent of individual cutoff levels, in predicting mortality in patients undergoing transcatheter aortic valve replacement (TAVR). Elevated levels of natriuretic peptides are associated with adverse outcomes across a wide spectrum of cardiovascular diseases. However, cutoff values differ according to age, gender, and body weight. 244 TAVR patients with preprocedural NT-proBNP levels were analyzed, and the predictive value of NT-proBNP-ratio (measured NT-proBNP/maximal normal NT-proBNP values specific for age and gender) on all-cause-mortality was assessed in a multivariate model. Median NT-proBNP-ratio was 4.2 [IQR 1.8-9.7]. All-cause mortality at 30 days was 3.4% in patients with less than median NT-proBNP-ratio, and 14.0% in patients with more than median NT-proBNP-ratio (P=0.02). All-cause mortality at 1 year was 8.5% in patients with less than median NT-proBNP-ratio, and 32.1% in those with more than median NT-proBNP-ratio (P=0.001). Cumulative survival declined with increasing quartiles of NT-proBNP-ratio (log rank P=0.001). All patients with a NT-proBNP-ratio below 1.5 survived at 1-year follow-up. In ROC analysis, NT-proBNP-ratio significantly predicted 30-day (AUC=0.72; P=0.002) and 1-year all-cause mortality (AUC=0.72; P<0.001). By multivariate Cox regression analysis, NT-proBNP-ratio, chronic obstructive pulmonary disease, and serum creatinine were the only independent predictors of all-cause mortality. Elevated NT-proBNP-ratio was associated with increased short- and long-term mortality after TAVR, and independently predicted all-cause mortality. NT-proBNP-ratio should be considered in the risk stratification of patients undergoing TAVR.


Effects of polymorphisms in the porcine microRNA MIR206 / MIR133B cluster on muscle fiber and meat quality traits.
MicroRNAs are a class of small non-coding RNA molecules that repress gene expression primarily at the post-transcriptional level. Genetic variations in microRNA genes may contribute to phenotypic differences by altering the expression of microRNAs and their targets. Here, we identified 12 single nucleotide polymorphisms (SNPs) in the genomic region of the porcine MIR206 / MIR133B cluster, 10 and 2 of which were associated with MIR206 and MIR133B respectively. All 12 SNPs were located within primary microRNAs. Allele frequency determination in different pig breeds (Berkshire, n = 153; Landrace, n = 125; Yorkshire, n = 173) and association studies of muscle fiber characteristics, lean meat production and meat quality traits were performed on the MIR206 and MIR133B SNPs. The MIR206 SNPs were associated with the percentage of type IIa and IIb fibers for muscle fiber area composition, meat quality traits including drip loss and lightness, and backfat thickness, a parameter of lean meat production. In addition, we found significant association of the MIR133B SNPs with total muscle fiber number, loin eye area, and muscle pH. Furthermore, these SNPs significantly affected the levels of mature MIR206 and MIR133B , respectively, primarily by regulating the processing of primary microRNAs into precursor microRNAs. Interestingly, altered MIR206 levels correlated with phenotypic variability among genotypes of the MIR206 SNP. Our data suggest that polymorphisms in the porcine MIR206 / MIR133B cluster are a genetic factor affecting muscle and meat quality traits.


Revealing metabolic phenotypes in plants: inputs from NMR analysis.
Assessing the performance of the plant metabolic network, with its varied biosynthetic capacity and its characteristic subcellular compartmentation, remains a considerable challenge. The complexity of the network is such that it is not yet possible to build large-scale predictive models of the fluxes it supports, whether on the basis of genomic and gene expression analysis or on the basis of more traditional measurements of metabolites and their interconversions. This limits the agronomic and biotechnological exploitation of plant metabolism, and it undermines the important objective of establishing a rational metabolic engineering strategy. Metabolic analysis is central to removing this obstacle and currently there is particular interest in harnessing high-throughput and/or large-scale analyses to the task of defining metabolic phenotypes. Nuclear magnetic resonance (NMR) spectroscopy contributes to this objective by providing a versatile suite of analytical techniques for the detection of metabolites and the fluxes between them. The principles that underpin the analysis of plant metabolism by NMR are described, including a discussion of the measurement options for the detection of metabolites in vivo and in vitro, and a description of the stable isotope labelling experiments that provide the basis for metabolic flux analysis. Despite a relatively low sensitivity, NMR is suitable for high-throughput system-wide analyses of the metabolome, providing methods for both metabolite fingerprinting and metabolite profiling, and in these areas NMR can contribute to the definition of plant metabolic phenotypes that are based on metabolic composition. NMR can also be used to investigate the operation of plant metabolic networks. Labelling experiments provide information on the operation of specific pathways within the network, and the quantitative analysis of steady-state labelling experiments leads to the definition of large-scale flux maps for heterotrophic carbon metabolism. These maps define multiple unidirectional fluxes between branch-points in the metabolic network, highlighting the existence of substrate cycles and discriminating in favourable cases between fluxes in the cytosol and plastid. Flux maps can be used to define a functionally relevant metabolic phenotype and the extensive application of such maps in microbial systems suggests that they could have important applications in characterising the genotypes produced by plant genetic engineering.


Hemodynamic forces regulate mural macrophage infiltration in experimental aortic aneurysms.
Blood flow (BF) and wall shear stress (WSS) influence reactive oxygen species production and oxidative stress in abdominal aortic aneurysm (AAA) disease. To gain further insight into the mechanisms of hemodynamic influences on AAA inflammation, we examined aneurysm macrophage density, chemotaxis and survival under varying aortic flow conditions. Rat AAAs were created via porcine pancreatic elastase (PPE) infusion. In selected cohorts, AAA flow was increased via left common femoral arteriovenous fistula (AVF) creation (HF-AAA) or decreased by left common iliac ligation (LF-AAA). WSS was highest in HF-AAA (10.4 +/- 2.3 dyn/cm(2) vs. 2.4 +/- 0.4 and 0.5 +/- 0.2 for NF- and LF-AAA, respectively, P < 0.001) 7 days after PPE infusion, with reduced medial macrophage density and increased apoptosis. Adventitial macrophage density was not significantly influenced by flow. Monocyte chemoattractant protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression correlated with observed macrophage densities in the media and adventitia. Luminal flow conditions regulate AAA inflammation in part via influences on medial macrophage density. Hemodynamic forces may modulate AAA inflammation and diameter enlargement via direct regulation of intimal macrophage adhesion, transmural migration or survival.


Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects.
Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact). Study 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective). Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h x μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower. Considering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria.


First Report of Euphorbia larica Dieback Caused by Fusarium brachygibbosum in Oman.
Euphorbia larica Boiss. (Arabic = Isbaq) is a dominant and common component of the native desert flora of northern Oman. Traditional ethnobotanical uses have included use of the latex for treating camels with parasites. In February 2011, E. larica plants showing stem lesions up to several cm long and in many cases with stem dieback were collected from Al-Khoudh 50 km west of Muscat. The disease appeared widespread within the location where several dead specimens were also recorded, although the cause was unclear. Sections (5 mm) of five diseased branches taken from different plants and placed on potato dextrose agar (PDA) in all cases yielded Fusarium-like colonies. Colonies recovered were initially white becoming rose to medium red in color with abundant aerial mycelium. Macroconidia were scarce and scattered (mean of 20 spores: 26.83 × 4.73 μm) with three to four septa per spore; microconidia were slightly curved, ovoid, and fusiform (mean of 20 spores: 11.64 × 4.03 μm) with zero to two septa per spore. Spherical chlamydospores (mean of 20 spores: 11.05 μm) were terminal and intercalary, single, and in chains. In vitro characters and spores measurements conformed to previously described features of Fusarium brachygibbosum Padwick (1). Mycelial plugs (5 mm) were taken from 7-day-old cultures of the fungus grown on 2.5% PDA and applied to a small incision (3 mm) on the stems of healthy E. larica grown in situ and protected with wet cotton and Parafilm. The residual agar, mycelium, cotton, and Parafilm were removed after 7 days and symptoms were recorded. Control stems were inoculated using PDA (5 mm) plugs alone and inoculations were repeated twice. Artificial inoculations resulted in dieback of all stems within 11 days and fungal colonies identical to initial isolations were recovered from artificially infected surface-sterilized stem pieces. Identification of F. brachygibbosum was confirmed by comparing sequences generated from the internal transcribed spacer (ITS) region of the ribosomal DNA (ITS1 and ITS4 primers) and the intron region of translation elongation factor alpha (EF1-α) (EF-1-986 and EF-728 primers). The ITS and EF1-α sequences were found to share 100% and 99% nucleotide similarity to previously published sequences of the ITS (HQ443206) and EF1-α (JQ429370) regions of F. brachygibbosum in GenBank. The accession number of ITS sequence of one isolate assigned to EMBL-Bank was HF562936. The EF sequence was assigned to EMBL-Bank accession (submission number Hx2000027017; number will be sent later). This pathogen has previously been reported on date palm (2) in Oman but, to our knowledge, this is the first report of this pathogen on E. larica. References: (1) A. M. Al-Sadi et al. Crop Prot. 37:1, 2012. (2) G. W. Padwick. Mycol. Pap. 12:11, 1945.


Vector independent transmission of the vector-borne bluetongue virus.
Bluetongue is an economically important disease of ruminants. The causative agent, Bluetongue virus (BTV), is mainly transmitted by insect vectors. This review focuses on vector-free BTV transmission, and its epizootic and economic consequences. Vector-free transmission can either be vertical, from dam to fetus, or horizontal via direct contract. For several BTV-serotypes, vertical (transplacental) transmission has been described, resulting in severe congenital malformations. Transplacental transmission had been mainly associated with live vaccine strains. Yet, the European BTV-8 strain demonstrated a high incidence of transplacental transmission in natural circumstances. The relevance of transplacental transmission for the epizootiology is considered limited, especially in enzootic areas. However, transplacental transmission can have a substantial economic impact due to the loss of progeny. Inactivated vaccines have demonstrated to prevent transplacental transmission. Vector-free horizontal transmission has also been demonstrated. Since direct horizontal transmission requires close contact of animals, it is considered only relevant for within-farm spreading of BTV. The genetic determinants which enable vector-free transmission are present in virus strains circulating in the field. More research into the genetic changes which enable vector-free transmission is essential to better evaluate the risks associated with outbreaks of new BTV serotypes and to design more appropriate control measures.


Incidence of Epilepsy and Seizures Over the First 6 Months After a COVID-19 Diagnosis: A Retrospective Cohort Study.
The relationship between COVID-19 and epilepsy is uncertain. We studied the potential association between COVID-19 and seizures or epilepsy in the 6 months after infection. We applied validated methods to an electronic health records network (TriNetX Analytics) of 81 million people. We closely matched people with COVID-19 infections to those with influenza. In each cohort, we measured the incidence and hazard ratios (HRs) of seizures and epilepsy. We stratified data by age and by whether the person was hospitalized during the acute infection. We then explored time-varying HRs to assess temporal patterns of seizure or epilepsy diagnoses. We analyzed 860,934 electronic health records. After matching, this yielded 2 cohorts each of 152,754 patients. COVID-19 was associated with an increased risk of seizures and epilepsy compared with influenza. The incidence of seizures within 6 months of COVID-19 was 0.81% (95% CI 0.75-0.88; HR compared with influenza 1.55 [1.39-1.74]). The incidence of epilepsy was 0.30% (0.26-0.34; HR compared with influenza 1.87 [1.54-2.28]). The HR of epilepsy after COVID-19 compared with influenza was greater in people who had not been hospitalized and in individuals younger than 16 years. The time of peak HR after infection differed by age and hospitalization status. The incidence of new seizures or epilepsy diagnoses in the 6 months after COVID-19 was low overall, but higher than in matched patients with influenza. This difference was more marked in people who were not hospitalized, highlighting the risk of epilepsy and seizures even in those with less severe infection. Children appear at particular risk of seizures and epilepsy after COVID-19 providing another motivation to prevent COVID-19 infection in pediatric populations. That the varying time of peak risk related to hospitalization and age may provide clues as to the underlying mechanisms of COVID-associated seizures and epilepsy.