Detection of Helicobacter pylori colonization in dental plaques and tongue scrapings of patients with chronic gastritis.
It has been suggested that the oral cavity and dental plaque might be a reservoir for Helicobacter pylori (Hp). In this study, our aims were to detect the prevalence of Hp colonization in dental plaque and tongue scrapings of patients with chronic gastritis and to investigate the effect of systemic treatment upon this colonization and eradication of Hp from gastric mucosa. Eighty-one patients (49 men, 32 women) were included in the study. Dental plaque and tongue scraping specimens were obtained and assessed with Campylobacter-like organism (CLO) test, prior to endoscopic examination. By endoscopy, 2 antral and 1 corpus biopsy samples were taken for histologic examination, and 1 antral biopsy sample was taken for CLO test examination. Chronic gastritis was diagnosed in 63 (77.7%) of 81 patients. Dental plaque samples of 64 (79%) patients and tongue scraping samples of 48 (59.2%) patients were urease positive. Of the 63 patients with chronic gastritis, dental plaque and tongue scrapings were urease positive in 52 (83%) and 37 (59%) patients, respectively. After 14 days of triple drug therapy (omeprazole, clarithromycin, and amoxicillin), Hp was eradicated from the gastric mucosa of almost all of the patients, whereas no changes were detected in dental plaque and tongue scrapings by CLO test examination. Helicobacter pylori colonization, which seemed to be high in dental plaque and on the tongue, might play an important role in the pathogenesis of the reinfection process. In order to eradicate Hp from both the oral cavity and the gastric mucosa, studies should be performed to assess the effects of plaque control procedures in addition to present treatment modalities.


Screening for dysglycaemia using anthropometric indices in an adult population in Oman.
A previous community-based cross-sectional survey conducted in a semi-urban community revealed that 44% of people aged 18+ years manifest dysglycaemia, which appears to echo the national trend. There is lack of studies examining the role of anthropometric indices in people with dysglycaemia. We explored the screening ability of anthropometric indices, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) to detect dysglycaemia in the adult Omani population based on a community-based survey conducted in 2005. The potential of anthropometric indices to detect the presence of glycaemic disorder could aid in detection, prevention and health education. A total of 480 male and 795 female subjects aged 18+ years were included in this study. The prevalence of dysglycaemia was analysed using the American Diabetic Association criteria. Logistic regression approach and Receiver- Operating Characteristic (ROC) curve analysis was performed. The analysis revealed that mean values of age, BMI, WC, WHR and WHtR increased significantly from normoglycemic to pre-diabetic and further to diabetic in both sexes (P<0.0001). Dysglycemia showed an increasing prevalence with age. WHtR showed the highest sensitivity for detecting dysglycemia in all age groups compared to other anthropometric indices with sensitivity rate of 94.4% in ≥45 years, 88.6% in (25- 44) years and 45.6% in age group <25 years. Among the anthropometric indices we investigated, WHtR was the best predictor of dysglycaemia among Omani adults aged > 25 years.


Malaria infection in infancy in rural Malawi.
Malaria infection is thought to be relatively infrequent in infants less than 90 days of age in sub-Saharan Africa. In a rural area of Malawi with intense malaria transmission, we examined the occurrence of malaria infection during infancy and risk factors for parasitemia in the first three months of life in the cohort of infants delivered to women in the Mangochi Malaria Research Project. Among 3,915 liveborn singleton infants, 3,432 (87.7%) were seen at least once during infancy (first 12 months of life); of these, malaria blood smear results were available on 2,649 (77.2%). Overall, in a cross-sectional analysis, 23.3% of infants at three months of age were infected with Plasmodium falciparum; this proportion increased to more than 30% during the high transmission season. By the age of 10 months, 60-80% of the infants were infected, depending on the season. Geometric mean parasite density increased each month after two months of age and plateaued at seven months of age. In a life-table analysis, the median time to acquisition of a positive smear was 199 days. Factors independently associated with smear positivity at < 4 months of age included visit during high transmission season (adjusted odds ratio [AOR] = 4.1), maternal smear positivity at the same visit (AOR = 3.5), history of infant fever in the previous two weeks (AOR = 2.8), birth during the rainy season (AOR = 1.7), low socioeconomic status (AOR = 1.6), and low maternal education (AOR = 1.5). The specificity of a recent fever history for malaria infection in early infancy was high (> 70%). Intervention strategies to reduce the risk of early infant infection need to be targeted toward mothers of infants at high risk.


An ontology-based annotation of cardiac implantable electronic devices to detect therapy changes in a national registry.
The patient population benefitting from cardiac implantable electronic devices (CIEDs) is increasing. This study introduces a device annotation method that supports the consistent description of the functional attributes of cardiac devices and evaluates how this method can detect device changes from a CIED registry. We designed the Cardiac Device Ontology, an ontology of CIEDs and device functions. We annotated 146 cardiac devices with this ontology and used it to detect therapy changes with respect to atrioventricular pacing, cardiac resynchronization therapy, and defibrillation capability in a French national registry of patients with implants (STIDEFIX). We then analyzed a set of 6905 device replacements from the STIDEFIX registry. Ontology-based identification of therapy changes (upgraded, downgraded, or similar) was accurate (6905 cases) and performed better than straightforward analysis of the registry codes (F-measure 1.00 versus 0.75 to 0.97). This study demonstrates the feasibility and effectiveness of ontology-based functional annotation of devices in the cardiac domain. Such annotation allowed a better description and in-depth analysis of STIDEFIX. This method was useful for the automatic detection of therapy changes and may be reused for analyzing data from other device registries.


Isolation and characterization of Saccharomyces cerevisiae mRNA transport-defective (mtr) mutants.
To understand the mechanisms of mRNA transport in eukaryotes, we have isolated Saccharomyces cerevisiae temperature-sensitive (ts) mutants which accumulate poly(A)+ RNA in the nucleus at the restrictive temperature. A total of 21 recessive mutants were isolated and classified into 16 complementation groups. Backcrossed mRNA transport-defective strains from each complementation group have been analyzed. A strain which is ts for heat shock transcription factor was also analyzed since it also shows nuclear accumulation of poly(A)+ RNA at 37 degrees C. At 37 degrees C the mRNA of each mutant is characterized by atypically long polyA tails. Unlike ts pre-mRNA splicing mutants, these strains do not interrupt splicing of pre-mRNA at 37 degrees C; however four strains accumulate oversized RNA polymerase II transcripts. Some show inhibition of rRNA processing and a further subset of these strains is also characterized by inhibition of tRNA maturation. Several strains accumulate nuclear proteins in the cytoplasm when incubated at semipermissive temperature. Remarkably, many strains exhibit nucleolar fragmentation or enlargement at the restrictive temperature. Most strains show dramatic ultrastructural alterations of the nucleoplasm or nuclear membrane. Distinct mutants accumulate poly(A)+ RNA in characteristic patterns in the nucleus.


Primum non nocere: shared informed decision making in low back pain--a pilot cluster randomised trial.
Low back pain is a common and disabling condition leading to large health service and societal costs. Although there are several treatment options for back pain little is known about how to improve patient choice in treatment selection. The purpose of this study was to pilot a decision support package to help people choose between low back pain treatments. This was a single-centred pilot cluster randomised controlled trial conducted in a community physiotherapy service. We included adults with non-specific low back pain referred for physiotherapy. Intervention participants were sent an information booklet prior to their first consultation. Intervention physiotherapists were trained to enhance their skills in shared informed decision making. Those in the control arm received care as usual. The primary outcome was satisfaction with the treatment received at four months using a five-point Likert Scale dichotomised into "satisfaction" (very satisfied or somewhat satisfied) and "non-satisfaction" (neither satisfied nor dissatisfied, somewhat dissatisfied or very dissatisfied). We recruited 148 participants. In the control arm 67% of participants were satisfied with their treatment and in the intervention arm 53%. The adjusted relative risk of being satisfied was 1.28 (95% confidence interval 0.79 to 2.09). For most secondary outcomes the trend was towards worse outcomes in the intervention group. For one measure; the Roland Morris Disability Questionnaire, this difference was clinically important (2.27, 95% confidence interval 0.08 to 4.47). Mean healthcare costs were slightly lower (£38 saving per patient) within the intervention arm but health outcomes were also less favourable (0.02 fewer QALYs); the estimated probability that the intervention would be cost-effective at an incremental threshold of £20,000 per QALY was 16%. We did not find that this decision support package improved satisfaction with treatment; it may have had a substantial negative effect on clinical outcome, and is very unlikely to prove cost-effective. That a decision support package might have a clinically important detrimental effect is of concern. To our knowledge this has not been observed previously. Decision support packages should be formally tested for clinical and cost-effectiveness, and safety before implementation. Current Controlled Trials ISRCTN46035546 registered on 11/02/10.


cpFBPaseII, a novel redox-independent chloroplastic isoform of fructose-1,6-bisphosphatase.
A full-length FBPase cDNA has been isolated from Fragaria x ananassa (strawberry) corresponding to a novel putative chloroplastic FBPase but lacking the regulatory redox domain, a characteristic of the plastidial isoenzyme (cpFBPaseI). Another outstanding feature of this novel isoform, called cpFBPaseII, is the absence of the canonical active site. Enzymatic assays with cpFBPaseII evidenced clear Mg(2+)-dependent FBPase activity and a K(m) for fructose-1,6-bisphosphate (FBP) of 1.3 mM. Immunolocalization experiments and chloroplast isolation confirmed that the new isoenzyme is located in the stroma. Nevertheless, unlike cpFBPaseI, which is redox activated, cpFBPaseII did not increase its activity in the presence of either DTT or thioredoxin f (TRX f) and is resistant to H(2)O(2) inactivation. Additionally, the novel isoform was able to complement the growth deficiency of the yeast FBP1 deletion fed with a non-fermentable carbon source. Furthermore, orthologues are restricted to land plants, suggesting that cpFBPaseII is a novel and an intriguing chloroplastic FBPase that emerged late in the evolution of photosynthetic organisms, possibly because of a pressing need of land plants.


Differential protein expression and novel biomarkers related to 5-FU resistance in a 3D colorectal adenocarcinoma model.
The multicellular spheroid (MCS) is an in vitro model which is highly representative of the avascular region of solid tumors by reflecting microenvironmental conditions in vivo. Hence, it is considered the most appropriate model for studying drug resistance. We compared chemosensitivity to 5-fluorouracil (5-FU) and differential protein expression between the 3D MCS model and the 2D monolayers using DLD-1 cells. We analyzed several significant signaling molecules through western blot analysis. Although various changes in the expression level were observed depending on the samples, we did not obtained remarkable findings. Notably, the level of p-mTOR decreased upon 5-FU exposure in the monolayers, while its level was higher in the MCSs. Nine novel proteins were identified by 2-DE and MALDI-TOF analysis for exhibiting differential expression between the MCS model and the monolayers. Among these, collapsin response mediator protein 2 (CRMP-2), DNA replication complex GINS protein PSF2 (PSF-2) and selenium-binding protein 1 (SBP-1) were notable not only for their differential expression but also for decreased expression following 5-FU exposure, indicating their possible roles as novel biomarkers for sensitivity (CRMP-2, PSF-2) as well as resistance (SBP-1) to 5-FU. Overall, the present study demonstrated greater 5-FU resistance in human colorectal cancer cells grown as MCSs compared to monolayers and identified p-mTOR, CRMP-2, PSF-2 and SBP-1 as novel potential biomarkers of 5-FU chemosensitivity/resistance for human colorectal cancer, findings which warrant further investigation.


Severe burn and disuse in the rat independently adversely impact body composition and adipokines.
Severe trauma is accompanied by a period of hypermetabolism and disuse. In this study, a rat model was used to determine the effects of burn and disuse independently and in combination on body composition, food intake and adipokines. Male rats were assigned to four groups 1) sham ambulatory (SA), 2) sham hindlimb unloaded (SH), 3) 40% total body surface area full thickness scald burn ambulatory (BA) and 4) burn and hindlimb unloaded (BH). Animals designated to the SH and BH groups were placed in a tail traction system and their hindlimbs unloaded. Animals were followed for 14 days. Plasma, urine, fecal and tissue samples were analyzed. SA had a progressive increase in body mass (BM), SH and BA no change and BH a reduction. Compared to SA, BM was reduced by 10% in both SH and BA and by 17% when combined in BH. Compared to SA, all groups had reductions in lean and fat body mass with BH being greater. The decrease in lean mass was associated with the rate of urinary corticosterone excretion. The loss in fat mass was associated with decreases in plasma leptin and adiponectin and an increase in ghrelin. Following the acute response to injury, BH had a greater food intake per 100 g BM. Food intake was associated with the levels of leptin, adiponectin and ghrelin. The effects of the combination of burn and disuse in this animal model were additive, therefore in assessing metabolic changes with severe trauma both injury and disuse should be considered. Furthermore, the observed changes in adipokines, corticosterone and ghrelin provide insights for interventions to attenuate the hypermetabolic state following injury, possibly reducing catabolism and muscle loss and subsequent adverse effects on recovery and function.


Two-Drug Combinations as First-Step Antihypertensive Treatment.
Blood pressure (BP) control in patients with hypertension is variable worldwide, and in general, it results largely unsatisfactory. Factors responsible for this phenomenon include insufficient national cardiovascular healthcare policies for prevention, poor patient compliance with prescribed treatment schedules, and the reluctance of physicians to modify treatment strategies when BP is still elevated, that is, the so-called therapeutic inertia. A further important factor favoring poor BP control is the limited use of combination drug treatment, despite evidence of its superior ability to control BP in patients with difficult-to-treat hypertension. In addition, combination treatment allows to achieve BP control more easily (and more quickly) as compared with monotherapy. This article, after briefly examining the main features of BP control, will review the importance in the treatment of hypertension of the drug combination strategy, based on the recommendations of the 2018 European Society of Cardiology/European Society of Hypertension guidelines. Empahsis will be given to the drug combination treatment as first step of the antihypertensive therapeutic intervention. The potential drawbacks and barriers to combination drug treatment as initial therapeutic strategy will also be briefly discussed.


Sequential injection affinity chromatography utilizing an albumin immobilized monolithic column to study drug-protein interactions.
In this study, sequential injection affinity chromatography was used for drug-protein interactions studies. The analytical system used consisted of a sequential injection analysis (SIA) manifold directly connected with convective interaction media (CIM) monolithic epoxy disks modified by ligand-immobilization of protein. A non-steroidal, anti-inflammatory drug, naproxen (NAP) and bovine serum albumin (BSA) were selected as model drug and protein, respectively. The SIA system was used for sampling, introduction and propulsion of drug towards to the monolithic column. Association equilibrium constants, binding capacity at various temperatures and thermodynamic parameters (free energy DeltaG, enthalpy DeltaH) of the binding reaction of naproxen are calculated by using frontal analysis mathematics. The variation of incubation time and its effect in on-line binding mode was also studied. The results indicated that naproxen had an association equilibrium constant of 2.90 x 10(6)M(-1) at pH 7.4 and 39 degrees C for a single binding site. The associated change in enthalpy (DeltaH) was -27.36 kcal mol(-1) and the change in entropy (DeltaS) was -73 cal mol(-1)K(-1) for a single type of binding sites. The location of the binding region was examined by competitive binding experiments using a biphosphonate drug, alendronate (ALD), as a competitor agent. It was found that the two drugs occupy the same class of binding sites on BSA. All measurements were performed with fluorescence (lambda(ext)=230 nm, lambda(em)=350 nm) and spectrophotometric detection (lambda=280 nm).


Development and application of a multilocus sequence analysis method for the identification of genotypes within genus Bradyrhizobium and for establishing nodule occupancy of soybean (Glycine max L. Merr).
A multilocus sequence typing (MLST) method based on allelic variation of seven chromosomal loci was developed for characterizing genotypes (GT) within the genus Bradyrhizobium. With the method, 29 distinct multilocus GT were identified among 190 culture collection soybean strains. The occupancy of 347 nodules taken from uninoculated field-grown soybean plants also was determined. The bacteroid GT were either the same as or were closely related to GT identified among strains in the culture collection. Double-nodule occupancy estimates of 2.9% were much lower than values published based on serology. Of the 347 nodules examined, 337 and 10 were occupied by Bradyrhizobium japonicum and B. elkanii, respectively. The collection strains within the species B. japonicum and B. elkaniialso were compared with Bradyrhizobium cultures from other legumes. In many cases, the observed GT varied more according to their geographic origin than by their trap hosts of isolation. In other cases, there were no apparent relationships with either the legume or geographic source. The MLST method that was developed should be a useful tool in determining the influence of geographic location, temperature, season, soil type, and host plant cultivar on the distribution of GT of Bradyrhizobium spp.


The effects of sprint running training on sloping surfaces.
The aim of this study was to examine the effects of sprint running training on sloping surfaces (3 degrees ) on selected kinematic and physiological variables. Thirty-five sport and physical education students were randomized into 4 training groups (uphill-downhill, downhill, uphill, and horizontal) and a control group, with 7 participants in each group. Pre- and posttraining tests were performed to examine the effects of 6 weeks of training on the maximum running speed at 35 m, step rate, step length, step time, contact time, eccentric and concentric phase of contact time, flight time, selected posture characteristics of the step cycle, and peak anaerobic power performance. Maximum running speed and step rate were increased significantly (p < 0.05) in a 35-m running test after training by 0.29 m.s(-1) (3.5%) and 0.14 Hz (3.4%) for the combined uphill-downhill group and by 0.09 m.s(-1) (1.1%) and 0.03 Hz (2.4%) for the downhill group, whereas flight time shortened only for the combined uphill-downhill training group by 6 milliseconds (4.3%). There were no significant changes in the horizontal and control groups. Overall, the posture characteristics and the peak anaerobic power performance did not change with training. It can be suggested that the novel combined uphill-downhill training method is significantly more effective in improving the maximum running velocity at 35 m and the associated horizontal kinematic characteristics of sprint running than the other training methods are.


Prevalence and severity of facial and truncal acne in a referral cohort.
There is a paucity of information on the prevalence and severity of acne of the face, chest, and back. This study was designed to examine the prevalence and severity of acne on the face, chest, and back in a referral cohort of patients with acne using a validated global acne severity scale. Acne patients referred to dermatologists were evaluated at the face, chest, and back. Chi-square testing was performed to assess consistency between patient and physician assessments of each region. The correlation of acne severity between regions was evaluated by Spearman's rank correlation. In 965 patients, the prevalence of acne on the face, chest, and back was 92%, 45%, and 61%, respectively. Acne severity was significantly correlated for all regional pairs (P<.001): face and back (r=0.11); face and chest (r=0.12); and chest and back (r=0.67). The consistency of patient reporting and clinical evaluation for the presence of acne varied by region: face=92%, chest=69%, and back=74%. The proportions of patients reporting no occurrence of acne when clinical acne was indeed absent (negative predictive value) were 67% and 65% for the chest and back, respectively. The operational threshold for clinical acne (>mild) may underestimate the total proportion of affected patients. These patients were referred to dermatologists for care and may represent a more severe cohort. Acne affected the face in 92% and the trunk in just over 60% (with the back more frequently and severely affected than the chest). Acne severity was observed to have a much higher correlation between chest and back than face and back or face and chest. Patient-reporting evaluations of absence of acne on the chest and back are frequently erroneous, mandating clinical evaluations of these sites for assessment of overall extent.


Sex Steroid Hormone Levels May Not Explain Gender Differences in Development of Nephrolithiasis.
To determine whether serum sex steroid hormone levels, or the subsequent change in those levels over time, represent a risk factor for the development of nephrolithiasis in men. We retrospectively identified patients participating in a long-term cohort study (Rochester Epidemiology Project) in Olmsted County, Minnesota. Patients had previously undergone baseline detailed clinical examination and sex steroid hormone studies, including estradiol, testosterone, and bioavailable testosterone. Patients were followed on a biennial basis. Records were then reviewed to assess for formation of nephrolithiasis. We identified 684 patients, with a median follow-up for stone formation of 12.8 years. All 684 patients had measurement of testosterone, of which 78.9% were in normal range. Five hundred eighteen men had baseline-free testosterone, of whom 88.6% were normal. Three hundred seventy-one patients had baseline estradiol, of whom 88.7% were normal. One hundred two men (14.9%) were found to have stones, with 61 of those (59.8%) occurring before first hormone measurement and 41 (40.2%) occurring after. On multivariate analysis, there was no significant association of serum hormones with nephrolithiasis, although a trend toward higher baseline testosterone and stones was seen (odds ratio [OR] 1.29; 95% confidence intervals [CI] 0.71, 2.33). Using a time-to-event for incident stone formation, we found no significant association of baseline hormones or percentage change in hormone levels over time with risk of stones. We found no significant association of sex steroid hormone levels with the risk of nephrolithiasis formation in men, although a weak trend toward an increased risk with elevated testosterone was seen.


First reports of Phytophthora ramorum clonal lineages NA1 and EU1 causing Sudden Oak Death on tanoaks in Del Norte County, California.
A year of forest health surveys has led to the first detection of Phytophthora ramorum in Del Norte County followed by the first wildland detection of the EU1 clonal lineage (Grunwald et al. 2009) of this pathogen in California. In July 2019, leaves were sampled from two tanoaks (Notholithocarpus densiflorus) and 16 California bay laurels (Umbellularia californica) in Jedediah Smith State Park in Del Norte County, the northernmost coastal County of California. Leaves displayed lesions normally associated with Sudden Oak Death (SOD) caused by P. ramorum and were discovered during the citizen science-based survey known as SOD Blitz (Meentemeyer et al. 2015). Samples were surface sterilized using 75% Ethanol and plated on PARPH-V8 agar (Jeffers and Martin 1986). After plating, DNA was extracted and amplified using two P. ramorum-specific assays (Hayden et al. 2006, Kroon et al. 2004). Leaves from two tanoaks exhibiting twig die-back had typical SOD lesions along the midvein, gave positive PCR results and yielded cultures with colony morphology, sporangia and chlamydospores typical of the NA1 lineage of P. ramorum originally isolated in California from tanoaks and coast live oaks (Quercus agrifolia) (Rizzo et al. 2002). The ITS locus and a portion of the Cox-1 locus were sequenced from DNA extracts of each culture using primers DC6-ITS4 (Bonants et al. 2004) and COXF4N-COXR4N (Kroon et al. 2004), respectively. ITS sequences (GB MN540639-40) were typical of P. ramorum and Cox-1 sequences (GB MN540142-3) perfectly matched the Cox-1 sequence of the NA1 lineage (GB DQ832718) (Kroon et al. 2004). Microsatellite alleles were generated as described in Croucher et al. (2013) for the two Del Norte cultures and for eight P. ramorum cultures, representative of the four main multilocus genotypes (MLGs) present in California, namely c1 (Santa Cruz/Commercial Nurseries), c3 (San Francisco Bay Area), c2 (Monterey County), and c4 (Humboldt County) (Croucher et al. 2013). The two Del Norte MLGs were identical to one another and most similar to MLG c1, with a single repeat difference at a single locus. SSR results suggest the inoculum source may not be from Humboldt County, neighboring to the South, but from a yet unidentified outbreak, possibly associated with ornamental plants. Jedediah Smith State Park was surveyed for 12 months following the initial detection, however the pathogen has yet to be re-isolated in that location. In July 2020, SOD symptomatic leaves from two tanoak trees exhibiting twig cankers were collected 8 Km north of Jedediah Smith State Park, where three additional tanoak trees displayed rapidly browned dead canopies consistent with late stage SOD. Leaves were processed as above. Colonies from these samples produced chlamydospores and sporangia typical of P. ramorum on PARPH-V8 agar, but displayed a growth rate faster than that of NA1 genotypes and were characterized by aerial hyphae, overall resembling the morphology of EU1 lineage colonies (Brasier 2003). The EU1 lineage was confirmed by the perfect match of the sequence of a portion of the Cox-1 gene (GB MW349116-7) with the Cox-1 sequence of EU1 genotypes (GB EU124926). The EU1 clonal lineage has been previously isolated from tanoaks in Oregon forests, approximately 55 Km to the North (Grünwald et al. 2016), but this is the first report for California wildlands and will require containment and government regulations. It is unknown whether the EU1 strains in Del Norte County originated from Oregon forests or elsewhere.


A method to improve quantitative radiotracing-based analysis of the in vivo biodistribution of drug carriers.
Biodistribution studies are essential in drug carrier design and translation, and radiotracing provides a sensitive quantitation for this purpose. Yet, for biodegradable formulations, small amounts of free-label signal may arise prior to or immediately after injection in animal models, causing potentially confounding biodistribution results. In this study, we refined a method to overcome this obstacle. First, we verified free signal generation in animal samples and then, mimicking it in a controllable setting, we injected mice intravenously with a radiolabeled drug carrier formulation (125I-antibody/3DNA) containing a known amount of free radiolabel (125I), or free 125I alone as a control. Corrected biodistribution data were obtained by separating the free radiolabel from blood and organs postmortem, using trichloroacetic acid precipitation, and subtracting the confounding signal from each tissue measurement. Control free 125I-radiolabel was detected at ≥85% accuracy in blood and tissues, validating the method. It biodistributed very heterogeneously among organs (0.6-39 %ID/g), indicating that any free 125I generated in the body or present in an injected formulation cannot be simply corrected to the free-label fraction in the original preparation, but the free label must be empirically measured in each organ. Application of this method to the biodistribution of 125I-antibody/3DNA, including formulations directed to endothelial target ICAM-1, showed accurate classification of free 125I species in blood and tissues. In addition, this technique rendered data on the in vivo degradation of the traced agents over time. Thus, this is a valuable technique to obtain accurate measurements of biodistribution using 125I and possibly other radiotracers.


Daily activity patterns of two co-occurring tropical satyrine butterflies.
Adult males and females of many insect species are expected to adjust their daily activity pattern in order to avoid stressful climatic conditions and increase the chances to encounter sexual partners. Using scan sampling methods associated with focal individual observations it was found that two satyrine butterflies of similar size and morphology, Hermeuptychia hermes (Fabricius) (Leptidoptera: Nymphalidae) and Paryphthimoides phronius (Godart), show completely different daily activity patterns on forest edges in southeastern Brazil. Hermeuptychia hermes presents one abundance peak in the morning and another in the late afternoon, while P. phronius abundance peaks in the mid-day, remaining stable until 1700 h. This difference is probably due to the occurrence of territorial behavior in the later species. The beginning of territorial defense by P. phronius males coincided with the time of new-born female activity. However, newly hatched females were not sexually receptive. The afternoon territoriality in male P. phronius may be in part related to mate acquisition. However, why the abundance of H. hermes decreases when the abundance of P. phronius increases is less clear.


Parameters influencing pulsed flow mixing in microchannels.
The rapid mixing of reagents is a crucial step for on-chip chemical and biological analysis. It has been recently suggested that microfluidic mixing can be greatly enhanced by simply using time pulsing of the incoming flow rates of the two fluids to be mixed (Glasgow, I.; Aubry, N. Lab Chip 2003, 3, 114-120). This paper elaborates on the latter technique, showing through computational fluid dynamics how the mixing efficiency strongly depends on certain dimensionless parameters of the system, while remaining nearly insensitive to others. In particular, it is demonstrated that higher Strouhal numbers (ratio of flow characteristic time scale to the pulsing time period) and pulse volume ratios (ratio of the volume of fluid pulsed to the volume of inlet/outlet intersection) lead to better mixing. This paper also presents a physical device capable of mixing two reagents using pulsing, which shows improved mixing with greater values of the Strouhal number.


The collagenase gene family in humans consists of at least four members.
Stromelysin is a collagenase-related connective-tissue-degrading metalloproteinase. We have detected RNAs capable of hybridizing to a rat stromelysin cDNA in 11 of 69 human tumours tested. Molecular cloning of cDNAs to these RNAs has identified them as a mixture of stromelysin RNA and a transcript of a hitherto-undescribed related human gene, the stromelysin-2 gene. We have also isolated cDNAs corresponding to a more distantly related new human gene, the pump-1 gene. A comparison of the cDNA-derived amino acid sequences of stromelysin-2 and pump-1 with the known sequences of stromelysin and collagenase reveals significant similarities, with conservation of sequence motifs believed to have functional importance in metalloproteinase action. We conclude that the collagenase gene family in humans consists of at least four members, and speculate that expression of these genes plays a role in cancer.


Pain Reconceptualisation after Pain Neurophysiology Education in Adults with Chronic Low Back Pain: A Qualitative Study.
Pain neurophysiology education (PNE) is an educational intervention for patients with chronic pain. PNE purports to assist patients to reconceptualise their pain away from the biomedical model towards a more biopsychosocial understanding by explaining pain biology. This study aimed to explore the extent, and nature, of patients' reconceptualisation of their chronic low back pain (CLBP) following PNE. Eleven adults with CLBP underwent semistructured interviews before and three weeks after receiving PNE. Interviews were transcribed verbatim and thematically analysed in a framework approach using four a priori themes identified from our previous research: (1) degrees of reconceptualisation, (2) personal relevance, (3) importance of prior beliefs, and (4) perceived benefit of PNE. We observed varying degrees of reconceptualisation from zero to almost complete, with most participants showing partial reconceptualisation. Personal relevance of the information to participants and their prior beliefs were associated with the degree of benefit they perceived from PNE. Where benefits were found, they manifested as improved understanding, coping, and function. Findings map closely to our previous studies in more disparate chronic pain groups. The phenomenon of reconceptualisation is applicable to CLBP and the sufficiency of the themes from our previous studies increases confidence in the certainty of the findings.


Corn silk extract improves cholesterol metabolism in C57BL/6J mouse fed high-fat diets.
Corn silk (CS) extract contains large amounts of maysin, which is a major flavonoid in CS. However, studies regarding the effect of CS extract on cholesterol metabolism is limited. Therefore, the purpose of this study was to determine the effect of CS extract on cholesterol metabolism in C57BL/6J mouse fed high-fat diets. Normal-fat group fed 7% fat diet, high-fat (HF) group fed 25% fat diet, and high-fat with corn silk (HFCS) group were orally administered CS extract (100 mg/kg body weight) daily. Serum and hepatic levels of total lipids, triglycerides, and total cholesterol as well as serum free fatty acid, glucose, and insulin levels were determined. The mRNA expression levels of acyl-CoA: cholesterol acyltransferase (ACAT), cholesterol 7-alpha hydroxylase (CYP7A1), farnesoid X receptor (FXR), lecithin cholesterol acyltransferase (LCAT), low-density lipoprotein receptor, 3-hyroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), adiponectin, leptin, and tumor necrosis factor α were determined. Oral administration of CS extract with HF improved serum glucose and insulin levels as well as attenuated HF-induced fatty liver. CS extracts significantly elevated mRNA expression levels of adipocytokines and reduced mRNA expression levels of HMG-CoA reductase, ACAT, and FXR. The mRNA expression levels of CYP7A1 and LCAT between the HF group and HFCS group were not statistically different. CS extract supplementation with a high-fat diet improves levels of adipocytokine secretion and glucose homeostasis. CS extract is also effective in decreasing the regulatory pool of hepatic cholesterol, in line with decreased blood and hepatic levels of cholesterol though modulation of mRNA expression levels of HMG-CoA reductase, ACAT, and FXR.


Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas.
This multicenter phase II study evaluated the efficacy, dosimetry methodology, and safety of iodine-131 tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL). Patients received a dosimetric dose that consisted of 450 mg of anti-B1 antibody followed by 35 mg (5 mCi) of iodine-131 tositumomab. Serial total-body gamma counts were then obtained to calculate the patient-specific millicurie activity required to deliver the therapeutic dose. A therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 101,000 to 149,000 cells/mm(3)) was given 7 to 14 days after the dosimetric dose. Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The response rate was similar in patients with low-grade (57%) or transformed low-grade (60%) NHL. The median duration of response was 9.9 months. Fifteen patients (32%) achieved a complete response (CR; 10 CRs and five clinical CRs), including five patients (50%) with transformed low-grade NHL. The median duration of CR was 19.9 months, and six patients have an ongoing CR. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities that were considered to be possibly related to the treatment included mild to moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, one patient developed human-antimouse antibodies. Iodine-131 tositumomab produced a high overall response rate, and approximately one third of patients had a CR despite having chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL.


Cutting edge: FcγRIII (CD16) and FcγRI (CD64) are responsible for anti-glycoprotein 75 monoclonal antibody TA99 therapy for experimental metastatic B16 melanoma.
mAb therapy for experimental metastatic melanoma relies on activating receptors for the Fc portion of IgG (FcγR). Opposing results on the respective contribution of mouse FcγRI, FcγRIII, and FcγRIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of FcγRs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-FcγR blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating FcγRs. The combination therapy, however, was not more efficient than mAb therapy alone. We demonstrate that FcγRI and, unexpectedly, FcγRIII contributed to TA99 mAb therapeutic effects, whereas FcγRIV did not. Therefore, FcγRIII and FcγRI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse FcγRIII contributes to Ab-induced tumor reduction correlates with clinical data on its human functional equivalent human FcγRIIIA (CD16A).


Fatty acid synthase regulates the chemosensitivity of breast cancer cells to cisplatin-induced apoptosis.
Fatty acid synthase (FASN) is a key enzyme in fat biosynthesis that is over-expressed in advanced breast cancer stages. Cisplatin (CDDP) is a platinum-based drug used in the treatment of certain types of this disease. Although it was shown that FASN inhibition induced apoptosis by enhancing the cytotoxicity of certain drugs in breast cancer, its role in regulating the chemosensitivity of different types of breast cancer cells to CDDP-induced apoptosis is not established yet. Therefore, two different breast cancer cell lines; triple negative breast cancer (TNBC; MDA-MB-231) and triple positive breast cancer (TPBC; BT-474) cells were used to examine such role. We show that TNBC cells had naturally less fat content than TPBC cells. Subsequently, the fat content increased in both cells when treated with Palmitate rather than Oleate, whereas both fatty acids produced apoptotic ultra-structural effects and attenuated FASN expression. However, Oleate increased FASN expression in TPBC cells. CDDP decreased FASN expression and increased apoptosis in TNBC cells. These effects were further enhanced by combining CDDP with fatty acids. We also illustrate that the inhibition of FASN by either siRNA or exogenous inhibitor decreased CDDP-induced apoptosis in TPBC cells suggesting its role as an apoptotic factor, while an opposite finding was observed in TNBC cells when siRNA and fatty acids were used, suggesting its role as a survival factor. To our knowledge, we are the first to demonstrate a dual role of FASN in CDDP-induced apoptosis in breast cancer cells and how it can modulate their chemosensitivity.


Quality of medical care provided to service members with combat-related limb amputations: report of patient satisfaction.
A group of 158 service members who sustained major limb amputations during the global war on terrorism were surveyed on their satisfaction with the quality of care received from the Walter Reed Army Medical Center (WRAMC) Amputee Clinic from the time of their injury to their inpatient discharge. Of these participants, 96% were male, 77% were Caucasian, 89% were enlisted personnel, and 68% had sustained lower-limb amputations. WRAMC inpatient therapy, peer visitors, overall medical care, and pain management received particularly high satisfaction ratings. Age, race, rank, and level and side of amputation had little effect on overall satisfaction ratings. Significant differences, however, were found by location of injury (Iraq vs Afghanistan, Cuba, and Africa) regarding satisfaction with care received while in Europe and with the education process at WRAMC. Study findings strongly support the rehabilitation-based, integrative care approach designed by the U.S. military to care for service members with amputations.


Asymptomatic Pulmonary Artery Intimal Sarcoma with Chest Wall Metastasis as an Initial Manifestation: An Autopsy Case.
Pulmonary artery intimal sarcoma (PAIS) is a rare mesenchymal malignancy arising in the pulmonary trunk or proximal pulmonary artery and shows intraluminal growth. Clinical manifestations in PAIS are predominantly related to the pulmonary artery embolism, so cases with initial symptoms related to an extrapulmonary metastasis are unusual. The present report describes an 82-year-old man without any cardiopulmonary symptoms who was detected with an abnormal shadow on chest radiography during a routine health checkup. Contrast medium-enhanced chest computed tomography revealed an enhancing mass in the right pulmonary artery, pulmonary nodules, and a chest wall tumor corresponding to the abnormal shadow observed using chest radiography. A core needle biopsy for the chest wall tumor determined a pathological diagnosis of unclassified sarcoma. The patient was diagnosed with PAIS on the basis of clinical, radiological, and pathological correlations. He was scheduled to receive supportive care, but died of respiratory failure 1 year from the first visit. An autopsy revealed the pleomorphic sarcoma occupying the entire lumen of the right pulmonary artery with the only site of extrapulmonary metastasis in the chest wall. We should be aware of rare cases of asymptomatic PAIS found through routine health checkups.


Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape.
We have studied the expression patterns of the newly isolated homeobox gene, Hox-8 by in situ hybridisation to sections of the developing heads of mouse embryos between E9 and E17.5, and compared them to Hox-7 expression patterns in adjacent sections. This paper concentrates on the interesting expression patterns of Hox-8 during initiation and development of the molar and incisor teeth. Hox-8 expression domains are present in the neural crest-derived mesenchyme beneath sites of future tooth formation, in a proximo-distal gradient. Tooth development is initiated in the oral epithelium which subsequently thickens in discrete sites and invaginates to form the dental lamina. Hox-8 expression in mouse oral epithelium is first evident at the sites of the dental placodes, suggesting a role in the specification of tooth position. Subsequently, in molar teeth, this patch of Hox-8 expressing epithelium becomes incorporated within the buccal aspect of the invaginating dental lamina to form part of the external enamel epithelium of the cap stage tooth germ. This locus of Hox-8 expression becomes continuous with new sites of Hox-8 expression in the enamel navel, septum, knot and internal enamel epithelium. The transitory enamel knot, septum and navel were postulated, long ago, to be involved in specifying tooth shape, causing the inflection of the first buccal cusp, but this theory has been largely ignored. Interestingly, in the conical incisor teeth, the enamel navel, septum and knot are absent, and Hox-8 has a symmetrical expression pattern. Our demonstration of the precise expression patterns of Hox-8 in the early dental placodes and their subsequent association with the enamel knot, septum and navel provide the first molecular clues to the basis of patterning in the dentition and the association of tooth position with tooth shape: an association all the more intriguing in view of the evolutionary robustness of the patterning mechanism, and the known role of homeobox genes in Drosophila pattern formation. At the bell stage of tooth development, Hox-8 expression switches tissue layers, being absent from the differentiating epithelial ameloblasts and turned on in the differentiating mesenchymal odontoblasts. Hox-7 is expressed in the mesenchyme of the dental papilla and follicle at all stages. This reciprocity of expression suggests an interactive role between Hox-7, Hox-8 and other genes in regulating epithelial mesenchymal interactions during dental differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)


The role of evidence in the decision-making process of selecting essential medicines in developing countries: the case of Tanzania.
Insufficient access to essential medicines is a major health challenge in developing countries. Despite the importance of Standard Treatment Guidelines and National Essential Medicine Lists in facilitating access to medicines, little is known about how they are updated. This study aims to describe the process of updating the Standard Treatment Guidelines and National Essential Medicine List in Tanzania and further examines the criteria and the underlying evidence used in decision-making. This is a qualitative study in which data were collected by in-depth interviews and document reviews. Interviews were conducted with 18 key informants who were involved in updating the Standard Treatment Guidelines and National Essential Medicine List. We used a thematic content approach to analyse the data. The Standard Treatment Guidelines and National Essential Medicine List was updated by committees of experts who were recruited mostly from referral hospitals and the Ministry of Health and Social Welfare. Efficacy, safety, availability and affordability were the most frequently utilised criteria in decision-making, although these were largely based on experience rather than evidence. In addition, recommendations from international guidelines and medicine promotions also influenced decision-making. Cost-effectiveness, despite being an important criterion for formulary decisions, was not utilised. Recent decisions about the selection of essential medicines in Tanzania were made by committees of experts who largely used experience and discretionary judgement, leaving evidence with only a limited role in decision-making process. There may be several reasons for the current limited use of evidence in decision-making, but one hypothesis that remains to be explored is whether training experts in evidence-based decision-making would lead to a better and more explicit use of evidence.


Ca(2+) regulation in guinea-pig colonic smooth muscle: the role of the Na(+)-Ca(2+) exchanger and the sarcoplasmic reticulum.
To study the contribution of the Na(+)-Ca(2+) exchanger to Ca(2+) regulation and its interaction with the sarcoplasmic reticulum (SR), changes in cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) were measured in single, voltage clamped, smooth muscle cells. Increases in [Ca(2+)](c) were evoked by either depolarisation (-70 mV to 0 mV) or by release from the SR by caffeine (10 mM) or flash photolysis of caged InsP(3) (InsP(3)). Depletion of the SR of Ca(2+) (verified by the absence of a response to caffeine and InsP(3)) by either ryanodine (50 microM), to open the ryanodine receptors (RyRs), or thapsigargin (500 nM) or cyclopiazonic acid (CPA, 10 microM), to inhibit the SR Ca(2+) pumps, reduced neither the magnitude of the Ca(2+) transient nor the relationship between the influx of and the rise in [Ca(2+)](c) evoked by depolarisation. This suggested that Ca(2+)-induced Ca(2+) release (CICR) from the SR did not contribute significantly to the depolarisation-evoked rise in [Ca(2+)](c). However, although Ca(2+) was not released from it, the SR accumulated the ion following depolarisation since ryanodine and thapsigargin each slowed the rate of decline of the depolarisation-evoked Ca(2+) transient. Indeed, the SR Ca(2+) content increased following depolarisation as assessed by the increased magnitude of the [Ca(2+)](c) levels evoked each by InsP(3) and caffeine, relative to controls. The increased SR Ca(2+) content following depolarisation returned to control values in approximately 12 min via Na(+)-Ca(2+) exchanger activity. Thus inhibition of the Na(+)-Ca(2+) exchanger by removal of external Na(+) (by either lithium or choline substitution) prevented the increased SR Ca(2+) content from returning to control levels. On the other hand, the Na(+)-Ca(2+) exchanger did not appear to regulate bulk average Ca(2+) directly since the rates of decline in [Ca(2+)](c), following either depolarisation or the release of Ca(2+) from the SR (by either InsP(3) or caffeine), were neither voltage nor Na(+) dependent. Thus, no evidence for short term (seconds) control of [Ca(2+)](c) by the Na(+)-Ca(2+) exchanger was found. Together, the results suggest that despite the lack of CICR, the SR removes Ca(2+) from the cytosol after its elevation by depolarisation. This Ca(2+) is then removed from the SR to outside the cell by the Na(+)-Ca(2+) exchanger. However, the exchanger does not contribute significantly to the decline in bulk average [Ca(2+)](c) following transient elevations in the ion produced either by depolarisation or by release from the store.


Circulating dehydroepiandrosterone sulfate concentrations during the menopausal transition.
A previous report from the Study of Women Across the Nation indicated a rise in dehydroepiandrosterone sulfate (DHEAS) during the menopausal transition using data from three annual visits. Our objective was to examine changes in DHEAS with chronological and ovarian aging, expanding the original analyses to include 10 yr of annual data. A longitudinal observational study and cross-sectional analyses of baseline data were conducted. OUTCOME MEASURES AND SUBJECTS: DHEAS, age, menopause status, ethnicity, smoking, weight, and height were assessed in 2886 women from five ethnic groups aged 42-52 yr at entry. Hysterectomy, bilateral oophorectomy, and hormone use were excluded. Cross-sectional analysis at baseline showed a linear decline in circulating log-transformed DHEAS with increasing age for either the entire cohort (2.81% per year) or for individual ethnicities. A similar negative association with baseline age (2.44% decline per year) was seen in longitudinal linear mixed modeling including observations from premenopause through late postmenopause, an additional 0.33% decline/year. In contradistinction, a late-transition rise in DHEAS was detected when the same women were analyzed by ovarian status. The average increase in mean circulating DHEAS level between early and late menopause transition, beyond changes predicted by aging, was 3.95%, followed by an average decline of 3.96% during the late postmenopause. Approximately 84.5% of the women had an estimated within-woman increase in DHEAS from premenopause/early perimenopause to late perimenopause/early postmenopause. These observations underscore differences between cross-sectional and longitudinal studies and the importance of considering ovarian status. Additional investigations regarding adrenal contribution to sex steroids in mid-aged women are warranted.


Chromosomal size variation in Trypanosoma cruzi is mainly progressive and is evolutionarily informative.
The evolutionary significance of chromosome size polymorphism was explored in a representative panel of 26 Trypanosoma cruzi stocks. We tested a progressive model (aCSDI) assuming that the larger the size difference between homologous chromosomes, the more divergent the parasites are. This was contrasted with a non-progressive model (Jaccard's distance), in which any chromosome size difference has the same weight. ACSDI-based dendrograms were very similar to those built-up from multilocus enzyme electrophoresis (MLEE) and random amplified polymorphic DNA (RAPD) data: structuring in 2 major lineages (T. cruzi I and T. cruz II) and 5 small subdivisions within T. cruzi II was identical, and branching was very similar. Furthermore, a significant correlation (P < 0.001) was observed between aCSDI and phenetic distances calculated from MLEE and RAPD data. In contrast, analysis of chromosome size polymorphism with Jaccard's distance generated dendrograms with relatively long branches, causing most branching points to cluster close together, which generates statistically uncertain branching points. Our results thus support a model of progressive chromosome size-variation and show that despite an extensive polymorphism, chromosomal sizes constitute valuable characters for evolutionary analyses. Furthermore, our data are consistent with the clonal evolution model previously proposed for T. cruzi.


Medical education and primary health care in tropical Africa: evidence for change.
Many aspects of Primary Health Care call for a complete revision of approach, emphasis and mental attitudes in medical education. This appears to be a pre-requisite for the promotion of total health involving all elements (i.e. favourable biological, social and physical environment) in the improvement of the general health status of the community. However, the training of medical students is still, in the main, hospital based, with a relatively insignificant clinical exposure in the community setting. Consequently, medical students have been ill-equipped by the training institutions to appreciate the necessary comprehensive health role they would be expected to perform, especially in relation to Primary Health Care, on their eventual return to the community as medical practitioners. An assessment of the attitude and response of a group of final year medical students to the traditional basic medical and clinical disciplines revealed important deficiencies which are discussed: Suggestions are proffered for wider adoption of a community based training programme.


PET imaging of soluble yttrium-86-labeled carbon nanotubes in mice.
The potential medical applications of nanomaterials are shaping the landscape of the nanobiotechnology field and driving it forward. A key factor in determining the suitability of these nanomaterials must be how they interface with biological systems. Single walled carbon nanotubes (CNT) are being investigated as platforms for the delivery of biological, radiological, and chemical payloads to target tissues. CNT are mechanically robust graphene cylinders comprised of sp(2)-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. In order to evaluate the potential usefulness of this CNT scaffold, we undertook an imaging study to determine the tissue biodistribution and pharmacokinetics of prototypical DOTA-functionalized CNT labeled with yttrium-86 and indium-111 ((86)Y-CNT and (111)In-CNT, respectively) in a mouse model. The (86)Y-CNT construct was synthesized from amine-functionalized, water-soluble CNT by covalently attaching multiple copies of DOTA chelates and then radiolabeling with the positron-emitting metal-ion, yttrium-86. A gamma-emitting (111)In-CNT construct was similarly prepared and purified. The constructs were characterized spectroscopically, microscopically, and chromatographically. The whole-body distribution and clearance of yttrium-86 was characterized at 3 and 24 hours post-injection using positron emission tomography (PET). The yttrium-86 cleared the blood within 3 hours and distributed predominantly to the kidneys, liver, spleen and bone. Although the activity that accumulated in the kidney cleared with time, the whole-body clearance was slow. Differential uptake in these target tissues was observed following intravenous or intraperitoneal injection. The whole-body PET images indicated that the major sites of accumulation of activity resulting from the administration of (86)Y-CNT were the kidney, liver, spleen, and to a much less extent the bone. Blood clearance was rapid and could be beneficial in the use of short-lived radionuclides in diagnostic applications.


Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study.
Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM. The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005-2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4-3.8, p<0.001) than men (2.3: 2.0-2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2-3.0, p<0.001) in men and 2.7 (2.2-3.4, p<0.001) in women. Between 2005-2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60-69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA(1c) of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used. Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed. Please see later in the article for the Editors' Summary.


Ammonium decreases human polymorphonuclear leukocyte cytoskeletal actin.
Ammonium, a weak base produced as a metabolic by-product of urea metabolism by bacterial pathogens, inhibits a variety of motile polymorphonuclear leukocyte (PMN) functions. It was initially assumed that the mechanism of leukocyte inhibition was due to cytoplasmic alkalinization. However, while it is clear that ammonium can effect cytoplasmic alkalinization, current data indicate that alterations in chemotaxis, degranulation, and receptor recycling occur independently of cytoplasmic alkalinization. Since these are motility-related events, we examined the possibility that alterations in cytoskeletal actin may account for the effects of ammonium on PMN function. The results indicate that ammonium can inhibit degranulation, decrease cytoskeletal actin, and increase actin depolymerization rates. These findings are supported by five lines of evidence. First, formylmethionyl-leucyl-phenylalanine (fMLP)-induced elastase release was inhibited by 85% +/- 3% in the presence of ammonium, and ammonium by itself did not stimulate elastase release. Second, ammonium treatment of resting PMNs caused a rapid 38% +/- 6% decrease in cytoskeletal actin. Third, ammonium treatment accelerated the fMLP-induced depolymerization phase of the cytoskeletal actin transient by 150% +/- 12%. Fourth, in resting PMNs treated with cytochalasin B or D, ammonium induced a 21% +/- 4% and a 25% +/- 5% decrease in cytoskeletal actin, respectively. Conversely, ammonium did not affect the ability of the cytochalasins to inhibit an fMLP-induced cytoskeletal actin transient. Fifth, pertussis toxin treatment of neutrophils did not affect the ammonium-stimulated decrease in cytoskeletal actin. These results suggest that ammonium can inhibit neutrophil function by altering cytoskeletal actin and therefore provide new information regarding potential pathogenic mechanisms for bacterial pathogens.


Evidence for extremely rapid magma ocean crystallization and crust formation on Mars.
The formation of a primordial crust is a critical step in the evolution of terrestrial planets but the timing of this process is poorly understood. The mineral zircon is a powerful tool for constraining crust formation because it can be accurately dated with the uranium-to-lead (U-Pb) isotopic decay system and is resistant to subsequent alteration. Moreover, given the high concentration of hafnium in zircon, the lutetium-to-hafnium (176Lu-176Hf) isotopic decay system can be used to determine the nature and formation timescale of its source reservoir1-3. Ancient igneous zircons with crystallization ages of around 4,430 million years (Myr) have been reported in Martian meteorites that are believed to represent regolith breccias from the southern highlands of Mars4,5. These zircons are present in evolved lithologies interpreted to reflect re-melted primary Martian crust 4 , thereby potentially providing insight into early crustal evolution on Mars. Here, we report concomitant high-precision U-Pb ages and Hf-isotope compositions of ancient zircons from the NWA 7034 Martian regolith breccia. Seven zircons with mostly concordant U-Pb ages define 207Pb/206Pb dates ranging from 4,476.3 ± 0.9 Myr ago to 4,429.7 ± 1.0 Myr ago, including the oldest directly dated material from Mars. All zircons record unradiogenic initial Hf-isotope compositions inherited from an enriched, andesitic-like crust extracted from a primitive mantle no later than 4,547 Myr ago. Thus, a primordial crust existed on Mars by this time and survived for around 100 Myr before it was reworked, possibly by impacts4,5, to produce magmas from which the zircons crystallized. Given that formation of a stable primordial crust is the end product of planetary differentiation, our data require that the accretion, core formation and magma ocean crystallization on Mars were completed less than 20 Myr after the formation of the Solar System. These timescales support models that suggest extremely rapid magma ocean crystallization leading to a gravitationally unstable stratified mantle, which subsequently overturns, resulting in decompression melting of rising cumulates and production of a primordial basaltic to andesitic crust6,7.


Mycotoxin contamination of sorghum and its contribution to human dietary exposure in four sub-Saharan countries.
This research aimed at evaluating the safety, and the type, level and prevalence of mycotoxins in grain sorghum of four sub-Saharan African (SSA) countries (Burkina Faso, Ethiopia, Mali and Sudan). A multi-analyte LC-MS/MS method for quantification of 23 mycotoxins (nivalenol, deoxynivalenol, fusarenon X, neosolaniol, 3-acetyl deoxynivalenol, 15-acetyl deoxynivalenol, diacetoxyscirpenol, roquefortine C, HT-2 toxin, alternariol, T-2 toxin, FB1, FB2, FB3, zearalenone, aflatoxin G1, aflatoxin G2, aflatoxin B1, aflatoxin B2, sterigmatocystin, OTA, altenuene, alternariol monomethylether) was applied to different sorghum matrices. Of the 1533 analysed samples, 33% were contaminated with at least one of the following mycotoxins: aflatoxins, fumonisins, sterigmatocystin, Alternaria toxins, OTA and zearalenone. Country of origin, colour, source and collection period of sorghum samples significantly influenced the type, level and prevalence of mycotoxins. Sterigmatocystin (15%), fumonisins (17%) and aflatoxins (13%) were the most prevalent. FB1 (274 ± 585 µg/kg) had the highest mean concentration followed by FB2 (214 ± 308 µg/kg) while diacetoxyscirpenol (8.12 ± 19.2 µg/kg) and HT-2 (11.9 ± 0.00 µg/kg) had the lowest concentrations. Neosolaniol, fusarenon-X, 3-acetyl deoxynivalenol, 15-acetyl deoxynivalenol, T-2 toxin, nivalenol and roquefortine C were not detected in any of the samples. Sudan had the lowest prevalence and mean concentration of all mycotoxins. Pink sorghum had the highest concentrations of fumonisins and aflatoxins. Mycotoxins from Aspergillus spp. and Alternaria spp. are the mycotoxins of concern in SSA grain sorghum with regard to prevalence, concentration and possible health risk from exposure. Based on the performed risk characterisation, daily consumption of sorghum containing aflatoxins, alternariol, alternariol monomethyl ether, sterigmatocystin and OTA could result in exceeding the established health-based guidance values for these toxins.


The mRNA of the Arabidopsis gene FT moves from leaf to shoot apex and induces flowering.
Day length controls flowering time in many plants. The day-length signal is perceived in the leaf, but how this signal is transduced to the shoot apex, where floral initiation occurs, is not known. In Arabidopsis, the day-length response depends on the induction of the FLOWERING LOCUS T (FT) gene. We show here that local induction of FT in a single Arabidopsis leaf is sufficient to trigger flowering. The FT messenger RNA is transported to the shoot apex, where downstream genes are activated. These data suggest that the FT mRNA is an important component of the elusive "florigen" signal that moves from leaf to shoot apex.


Classical and emerging techniques to identify and quantify localized RNAs.
In essentially every cell, proteins are asymmetrically distributed according to their function. For many genes, this protein sorting problem is solved by transporting RNA molecules encoding the protein, rather than the protein itself, to the desired subcellular location. The protein is then translated on-site to immediately produce a correctly localized protein. This strategy is widely used as thousands of RNAs localize to distinct locations across diverse cell types and species. One of the fundamental challenges to study this process is the determination of the subcellular spatial distribution of any given RNA. The number of tools available for the study of RNA localization, from classical and state-of-the-art methods for the visualization of individual RNA molecules within cells to the profiling of localized transcriptomes, is rapidly growing. These include imaging-based approaches, a variety of biochemical and mechanical fractionation techniques, and proximity-labeling methods. These procedures allow for both the detailed study of the molecular requirements for the localization of individual RNA molecules and computational studies of RNA transport on a genomic scale. Together, they have the ability to allow insight into the regulatory principles that govern the localization of diverse RNAs. These new techniques provide the framework for integrating our knowledge of the regulation of RNA localization with that of other posttranscriptional processes. This article is categorized under: RNA Export and Localization > RNA Localization RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Methods > RNA Analyses in Cells.


Leading the way: competencies of leadership to prevent mis-implementation of public health programs.
Public health agencies are increasingly concerned with ensuring that they are maximizing limited resources by delivering effective programs to enhance population-level health outcomes. Preventing mis-implementation (ending effective activities prematurely or continuing ineffective ones) is necessary to sustain public health efforts and resources needed to improve health and well-being. The purpose of this paper is to identify the important qualities of leadership in preventing mis-implementation of public health programs. In 2019, 45 state health department chronic disease employees were interviewed via phone and audio-recorded, and the conversations were transcribed verbatim. Thematic analysis focused on items related to mis-implementation and the manners in which leadership were involved in continuing ineffective programs. Final themes were based on a Public Health Leadership Competency Framework. The following themes emerged from their interviews regarding the important leadership competencies to prevent mis-implementation: '(1) leadership and communication; (2) collaborative leadership (3) leadership to adapt programs; (4) leadership and organizational learning and development; and (5) political leadership'. This first of its kind study showed the close interrelationship between mis-implementation and leadership. Increased attention to public health leader competencies might help to reduce mis-implementation in public health practice and lead to more effective and efficient use of limited resources.


Tris-heteroleptic Iridium Complexes Based on Cyclometalated Ligands with Different Cores.
A series of tris-heteroleptic iridium complexes of the form [Ir(C^N1)(C^N2)(acac)] combining 2-phenylpyridine (ppy), 2-(2,4-difluorophenyl)pyridine (dFppy), 1-phenylpyrazole (ppz), and 1-(2,4-difluorophenyl)pyrazole (dFppz) as the C^N ligands have been synthesized and fully characterized by NMR, X-ray crystallography, UV-vis absorption and emission spectroscopy, and electrochemical methods. It is shown that "static properties" (e.g., absorption and emission spectra and redox potentials) are primarily dictated by the overall architecture of the complex, while "dynamic properties" (e.g., excited-state lifetime and radiative and nonradiative rate constants) are, in addition, sensitive to the specific positioning of the substituents. As a result, the two complexes [Ir(dFppy)(ppz)(acac)] and [Ir(ppy)(dFppz)(acac)] have the same emission maxima and redox potentials, but their radiative and nonradiative rate constants differ significantly by a factor ∼2. Then acetylacetonate (acac) was replaced by picolinate (pic), and two pairs of diastereoisomers were obtained. As expected, the use of pic as the ancillary ligand results in blue-shifted emission, stabilization of the oxidation potential, and improvement of the photoluminescence quantum yield, and only minor differences in the optoelectronic properties are found between the two diastereoisomers of each pair.


The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes.
The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes. In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57-85 years, HbA1c: 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed. Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9-39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163). We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.


ESR study of atomic hydrogen and tritium in solid T2 and T2:H2 matrices below 1 K.
We report on the first ESR study of atomic hydrogen and tritium stabilized in solid T2 and T2:H2 matrices down to 70 mK. The concentrations of T atoms in pure T2 approached 2 × 1020 cm-3 (0.60%) and record-high concentrations of H atoms ∼1 × 1020 cm-3 (0.33%) were reached in T2:H2 solid mixtures where a fraction of T atoms became converted into H due to the isotopic exchange reaction T + H2 → TH + H. The maximum concentrations of unpaired T and H atoms were limited by their recombination which becomes enhanced by efficient atomic diffusion due to the presence of a large number of vacancies and phonons generated in the matrices by β-particles. Recombination also appeared in an explosive manner, both being stimulated and spontaneously in thick films where sample cooling was insufficient. We suggest that the main mechanism for H and T migration is physical diffusion related to tunneling or hopping to vacant sites in contrast to tunneling chemical exchange reactions which govern diffusion of H and D atoms created in H2 and D2 matrices by other methods.


Prevalence of advance care directives in the community: a telephone survey of three Australian States.
The community prevalence of advance care directives (ACD) is low despite known benefits of advance care planning for patients, families and health professionals. To determine the community prevalence of instructional and appointing ACD in New South Wales, Victoria and Queensland and factors associated with completion of these documents. A telephone survey of adults living in New South Wales, Victoria and Queensland (n = 1175) about completion of instructional ACD (making their own decisions about future healthcare) and appointing ACD (appointing another to decide). Quota sampling occurred based on population size by state, gender and age, with oversampling in smaller jurisdictions (Victoria and Queensland). Overall response rate was 33%. Six per cent of respondents reported completing an instructional ACD while 12% reported completing an appointing ACD. Female gender, higher educational level, personal experience of a major health scare and being widowed were significant predictors of completing an instructional ACD. Older age, higher educational level and being widowed were significant predictors of completing an appointing ACD. Despite long-standing efforts to increase advance care planning, community prevalence of ACD remains low, particularly for instructional ACD. This study found some different predictors for instructional ACD compared with appointing ACD, and also a potential role for experiential factors in triggering uptake. These findings suggest supplementing general community awareness campaigns with more nuanced and targeted efforts to improve ACD completion.


Sickle cell disease complications: Prevalence and resource utilization.
This study evaluated the prevalence rate of vaso-occlusive crisis (VOC) episodes, rates of uncomplicated and complicated VOC episodes, and the primary reasons for emergency room (ER) visits and inpatient admissions for sickle cell disease (SCD) patients. The Medicaid Analytic extracts database was used to identify adult SCD patients using claims from 01JUL2009-31DEC2012. The date of the first observed SCD claim was designated as the index date. Patients were required to have continuous medical and pharmacy benefits for ≥6 months baseline and ≥12 months follow-up period. Patient demographics, baseline clinical characteristics, the rate of uncomplicated and complicated VOC (VOC with concomitant SCD complications) episodes, and reasons for ER visits and inpatient stays were analyzed descriptively. A total of 8,521 patients were included in the analysis, with a median age of 30 years. The average follow-up period was 2.7 years. The rate of VOC episodes anytime in the follow-up was 3.31 in person-years. During the first-year follow-up period, an average of 2.79 VOC episodes were identified per SCD patients, with 1.06 VOC episodes treated in inpatient setting and 0.90 VOC episodes in ER without admission. A total of 76,154 VOC episodes were identified during the entire follow-up period for the overall SCD patients. Most of the VOC episodes (70.3% [n = 53,523]) were uncomplicated episodes, and 29.7% were complicated episodes. Using primary diagnosis claims only, the most frequent complications during the VOC episode were infectious diseases (25.9%), fever (21.8%), and pulmonary disorders (16.2%). Among ER and hospitalizations related to VOC or SCD complication, ~85.0% had VOCs as the primary reason for admission; 15.0% had SCD complications as the primary reason. In summary, SCD and its related comorbidities and complications result in high acute health care utilization. In addition, VOC remains the primary reason for SCD patients' ER visits and inpatient admissions.


Evaluation of Diffuse Type 2 Dominant or Eosinophilic Chronic Rhinosinusitis With Corticosteroid Irrigation After Surgical Neosinus Cavity Formation.
Eosinophilic chronic rhinosinusitis (eCRS), contemporarily classified as diffuse type 2 dominant chronic rhinosinusitis (CRS), is characterized by eosinophil-dominant mucosal inflammation. Contemporary management of eCRS as an inflammatory airway condition is multimodal with corticosteroid irrigations after the surgical creation of a neosinus cavity. To assess long-term treatment outcomes in patients with primary diffuse type 2 CRS or eCRS receiving multimodal treatment. A prospective cohort study of patients seen in a tertiary rhinology practice recruited from May 2010 to November 2018 was conducted. Follow-up duration was 12 months or more following endoscopic sinus surgery (ESS) with a neosinus cavity formed. Data analysis was performed from August to November 2020. Consecutive adult (≥18 years) patients diagnosed with primary diffuse type 2 dominant CRS or eCRS based on the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 criteria were included. Type 2 inflammation was defined as more than 10 eosinophils per high-power field obtained from sinus mucosal biopsy and managed with neosinus cavity ESS and ongoing corticosteroid irrigations. Exclusion criteria were less than 12 months of follow-up and secondary CRS. Endoscopic sinus surgery with complete removal of intersinus bony partitions to create a neosinus cavity. Nasal irrigation (240 mL) with betamethasone, 1 mg, or budesonide, 1 mg, daily for 3 to 6 months after ESS and tapered to an as-needed basis (minimum, 2-3 per week). Poor control was defined as polyp recurrence (polyp growth in >1 sinus area on a single side), use of long-term systemic therapy (biologic therapy or ≥3 consecutive months of oral corticosteroids), and revision surgery involving polypectomy. The disease in patients with no poor control criteria was defined as well controlled, and the disease in those with 1 or more criteria was considered poorly controlled. Maintenance medical therapy use and patient-reported outcomes based on the 22-item Sinonasal Outcomes Test for preoperative and last follow-up were collected. Of the 222 participants recruited with primary diffuse type 2 dominant CRS or eCRS and minimum of year of follow-up, 126 were men (56.8%). Mean (SD) age was 54.8 (13.6) years, and median (SD) follow-up was 2.2 (2.2) years. Of the 222 patients, 195 (87.8%) had well-controlled disease, 16 (7.2%) had polyp recurrence, 7 (3.2%) continued to receive long-term oral corticosteroid therapy, 5 (2.3%) received biologic therapy, and 8 (3.6%) underwent a revision polypectomy. Clinically meaningful change on the 22-item Sinonasal Outcomes Test and the nasal subdomain score was maintained at the last follow-up in 134 patients (67.0%). Poor disease control was not associated with poor adherence to irrigation use. The findings of this cohort study suggest that long-term disease control and reduction in symptom burden in patients with primary diffuse type 2 CRS or eCRS might be achieved when managed as an inflammatory disorder. Maintenance corticosteroid irrigations in the population examined appeared to be successfully self-tapered to disease activity.


Neurotoxic peptides from the venom of the giant Australian stinging tree.
Stinging trees from Australasia produce remarkably persistent and painful stings upon contact of their stiff epidermal hairs, called trichomes, with mammalian skin. Dendrocnide-induced acute pain typically lasts for several hours, and intermittent painful flares can persist for days and weeks. Pharmacological activity has been attributed to small-molecule neurotransmitters and inflammatory mediators, but these compounds alone cannot explain the observed sensory effects. We show here that the venoms of Australian Dendrocnide species contain heretofore unknown pain-inducing peptides that potently activate mouse sensory neurons and delay inactivation of voltage-gated sodium channels. These neurotoxins localize specifically to the stinging hairs and are miniproteins of 4 kDa, whose 3D structure is stabilized in an inhibitory cystine knot motif, a characteristic shared with neurotoxins found in spider and cone snail venoms. Our results provide an intriguing example of inter-kingdom convergent evolution of animal and plant venoms with shared modes of delivery, molecular structure, and pharmacology.


Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.
Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide- excision repair (NER) pathway has not yet been identified. Here we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape.


Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.
Hippocampal sharp waves (SPWs) and associated fast ("ripple") oscillations (SPW-Rs) in the CA1 region are among the most synchronous physiological patterns in the mammalian brain. Using two-dimensional arrays of electrodes for recording local field potentials and unit discharges in freely moving rats, we studied the emergence of ripple oscillations (140-220 Hz) and compared their origin and cellular-synaptic mechanisms with fast gamma oscillations (90-140 Hz). We show that (1) hippocampal SPW-Rs and fast gamma oscillations are quantitatively distinct patterns but involve the same networks and share similar mechanisms; (2) both the frequency and magnitude of fast oscillations are positively correlated with the magnitude of SPWs; (3) during both ripples and fast gamma oscillations the frequency of network oscillation is higher in CA1 than in CA3; and (4) the emergence of CA3 population bursts, a prerequisite for SPW-Rs, is biased by activity patterns in the dentate gyrus and entorhinal cortex, with the highest probability of ripples associated with an "optimum" level of dentate gamma power. We hypothesize that each hippocampal subnetwork possesses distinct resonant properties, tuned by the magnitude of the excitatory drive.


Prediction for human motion tracking failures.
We propose a new and effective method of predicting tracking failures and apply it to the robust analysis of gait and human motion. We define a tracking failure as an event and describe its temporal characteristics using a hidden Markov model (HMM). We represent the human body using a three-dimensional, multicomponent structural model, where each component is designed to independently allow the extraction of certain gait variables. To enable a fault-tolerant tracking and feature extraction system, we introduce a single HMM for each element of the structural model, trained on previous examples of tracking failures. The algorithm derives vector observations for each Markov model using the time-varying noise covariance matrices of the structural model parameters. When transformed with a logarithmic function, the conditional output probability of each HMM is shown to have a causal relationship with imminent tracking failures. We demonstrate the effectiveness of the proposed approach on a variety of multiview video sequences of complex human motion.


A comprehensive impedance journey to continuous microbial fuel cells.
The aim of the present work was to characterize the impedance response of an air-cathode MFC operating in a continuous mode and to determine intrinsic properties that define its performance which are crucial to be controlled for scalability purposes. The limiting step on electricity generation is the anodic electrochemically-active biofilm, independently of the external resistance, Rext, utilized. However, for Rext below 3 kΩ the internal impedance of the bioanode remained invariable, in good correspondence to the power density profile. The hydraulic retention time (HRT) had an effect on the impedance of both the bioanode and the air-cathode and especially on the overall MFC. The lowest HRT at which the MFC was operable was 3h. Yet, the variation on the HRT did not have a significant impact on power generation. A two constant phase element-model was associated with the EIS response of both bioanode and air-cathode, respectively. Consistency was found between the CPE behaviour and the normal power-law distribution of local resistivity with a uniform dielectric constant, which represented consistent values with the electrical double layer, the Nernst diffusion layer and presumably the biofilm thickness. These results have future implications on MFC monitoring and control, as well as in providing critical parameters for scale-up.


Managing Diabetic Foot Ulcers: Pharmacotherapy for Wound Healing.
Historically, there has been a scarcity of evidence-based topical therapy to hasten the healing of diabetic foot ulcers. But recently new evidence-based treatments have emerged from multicentre, randomised, controlled trials. This article highlights those trials, and describes the current pharmacological management of the diabetic foot ulcer and the advances that have been made in wound therapy to date. It provides an overview of topical and systemic pharmacotherapies in current use and those in development for future use in managing the diabetic foot. For each treatment, proposed mechanisms of action and evidence available to support their clinical use are presented. There is supporting randomised, controlled evidence for sucrose octasulfate in the treatment of neuro-ischaemic ulcers, and multi-layered patch of autologous leucocytes, platelets and fibrin in ulcers with or without ischaemia. There is also evidence for placentally derived products and for topical and systemic oxygen therapy in the healing of diabetic foot ulcers. Growth factors, bio-engineered tissues, stem cell therapy, gene therapy and peptide therapy also have some supporting evidence in the healing of diabetic foot ulcers. Nonsurgical debriding agents may be useful when the optimum approach of sharp debridement is not possible, and immunomodulators may be helpful for their antimicrobial effects, but robust data is still required to strengthen the case for general use. The review does not cover antimicrobials as their primary role are as anti-infectives and not in wound healing. The development of nanotechnology has created a means of prolonging the bioavailability of target molecules at the wound site, with the use of glass/hydrogel nanoparticles, polyethylene glycol and hyaluronic acid. Looking forward, novel therapies, including traction force-activated payloads, local delivery of short-interfering RNA and finally hydrogels incorporating bioactive agents or cells may provide possibilities for pharmacotherapy in the future.


Factors associated with Allergic Rhinitis in Colombian subpopulations aged 1 to 17 and 18 to 59.
Several studies have shown variations in the prevalence of allergic rhinitis (AR) around the world, and different potential predisposing factors. More studies are needed on risk factors, specifically in developing countries. This study explored the association of several factors and AR among urban residents in six cities of Colombia. A cross-sectional study and a nested case-control study were carried out between 2009 and 2010 involving two Colombian subpopulations: children/adolescents and adults. Cases were affirmative respondents to "In the past 12 months, have you (or your child) had a problem with sneezing or a running or blocked nose, when you (or your child) did not have a cold or the flu?" "Controls" were subjects who never had been diagnosed with asthma, AR or atopic eczema by a physician, and whom did not report any symptoms in the past twelve months. Weighted logistic regression was used to assess the association of different factors with case/control status. Factors associated with AR in children/adolescents were family history of AR, acetaminophen consumption and high socioeconomic status. Among adults, family history of asthma, AR and atopic eczema, and cetaminophen consumption were associated with AR. Consumption of cereals among children/adolescents and eating eggs among adults showed protective associations. Our findings suggest the presence of previously unknown cultural, environmental and family factors associated with the presence of AR in Colombia.


Azobenzene-benzoylphenylureas as photoswitchable chitin synthesis inhibitors.
Benzoylphenylureas (BPUs) are used as synthetic insect growth regulators for inhibiting chitin synthesis. Merging insecticidal BPUs with photoswitchable azobenzene generated photoresponsive chitin synthesis inhibitors. A prepared azobenzene-benzoylphenylurea can be activated upon irradiation with UV light, and shows 6-fold and 2-fold activity difference to armyworm (Mythimna separata) and German cockroach (Blattella germanica) sulfonylurea receptors, respectively. This is the first example of a photoswitchable BPU insecticide. The generation of such a photoresponsive BPU insecticide allows for modulation of the insecticidal activity by light, and may facilitate the spatiotemporal control over the sulfonylurea receptor and the mechanistic study of this kind of insecticide.


Carbonic anhydrase inhibitors in corneal endothelial transport.
Carbonic anhydrases play a central buffering role in current models of fluid transport in corneal endothelium, but in humans, clinical use of carbonic anhydrase inhibitors (CAIs) for the management of glaucoma does not cause corneal swelling. This study compares species differences in response to CAIs in human versus bovine corneal endothelial transport. Short-circuit current (Isc) measurements were performed on bovine and human corneal endothelium under identical conditions. The effects of four CAIs (acetazolamide, brinzolamide, dorzolamide, and ethoxzolamide) were measured. Endothelial expression of carbonic anhydrase II and IV was evaluated by immunofluorescence microscopy. Functional presence of carbonic anhydrase activity was determined using the Hansson's cobalt sulfide histochemical method. All four CAIs decreased bovine Isc (% change in Isc: acetazolamide, -21.0 ± 9.5, n = 8; brinzolamide, -35.5 ± 13.5, n = 9; dorzolamide, -33.6 ± 7.2, n = 8; ethoxzolamide, -35.3 ± 12.9, n = 8). That decrease was not present in humans (% change in Isc: acetazolamide, 16.2 ± 20.1, n = 3; brinzolamide, 6.7 ± 13.9, n = 3; dorzolamide, 8.0 ± 20.4, n = 3; ethoxzolamide, -4.8 ± 10.3, n = 2). Despite no functional effect of CAIs on Isc, both carbonic anhydrase II and IV were present in human corneal endothelium by immunofluorescence microscopy. Histochemical analysis of human corneal endothelium revealed functionally active carbonic anhydrase activity inhibited by brinzolamide. Carbonic anhydrase facilitates ion transport impacting the corneal endothelial Isc in bovine but not human corneal endothelium, despite its presence and functional activity in human tissue. This finding supports the clinical observation of no corneal swelling in humans administered CAIs and suggests that alternative ion transport mechanisms may be operational in corneal endothelium of different species.


Asterias: integrated analysis of expression and aCGH data using an open-source, web-based, parallelized software suite.
Asterias (http://www.asterias.info) is an open-source, web-based, suite for the analysis of gene expression and aCGH data. Asterias implements validated statistical methods, and most of the applications use parallel computing, which permits taking advantage of multicore CPUs and computing clusters. Access to, and further analysis of, additional biological information and annotations (PubMed references, Gene Ontology terms, KEGG and Reactome pathways) are available either for individual genes (from clickable links in tables and figures) or sets of genes. These applications cover from array normalization to imputation and preprocessing, differential gene expression analysis, class and survival prediction and aCGH analysis. The source code is available, allowing for extention and reuse of the software. The links and analysis of additional functional information, parallelization of computation and open-source availability of the code make Asterias a unique suite that can exploit features specific to web-based environments.


Hip fracture mortality: is it affected by anesthesia techniques?
We hypothesized that combined peripheral nerve block (CPNB) technique might reduce mortality in hip fracture patients with the advantage of preserved cardiovascular stability. We retrospectively analyzed 257 hip fracture patients for mortality rates and affecting factors according to general anesthesia (GA), neuraxial block (NB), and CPNB techniques. Patients' gender, age at admission, trauma date, ASA status, delay in surgery, followup period, and Barthel Activities of Daily Living Index were determined. There were no differences between three anesthesia groups regarding to sex, followup, delay in surgery, and Barthel score. NB patients was significantly younger and CPNB patients' ASA status were significantly worse than other groups. Mortality was lower for regional group (NB + CPNB) than GA group. Mortality was increased with age, delay in surgery, and ASA and decreased with CPNB choice; however, it was not correlated with NB choice. Since the patients' age and ASA status cannot be changed, they must be operated immediately. We recommend CPNB technique in high-risk patients to operate them earlier.