The incidence of new and the prevalence and persistence of recurrent trypanosome infections in cattle in southwest Ethiopia exposed to a high challenge with drug-resistant parasites.
A method is described for calculating new infection incidence from monthly field data collected between April 1994 and February 1998 from an average of 770 Ethiopian Highland Zebu cattle maintained under traditional management in the Ghibe valley, southwest Ethiopia and exposed to a high challenge with drug-resistant parasites. Each month cattle with a packed cell volume (PCV)<26% and detected as parasitaemic, or cattle showing clinical signs of trypanosomosis, were treated with diminazene aceturate at 3.5 mg/kg body weight. An infection was defined as a new infection if it was preceded by 2 previous months in which both samples had a PCV>/=26% and were not detected with trypanosomes. Using this definition the average monthly incidence of infections of Trypanosoma congolense in cattle over 36 months of age was 13.3%, and the prevalence of recurrent infections 13.0%. Assuming that an animal had recovered from infection when PCV again returned to 26% without parasites being detected, mean persistence of infection was 3.8 months (median between 2 and 3 months). In contrast, T. vivax infections were susceptible to diminazene. The incidence of T. vivax infections in adults was lower than for T. congolense (2.8%), and they were less pathogenic (mean reduction of 3.1% units of PCV due to T. vivax infection compared with 4.6% units for T. congolense). Also, fewer cases were treated. Calves were first detected parasitaemic at an average age of 8.8 months and their infections persisted longer than those in adults. The effect of age on incidence of infection was not significant beyond 15 months of age. Adult male cattle appeared to be more susceptible to T. congolense infection than adult female cattle.


Characterisation of the nitrile hydratase gene clusters of Rhodococcus erythropolis strains AJ270 and AJ300 and Microbacterium sp. AJ115 indicates horizontal gene transfer and reveals an insertion of IS1166.
The nitrile metabolising strains AJ270, AJ300 and AJ115 were isolated from the same location. The strains have very similar nitrile metabolising profiles. Sequencing of the 16S rRNA gene indicates that strains AJ270 and AJ300 are novel strains of Rhodococcus erythropolis while strain AJ115 is a novel Microbacterium strain very closely related to Microbacterium oxydans and Microbacterium liquefaciens. Analysis of the structure of the nitrile hydratase/amidase gene clusters in the three strains indicates that this region is identical in these strains and that this structure is different to other nitrile hydratase/amidase gene clusters. The major difference seen is the insertion of a complete copy of the insertion sequence IS1166 in the nhr2 gene. This copy of IS1166 generates a 10 bp direct duplication at the point of insertion and has one ORF encoding a protein of 434 amino acids, with 98% homology to the transposase of IS666 from Mycobacterium avium. A gene oxd, encoding aldoxime dehydratase is found upstream of the nitrile hydratase gene cluster and an open reading frame encoding a protein with homology to GlnQ type ABC transporters is found downstream of the nitrile hydratase/amidase genes. The identity of the nitrile hydratase/amidase gene clusters in the three strains suggests horizontal gene transfer of this region. Analysis of the strains for both linear and circular plasmids indicates that both are present in the strains but hybridisation studies indicate that the nitrile hydratase/amidase gene cluster is chromosomally located. The nitrile hydratase/amidase enzymes of strain AJ270 are inducible with acetonitrile or acetamide. Interestingly although a number of Fe-type nitrile hydratases have been shown to be photosensitive, the enzyme from strain AJ270 is not.


Improved real-time PCR assays for the detection of fecal indicator bacteria in surface waters with different instrument and reagent systems.
Previously reported and redesigned primer and probe assays were evaluated for the quantitative analysis of the fecal indicator bacterial groups, Enterococcus and Bacteroidetes with three real-time PCR instrument and reagent systems. The efficiency and sensitivity of the original assays varied between systems in analyses of DNA extracts from pure cultures of Enterococcus faecalis and Bacteroides fragilis, whereas the modified assays gave more consistent results. Distinctions between original and modified assays also occurred in analyses of known spike levels of E. faecalis and B. fragilis cells on filters with diverse surface water retentates. Percentages of samples causing PCR failures due to inhibition were lower using the modified assays. The accuracy and precision of spiked bacteria measurements were also generally higher, although mean measurements of both target organisms were still significantly different between systems (p < 0.05). The accuracy and precision of spiked bacteria measurements by both modified assays were further improved using a new sample matrix control spike consisting of cultured Lactococcus lactis cells and a reference assay for this organism. Corrections provided by the L. lactis assay eliminated significant differences in E. faecalis measurements between all three systems and between two of the three systems in B. fragilis measurements.


Identification of cis-elements regulating expression of Fgf10 during limb development.
Fibroblast growth factor 10 (FGF10) is known to be expressed in limb mesenchymal cells and to function as a mesenchymal signaling factor involved in epithelial-mesenchymal interactions during limb development. To elucidate regulation of Fgf10 expression, we isolated the promoter region of Fgf10 containing its 2.0 kb upstream 5'-fragment from the initiation codon and its 0.9 kb downstream fragment. Transcriptional activity of the fragment was examined with transgenic mice, using a lacZ-reporter system. Although no significant expression of the reporter gene was observed for the 0.2 kb 5'-fragment, expression was detected in the apical ectodermal ridge of the limb bud and developing cartilage of the limb for the 2.0 kb and 0.7 kb 5'-fragments, respectively. From comparison of the mouse sequences of the 2.0 kb fragment with corresponding sequences of human and chicken Fgf10, we identified 17 conserved putative enhancer motifs for AER expression and other unidentified expressions. For limb cartilage expression, we found putative enhancer sequences conserved among the three species in the 0.7 kb 5'-fragment. In the fragment, three DNA binding motifs were identified in the mouse and human sequence, although they are not conserved in the corresponding chicken sequence.


Regulation of p190 Rho-GAP by v-Src is linked to cytoskeletal disruption during transformation.
The v-Src oncoprotein perturbs the dynamic regulation of the cellular cytoskeletal and adhesion network by a mechanism that is poorly understood. Here, we have examined in detail the effects of a temperature-dependent v-Src protein on the regulation of p190 RhoGAP, a GTPase activating protein (GAP) that has been implicated in disruption of the organised actin cytoskeleton, and addressed the dependence of v-Src-induced stress fibre loss on inhibition of Rho activity. We found that activation of v-Src induced association of tyrosine phosphorylated p190 with p120(RasGAP) and stimulation of p120(RasGAP)-associated RhoGAP activity, although p120(RasGAP) itself was not a target for phosphorylation by v-Src in chicken embryo cells. These events required the catalytic activity of v-Src and were linked to loss of actin stress fibres during morphological transformation and not mitogenic signalling. Furthermore, these effects were rapidly reversible since switching off v-Src led to dissociation of the p190/p120(RasGAP) complex, inactivation of p120(RasGAP)-associated RhoGAP activity and re-induction of actin stress fibres. In addition, transient transfection of Val14-RhoA, a constitutively active Rho protein that is insensitive to RhoGAPs, suppressed v-Src-induced stress fibre loss and cell transformation. Thus, we show here for the first time that an activated Src kinase requires the inactivation of Rho-mediated actin stress fibre assembly to induce its effects on actin disorganisation. Moreover, our work supports p190 as a strong candidate effector of v-Src-induced cytoskeletal disruption, most likely mediated by antagonism of the cellular function of Rho.


Death due to microvascular occlusion in sickle-cell trait following physical exertion.
The heterozygous condition characterized by the presence of hemoglobin AS (sickle-cell trait) occurs in approximately 8% of the American black population. Unlike the homozygous state (sickle-cell disease), sickle-cell trait is not widely recognized as a cause of life-threatening illness or death despite over 30 case reports describing fatal or serious complications of exercise in young black males with this condition. These reports identify heat stress, dehydration, viral illness, and poor physical conditioning as factors which may contribute to exertional rhabdomyolysis and sudden death, suggesting multifactorial etiology. However, since sickling is known to occur postmortem, it remains controversial as to whether the pathogenesis of these exercise related deaths involves microvascular obstruction by sickled erythrocytes. We describe three young black individuals with no significant past medical history who died following physical exertion. In all three cases, postmortem hemoglobin electrophoresis demonstrated hemoglobin AS. In none of the cases was the body temperature found to be elevated. These cases serve to remind the forensic community that, in the proper setting, sickle-cell trait must be viewed as a potentially fatal disorder.


Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy.
Spinal muscular atrophy is an autosomal recessive disease of motor neurone degeneration which shows a variable phenotype. Two candidate genes show deletions in affected subjects but with no distinction between different forms of the disease. We report an unusual family in which mild and severe SMA coexists and patients are deleted for the SMN gene. The father is affected with late onset SMA; therefore this family shows pseudodominant inheritance. When typed using closely linked flanking markers the severely affected son does not share the same haplotype as his sib, who is deleted for SMN but shows no signs yet of SMA. This supports the hypothesis that differences in SMA phenotype can be explained by a multiple allele model.


Renal handling of enalapril and enalaprilat: studies in the isolated red blood cell-perfused rat kidney.
An isolated recirculating or single pass red cell-perfused rat kidney preparation (IPK) was used to examine the differential handling of renal metabolites. In single pass experiments, enalapril was primarily metabolized to its polar, dicarboxylic acid metabolite, enalaprilat, and its fractional excretion (FE) was less than unity, suggesting net reabsorption. Its steady-state extraction ratio decreased from 0.3 to 0.2 at concentrations of 1.06 to 12.7 microM, due to a saturation of enzymes for esterolysis. Enalaprilat administered to the IPK was excreted into urine in a concentration-independent (0.41-35.3 microM) fashion, with FE values approximating unity, suggesting net filtration. Differences in handling were observed for enalaprilat, as a metabolite formed from enalapril and as an administered (preformed) species in the single pass IPK, when tracer concentrations of [14C]enalapril and [3H]enalaprilat were given simultaneously. A comparison made between steady-state extraction ratio Ess[mi] [generated metabolite]/glomerular filtration rate (GFR) and Ess[pmi] [preformed metabolite]/GFR, respectively, revealed a 2-fold difference. The finding suggests the presence of a barrier for entry of enalaprilat into the kidney. Or else, in absence of the barrier, the opposite would be observed, that is, Ess [pmi]/GFR greater than Ess [mi]/GFR because preformed enalaprilat, in contrast to generated enalaprilat, undergoes filtration and utilizes facilitative transport carriers at the basolateral membrane. In recirculating IPKs which received simultaneously a tracer bolus dose of [14C]enalapril and [3H]enalaprilat, the FE values for generated [14C]enalaprilat were high and variable, decreasing with perfusion time and exceeding those for preformed [3H]enalaprilat, which approached unity with perfusion time. The variable FE values for [14C]enalaprilat are due to time-dependent contributions of circulating enalaprilat (which behaves identically to preformed enalaprilat) and the intrarenally generated enalaprilat. Hence, with renal drug metabolism, the conventional method of estimating urinary clearance (or Fe[mi]) for the metabolite [(total) excretion rate/midpoint plasma FE[mi] metabolite concentration] results in a greater metabolite clearance than that predicted from the administration of preformed metabolite.


The control of phosphate ion release from ion permeable microcapsules formulated into rosin varnish and resin glaze.
The occurrence of recurrent caries at the interface of dental materials and the enamel surface is an important performance issue. The objective of this study was to investigate the most effective way to control the release rate of bioavailable phosphate ions contained in aqueous solutions within ion permeable microcapsules formulated into rosin based varnishes and resin based sealants, in order to promote remineralization. Microcapsules that contained aqueous solutions of K2HPO4 with concentrations from 0.8 to 7.4M were prepared. 3-50w/w% of microcapsules were loaded into both rosin and resin based dental formulations. The effect of initial salt solution concentration inside the microcapsules and weight percent loading of the microcapsules on release rate were contrasted. The effect of microcapsule loading was found to be highly dependent on the continuous phase. In rosin, 3-15w/w% loading resulted in rapid release of ions. Higher weight percent loadings were initially slower but resulted in sustained release of ions. In resin, 3-15w/w% formulations slowly released ions for at least 300 days, while higher loading formulations released an initial burst of ions. Initial salt solution concentration contained inside the microcapsule affected ion release rate. Initial rate of ion release was greatest at a concentration that was less than the maximum concentration studied in both continuous phases. Phosphate ion release can be controlled from resin or rosin based dental material by adjusting initial salt solution concentration in microcapsules or percent loading of microcapsules. The potential for burst release from a varnish or slow, sustained release from a sealant has been demonstrated.


Genetic testing for hereditary breast cancer in Asia-moving forward.
Genetic screening for hereditary breast and ovarian cancer (HBOC) has gained much attention for the past decades. With the development of advanced sequencing technology, other novel breast cancer associated susceptibility genes, other than BRCA genes, have been identified recently. The prevalence of BRCA mutation is known to be different in the West and in the East, therefore it is important to understand the mutation spectrum locally and in Asia to improve early diagnosis and clinical management of hereditary breast cancer in the region. In this editorial, we sought to highlight the need of genetic screening in HBOC, and also highlight specific issues within Asia which may need to be addressed to help popularize its appropriate use in this region.


Modeling extended lactations of Holsteins.
Modeling extended lactations for the US Holsteins is useful because a majority (>55%) of the cows in the present population produce lactations longer than 305 d. In this study, 9 empirical and mechanistic models were compared for their suitability for modeling 305-d and 999-d lactations of US Holsteins. A pooled data set of 4,266,597 test-day yields from 427,657 (305-d complete) lactation records from the AIPL-USDA database was used for model fitting. The empirical models included Wood (WD), Wilmink (WIL), Rook (RK), monophasic (MONO), diphasic (DIPH), and lactation persistency (LPM) functions; Dijkstra (DJ), Pollott (POL), and new-multiphasic (MULT) models comprised the mechanistic counterparts. Each model was separately tested on 305-d (>280 days in milk) and 999-d (>800 days in milk) lactations for cows in first parity and those in third and greater parities. All models were found to produce a significant fit for all 4 scenarios (2 parity groups and 2 lactation lengths). However, the resulting parameter estimates for the 4 scenarios were different. All models except MONO, DIPH, and LPM yielded residuals with absolute values smaller than 2 kg for the entire period of the 305-d lactations. For the extended lactations, the prediction errors were larger. However, the RK, DJ, POL, and MULT models were able to predict daily yield within a +/- 3 kg range for the entire 999-d period. The POL and MULT models (having 6 and 12 parameters, respectively) produced the lowest mean square error and Bayesian information criteria values, although the differences from the other models were small. Conversely, POL and MULT were often associated with poor convergence and highly correlated, unreliable, or biologically atypical parameter estimates. Considering the computational problems of large mechanistic models and the relative predictive ability of the other models, smaller models such as RK, DJ, and WD were recommended as sufficient for modeling extended lactations unless mechanistic details on the extended curves are needed. The recommended models were also satisfactory in describing fat and protein yields of 305-d and 999-d lactations of all parities.


Impact of asbestos on public health: a retrospective study on a series of subjects with occupational and non-occupational exposure to asbestos during the activity of Fibronit plant (Broni, Italy).
The goal of this study is to understand more about the role of asbestos in causing human diseases, first of all mesothelioma, by investigating a large series of deaths due to asbestos-related diseases (ARDs). The main aim is to clarify if even very low amounts of asbestos can cause mesothelioma and other ARDs, as well as to find out if a different individual vulnerability can be important. This retrospective study included 188 subjects who died from asbestos related diseases in 2000-2017 in the area around Broni, Italy, where an important asbestos cement factory had been active from 1932 until 1993. In each case, a forensic autopsy has been performed. In order to perform the present study, the records were retrieved, including the clinical files, the autopsy, and the histological report. The statistical analysis performed showed that there was a significant relation between the cause of death (mesothelioma, lung cancer or asbestosis) and the kind of exposure (occupational, neighborhood or household), showing that all the subjects not exposed occupationally (and, therefore, exposed to lower amounts of asbestos) died from mesothelioma, whereas the individuals who used to work at the plant died also from other caused (asbestosis, lung cancer). Significant differences were highlighted examining the distribution of the causes of death according to the smoking habits. Moreover, among the mesothelioma patients, the survival time was shorter in the subjects with a neighborhood or household exposure than in the occupationally exposed individuals. The study provided meaningful data about the role of asbestos in causing human pathologies. In particular, the present data appear to support the hypothesis that even an exposure to a very little amount of asbestos can cause mesothelioma in hypersusceptible subjects (probably, on a genetic basis).


Effect of supplementation of micronutrients and phytochemicals to fructooligosaccharides on growth response of probiotics and E. coli.
Probiotics and prebiotics, which can change the colonic microenvironment, are the areas of current interest. Unutilizable fractions of the foods and fortificants, which reach the colon can affect the profile of probiotics. Effects of eight such factors viz. zinc sulphate, zinc carbonate, ferrous sulphate, ferric citrate, quercetin, gallic acid, phytic acid, and oxalic acid were, therefore, investigated on 24 H growth of Lactobacillus acidophilus (L1) and Lactobacillus plantarum (L2), two isolates of bifidobacteria (longum (L3) and bifidum (L4)) and a marketed consortium (L5) of eight probiotic cultures. MRS medium with marketed fructooligosaccharide as the only source of carbon was used for study of dose response curves. Quercetin and zinc sulphate showed significant positive effect for L1 and L5 (P < 0.01), whereas there was slight positive effect or no effect on growth of other probiotics. Phytic acid showed a significant inhibitory effect for L2 and a slight inhibitory effect on L3 and L4 whereas L5 were able to tolerate phytic acid. Oxalic acid had slight positive effect for L1 (P < 0.05) and L5 and no effect on growth of other probiotics (P > 0.05). Further, zinc sulphate, ferrous sulphate, quercetin, and oxalic acid significantly inhibited growth of E. coli (P < 0.05)


Selecting precise reference normal tissue samples for cancer research using a deep learning approach.
Normal tissue samples are often employed as a control for understanding disease mechanisms, however, collecting matched normal tissues from patients is difficult in many instances. In cancer research, for example, the open cancer resources such as TCGA and TARGET do not provide matched tissue samples for every cancer or cancer subtype. The recent GTEx project has profiled samples from healthy individuals, providing an excellent resource for this field, yet the feasibility of using GTEx samples as the reference remains unanswered. We analyze RNA-Seq data processed from the same computational pipeline and systematically evaluate GTEx as a potential reference resource. We use those cancers that have adjacent normal tissues in TCGA as a benchmark for the evaluation. To correlate tumor samples and normal samples, we explore top varying genes, reduced features from principal component analysis, and encoded features from an autoencoder neural network. We first evaluate whether these methods can identify the correct tissue of origin from GTEx for a given cancer and then seek to answer whether disease expression signatures are consistent between those derived from TCGA and from GTEx. Among 32 TCGA cancers, 18 cancers have less than 10 matched adjacent normal tissue samples. Among three methods, autoencoder performed the best in predicting tissue of origin, with 12 of 14 cancers correctly predicted. The reason for misclassification of two cancers is that none of normal samples from GTEx correlate well with any tumor samples in these cancers. This suggests that GTEx has matched tissues for the majority cancers, but not all. While using autoencoder to select proper normal samples for disease signature creation, we found that disease signatures derived from normal samples selected via an autoencoder from GTEx are consistent with those derived from adjacent samples from TCGA in many cases. Interestingly, choosing top 50 mostly correlated samples regardless of tissue type performed reasonably well or even better in some cancers. Our findings demonstrate that samples from GTEx can serve as reference normal samples for cancers, especially those do not have available adjacent tissue samples. A deep-learning based approach holds promise to select proper normal samples.


Contagious yawning in chimpanzees.
Six adult female chimpanzees were shown video scenes of chimpanzees repeatedly yawning or of chimpanzees showing open-mouth facial expressions that were not yawns. Two out of the six females showed significantly higher frequencies of yawning in response to yawn videos; no chimpanzees showed the inverse. Three infant chimpanzees that accompanied their mothers did not yawn at all. These data are highly reminiscent of the contagious yawning effects reported for humans. Contagious yawning is thought to be based on the capacity for empathy. Contagious yawning in chimpanzees provides further evidence that these apes may possess advanced self-awareness and empathic abilities.


Self-reported current sleep behaviors of adult athletes from different competitive levels and sports.
To quantify self-reported current sleep behaviors in a range of adult athletes. In addition, to determine any differences in sleep duration and sleep quality, depending on sport type and competitive level. In this cross-sectional study, 313 athletes (243 male, 70 female), competing in a variety of sports and competitive level, completed the Pittsburgh sleep quality index (PSQI) and a questionnaire which captured current sleep behaviors. Sleep quality was calculated using the global PSQI score (≥ 5 indicative of poor sleep quality). On average, athletes self-reported sleep duration was 7:34 ± 1:00 h:min. Overall, 19% of athletes achieved less than 7 h of sleep, 50% achieved less than 8 h. Global PSQI score was 5.0 ± 2.4, with poor sleep quality found in 55% of athletes. Sleep duration was significantly shorter in runners compared to basketball, soccer and rugby players (p < 0.05). Recreational athletes slept significantly less (7:08 ± 0:54 h:min) than competitive (7:32 ± 1:00 h:min), national (7:50 ± 1:00 h:min) and elite level athletes (7:49 ± 0:51 h:min). No differences in sleep quality were found between sport or competitive level. Half of the athletes failed to achieve 8 h of sleep per night and the majority reported compromised sleep quality. Sport type and competitive level may influence sleep duration; however, these factors do not seem to cause discrepancies in sleep quality. This study provides novel data into the sleep behaviors of adult athletes, and suggests strategies to improve sleep duration and quality may be warranted.


Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis.
Delayed postexercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. The usefulness of HRR to predict exercise impairment and mortality in patients with pulmonary arterial hypertension (PAH), however, remains largely unexplored. Seventy-two patients with PAH of varied etiology (New York Heart Association classes I-IV) and 21 age- and gender-matched controls underwent a maximal incremental cardiopulmonary exercise test (CPET), with heart rate being recorded up to the fifth minute of recovery. Heart rate recovery was consistently lower in the patients compared with the controls (P < .05). The best cutoff for HRR in 1 minute (HRR(1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR(1 min) ≤ 18 (n = 40), those with HRR(1 min) >18 (n = 32) had better New York Heart Association scores, resting hemodynamics and 6-minute walking distance. In fact, HRR(1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < .05). The single independent predictor of HRR(1 min) ≤ 18 was the 6-minute walking distance (odds ratio [95% CI] 0.99 [0.98-1.00], P < .05). On a multiple regression analysis that considered only CPET-independent variables, HRR(1 min) ≤ 18 was the single predictor of mortality (hazard ratio [95% CI] 1.19 [1.03-1.37], P < .05). Preserved HRR(1 min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PAH. Conversely, a delayed HRR(1 min) response has negative prognostic implications, a finding likely to be clinically useful when more sophisticated (and costlier) analyses provided by a full CPET are not available.


Treatment of de Quervain disease with triamcinolone injection with or without nimesulide. A randomized, double-blind, placebo-controlled trial.
There is uncertainty as to whether supplemental oral nonsteroidal anti-inflammatory medication improves the effectiveness of steroid injections in the treatment of de Quervain disease. We tested the hypothesis that there are no significant differences in the success rates when this condition is treated with triamcinolone injection with or without supplemental oral nimesulide. In a randomized, double-blind trial, 160 patients with de Quervain disease received an injection of 10 mg of triamcinolone acetonide and either 200 mg of oral nimesulide for seven days (eighty patients) or placebo tablets for seven days (eighty patients). An independent, blinded evaluator assessed the primary outcomes (tenderness, pain, and the result on the Finkelstein test) at three weeks after injection. Adverse reactions were assessed, and probabilities of recurrence for both groups were compared. Factors possibly predictive of disease recurrence were also assessed. The success rate after one injection was 67% in the nimesulide group and 68% in the placebo group. The overall success rates after single or multiple injections with a mean follow-up of 13.6 months were 95% for both groups. No significant differences were noted with respect to the success rates (p = 0.69) or pain scores after treatment (p = 0.11). The most common adverse reactions to triamcinolone injection and nimesulide were pain after injection and dyspepsia, respectively. The symptoms of de Quervain disease recurred in 33% of the patients in the nimesulide group and in 37% of those in the placebo group. The median time of recurrence was at the fifth month in the nimesulide group and at the fourth month in the placebo group. The recurrence of symptoms was significantly (p = 0.01) related to the presence of crepitation (relative risk, 2.13; 95% confidence interval, 1.19 to 3.80). Supplemental oral administration of the nonsteroidal anti-inflammatory drug nimesulide does not improve the effectiveness of a single injection of triamcinolone acetonide in the treatment of de Quervain disease. Patients with crepitation in the first dorsal compartment during thumb extension or abduction are at increased risk for recurrence of this disease. Therapeutic study, Level I-1b (randomized controlled trial [no significant difference but narrow confidence intervals]).


Dipolar magnetism in ordered and disordered low-dimensional nanoparticle assemblies.
Magnetostatic (dipolar) interactions between nanoparticles promise to open new ways to design nanocrystalline magnetic materials and devices if the collective magnetic properties can be controlled at the nanoparticle level. Magnetic dipolar interactions are sufficiently strong to sustain magnetic order at ambient temperature in assemblies of closely-spaced nanoparticles with magnetic moments of ≥ 100 μ(B). Here we use electron holography with sub-particle resolution to reveal the correlation between particle arrangement and magnetic order in self-assembled 1D and quasi-2D arrangements of 15 nm cobalt nanoparticles. In the initial states, we observe dipolar ferromagnetism, antiferromagnetism and local flux closure, depending on the particle arrangement. Surprisingly, after magnetic saturation, measurements and numerical simulations show that overall ferromagnetic order exists in the present nanoparticle assemblies even when their arrangement is completely disordered. Such direct quantification of the correlation between topological and magnetic order is essential for the technological exploitation of magnetic quasi-2D nanoparticle assemblies.


Bioactive components and anti-diabetic properties of Moringa oleifera Lam.
Moringa oleifera Lam. is a perennial tropical deciduous tree with high economic and pharmaceutical value. As an edible plant, M. oleifera Lam. is rich in nutrients, such as proteins, amino acids, mineral elements and vitamins. Besides, it also contains an important number of bioactive phytochemicals, such as polysaccharides, flavonoids, alkaloids, glucosinolates and isothiocyanates. M. oleifera for long has been used as a natural anti-diabetic herb in India and other Asian countries. Thus, the anti-diabetic properties of Moringa plant have evolved highly attention to the researchers. In the last twenty years, a huge number of new chemical structures and their pharmacological activities have been reported in particularly the anti-diabetic properties. The current review highlighted the bioactive phytochemicals from M. Oleifera. Moreover, evidence regarding the therapeutic potential of M. oleifera for diabetes including experimental and clinical data was presented and the underlying mechanisms were revealed in order to provide insights for the development of novel drugs.


Multidrug-resistant Mycobacterium tuberculosis, Bangui, Central African Republic.
We investigated multidrug-resistant (MDR) Mycobacterium tuberculosis strains in Bangui, Central African Republic. We found 39.6% with the same spoligotype and synonymous single nucleotide polymorphism in the mutT1 gene. However, strains had different rpoB mutations responsible for rifampin resistance. MDR strains in Bangui may emerge preferentially from a single, MDR-prone family.


Treatment of ethylene glycol poisoning.
Ingestion of ethylene glycol may be an important contributor in patients with metabolic acidosis of unknown cause and subsequent renal failure. Expeditious diagnosis and treatment will limit metabolic toxicity and decrease morbidity and mortality. Ethylene glycol poisoning should be suspected in an intoxicated patient with anion gap acidosis, hypocalcemia, urinary crystals, and nontoxic blood alcohol concentration. Fomepizole is a newer agent with a specific indication for the treatment of ethylene glycol poisoning. Metabolic acidosis is resolved within three hours of initiating therapy. Initiation of fomepizole therapy before the serum creatinine concentration rises can minimize renal impairment. Compared with traditional ethanol treatment, advantages of fomepizole include lack of depression of the central nervous system and hypoglycemia, and easier maintenance of effective plasma levels.


Anti-fibrotic Effects of Cardiac Progenitor Cells in a 3D-Model of Human Cardiac Fibrosis.
Cardiac fibroblasts play a key role in chronic heart failure. The conversion from cardiac fibroblast to myofibroblast as a result of cardiac injury, will lead to excessive matrix deposition and a perpetuation of pro-fibrotic signaling. Cardiac cell therapy for chronic heart failure may be able to target fibroblast behavior in a paracrine fashion. However, no reliable human fibrotic tissue model exists to evaluate this potential effect of cardiac cell therapy. Using a gelatin methacryloyl hydrogel and human fetal cardiac fibroblasts (hfCF), we created a 3D in vitro model of human cardiac fibrosis. This model was used to study the possibility to modulate cellular fibrotic responses. Our approach demonstrated paracrine inhibitory effects of cardiac progenitor cells (CPC) on both cardiac fibroblast activation and collagen synthesis in vitro and revealed that continuous cross-talk between hfCF and CPC seems to be indispensable for the observed anti-fibrotic effect.


Control of stochasticity in eukaryotic gene expression.
Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.


Advanced Reach Tool (ART): development of the mechanistic model.
This paper describes the development of the mechanistic model within a collaborative project, referred to as the Advanced REACH Tool (ART) project, to develop a tool to model inhalation exposure for workers sharing similar operational conditions across different industries and locations in Europe. The ART mechanistic model is based on a conceptual framework that adopts a source receptor approach, which describes the transport of a contaminant from the source to the receptor and defines seven independent principal modifying factors: substance emission potential, activity emission potential, localized controls, segregation, personal enclosure, surface contamination, and dispersion. ART currently differentiates between three different exposure types: vapours, mists, and dust (fumes, fibres, and gases are presently excluded). Various sources were used to assign numerical values to the multipliers to each modifying factor. The evidence used to underpin this assessment procedure was based on chemical and physical laws. In addition, empirical data obtained from literature were used. Where this was not possible, expert elicitation was applied for the assessment procedure. Multipliers for all modifying factors were peer reviewed by leading experts from industry, research institutes, and public authorities across the globe. In addition, several workshops with experts were organized to discuss the proposed exposure multipliers. The mechanistic model is a central part of the ART tool and with advancing knowledge on exposure, determinants will require updates and refinements on a continuous basis, such as the effect of worker behaviour on personal exposure, 'best practice' values that describe the maximum achievable effectiveness of control measures, the intrinsic emission potential of various solid objects (e.g. metal, glass, plastics, etc.), and extending the applicability domain to certain types of exposures (e.g. gas, fume, and fibre exposure).


Home warmth and health status of COPD patients.
Home Energy Efficiency guidelines recommend domestic indoor temperatures of 21 degrees C for at least 9 h per day in living areas. Is health status of patients with Chronic Obstructive Pulmonary Disease (COPD) associated with maintaining this level of warmth in their homes? In a cross-sectional observational study of patients, living in their own homes, living room (LR) and bedroom (BR) temperatures were measured at 30 min intervals over 1 week using electronic dataloggers. Health status was measured with the St George's Respiratory Questionnaire (SGRQ) and EuroQol: EQ VAS. Outdoor temperatures were provided by Met Office. One hundred and forty eight patients consented to temperature monitoring. Patients' mean age was 69 (SD 8.5) years, 67 (45%) male, mean percentage of predicted Forced Expiratory Volume in one second (FEV(1)) 41.7 (SD 17.4). Fifty-eight (39%) were current smokers. Independent of age, lung function, smoking and outdoor temperatures, poorer respiratory health status was significantly associated (P = 0.01) with fewer days with 9 h of warmth at 21 degrees C in the LR. A sub analysis showed that patients who smoked experienced more health effects than non-smokers (P < 0.01). Maintaining the warmth guideline of 21 degrees C in living areas for at least 9 h per day was associated with better health status for COPD patients. Patients who were continuing smokers were more vulnerable to reduction in warmth.


Molecular biology. The mad ways of meiosis.
Reproductive cells that are destined to become sperm or egg undergo meiotic division during which the chromosome number is halved. As Sluder and McCollum explain in their Perspective, new findings (Shonn et al.) in yeast show that there is a spindle checkpoint that operates during meiosis to ensure that an equal number of replicated chromosomes arrives at each pole of the cell. One of the components of this meiotic spindle checkpoint turns out to be Mad2, which gives the signal to halt meiosis if it looks like unequal chromosome segregation is taking place.


The citation of relevant systematic reviews and randomised trials in published reports of trial protocols.
It is important that planned randomised trials are justified and placed in the context of the available evidence. The SPIRIT guidelines for reporting clinical trial protocols recommend that a recent and relevant systematic review should be included. The aim of this study was to assess the use of the existing evidence in order to justify trial conduct. Protocols of randomised trials published over a 1-month period (December 2015) indexed in PubMed were obtained. Data on trial characteristics relating to location, design, funding, conflict of interest and type of evidence included for trial justification was extracted in duplicate and independently by two investigators. The frequency of citation of previous research including relevant systematic reviews and randomised trials was assessed. Overall, 101 protocols for RCTs were identified. Most proposed trials were parallel-group (n = 74; 73.3%). Reference to an earlier systematic review with additional randomised trials was found in 9.9% (n = 10) of protocols and without additional trials in 30.7% (n = 31), while reference was made to randomised trials in isolation in 21.8% (n = 22). Explicit justification for the proposed randomised trial on the basis of being the first to address the research question was made in 17.8% (n = 18) of protocols. A randomised controlled trial was not cited in 10.9% (95% CI: 5.6, 18.7) (n = 11), while in 8.9% (95% CI: 4.2, 16.2) (n = 9) of the protocols a systematic review was cited but did not inform trial design. A relatively high percentage of protocols of randomised trials involves prior citation of randomised trials, systematic reviews or both. However, improvements are required to ensure that it is explicit that clinical trials are justified and shaped by contemporary best evidence.


Hand grip strength is associated with forced expiratory volume in 1 second among subjects with COPD: report from a population-based cohort study.
Cardiovascular diseases and skeletal muscle dysfunction are common comorbidities in COPD. Hand grip strength (HGS) is related to general muscle strength and is associated with cardiovascular disease and all-cause mortality, while the results from small selected COPD populations are contradictory. The aim of this population-based study was to compare HGS among the subjects with and without COPD, to evaluate HGS in relation to COPD severity, and to evaluate the impact of heart disease. Data were collected from the Obstructive Lung disease in Northern Sweden COPD study, where the subjects with and without COPD have been invited to annual examinations since 2005. In 2009-2010, 441 subjects with COPD (postbronchodilator forced expiratory volume in 1 second [FEV1]/vital capacity <0.70) and 570 without COPD participated in structured interviews, spirometry, and measurements of HGS. The mean HGS was similar when comparing subjects with and without COPD, but those with heart disease had lower HGS than those without. When compared by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, the subjects with GOLD 3-4 had lower HGS than those without COPD in both sexes (females 21.4 kg vs 26.9 kg, P=0.010; males 41.5 kg vs 46.3 kg, P=0.038), and the difference persisted also when adjusted for confounders. Among the subjects with COPD, HGS was associated with FEV1% of predicted value but not heart disease when adjusted for height, age, sex, and smoking habits, and the pattern was similar among males and females. In this population-based study, the subjects with GOLD 3-4 had lower HGS than the subjects without COPD. Among those with COPD, HGS was associated with FEV1% of predicted value but not heart disease, and the pattern was similar in both sexes.


Osteopetrosis. A case report.
Osteopetrosis congenita is invariably a fatal disease that is diagnosed within the first decade of the child's life. Although some steps have been taken to overcome this disease by bone marrow transplantation, further research is needed to determine the long-term effectiveness of this treatment. Osteopetrosis tarda is often detected as an incidental finding. Many cases are asymptomatic, yet many patients do suffer from general bone pain, infections, and repeated incidents of pathologic fractures. Such cases may present within the bones of the foot. Treatment is directed at addressing the pathology that may have resulted from the disease state. Osteopetrosis tarda, although rare, can affect the foot. Steps toward treatment of the primary disease entity are still being taken; however, recognition and treatment of the pathology is the primary goal in the adequate treatment of these patients.


Neonatal admissions, quality of care and outcome: 4 years of inpatient audit data from The Gambia's teaching hospital.
National facility-based neonatal mortality audits are an important source of data to identify areas for improvement of service delivery and outcome of care. To examine admissions to the neonatal unit, Edward Francis Small Teaching Hospital, Banjul, The Gambia and make recommendations for programme action to reduce mortality through improvements in the quality of care, particularly with respect to suspected neonatal infections. Case notes were reviewed for all neonates admitted to the neonatal unit during a 5-year period (1 January 2009 to 31 December 2013) to assess outcome and quality of care. Data for 2009 were subsequently excluded because of the low proportion of records retrieved. Of the 4944 admissions between 1 January 2010 and 31 December 2013, 1734 infants (35%) died, with 57% of all deaths occurring within the first 48 hours of admission. There were 1267 early neonatal deaths (deaths occurring during the first 7 days of life), 67% of which occurred during the first 48 hours of life. Independent predictors of neonatal death in the multivariable analysis were; maternal lack of antenatal care, non-teaching hospital delivery, admission weight < 1500 g, abnormal blood glucose concentration ( < 2.6 mmol/L or >6.9 mmol/L) and hypothermia (axillary temperature < 36.5 ˚C). Forty-eight per cent of newborns had point-of-admission hypothermia. Possible severe bacterial infection (pSBI) accounted for 44% (2166/4944) of admissions, prematurity/low birthweight for 27% (1340/4944) and intrapartum-related conditions for 20%. Only 5% (104/2166) of pSBI cases had at least one supportive investigation; 41 had a chest radiograph, 26 had a blood culture and 43 had a lumbar puncture. Although 94% of the newborns received intravenous antibiotics, 55% of those who did lacked clinical evidence of pSBI and had no diagnostic work-up. Priority areas for action include infection prevention and improved diagnosis and management. There is also scope to reduce hypothermia with feasible interventions particularly targeting preterm infants. Improved patient records and audit data with linked action and accountability are interventions which could prevent such deaths of newborns in The Gambia and other developing countries.


Preventing clinical progression and need for treatment in patients on active surveillance for prostate cancer.
Active surveillance is an established treatment option for men with localized, low-risk prostate cancer (CaP). It entails the postponement of immediate therapy with the option of delayed intervention upon disease progression. The rate of clinical progression and need for treatment on active surveillance is approximately 50% over 15 years. The present review summarizes recent data on current methods, attempting to prevent clinical progression. Patient selection for active surveillance is the first mandatory step required to lower progression. Adherence to active surveillance protocols is critical in making sure patients are monitored well and treated early when progression occurs. Before active surveillance allocation and during active surveillance follow-up, methods involving multiparametric MRI, prostate specific antigen derivatives, biopsy factors, urinary, tissue and genetic markers can be used to prevent clinical progression and/or identify those at risk for progression. Medications such as 5α-reductase inhibitors and others might inhibit disease progression in patients on active surveillance. Active surveillance is required because of overdiagnosis, along with our inability to accurately predict individual CaP behavior. Several methods can potentially reduce the risk of CaP progression in patients with active surveillance. However, a measure of uncertainty and fear of progression will always accompany patients with active surveillance and the physicians treating them.


Long-term rates of change in musculoskeletal aging and body composition: findings from the Health, Aging and Body Composition Study.
Musculoskeletal disorders are common among older people. Preventive strategies require understanding of age-related changes in strength, function and body composition, including how they interrelate. We have described, and examined associations between, 9-year changes in these parameters among 2917 Health, Aging and Body Composition Study participants (aged 70-79 years). Appendicular lean mass (ALM), whole body fat mass and total hip BMD were ascertained using DXA; muscle strength by grip dynamometry; and muscle function by gait speed. For each characteristic annualised percentage changes were calculated; measures of conditional change (independent of baseline) were derived and their interrelationships were examined using Pearson correlations; proportion of variance at 9-year follow-up explained by baseline level was estimated; and mean trajectories in relation to age were estimated using linear mixed models. Analyses were stratified by sex. Median [lower quartile, upper quartile] annual percentage declines were grip strength (1.5 [0.0, 2.9]), gait speed (2.0 [0.6, 3.7]), ALM (0.7 [0.1, 1.4]), fat mass (0.4 [- 1.1, 1.9]) and hip BMD (0.5 [0.0, 1.1]). Declines were linear for ALM and accelerated over time for other characteristics. Most conditional change measures were positively correlated, most strongly between ALM, fat mass and hip BMD (r > 0.28). Proportion of variation at follow-up explained by baseline was lower for grip strength and gait speed (39-52%) than other characteristics (69-86%). Strength and function declined more rapidly, and were less correlated between baseline and follow-up, than measures of body composition. Therefore, broader intervention strategies to prevent loss of strength and function in later life are required as those targeting body composition alone may be insufficient.


3-Chloro-N'-(2-hydroxybenzylidene) benzohydrazide: An LSD1-Selective Inhibitor and Iron-Chelating Agent for Anticancer Therapy.
Despite the discovery and development of novel therapies, cancer is still a leading cause of death worldwide. In order to grow, tumor cells require large quantities of nutrients involved in metabolic processes, and an increase in iron levels is known to contribute to cancer proliferation. Iron plays an important role in the active site of a number of proteins involved in energy metabolism, DNA synthesis and repair, such as ribonucleotide reductase, which induce G0/S phase arrest and exert a marked antineoplastic effect, particularly in leukemia and neuroblastoma. Iron-depletion strategies using iron chelators have been shown to result in cell cycle arrest and apoptosis. Deferoxamine (DFO) was the first FDA-approved drug for the treatment of iron overload pathologies, and has also been recognized as having anticancer properties. The high cost, low permeability and short plasma half-life of DFO led to the development of other iron-chelating drugs. Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs chelate cellular iron by tridentate binding, and inhibit DNA synthesis more robustly than DFO, demonstrating an effective antiproliferative activity. Here, we investigated the biological effects of a PIH derivative, 3-chloro-N'-(2-hydroxybenzylidene)benzohydrazide (CHBH), known to be a lysine-specific histone demethylase 1A inhibitor. We showed that CHBH is able to induce cell proliferation arrest in several human cancer cell lines, including lung, colon, pancreas and breast cancer, at micromolar levels. Our findings indicate that CHBH exerts a dual anticancer action by strongly impairing iron metabolism and modulating chromatin structure and function.


Label-free mass spectrometry proteome quantification of human embryonic kidney cells following 24 hours of sialic acid overproduction.
Cell surface glycoprotein sialylation is one of the most ubiquitous glycan modifications found on higher eukaryotes. The surface sialylation pattern of cells is influenced by the cellular environment but also by the Golgi sialyltransferase activity and flux of metabolites through sialic acid producing pathways. Altered cell surface sialic acid patterns have been observed in several cancers and other pathological conditions. In this experiment we examined the cellular proteomic changes that occur in human embryonic kidney cells after 24 hours of sialic acid overproduction using N-Acetylmannosamine. We utilized high resolution mass spectrometry and label free protein quantification to characterize the relative changes in protein abundance as well as multiple reaction monitoring to quantify the cellular sialic acid levels. Using N-Acetylmannosamine we were able to induce sialic acid production to almost 70-fold compared to non-induced control cells. Mass spectrometric analysis of cellular proteome of control and induced cells identified 1802 proteins of which 105 displayed significant changes in abundance. Functional analysis of the resulting relative changes in protein abundance revealed regulation of several cellular pathways including protein transport, metabolic and signaling pathways and remodeling of epithelial adherens junctions. We also identified several physically interacting co-regulated proteins in the set of changed proteins. In this experiment we show that increased metabolic flux through sialic acid producing pathway affects the abundance of several protein transport, epithelial adherens junction, signaling and metabolic pathway related proteins.


Mechanistic insights into influenza vaccine-associated narcolepsy.
We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) - one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2) the contributing factor likely for the discordant association of narcolepsy between the AS03-adjuvanted pandemic vaccines Pandemrix and Arepanrix (GlaxoSmithKline Biologicals, s.a.), 3) the significance of detecting HCRT receptor 2 (HCRTr2) antibodies in some Finnish control subjects, 4) the approach used for the detection of HCRTr2 antibodies in vaccine-associated narcolepsy, and 5) the plausibility of the proposed mechanism involving HCRTr2 modulation in vaccine-associated narcolepsy.


Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat.
Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.


Dielectrophoretic isolation and detection of cancer-related circulating cell-free DNA biomarkers from blood and plasma.
Conventional methods for the isolation of cancer-related circulating cell-free (ccf) DNA from patient blood (plasma) are time consuming and laborious. A DEP approach utilizing a microarray device now allows rapid isolation of ccf-DNA directly from a small volume of unprocessed blood. In this study, the DEP device is used to compare the ccf-DNA isolated directly from whole blood and plasma from 11 chronic lymphocytic leukemia (CLL) patients and one normal individual. Ccf-DNA from both blood and plasma samples was separated into DEP high-field regions, after which cells (blood), proteins, and other biomolecules were removed by a fluidic wash. The concentrated ccf-DNA was detected on-chip by fluorescence, and then eluted for PCR and DNA sequencing. The complete process from blood to PCR required less than 10 min; an additional 15 min was required to obtain plasma from whole blood. Ccf-DNA from the equivalent of 5 μL of CLL blood and 5 μL of plasma was amplified by PCR using Ig heavy-chain variable (IGHV) specific primers to identify the unique IGHV gene expressed by the leukemic B-cell clone. The PCR and DNA sequencing results obtained by DEP from all 11 CLL blood samples and from 8 of the 11 CLL plasma samples were exactly comparable to the DNA sequencing results obtained from genomic DNA isolated from CLL patient leukemic B cells (gold standard).


Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease.
Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE. Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy. Initially, 95% of patients had nephrotic syndrome with proteinuria of 3-12 g per 24 hours, creatinine levels of 0.6-9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%-77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2-3.6 mg/dl with proteinuria of 0.37-4 g per 24 hours. Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.


Cardiomyopathy, familial dilated.
Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.


Effects of lidocaine on conduction through depolarized canine false tendons and on a model of reflected reentry.
Reflected reentry was produced in canine false tendons, mounted in a three-chamber bath, in which the central fiber segment was partially depolarized with an "ischemic" solution to provide an area of impaired conduction. Lidocaine (3-5 mg/l) added to the central chamber further impaired conduction; consequently, reflections were obtained at lower frequencies and over a wider range of stimulation cycle lengths. Complete block followed drug exposure in some preparations. At moderate stimulation rates, the drug-induced shift of the frequency-dependence of manifest reflected reentries was either arrhythmogenic or antiarrhythmic. The action of lidocaine can be explained on the basis of effects on depressed fast or slow response activity at the boundary regions of the ischemic gap. Under slow response conditions, in false tendons homogeneously exposed to a solution containing 20 mM K+ and 9 mM Ca++, lidocaine delayed propagation or induced complete block. In fibers mounted in a single sucrose gap, the drug increased the current required to reach threshold without significant changes in resting potential, threshold voltage or input resistance. The effect of lidocaine on threshold current was lost in Na+-deficient solutions. Thus, lidocaine impairs conduction through K+-depolarized false tendons, an effect that may be related to the Na+ background current.


Architecture of the photosynthetic oxygen-evolving center.
Photosynthesis uses light energy to drive the oxidation of water at an oxygen-evolving catalytic site within photosystem II (PSII). We report the structure of PSII of the cyanobacterium Thermosynechococcus elongatus at 3.5 angstrom resolution. We have assigned most of the amino acid residues of this 650-kilodalton dimeric multisubunit complex and refined the structure to reveal its molecular architecture. Consequently, we are able to describe details of the binding sites for cofactors and propose a structure of the oxygen-evolving center (OEC). The data strongly suggest that the OEC contains a cubane-like Mn3CaO4 cluster linked to a fourth Mn by a mono-micro-oxo bridge. The details of the surrounding coordination sphere of the metal cluster and the implications for a possible oxygen-evolving mechanism are discussed.


Serial, parallel and hierarchical decision making in primates.
The study of decision-making has mainly focused on isolated decisions where choices are associated with motor actions. However, problem-solving often involves considering a hierarchy of sub-decisions. In a recent study (Lorteije et al. 2015), we reported behavioral and neuronal evidence for hierarchical decision making in a task with a small decision tree. We observed a first phase of parallel evidence integration for multiple sub-decisions, followed by a phase in which the overall strategy formed. It has been suggested that a 'flat' competition between the ultimate motor actions might also explain these results. A reanalysis of the data does not support the critical predictions of flat models. We also examined the time-course of decision making in other, related tasks and report conditions where evidence integration for successive decisions is decoupled, which excludes flat models. We conclude that the flexibility of decision-making implies that the strategies are genuinely hierarchical.


[Skin and bone findings in mastocytosis].
The syndrome of mastocytosis extends from cutaneous urticaria pigmentosa through systemic mastocytosis to the rarely occurring mast cell leukaemia. Our investigations with a large patient collective have shown that systemic forms of the disease occur more often than is generally supposed. In particular the incidence of bone marrow manifestations deserve more attention. The inflammatory-granulomatous findings in the bone marrow suggest an immunoactive component in the pathogenesis of this disease. The bone lesions that occur in about 50% of patients are probably the result of the common endosteal site of the mastocytosis granuloma. These lesions can be generalized (osteoporosis-osteosclerosis) or localized (osteolytic-osteosclerotic foci). In clinical practice bone biopsy and skeletal radiology complement one another; in addition to skin biopsy bone biopsy supplies the initial diagnosis of mastocytosis and documents systemic manifestation; the X-ray picture informs the clinician about the type and extent of the bone pathology.


A model of intervention for prevention of early essential hypertension in the 1980s.
The onset of essential hypertension early in life is indicated by the high tracking of blood pressure during adolescence; intervention in adults with mild hypertension has been found successful. How, then, can high blood pressure levels in children be modified to prevent early hypertensive cardiovascular disease in adulthood? In an entire biracial town (population 9000) we surveyed 1604 (89%) of all children aged 8--18 years for blood pressure and reexamined those in the upper decile of mean blood pressure (for each race, sex, and height) on three additional occasions. On each examination nine blood pressures were taken by trained observers. All children consistently in the top decile were randomly allocated into either a treatment (n = 50) or comparison (n = 50) group. These two groups and an additional midrange blood pressure comparison group (n = 50) were followed regularly using school facilities including community and school programs. Treatment consisted of 1) dietary guidance; 2) modifications of school lunches and snacks with healthy substitutes; 3) parental involvement; 4) a low dose diuretic and beta-antagonist given by usual standards. All study groups were monitored for blood pressure in a blind manner. In 6 months of observation, blood pressure in the treatment group remained 5 and 3 mm Hg (systolic and diastolic) less than controls (p less than 0.001 and p less than 0.01). An orchestrated community-wide attack on early-stage hypertension is feasible and seems to offer exciting potential for prevention of early hypertensive disease.


Deep Multi-dictionary Learning for Survival Prediction with Multi-zoom Histopathological Whole Slide Images.
Survival prediction based on histopathological whole slide images (WSIs) is of great significance for risk-benefit assessment and clinical decision. However, complex microenvironments and heterogeneous tissue structures in WSIs bring challenges to learning informative prognosis-related representations. Additionally, previous studies mainly focus on modeling using mono-scale WSIs, which commonly ignore useful subtle differences existed in multi-zoom WSIs. To this end, we propose a deep multi-dictionary learning framework for cancer survival prediction with multi-zoom histopathological WSIs. The framework can recognize and learn discriminative clusters (i.e., microenvironments) based on multi-scale deep representations for survival analysis. Specifically, we learn multi-scale features based on multi-zoom tiles from WSIs via stacked deep autoencoders network followed by grouping different microenvironments by cluster algorithm. Based on multi-scale deep features of clusters, a multi-dictionary learning method with a post-pruning strategy is devised to learn discriminative representations from selected prognosis-related clusters in a task-driven manner. Finally, a survival model (i.e., EN-Cox) is constructed to estimate the risk index of an individual patient. The proposed model is evaluated on three datasets derived from The Cancer Genome Atlas (TCGA), and the experimental results demonstrate that it outperforms several state-of-the-art survival analysis approaches.


Ethical Considerations for Interdisciplinary Collaboration with Prescribing Professionals.
Behavior analysts often work as part of an interdisciplinary team, and different team members may prescribe different interventions for a single client. One such intervention that is commonly encountered is a change in medication. Changes in medication regimens have the potential to alter behavior in a number of ways. As such, it is important for all team members to be aware of every intervention and to consider how different interventions may interact with each other. These facts make regular and clear communication among team members vital for treatment success. While working as part of an interdisciplinary team, behavior analysts must abide by their ethics code, which sometimes means advocating for their client with the rest of the team. This article will review some possible implications of medicinal interventions, potential ethical issues that can arise, and a case study from the authors' experience. Finally, the authors propose a decision-making tree that can aid in determining the best course of action when a team member proposes an intervention in addition to, or concurrent with, interventions proposed by the behavior analyst.


Microsatellite Analysis of Museum Specimens Reveals Historical Differences in Genetic Diversity between Declining and More Stable Bombus Species.
Worldwide most pollinators, e.g. bumblebees, are undergoing global declines. Loss of genetic diversity can play an essential role in these observed declines. In this paper, we investigated the level of genetic diversity of seven declining Bombus species and four more stable species with the use of microsatellite loci. Hereto we genotyped a unique collection of museum specimens. Specimens were collected between 1918 and 1926, in 6 provinces of the Netherlands which allowed us to make interspecific comparisons of genetic diversity. For the stable species B. pascuorum, we also selected populations from two additional time periods: 1949-1955 and 1975-1990. The genetic diversity and population structure in B. pascuorum remained constant over the three time periods. However, populations of declining bumblebee species showed a significantly lower genetic diversity than co-occurring stable species before their major declines. This historical difference indicates that the repeatedly observed reduced genetic diversity in recent populations of declining bumblebee species is not caused solely by the decline itself. The historically low genetic diversity in the declined species may be due to the fact that these species were already rare, making them more vulnerable to the major drivers of bumblebee decline.


Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency.
Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.


Seasonal and diel acoustic presence of North Atlantic minke whales in the North Sea.
Despite frequent records from other parts of the North Atlantic, minke whales have never been acoustically recorded in the North Sea. This study investigated the detectability of pulse trains previously associated with this species in other regions, in acoustic data from ten sites along the east coast of Scotland. Since preliminary results confirmed pulse train presence, subsequently, an automated detector was applied to these data to record the seasonal and diel presence of minke whale pulse trains. Minke whales were detected from May to November, with most detections occurring in June, July and October. No acoustic detections were made in December, January or in the month of April, whilst no data were available for February and March. This pattern of acoustic presence supports available visual data and suggested an absence of minke whales from the study area during winter. Minke whale acoustic presence showed a statistically significant diel pattern, with a detection peak during night time. This study established the acoustic detectability of minke whales in the North Sea and highlights the potential of using passive acoustic monitoring to study the seasonal presence and spatial distribution of minke whales in the North Sea and wider Northeast Atlantic.


Fit of bicycle safety helmets and risk of head injuries in children.
Although bicycle helmets are effective in preventing head and brain injury, some helmeted individuals nevertheless sustain head injury. One of the possible reasons may be poor fit of the helmet on the head. This study was undertaken to examine the relationship between helmet fit and risk of injury. 1718 individuals who were helmeted riders in a crash were queried on helmet fit and position. A sample of 28 children 2-14 years of age who sustained a head injury while wearing a bicycle helmet and 98 helmeted individuals of the same age treated in the same hospital emergency departments for injuries other than to the head, underwent anthropometric measurements of helmet fit. Measurements were made of the child's head, the helmet, and on a cast made of the child's head. Individuals whose helmets were reported to fit poorly had a 1.96-fold increased risk of head injury compared with those whose helmets fit well. Children with head injuries had helmets which were significantly wider than their heads compared with children without head injuries. Helmet fit was poorer among males and among younger children. Poor fit of helmets may be associated with an increased risk of head injury in children, especially in males. Helmets may not be designed to provide optimal protection.


Prediction of Conversion From Amnestic Mild Cognitive Impairment to Alzheimer's Disease Based on the Brain Structural Connectome.
Background: Early prediction of disease progression in patients with amnestic mild cognitive impairment (aMCI) is important for early diagnosis and intervention of Alzheimer's disease (AD). Previous brain network studies have suggested topological disruptions of the brain connectome in aMCI patients. However, whether brain connectome markers at baseline can predict longitudinal conversion from aMCI to AD remains largely unknown. Methods: In this study, 52 patients with aMCI and 26 demographically matched healthy controls from a longitudinal cohort were evaluated. During 2 years of follow-up, 26 patients with aMCI were retrospectively classified as aMCI converters and 26 patients remained stable as aMCI non-converters based on whether they were subsequently diagnosed with AD. For each participant, diffusion tensor imaging at baseline and deterministic tractography were used to map the whole-brain white matter structural connectome. Graph theoretical analysis was applied to investigate the convergent and divergent connectivity patterns of structural connectome between aMCI converters and non-converters. Results: Disrupted topological organization of the brain structural connectome were identified in both aMCI converters and non-converters. More severe disruptions of structural connectivity in aMCI converters compared with non-converters were found, especially in the default-mode network regions and connections. Finally, a support vector machine-based classification demonstrated the good discriminative ability of structural connectivity in differentiating aMCI patients from controls with an accuracy of 98%, and in discriminating converters from non-converters with an accuracy of 81%. Conclusion: Our study provides potential structural connectome/connectivity-based biomarkers for predicting disease progression in aMCI, which is important for the early diagnosis of AD.


Noise-figure limit of fiber-optical parametric amplifiers and wavelength converters: experimental investigation.
Recent theoretical work predicts that the quantum-limited noise figure of a x(3)-based fiber-optical parametric amplifier operating as a phase-insensitive in-line amplifier or as a wavelength converter exceeds the standard 3-dB limit at high gain. The degradation of the noise figure is caused by the excess noise added by the unavoidable Raman gain and loss occurring at the signal and the converted wavelengths. We present detailed experimental evidence in support of this theory through measurements of the gain and noise-figure spectra for phase-insensitive parametric amplification and wavelength conversion in a continuous-wave amplifier made from 4.4 km of dispersion-shifted fiber. The theory is also extended to include the effect of distributed linear loss on the noise figure of such a long-length parametric amplifier and wavelength converter.


Trends in the use of preconditioning to hypoxia for early prevention of future life diseases.
Environmental factors during fetal life program the health outcomes regarding many diseases in future life. This idea has been supported by worldwide epidemiological studies, but the underlying mechanisms are still poorly understood. Three questions should be answered. (i) Does a common underlying cause of ordinary pathological fetal development exist? (ii) If such a cause exists, which mechanism might develop disease in later life? (iii) Is it possible to prevent this underlying cause and therefore the associated obstetric complications to primarily prevent future life diseases? The objective of this review is to attempt to answer these three questions by using PubMed (extending to October 2012) and other sources. Three data-based answers corresponding to these questions were found: (i) hypoxia, (ii) excessive stimulation of neurogenesis, and (iii) preconditioning/adaptation to hypoxia. The method for such preconditioning/adaptation is intermittent hypoxic training (IHT), in which air with low oxygen concentration is breathed through a mask to protect against subsequent strong adverse influences. Data are cited for IHT applications for the prevention/treatment of diseases in different fields, particularly in obstetrics. Data suggested that all common fetal origins of adult diseases are likely predetermined by changes in the fetal brain; therefore, early detection of these changes must be very important. The use of IHT may be a real means to primarily prevent obstetric complications and therefore, prevent future life diseases.


Extremes of temperature, oxygen and blooms in the Baltic sea in a changing climate.
In the future, the Baltic Sea ecosystem will be impacted both by climate change and by riverine and atmospheric nutrient inputs. Multi-model ensemble simulations comprising one IPCC scenario (A1B), two global climate models, two regional climate models, and three Baltic Sea ecosystem models were performed to elucidate the combined effect of climate change and changes in nutrient inputs. This study focuses on the occurrence of extreme events in the projected future climate. Results suggest that the number of days favoring cyanobacteria blooms could increase, anoxic events may become more frequent and last longer, and salinity may tend to decrease. Nutrient load reductions following the Baltic Sea Action Plan can reduce the deterioration of oxygen conditions.


Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results.
Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.


Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups.
Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.


A murC gene in Porphyromonas gingivalis 381.
The gene encoding a 51 kDa polypeptide of Porphyromonas gingivalis 381 was isolated by immunoblotting using an antiserum raised against P. gingivalis alkaline phosphatase. DNA sequence analysis of a 2.5 kb DNA fragment containing a gene encoding the 51 kDa protein revealed one complete and two incomplete ORFs. Database searches using the FASTA program revealed significant homology between the P. gingivalis 51 kDa protein and the MurC protein of Escherichia coli, which functions in peptidoglycan synthesis. The cloned 51 kDa protein encoded a functional product that complemented an E. coli murC mutant. Moreover, the ORF just upstream of murC coded for a protein that was 31% homologous with the E. coli MurG protein. The ORF just downstream of murC coded for a protein that was 17% homologous with the Streptococcus pneumoniae penicillin-binding protein 2B (PBP2B), which functions in peptidoglycan synthesis and is responsible for antibiotic resistance. These results suggest that P. gingivalis contains a homologue of the E. coli peptidoglycan synthesis gene murC and indicate the possibility of a cluster of genes responsible for cell division and cell growth, as in the E. coli mra region.


The test-retest reliability of the child-initiated pretend play assessment.
The purpose of this study is to establish the test-retest reliability of the Child-Initiated Pretend Play Assessment (ChIPPA) (Stagnitti, 2002a; Stagnitti, Unsworth, & Rodger, 2000). The first author rated 38 preschool children ages 4 and 5 years (4 with developmental delay and 34 typically developing) on the ChIPPA. The ChIPPA employs conventional play materials and unstructured play materials to assess three qualities of a child's play ability: elaborateness of play action, ability to substitute objects during play, and the child's need to imitate the modelled actions of the examiner. The ChIPPA was administered twice, at a 2-week interval, to each participant. Test-retest intraclass correlation coefficients (ICCs) (Type 2,1) calculated for each of the three elaborate play measures ranged from .73 to .84. A test-retest ICC of .56 was obtained for object substitution with unstructured play materials. The test-retest ICC obtained for the combined score for unstructured and conventional play materials was .57. Percentage agreement figures ranging from 63.2% to 84.2% were obtained on test-retest of the object substitution with conventional toys and imitated actions measures. There was no significant difference between test and retest scores for these measures based on a Wilcoxon Matched Pairs Signed-Ranks Test (Wilcoxon Sign Test). Elaborate play scores, object substitution with conventional toys score, and imitation scores on the ChIPPA showed stability over time. Object substitution scores using unstructured materials were the least stable play measures and appeared to be related to the child's play themes. Since play is the primary occupation of children, it is essential that therapists have a reliable measure of play behavior. The test-retest reliability results from the ChIPPA provide evidence that this assessment produces a stable measure of play behavior that can then guide therapists when planning intervention strategies for children.


[Cancer morbidity risks among workers of asbestos-cement productions].
The retrospective assessment of morbidity rates and cancer pathology risks in workers of asbestosis-cement enterprises of Ukraine has been made. It was established that annual cancer morbidity among workers makes 88,1 per 100 000 of workers (RR = 0.26, CI 95 % 0.06-1.01). The most often cancer pathology was located in digestive organs (48.1%), respiratory organs (18.5%) (lung cancer--11.1%). The mesothelioma of pleura, peritoneum and pericardium were not found. The risks (odds ratio--OR) of cancer morbidity were increased for such organs as: respiratory organs (OR = 2.37), skin (OR = 1.78), digestive organs (OR = 1.34).


National disability-adjusted life years (DALYs) for 257 diseases and injuries in Ethiopia, 1990-2015: findings from the global burden of disease study 2015.
Disability-adjusted life years (DALYs) provide a summary measure of health and can be a critical input to guide health systems, investments, and priority-setting in Ethiopia. We aimed to determine the leading causes of premature mortality and disability using DALYs and describe the relative burden of disease and injuries in Ethiopia. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for non-fatal disease burden, cause-specific mortality, and all-cause mortality to derive age-standardized DALYs by sex for Ethiopia for each year. We calculated DALYs by summing years of life lost due to premature mortality (YLLs) and years lived with disability (YLDs) for each age group and sex. Causes of death by age, sex, and year were measured mainly using Causes of Death Ensemble modeling. To estimate YLDs, a Bayesian meta-regression method was used. We reported DALY rates per 100,000 for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non-communicable diseases, and injuries, with 95% uncertainty intervals (UI) for Ethiopia. Non-communicable diseases caused 23,118.1 (95% UI, 17,124.4-30,579.6), CMNN disorders resulted in 20,200.7 (95% UI, 16,532.2-24,917.9), and injuries caused 3781 (95% UI, 2642.9-5500.6) age-standardized DALYs per 100,000 in Ethiopia in 2015. Lower respiratory infections, diarrheal diseases, and tuberculosis were the top three leading causes of DALYs in 2015, accounting for 2998 (95% UI, 2173.7-4029), 2592.5 (95% UI, 1850.7-3495.1), and 2562.9 (95% UI, 1466.1-4220.7) DALYs per 100,000, respectively. Ischemic heart disease and cerebrovascular disease were the fourth and fifth leading causes of age-standardized DALYs, with rates of 2535.7 (95% UI, 1603.7-3843.2) and 2159.9 (95% UI, 1369.7-3216.3) per 100,000, respectively. The following causes showed a reduction of 60% or more over the last 25 years: lower respiratory infections, diarrheal diseases, tuberculosis, neonatal encephalopathy, preterm birth complications, meningitis, malaria, protein-energy malnutrition, iron-deficiency anemia, measles, war and legal intervention, and maternal hemorrhage. Ethiopia has been successful in reducing age-standardized DALYs related to most communicable, maternal, neonatal, and nutritional deficiency diseases in the last 25 years, causing a major ranking shift to types of non-communicable disease. Lower respiratory infections, diarrheal disease, and tuberculosis continue to be leading causes of premature death, despite major declines in burden. Non-communicable diseases also showed reductions as premature mortality declined; however, disability outcomes for these causes did not show declines. Recently developed non-communicable disease strategies may need to be amended to focus on cardiovascular diseases, cancer, diabetes, and major depressive disorders. Increasing trends of disabilities due to neonatal encephalopathy, preterm birth complications, and neonatal disorders should be emphasized in the national newborn survival strategy. Generating quality data should be a priority through the development of new initiatives such as vital events registration, surveillance programs, and surveys to address gaps in data. Measuring disease burden at subnational regional state levels and identifying variations with urban and rural population health should be conducted to support health policy in Ethiopia.


"Renalism": inappropriately low rates of coronary angiography in elderly individuals with renal insufficiency.
Higher risk patients (including the elderly) receive more conservative therapy for cardiovascular diseases, even though the relative benefits of therapy tend to be greater. The perceived risk of radiocontrast-associated nephrotoxicity may influence the provision of coronary angiography and subsequent revascularization, especially among individuals with chronic kidney disease (CKD). The aim of this study was to determine whether there is excessive variation in the provision of coronary angiography after acute myocardial infarction on the basis of the presence of CKD and whether there is an association between angiography and mortality. Elderly (age 65 to 89 yr) individuals with acute myocardial infarction from the Cooperative Cardiovascular Project were classified by the presence or absence of CKD (defined as a baseline serum creatinine of 1.5 to 5.0 mg/dl). In CKD patients, the propensity to undergo coronary angiography was determined and the effect of coronary angiography on mortality was estimated using multivariable logistic regression and stratification. Mortality was significantly higher with CKD (52.6 versus 26.4%). Fewer patients with CKD underwent coronary angiography (25.2 versus 46.8%) despite the observation that a similar proportion of patients were deemed appropriate for angiography by standard, published criteria. When limiting the analysis to CKD patients who are considered appropriate, the multivariable estimate of the odds of death associated with coronary angiography was 0.58 (95% confidence interval, 0.50 to 0.67). With adjustment using propensity scores, the odds ratio averaged across propensity score quintiles was 0.62 (95% confidence interval, 0.54 to 0.70). Results were qualitatively similar when patients were stratified by CKD stage IV (estimated GFR <30 ml/min per 1.73 m(2)). There is a large relative decrease in utilization of coronary angiography among patients with CKD. Alteration in practice because of an aversion to the risk of radiocontrast-associated nephrotoxicity ("renalism") is inappropriate, even if the true relative benefit of invasive strategies is a fraction of what is estimated here.


On chaotic dynamics in transcription factors and the associated effects in differential gene regulation.
The control of proteins by a transcription factor with periodically varying concentration exhibits intriguing dynamical behaviour. Even though it is accepted that transcription factors vary their dynamics in response to different situations, insight into how this affects downstream genes is lacking. Here, we investigate how oscillations and chaotic dynamics in the transcription factor NF-κB can affect downstream protein production. We describe how it is possible to control the effective dynamics of the transcription factor by stimulating it with an oscillating ligand. We find that chaotic dynamics modulates gene expression and up-regulates certain families of low-affinity genes, even in the presence of extrinsic and intrinsic noise. Furthermore, this leads to an increase in the production of protein complexes and the efficiency of their assembly. Finally, we show how chaotic dynamics creates a heterogeneous population of cell states, and describe how this can be beneficial in multi-toxic environments.